Lipid analogs, liposomes comprising same and uses thereof

Abstract

Disclosed are newly designed polymeric compounds (lipid-polymer conjugates) useful for forming lipid bilayers and liposomes comprising them, lipid bilayers and liposomes formed thereby, and uses thereof. Also disclosed is a method of preparing a new design of a polymeric compound (lipid-polymer conjugate).

Description

[0001] Related Applications

[0002] This application claims the priority benefits of U.S. Patent Application No. 63 / 402,097, filed on August 30, 2022, and U.S. Patent Application No. 63 / 427,943, filed on November 25, 2022, the entire contents of which are incorporated herein by reference.

[0003] Field and Background of the Invention

[0004] In some embodiments thereof, the present invention relates to materials science, and more particularly, but not exclusively, to novel polymeric compounds that are particularly useful for forming liposomes and the use of such liposomes in, for example, biomedical applications.

[0005] Phosphatidylcholine (PC) liposomes on a surface are known to be very good lubricants, even under high pressure [Goldberg et al., Adv Materials 2011, 23:3517 - 3521; Goldberg et al., Biophys J 2011, 100:2403 - 2411; Sorkin et al., Biomaterials 2014, 34:5465 - 5475].

[0006] The aggregation of liposomes into macroscopic aggregates can interfere with the application of liposomes in different ways. Large aggregates can precipitate and deposit out of the dispersion, rendering the dispersion unusable; aggregates larger than about 200 - 300 nm scatter visible light, resulting in turbidity, which can interfere with applications of liposomes where transparency is important; in addition, large aggregates injected into the body are more prone to protein adsorption and are attacked and cleared by macrophages [Moghimi & Szebeni, Prog Lipid Res 2003, 42:463 - 478].

[0007] PEGylated PC small unilamellar vesicles (SUVs) have been used for drug delivery, where PEG brushes are incorporated into the membrane bilayer; these brushes protrude from the SUV surface and sterically stabilize them against aggregation [Harris & Chess, Nat Rev Drug Discov 2003, 2:214 - 221]. However, it has been reported that PEGylation reduces the lubrication efficiency of SUVs under high pressure (e.g., in joints) because the PEG chains are not highly hydrated and cannot form good lubricants themselves under high pressure [Goldberg et al., Adv Materials 2011, 23:3517 - 3521].

[0008] U.S. Patent No. 8,617,592 describes block copolymers and conjugates that self-assemble into particles, which comprise zwitterionic poly(carboxybetaine), poly(sulfobetaine), or poly(phosphobetaine) blocks and hydrophobic blocks, and the use of such particles in the delivery of therapeutic and diagnostic agents.

[0009] Chen et al. [Science 2009, 323:1698 - 1702] described the effective lubrication of poly[2-(methacryloyloxy)ethyl phosphorylcholine] (PMPC) brushes and attributed this phenomenon to the strong hydration of zwitterionic monomers.

[0010] WO 2017 / 109784 describes the design and preparation of polymer compounds bearing phosphocholine analogs as side groups and conjugated to lipid moieties. This document further describes liposomes comprising such compounds that exhibit enhanced stability in an aqueous environment.

[0011] WO 2018 / 150429 describes the use of lipid-derived polymer compounds as described in WO 2017 / 109784 in delivering a therapeutic active agent to a body part of an individual and thereby treating a medical condition treatable by the therapeutic active agent.

[0012] Additional background art includes Goldberg & Klein [Chem Phys Lipids 2012, 165:374 - 381]; WO 2011 / 158237, WO 2015 / 001564, WO 2015 / 193887, WO 2015 / 193888, WO 2016 / 051413, and WO 2018 / 150429. Summary of the Invention

[0014] According to one aspect of some embodiments of the present invention, there is provided a polymer compound represented by Formula I:

[0015]

[0016] Wherein:

[0017] m is 0 or a positive integer;

[0018] n is an integer that is at least 2, at least 5, preferably at least 10 (e.g., an integer from 10 - 200);

[0019] Y is a backbone unit that forms the polymer backbone of the polymer compound;

[0020] L is absent or is a linking moiety; and

[0021] Z has the general formula II:

[0022]

[0023] Wherein:

[0024] The dashed (curved) line represents the connection point to the corresponding Y main chain unit or to the connecting part L (if present);

[0025] A is a substituted or unsubstituted hydrocarbon;

[0026] B is an oxygen atom or absent;

[0027] R1 - R3 are each independently selected from hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl;

[0028] X is a lipid moiety represented by Formula IV:

[0029]

[0030] Wherein:

[0031] The dashed (curved) line represents the connection point to the polymer main chain;

[0032] F1, F2, F3, and F4 are each independently selected from hydrogen, alkyl, alkenyl, alkynyl, acyl, alkoxy, thioalkoxy, carboxyl, thio - carboxyl, wherein at least one of F1, F2, F3, and F4 is not hydrogen and has a length of at least 10 carbon atoms;

[0033] J is -O - P(=O)(OH)-O - or absent;

[0034] K is a substituted or unsubstituted hydrocarbon having a length of 1 - 10 carbon atoms or absent;

[0035] M is a linking group selected from -O -, -S -, amino, sulfinyl, sulfonyl, phosphate, phosphonyl, phosphino, carbonyl, thiocarbonyl, urea, thiourea, carbamoyl, thiocarbamoyl, acylamino, carboxyl, and sulfonamide, or absent; and

[0036] Q is a substituted or unsubstituted hydrocarbon having a length of 1 - 10 carbon atoms or absent,

[0037] wherein when M is absent, Q is also absent, and when J is absent, M is not absent,

[0038] Provided that:

[0039] when J is -O - P(=O)(OH)-O -, M is not acylamino and / or Q contains an aryl moiety.

[0040] In some of any of the embodiments described herein, at least one of F1, F2, F3, and F4 is an alkoxy, thioalkoxy, acyl, or carboxyl group having a carbon atom length of at least 10.

[0041] In some of any of the embodiments described herein, at least one of F1, F2, F3, and F4 is derived from a fatty acid and is selected from lauroyl, myristoyl, palmitoyl, stearoyl, palmitoleoyl, oleoyl, and linoleoyl.

[0042] In some of any of the embodiments described herein, M is a carboxyl group.

[0043] In some of any of the embodiments described herein, K is an alkyl group.

[0044] In some of any of the embodiments described herein, J is -P(=O)(OH)-O-; M is an amido group; and Q is a hydrocarbon substituted with at least one aryl group (such as a phenyl group).

[0045] In some of any of the embodiments described herein, Q is a methylene group substituted with at least one aryl group.

[0046] In some of any of the embodiments described herein, J is absent.

[0047] In some of any of the embodiments described herein, both J and K are absent.

[0048] In some of any of the embodiments described herein, both J and K are absent and M is a carboxyl group.

[0049] In some of any of the embodiments described herein, at least one or at least two of F1, F2, F3, and F4 are independently thioalkoxy groups.

[0050] In some of any of the embodiments described herein, at least one or at least two of F1, F2, F3, and F4 are independently carboxyl groups.

[0051] In some of any of the embodiments described herein, at least one or two of F1 and F2 are carboxyl groups and at least one of F3 and F4 is an alkyl group.

[0052] In some of any of the embodiments described herein, Q is -C(CH3)2-.

[0053] In some of any of the embodiments described herein, Y is a substituted or unsubstituted alkylene unit.

[0054] In some of any of the embodiments described herein, Y is a substituted or unsubstituted ethylene unit.

[0055] In some of any of the embodiments described herein, Y has the formula -CR4R5-CR6D-, where:

[0056] When Y is a main chain unit not connected to L or Z, D is R7; and when Y is a main chain unit connected to L or Z, D is a covalent bond or a linking group that connects Y to L or Z, and the linking group is selected from -O-, -S-, alkylene, arylene, sulfinyl, sulfonyl, phosphate, phosphonyl, phosphino, carbonyl, thiocarbonyl, urea, thiourea, O-carbamoyl, N-carbamoyl, O-thiocarbamoyl, N-thiocarbamoyl, C-acylamino, N-acylamino, C-carboxy, O-carboxy, sulfonamido, and amino; and

[0057] R4 - R7 are each independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, halogen, hydroxy, alkoxy, aryloxy, mercapto, thioalkoxy, thioaryloxy, sulfinyl, sulfonyl, cyano, nitro, azide, azo, phosphate, phosphonyl, phosphino, oxo, carbonyl, thiocarbonyl, urea, thiourea, O-carbamoyl, N-carbamoyl, O-thiocarbamoyl, N-thiocarbamoyl, C-acylamino, N-acylamino, C-carboxy, O-carboxy, sulfonamido, and amino.

[0058] In some of any of the embodiments described herein, R4 - R7 are each independently selected from hydrogen and alkyl.

[0059] In some of any of the embodiments described herein, R4 and R5 are each hydrogen.

[0060] In some of any of the embodiments described herein, R6 is hydrogen.

[0061] In some of any of the embodiments described herein, the linking group is selected from -O-, -C(=O)O-, -C(=O)NH-, and phenylene.

[0062] In some of any of the embodiments described herein, the linking group is -C(=O)O-.

[0063] In some of any of the embodiments described herein, L is a substituted or unsubstituted hydrocarbon having a length of 1 - 10 carbon atoms.

[0064] In some of any of the embodiments described herein, L is a substituted or unsubstituted ethylene.

[0065] In some of any of the embodiments described herein, B is an oxygen atom.

[0066] In some of any of the embodiments described herein, A is a hydrocarbon having 1 to 4 carbon atoms, which may be substituted or unsubstituted.

[0067] In some of any of the embodiments described herein, A is an ethylene group, which may be substituted or unsubstituted.

[0068] In some of any of the embodiments described herein, R1-R3 are each independently hydrogen or C 1-4 -alkyl.

[0069] In some of any of the embodiments described herein, R1-R3 are each methyl.

[0070] In some of any of the embodiments described herein, n ranges from 10 to 200.

[0071] In some of any of the embodiments described herein, n is at least 30.

[0072] In some of any of the embodiments described herein, n ranges from 30 to 70.

[0073] In some of any of the embodiments described herein, n is at least 50 or at least 60.

[0074] In some of any of the embodiments described herein, n ranges from 50 to 150 or 50 to 80.

[0075] In some of any of the embodiments described herein, n is at least 80.

[0076] In some of any of the embodiments described herein, n ranges from 80 to 120.

[0077] In some of any of the embodiments described herein, n ranges from 10 to 50.

[0078] In some of any of the embodiments described herein, m ranges from 0 to 50.

[0079] In some of any of the embodiments described herein, as described herein, at least a portion of the main chain units Y, L, and / or Z includes at least one targeting moiety.

[0080] In one aspect of some embodiments of the present invention, there is provided a lipid bilayer comprising at least one bilayer-forming lipid and a polymeric compound as described herein in any of the corresponding embodiments and any combination thereof.

[0081] For some of any of the embodiments described herein, the molar ratio of at least one lipid forming a bilayer to the polymer compound ranges from 5:1 - 5000:1 or 10:1 - 1000:1 or 10:1 - 100:1 or 10:1 - 50:1 (e.g., 30:1 - 40:1) or 100:1 - 200:1.

[0082] For some of any of the embodiments described herein, at least one lipid forming a bilayer comprises at least one zwitterionic glycerophospholipid.

[0083] For some of any of the embodiments described herein, at least one lipid forming a bilayer further comprises a negatively charged lipid forming a bilayer (e.g., DPPG).

[0084] For some of any of the embodiments described herein, the amount of the negatively charged lipid forming a bilayer ranges from 0.1 - 40 or 1 - 40 or 1 - 20 mol% of the lipid bilayer.

[0085] For some of any of the embodiments described herein, n is at least 50.

[0086] In one aspect of some embodiments of the present invention, liposomes are provided that comprise at least one lipid bilayer as described herein in any corresponding embodiment and any combination thereof.

[0087] For some of any of the embodiments described herein, the liposomes further comprise at least one functional moiety or functional agent bound to the surface of the liposome and / or within the lipid bilayer and / or in the liposome core.

[0088] For some of any of the embodiments described herein, the functional moiety or functional agent is a therapeutic active agent or a part thereof, a labeling moiety or labeling agent, and / or a targeting moiety or targeting agent.

[0089] In one aspect of some embodiments of the present invention, a composition is provided that comprises a liposome as described herein in any corresponding embodiment and any combination thereof and a carrier, preferably an aqueous carrier.

[0090] For some of any of the embodiments described herein, the composition is a sterile composition.

[0091] For some of any of the embodiments described herein, the composition is a lubricant composition.

[0092] For some of any of the embodiments described herein, the lubricant composition further comprises a water-soluble polymer.

[0093] For some of any of the embodiments described herein, the lubricant composition is used to lubricate a physiological surface, wherein the carrier is a physiologically acceptable carrier.

[0094] In one aspect of some embodiments of the present invention, a method for reducing the surface friction coefficient is provided, the method comprising contacting the surface with liposomes as described herein in any corresponding embodiment and any combination thereof.

[0095] In some of any of the embodiments described herein, the method comprises contacting the surface with a composition comprising liposomes and a carrier (preferably an aqueous carrier).

[0096] In some of any of the embodiments described herein, the method further comprises contacting the surface with a water-soluble polymer.

[0097] In some of any of the embodiments described herein, the surface is a hydrogel surface.

[0098] In some of any of the embodiments described herein, the surface is a contact lens surface.

[0099] In some of any of the embodiments described herein, the surface is a physiological surface and the carrier is a physiologically acceptable carrier.

[0100] In some of any of the embodiments described herein, the surface is the articular surface of a synovial joint.

[0101] In one aspect of some embodiments of the present invention, liposomes as described herein in any corresponding embodiment and any combination thereof are provided for treating synovial joint disorders associated with an increased coefficient of friction of the articular surface in a synovial joint.

[0102] In one aspect of some embodiments of the present invention, a method for inhibiting biofilm formation on a substrate surface is provided, the method comprising contacting the substrate with a composition comprising liposomes as described herein in any corresponding embodiment and any combination thereof.

[0103] In one aspect of some embodiments of the present invention, an article comprising a material composition is provided, the material composition comprising a substrate having a lipid bilayer or liposomes as described herein in any corresponding embodiment and any combination thereof coated on at least a portion of its surface.

[0104] In one aspect of some embodiments of the present invention, lipid bilayers, liposomes or compositions comprising them as described herein in any corresponding embodiment and any combination thereof are provided for treating synovial joint disorders.

[0105] In some of any of the embodiments described herein, the treatment comprises intra-articular administration of the lipid bilayer, liposome or composition.

[0106] In one aspect of some embodiments of the present invention, there is provided a liposome or a composition comprising them as described herein in any corresponding embodiment and any combination thereof, wherein the liposome has a therapeutic active agent associated therewith, and the liposome or the composition is for delivering the therapeutic active agent to a body part of an individual.

[0107] In some of any of the embodiments described herein, the liposome or the composition is for treating a medical condition in an individual that can be treated by the therapeutic active agent.

[0108] In one aspect of some embodiments of the present invention, there is provided a method for preparing a polymer compound as described herein in any corresponding embodiment and any combination thereof, the method comprising contacting an initiator compound having formula V:

[0109]

[0110] wherein:

[0111] F1, F2, F3, F4, J, K, M and Q are as defined for formula IV; and

[0112] Ri is an electron transfer functional group,

[0113] with a plurality of monomers that form a -[Y-L-Z]n-[Y]m- polymer backbone under conditions that promote atom transfer radical polymerization (ATRP).

[0114] In some of any of the embodiments described herein, the ATRP is ARGET-ATRP.

[0115] In some of any of the embodiments described herein, the method further comprises separating the polymer compound.

[0116] In some of any of the embodiments described herein, the separation is by precipitation.

[0117] Unless otherwise defined, all technical and / or scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of embodiments of the present invention, exemplary methods and / or materials are described below. In case of conflict, the present patent specification (including definitions) will control. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting necessarily.

[0118] Brief Description of Several Views of the Drawings

[0119] The present invention has been described by way of examples with reference to the accompanying drawings. At present, with specific and detailed reference to the accompanying drawings, it should be emphasized that the details shown are by way of examples and are intended to discuss the embodiments of the present invention exemplarily. In this regard, the description in conjunction with the accompanying drawings enables those skilled in the art to clearly understand how to implement the embodiments of the present invention.

[0120] In the drawings:

[0121] Figure 1 (background art) is a scheme showing the preparation of a lipid-containing polymer compound (LPC) DSPE-pMPC from 1,2-distearoyl-sn-glycero-3-phosphoethanolamine (DSPE) and 2-methacryloyloxyethyl phosphorylcholine (MPC) via brominated derivative -DSPE (DSPE-Br), as described in WO 2017 / 109784.

[0122] Figure 2 A scheme showing an exemplary two-step synthesis of LPC DPPE-dm-pMPC: the synthesis of the DPPE-dm-Br initiator and the polymerization of MPC using the DPPE-dm-Br initiator by atom transfer radical polymerization (ATRP) to obtain LPC DPPE-dm pMPC.

[0123] Figure 3A -B presents an overall scheme showing the activator regenerated by electron transfer-atom transfer radical polymerization catalytic process (ARGET-ATRP; Figure 3A ); and GPC chromatograms showing the overlay of batch LS1 of DPPE-dm-pMPC polymerized by ATRP using DPPE-dm-Br (Method 1) and PPE-dm-pMPC30 polymerized by ARGET-ATRP using DPPE-dm-Br (Method 2) ( Figure 3B ).

[0124] Figure 4A -B is a scheme presenting an exemplary two-step method (Method 2) for the preparation of a phenylated brominated derivative -DPPE initiator (DPPE-Ph-Br; Figure 4A ) and the polymerization of MPC by ARGET-ATRP using the DPPE-Ph-Br initiator to obtain LPC DPPE-Ph-pMPC ( Figure 4B ).

[0125] Figure 4C-D presents the GPC chromatograms showing the overlay of DPPE-Ph-pMPC prepared by ARGET-ATRP using DPPE-Ph-Br (Method 2, Batch 1056; dashed line graph) and DPPE-dm-pMPC30 polymerized by ARGET-ATRP using DPPE-dm-Br (Method 2, dotted line graph) ( Figure 4C ); and the overlay of DPPE-Ph-pMPC prepared by ARGET-APRP using DPPE-Ph-Br (Method 2; Batch 1056, dashed line graph) and DPPE-dm-pMPC Batch LS1 polymerized by ATRP using DPPE-dm-Br (Method 1, LS1; solid line graph) ( Figure 4D ).

[0126] Figure 5A -B shows the exemplary two-step synthesis of the bis-thiolated brominated initiator (2C16S-Prop-Br) from propargyl alcohol ( Figure 5A ), and the polymerization of MPC using the exemplary 2C16S-Prop-Br initiator to obtain LPC 2C16S-Prop-pMPC ( Figure 5B ).

[0127] Figure 6A -B shows the exemplary two-step synthesis of the bis-palmitoyl brominated initiator (2C16-TMP-Br) from trimethylolpropane (TMP) ( Figure 6A ) and the polymerization of MPC using the exemplary 2C16-TMP-Br initiator to obtain LPC 2C16-TMP-pMPC ( Figure 6B ).

[0128] Figure 7A -C shows the DSC thermograms of a series of lipid systems with 0.7% exemplary liposome samples, said exemplary liposome samples comprising long (_L) and short (_S) LPCs (DPPE-dm-pMPC (DM), DPPE-Ph-pMPC (Ph), 2C16S-Prop-pMPC (Prop), 2C16-TMP-pMPC (TMP); Figure 7A ), as well as propargyl-based polymers of different lengths (Prop_S and Prop_L; Figure 7B ) and TMP-based polymers (TMP_S and TMP_L; Figure 7C ), all prepared by Method 2 as described herein.

[0129] Figure 8A -D is from a sample with 3.5% DPPE-Ph-pMPC_S ( Figure 8A ; scale bar is 100 nm); DPPE-Ph-pMPC_L (Figure 8B ; scale bar = 0.2 μm); 2C16-TMP-pMPC_S( Figure 8C ; scale bar = 0.2 μm); and 2C16-TMP-pMPC_L( Figure 8D ; scale bar = 0.2 μm) of exemplary liposome samples.

[0130] Figure 9 is a bar graph showing the % survival of L929 mouse cells after 72 h of incubation with liposome samples containing long (_L) and short (_S) LPCs (DPPE-dm-pMPC (DM), DPPE-Ph-pMPC (Ph), 2C16S-Prop-pMPC (Prop), 2C16-TMP-pMPC (TMP)) compared to two 0.7% short DPPE-dm-pMPC (0.7% DM_S) samples after one-year storage (labeled 1-year storage A and B) in a cytotoxicity assay. The horizontal line marks 70% survival.

[0131] Figure 10A -B is a bar graph showing C-activation of liposomes containing different types of LPC.

[0132] Figure 11 A comparative plot of the ζ-potential (ZP) of pMPC as a function of pH is presented. The ζ-potentials of liposomes composed of DSPC, zwitterionic lipids, and LPC (blue circles) and a water-soluble pMPC polymer (orange squares) were measured.

[0133] Figure 12 A comparative plot showing the ζ-potential of liposome formulations in low-salt solution is presented. The curves reflect the increase in LPC membrane content and the dependence on LPC size.

[0134] Figure 13A -B presents a comparative plot of the ζ-potential as a function of total ionic concentration of liposome formulations incorporating short LPC ( Figure 13A ) and long LPC ( Figure 13B ). For formulations with long LPC, the ZP decays very rapidly with salt and thus ZP measurements at higher salt are not applicable. The dashed line is a fit to a linear equation. The slope is the slope of the LPC layer thickness.

[0135] Figure 14 A comparative plot of the average LPC layer thickness as a function of LPC length in a certain concentration range is presented. The rate of increase in layer thickness of short LPC is lower than that of long LPC. The thickness of the long LPC layer is three times that of the short LPC.

[0136] Figure 15A -B presents a plot showing for short LPC ( Figure 15A) and long LPC( Figure 15A ) Comparative plot of the correlation between the surface properties of liposomes and the immunogenic response determined according to complement activation-related pseudoallergy (CARPA).

[0137] Description of Specific Embodiments of the Invention

[0138] In some embodiments, the present invention relates to materials science, and more particularly, but not exclusively, to novel polymer compounds that are particularly useful for forming liposomes and the use of such liposomes in, for example, biomedical applications.

[0139] Before explaining in detail at least one embodiment of the present invention, it should be understood that the application of the present invention is not necessarily limited to the details set forth in the following description or exemplified by the examples. The present invention is capable of including other embodiments or of being practiced or carried out in various ways.

[0140] As described above, WO 2017 / 109784 describes the design and preparation of polymer compounds with phosphocholine analogs as side groups and conjugated to lipid moieties.

[0141] These polymer compounds can stabilize lipid layers, such as those of liposomes, while exhibiting significantly enhanced stability and effective lubrication between sliding surfaces, particularly in saline environments (such as physiological environments) and / or under high pressure.

[0142] Given the very favorable properties of these lipid-containing polymer compounds (also referred to herein as lipid-polymer conjugates or LPCs), the inventors sought improved methods for preparing such LPCs. As discussed in further detail in the Examples section below, the inventors have designed and successfully prepared a new synthetic method for preparing LPCs, as well as new LPCs thus prepared. More particularly, the inventors have designed and successfully implemented a new synthetic method and a newly designed lipid-containing compound for preparing LPCs, which provide improved control over the polymer portion of the LPC and LPCs characterized by improved performance.

[0143] Accordingly, embodiments of the present invention relate to newly designed polymer compounds having phosphocholine analogs as side groups and conjugated to lipid (e.g., phospholipid) moieties. Exemplary such polymer compounds are represented by Formula I. These polymer compounds are also referred to herein as "lipid-containing polymer compounds" or simply "polymer compounds" or "lipid-polymer conjugates", or abbreviated as "LPCs".

[0144] The lipid-containing polymer compounds disclosed herein are capable of stabilizing liposomes for a variety of applications (including in vivo applications) for preventing aggregation and fusion, thereby extending the shelf life while retaining and even enhancing properties associated with liposome and other phospholipid bilayer surfaces, such as biocompatibility and lubricant activity (e.g., by hydration lubrication). The disclosed polymer compounds themselves are also capable of forming stable micelles in an aqueous environment, which can be used as stable alternatives to liposomes in a variety of applications (including in vivo applications), such as lubrication, including interfacial lubrication with physiological surfaces. The disclosed polymer compounds and / or the liposomes formed therefrom can also be used as drug delivery vehicles in ophthalmic applications and other uses, as described herein.

[0145] The inventors have found that liposomes made from newly designed polymer compounds exhibit significantly reduced immunogenicity, even when formed from negatively charged bilayer-forming lipids.

[0146] The inventors have further found that lipid bilayers (e.g., in the form of liposomes) can be effectively used to deliver therapeutic agents to body sites of an individual, the lipid bilayers comprising the newly designed polymer compounds described herein and optionally negatively charged bilayer-forming lipids and / or sterols, such as cholesterol.

[0147] Polymer compound (LPC):

[0148] In one aspect of some embodiments of the present invention, there is provided a polymer compound represented by formula I:

[0149]

[0150] Wherein:

[0151] m is 0 or a positive integer;

[0152] n is an integer that is at least 2, at least 5, preferably at least 10 (e.g., an integer from 10 - 200);

[0153] Y is a backbone unit that forms the polymer backbone of the polymer compound;

[0154] X is a lipid moiety as described in any of the corresponding embodiments herein;

[0155] L is absent or is a linking moiety; and

[0156] Z has the general formula II:

[0157]

[0158] Wherein:

[0159] The dashed (curved) line represents the point of attachment to the corresponding Y backbone unit or to the linking moiety L (if present);

[0160] A is a substituted or unsubstituted hydrocarbon;

[0161] B is an oxygen atom or absent; and

[0162] R1 - R3 are each independently selected from hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl,

[0163] as described in more detail below.

[0164] Formula I can also be abbreviated herein as:

[0165] X - [Y(-L-Z)]n[Y]m -

[0166] which should be considered interchangeable with the schematic diagram above, where X is a lipid moiety conjugated to the -[Y(-L-Z)]n[Y]m - polymer moiety.

[0167] Polymer Portion:

[0168] As used herein, the term "polymer" refers to a compound having at least 2 repeating units (and more preferably at least 3 repeating units), the repeating units being the same or similar. It should be understood that when n is at least 2, by definition, the compounds of general formula I are polymers because they contain at least 2 of the backbone units represented by Y.

[0169] As used herein, the term "polymer moiety" refers to a part of a polymer compound (according to any of the embodiments described herein relating to general formula I) having the general formula Ia:

[0170]

[0171] where m, n, Y, L, and Z are as defined herein for general formula I, and the dashed (curved) line represents the point of attachment to the X lipid moiety.

[0172] General formula Ia can also be abbreviated herein as:

[0173] - [Y(-L-Z)]n[Y]m -

[0174] which should be considered interchangeable with the schematic diagram above.

[0175] As used herein, the term "polymeric compound" also includes compounds having a "polymeric moiety" as described herein, which has at least one unit (e.g., according to Formula Ia, where n is at least 1), provided that the lipid moiety (e.g., the lipid moiety represented by X) as described herein has a similar unit. For example, when the lipid moiety contains a phosphate group (e.g., the lipid moiety is a glycerophospholipid moiety) and a single unit of the polymeric moiety has a phosphate group, the two phosphate groups can be considered repeating units.

[0176] However, in a preferred embodiment, n is at least 2 such that the polymeric moiety itself has at least two units. In some embodiments, n is at least 3.

[0177] As used herein, the term "backbone unit" refers to a repeating unit, the linkage (e.g., sequential linkage) of multiple repeating units forming a polymer backbone. Multiple linked repeating units themselves are also referred to herein as a "polymer backbone". The polymeric moiety as described herein can comprise multiple repeating backbone units that are identical to one another and thereby form a homopolymeric moiety, or alternatively, can comprise two or more types of repeating backbone units that can be linked to one another randomly or in a defined order (e.g., as two or more blocks or in an alternating order) and thereby form a copolymeric moiety.

[0178] As shown in Formulas I and Ia, L and Z together form a side group of at least a portion of the backbone unit, which for brevity is referred to herein simply as a "side group".

[0179] Each backbone unit Y having a side group (i.e., the unit represented by Y(-L-Z), the number of which is represented by the variable n) and each backbone unit Y without a side group (the number of which is represented by the variable m) are also referred to herein as "monomer units".

[0180] The backbone unit can optionally be a unit of a polymerizable monomer or a polymerizable portion of a monomer. Those skilled in the art are aware of a variety of polymerizable monomers and portions, and those skilled in the art are also aware of the structure of the units of such monomers (e.g., monomer units) that result upon polymerization.

[0181] "Unit of a polymerizable monomer" refers to a modified form of a polymerizable monomer and / or a portion of a polymerizable monomer that remains after polymerization.

[0182] Can form a part of a polymerizable monomer, for example, by a condensation reaction, e.g., where at least one atom or group in the monomer (e.g., a hydrogen atom or a hydroxyl group) and optionally at least two atoms or groups in the monomer (e.g., a hydrogen atom and a hydroxyl group) are replaced by a covalent bond with another polymerizable monomer.

[0183] Modified forms of polymerizable monomers can be formed, for example, by ring opening (wherein a covalent bond between two atoms in the ring is broken and each of the two atoms is optionally linked to another polymerizable monomer); and / or by adding an unsaturated bond, wherein the unsaturated bond between two adjacent atoms is broken (e.g., an unsaturated double bond is converted to a saturated bond or an unsaturated triple bond is converted to an unsaturated double bond), and the two atoms are optionally each linked to another polymerizable monomer.

[0184] The modified forms of polymerizable monomers can consist essentially of the same atoms as the original monomer, for example, differing only in the rearrangement of covalent bonds, or alternatively, can have a different atomic composition, for example, wherein the polymerization involves a condensation reaction (such as described herein).

[0185] Examples of main chain units include, but are not limited to, substituted or unsubstituted hydrocarbons (which can form a substituted or unsubstituted hydrocarbon main chain), such as alkylene units; hydroxycarboxylic acid units (which can form a polyester main chain), such as glycolate, lactate, hydroxybutyrate, hydroxypentanoate, hydroxyhexanoate, and hydroxybenzoate units; dicarboxylic acid units (which can combine with diols to form a polyester main chain and / or with diamines to form a polyamide), such as adipate, succinate, terephthalate, and naphthalenedicarboxylate units; diol units (which can form a polyether main chain or combine with dicarboxylic acids to form a polyester main chain), such as ethylene glycol, 1,2 - propanediol, 1,3 - propanediol, 1,4 - butanediol, and bisphenol A units; diamine units (which can combine with dicarboxylic acids to form a polyamide main chain), such as p - phenylenediamine and alkylenediamines, such as hexamethylenediamine; urethane units (which can form a polyurethane main chain); amino acid residues (which can form a polypeptide main chain); and sugar moieties (which can form a polysaccharide main chain).

[0186] In some embodiments of any of the embodiments described herein, Y is a substituted or unsubstituted alkylene unit.

[0187] In some embodiments, Y is a substituted or unsubstituted ethylene unit, i.e., an alkylene unit of 2 - atom length.

[0188] A polymer main chain wherein Y is a substituted or unsubstituted ethylene unit can optionally be a polymer main chain, for example, formed by polymerizing ethylene (CH2═CH2) and / or its substituted derivatives (also referred to herein as "vinyl monomers"). Such polymerization is a well - studied and well - known method, and many techniques for achieving such polymerization are known to those of ordinary skill in the art.

[0189] It should be understood that any embodiment related to a polymer backbone formed by polymerization as described herein includes any polymer backbone having a structure that can be formed by such polymerization, regardless of whether the polymer backbone is actually formed by such polymerization (or any other type of polymerization) in practice.

[0190] As is well known in the art, the unsaturated bonds of ethylene and substituted ethylene derivatives become saturated upon polymerization, such that the backbone units on the polymer backbone formed by polymerization are saturated. However, they can be referred to as units of the unsaturated compounds to which they are analogous (e.g., "vinyl monomers" or "olefin monomers").

[0191] Polymers formed from unsaturated monomers such as vinyl monomers and olefin monomers are also referred to as the terms "polyethylene" and "polyolefin", respectively.

[0192] In this document, an "unsubstituted" alkylene unit (e.g., an ethylene unit) refers to an alkylene unit that does not carry any substituents other than the side groups discussed herein (represented as (-L-Z)). That is, if there are no substituents at any other position on the alkylene unit, the alkylene unit connected to the above side group is considered unsubstituted.

[0193] In some embodiments of any of the embodiments described herein, Y has the formula -CR4R5-CR6D-.

[0194] When Y is a backbone unit not connected to L or Z (i.e., not connected to the side group as described herein), D is R7 (a terminal group, as defined herein); and when Y is a backbone unit connected to L or Z, D is a covalent bond or a linking group that connects Y to L or Z. The linking group can optionally be -O-, -S-, arylene, sulfinyl, sulfonyl, phosphate, phosphonyl, phosphino, carbonyl, thiocarbonyl, urea, thiourea, O-carbamoyl, N-carbamoyl, O-thiocarbamoyl, N-thiocarbamoyl, C-acylamino, N-acylamino, C-carboxy, O-carboxy, sulfonamido, or amino.

[0195] R4 - R7 are each independently hydrogen, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, halogen, hydroxy, alkoxy, aryloxy, thiol, thioalkoxy, thioaryloxy, sulfinyl, sulfonyl, cyano, nitro, azide, azo, phosphate, phosphonyl, phosphino, oxo, carbonyl, thiocarbonyl, urea, thiourea, O-carbamoyl, N-carbamoyl, O-thiocarbamoyl, N-thiocarbamoyl, C-acylamino, N-acylamino, C-carboxy, O-carboxy, sulfonamido, or amino.

[0196] The term "linking group" throughout this document describes a group (e.g., a substituent) that connects to two or more moieties in a compound.

[0197] The term "end group" as used throughout this text describes a group (e.g., a substituent) that is attached to a single moiety in a compound through one of its atoms.

[0198] When each of R4 - R6 is hydrogen and D is a covalent bond or a linking group, Y is an unsubstituted ethylene group that is linked (through D) to a side group as described herein.

[0199] When each of R4 - R7 is hydrogen (and D is R7), Y is an unsubstituted ethylene group that is not linked to a side group as described herein.

[0200] In some embodiments of any of the embodiments described herein, R4 and R5 are each hydrogen. Such embodiments include polymer backbones formed from many widely used vinyl monomers, including ethylene, such as olefins (e.g., ethylene, propylene, 1 - butene, isobutene, 4 - methyl - 1 - pentene), vinyl chloride, styrene, vinyl acetate, acrylonitrile, acrylates and their derivatives (e.g., acrylate, acrylamide), and methacrylates and their derivatives (e.g., methacrylate, methacrylamide).

[0201] In some embodiments of any of the embodiments described herein, R6 is hydrogen. In some such embodiments, R4 and R5 are each hydrogen.

[0202] In some embodiments of any of the embodiments described herein, R6 is methyl. In some such embodiments, R4 and R5 are each hydrogen. In some such embodiments, the backbone unit is a unit of methacrylate or its derivative (e.g., methacrylate, methacrylamide).

[0203] In some embodiments of any of the embodiments described herein, the linking group represented by the variable D is -O-, -C(=O)O-, -C(=O)NH-, or phenylene. In an exemplary embodiment, D is -C(=O)O-.

[0204] For example, the backbone unit can optionally be a vinyl alcohol derivative (e.g., an ester or ether of a vinyl alcohol unit), in which case D is -O-; an acrylate or methacrylate derivative (e.g., an acrylate or methacrylate unit), in which case D is -C(=O)O-; an acrylamide or methacrylamide unit, in which case D is -C(=O)NH-; and / or a styrene derivative (e.g., a substituted styrene unit), in which case D is phenylene.

[0205] In some embodiments of any of the embodiments described herein, L is a substituted or unsubstituted hydrocarbon having a length of 1 to 10 carbon atoms. In some embodiments, the hydrocarbon is unsubstituted. In some embodiments, the hydrocarbon is a straight-chain unsubstituted hydrocarbon, i.e., -(CH2) i -, where i is an integer from 1 to 10.

[0206] In some embodiments of any of the embodiments described herein, L is a substituted or unsubstituted ethylene group. In some embodiments, L is an unsubstituted ethylene group (-CH2CH2-).

[0207] In some embodiments of any of the embodiments described herein, B is an oxygen atom. In some such embodiments, L is a hydrocarbon of any of the corresponding embodiments described herein (i.e., L is not absent), and Z is a phosphate group attached to L.

[0208] In some embodiments of any of the embodiments described herein, B is absent. In some such embodiments, L is a hydrocarbon of any of the corresponding embodiments described herein (i.e., L is not absent), and Z is a phosphonate group attached to L. In some embodiments, L is also absent, such that the phosphorus atom of Formula II is directly attached to Y.

[0209] In some embodiments of any of the embodiments described herein, A is a substituted or unsubstituted hydrocarbon having a length of 1 to 4 carbon atoms.

[0210] In some embodiments of any of the embodiments described herein, A is an unsubstituted hydrocarbon. In some such embodiments, the unsubstituted hydrocarbon has a length of 1 to 4 carbon atoms. In some embodiments, the hydrocarbon is a straight-chain unsubstituted hydrocarbon, i.e., -(CH2) j -, where j is an integer from 1 to 4.

[0211] In some embodiments of any of the embodiments described herein, A is a substituted or unsubstituted ethylene group.

[0212] In some embodiments of any of the embodiments described herein, A is an unsubstituted ethylene group (-CH2CH2-). In such embodiments, the moiety of general formula II (represented by the variable Z) is similar or identical to a phosphoethanolamine or phosphocholine moiety. Phosphoethanolamine or phosphocholine is present in many naturally occurring compounds (e.g., phosphatidylcholine, phosphatidylethanolamine).

[0213] In some embodiments of any of the embodiments described herein, A is an ethylene group substituted with a C-carboxyl group. In some embodiments, the C-carboxyl group is attached to the carbon atom adjacent to the nitrogen atom shown in Formula II (rather than the carbon atom attached to the shown oxygen atom). In such embodiments, the moiety having the general formula II (represented by the variable Z) is similar or identical to the phosphoserine moiety. Phosphoserine is present in many naturally occurring compounds (such as phosphatidylserine).

[0214] Without being bound by any particular theory, it is believed that moieties similar or identical to naturally occurring moieties (such as phosphocholine, phosphoethanolamine, and / or phosphoserine) may be particularly biocompatible.

[0215] In some embodiments of any of the embodiments described herein, R1-R3 (the substituents of the nitrogen atom shown in General Formula II) are each independently hydrogen or C 1-4 -alkyl. In some embodiments, R1-R3 are each independently hydrogen or methyl. In some embodiments, R1-R3 are each methyl. In some such embodiments, R1-R3 are each hydrogen.

[0216] The variable n can be considered to represent the number of main chain units (represented by the variable Y) substituted with side chains represented by (-L-Z), and the variable m can be considered to represent the number of main chain units not substituted with such side chains. The sum of n + m can be considered to represent the total number of main chain units in the polymer main chain. The ratio n / (n + m) can be considered to represent the fraction of main chain units substituted with side chains represented by (-L-Z).

[0217] In some embodiments of any of the embodiments described herein, the percentage of main chain units (represented by the variable Y) substituted with side chains represented by (-L-Z) (as shown by the formula 100%*n / (n + m)) is at least 20%. In some embodiments, the percentage of main chain units substituted with the above side chains is at least 30%. In some embodiments, the percentage of main chain units substituted with the above side chains is at least 40%. In some embodiments, the percentage of main chain units substituted with the above side chains is at least 50%. In some embodiments, the percentage of main chain units substituted with the above side chains is at least 60%. In some embodiments, the percentage of main chain units substituted with the above side chains is at least 70%. In some embodiments, the percentage of main chain units substituted with the above side chains is at least 80%. In some embodiments, the percentage of main chain units substituted with the above side chains is at least 90%. In some embodiments, the percentage of main chain units substituted with the above side chains is at least 95%. In some embodiments, the percentage of main chain units substituted with the above side chains is at least 98%.

[0218] In some embodiments of any of the embodiments described herein, m is 0 such that each of the main chain units (represented by the variable Y) is substituted with a side group represented by (-L-Z).

[0219] In some embodiments of any of the embodiments described herein, n is at least 5. In some embodiments, n is at least 10. In some embodiments, n is at least 15.

[0220] In some embodiments of any of the embodiments described herein, n ranges from 2 to 1000, including any intermediate values and subranges therebetween. In some embodiments of any of the embodiments described herein, n ranges from 2 to 500, including any intermediate values and subranges therebetween. In some embodiments of any of the embodiments described herein, n ranges from 2 to 200, including any intermediate values and subranges therebetween. In some embodiments of any of the embodiments described herein, n ranges from 2 to 100, including any intermediate values and subranges therebetween. In some embodiments of any of the embodiments described herein, n ranges from 2 to 50, including any intermediate values and subranges therebetween. In some such embodiments, m is 0.

[0221] In some embodiments of any of the embodiments described herein, n ranges from 3 to 1000, including any intermediate values and subranges therebetween. In some embodiments of any of the embodiments described herein, n ranges from 3 to 500, including any intermediate values and subranges therebetween. In some embodiments of any of the embodiments described herein, n ranges from 3 to 200, including any intermediate values and subranges therebetween. In some embodiments of any of the embodiments described herein, n ranges from 3 to 100, including any intermediate values and subranges therebetween. In some embodiments of any of the embodiments described herein, n ranges from 3 to 50, including any intermediate values and subranges therebetween. In some embodiments of any of the embodiments described herein, n ranges from 5 to 50, including any intermediate values and subranges therebetween. In some embodiments of any of the embodiments described herein, n ranges from 10 to 50, including any intermediate values and subranges therebetween. In some embodiments of any of the embodiments described herein, n ranges from 10 to 25, including any intermediate values and subranges therebetween. In some such embodiments, m is 0.

[0222] In some embodiments of any of the embodiments described herein, n ranges from 10 to 200, including any intermediate value and sub-range therebetween. In some embodiments of any of the embodiments described herein, n ranges from 10 to 180, including any intermediate value and sub-range therebetween. In some embodiments of any of the embodiments described herein, n ranges from 10 to 150, including any intermediate value and sub-range therebetween. In some embodiments of any of the embodiments described herein, n ranges from 10 to 120, including any intermediate value and sub-range therebetween. In some such embodiments, m is 0.

[0223] In some embodiments of any of the embodiments described herein, n is at least 30.

[0224] In some embodiments of any of the embodiments described herein, n ranges from 30 to 200, including any intermediate value and sub-range therebetween. In some embodiments of any of the embodiments described herein, n ranges from 30 to 180, including any intermediate value and sub-range therebetween. In some embodiments of any of the embodiments described herein, n ranges from 30 to 150, including any intermediate value and sub-range therebetween. In some embodiments of any of the embodiments described herein, n ranges from 30 to 120, including any intermediate value and sub-range therebetween. In some such embodiments, m is 0.

[0225] In some embodiments of any of the embodiments described herein, n ranges from 30 to 70, including any intermediate value and sub-range therebetween. In some embodiments of any of the embodiments described herein, n ranges from 35 to 65, including any intermediate value and sub-range therebetween. In some such embodiments, m is 0.

[0226] In some embodiments of any of the embodiments described herein, n is at least 50 or at least 60 or at least 80.

[0227] In some embodiments of any of the embodiments described herein, n ranges from 50 to 200, including any intermediate values and sub - ranges therebetween. In some embodiments of any of the embodiments described herein, n ranges from 50 to 180, including any intermediate values and sub - ranges therebetween. In some embodiments of any of the embodiments described herein, n ranges from 50 to 150, including any intermediate values and sub - ranges therebetween. In some embodiments of any of the embodiments described herein, n ranges from 50 to 120, including any intermediate values and sub - ranges therebetween. In some embodiments of any of the embodiments described herein, n ranges from 80 to 120, including any intermediate values and sub - ranges therebetween. In some embodiments of any of the embodiments described herein, n ranges from 50 to 100, including any intermediate values and sub - ranges therebetween. In some embodiments of any of the embodiments described herein, n ranges from 50 to 80, including any intermediate values and sub - ranges therebetween. In some such embodiments, m is 0.

[0228] In some embodiments of any of the embodiments described herein, when n is less than 80 or less than 70 or less than 50 or less than 30 or ranges from 10 - 50 or 30 - 60 or 30 - 80 or 30 - 70 or 50 - 80, as described herein in any of the corresponding embodiments, the polymeric compound is referred to herein as "short" or "S".

[0229] In some embodiments of any of the embodiments described herein, when n is greater than 80 or greater than 100 or ranges from 50 - 150 or 50 - 120 or 80 - 150 or 80 - 120, as described herein in any of the corresponding embodiments, the polymeric compound is referred to herein as "long" or "L".

[0230] In some embodiments of any of the embodiments described herein, n ranges from 10 to 50, including any intermediate values and sub - ranges therebetween. In some such embodiments, m is 0.

[0231] In some embodiments of any of the embodiments described herein, n ranges from 50 to 80, including any intermediate values and sub - ranges therebetween. In some such embodiments, m is 0.

[0232] In some embodiments of any of the embodiments described herein, n ranges from 80 to 120, including any intermediate values and sub - ranges therebetween. In some such embodiments, m is 0.

[0233] In some embodiments of any of the embodiments described herein, m ranges from 0 to 1000, including any intermediate value and sub-range therebetween. In some such embodiments, n ranges from 2 to 1000, including any intermediate value and sub-range therebetween, such that the total number of main chain units ranges from 2 to 2000, including any intermediate value and sub-range therebetween. In some such embodiments, n ranges from 3 to 1000, including any intermediate value and sub-range therebetween. In some embodiments, n ranges from 3 to 500, including any intermediate value and sub-range therebetween. In some embodiments, n ranges from 3 to 200, including any intermediate value and sub-range therebetween. In some embodiments, n ranges from 3 to 100, including any intermediate value and sub-range therebetween. In some embodiments, n ranges from 3 to 50, including any intermediate value and sub-range therebetween. In some embodiments, n ranges from 5 to 50, including any intermediate value and sub-range therebetween. In some embodiments, n ranges from 10 to 50, including any intermediate value and sub-range therebetween. In some embodiments, n ranges from 50 to 80, including any intermediate value and sub-range therebetween. In some embodiments, n ranges from 80 to 120, including any intermediate value and sub-range therebetween.

[0234] In some embodiments of any of the embodiments described herein, m ranges from 0 to 500, including any intermediate value and sub-range therebetween. In some such embodiments, n ranges from 2 to 1000, including any intermediate value and sub-range therebetween. In some such embodiments, n ranges from 3 to 1000, including any intermediate value and sub-range therebetween. In some embodiments, n ranges from 3 to 500, including any intermediate value and sub-range therebetween. In some embodiments, n ranges from 3 to 200, including any intermediate value and sub-range therebetween. In some embodiments, n ranges from 3 to 100, including any intermediate value and sub-range therebetween. In some embodiments, n ranges from 3 to 50, including any intermediate value and sub-range therebetween. In some embodiments, n ranges from 5 to 50, including any intermediate value and sub-range therebetween. In some embodiments, n ranges from 10 to 50, including any intermediate value and sub-range therebetween. In some embodiments, n ranges from 50 to 80, including any intermediate value and sub-range therebetween. In some embodiments, n ranges from 80 to 120, including any intermediate value and sub-range therebetween.

[0235] In some embodiments of any of the embodiments described herein, m ranges from 0 to 200, including any intermediate values and sub-ranges therebetween. In some such embodiments, n ranges from 2 to 1000, including any intermediate values and sub-ranges therebetween. In some such embodiments, n ranges from 3 to 1000, including any intermediate values and sub-ranges therebetween. In some embodiments, n ranges from 3 to 500, including any intermediate values and sub-ranges therebetween. In some embodiments, n ranges from 3 to 200, including any intermediate values and sub-ranges therebetween. In some embodiments, n ranges from 3 to 100, including any intermediate values and sub-ranges therebetween. In some embodiments, n ranges from 3 to 50, including any intermediate values and sub-ranges therebetween. In some embodiments, n ranges from 5 to 50, including any intermediate values and sub-ranges therebetween. In some embodiments, n ranges from 10 to 50, including any intermediate values and sub-ranges therebetween. In some embodiments, n ranges from 50 to 80, including any intermediate values and sub-ranges therebetween. In some embodiments, n ranges from 80 to 120, including any intermediate values and sub-ranges therebetween.

[0236] In some embodiments of any of the embodiments described herein, m ranges from 0 to 100, including any intermediate values and sub-ranges therebetween. In some such embodiments, n ranges from 2 to 1000, including any intermediate values and sub-ranges therebetween. In some such embodiments, n ranges from 3 to 1000, including any intermediate values and sub-ranges therebetween. In some embodiments, n ranges from 3 to 500. In some embodiments, n ranges from 3 to 200, including any intermediate values and sub-ranges therebetween. In some embodiments, n ranges from 3 to 100, including any intermediate values and sub-ranges therebetween. In some embodiments, n ranges from 3 to 50. In some embodiments, n ranges from 5 to 50, including any intermediate values and sub-ranges therebetween. In some embodiments, n ranges from 10 to 50, including any intermediate values and sub-ranges therebetween. In some embodiments, n ranges from 50 to 80, including any intermediate values and sub-ranges therebetween. In some embodiments, n ranges from 80 to 120, including any intermediate values and sub-ranges therebetween.

[0237] In some embodiments of any of the embodiments described herein, m ranges from 0 to 50, including any intermediate value and sub-range therebetween. In some such embodiments, n ranges from 2 to 1000, including any intermediate value and sub-range therebetween. In some such embodiments, n ranges from 3 to 1000, including any intermediate value and sub-range therebetween. In some embodiments, n ranges from 3 to 500, including any intermediate value and sub-range therebetween. In some embodiments, n ranges from 3 to 200, including any intermediate value and sub-range therebetween. In some embodiments, n ranges from 3 to 100, including any intermediate value and sub-range therebetween. In some embodiments, n ranges from 3 to 50, including any intermediate value and sub-range therebetween. In some embodiments, n ranges from 5 to 50, including any intermediate value and sub-range therebetween. In some embodiments, n ranges from 10 to 50, including any intermediate value and sub-range therebetween. In some embodiments, n ranges from 50 to 80, including any intermediate value and sub-range therebetween. In some embodiments, n ranges from 80 to 120, including any intermediate value and sub-range therebetween.

[0238] In some embodiments of any of the embodiments described herein, m ranges from 0 to 20, including any intermediate value and sub-range therebetween. In some such embodiments, n ranges from 2 to 1000, including any intermediate value and sub-range therebetween. In some such embodiments, n ranges from 3 to 1000, including any intermediate value and sub-range therebetween. In some embodiments, n ranges from 3 to 500, including any intermediate value and sub-range therebetween. In some embodiments, n ranges from 3 to 200, including any intermediate value and sub-range therebetween. In some embodiments, n ranges from 3 to 100, including any intermediate value and sub-range therebetween. In some embodiments, n ranges from 3 to 50, including any intermediate value and sub-range therebetween. In some embodiments, n ranges from 5 to 50, including any intermediate value and sub-range therebetween. In some embodiments, n ranges from 10 to 50, including any intermediate value and sub-range therebetween. In some embodiments, n ranges from 50 to 80, including any intermediate value and sub-range therebetween. In some embodiments, n ranges from 80 to 120, including any intermediate value and sub-range therebetween.

[0239] In some embodiments of any of the embodiments described herein, m ranges from 0 to 10, including any intermediate values and subranges therebetween. In some such embodiments, n ranges from 2 to 1000, including any intermediate values and subranges therebetween. In some such embodiments, n ranges from 3 to 1000, including any intermediate values and subranges therebetween. In some embodiments, n ranges from 3 to 500, including any intermediate values and subranges therebetween. In some embodiments, n ranges from 3 to 200, including any intermediate values and subranges therebetween. In some embodiments, n ranges from 3 to 100, including any intermediate values and subranges therebetween. In some embodiments, n ranges from 3 to 50, including any intermediate values and subranges therebetween. In some embodiments, n ranges from 5 to 50, including any intermediate values and subranges therebetween. In some embodiments, n ranges from 10 to 50, including any intermediate values and subranges therebetween. In some of any of the embodiments described herein for m, n ranges from 30 to 70, as described in any of the corresponding embodiments herein, or represents a short polymer moiety as described herein. In some such embodiments, n ranges from 50 to 80, including any intermediate values and subranges therebetween.

[0240] In some of any of the embodiments described herein for m, n ranges from 80 to 120, as described in any of the corresponding embodiments herein, or represents a long polymer moiety as described herein.

[0241] In some embodiments of any of the embodiments described herein, the main chain unit Y substituted with a side group represented by (-L-Z) is the same as the main chain unit Y not substituted with a side group (e.g., when m is at least 1). In an alternative embodiment, at least a portion of the main chain unit Y substituted with a side group is different from a portion of the main chain unit Y not substituted with a side group (e.g., when m is at least 1).

[0242] In some embodiments of any of the embodiments described herein, a plurality (represented by the variable n) of main chain units Y substituted with a side group represented by (-L-Z) are the same as each other. In an alternative embodiment, at least a portion of the plurality of main chain units Y substituted with a side group represented by (-L-Z) is different from a second portion of the plurality of main chain units Y substituted with a side group.

[0243] In some embodiments of any of the embodiments described herein, a plurality (represented by the variable n) of side groups (-L-Z) attached to a plurality of main chain units Y are the same as each other. In an alternative embodiment, at least a portion of the side groups (-L-Z) attached to a plurality of main chain units Y are different from each other (e.g., the identity of any one or more of A, B, R1, R2, R3, and L is different).

[0244] In any of the embodiments described herein, where more than one main chain unit Y is not substituted by a side group as described herein (i.e., when m is greater than 1), the plurality (represented by the variable m) of main chain units Y that are not substituted by a side group are identical to each other. In an alternative embodiment, where m is greater than 1, at least a portion of the main chain units Y that are not substituted by a side group as described herein is different from at least a second portion of the plurality of main chain units Y that are not substituted by a side group.

[0245] The number of types of main chain units substituted by side groups, the number of types of main chain units not substituted by side groups (if any such units exist), and / or the number of types of side groups in the polymer portion can each independently be any number (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more).

[0246] In some embodiments of any of the embodiments described herein, the polymer portion is a copolymer portion, i.e., the polymer portion comprises at least two different types of monomer units. In some such embodiments, according to any of the corresponding embodiments described herein, the different types of monomer units differ in whether they contain a side group (-L-Z) (e.g., when m is at least 1), and / or the different types of monomer units differ in the type of main chain unit Y, and / or the different types of monomer units differ in the type of side group (-L-Z).

[0247] For example, in some embodiments of any of the embodiments described herein, the main chain unit Y in each Y(-L-Z) unit can optionally be the same or different, while the L and Z moieties are the same in the Y(-L-Z) units. In some such embodiments, the main chain units not substituted by side groups (if any such units exist) can optionally be the same as the main chain unit Y in each Y(-L-Z) unit. Alternatively, the main chain units not substituted by side groups (if any such units exist) can optionally be different from the main chain unit Y in each Y(-L-Z) unit (while optionally being the same in all main chain units not substituted by side groups).

[0248] In some embodiments of any of the embodiments described herein, the L moiety in each Y(-L-Z) unit can optionally be the same or different, while the main chain unit Y and the Z moiety are the same in the Y(-L-Z) units. In some such embodiments, the main chain units not substituted by side groups (if any such units exist) can optionally be the same as the main chain unit Y in each Y(-L-Z) unit. Alternatively, the main chain units not substituted by side groups (if any such units exist) can optionally be different from the main chain unit Y in each Y(-L-Z) unit (while optionally being the same in all main chain units not substituted by side groups).

[0249] In some embodiments of any of the embodiments described herein, the Z moieties in each Y(-L-Z) unit may be the same or different, optionally, while the main chain unit Y and the Z moiety are the same in the Y(-L-Z) unit. In some such embodiments, the main chain unit not substituted by side groups (if any such units exist) may optionally be the same as the main chain unit Y in each Y(-L-Z) unit. Alternatively, the main chain unit not substituted by side groups (if any such units exist) may optionally be different from the main chain unit Y in each Y(-L-Z) unit (while optionally being the same in all main chain units not substituted by side groups).

[0250] In any of the embodiments described herein, where the polymer moiety is a copolymer moiety, any two or more different types of monomer units may be distributed randomly or non-randomly throughout the polymer moiety. When the different types of monomer units are non-randomly distributed, the copolymer may be a copolymer characterized by any non-random distribution, e.g., an alternating copolymer, a periodic copolymer, and / or a block copolymer.

[0251] In some of any of the embodiments described herein, the polymer moiety (attached at one of its ends to which it is attached to the lipid moiety X) may carry a variety of end groups at the other end (i.e., at the end proximal to the main chain unit Y without side groups, where m is at least 1; or at the other end proximal to the main chain unit Y with side groups, where m is 0).

[0252] The end groups may be inherent end groups, which are derived from the monomers used to form the polymer compound and / or the method for polymerizing the monomers, or may be conjugated to or generated in the ends of the polymer moiety. For example, the end groups may be hydrogen, halogen, alkyl, hydroxyl, carboxyl, etc., or may be targeting moieties, as described in further detail below. In some of any of the embodiments described herein, the end groups are hydrogen or halogen. In some of the embodiments described herein, the end groups are derived from the initiator used to form the polymer compound, as described in any of the corresponding embodiments herein and exemplified in the following Examples section, and in some of these embodiments, the end groups are halogen (e.g., chlorine or bromine).

[0253] In some of any of the embodiments described herein, the end groups are functional groups suitable for electron transfer radical polymerization, e.g., the variable Ri in Formula V, as described in any of the corresponding embodiments herein.

[0254] Lipid Portion:

[0255] The lipid moiety (represented by the variable X in Formula I herein) of any of the embodiments in this section may be attached to the polymer moiety of any of the embodiments described in the sections related to the polymer moiety herein.

[0256] The lipid moiety may optionally be derived from any lipid known in the art (including but not limited to naturally occurring lipids). Deriving the lipid moiety from a lipid may optionally consist of replacing a hydrogen atom at any position on the lipid with a polymeric moiety represented by [Y(-L-Z)]n[Y]m in Formula I (i.e., a polymer moiety represented by General Formula Ia).

[0257] In some embodiments of any of the embodiments described herein, the lipid moiety (according to any of the corresponding embodiments described herein) is linked to a Y(-L-Z) unit (according to any of the embodiments related to Y, L, and / or Z described herein), i.e., a backbone unit substituted with a side group as described herein (e.g., not a backbone unit not substituted with a side group).

[0258] Optionally or additionally, in some embodiments of any of the embodiments described herein, where m is at least 1, the lipid moiety (according to any of the corresponding embodiments described herein) may optionally be linked to a backbone unit (Y) not substituted with a side group as described herein (e.g., not linked to a backbone unit substituted with a side group). For example, the polymer moiety may optionally be a copolymer, where the identity of the backbone unit linked to the lipid moiety varies randomly between molecules. Thus, the description in Formula I that X is linked to a backbone unit substituted with a side group (i.e., Y-(L-Z)) rather than an unsubstituted backbone unit Y is arbitrary and not meant to be limiting.

[0259] In some embodiments of any of the embodiments described herein, the lipid moiety is part of a lipid that is a fatty acid, a monoglyceride, a diglyceride, a triglyceride, a glycerophospholipid, a sphingolipid, or a sterol. In some embodiments, the lipid is a glycerophospholipid.

[0260] In some embodiments of any of the embodiments described herein, the lipid moiety contains at least one fatty acid moiety (e.g., an acyl group derived from a fatty acid). The fatty acid moiety may be derived from a saturated or unsaturated fatty acid. For example, the lipid moiety may consist of a fatty acid moiety, or be a monoglyceride moiety containing one fatty acid moiety, a diglyceride moiety containing two fatty acid moieties, or a triglyceride moiety containing three fatty acid moieties.

[0261] Examples of fatty acid moieties that may optionally be contained in the lipid moiety include but are not limited to lauroyl, myristoyl, palmitoyl, stearoyl, palmitoleoyl, oleoyl, and linoleoyl.

[0262] Suitable examples of glycerophospholipids include but are not limited to phosphatidylethanolamine, phosphatidylserine, phosphatidylglycerol, and phosphatidylinositol.

[0263] In some embodiments of any of the embodiments described herein, the lipid moiety represented by variable X in General Formula I is represented by Formula IV:

[0264]

[0265] Wherein:

[0266] The dashed (curved) line represents the point of attachment to the polymer backbone (i.e., through the corresponding Y backbone unit);

[0267] F1, F2, F3, and F4 are each independently selected from hydrogen, alkyl, alkenyl, alkynyl, acyl, alkoxy, thioalkoxy, carboxyl, thio-carboxyl, where at least one of F1, F2, F3, and F4 is not hydrogen and is at least 10 carbon atoms in length;

[0268] J is -O-P(=O)(OH)-O- or absent;

[0269] K is a substituted or unsubstituted hydrocarbon of 1 to 10 carbon atoms in length or absent;

[0270] M is a linking group selected from -O-, -S-, amino, sulfinyl, sulfonyl, phosphate, phosphonyl, phosphino, carbonyl, thiocarbonyl, urea, thiourea, carbamoyl, thiocarbamoyl, acylamino, carboxyl, and sulfonamide, or absent; and

[0271] Q is a substituted or unsubstituted hydrocarbon of 1 to 10 carbon atoms in length or absent,

[0272] where when M is absent, Q is also absent.

[0273] Q is attached to the backbone unit of the polymer backbone of any of the corresponding embodiments described herein, or alternatively, when Q is absent, M is attached to the above backbone unit.

[0274] When M is absent, Q is also absent, and K is attached to the backbone unit of the polymer backbone of any of the corresponding embodiments described herein.

[0275] In some embodiments of any of the embodiments described herein for Formula IV, when J is absent, M is not absent.

[0276] In some embodiments of any of the embodiments described herein for Formula IV, when J is -O-P(=O)(OH)-O-, M is not acylamino and / or Q contains an aryl moiety.

[0277] In some embodiments of any of the embodiments of Formula IV described herein, at least one of F1, F2, F3, and F4 is an alkoxy, thioalkoxy, acyl, or carboxyl group, preferably having a length of at least 10 carbon atoms, such as 8 - 40 or 10 - 40 or 10 - 30 carbon atoms in length.

[0278] In some such embodiments, the alkoxy, thioalkoxy, acyl, and / or carboxyl group has an alkyl moiety derived from a fatty acid acyl group such as those described herein and exemplified by lauroyl, myristoyl, palmitoyl, stearoyl, palmitoleoyl, oleoyl, and linoleoyl.

[0279] In some embodiments of any of the embodiments of Formula IV described herein, at least one or at least two of F1, F2, F3, and F4 are independently thioalkoxy groups. In some of these embodiments, the thioalkoxy group has a length of at least 10 carbon atoms, such as 8 - 40 or 10 - 40 or 10 - 30 carbon atoms in length. In an exemplary embodiment, the alkyl group is 15 carbon atoms in length and is derived from palmitic acid. In some of these embodiments, the thioalkoxy group has an alkyl group of lauric acid, myristic acid, palmitic acid, stearic acid, oleic acid, or linoleic acid. In some of these embodiments, F1 and F2 are each independently a thioalkoxy group as described herein, and may be the same or different, preferably the same. In some of these embodiments, F3 and F4 are each hydrogen.

[0280] In some embodiments of any of the embodiments described herein, at least one or at least two of F1, F2, F3, and F4 are independently carboxyl groups. In some of these embodiments, the carboxyl group has a length of at least 10 carbon atoms, such as 8 - 40 or 10 - 40 or 10 - 30 carbon atoms in length. In an exemplary embodiment, the carboxyl group is 16 carbon atoms in length and is derived from palmitic acid. In some of these embodiments, the carboxyl group has an alkyl group of lauric acid, myristic acid, palmitic acid, stearic acid, oleic acid, or linoleic acid. In some of these embodiments, at least one or two of F1 and F2 are carboxyl groups as described in any of the corresponding embodiments herein. In some of these embodiments, both F1 and F2 are carboxyl groups as described in any of the corresponding embodiments herein, which may be the same or different and are preferably the same. In some of any of these embodiments, at least one of F3 and F4 is an alkyl group, which may be the same or different. In some such embodiments, the alkyl group is a short alkyl group of 1 - 6 or 1 - 4 carbon atoms in length, such as methyl. Alternatively, F3 and F4 are each hydrogen.

[0281] In some of any of the embodiments described herein, M is not an amido group.

[0282] In some of any of the embodiments described herein, M is a carboxyl group.

[0283] In some of any of the embodiments described herein, M is a carboxyl group, and at least one or at least two of F1, F2, F3, and F4 are independently a thioalkoxy group. In some of these embodiments, the thioalkoxy group has a length of at least 10 carbon atoms, such as a length of 8 - 40 or 10 - 40 or 10 - 30 carbon atoms. In an exemplary embodiment, the alkyl group has 15 carbon atoms and is derived from palmitic acid. In some of these embodiments, the thioalkoxy group has an alkyl group of lauric acid, myristic acid, palmitic acid, stearic acid, oleic acid, or linoleic acid. In some of these embodiments, F1 and F2 are each independently a thioalkoxy group as described herein and may be the same or different, preferably the same. In some of these embodiments, F3 and F4 are each hydrogen.

[0284] In some of any of the embodiments described herein, M is a carboxyl group, and at least one or at least two of F1, F2, F3, and F4 are independently a carboxyl group. In some of these embodiments, the carboxyl group has a length of at least 10 carbon atoms, such as a length of 8 - 40 or 10 - 40 or 10 - 30 carbon atoms. In an exemplary embodiment, the carboxyl group has 16 carbon atoms and is derived from palmitic acid. In some of these embodiments, the carboxyl group has an alkyl group of lauric acid, myristic acid, palmitic acid, stearic acid, oleic acid, or linoleic acid. In some of these embodiments, at least one or two of F1 and F2 are a carboxyl group as described in any of the corresponding embodiments herein. In some of these embodiments, both F1 and F2 are a carboxyl group as described in any of the corresponding embodiments herein, which may be the same or different, and preferably the same. In some of any of these embodiments, at least one of F3 and F4 is an alkyl group, which may be the same or different. In some such embodiments, the alkyl group is a short alkyl group with 1 - 6 or 1 - 4 carbon atoms, such as methyl. Alternatively, F3 and F4 are each hydrogen.

[0285] In some of any of the embodiments described herein, J is absent.

[0286] In some of any of the embodiments described herein, J is absent, and M is not an amido group.

[0287] In some of any of the embodiments described herein, J is absent, and M is a carboxyl group.

[0288] In some of any of the embodiments described herein, J is absent, and at least one or at least two of F1, F2, F3, and F4 are independently thioalkoxy groups. In some of these embodiments, the thioalkoxy group has a length of at least 10 carbon atoms, for example, a length of 8 - 40 or 10 - 40 or 10 - 30 carbon atoms. In an exemplary embodiment, the alkyl group has a length of 15 carbon atoms and is derived from palmitic acid. In some of these embodiments, the thioalkoxy group has an alkyl group of lauric acid, myristic acid, palmitic acid, stearic acid, oleic acid, or linoleic acid. In some of these embodiments, F1 and F2 are each independently a thioalkoxy group as described herein, and may be the same or different, preferably the same. In some of these embodiments, F3 and F4 are each hydrogen.

[0289] In some of any of the embodiments described herein, J is absent, M is a carboxyl group, and at least one or at least two of F1, F2, F3, and F4 are independently thioalkoxy groups. In some of these embodiments, the thioalkoxy group has a length of at least 10 carbon atoms, for example, a length of 8 - 40 or 10 - 40 or 10 - 30 carbon atoms. In an exemplary embodiment, the alkyl group has a length of 15 carbon atoms and is derived from palmitic acid. In some of these embodiments, the thioalkoxy group has an alkyl group of lauric acid, myristic acid, palmitic acid, stearic acid, oleic acid, or linoleic acid. In some of these embodiments, F1 and F2 are each independently a thioalkoxy group as described herein, and may be the same or different, preferably the same. In some of these embodiments, F3 and F4 are each hydrogen.

[0290] In some of any of the embodiments described herein, J is absent, and at least one or at least two of F1, F2, F3, and F4 are independently carboxyl groups. In some of these embodiments, the carboxyl group has a length of at least 10 carbon atoms, for example, a length of 8 - 40 or 10 - 40 or 10 - 30 carbon atoms. In an exemplary embodiment, the carboxyl group has a length of 16 carbon atoms and is derived from palmitic acid. In some of these embodiments, the carboxyl group has an alkyl group of lauric acid, myristic acid, palmitic acid, stearic acid, oleic acid, or linoleic acid. In some of these embodiments, at least one or two of F1 and F2 are carboxyl groups as described in any of the corresponding embodiments herein. In some of these embodiments, both F1 and F2 are carboxyl groups as described in any of the corresponding embodiments herein, which may be the same or different, and preferably the same. In some of any of these embodiments, at least one of F3 and F4 is an alkyl group, which may be the same or different. In some such embodiments, the alkyl group is a short alkyl group having a length of 1 - 6 or 1 - 4 carbon atoms, such as methyl. Alternatively, F3 and F4 are each hydrogen.

[0291] In some of any of the embodiments described herein, J is absent, M is a carboxyl group, and at least one or at least two of F1, F2, F3, and F4 are independently carboxyl groups. In some of these embodiments, the carboxyl group has a length of at least 10 carbon atoms, for example, a length of 8 - 40 or 10 - 40 or 10 - 30 carbon atoms. In an exemplary embodiment, the carboxyl group has a length of 16 carbon atoms and is derived from palmitic acid. In some of these embodiments, the carboxyl group has an alkyl group of lauric acid, myristic acid, palmitic acid, stearic acid, oleic acid, or linoleic acid. In some of these embodiments, at least one or two of F1 and F2 are carboxyl groups as described herein in any of the corresponding embodiments. In some of these embodiments, both F1 and F2 are carboxyl groups as described herein in any of the corresponding embodiments, which may be the same or different, and are preferably the same. In some of any of these embodiments, at least one of F3 and F4 is an alkyl group, which may be the same or different. In some such embodiments, the alkyl group is a short alkyl group of 1 - 6 or 1 - 4 carbon atoms in length, such as methyl. Alternatively, F3 and F4 are each hydrogen.

[0292] In some of any of the embodiments described herein for formula IV, when J is absent, Q is -C(CH3)2-.

[0293] In some of any of the embodiments described herein for formula IV, when J is absent and M is a carboxyl group, Q is -C(CH3)2-.

[0294] In the present text, the length of the hydrocarbon represented by the variable K refers to the number of atoms separating J and M (i.e., along the shortest path between J and M), as shown in formula IV when J is not absent, or the number of atoms separating M and the lipid backbone formed by F1, F2, F3, and F4.

[0295] When K is a substituted hydrocarbon, M can be attached to a carbon atom of the hydrocarbon itself or to a substituent of the hydrocarbon.

[0296] In some embodiments, K is a hydrocarbon consisting entirely of carbon atoms.

[0297] In some embodiments, K is an unsubstituted hydrocarbon.

[0298] In some embodiments, K is an unsubstituted hydrocarbon consisting entirely of carbon atoms.

[0299] In some of any of these embodiments, K is an alkyl group (an alkylene chain or a linker), preferably unsubstituted, and optionally a short alkyl or alkylene group of 1 - 6 or 1 - 4 or 1 - 2 carbon atoms in length.

[0300] In some of any of the embodiments described herein, K is absent.

[0301] In some of any of the embodiments described herein, J is absent, as described herein in any of the corresponding embodiments, and K is absent. In some of these embodiments, M is a carboxyl group.

[0302] In some of any of the embodiments described herein, Q is a hydrocarbon substituted by at least one aryl group (such as a phenyl group).

[0303] In some of these embodiments, Q is a hydrocarbon, which is a fully carbonaceous hydrocarbon, and in some of these embodiments, the hydrocarbon is an alkyl group (an alkylene linker), preferably a short alkyl group (or alkylene) having 1-6 or 1-4, preferably 1 or 2 carbon atoms in length, which is substituted by at least one aryl group (such as a phenyl group).

[0304] In some of any of the embodiments described herein, Q is a methylene group substituted by at least one aryl group (such as a phenyl group).

[0305] In some of any of the embodiments described herein, J is -P(=O)(OH)-O-; M is an acylamino group; and Q is a hydrocarbon substituted by at least one aryl group (such as a phenyl group), as described herein in any of the corresponding embodiments and any combination thereof.

[0306] In some of any of the embodiments described herein, J is -P(=O)(OH)-O-; M is an acylamino group; and Q is a methylene group substituted by at least one aryl group (such as a phenyl group).

[0307] In some embodiments of any of the embodiments described herein for Formula I, the lipid moiety represented by the variable X has Formula III:

[0308]

[0309] Wherein:

[0310] The dashed (curved) line represents the point of attachment to the corresponding Y backbone unit;

[0311] W1 and W2 are each independently hydrogen, an alkyl group, an alkenyl group, an alkynyl group, or an acyl group, where at least one of W1 and W2 is not hydrogen;

[0312] J is -P(=O)(OH)-O- or J is absent (such that K is directly attached to the indicated oxygen atom of the glycerol moiety);

[0313] K is a substituted or unsubstituted hydrocarbon having 1-10 carbon atoms in length;

[0314] M is a linking group, which is -O-, -S-, an amino group, a sulfinyl group, a sulfonyl group, a phosphate group, a phosphonyl group, a phosphino group, a carbonyl group, a thiocarbonyl group, a urea group, a thiourea group, a carbamoyl group, a thiocarbamoyl group, an acylamino group, a carboxyl group or a sulfonamide or M is absent (such that K is directly linked to Q); and

[0315] Q is a substituted or unsubstituted hydrocarbon having a length of 1 to 10 carbon atoms or Q is absent.

[0316] Q is linked to the backbone unit of the polymer backbone of any of the corresponding embodiments described herein, or alternatively, when Q is absent, M is linked to the above backbone unit.

[0317] When M is absent, Q is also absent, and K is linked to the backbone unit of the polymer backbone of any of the corresponding embodiments described herein.

[0318] In some embodiments of any of the embodiments of formula III described herein, one of W1 and W2 is hydrogen and the other is not hydrogen.

[0319] In some embodiments of any of the embodiments of formula III described herein, neither W1 nor W2 is hydrogen.

[0320] In some embodiments of any of the embodiments of formula III described herein, at least one of W1 and W2 is an alkyl, alkenyl, alkynyl or acyl group having a length of 10 to 30 carbon atoms. In some embodiments, each of W1 and W2 has a length of 10 to 30 carbon atoms.

[0321] Examples of acyl groups that can optionally and independently be used as W1 and / or W2 include, but are not limited to, lauroyl, myristoyl, palmitoyl, stearoyl, palmitoleoyl, oleoyl and linoleoyl.

[0322] In some embodiments of any of the embodiments of formula III described herein, J is -P(=O)(OH)-O- (for example, the lipid moiety is glycerophospholipid).

[0323] In this document, the length of the hydrocarbon represented by the variable K refers to the number of atoms separating J and M (i.e., along the shortest path between J and M), as shown in formula III.

[0324] When K is a substituted hydrocarbon, M can be linked to a carbon atom of the hydrocarbon itself or to a substituent of the hydrocarbon.

[0325] In some embodiments of any of the described embodiments of Formula III herein, K is an acyl moiety (e.g., -C(=O)-C(CH3)2-). In some such embodiments, J is absent such that K is directly attached to the indicated oxygen atom of the glycerol moiety. In some such embodiments, K contains a carbonyl linker (-C(=O)-) which is attached to the oxygen atom of the glycerol moiety via an ester bond.

[0326] In some embodiments of any of the described embodiments of Formula III herein, K is an ethanolamine moiety (e.g., -CH2-CH2-NH- or -CH2-CH2- attached to a nitrogen atom), a serine moiety (e.g., -CH2-CH(CO2H)-NH- or -CH2-CH(CO2H)- attached to a nitrogen atom), a glycerol moiety (e.g., -CH(OH)-CH(OH)-CH-O-), and an inositol moiety (e.g., -cyclohexyl(OH)4-O-). In some embodiments, J is -P(=O)(OH)-O-.

[0327] In some embodiments of any of the described embodiments of Formula III herein, M is an acylamino group, optionally -C(=O)NH-.

[0328] In some embodiments, the nitrogen atom of the acylamino group is attached to K. In some such embodiments, K is the ethanolamine or serine moiety as described herein.

[0329] In some embodiments of any of the described embodiments of Formula III herein, Q is a substituted alkylene group (e.g., having a length of 1-6 or 1-4 or 1-2 carbon atoms, such as methylene). In some such embodiments, M is an acylamino group or a carboxyl group. In some embodiments, the C(=O) of the acylamino group or carboxyl group is attached to Q.

[0330] In some embodiments of any of the described embodiments of Formula III herein, Q is an alkylene group as described herein and the methylene group is substituted with one or two substituents, and at least one of these substituents is or contains an aryl group (e.g., phenyl). In some such embodiments, M is an acylamino group. In some embodiments, the C(=O) of the acylamino group is attached to Q. Alternatively, M is a carboxyl group and the C(=O) of the carboxyl group is attached to Q.

[0331] In some embodiments of any of the described embodiments of Formula III herein, Q is a methylene group substituted with two substituents, at least one of the substituents is or contains an aryl group (e.g., phenyl), and the other can be, for example, an aryl group (e.g., phenyl) or an alkyl group (e.g., having a length of 1-6 or 1-4 carbon atoms). In some embodiments, the methylene group is substituted with an alkyl group (e.g., C 1-4-alkyl) and aryl (such as phenyl) substituents. In some such embodiments, M is an acylamino group. In some such embodiments, M is a carboxyl group.

[0332] In some embodiments of any of the embodiments of Formula III herein, Q is a substituted alkylene group (such as having a length of 1-6 or 1-4 or 1-2 carbon atoms, such as methylene). In some such embodiments, M is an acylamino group or a carboxyl group. In some embodiments, the C(=O) of the acylamino group or carboxyl group is linked to Q.

[0333] In some embodiments of any of the embodiments of Formula III herein, Q is an alkylene group as described herein, and the methylene group is substituted with one or two substituents. In some embodiments, the methylene group is substituted with one or two alkyl groups (such as C 1-4 -alkyl). In some such embodiments, M is not an acylamino group. In some such embodiments, M is a carboxyl group.

[0334] In some embodiments of any of the embodiments of Formula III herein, Q is a methylene group substituted with two substituents. In some embodiments, the methylene group is substituted with two alkyl groups (such as C 1-4 -alkyl). In some embodiments, the alkyl group is methyl, such that Q is dimethylmethylene (-C(CH3)2-). In some such embodiments, M is not an acylamino group. In some such embodiments, M is a carboxyl group.

[0335] According to some of any of the embodiments of Formula III described herein, when M is an acylamino group, Q is an alkylene group substituted with at least one aryl group as described in any of the corresponding embodiments herein.

[0336] According to some of any of the embodiments described herein, M is not an acylamino group, and Q is as described in any of the corresponding embodiments herein.

[0337] In some embodiments of any of the embodiments of Formula III herein, both M and Q are absent, and K is terminated by a substituted or unsubstituted methylene group, according to any of the corresponding embodiments regarding Q described herein, such as a methylene group substituted with two substituents (such as dimethylmethylene (-C(CH3)2-)). In some embodiments, K also contains a carbonyl group of any of the corresponding embodiments described herein.

[0338] In some embodiments of any of the embodiments described herein, J, M, and Q are each absent. In some such embodiments, K comprises a carbonyl linking group (-C(=O)-) directly attached (by an ester bond) to the depicted oxygen atom of the glycerol moiety, and further comprises a substituted or unsubstituted methylene group (such as dimethylmethylene). In some embodiments, K consists of a carbonyl linking group directly attached (by an ester bond) to the depicted oxygen atom of the glycerol moiety and a substituted or unsubstituted methylene group, for example, K is -C(=O)-C(CH3)2-.

[0339] In some of any of the embodiments described herein for Formula IV, F1 is as described herein for OW1. In some of these embodiments, F3 and F4 are each hydrogen. In some of these embodiments, J is absent. In some of these embodiments, M is not an amido group.

[0340] In some of any of the embodiments described herein for Formula IV, F2 is as described herein for OW2. In some of these embodiments, F3 and F4 are each hydrogen. In some of these embodiments, J is absent. In some of these embodiments, M is not an amido group.

[0341] In some of any of the embodiments described herein for Formula IV, F1 is as described herein for OW1 and F2 is as described herein for OW2. In some of these embodiments, F3 and F4 are each hydrogen. In some of these embodiments, J is absent. In some of these embodiments, M is not an amido group.

[0342] In some of any of the embodiments described herein, the lipid moiety does not contain a moiety of Formula III as described herein.

[0343] In some of any of the embodiments described herein, the lipid moiety has a moiety of Formula III as described herein, provided that M is not an amido group (such as M is a carboxyl group) and / or Q comprises an aryl substituent as described herein.

[0344] In some of any of the embodiments described herein for Formula IV, the lipid moiety X, which is a polymeric compound as described in WO 2017 / 109784, is excluded from the scope of this embodiment.

[0345] Targeting Portion:

[0346] In some embodiments of any of the embodiments described herein, at least a portion of the monomer units of the polymeric moiety comprises a targeting moiety (according to any of the embodiments related to the targeting moiety described herein).

[0347] As used herein, a "targeting moiety" refers to a moiety that enables a compound (e.g., a compound of some embodiments of the present invention) to approach a selected substance and / or material (referred to herein as a "target"). The target is optionally a cell (e.g., a proliferating cell associated with a proliferative disease or disorder), where the approach enables the targeting moiety to facilitate attachment and / or internalization of the compound into the target cell, and enables the compound to exert a therapeutic effect.

[0348] In some of any of the embodiments described herein, the targeting moiety comprises a backbone unit Y of any of the corresponding embodiments described herein, and optionally a linking moiety L and / or a moiety Z of any of the corresponding embodiments described herein, e.g., where the substituent of any of the corresponding embodiments described herein comprises (and optionally consists of) the targeting moiety.

[0349] For example, in some embodiments, where at least a portion of the backbone unit Y has the formula -CR4R5-CR6D- (as described herein in any of the corresponding embodiments), any one or more of R4-R6 and D (optionally where D is R7 as described herein) comprises the targeting moiety of any of the corresponding embodiments described herein (e.g., where any one or more of R4-R6 and D is a substituent that comprises a substituent as the targeting moiety), and optionally any one or more of D of R4-R6 and D is the targeting moiety. However, many other structures of monomer units comprising substituents that comprise (and optionally consist of) the targeting moiety are also included in the embodiments of the present invention.

[0350] In some embodiments, the polymeric moiety is a copolymer moiety as described herein in any of the corresponding embodiments, where at least one monomer unit as described herein comprises a targeting moiety (as described herein in any of the corresponding embodiments), and at least one other monomer unit does not comprise such a targeting moiety. The distribution of monomer units comprising the targeting moiety can be consistent with any distribution of monomer units in the copolymer moieties described herein (e.g., random, alternating, periodic copolymers, and / or block copolymers). In any of the embodiments described herein, where m is at least 1, at least a portion of the monomer units comprises the targeting moiety of any of the corresponding embodiments described herein. In some such embodiments, at least a portion of the monomer units comprising the targeting moiety of any of the corresponding embodiments described herein are monomer units that do not comprise a side group represented by (-L-Z) as described herein in any of the corresponding embodiments. In some such embodiments, the number of monomer units comprising the targeting moiety of any of the corresponding embodiments described herein is represented by the variable m of any of the corresponding embodiments described herein. In some such embodiments, none of the monomer units comprising a side group represented by (-L-Z) comprises the above-described targeting moiety.

[0351] In any of the embodiments described herein, where m is at least 1, each monomer unit that does not contain a side group represented by (-L-Z) (the number thereof being represented by the variable m) contains a targeting moiety (according to any of the corresponding embodiments described herein). In some such embodiments, each monomer unit that contains a targeting moiety (according to any of the corresponding embodiments described herein) is a monomer unit that does not contain a side group represented by (-L-Z), i.e., none of the monomer units that contain a side group represented by (-L-Z) contains the above-mentioned targeting moiety, and each monomer unit that does not contain a side group represented by (-L-Z) contains the above-mentioned targeting moiety.

[0352] In any of the embodiments described herein, where m is at least 1, the monomer units that contain a targeting moiety may consist essentially of a main chain unit Y (according to any of the corresponding embodiments herein) substituted by one or more targeting moieties (according to any of the corresponding embodiments described herein).

[0353] In some of any of the embodiments described herein, at least a portion of the monomer units that contain a targeting moiety according to any of the corresponding embodiments described herein are monomer units that contain a side group represented by (-L-Z) as described herein in any of the corresponding embodiments. In some such embodiments, the number of monomer units that contain a targeting moiety according to any of the corresponding embodiments described herein is represented by the variable n in any of the corresponding embodiments described herein (i.e., each monomer unit that contains a targeting moiety according to any of the corresponding embodiments described herein is a monomer unit that contains a side group). In some such embodiments, none of the monomer units that do not contain a side group represented by (-L-Z) contains the above-mentioned targeting moiety.

[0354] In some of any of the embodiments described herein, the monomer units that contain a targeting moiety may optionally be different (optionally significantly different) in structure (i.e., if present, the structure of Y and / or L and / or Z as defined in any of the embodiments described herein) from another monomer unit that contains a targeting moiety. For example, the main chain unit Y of the monomer units that contain a targeting moiety may optionally be different in structure from the main chain unit Y of the other monomer units in the polymer moiety (according to any of the corresponding embodiments described herein).

[0355] In any of the embodiments described herein, where m is at least 1, the polymer moiety contains monomer units that contain a targeting moiety, and the monomer units are located at the end of the polymer moiety away from the lipid moiety. In such embodiments, the compound represented by general formula I has formula Ib:

[0356]

[0357] Wherein:

[0358] T is a monomer unit comprising a targeting moiety (any of the corresponding embodiments described herein).

[0359] X and T are attached to the distal end of a moiety represented by [Y(-L-Z)]n[Y]m-1; and

[0360] X, Y, L, Z, n, and m are defined according to any of the embodiments related to Formula I described herein, provided that m is at least 1.

[0361] It should be understood that T in Formula Ib is the type of monomer unit represented by Y in Formulas I and Ia (i.e., without the side group represented by (-L-Z)). Except for T, the number of monomer units represented by Y (i.e., without the side group represented by (-L-Z)) is represented by the numerical value m-1, such that the total number of monomer units without the side group represented by (-L-Z), including T, is represented by the variable m, as shown in Formulas I and Ia.

[0362] In some embodiments, m is 1, such that m-1 is 0, and the compound represented by Formula Ib thus has the following formula: X-[Y(-L-Z)]n-T, where L, T, X, Y, Z, and n are defined according to any of the embodiments described herein.

[0363] The monomer unit comprising a targeting moiety of any of the corresponding embodiments described herein can be optionally prepared by a method of preparing a monomer comprising the targeting moiety and using the monomer to prepare the polymer moiety described herein (e.g., by polymerizing monomers according to any of the corresponding embodiments described herein) and / or by modifying the monomer unit in the polymer moiety after preparing the polymer moiety (e.g., by polymerizing monomers according to any of the corresponding embodiments described herein), using any suitable techniques known in the art, including but not limited to conjugation techniques.

[0364] In some embodiments of any of the embodiments described herein regarding the targeting moiety, the targeting moiety does not comprise a moiety having the general formula II (any of the corresponding embodiments described herein). For example, even though the moiety represented by Formula II can form a bond with a target described herein, the term "targeting moiety" should be understood in some embodiments to be related to a moiety different from the moiety represented by the variable Z (having the general formula II).

[0365] In some embodiments of any of the embodiments described herein, the side group represented by (-L-Z) is selected such that it does not form a bond with the target and / or does not comprise the structure and / or properties of the targeting moiety as described herein in any of the corresponding embodiments. For example, in such an embodiment, where the targeting moiety comprises a nucleophilic group (according to any of the corresponding embodiments described herein) - such as an amine group - capable of forming a bond (such as a covalent bond) with the target, the variable Z (having general formula II) is optionally selected such that the amine / ammonium group is a tertiary amine / ammonium (i.e., no more than one of R1 - R3 is hydrogen) or a quaternary ammonium (i.e., none of R1 - R3 is hydrogen), preferably a quaternary ammonium (such as comprising a trimethylamino group, such as in phosphocholine). Tertiary amine groups and especially quaternary ammonium groups may be much less reactive nucleophilic groups than primary and secondary amine groups.

[0366] In some embodiments of any of the embodiments described herein with respect to the targeting moiety, the targeting moiety comprises at least one functional group (and optionally consists thereof) capable of forming a covalent or non-covalent bond (preferably a selective non-covalent bond) with a substance and / or material (referred to herein as the "target"), such as on the surface of the target (such as the surface of a cell and / or tissue).

[0367] As used herein, the term "functional group" includes chemical groups and moieties of any size and any functionality described herein (e.g., any functionality capable of forming a covalent or non-covalent bond with a target).

[0368] The non-covalent bonds of any of the corresponding embodiments described herein can optionally be achieved through non-covalent interactions, such as but not limited to electrostatic attraction, hydrophobic bonds, hydrogen bonds, and aromatic interactions.

[0369] In some embodiments, the targeting moiety comprises a functional group capable of forming a non-covalent bond selective for the target, e.g., the affinity of the targeting moiety and / or the functional group for the target (e.g., determined based on the dissociation constant) is greater than the affinity of the targeting moiety and / or the functional group for most (or all) other compounds capable of forming a non-covalent bond with the targeting moiety.

[0370] In some embodiments of any of the embodiments described herein, the functional group is capable of forming a covalent bond with one or more specific functional groups (such as hydroxyl, amine, thiol, and / or oxo groups) present on the target (such as the target of any of the corresponding embodiments described herein).

[0371] Examples of functional groups (in the targeting moiety) capable of forming a covalent bond with the target (according to any of the corresponding embodiments described herein) and the types of covalent bonds they can form include but are not limited to:

[0372] Nucleophilic groups, such as thiol, amines (e.g., primary or secondary amines), and hydroxyl groups, which can form covalent bonds with, for example, nucleophilic leaving groups in a target (e.g., any of the nucleophilic groups described herein), Michael acceptors (e.g., any of the Michael acceptors described herein), acyl halides, isocyanates, and / or isothiocyanates (e.g., as described herein);

[0373] Nucleophilic leaving groups, such as halogens, azides (-N3), sulfates, phosphates, sulfonyl groups (e.g., mesyl, tosyl), N-hydroxysuccinimide (NHS) (e.g., NHS esters), sulfo-N-hydroxysuccinimide, and acid anhydrides, which can form covalent bonds with, for example, nucleophilic groups in a target (e.g., as described herein);

[0374] Michael acceptors, such as ketenes (e.g., maleimides, acrylates, methacrylates, acrylamides, methacrylamides), nitro groups, and vinyl sulfones, which can form covalent bonds with, for example, nucleophilic groups in a target (e.g., as described herein), and optionally thiol groups;

[0375] Dihydroxyphenyl (any of the corresponding embodiments described herein), which can form covalent bonds with, for example, nucleophilic groups in a target (e.g., as described herein) and / or substituted or unsubstituted phenyl groups (e.g., another dihydroxyphenyl);

[0376] Acyl halide (-C(=O)-halogen), isocyanate (-NCO), and isothiocyanate (-N=C=S) groups, which can form covalent bonds with, for example, nucleophilic groups in a target (e.g., as described herein);

[0377] Carboxylate (-C(=O)OH) groups, which can form ester bonds with, for example, hydroxyl groups in a target and / or amide bonds with amine groups in a target (e.g., primary amines) (optionally by reaction with a coupling reagent such as carbodiimide), to form covalent bonds; and / or carboxylate groups in a target and can form amide or ester bonds with amines or hydroxyl groups in a targeting moiety, respectively;

[0378] Oxo groups (optionally in aldehyde groups (-C(=O)H)), which can form covalent imine bonds with amine groups in a target (e.g., primary amines); and / or oxo groups (optionally in aldehyde groups) in a target and can form covalent imine bonds with amine groups in a targeting moiety; and / or

[0379] Thiol groups, which can form covalent disulfide bonds (-S-S-) with thiol groups in a target.

[0380] Modification of monomers (e.g., prior to polymerization) or monomer units of a polymer moiety (e.g., after polymerization) to include any of the functional groups described herein can be carried out, optionally, using any suitable technique for conjugation known in the art. Those skilled in the art can readily select a suitable technique for any given molecule to be modified.

[0381] As used herein, the term "dihydroxyphenyl" refers to an aryl group (e.g., as defined herein) that is a phenyl group substituted with two hydroxyl groups at any position thereof. The phenyl group can optionally be substituted with additional substituents (which can optionally include additional hydroxyl groups), thereby forming a substituted dihydroxyphenyl; alternatively, the phenyl group contains no substituents other than the two hydroxyl groups, such that the dihydroxyphenyl is an unsubstituted dihydroxyphenyl.

[0382] In some embodiments of any of the embodiments described herein, the dihydroxyphenyl is an ortho-dihydroxyphenyl (wherein the hydroxyl groups are attached to the phenyl group at adjacent positions) or a para-dihydroxyphenyl (wherein the hydroxyl groups are attached to opposite sides of the benzene ring), each of which is a substituted or unsubstituted dihydroxyphenyl. In some such embodiments, the ortho-dihydroxyphenyl or para-dihydroxyphenyl is an unsubstituted dihydroxyphenyl.

[0383] The dihydroxyphenyl of any of the corresponding embodiments described herein can optionally be covalently bonded and / or conjugated to a target according to any one or more of the linking mechanisms described for para-dihydroxyphenyl (catechol), as described in the following references: Lee et al. [PNAS 2006, 103:12999-13003], Brodie et al. [Biomedical Materials 2011, 6:015014] and / or International Patent Application PCT / IL2015 / 050606 (published as WO 2015 / 193887).

[0384] In some embodiments of any of the embodiments described herein, the functional group capable of forming a bond with a target is a functional group capable of forming a covalent bond with an amino group, optionally a primary amino group. In some such embodiments, the target comprises one or more amino acids or amino acid residues, such as a peptide or polypeptide of any length (e.g., at least two amino acid residues, such as a protein), and the amine group can optionally be a lysine side chain amine group and / or an N-terminal amine group. In some embodiments, the target comprises an extracellular matrix protein, such as, for example, collagen. In some embodiments, the target comprises cartilage (e.g., articular cartilage).

[0385] In some embodiments of any of the embodiments described herein, the targeting moiety comprises at least one (and optionally consists of) functional group capable of forming a non-covalent bond with a target (e.g., as described in any of the corresponding embodiments herein).

[0386] In some embodiments of any of the embodiments described herein, the functional group capable of forming a non-covalent bond with a target comprises a polysaccharide and / or a polypeptide (such as a protein and / or a fragment thereof) (and optionally consists of the same), wherein the target optionally comprises a ligand for the polysaccharide and / or the polypeptide; and / or the target comprises a polysaccharide and / or a polypeptide (such as a protein and / or a fragment thereof), and the functional group capable of forming a non-covalent bond with the target is a ligand for the polysaccharide and / or the polypeptide.

[0387] Examples of suitable polysaccharides and / or polypeptides and their ligands include, but are not limited to:

[0388] Avidin or streptavidin as a polypeptide described herein and biotin as its ligand;

[0389] A polysaccharide-binding polypeptide as a polypeptide described herein and a complementary polysaccharide as its ligand (or a complementary polysaccharide-binding polypeptide as a polysaccharide ligand described herein);

[0390] A collagen-binding polypeptide as a polypeptide described herein and a complementary collagen as its ligand (or a collagen as a polypeptide described herein and a complementary collagen-binding polypeptide as its ligand);

[0391] A cell-expressed cell receptor and a ligand selectively bound by the receptor;

[0392] An antibody against any antigen (e.g., wherein the target described herein optionally comprises the antigen) or a fragment of such an antibody as a polypeptide described herein and the corresponding antigen as its ligand; and

[0393] An antibody mimetic against any antigen (e.g., wherein the target described herein optionally comprises the antigen).

[0394] Examples of cell-expressed cell receptors include, but are not limited to, receptors that are characteristic of a particular type of cell and / or tissue and receptors that are overexpressed in cancer cells. The cell receptor or cell is optionally a target as described herein, and the targeting moiety optionally comprises any ligand of the receptor. Examples of such ligands include, but are not limited to, transferrin, which is a ligand of the transferrin receptor and which can optionally target transferrin receptors overexpressed in certain cancer cells; keratinocyte growth factor (KGF or FGF7), which is specific for cells of epithelial origin and which can optionally target KGF receptors, such as those overexpressed in endometrial or pancreatic cancer [Visco et al., Int J Oncol 1999, 15:431-435; Siegfried et al., Cancer 1997, 79:1166-1171]; and epidermal growth factor (EGF), which can optionally target EGF receptors, optionally erbB, such as those overexpressed in glioma and endometrial cancer [Normanno et al., Curr Drug Targets 2005, 6:243-257]).

[0395] As used herein, the term "antibody" includes any type of immunoglobulin.

[0396] As used herein, the term "antibody mimetic" includes any type of molecule, optionally a polypeptide, which in the art refers to those that are capable of selectively binding an antigen (e.g., in the form of a non-covalent bond). Non-limiting examples of antibody mimetics include affibody, affilin, affimer, affitin, α-body, anticalin, avimer, DARPin, Fynomer, Kunitz domain peptides and monomers, such as those described in Nygren [FEBS J 2008,275:2668-2676], Ebersbach et al. [J Mol Biol 2007,372:172-185], Johnson et al. [Anal Chem2012,84:6553-6560], Krehenbrink et al. [J Mol Biol 2008,383:1058-1068], Desmet et al. [Nature Comm 2014,5:5237], Skerra [FEBS J 2008,275:2677-2683], Silverman et al. [Nature Biotechnol 2005,23:1556-1561], Stumpp et al. [Drug Discov Today 2008,13:695-701], Grabulovski et al. [J Biol Chem 2007,282:3196-3204], Nixon & Wood [Curr OpinDrug Discov Devel 2006,9:261-268], Koide & Koide [Methods Mol Biol 2007,325:95-109], and Gebauer & Skerra [Curr Opin Chem Biol 2009,13:245-255], the content of each of which is incorporated herein by reference in its entirety, and in particular with respect to the content on specific types of antibody mimetics.

[0397] As used herein, the term "polysaccharide-binding polypeptide" includes any polypeptide or oligopeptide (a peptide chain of at least 2 and preferably at least 4 amino acid residues in length) that is capable of selectively binding (e.g., non-covalently binding) a polysaccharide. A variety of polysaccharide-binding polypeptides and their binding specificities are known to those skilled in the art and include short peptide sequences (e.g., 4-50, optionally 4-20 amino acid residues in length) and longer polypeptides, such as proteins or fragments thereof (e.g., carbohydrate-binding modules and / or domains). In addition, the term "polysaccharide-binding polypeptide" includes antibodies that are capable of specifically binding a polysaccharide. Such antibodies will be available to those skilled in the art and / or those skilled in the art will know how to prepare such antibodies using immunological techniques known in the art.

[0398] Examples of polysaccharide-binding polypeptides that can be used in some of any of the embodiments of the present invention include, but are not limited to, carbohydrate-binding modules (CBMs); and hyaluronic acid-binding peptides, polypeptides, and / or modules (e.g., having sequences described in any of the following: International Patent Application Publication No. WO 2013 / 110056; International Patent Application Publication No. WO 2014 / 071132; Barta et al. [Biochem J 1993, 292:947-949], Kohda et al. [Cell 1996, 86:767-775], Brisset & Perkins [FEBS Lett 1996, 388:211-216], Peach et al. [J Cell Biol 1993, 122:257-264], Singh et al. [Nature Materials 2014, 13:988-995], and Zaleski et al. [Antimicrob Agents Chemother 2006, 50:3856-3860], the contents of each of which are incorporated by reference in their entirety, and in particular the content regarding specific polysaccharide-binding polypeptides), e.g., GAHWQFNALTVR (hyaluronic acid-binding peptide sequence).

[0399] Examples of CBMs that can be used in some of any of the embodiments of the present invention include, but are not limited to, CBMs belonging to families CBM3, CBM4, CBM9, CBM10, CBM17, and / or CBM28 (which can optionally be used for binding cellulose, e.g., in a cellulose-containing target); CBM5, CBM12, CBM14, CBM18, CBM19, and / or CBM33 (which can optionally be used for binding chitosan and / or other polysaccharides containing N-acetylglucosamine, e.g., in a chitosan-containing target); CBM15 (which can optionally be used for binding hemicellulose, e.g., in a hemicellulose-containing target); and / or CBM20, CBM21, and / or CBR48 (which can optionally be used for binding starch and / or glycogen, e.g., in a starch- and / or glycogen-containing target).

[0400] As used herein, the term "collagen-binding polypeptide" includes any polypeptide or oligopeptide (a peptide chain at least 2 and preferably at least 4 amino acid residues in length), including glycosylated polypeptides and oligopeptides such as peptidoglycans and proteoglycans, that is capable of selectively binding (e.g., non-covalently binding) to collagen (e.g., one type of collagen, some types of collagen, all types of collagen). Those skilled in the art are aware of a variety of collagen-binding polypeptides and their binding specificities, and include short peptide sequences (e.g., 4 - 50, optionally 4 - 20 amino acid residues in length) and longer polypeptides such as proteins or fragments thereof (e.g., collagen-binding domains). In addition, the term "collagen-binding polypeptide" includes antibodies that are capable of specifically binding to collagen. Such antibodies are available to those skilled in the art and / or those skilled in the art will know how to prepare such antibodies using immunological techniques known in the art.

[0401] Examples of collagen-binding polypeptides that can be used in embodiments of the present invention include, but are not limited to, collagen-binding proteins (e.g., decorin), fragments thereof, and / or other polypeptides as described in the following documents: U.S. Patent No. 8,440,618, Abd-Elgaliel & Tung [Biopolymers 2013, 100:167 - 173], Paderi et al. [Tissue Eng Part A 2009, 15:2991 - 2999], Rothenfluh et al. [Nat Mater 2008, 7:248 - 254], and Helms et al. [J Am Chem Soc 2009, 131:11683 - 11685] (the respective contents of which are incorporated by reference in their entirety, and in particular the content regarding specific collagen-binding polypeptides), e.g., the sequence WYRGRL.

[0402] It is expected that many related functional groups and moieties for binding will be developed and / or discovered during the patent term of this application, and terms such as "targeting moiety", "functional group", "cell receptor", "antibody", "antibody mimetic", "collagen-binding polypeptide", and "polysaccharide-binding polypeptide" are intended to presumptively include all such new technologies.

[0403] In some embodiments of any of the embodiments described herein, the functional group in the targeting moiety (according to any of the corresponding embodiments described herein) is linked to a linker (e.g., as defined herein). The linker can optionally be any linker or linking moiety described herein, including but not limited to substituted or unsubstituted hydrocarbons. In some embodiments, the targeting moiety (optionally a substituent of the backbone unit Y) consists essentially of a functional group linked to the remainder of the polymer moiety via a linker.

[0404] The functional group can optionally be covalently linked to the linker moiety, and the covalent bond can be obtained through the reaction between two functional groups, such as any covalent bond and / or functional group described herein in the context of forming a covalent bond between a functional group and a target.

[0405] In some embodiments of any of the embodiments described herein involving functional groups containing peptides or polypeptides, the amino acid residues of the peptide or polypeptide are optionally linked to a linker of the targeting moiety, for example, through an amide bond formed by an amine or carboxylate group in the peptide or polypeptide (such as in the N-terminus, lysine side chain, C-terminus, glutamate side chain, and / or aspartate side chain), an ester bond formed by a hydroxyl or carboxylate group in the peptide or polypeptide (such as in the serine side chain, threonine side chain, C-terminus, glutamate side chain, and / or aspartate side chain), and / or a disulfide bond formed by a thiol group in the peptide or polypeptide (such as in the cysteine side chain). In some embodiments, the amino acid residues linked to the linker are N-terminal and / or C-terminal residues, such as any amino acid residue linked through an N-terminal amino group or a C-terminal carboxylate group, and / or terminal lysine, glutamate, aspartate, serine, threonine, and / or cysteine residues linked through their side chains.

[0406] In some embodiments, an amino acid residue and / or a peptide (such as 2 - 20 amino acid residues in length) are added to the N-terminus and / or C-terminus of the peptide or polypeptide sequence of the functional group (according to any of the corresponding embodiments described herein), and the above sequence is linked to the linker. Examples of such terminal amino acid residues and / or peptides include, but are not limited to: glycine residues and peptides having a terminal glycine residue (which can be used to link the linker to the N-terminus or C-terminus (according to any of the corresponding embodiments described herein)); serine and threonine residues and peptides having a terminal serine or threonine residue (which can be used to optionally link the linker to the hydroxyl group in the serine or threonine side chain (according to any of the corresponding embodiments described herein)); and cysteine residues and peptides having a terminal cysteine residue (which can be used to link the linker to the peptide through a disulfide bond (according to any of the corresponding embodiments described herein).

[0407] In some embodiments, linking a peptide or polypeptide to a linker through a terminal amino acid residue can minimize interference (such as steric interference) with the functionality of the peptide or polypeptide after linking to the linker.

[0408] In some embodiments, linking a peptide or polypeptide to a linker through a terminal glycine is beneficial for linking by minimizing interference (such as steric interference) from amino acid side chains (excluding glycine) with the linker.

[0409] In some embodiments of any of the embodiments described herein, at least a portion of the monomeric units that include the targeting moiety, i.e., the monomeric units that include the targeting moiety, on average, are closer to the end of the polymeric moiety that is distal from the lipid moiety. For example, the average distance of the monomeric units that include the targeting moiety from the lipid moiety (e.g., measured along the backbone of the polymeric moiety in terms of atoms or backbone units) is greater than the average distance of the other monomeric units from the lipid moiety.

[0410] In some embodiments, at least a portion (and optionally all) of the monomeric units that include the targeting moiety form a (one or more monomeric unit) block near (and optionally at) the end of the polymeric moiety that is distal from the lipid moiety. In some such embodiments, the copolymeric moiety includes a single monomeric unit that contains the targeting moiety, and the monomeric unit is located at the end of the polymeric moiety that is distal from the lipid moiety.

[0411] Without being bound by any particular theory, it is hypothesized that the targeting moiety located distal to the lipid moiety can function more effectively as a targeting moiety (e.g., bind to a target more effectively). For example, this is attributed to less steric shielding of the targeting moiety (e.g., shielded by the surface associated with the lipid moiety), and thus it is more readily exposed to the target in the aqueous environment, enabling better contact with the target.

[0412] In alternative embodiments, the polymeric moiety does not include a targeting moiety as described in any of the corresponding embodiments herein.

[0413] Lipid layer and liposome:

[0414] According to one aspect of some embodiments of the present invention, there is provided a lipid bilayer (which may be interchangeably referred to herein as "bilayer") that includes a polymeric compound of any of the corresponding embodiments described herein. In some such embodiments, in addition to the polymeric compound, the bilayer further includes at least one bilayer-forming lipid. In some or any combination of the embodiments described herein, at least one bilayer-forming lipid includes at least one zwitterionic bilayer-forming lipid as described herein, and optionally further includes at least one negatively charged bilayer-forming lipid.

[0415] As used herein, the term "bilayer-forming lipid" includes any compound from which a bilayer can be formed from an aqueous solution of the compound, and the bilayer includes two parallel molecular layers of the compound (referred to as "lipids").

[0416] Generally, the bilayer includes the relatively polar portions of the lipids on the two surfaces of the bilayer, which may optionally include an interface with an aqueous solution and / or an interface with a solid surface; and the relatively hydrophobic portions of the lipids within the bilayer, which are located at the interface between the two layers of lipid molecules that form the bilayer.

[0417] In some embodiments, the lipids forming the bilayer are amphiphilic lipids.

[0418] As used herein, the term "amphiphilic lipid" refers to a compound comprising at least one hydrophilic moiety and at least one lipophilic moiety. Examples of amphiphilic lipids include, but are not limited to, fatty acids (e.g., at least 6 carbon atoms in length) and their derivatives, such as phospholipids and glycolipids; sterols (e.g., cholesterol) and steroid acids.

[0419] As used herein, the term "phospholipid" refers to a compound comprising a substituted or unsubstituted phosphate group and at least one alkyl chain (optionally at least two alkyl chains), the alkyl chain optionally being at least 5 carbon atoms in length, optionally at least 7 carbon atoms in length, and optionally at least 9 carbon atoms in length. The at least one alkyl chain is optionally part of an acyl group (e.g., a fatty acid moiety) or an alkyl itself (e.g., a fatty alcohol moiety). In some embodiments, the phosphate group and one or two (optionally two) alkyl chains (e.g., acyl or alkyl) are attached to a glycerol moiety through the oxygen atoms of glycerol.

[0420] In the context of this embodiment, the term "phospholipid" includes lipids having a (phosphorylated) glycerol backbone (e.g., monoacylglycerol and / or diacylglycerol phospholipids), referred to as glycerophospholipids.

[0421] In some embodiments of any of the embodiments described herein, the phospholipid is a glycerophospholipid. In some embodiments, the glycerophospholipid is a diacylglycerol, which comprises two fatty acyl groups and a phosphate group attached to the glycerol backbone.

[0422] Examples of the lipids forming the bilayer include glycerophospholipids (e.g., glycerophospholipids of any of the corresponding embodiments described herein). It should be understood that the polymeric compounds described herein can optionally be lipids forming the bilayer, which can form a bilayer by themselves or in combination with one or more additional bilayer-forming lipids.

[0423] In some embodiments of any of the embodiments described herein, the lipids forming the bilayer comprise at least one charged group (e.g., one or more negatively charged groups and / or one or more positively charged groups).

[0424] In some embodiments, the lipids forming the bilayer are zwitterionic; they comprise both (e.g., an equal number of) negatively charged groups and positively charged groups (e.g., one each).

[0425] In some embodiments of any of the embodiments described herein, the molar ratio of the lipid forming the bilayer (which is also included in addition to the polymeric compound) to the polymeric compound (any of the corresponding embodiments described herein) in the liposome ranges from 5:1 to 5000:1 (lipid forming the bilayer: polymeric compound), optionally ranging from 10:1 to 2500:1, optionally ranging from 25:1 to 1000:1 and optionally ranging from 50:1 to 500:1, including any intermediate values and sub-ranges therebetween.

[0426] Throughout this document, the terms "mol ratio" and "molar ratio" can be used interchangeably and describe the ratio of mol% of the indicated components in a lipid bilayer or liposome.

[0427] In some embodiments of any of the embodiments described herein that relate to a bilayer, the molar ratio of the lipid forming the bilayer (which is also included in addition to the polymeric compound) to the polymeric compound in the bilayer ranges from 10:1 to 1000:1 (lipid forming the bilayer: polymeric compound), optionally ranging from 10:1 to 500:1, optionally ranging from 10:1 to 100:1, and optionally ranging from 10:1 to 50:1, including any intermediate values and sub-ranges therebetween.

[0428] In some embodiments of any of the embodiments described herein that relate to a bilayer, the molar ratio of the lipid forming the bilayer (which is also included in addition to the polymeric compound) to the polymeric compound in the bilayer ranges from 10:1 to 100:1 (lipid forming the bilayer: polymeric compound), optionally ranging from 10:1 to 50:1, optionally ranging from 30:1 to 40:1, including any intermediate values and sub-ranges therebetween.

[0429] In some embodiments of any of the embodiments described herein that relate to a bilayer, the molar ratio of the lipid forming the bilayer (which is also included in addition to the polymeric compound) to the polymeric compound in the bilayer ranges from 10:1 to 1000:1 (lipid forming the bilayer: polymeric compound), optionally ranging from 100:1 to 1000:1, optionally ranging from 101:1 to 500:1, and optionally ranging from 100:1 to 200:1, including any intermediate values and sub-ranges therebetween.

[0430] Some bilayers of this embodiment can optionally be self-closed (e.g., making the bilayer have no edges), thereby forming an internal volume separated from the surrounding environment by the bilayer, which is referred to as a "liposome" in this document and in the art. Alternatively or additionally, the bilayer can be open-faced and / or have edges.

[0431] In one aspect of some embodiments according to the present invention, liposomes are provided that comprise at least one lipid bilayer of any one of the corresponding embodiments described herein.

[0432] As used herein and in the art, the term "liposome" refers to an artificially prepared vesicle that comprises a bilayer composed of amphiphilic lipid molecules. In an aqueous medium, the bilayer is typically configured such that the hydrophilic portions of the amphiphilic lipids are exposed to the medium on both surfaces of the bilayer, while the lipophilic portions of the lipids are located within the bilayer and are thus less exposed to the medium. Examples of liposomes that can be used in any one of the embodiments described herein include, but are not limited to, small unilamellar vesicles (SUVs), large unilamellar vesicles, and multilamellar vesicles (MLVs).

[0433] As described herein, liposomes according to embodiments particularly comprise at least one bilayer-forming lipid.

[0434] It should be understood that the polymeric compounds comprised by liposomes (any one of the corresponding embodiments described herein) can optionally be bilayer-forming lipids, which can themselves form a bilayer or can combine with one or more additional bilayer-forming lipids to form a bilayer.

[0435] Liposomes can optionally comprise a single bilayer (e.g., unilamellar vesicles) or multiple bilayers (e.g., multilamellar vesicles), where each bilayer optionally independently forms a closed vesicle, e.g., comprising concentric bilayer vesicles and / or multiple individual bilayer vesicles surrounded by the same bilayer vesicle.

[0436] As used herein, the term "unilamellar" refers to liposomes characterized by a single lipid bilayer, while the term "multilamellar" refers to liposomes characterized by multiple lipid bilayers, e.g., concentric bilayers.

[0437] As used herein, the term "small unilamellar vesicles" refers to unilamellar liposomes having a diameter of less than 100 nm, while the term "large unilamellar vesicles" refers to unilamellar liposomes having a diameter of at least 100 nm.

[0438] As used herein, the term "small multilamellar vesicles" refers to multilamellar liposomes having a diameter of less than 100 nm, while the term "multilamellar vesicles" MLV refers to multilamellar liposomes having a diameter of at least 100 nm.

[0439] In some embodiments of any one of the embodiments described herein, the liposomes comprise multilamellar vesicles. In some embodiments, the liposomes are predominantly (more than 50 wt%) multilamellar vesicles, preferably multilamellar vesicles (MLVs).

[0440] In some embodiments of any one of the embodiments described herein, the liposomes comprise small unilamellar vesicles. In some embodiments, the liposomes are predominantly (more than 50 wt%) small unilamellar vesicles.

[0441] In some embodiments of any of the embodiments described herein, the liposome comprises large unilamellar vesicles. In some embodiments, the liposome is predominantly (more than 50% by weight) large unilamellar vesicles.

[0442] The liposome of any of the corresponding embodiments described herein can be approximately spherical or can have any alternative shape, such as an elongated tube and / or a flattened (e.g., sheet-like) shape.

[0443] In some embodiments of any of the embodiments described herein, the concentration range of phospholipids within the liposome in the composition or formulation as described herein is from 0.5 mM to 500 mM. In some embodiments, the concentration range is from 0.5 mM to 150 mM. In some embodiments, the concentration range is from 0.5 mM to 50 mM. In some embodiments, the concentration range is from 0.5 mM to 10 mM. In some embodiments, the concentration range is from 0.5 mM to 5 mM. In some embodiments, the concentration range is from 1 mM to 10 mM. In some embodiments, the concentration range is from 1 mM to 5 mM (e.g., 3 mM).

[0444] In some or any combination thereof of any of the embodiments described herein, the total amount of at least one bilayer-forming lipid in the liposome ranges from 50 - 99 mol%, including any intermediate value and sub-range therebetween.

[0445] In some of any of the embodiments described herein, the amount of the polymeric compound (LPC) ranges from 0.1 - 10, or 0.1 - 5, or 0.1 - 3, or 0.1 - 1, or 0.2 - 0.8 mol% of the total lipids in the liposome, including any intermediate value and sub-range therebetween.

[0446] In some of any of the embodiments described herein, the amount of the polymeric compound (LPC) ranges from 1 - 50, or 1 - 40, or 1 - 30, or 5 - 50, or 5 - 40, or 5 - 30 wt% of the total lipids in the liposome, including any intermediate value and sub-range therebetween, the remainder being bilayer-forming lipids.

[0447] In some of any of the embodiments described herein, the average diameter of the liposome ranges from about 100 nm to about 2000 nm, or about 100 nm to about 1000 nm, about 100 nm to about 500 nm, or about 100 nm to about 200 nm, or about 150 nm to about 200 nm, or about 150 nm to about 180 nm, including any intermediate value and sub-range therebetween.

[0448] The average diameter of any of the corresponding embodiments described herein can optionally be the arithmetic mean (the ratio of the sum of the values to the number of values) or the Z-average, as defined in the field of dynamic light scattering (briefly, the intensity-weighted harmonic mean). In an exemplary embodiment, the average diameter is the Z-average diameter determined by dynamic light scattering.

[0449] The number-average molecular weight (Mn) and / or molecular weight (Mw) and / or number-average degree of polymerization (DPn) of the liposomes in the composition can optionally be determined by gel permeation chromatography (GPC) analysis.

[0450] The polydispersity index (PDI) and / or average diameter of the liposomes in the composition can optionally be determined by dynamic light scattering using a bi-parameter fit (e.g., according to ISO 13321 and ISO 22412 standards) of the data used to determine the PDI and Z-average diameter (e.g., using a commercially available instrument).

[0451] In some of any of the embodiments described herein, the PDI of the liposomes is less than 1.

[0452] In some of any of the embodiments described herein, the ζ-potential of the liposomes ranges from 10 mV to -50 mV, or 0 mV to -50 mV, or 0 mV to -30 mV, or -5 mV to -25 mV, or -10 mV to -25 mV, including any intermediate values and sub-ranges therebetween.

[0453] In some of any of the embodiments described herein, the ζ-potential of the liposomes is at least -3 mV (i.e., -3 mV or a more negative value), optionally at least -3.5 mV, and optionally at least -4 mV.

[0454] In some of any of the embodiments described herein that relate to polymeric compounds comprising negatively charged bilayer-forming lipids (e.g., DPPG), the ζ-potential of the liposomes ranges from 10 mV to -10 mV (e.g., 5 mV to -5 mV), optionally in the range 0 to -10 mV (e.g., 0 to -5 mV or -3 mV to -5 mV).

[0455] The ζ-potential can optionally be determined using any suitable technique known in the art (e.g., using a commercially available instrument), for example, electrophoretic light scattering. The ζ-potential of the liposomes can be determined by diluting the liposomes in a saline solution (e.g., NaCl) having a predetermined salt concentration (e.g., 10 μM).

[0456] In some of any of the embodiments described herein, the bilayer-forming lipid or liposome comprises at least one zwitterionic bilayer-forming lipid, for example, zwitterionic glycerophospholipids.

[0457] In some of any of the embodiments described herein, according to any of the embodiments described herein, the lipids or liposomes forming the bilayer comprise at least one zwitterionic bilayer-forming lipid, such as a zwitterionic glycerophospholipid, and at least one negatively charged bilayer-forming lipid, such as a negatively charged phosphatidylglycerol.

[0458] In some or any combination of any of the embodiments described herein, at least one negatively charged bilayer-forming lipid is phosphatidylglycerol (such as DPPG).

[0459] In some or any combination of any of the embodiments described herein, at least one bilayer-forming lipid further comprises at least one zwitterionic glycerophospholipid (such as phosphatidylcholine, such as DSPC, and / or phosphatidylethanolamine, such as DPPE).

[0460] In this text and in the art, the term "phosphatidylcholine" refers to a glycerophospholipid comprising a phosphocholine group and two fatty acyl groups attached to the glycerol backbone (i.e., a diacylglycerol ester).

[0461] In this text and in the art, the term "phosphatidylethanolamine" refers to a glycerophospholipid comprising a phosphoethanolamine group and two fatty acyl groups attached to the glycerol backbone (i.e., a diacylglycerol ester).

[0462] In some embodiments according to any of the embodiments of the present invention, the bilayer-forming lipid comprises a negatively charged bilayer-forming lipid (such as phosphatidylglycerol, such as DPPG).

[0463] In some embodiments according to any of the embodiments of the present invention, the bilayer-forming lipid comprises a zwitterionic glycerophospholipid (such as phosphatidylcholine, such as DSPC, or phosphatidylethanolamine, such as DPPE) and a negatively charged glycerophospholipid (such as phosphatidylglycerol, such as DPPG). In some embodiments according to any of the embodiments of the present invention, the total amount of the bilayer-forming lipid in the liposome ranges from 50-99 mol%, including any intermediate value and sub-range therebetween.

[0464] In some embodiments according to any of the embodiments of the present invention, in the liposome (the bilayer-forming lipid, LPC, and cholesterol, if present), the amount of the negatively charged bilayer-forming lipid (if present) ranges from 0.1-40 mol%, or 0.1-20 mol%, or 0.1-20 mol% of the lipids, including any intermediate value and sub-range therebetween.

[0465] In some embodiments according to any of the embodiments of the present invention, the liposome further comprises a sterol, such as cholesterol.

[0466] In some embodiments according to any of the embodiments of the present invention, sterols (such as cholesterol) are associated with the lipid bilayer (but do not form the lipid bilayer).

[0467] As used herein, the term "sterol" includes all sterols derived from any source, and includes synthetic sterols, animal-derived sterols, and plant-derived sterols (such as "phytosterols" as known in the art), as well as sterols in their saturated forms (i.e., stanols). Thus, as used herein, the term "sterol" includes sterols and stanols. Sterols are steroids that have a hydroxyl group at (steroid) C3 and have most of the skeleton of cholestane (IUPAC steroid nomenclature, 1987). Additional carbon atoms may be present in the side chain, typically at the C 17 position. In nature, sterols are found as C 26 -C 30 -steroids. The cyclopentanoperhydrophenanthrene ring structure is common to all sterols, while the structure of the side chain may vary. In nature, sterols can be found as conjugates (such as glycoconjugates, fatty-acid conjugates, etc.). Thus, as used herein, the term "sterol" is further intended to cover conjugated sterols, including but not limited to phytosterol fatty acid esters and phytostanol fatty acid esters. An exemplary sterol is cholesterol. In some embodiments according to any of the embodiments of the present invention, the amount of sterol (such as cholesterol) ranges from 0.1 - 50 mol% of the total lipids in the liposome, including any intermediate values and sub-ranges therebetween.

[0468] In some embodiments according to any of the embodiments of the present invention, the amount of the polymeric compound (LPC) ranges from 0.1 - 10, or 0.1 - 5, or 0.1 - 1 mol% of the total lipids in the liposome, including any intermediate values and sub-ranges therebetween.

[0469] In some or any combination of any of the embodiments described herein, the amount of at least one negatively charged bilayer-forming lipid (if present) ranges from 0.1 - 40 mol% or 0.1 - 20 mol% of the lipids in the liposome, including any intermediate values and sub-ranges therebetween.

[0470] In some embodiments of any of the embodiments described herein related to liposomes, the liposome further comprises at least one functional moiety or functional agent that binds or associates with the liposome surface and / or the lipid bilayer and / or the core of the liposome (such as within the liposome bilayer and / or encapsulated by the liposome bilayer). In an exemplary embodiment, the functional moiety binds to the liposome, for example, it covalently binds to the liposome by covalently bonding to one or more lipids. In an exemplary embodiment, the functional agent associates with the liposome chemically through, for example, covalent or electrostatic bonds and / or physically by being entrapped or incorporated within the lipid bilayer or the core.

[0471] Examples of functional moieties and functional agents suitable for inclusion in the embodiments described herein include, but are not limited to, a therapeutic active agent or a moiety of a therapeutic active agent (e.g., where the active agent is releasable upon cleavage of the moiety), a labeling moiety or labeling agent, and / or a targeting moiety or targeting agent (e.g., targeting moieties and agents on the surface of a liposome). Consider any other moiety or substance that can contribute to or improve the indicated use of the liposome. According to some embodiments, the liposome also contains a sterol, such as cholesterol. According to some of these embodiments, cholesterol is incorporated into and / or associated with the lipid bilayer.

[0472] According to some of any of the embodiments described herein, the functional moiety or functional agent is a therapeutic active agent or a moiety thereof, a labeling moiety or labeling agent, and / or a targeting moiety or targeting agent.

[0473] According to some of any of the embodiments described herein, the functional moiety or functional agent is a therapeutic active agent or a moiety thereof, and in some of these embodiments, the therapeutic active agent and / or a moiety thereof is located within the lipid bilayer and / or core of the liposome. According to some of these embodiments, the liposome also contains a sterol, such as cholesterol, in an amount of 0.1 - 50 mol% of the total lipids in the liposome. According to some of these embodiments, the polymeric compound is a long polymeric compound as described and defined herein in any of the corresponding embodiments.

[0474] According to some embodiments, the liposome contains a therapeutic active agent that is bound to or associated with the surface of the liposome and / or within the lipid bilayer and / or core of the liposome (e.g., within the liposome bilayer and / or encapsulated by the liposome bilayer); and cholesterol (e.g., associated within the lipid bilayer).

[0475] In some of any of the embodiments described herein, the liposome does not contain a therapeutic active agent.

[0476] In some of any of the embodiments described herein, the liposome contains a therapeutic active agent that is optionally incorporated into the liposome and / or on the surface of the liposome. In some such embodiments, the therapeutic active agent is the therapeutic active agent described in International Patent Application Publication No. WO 2018 / 150429.

[0477] As used herein, the term "therapeutic active agent" refers to any active agent (e.g., a compound) having a therapeutic effect, provided that the compound is not a bilayer-forming lipid or polymeric compound contained in a liposome (any of the corresponding embodiments described herein), and any moiety (e.g., a moiety of a compound) that produces an active agent having a therapeutic effect upon release (e.g., upon cleavage of one or more covalent bonds), including moieties of bilayer-forming lipid or polymeric compounds. Thus, bilayer-forming lipid and polymeric compounds per se are excluded from the definition of therapeutic active agents, but bilayer-forming lipid and / or polymeric compounds may optionally produce a therapeutic active agent upon release, in which case the moieties of the bilayer-forming lipid and / or polymeric compounds that produce the therapeutic activity are also considered therapeutic active agents as defined herein.

[0478] When associated with a liposome, a therapeutic active agent may optionally be linked to the liposome (e.g., to the outer and / or inner surface of the liposome membrane) by covalent or non-covalent (e.g., electrostatic and / or hydrophobic) bonds, incorporated within the liposome membrane (e.g., a lipophilic agent stably partitioned into the liposome lipid phase), and / or encapsulated within the core of the liposome (e.g., a hydrophilic agent within the aqueous compartment of the liposome). A therapeutic active agent may optionally be a moiety covalently linked to a liposome (e.g., linked to a lipid to form a lipid derivative containing the moiety). In some embodiments, such linkages can be obtained by using techniques known in the art (e.g., amide bond formation).

[0479] In some embodiments, a therapeutic active agent is linked to a liposome by electrostatic interactions. For example, the therapeutic active agent is a positively charged active agent that is linked to or complexed with a negatively charged bilayer-forming lipid as described herein.

[0480] In some embodiments of any of the embodiments described herein, the therapeutic active agent is, for example, an analgesic, an anti-inflammatory agent, an anti-proliferative agent, an anti-microbial agent (including antibacterial agents, anti-mycobacterial agents, antiviral agents, anti-fungal agents, anti-protozoal agents, and / or anti-parasitic agents), and / or a vaccine antigen. In some such embodiments, the therapeutic active agent is an analgesic and / or an anti-inflammatory agent. In some such embodiments, the therapeutic active agent can be used alone or in combination with another therapeutic active agent for the treatment of osteoarthritis.

[0481] As used herein, the term "anti-microbial" refers to the property of a substance (e.g., a compound or composition) that is capable of affecting microbial parameters, as defined herein, including death, eradication, elimination, reduction in number, decreased growth rate, growth inhibition, and alteration of population distribution of one or more species of microbial life forms. The term includes antibacterial agents, also referred to herein as antibiotics. Examples of anti-microbial agents include, but are not limited to, antibacterial agents, anti-mycobacterial agents, antiviral agents, anti-fungal agents, anti-protozoal agents, and / or anti-parasitic agents known in the art.

[0482] As used herein, the term "vaccine antigen" refers to a substance in a vaccine that can stimulate the immune system to recognize and respond to a specific pathogen or external substance. When introduced into a patient, the antigen triggers an immune response, leading to the production of antibodies in the patient's body. Examples of vaccine antigens include, but are not limited to, inactivated vaccines or subunit vaccines (such as influenza vaccines; hepatitis B vaccines), live attenuated vaccines (such as yellow fever vaccines), viral vector vaccines (such as COVID-19 vaccines), toxoid vaccines (such as tetanus vaccines), and / or conjugate vaccines (Haemophilus influenzae type b (Hib) vaccines).

[0483] Examples of suitable anti-proliferative agents include, but are not limited to: asivicin; aclarubicin; acodazole (e.g., acodazole hydrochloride); acronine; adriamycin; adozelesin; aldesleukin; altretamine; ambruticin; ametantrone (e.g., ametantrone acetate); aminoglutethimide; amsacrine; anastrozole; anthramycin; asparaginase; aristocortin; azacitidine; altretamine; azotomycin; batimastat; benzodepa; bicalutamide; bisantrene (e.g., bisantrene hydrochloride); bisnafide (e.g., bisnafide dimethanesulfonate); bizelesin; bleomycin (e.g., bleomycin sulfate); brequinar (e.g., brequinar sodium); brostallicin; busulfan; actinomycin; calusterone; caracemide; carbetimer; carboplatin; carmustine; carubicin (e.g., carubicin hydrochloride); carzelesin; cedefingol; chlorambucil; cineromycin; cisplatin; cladribine; combesin phosphate A-4; clanatoc (e.g., clanatoc mesylate); cyclophosphamide; cytarabine; dacarbazine; dactinomycin; daunorubicin (e.g., daunorubicin hydrochloride); decitabine; dexormaplatin; dizoguanine (e.g., dizoguanine mesylate); diaziquone; docetaxel; doxorubicin (e.g., doxorubicin hydrochloride); droloxifene (e.g., droloxifene citrate); drostanolone (e.g., drostanolone propionate); drazomycin; edatrexate; eflornithine (e.g., eflornithine hydrochloride); elsamitrucin; enloplatin; enpromate; epipropidine; epirubicin (e.g., epirubicin hydrochloride); erboulazole; esorubicin (e.g., esorubicin hydrochloride); estramustine (e.g., estramustine phosphate sodium); etanidazole; etoposide (e.g., etoposide phosphate); ethamivan; azelastine (e.g., azelastine hydrochloride); fazarabine; fenretinide; floxuridine; fludarabine (e.g., fludarabine phosphate); fluorouracil; flucytosine; fostriecin (e.g., fostriecin sodium); gemcitabine (e.g., gemcitabine hydrochloride); hydroxyurea; idarubicin (e.g., idarubicin hydrochloride); ifosfamide; ilmofosine; interferon α-2a; interferon α-2b; interferon α-n1; interferon α-n3; interferon β-Ia; interferon γ-Ib; isoproterenol; irinotecan (e.g., irinotecan hydrochloride); lanreotide (e.g., lanreotide acetate); letrozole; leuprorelin (e.g., leuprorelin acetate); liarozole (e.g., liarozole hydrochloride); lometrexol (e.g., lometrexol sodium); lomustine; losoxantrone (e.g., losoxantrone hydrochloride); masoprocol; maytansine; mechlorethamine (e.g., mechlorethamine hydrochloride); medroxyprogesterone (e.g., medroxyprogesterone acetate); melengestrol (e.g., melengestrol acetate); melphalan; menogaril; mercaptopurine; methotrexate (e.g., methotrexate sodium); metopimazine; meturedepa; mitindomide; mitocarcin; mitomalcin; mitomycin; mitosper; mitotane; mitoxantrone (e.g., mitoxantrone hydrochloride); mycophenolic acid; nocodazole; nogalamycin; olaplarin; oxaliplatin; oxisuran; paclitaxel; pegaspargase;Peliomycin; pentamustine; peplomycin (e.g., peplomycin sulfate); pephosphamide; pipobroman; piposulfan; pirarubicin (e.g., pirarubicin hydrochloride); primycin; promestriene; porfimer (e.g., porfimer sodium); porfiromycin; prednimustine; procarbazine (e.g., procarbazine hydrochloride); puromycin (e.g., puromycin hydrochloride); pyrazomycin; riboadenosine; rogletimide; safingol (e.g., safingol hydrochloride); semustine; sintetrin; phosphoacetylaspartic acid (e.g., phosphoacetylaspartic acid sodium); sparsomycin; spirogermanium (e.g., spirogermanium hydrochloride); spiro mustard; spiroplatin; streptothricin; streptozocin; sulfachlorophen; telithromycin; tecogalan (e.g., tecogalan sodium); tegafur; teloxantrone (e.g., teloxantrone hydrochloride); temoporfin; teniposide; teroxirone; testolactone; thioguanine; thiotepa; thiazofurin; tirapazamine; topotecan (e.g., topotecan hydrochloride); toremifene (e.g., toremifene citrate); tretolone (e.g., tretolone acetate); triciribine (e.g., triciribine phosphate); trimetrexate (e.g., trimetrexate glucuronate); triptorelin; tobutrozole (e.g., tobutrozole hydrochloride); uracil mustard; uredepa; vapreotide; verteporfin; vinblastine; vincristine (e.g., vincristine sulfate); vindesine (e.g., vindesine sulfate); vinpocetine; vinglycinate; vinorelbine (e.g., vinorelbine tartrate); vinflunine; vinleurosine; vorozole; zeniplatin; nesiritide; and zorubicin (e.g., zorubicin hydrochloride). Additional anti-cancer agents include those disclosed in the following literature: Chapter 52 Antineoplastic Agents (Paul Calabresi and Bruce A. Chabner) and its introduction in "The Pharmacological Basis of Therapeutics", 8th Edition, 1990 by Goodman and Gilman, 1202 - 1263, McGraw-Hill, Inc. (Health Professions Division), the content of which is incorporated herein by reference.;

[0484] In some of any of the embodiments described herein, sterols such as cholesterol are included in the lipid bilayer of the liposomes of any of the embodiments described herein.

[0485] In some of any of the embodiments described herein, the amount of sterol (e.g., cholesterol) ranges from 0.1 - 50 mol% of the total lipids in the liposome, including any intermediate values and sub-ranges therebetween. Therapeutic active agents suitable for inclusion in liposomes (e.g., molecules or moieties as active agents) include, but are not limited to, amphotericin B, cisplatin, cytarabine, daunorubicin, doxorubicin, estradiol, influenzavirus, morphine, surfactant protein B, surfactant protein C, verteporfin, and vincristine.

[0486] Examples of labeling moieties or labeling agents include chromogenic (e.g., absorbing visible light), fluorescent, phosphorescent, and / or radioactive moieties and compounds. Many such compounds and moieties (and techniques for preparing such moieties) are well known to those skilled in the art.

[0487] The targeting moiety in the liposome of any of the corresponding embodiments described herein can optionally be the targeting moiety of any of the corresponding embodiments described herein. The targeting moiety in the liposome can be comprised by a polymeric compound of some embodiments of the present invention (any of the corresponding embodiments described herein), and the liposome comprises the polymeric compound. Alternatively or additionally, the targeting moiety in the liposome can optionally be comprised by another compound in the liposome, a bilayer-forming lipid (any of the corresponding embodiments described herein) optionally conjugated to the targeting moiety of any of the corresponding embodiments described herein.

[0488] As used herein, a "targeting agent" refers to a compound ("active agent") that comprises (and optionally consists essentially of) the targeting moiety of any of the corresponding embodiments described herein (e.g., in the context of a targeting group comprised by a polymeric compound described herein). Generally, the term "targeting agent" is used to refer to a compound other than a polymeric compound that comprises a targeting moiety as described herein.

[0489] In some embodiments, a functional moiety (e.g., a targeting moiety or a labeling moiety) is covalently linked to the liposome. In some embodiments, such linkage can be achieved by using techniques known in the art (e.g., amide bond formation).

[0490] Substance Compositions and Articles:

[0491] In another aspect according to an embodiment of the present invention, there is provided a substance composition comprising a substrate coated on at least a portion of its surface on the lipid bilayer of any of the corresponding embodiments described herein.

[0492] In another aspect according to an embodiment of the present invention, there is provided an article comprising the substance composition of any of the embodiments described herein.

[0493] As used herein, the term "substance composition" refers to any composition that comprises a plurality of substances (e.g., a substrate, a water-soluble polymer, and an amphiphilic lipid), which form does not exist in nature and does not include parts of a human. The form that does not exist in nature can optionally comprise combinations of natural substances that do not exist in nature, and / or can optionally comprise one or more substances that do not occur in nature. It should be understood that this definition is not necessarily the same as the standard legal definition of the term.

[0494] As used herein, the term "article" refers to any item made of material in a manner that results in a new form, quality, property, or combination of materials. It should be understood that this definition is not necessarily the same as the standard statutory definition of the term. The articles described herein can optionally consist essentially of a material composition or, alternatively, can include additional materials and / or components.

[0495] At least a portion of the amphiphilic lipid molecules is oriented such that its polar groups (e.g., charged groups) face outward at the surface of the material composition.

[0496] As used herein, the phrase "face outward" refers to a group in a molecule (e.g., a lipid) that is closer to the surface of the material composition than the center of gravity of the molecule and farther from the substrate than the center of gravity of the molecule.

[0497] As described herein and without being bound by any particular theory, it is believed that, according to some embodiments of the present invention, the outward polar groups (e.g., charged groups) are effective for high-efficiency lubrication and / or inhibition of adhesion, biofouling, and / or biofilm formation (e.g., as described herein), at least in part due to the nature of the hydrated polar groups (e.g., hydrated lubrication), particularly hydrated charged groups.

[0498] In any of the embodiments described herein, the substrate can comprise any type of material or a combination of different types of materials, including inorganic materials and / or organic materials in crystalline, amorphous, and / or gel (e.g., hydrogel) form, such as metals, minerals, ceramics, glass, polymers (e.g., synthetic polymers, biopolymers), plant and / or animal biomass, and combinations thereof.

[0499] In some embodiments, the substrate comprises a physiological surface (e.g., physiological tissue) and / or a surface that contacts and / or is intended to contact a physiological surface (e.g., as described in any of the corresponding embodiments herein).

[0500] In some embodiments of any of the embodiments described herein, the article is a medical device, such as a medical device having lipids attached to at least a portion of its surface. In some embodiments, the medical device is a device designed to contact a body part vulnerable to infection, such as the interior of the body, mucous membranes, and / or the surface of the eye. Examples of such medical devices include, but are not limited to, surgical tools and implants (for contacting the interior of the body) and contact lenses (for contacting the surface of the eye).

[0501] As used throughout this text, the term "medical device" includes any material or device used on, in, or throughout an individual, for example, during a medical procedure (such as due to disease or injury). The individual can be a human or non-human animal, such that the term "medical device" includes veterinary devices. Medical devices include, but are not limited to, medical implants (including permanent and temporary implants), wound care devices, medical devices for drug delivery, contact lenses and body cavities, and personal protective devices. Medical implants include, but are not limited to, catheters (such as urinary catheters, intravascular catheters), injection ports, cannulation devices, dialysis shunts, wound drainage tubes, skin sutures, vascular grafts, implantable meshes, intraocular devices, heart valves, etc. Wound care devices include, but are not limited to, conventional wound dressings, biological graft materials, tape closures and dressings, and surgical drapes. Medical devices for drug delivery include, but are not limited to, needles, drug delivery skin patches, drug delivery mucosal patches, and medical sponges. Body cavities and personal protective devices include, but are not limited to, tampons, sponges, surgical and examination gloves, and toothbrushes. Birth control devices include, but are not limited to, intrauterine devices (IUDs), diaphragms, and condoms.

[0502] In the context of medical devices, it should be understood that the bilayer-coated medical devices described herein, and lipid bilayers or liposomes containing bilayers are not themselves considered medical devices in this text.

[0503] Examples of suitable articles include, but are not limited to:

[0504] Medical devices (such as contact lenses, pacemakers, heart valves, replacement joints, catheters, catheter access ports, dialysis tubes, gastric bands, shunts, screw plates, artificial disc replacements, implantable cardioverter defibrillators, cardiac resynchronization therapy devices, implantable cardiac monitors, mitral annuloplasty devices, left ventricular assist devices (LVADs), artificial hearts, implantable infusion pumps, implantable insulin pumps, stents, implantable nerve stimulators, maxillofacial implants, dental implants, etc.);

[0505] Packages or containers, such as packages or containers for food and / or beverages (such as packages for meat and / or dairy products and / or containers for storing or transporting meat and / or dairy products, such as storage tanks, raw milk storage equipment, conveyor belts for dairy processing operations, pipe walls, gaskets, rubber seals, stainless steel sampling tubes, pipe systems, filling machines, silo tanks, heat exchangers, post-pasteurization equipment, pumps, valves, separators, and spray devices), medical device packages, agricultural packages and containers (agrochemical packages and containers), blood sample or other biological sample packages and containers, and any other package or container for various articles; and

[0506] Elements of a water treatment system (such as for containing and / or transporting and / or treating an aqueous medium or water), devices, containers, filters, tubes, solutions, and gases, etc.

[0507] In the context of medical devices, it should be understood that the double-coated medical devices described herein, and liposomes that are double-layered or contain double-layers are not themselves considered medical devices in this document.

[0508] Exemplary articles include the following:

[0509] Medical devices such as, but not limited to, pacemakers, heart valves, replacement joints, catheters, catheter access ports, dialysis tubes, gastric bands, shunts, screw plates, artificial disc replacements, implantable cardioverter defibrillators, cardiac resynchronization therapy devices, implantable cardiac monitors, mitral annuloplasty devices, left ventricular assist devices (LVADs), artificial hearts, implantable infusion pumps, implantable insulin pumps, stents, implantable nerve stimulators, maxillofacial implants, dental implants, etc.;

[0510] Packages or containers such as food packages and containers, beverage packages and containers, medical device packages, agricultural packages and containers (agrochemical packages and containers), blood sample or other biological sample packages and containers, and any other packages or containers for a variety of articles;

[0511] Food packages such as dairy product packages and / or containers for storing or transporting dairy products;

[0512] Milk storage and processing devices such as, but not limited to, containers, storage tanks, raw milk storage equipment, conveyor belts for dairy product processing operations, pipe walls, gaskets, rubber seals, stainless steel sampling tubes, pipe systems, filling machines, silo tanks, heat exchangers, post-pasteurization equipment, pumps, valves, separators, and spray devices;

[0513] Energy harvesting devices such as microelectronic devices, microelectromechanical devices, photovoltaic devices, etc.;

[0514] Microfluidic devices such as micropumps or microvalves, etc.;

[0515] Seals such as O-rings, etc.;

[0516] Articles having a surface prone to corrosion;

[0517] Agricultural devices such as as described herein;

[0518] Textiles such as tough cotton;

[0519] Fuel transportation devices;

[0520] Building components such as, but not limited to, paints, walls, windows, door handles, etc.;

[0521] Elements of a water treatment system (e.g., for containing and / or transporting and / or treating an aqueous medium or water), devices, containers, filters, pipes, solutions, and gases, etc.; and

[0522] Components of an organic waste treatment system (such as for containing and / or disposing of and / or transporting and / or treating organic waste), devices, containers, filters, tubes, solutions, gases, etc.

[0523] In some of any of the embodiments described herein, the article comprises a hydrogel surface, for example, a lipid is attached to at least a portion thereof.

[0524] Contact lenses are exemplary articles that comprise a hydrogel surface. In some embodiments, the contact lens comprises a hydrogel surface and a rigid center. In some embodiments, the contact lens consists primarily of a hydrogel.

[0525] The hydrogel may comprise any material known in the art for use in contact lens hydrogels. Examples of such hydrogel materials include, but are not limited to, alphafilcon A, asmofilcon A, balafilcon A, bufilcon A, comfilcon A, crofilcon, deltafilcon A, dimefilcon, droxifilcon A, enfilcon A, etafilcon A, galyfilcon A, hefilcon A, hefilcon B, hilafilcon A, hilafilcon B, hioxifilcon A, hioxifilcon D, isofilcon, lidofilcon A, lidofilcon B, lotrafilcon B, mafilcon, methafilcon A, methafilcon B, narafilcon A, narafilcon B, ocufilcon A, ocufilcon B, oofilcon A, omafilcon A, perfilcon, phemfilcon A, polymacon, scafilcon A, senofilcon A, surfilcon, tefilcon, tetrafilcon A, tetrafilcon B, vifilcon A, and xylofilcon A.

[0526] In some embodiments of any of the embodiments described herein, the hydrogel comprises a polymer consisting of poly(2-hydroxyethyl methacrylate) and / or silicone. In some embodiments, the polymer comprises silicone. Such polymers may optionally comprise a small amount of additional monomers (e.g., crosslinking monomers) copolymerized with 2-hydroxyethyl methacrylate or silicone monomers. For example, 2-hydroxyethyl methacrylate may optionally be copolymerized with vinylpyrrolidone, methyl methacrylate, methacrylic acid (anionic monomer), ethylene glycol dimethacrylate (crosslinking monomer), and / or 3-(ethyldimethylammonium)propyl methacrylamide (cationic monomer) in contact lens hydrogels.

[0527] Sterile composition:

[0528] In one aspect of some embodiments of the present invention, there is provided a sterile composition comprising an aqueous carrier and a lipid bilayer of liposomes, wherein the lipid bilayer of the liposomes comprises at least one bilayer-forming lipid and a polymer compound of any of the corresponding embodiments described herein.

[0529] As used herein, the term "sterile" means the absence of observable microbial growth when the composition is placed under conditions (e.g., culture medium, incubation temperature) for a suitable period of time, e.g., according to any standard protocol for sterility testing. Optionally, sterility is tested in fluid thioglycollate medium, e.g., for up to 3 days in the temperature range of 30 - 35°C, and / or soybean-casein digest medium (also known as trypticase soy broth or trypticase soy agar), e.g., for up to 5 days in the temperature range of 20 - 25°C; e.g., wherein the composition is sterile if no microbial growth is observed in either medium. The content of fluid thioglycollate medium and / or soybean-casein digest medium and / or the method for sterility testing may optionally be as described in Chapter 71 of the United States Pharmacopeia, the content of which is incorporated herein by reference.

[0530] In some of any of the embodiments described herein, the sterile composition is further characterized in that the bacterial endotoxin concentration is below an acceptable threshold, e.g., below a threshold of 35 endotoxin units (EU) / mL (e.g., wherein endotoxin units are defined according to United States Pharmacopeia reference standards). The bacterial endotoxin level can be determined by any suitable assay known in the art, e.g., using Limulus amoebocyte lysate (e.g., according to Chapter 85 of the United States Pharmacopeia, the content of which is incorporated herein by reference), e.g., by comparison with a commercially available reference sample containing endotoxin.

[0531] In any of the corresponding embodiments, the sterile composition comprises an article immersed therein (which is also sterile as part of the sterile composition), such as a solid or semi-solid article that is typically packaged together with a liposome-containing aqueous composition. In some embodiments, the article is a contact lens, for example, where the aqueous carrier and liposomes represent a contact lens storage solution.

[0532] The sterile composition of any of the corresponding embodiments described herein can optionally be prepared according to the method described in any of the corresponding embodiments herein.

[0533] In one aspect of some embodiments of the present invention, a method for preparing a sterile composition is provided, the sterile composition comprising an aqueous carrier (such as in any of the corresponding embodiments described herein) and liposomes (such as in any of the corresponding embodiments described herein). The method includes: providing an aqueous composition comprising an aqueous carrier and liposomes, the liposomes comprising at least one bilayer-forming lipid (such as in any of the corresponding embodiments described herein) and a polymeric compound (such as in any of the corresponding embodiments described herein); and subjecting the aqueous composition to a temperature above 100 °C.

[0534] The sterile composition obtained according to the method can optionally be the sterile composition of any of the corresponding embodiments described herein.

[0535] In some of any of the corresponding embodiments described herein, the aqueous composition comprising an aqueous carrier and liposomes further comprises an article immersed therein (such as in any of the corresponding embodiments described herein), such that when the aqueous composition is subjected to a temperature above 100 °C, the article immersed in the aqueous composition becomes sterile. In some exemplary embodiments, the article comprises a contact lens. Such methods can allow for efficient and relatively low-cost simultaneous sterilization of solid or semi-solid articles and liposome-containing aqueous compositions (such as those typically packaged together), such as one or more contact lenses immersed in a liposome-containing contact lens solution (such as a contact lens storage solution).

[0536] In another aspect of some embodiments according to the present invention, there is provided a method for preparing a sterile article having lipids attached to at least a portion of its surface, the method comprising contacting at least a portion of the surface of the article with an aqueous composition comprising an aqueous carrier (e.g., any of the corresponding embodiments described herein) and liposomes (e.g., any of the corresponding embodiments described herein), thereby obtaining an article having lipids attached to at least a portion of its surface; and subjecting the article having lipids attached to at least a portion of its surface to a temperature above 100 °C. The liposomes comprise at least one bilayer-forming lipid (e.g., any of the corresponding embodiments described herein) and a polymeric compound (e.g., any of the corresponding embodiments described herein). In some exemplary embodiments, the article comprises a contact lens.

[0537] It should be understood that according to this aspect, the lipids attached to at least a portion of the surface can be in the form of liposomes and / or another form, such as an open bilayer (i.e., a bilayer that does not enclose a whole), which can be obtained, for example, by the "bursting" of liposomes upon contact with the surface. Optionally, before applying a temperature above 100 °C, at least a portion of the lipids attached to the surface can optionally be in a different form, and then a temperature above 100 °C is applied, for example, in the form of liposomes before heat sterilization and in a different form (e.g., an open bilayer) after heat sterilization. Alternatively or additionally, after heat sterilization (e.g., at least 1 hour or at least 1 day or even at least 1 month after sterilization), when the article is incubated in the aqueous composition, the form of the lipids gradually changes (e.g., from liposomes to another form).

[0538] Such a method can allow for efficient and relatively low-cost sterilization of solid or semi-solid articles having lipids attached to at least a portion of their surface, such as one or more lipid-coated contact lenses.

[0539] In some of any of the corresponding embodiments described herein, according to any of the aspects described herein, the temperature experienced by the aqueous composition does not exceed 150 °C, such as 110 °C - 150 °C, or 115 °C - 150 °C, or 121 °C - 150 °C, or 130 °C - 150 °C.

[0540] In some of any of the corresponding embodiments described herein, the temperature experienced by the aqueous composition does not exceed 140 °C, such as 110 °C - 140 °C, or 115 °C - 140 °C, or 121 °C - 140 °C, or 130 °C - 140 °C.

[0541] In some of any of the corresponding embodiments described herein, the temperature experienced by the aqueous composition does not exceed 134 °C, such as 110 °C - 134 °C, or 115 °C - 134 °C, or 121 °C - 134 °C.

[0542] In some of any of the corresponding embodiments described herein, the temperature experienced by the aqueous composition does not exceed 130 °C, for example, 110 °C - 130 °C, or 115 °C - 130 °C, or 121 °C - 130 °C.

[0543] In some of any of the corresponding embodiments described herein, the temperature experienced by the aqueous composition does not exceed 125 °C, for example, 110 °C - 125 °C, or 115 °C - 125 °C, or 121 °C - 125 °C.

[0544] In some of any of the corresponding embodiments described herein, the aqueous composition is subjected to a temperature above 100 °C at an elevated pressure, i.e., a pressure greater than ambient atmospheric pressure. Such a pressure can be obtained, for example, by heating the aqueous composition in a closed vessel such that the water vapor formed by the heating contributes to the elevated pressure. In some such embodiments, the pressure is such that the boiling point of the aqueous composition at that pressure is equal to or close to (e.g., ±10 °C or ±5 °C) the temperature to which the composition is subjected (any of the corresponding embodiments described herein).

[0545] Subjecting the composition to elevated temperature (and optionally elevated pressure) according to any of the corresponding embodiments described herein can optionally be carried out using commercially available equipment (such as an autoclave) configured for such use.

[0546] In some of any of the embodiments described herein, the sterile composition is prepared by or can be prepared by the methods described in any of the corresponding embodiments herein and any combination thereof.

[0547] Lubricating effect:

[0548] The liposomes and lipid bilayers described herein can optionally be used to lubricate surfaces, such as the surfaces described herein that are double-coated and / or in contact with the liposomes described herein.

[0549] According to one aspect of some embodiments of the present invention, there is provided a lubricant composition comprising a liposome or lipid bilayer of any of the corresponding embodiments described herein.

[0550] As used herein, "lubricant composition" refers to a composition intended to be used to reduce the coefficient of surface friction (e.g., according to the methods described herein).

[0551] In some embodiments, the lubricant composition comprises a carrier. The carrier can optionally be a liquid carrier. In some embodiments, the carrier comprises an aqueous liquid.

[0552] In some embodiments, the lubricant composition (or any other composition or formulation described herein that comprises liposomes) further comprises a water-soluble polymer, optionally as part of the carrier.

[0553] As used herein, the term "water-soluble polymer" includes polymers that have a solubility of at least 1 gram per liter in an aqueous (e.g., water) environment at pH 7 (at 25 °C).

[0554] In some embodiments of any of the embodiments described herein, the water-soluble polymer has a solubility of at least 2 grams per liter (under the above conditions). In some embodiments, the solubility is at least 5 grams per liter. In some embodiments, the solubility is at least 10 grams per liter. In some embodiments, the solubility is at least 20 grams per liter. In some embodiments, the solubility is at least 50 grams per liter. In some embodiments, the solubility is at least 100 grams per liter.

[0555] The water-soluble polymer of any of the embodiments described herein can comprise at least one ionic polymer and / or at least one non-ionic polymer, which are water-soluble as defined herein.

[0556] As used herein, the term "non-ionic polymer" refers to a polymer that does not have a charged group, and examples of suitable non-ionic water-soluble polymers include, but are not limited to, polyvinylpyrrolidone (which may also be interchangeably referred to as povidone and / or PVP herein) and polyoxyethylene (which may also be interchangeably referred to as PEO, PEG, and / or polyethylene glycol herein).

[0557] As used herein, the term "ionic polymer" refers to a polymer that has at least one charged group in an aqueous (e.g., water) environment at pH 7, and includes polymers having a net negative charge (also referred to as "anionic polymers" herein), polymers having a net positive charge (also referred to as "cationic polymers" herein), and polymers having no net charge (also referred to as "zwitterionic polymers" herein).

[0558] The term "charged group" throughout this document refers to any ionic (as defined herein) functional group (such as those described herein), including, for example, amines, carboxylic acids, sulfates, sulfonates, phosphates, and phosphonates. Thus, each charge in a moiety or molecule is associated with a charged group, however, a single charged group (e.g., an unsubstituted phosphate) can be associated with more than one charge of the same sign (e.g., a dianion, a dication).

[0559] The term "ion" throughout this document refers to the presence of a charge on at least one atom (in a moiety and / or molecule that represents 50% of a population) in an aqueous medium (e.g., water) at pH 7. The charge can be negative (anion) or positive (cation). If more than one charge is present, the charges can be negative (anion) and / or positive (cation), e.g., both negative and positive charges can be present (zwitterion).

[0560] Examples of ionic polymers include, but are not limited to, ionic polysaccharides such as hyaluronic acid, chondroitin sulfate, alginic acid, xanthan gum, chitosan, and N-alkyl chitosan derivatives.

[0561] According to another aspect of the embodiments described herein, a method of reducing the surface friction coefficient is provided, the method comprising contacting a surface with a liposome of any one of the corresponding embodiments described herein. In some embodiments, the method is carried out by contacting the surface with a composition comprising a liposome and a carrier (optionally a lubricant composition of any one of the corresponding embodiments described herein).

[0562] In some of any of the embodiments described herein with reference to lubrication, lubrication is achieved, optionally, according to any one of the aspects described herein, and / or according to any one of the embodiments described in International Patent Applications PCT / IL2015 / 050605 (published as WO 2015 / 193887) and / or PCT / IL2015 / 050606 (published as WO 2015 / 193888).

[0563] In some embodiments, the method further comprises contacting the surface with a water-soluble polymer (such as any one of the corresponding embodiments described herein) before and / or simultaneously with contacting the surface with the liposome, optionally. In some embodiments, the method is carried out by contacting the surface with a composition comprising a liposome and a water-soluble polymer (optionally a lubricant composition comprising a water-soluble polymer of any one of the corresponding embodiments described herein), optionally in combination with an aqueous liquid.

[0564] In some of any of the embodiments described herein relating to methods and / or lubricant compositions for reducing the surface friction coefficient, the surface is a hydrogel surface. In some embodiments, the hydrogel consists mainly of a polymer and an aqueous liquid (optionally water).

[0565] In some of any of the embodiments described herein relating to methods and / or lubricant compositions for reducing the surface friction coefficient, the surface is a contact lens surface.

[0566] In some of any of the embodiments described herein with reference to contact lenses, according to any one of the aspects described herein, the contact lens comprises a hydrogel surface. In some embodiments, the contact lens comprises a hydrogel surface and a rigid center. In some embodiments, the contact lens consists mainly of a hydrogel.

[0567] The hydrogel can comprise any material known in the art for contact lens hydrogels. Examples of such hydrogel materials include, but are not limited to, alphafilcon A, asmofilcon A, balafilcon A, bufilcon A, comfilcon A, crofilcon, deltafilcon A, dimefilcon, droxifilcon A, enfilcon A, etafilcon A, galyfilcon A, hefilcon A, hefilcon B, hilafilcon A, hilafilcon B, hioxifilcon A, hioxifilcon D, isofilcon, lidofilcon A, lidofilcon B, lotrafilcon B, mafilcon, methafilcon A, methafilcon B, narafilcon A, narafilcon B, ocufilcon A, ocufilcon B, oofilcon A, omafilcon A, perfilcon, phemfilcon A, polymacon, scafilcon A, senofilcon A, surfilcon, tefilcon, tetrafilcon A, tetrafilcon B, vifilcon A, and xylofilcon A.

[0568] In some embodiments of any of the embodiments described herein, the hydrogel comprises a polymer composed of poly(2-hydroxyethyl methacrylate) and / or silicone. In some embodiments, the polymer comprises silicone. Such polymers may optionally contain small amounts of additional monomers (e.g., crosslinking monomers) copolymerized with 2-hydroxyethyl methacrylate or silicone monomers. For example, 2-hydroxyethyl methacrylate may optionally be copolymerized with vinylpyrrolidone, methyl methacrylate, methacrylic acid (anionic monomer), ethylene glycol dimethacrylate (crosslinking monomer), and / or 3-(ethyldimethylammonium)propyl methacrylamide (cationic monomer) in contact lens hydrogels.

[0569] Physiological surface:

[0570] In some embodiments of any of the embodiments described herein related to methods and / or lubricant compositions for reducing the surface coefficient of friction, the surface is a physiological surface, and the carrier used with the liposome (e.g., in a lubricant composition according to any of the corresponding embodiments described herein) is a physiologically acceptable carrier.

[0571] In some embodiments, the surface for reducing the coefficient of friction according to any of the corresponding embodiments herein is the articular surface of a synovial joint.

[0572] In some embodiments, the method for reducing the surface coefficient of friction is used to treat synovial joint disorders associated with an increased coefficient of friction of the articular surface in a synovial joint.

[0573] In some embodiments of any of the embodiments described herein related to liposomes, the liposomes are used to treat synovial joint disorders associated with an increased coefficient of friction of the articular surface in a synovial joint.

[0574] According to another aspect of the embodiments described herein, there is provided the use of a liposome according to any of the corresponding embodiments described herein in the preparation of a medicament for treating synovial joint disorders associated with an increased coefficient of friction of the articular surface in a synovial joint.

[0575] Synovial joint disorders associated with an increased coefficient of friction of the articular surface and treatable according to the embodiments of various aspects of the present invention include, but are not limited to, arthritis, traumatic joint injuries, joint locking (also known as joint catching in the art), and surgery-related joint injuries.

[0576] In some embodiments, the arthritis is osteoarthritis, rheumatoid arthritis, and / or psoriatic arthritis.

[0577] In some embodiments, the joint locking is associated with osteochondritis dissecans and / or synovial osteochondromatosis.

[0578] Joint injuries associated with the procedures described herein can optionally be associated with procedures that directly damage the joint surface (e.g., through an incision) and / or procedures that only indirectly damage the joint surface. For example, procedures that repair or otherwise affect tissues near the joint (e.g., ligaments and / or menisci) may be associated with joint injuries caused by mechanical changes in the joint.

[0579] The traumatic joint injuries described herein can optionally be injuries directly caused by trauma (e.g., sustained at the time of trauma) and / or injuries caused by a prior trauma (e.g., a post-traumatic injury that occurs some time after the trauma).

[0580] In some of any of the corresponding embodiments, (e.g., sterile) compositions of any of the corresponding embodiments described herein and any combination thereof are used to treat synovial joint disorders, e.g., wherein the treatment comprises intra-articular administration of the (e.g., sterile) composition.

[0581] According to one aspect of some embodiments of the present invention, there is provided a (e.g., sterile) composition of any of the corresponding embodiments described herein for the preparation of a medicament for treating a synovial joint disorder, e.g., wherein the treatment comprises intra-articular administration of the (e.g., sterile) composition.

[0582] According to one aspect of some embodiments of the present invention, there is provided a method of treating a synovial joint disorder in an individual in need thereof, the method comprising administering to the individual a sterile composition of any of the corresponding embodiments described herein, e.g., by joint administration.

[0583] Examples of synovial joint disorders that can be treated according to embodiments of various aspects of the present invention include, but are not limited to, arthritis (such as osteoarthritis, rheumatoid arthritis, and / or psoriatic arthritis), bursitis, carpal tunnel syndrome, fibromyalgia, gout, joint locking (optionally associated with osteochondritis dissecans and / or synovial osteochondromatosis), tendinitis, traumatic joint injuries (optionally directly caused by trauma, e.g., sustained at the time of trauma, and / or caused by a previous trauma, e.g., a post-traumatic injury that occurs some time after the trauma), and joint injuries associated with surgery (optionally associated with surgery that directly damages the joint surface, e.g., through an incision and / or surgery that only indirectly damages the joint surface; for example, procedures that repair or otherwise affect tissues near the joint (e.g., ligaments and / or menisci) may be associated with joint injuries due to mechanical changes in the joint). Osteoarthritis is an exemplary synovial joint disorder that can be treated according to some embodiments of the present invention.

[0584] In some of any of the corresponding embodiments, treatment of a synovial joint disorder (e.g., osteoarthritis) is characterized by a reduction in pain, e.g., during movement, at night, and / or at rest.

[0585] In such embodiments, pain reduction can optionally be determined by any suitable technique known in the art. Examples of suitable techniques for determining pain reduction include, but are not limited to, pain survey questionnaires (e.g., short forms), physical activity tests (e.g., the Timed Up and Go test), VAS (Visual Analogue Scale) questionnaires for assessing pain (from painless to intolerable pain), the WOMAC (Western Ontario and McMaster Universities) scale, and / or the KOOS (Knee Injury and Osteoarthritis Outcome Score).

[0586] In some of any of the corresponding embodiments, the treatment of synovial joint disorders (e.g., osteoarthritis) is characterized by an improvement in joint physiology.

[0587] In some of any of the corresponding embodiments, the improvement in joint physiology is determined by the Kellgren Lawrence radiological severity scale, such as where the improvement is characterized by a reduction in severity. In some such embodiments, the treatment is further characterized by pain reduction (e.g., any of the corresponding embodiments described herein).

[0588] In some of any of the corresponding embodiments, the improvement in joint physiology is determined by the range of motion of the affected joint (e.g., where the improvement is characterized by an increase in the range of motion of the joint), optionally also characterized by a reduction in severity according to the Kellgren - LaLawrence scale. In some such embodiments, the treatment is further characterized by pain reduction (e.g., any of the corresponding embodiments described herein).

[0589] In some of any of the corresponding embodiments, the improvement in joint physiology is characterized by an increase in physical activity (e.g., activities involving the affected joint), optionally also characterized by a reduction in severity according to the Kellgren - LaLawrence scale and / or an increase in the range of motion (e.g., any of the corresponding embodiments described herein). In some such embodiments, the treatment is further characterized by pain reduction (e.g., any of the corresponding embodiments described herein).

[0590] In some of any of the corresponding embodiments, the improvement in joint physiology is characterized by an improvement in quality of life, optionally also characterized by a reduction in severity according to the Kellgren - LaLawrence scale, an increase in the range of motion, and / or an increase in physical activity (e.g., any of the corresponding embodiments described herein). In some such embodiments, the treatment is further characterized by pain reduction (e.g., any of the corresponding embodiments described herein).

[0591] In some of any of the corresponding embodiments, improvement in joint physiology is determined by at least one or at least two or at least three or all four of Kellgren - Lawrence radiological severity, range of joint motion, physical activity, and quality of life (any of the corresponding embodiments described herein). In some such embodiments, the treatment is further characterized by a reduction in pain (e.g., any of the corresponding embodiments described herein).

[0592] According to any of the corresponding embodiments described herein, a composition for treating a synovial joint disorder (such as osteoarthritis) may optionally comprise one or more therapeutic active agents (e.g., any of the corresponding embodiments described herein). Examples of therapeutic active agents for compositions suitable for treating synovial joint disorders include, but are not limited to, analgesics and anti - inflammatory agents.

[0593] Examples of suitable analgesics include, but are not limited to, allylprodine, α - methylfentanyl, AP - 237, bezitramide, butorphanol, buprenorphine, carfentanil, clonidine, codeine, desoxymorphine, dextromoramide, dezocine, difenoxin, dihydrocodeine, dihydroetorphine, dihydromorphine, diphenoxylate, dipipanone, ethoheptazine, ethylmorphine, etorphine, fentanyl, hydrocodone, hydromorphone, ketamine, ketomidine, levorphanol, levomethadyl acetate (e.g., levo - acetylmethadol), levomethorphan, levorphanol, loperamide, meptazinol, methadone, mexiletine, mitragynine, morphine, nalbuphine, oxymetholone, oxycodone, oxymorphone, paracetamol, pentazocine, pethidine, phenethyl phenylacetoxy - piperidine, piritramide, proadifen, remifentanil, sufentanil, tapentadol, tilidine, and tramadol.

[0594] Non - steroidal anti - inflammatory agents (such as the non - steroidal anti - inflammatory agents described herein) as well as steroidal anti - inflammatory agents can also be used as analgesics.

[0595] Examples of suitable anti-inflammatory agents include, but are not limited to, diclofenac; alclomethasone (e.g., alclomethasone dipropionate); algestrone (e.g., apregnantide); alpha-amylase; ancifar; ancifit; amfenac (e.g., amfenac sodium); amprisone (e.g., amprisone hydrochloride); anakinra; anirolic acid; anizafen; azapropazone; aspirin; balsalazide disodium; bendacid; benoxaprofen; bendamine (e.g., bendamine hydrochloride); bromelain; bropimol; budesonide; carprofen; ciprofen; cinpentazone; criprofen; clobetasol (e.g., clobetasol propionate, clobetasone butyrate); clopirac; clothiocarbone (clothiocarbone propionate); cortisone (cormethasone acetate); cortodoxone; deflazacort; desonide; desoximetasone; dexamethasone dexamethasone (e.g., dexamethasone dipropionate); diclofenac (e.g., diclofenac potassium, diclofenac sodium); diflorasone (e.g., diflorasone diacetate); diflumidone (e.g., diflumidone sodium); diflunisal; difluprednate; difutazone; hydroxycinonide; medizone; emomab; enroxicam (e.g., enroxicam sodium); epipyrazole; etodolac; etifenamol; felbinac, fenamox; fenbufen; fenclorac; fenclorac; fendosal; fenpyraclofen; fentiazolidinone; fentiazolidinone; fentiazolidinone; flurazepam; flufenamic acid; flumidazole; flunisolide (e.g., flunisolide acetate); flunixin (e.g., flunixin meglumine); fluocortine (e.g., butoflavone); fluorometholone (e.g., fluorometholone acetate); fluquinazone; flurbiprofen; fluretofen; fluticasone (e.g., fluticasone acetate); fluto ... e.g. fluticasone propionate); furanprofen; furobufen; clofosone; halobetasol (e.g. halobetasol propionate); halopednisone (e.g. halopednisone acetate); ibufenac; ibuprofen (e.g. aluminum ibuprofen, ibuprofen pyridinemethanol); elodapol; indomethacin (e.g. sodium indomethacin); indoprofen; indoxol; indotetrazole; isoflurane (e.g. isoflurane acetate); isoxacic acid; isoxicam; ketoprofen; lofemazole (e.g. lofemazole hydrochloride); lomoxicam; loteprednol (e.g. loteprednol etabonate); meclofenamic acid (e.g. sodium meclofenamic acid, meclofenamic acid); methylclosone (e.g. methylclosone dibutyrate); mefenamic acid; mesalazine; mesilazine; methylprednisolone (e.g. methylprednisolone sulfonate); momifungal esters; nabumetone; naproxen (e.g., naproxen sodium); naproxol; nemazone; olsalazine (e.g., olsalazine sodium); augutin; opanocin; oxaprozin; hydroxybutazone; renitolin (e.g., renitolin hydrochloride); pentosan polysulfate (e.g., pentosan polysulfate sodium); phenylbutazone (e.g., phenylbutazone sodium glycerol); pirfenidone; piroxicam (e.g., piroxicam cinnamate, piroxicam olamine); pirprofen; prenazad; prifezone; produracil; proquinezone; proxazole (e.g., proxazole citrate); tenoxicam; clomazaride; salcholesterol; salicylates (e.g., salicylic acid); sanacetin; salsalate; sanguinarine (e.g., sanguinarine hydrochloride); sclazone; sirmethicone; sudoxicam; sulindac; suprofen;Indometacin; Talniflumate; Talosalate; Tebufelone; Tenidap (e.g., Tenidap Sodium); Tenoxicam; Tixocam; Tiximide; Tetrahydro-1H-indazole; Tiopinac; Ticortolone (e.g., Ticortolone Pivalate); Tolmetin (e.g., Tolmetin Sodium); Triamcinolone Fluoride; Trifluperinol; Zidometacin; and Zomepirac (e.g., Zomepirac Sodium).;

[0596] Optionally or alternatively, the liposomal composition as described in any of the corresponding embodiments herein is co-administered to an individual with a therapeutic agent as described herein.

[0597] The liposomes (and optionally also the water-soluble polymers described herein) can be administered as part of a (e.g., sterile) composition (e.g., a solution) comprising a physiologically acceptable carrier, such as an aqueous carrier, which is a physiologically acceptable carrier.

[0598] Throughout the context of this disclosure, the term "physiologically acceptable carrier" refers to a carrier or diluent that does not cause significant irritation to an individual when administered in the intended manner and also does not disrupt the activity and properties of the (e.g., sterile) composition (e.g., the ability of the liposomes to treat a disorder and / or reduce the coefficient of surface friction as described in any of the corresponding embodiments herein). Examples of carriers include, but are not limited to: propylene glycol, saline, emulsions, and mixtures of organic solvents and water (or saline), as well as solid (e.g., powdered) and gaseous carriers.

[0599] Techniques for formulating and administering compounds (e.g., liposomes) can be found in the latest edition of "Remington’s Pharmaceutical Sciences", Mack Publishing Co., Easton, PA, which is incorporated herein by reference.

[0600] The (e.g., sterile) composition (e.g., solution) of any of the embodiments of the present invention can be prepared by methods well known in the art, such as by conventional mixing or dissolving methods.

[0601] Thus, the (e.g., sterile) composition (e.g., solution) for use in the present invention can be formulated in a conventional manner using one or more physiologically acceptable carriers, which facilitates the processing of the liposomes (and optionally also the water-soluble polymers described herein) into pharmaceutically useful formulations. Suitable formulations depend on the chosen route of administration.

[0602] For injection, the corresponding embodiments described herein (e.g., sterile) compositions or the liposomes described herein (optionally with the water-soluble polymers described herein) can be formulated in an aqueous solution using a suitable aqueous carrier, preferably a physiologically compatible buffer such as Hank's solution, Ringer's solution, histidine buffer or a physiological saline buffer with or without organic solvents such as propylene glycol, polyethylene glycol.

[0603] The corresponding embodiments described herein (e.g., sterile) compositions or the liposomes described herein (optionally with the water-soluble polymers described herein) can be formulated for parenteral administration, such as by bolus injection or continuous infusion. Injectable preparations can be presented in unit dosage forms, for example, in ampoules or multi-dose containers with an optionally added preservative. The (e.g., sterile) composition can be a suspension, solution or emulsion in an oil or aqueous vehicle and can contain formulating agents such as suspending agents, stabilizers and / or dispersing agents.

[0604] The corresponding embodiments described herein (e.g., sterile) compositions or the liposomes described herein (optionally with the water-soluble polymers described herein) can be formulated as an aqueous solution itself. Additionally, the (e.g., sterile) composition (e.g., solution) can be in the form of a suspension and / or emulsion (e.g., the aqueous phase of a suspension or an oil-in-water, water-in-oil or oil-in-oil-in-water emulsion), for example, in order to increase the viscosity of the formulation. An aqueous injectable suspension can contain a substance that increases the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol or dextran. Optionally, the suspension can also contain a suitable stabilizer or a substance that increases the solubility of the liposomes described herein (and / or optionally the water-soluble polymers described herein), for example, in order to be able to prepare a highly concentrated solution.

[0605] In some embodiments, the liposomes described herein (optionally with the water-soluble polymers described herein) can be in the form of a powder that is reconstituted with a suitable vehicle, such as sterile pyrogen-free water, before use.

[0606] The corresponding embodiments described herein (e.g., sterile) compositions can be formulated to contain an amount of liposomes effective to achieve the intended purpose, for example, an amount effective to prevent, alleviate or improve the symptoms of the disorder in the treated individual. Additionally or alternatively, the (e.g., sterile) composition can be in the form of a suspension and / or emulsion (e.g., an oil-in-water, water-in-oil or oil-in-oil-in-water emulsion), for example, in order to increase the viscosity of the formulation. An aqueous injectable suspension contains a substance that increases the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol or dextran. Optionally, the suspension can also contain a suitable stabilizer or a substance that increases the solubility and / or stability of the liposomes described herein, for example, in order to be able to prepare a highly concentrated solution.

[0607] The dosage can vary depending on the dosage form used, the route of administration employed, the site of administration (e.g., the volume and / or surface area of the region in contact with the liposomes), the judgment of the prescribing clinician, and the like.

[0608] Of course, the dosage of the composition depends on the individual being treated, the severity of the affliction, the mode of administration, the judgment of the prescribing clinician, and the like.

[0609] If desired, the (e.g., sterile) composition (e.g., solution) of an embodiment of the present invention can be placed in a packaging or dispensing device, such as an FDA (U.S. Food and Drug Administration)-approved kit, which can contain one or more unit dosage forms (e.g., liposomes as described herein) containing the active ingredient. The packaging can, for example, comprise a metal or plastic foil, such as, but not limited to, a blister pack. The packaging or dispensing device may be accompanied by instructions for administration. The packaging or dispenser may also be accompanied by a leaflet associated with the container, in a form prescribed by a government agency that regulates the manufacture, use, or sale of pharmaceuticals, which leaflet reflects the approval of the agency for the form of the (e.g., sterile) composition for human or veterinary administration. Such leaflet can, for example, be the approved prescription drug label or approved product insert of the U.S. Food and Drug Administration. A composition (e.g., sterile) comprising liposomes (optionally with a water-soluble polymer as described herein) formulated in a physiologically acceptable carrier can also be prepared, as described in any of the corresponding embodiments herein, placed in an appropriate container, and labeled for the treatment of the indicated disorders or for diagnosis, as described in detail herein.

[0610] Inhibition of biofilm formation and biofouling:

[0611] The liposomes and bilayers described herein can optionally be used to inhibit adhesion, biofouling, and / or biofilm formation on a surface, such as a surface coated with the bilayers described herein and / or in contact with the liposomes described herein.

[0612] In one aspect of some embodiments of the present invention, a method for inhibiting the adsorption of a biofouling promoter on a substrate surface is provided. The method of some embodiments of the present invention is carried out by contacting the substrate with a composition comprising liposomes of any of the corresponding embodiments described herein.

[0613] As used throughout this document, the term "biofouling promoter" refers to a substance whose presence promotes and / or participates in the formation of a biofilm (as defined herein) on a substrate surface. A substance is considered to contribute to the formation of a biofilm on a substrate surface when its presence enhances the formation of a biofilm on the same substrate surface compared to the formation of a biofilm in the absence of the substance. A substance is considered to participate in the formation of a biofilm on a substrate surface when the biofilm formed on the surface contains the substance as part of the biofilm.

[0614] In some embodiments of any of the embodiments described herein, a substance is identified as a biofouling promoter by comparing the growth of a biofilm (e.g., Pseudomonas aeruginosa (P. aeruginosa)) on a surface in the presence of an aqueous liquid (e.g., water or broth, optionally at 37 °C) and the substance, e.g., over the course of 1, 2, 3, 4, 5, 6, or 7 days, with the growth of the biofilm on the surface in the presence of the same aqueous liquid (e.g., water or broth) without the substance (under the same conditions). The substance is optionally mixed in the aqueous liquid or, alternatively, adsorbed on the surface prior to exposure of the surface to the aqueous liquid. The growth of the biofilm is considered as the biofilm load at the end of the growth period (e.g., 1, 2, 3, 4, 5, 6, or 7 days) minus the initial biofilm load. Optionally, the measurement is made such that the initial biofilm is substantially zero (e.g., absent or at least undetectable), e.g., the microorganism is in a planktonic form, such that the growth of the biofilm is considered as the biofilm load at the end of the growth period. In some embodiments of any of the embodiments described herein, the biofilm load is defined as the area of the biofilm.

[0615] In some embodiments of any of the embodiments described herein, the biofilm load is defined as the mass and / or volume of the biofilm.

[0616] In some embodiments of any of the embodiments described herein, the biofilm load is defined as the number of cells of the biofilm.

[0617] The biofilm load can optionally be determined using any technique known in the art for detecting and quantifying the amount of cells and / or microorganisms in a biofilm.

[0618] In some of these embodiments, if the growth of the biofilm in the presence of the substance is at least 10% higher than the growth of the biofilm in the absence of the substance, the substance is considered a biofouling promoter.

[0619] In some of these embodiments, if the growth of the biofilm in the presence of the substance is at least 20% higher than the growth of the biofilm in the absence of the substance, the substance is considered a biofouling promoter.

[0620] In some of these embodiments, if the growth of the biofilm in the presence of the substance is at least 50% higher than the growth of the biofilm in the absence of the substance, the substance is considered a biofouling promoter.

[0621] In some of these embodiments, if the growth of the biofilm in the presence of the substance is at least 100% (i.e., 2-fold) higher than the growth of the biofilm in the absence of the substance, the substance is considered a biofouling promoter.

[0622] Examples of biofouling promoters include, but are not limited to, biofouling promoting proteins and biofouling promoting polysaccharides, i.e., any protein or polysaccharide that is a biofouling promoter as defined herein.

[0623] In some embodiments of any of the embodiments described herein, the biofouling promoter is a protein.

[0624] In some embodiments of any of the embodiments described herein, when the method is capable of inhibiting the adsorption of a selected biofouling promoter, the method is considered to be capable of inhibiting biofouling promoter adsorption (e.g., the selected substance is considered representative of a typical biofouling promoter). In some embodiments, the selected biofouling promoter is a protein. In some embodiments, the selected protein is an antibody that does not exhibit any specific affinity for the substrate (e.g., an anti-IgG antibody, as exemplified herein).

[0625] As used throughout the context of this document, the term "biofilm" refers to an aggregate of living cells that adhere to one another and / or are immobilized as a colony on a surface. The cells are typically embedded in a self-secreted matrix of extracellular polymeric substances (EPS), also referred to as "slime", which is a viscous mixture of polymers of nucleic acids, proteins, and polysaccharides.

[0626] In the context of this embodiment, the living cells forming the biofilm can be cells of unicellular microorganisms, including prokaryotes (e.g., bacteria, archaea microorganisms) and eukaryotes, such as fungi and protists (e.g., algae, Euglena, protozoa, dinoflagellates, apicomplexans, trypanosomes, amoeba), etc.; or cells of multicellular organisms, in which case the biofilm can be considered a colony of cells (as in the case of unicellular organisms) or a lower form of tissue.

[0627] In some embodiments according to any of the embodiments of the present invention, the cells are derived from microorganisms, and the biofilm is a biofilm of microorganisms, such as bacteria, archaea microorganisms, protists, and fungi. Microbial cells growing in a biofilm are typically physiologically different from cells in the "planktonic" form of the same organism, which, in contrast, are single cells that can float or swim in a liquid medium.

[0628] The substrate can be any of the substrates described herein and includes any surface, structure, product, or material that can support, accommodate, or promote the growth of microorganisms. The substrate can be a part of an object (e.g., an article) that can support, accommodate, or promote the growth of microorganisms. A part of such an object can span only a portion of an area of the object such that the surface of the substrate represents only a portion of the surface of the object (e.g., the portion most likely to support, accommodate, or promote the growth of microorganisms); and / or only a portion of the thickness of the object (e.g., along an axis perpendicular to the substrate and the surface of the object) such that the substrate does not include the entire volume of the object located below the surface of the substrate (which can represent the entire surface of the object or only a portion of the surface of the object). Non-limiting examples include the inner walls of storage containers (e.g., boxes, cans) for organic products and / or conduits (e.g., tubes, pipes) that are prone to deterioration due to biofouling, such as food and / or beverages (e.g., food containers, water pipes), surfaces intended to come into contact with such organic products (e.g., agricultural and / or food processing machinery, kitchen surfaces, water purification equipment), and surfaces exposed to moisture (e.g., bathroom walls, water system components, exterior surfaces of houses exposed to rain, surfaces near leaks).

[0629] In some embodiments, the substrate is a medical device or any other device intended to contact living tissue, as defined herein.

[0630] In some embodiments of any of the embodiments described herein, the adsorption inhibition described herein is to reduce the adhesion of pathogenic microorganisms (e.g., microorganisms that form any potentially pathogenic biofilm described herein) to a medical device (any medical device as described herein).

[0631] In some embodiments of any of the embodiments described herein, the adsorption of a biofouling promoter (any biofouling promoter described herein) on the surface of a substrate that has undergone the method described herein (any of the corresponding embodiments) is reduced by at least 10% relative to its adsorption on the surface of the substrate in the absence of the liposome-containing composition. In some embodiments, the adsorption is reduced by at least 20%. In some embodiments, the adsorption is reduced by at least 30%. In some embodiments, the adsorption is reduced by at least 40%. In some embodiments, the adsorption is reduced by at least 50%. In some embodiments, the adsorption is reduced by at least 60%. In some embodiments, the adsorption is reduced by at least 70%. In some embodiments, the adsorption is reduced by at least 80%. In some embodiments, the adsorption is reduced by at least 90%.

[0632] The reduction in the amount of adsorbed biofouling promoter can be determined, optionally, using any technique known in the art for detecting and quantifying the amount of this substance, including but not limited to using a labeled biofouling promoter (such as exemplified in the Examples section herein). The reduction amount is optionally measured by contacting each of the above surfaces (e.g., for 2 hours) with an aqueous solution of a biofouling promoter (e.g., at 37 °C and / or pH 7), optionally containing a phosphate buffer (such as 0.1 M phosphate), and then repeatedly rinsing to remove the unadsorbed substance (such as exemplified in the Examples section herein). The concentration of the biofouling promoter in the aqueous solution is optionally 1 μg / mL or the concentration of a saturated solution of this substance, whichever is lower.

[0633] Throughout this document, the term "biofilm-promoting conditions" refers to conditions suitable for the formation and growth of a biofilm by cells (such as Pseudomonas aeruginosa), such as where a surface is contacted (e.g., for 1, 2, 3, 4, 5, 6, or 7 days) with an aqueous liquid containing such cells (such as water or broth, optionally at 37 °C).

[0634] In some embodiments of any of the embodiments described herein, the biofilm load is defined as the area of the biofilm.

[0635] In some embodiments of any of the embodiments described herein, the biofilm load is defined as the mass and / or volume of the biofilm.

[0636] In some embodiments of any of the embodiments described herein, the biofilm load is defined as the number of cells in the biofilm.

[0637] The biofilm load can be determined, optionally, using any technique known in the art for detecting and quantifying the amount of cells and / or microorganisms in a biofilm.

[0638] In some embodiments of any of the embodiments described herein, the time period of biofilm formation is determined based on the biofilm load, and then the biofilm load is determined. For example, the time period is the time period after which the biofilm covers 100%, 50%, or any other predetermined percentage of the substrate area in the absence of inhibition of biofilm formation by contact with a composition comprising liposomes. For example, if the biofilm grows to cover 50% of the surface in the absence of inhibition of biofilm formation, and during the same time period, the biofilm grows to cover 30% of the surface in the presence of a biofilm formation inhibitor, then the inhibition of biofilm formation can be considered to result in a 40% reduction in biofilm formation (i.e., (50% - 30%) / 50%).

[0639] In this document, the phrase "in the presence of the substance" means that, in addition to the biofilm-promoting conditions, the substance is present (such as in an aqueous liquid containing cells).

[0640] In one aspect of some embodiments according to the present invention, there is provided a method for inhibiting biofilm formation on a substrate (as described herein in any one of the corresponding embodiments and any combination of embodiments), the method comprising contacting the substrate with a composition comprising liposomes (as described in any one of the corresponding embodiments herein).

[0641] In some embodiments, "inhibiting biofilm formation" means preventing the formation of biofilms; and / or reducing the rate of biofilm accumulation; and / or a decrease in biofilm mass, biofilm area or volume, or the number of cells forming the biofilm.

[0642] In some embodiments of any one of the embodiments described herein, the adsorption inhibition described herein is to reduce the adhesion of pathogenic microorganisms (such as any potentially pathogenic biofilm-forming microorganisms described herein) to medical devices. Such reduction may result in the inhibition of biofilm formation, as defined in some embodiments herein.

[0643] In some embodiments of any one of the embodiments described herein, biofilm formation on the substrate surface that has undergone the method described herein (according to any one of the corresponding embodiments) is reduced by at least 10% relative to biofilm formation on the substrate surface in the absence of the composition comprising liposomes. In some embodiments, biofilm formation is reduced by at least 20%. In some embodiments, biofilm formation is reduced by at least 30%. In some embodiments, biofilm formation is reduced by at least 40%. In some embodiments, biofilm formation is reduced by at least 50%. In some embodiments, biofilm formation is reduced by at least 60%. In some embodiments, biofilm formation is reduced by at least 70%. In some embodiments, biofilm formation is reduced by at least 80%. In some embodiments, biofilm formation is reduced by at least 90%.

[0644] The reduction in biofilm formation is optionally determined by measuring the biofilm load of cells (such as Pseudomonas aeruginosa) on each surface after undergoing biofouling-promoting conditions (according to any one of the corresponding embodiments described herein), as defined herein (for example, over a period of 1, 2, 3, 4, 5, 6, or 7 days or any other time period described herein).

[0645] Any embodiment described herein relating to inhibiting biofilm formation and / or biofouling can optionally be achieved by a composition that is substantially the same as the lubricant composition of any one of the corresponding embodiments described herein (however, optionally characterized for inhibiting biofilm formation and / or biofouling rather than for lubrication).

[0646] In some of any of the embodiments herein involving inhibiting adhesion, biofilm formation, and / or biofouling, inhibition is achieved according to any of the aspects herein described, optionally according to any of the embodiments described in Israeli Patent Application No. 234929 and / or International Patent Application PCT / IL2015 / 050987 (published as WO 2016 / 051413).

[0647] Additional compositions and uses:

[0648] In view of their optional sterile nature, the compositions of the corresponding embodiments herein described can be used in physiological environments, such as in vivo physiological environments or ocular environments. Thus, the aqueous carrier of any of the corresponding embodiments herein described can be selected according to the intended use, such as a physiologically acceptable carrier and / or an ophthalmically acceptable carrier as described herein.

[0649] Use in a physiological environment can optionally be for reducing the coefficient of friction of a physiological surface (such as a joint surface or an ocular surface) and / or a non-physiological surface (such as a contact lens surface) in, for example, treating a disease or disorder associated with an increased coefficient of surface friction (also referred to herein as "lubrication", "lubricating", and variations thereof). Reducing the coefficient of friction of a surface can optionally be achieved by any one or more of the compounds present in the liposomes (any of the corresponding embodiments herein described), including bilayer-forming lipid and / or polymeric compounds of any of the corresponding embodiments herein described.

[0650] In some of any of the embodiments herein described, a (such as sterile) composition comprising liposomes as described herein is used for rinsing, cleaning, and / or immersing contact lenses therein. In some such embodiments, the composition comprises an ophthalmically acceptable carrier as described in any of the corresponding embodiments herein and can optionally allow it to remain on the contact lens after rinsing, cleaning, and / or immersing in the solution, since the residual solution will not harm the eye when the contact lens is placed on the eye. In some alternative embodiments, the aqueous carrier is not an ophthalmically acceptable carrier (e.g., where the carrier comprises a preservative and / or a non-ophthalmically acceptable concentration of a preservative), and the (such as sterile) composition (such as a composition for immersing a contact lens according to any of the corresponding embodiments herein described) can optionally be used for soaking the contact lens for an extended time period (e.g., when the contact lens is not in use, such as at night) and / or for storing for an extended time period (e.g., between contact lens manufacture and the start of use), while limiting the risk of bacterial growth in the solution; for example, where such a composition is rinsed with an ophthalmically acceptable liquid (such as water, saline) solution and then the contact lens is placed on the eye.

[0651] In some of any of the embodiments described herein that relate to contact lenses, a (e.g., sterile) composition is used to immerse a contact lens therein (e.g., to maintain the moisture of the contact lens, optionally while reducing the coefficient of friction of the contact lens). In some such embodiments, the carrier of the (e.g., sterile) composition contains additional ingredients suitable for achieving cleaning, such as preservatives. Such a composition may optionally be provided as a single product together with the contact lens immersed therein, e.g., where a sterile contact lens and a sterile composition are packaged together. The sterile composition may optionally be rinsed off with an ophthalmically more acceptable composition before being placed in the eye.

[0652] In some of any of the embodiments described herein that relate to contact lenses, a (e.g., sterile) composition is used to rinse a contact lens (e.g., to remove another composition from the contact lens, such liquid being ophthalmically unacceptable, and / or to reduce the coefficient of friction of the contact lens). Such a composition may optionally be provided as a product separate from the contact lens. In some such embodiments, the carrier of the sterile composition is an ophthalmically acceptable carrier as described herein in any of the corresponding embodiments.

[0653] In some of any of the embodiments described herein that relate to contact lenses, a (e.g., sterile) composition is used to clean used and / or new contact lenses (e.g., to remove bacteria and / or other impurities, optionally while reducing the coefficient of friction of the contact lens). In some such embodiments, the carrier of the (e.g., sterile) composition contains additional ingredients suitable for achieving cleaning, such as antimicrobial agents (e.g., peroxides and / or other oxidants) and / or detergents for removing impurities, and is an ophthalmically acceptable carrier as described herein in any of the corresponding embodiments. Such a composition may optionally be provided as a product separate from the contact lens and may optionally be rinsed off with an ophthalmically more acceptable composition before being placed in the eye.

[0654] In any of the corresponding embodiments, a (e.g., sterile) composition of any of the corresponding embodiments described herein is used to treat eye diseases, such as dry eye syndrome and any other eye diseases.

[0655] If desired, the compositions (such as solutions) according to embodiments of the present invention can be packaged in a packaging or dispenser device, such as an FDA (U.S. Food and Drug Administration) approved kit, which can contain one or more unit dosage forms containing the active ingredient (such as the liposomes described herein). The packaging can, for example, comprise a metal or plastic foil, such as, but not limited to, a blister pack. The packaging or dispenser device can be accompanied by instructions for administration. The packaging or dispenser can also be accompanied by regulations associated with the container, in a form prescribed by a government agency that regulates the manufacture, use, or sale of pharmaceuticals, which regulations reflect the approval of the agency for the form of the composition for human or veterinary administration. Such regulations can be, for example, the prescription drug label approved by the U.S. Food and Drug Administration or an approved product insert. A sterile composition containing liposomes formulated in a physiologically acceptable carrier, as described in any of the corresponding embodiments herein, can also be prepared, placed in an appropriate container, and labeled for the treatment of the indicated disorder, as described in detail herein.

[0656] In one aspect of some embodiments according to the present invention, there is provided a composition or formulation comprising at least one water-soluble polymer (as described in any of the corresponding embodiments herein), liposomes (as described in any of the corresponding embodiments herein), an ophthalmically acceptable carrier (such as an aqueous carrier) as described in any of the corresponding embodiments herein, and optionally a sugar (such as a polysaccharide).

[0657] As used herein, the term "ophthalmically acceptable carrier" refers to a carrier or diluent that does not cause significant irritation to an individual when in contact with the individual's eye (such as the cornea and / or sclera), and also does not eliminate the activity and properties of the composition (such as the ability of the liposomes therein to reduce the coefficient of friction on the surface of a contact lens and / or the eye surface).

[0658] In some of any of the embodiments described in this aspect, the composition or formulation as described herein is a liquid formulation and can also be interchangeably referred to herein as a "solution". It should be noted that the term "solution" throughout this document includes any liquid formulation in which the components, namely at least the water-soluble polymer and the liposomes / lipids, are contained in a liquid carrier, whereby the components can each be dissolved or dispersed in the carrier. Thus, as used herein, the term "solution" also includes a "dispersion". As used herein, the term "liquid formulation" includes solutions and dispersions.

[0659] According to some embodiments of this aspect, the lipids forming the bilayer comprise a first and a second glycerophospholipid as described in further detail below. In some such embodiments, the lipids forming the bilayer comprise at least two lipid materials: the first glycerophospholipid is characterized by a Tm below 25 °C, and the second glycerophospholipid is characterized by a Tm above 40 °C.

[0660] In some of the embodiments of this aspect, the weight ratio of the first and second glycerophospholipids is such that the lipids forming the bilayer are characterized by a Tm range of 25 - 40, or 26 - 39, or 26 - 33, or 28 - 33 °C.

[0661] In some of any of the embodiments described herein, the weight ratio of the first and second glycerophospholipids in the composition or formulation as described in this aspect is at least 2:1, such as 2:1, or 3:2, or 3:1, or 4:1, or 5:2, or 5:1, or 5:3 (first glycerophospholipid: second glycerophospholipid).

[0662] In some of any of the embodiments described herein, the weight ratio of the first and second glycerophospholipids in the composition or formulation as described in this aspect is 3:1 (first glycerophospholipid: second glycerophospholipid).

[0663] In some of any of the embodiments described herein, the weight ratio of the first and second glycerophospholipids in the composition or formulation as described in this aspect ranges from 4:1 - 1:4, or 3:1 - 1:3, or 3:1 - 1:1 (first glycerophospholipid: second glycerophospholipid), including any intermediate values and sub - ranges therebetween.

[0664] In some of any of the embodiments related to the composition or formulation as described in this aspect, at least 50%, or at least 60%, or at least 70% by weight of the total weight of the lipids forming the bilayer is the first glycerophospholipid as described herein.

[0665] In some of any of the embodiments related to the composition or formulation as described in this aspect, less than 50%, or less than 40%, or less than 30% by weight of the total weight of the lipids forming the bilayer is the second glycerophospholipid as described herein.

[0666] In some of any of the embodiments related to the composition or formulation as described in this aspect, the amount of the first glycerophospholipid as described herein ranges from 30% - 90%, or 30% - 80%, or 40% - 90%, or 40% - 80%, or 50% - 90%, or 50% - 80%, or 60% - 90%, or 60% - 80% by weight of the total weight of the lipids forming the bilayer, including any intermediate values and sub - ranges therebetween.

[0667] In some of any of the embodiments relating to a composition or formulation as described in this aspect, the amount of the second glycerophospholipid as described herein ranges from 5% to 50%, or 10% to 50%, or 5% to 40%, or 10% to 40%, or 5% to 30%, or 10% to 30%, or 20% to 50%, or 20% to 40%, or 20% to 30% by weight of the total weight of the lipids forming the bilayer, including any intermediate values and sub-ranges therebetween.

[0668] In some of any of the embodiments relating to a composition or formulation as described in this aspect, the amount of the first glycerophospholipid as described herein ranges from 30% to 90%, or 30% to 80%, or 40% to 90%, or 40% to 80%, or 50% to 90%, or 50% to 80%, or 60% to 90%, or 60% to 80% by weight of the total weight of the lipids forming the bilayer, including any intermediate values and sub-ranges therebetween, and the amount of the second glycerophospholipid as described herein ranges from 5% to 50%, or 10% to 50%, or 5% to 40%, or 10% to 40%, or 5% to 30%, or 10% to 30%, or 20% to 50%, or 20% to 40%, or 20% to 30% by weight of the total weight of the lipids forming the bilayer, including any intermediate values and sub-ranges therebetween.

[0669] In some of any of the embodiments relating to a composition or formulation as described in this aspect, the lipids forming the bilayer comprise a first glycerophospholipid characterized by a Tm below 25 °C and a second glycerophospholipid characterized by a Tm above 40 °C, wherein the weight ratio of the first to the second glycerophospholipid is such that the lipids forming the bilayer are characterized by a Tm range of 25 - 40, or 26 - 39, or 26 - 33, or 28 - 33 °C, including any intermediate values and sub-ranges therebetween.

[0670] In some of any of the embodiments relating to a composition or formulation as described in this aspect, the lipids forming the bilayer consist of the first and second glycerophospholipids as described herein.

[0671] In some of any of the embodiments relating to a composition or formulation as described in this aspect, the first glycerophospholipid is DMPC as described herein, however, other glycerophospholipids characterized by the indicated Tm are of interest.

[0672] In some of any of the embodiments relating to a composition or formulation as described in this aspect, the second glycerophospholipid is DPPC as described herein, however, other glycerophospholipids characterized by the indicated Tm are of interest.

[0673] According to some of any of the embodiments relating to the compositions or formulations as described in this aspect, the lipid material forming the bilayer comprises or consists of DMPC and DPPC.

[0674] According to some of any of the embodiments relating to the compositions or formulations as described in this aspect, the lipid material forming the bilayer comprises DMPC in an amount ranging from 30% - 90%, or 30% - 80%, or 40% - 90%, or 40% - 80%, or 50% - 90%, or 50% - 80%, or 60% - 90%, or 60% - 80% by weight of the total weight of the lipids forming the bilayer, including any intermediate values and sub - ranges therebetween.

[0675] According to some of any of the embodiments relating to the compositions or formulations as described in this aspect, the lipid material forming the bilayer comprises DMPC in an amount ranging from 50% - 90%, or 50% - 80%, or 60% - 90%, or 60% - 80% by weight of the total weight of the lipids forming the bilayer, including any intermediate values and sub - ranges therebetween.

[0676] According to some of any of the embodiments relating to the compositions or formulations as described in this aspect, the lipid material forming the bilayer comprises DPPC in an amount ranging from 5% - 50%, or 10% - 50%, or 5% - 40%, or 10% - 40%, or 5% - 30%, or 10% - 30%, or 20% - 50%, or 20% - 40%, or 20% - 30% by weight of the total weight of the lipids forming the bilayer, including any intermediate values and sub - ranges therebetween.

[0677] According to some of any of the embodiments relating to the compositions or formulations as described in this aspect, the lipid material forming the bilayer comprises: DMPC in an amount ranging from 50% - 90%, or 50% - 80%, or 60% - 90%, or 60% - 80% by weight of the total weight of the lipids forming the bilayer, including any intermediate values and sub - ranges therebetween; and DPPC in an amount ranging from 5% - 50%, or 10% - 50%, or 5% - 40%, or 10% - 40%, or 5% - 30%, or 10% - 30%, or 20% - 50%, or 20% - 40%, or 20% - 30% by weight of the total weight of the lipids forming the bilayer, including any intermediate values and sub - ranges therebetween. According to some of these embodiments, the lipid forming the bilayer consists of DPPC and DMPC.

[0678] According to some of any of the embodiments relating to the compositions or formulations as described in this aspect, the lipids forming the bilayer comprise or consist of DMPC and DPPC, and the weight ratio of DMPC:DPPC ranges from 1:1 - 5:1, or 1:1 - 4:1, or 1:1 - 3:1, preferably 2:1 - 4:1, or 2:1 - 3:1, including any intermediate values and sub - ranges therebetween.

[0679] According to some of any of the embodiments relating to the compositions or formulations as described in this aspect, the lipids forming the bilayer comprise or consist of DMPC and DPPC. The amount of DMPC ranges from 20% - 80%, or 50% - 80% by weight of the total weight of the lipids forming the bilayer, and the amount of DMPC ranges from 20% - 80%, or 20% - 50% by weight of the total weight of the lipids forming the bilayer, including any intermediate values and sub - ranges therebetween.

[0680] According to some of any of the embodiments relating to the compositions or formulations as described in this aspect, the lipids forming the bilayer comprise or consist of DMPC and DPPC. The amount of DMPC is about 75% by weight of the total weight of the lipids forming the bilayer, and the amount of DMPC is about 25% by weight of the total weight of the lipids forming the bilayer.

[0681] According to some of any of the embodiments relating to the compositions or formulations as described in this aspect, the lipids forming the bilayer comprise or consist of DMPC and DPPC. The amount of DMPC is about 80% by weight of the total weight of the lipids forming the bilayer, and the amount of DMPC is about 20% by weight of the total weight of the lipids forming the bilayer.

[0682] According to some of any of the embodiments relating to the compositions or formulations as described in this aspect, the lipids forming the bilayer comprise or consist of DMPC and DPPC. The amount of DMPC is about 70% by weight of the total weight of the lipids forming the bilayer, and the amount of DMPC is about 30% by weight of the total weight of the lipids forming the bilayer.

[0683] According to some of any of the embodiments relating to the compositions or formulations as described in this aspect, the lipids forming the bilayer comprise or consist of DMPC and DPPC. The amount of DMPC is about 65% by weight of the total weight of the lipids forming the bilayer, and the amount of DMPC is about 35% by weight of the total weight of the lipids forming the bilayer.

[0684] According to some of any of the embodiments relating to the compositions or formulations as described in this aspect, the lipids forming the bilayer comprise or consist of DMPC and DPPC. The amount of DMPC is about 60% by weight of the total weight of the lipids forming the bilayer, and the amount of DMPC is about 40% by weight of the total weight of the lipids forming the bilayer.

[0685] It should be understood that the phase transition, such as the melting point (Tm) of the lipid bilayer and liposomes containing the compositions or formulations described in this aspect, can be determined by those skilled in the art by selecting suitable fatty acyl groups contained in the lipids. For example, by selecting relatively short and / or unsaturated fatty acyl groups (such as myristoyl) to obtain a relatively low melting point; and / or by selecting relatively long and / or saturated fatty acyl groups (such as palmitoyl and / or stearoyl) to obtain a relatively high melting point.

[0686] In some embodiments of any of the embodiments described herein, the liposomes described in this aspect are characterized by a phase transition melting point within the range shown herein.

[0687] In some embodiments related to the ophthalmic compositions or formulations as described herein, the average diameter of the liposomes ranges from about 100 nm to about 200 nm, or from about 100 nm to about 180 nm, about 100 nm to about 160 nm, including any intermediate values and sub-ranges therebetween.

[0688] In some embodiments of any of the embodiments described herein, the liposomes described herein are characterized by a surface charge, which can be a positive surface charge or a negative surface charge.

[0689] As used herein, the term "surface charge" refers to the charge on or near the surface, such as the interface between the liposome and the solution. The term "surface charge" includes the charge associated with the surface potential (e.g., such that a positive potential on the surface represents a positive surface charge, while a negative potential on the surface represents a negative surface charge); and the charge that is closer to the surface than the charge of the opposite sign (e.g., in zwitterions, where the positive charge is closer to the surface than the negative charge, and vice versa), such that the ions near the surface mainly interact with the charge near the surface (due to proximity), as opposed to the charge of the opposite sign. For example, phosphatidylcholine liposomes typically exhibit a positive surface charge because the positive charge of the choline group is closer to the liposome surface than the negative charge of the phosphate group.

[0690] Optionally, the surface charge of the liposomes described herein is related to the net charge of the lipid molecules in the liposome. For example, liposomes containing anionic lipids have a negative surface charge, and / or liposomes containing cationic lipids have a positive surface charge.

[0691] Alternatively or additionally, the surface charge of the liposomes as described herein is related to the dipole of the lipid molecules (such as zwitterionic lipid molecules) in the liposome. For example, liposomes containing zwitterionic lipids containing a phosphocholine group can have a positive surface charge because the positively charged ammonium group (on average) in the phosphocholine group is closer to the liposome surface than the negatively charged phosphate group in the phosphocholine group.

[0692] Those skilled in the art can easily determine the surface charge. For example, the sign of the surface charge can be determined by comparing the tendency of the surface (such as the surface of a liposome) to bind anionic and cationic compounds (such as labeled compounds). Alternatively or in addition, the surface charge can be determined by measuring the zeta potential using techniques well known in the art.

[0693] In some embodiments of any of the embodiments described herein, the liposomes as described herein rupture when contacted with at least one water-soluble polymer as described herein in any of the corresponding embodiments (e.g., when contacting at least one water-soluble polymer on the liposome surface). Such liposome rupture can optionally cause the lipid bilayer in the liposome to transform from a curved geometry (such as a relatively spherical liposome) to a flatter geometry that is complementary to the surface geometry and / or the water-soluble polymer attached to the surface (e.g., thereby enhancing the affinity of the lipid for the surface); and / or result in a flatter and smoother lipid-coated surface (e.g., thereby further reducing friction).

[0694] In some embodiments of any of the embodiments described herein, the liposomes and water-soluble polymers as described herein are selected such that the selected water-soluble polymer effectively ruptures the selected liposomes.

[0695] In some embodiments of any of the embodiments in this aspect of the water-soluble polymers involving ionic polymers described herein, at least 75% of the ionic groups in the polymer have the same charge, i.e., at least 75% of the ionic groups are cationic groups or anionic groups, such that the polymer is substantially cationic or anionic, respectively. In some embodiments, at least 90% of the ionic groups in the polymer carry the same charge. In some embodiments, at least 95% of the ionic groups in the polymer carry the same charge. In some embodiments, at least 98% of the ionic groups in the polymer carry the same charge. In some embodiments, at least 99% of the ionic groups in the polymer carry the same charge.

[0696] In some embodiments of any of the embodiments described herein in this aspect, approximately 50% of the ionic groups in the polymer have a positive charge, and approximately 50% of the ionic groups in the polymer have a negative charge, such that the polymer is substantially zwitterionic.

[0697] In some embodiments of any of the embodiments described herein in this aspect, the ionic polymer is characterized by a charge density of 1 - 6 charged groups (ionic groups) / 1 kDa of polymer molecular weight. In some embodiments, the ionic polymer has 1.5 - 4 charged groups / 1 kDa. In some embodiments, the ionic polymer has 2 - 3 charged groups / 1 kDa.

[0698] In some embodiments of any of the embodiments described herein in this regard, the ionomer is characterized by a net charge of 1 - 6 charges (i.e., the difference between the number of anionic groups and the number of cationic groups) / 1 kDa polymer molecular weight. In some embodiments, the ionomer has a net charge of 1.5 - 4 charges / 1 kDa. In some embodiments, the ionomer has a net charge of 2 - 3 charges / 1 kDa.

[0699] In some embodiments of any of the embodiments described herein in this regard, the ionomer is an anionic polymer. For example, the polymer is characterized by a net negative charge of 1 - 6 charges / 1 kDa polymer molecular weight.

[0700] In some embodiments of any of the embodiments described herein in this regard, the ionomer is a polysaccharide (which is an ionic polysaccharide).

[0701] As used throughout this text, the term "polysaccharide" refers to a polymer composed primarily of (at least 50% by weight) monosaccharide units linked by glycosidic bonds.

[0702] As used herein, the term "monosaccharide" includes the carbohydrate itself (having the formula Cn(H2O)n, where n is at least 3, typically 3 - 10), and its derivatives, such as amino sugars, where at least one hydroxyl group is replaced by an amine or amide group; sugar acids, where one or two carbon atoms are oxidized to form carboxylate groups; acylated monosaccharides, where at least one hydroxyl group and / or amine group is replaced by an acyl group (such as an acetyl group); and sulfated monosaccharides, where at least one hydroxyl group is replaced by a sulfate group.

[0703] Examples of monosaccharides include, but are not limited to, hexoses (such as D - hexoses and / or L - hexoses), such as allose, altrose, glucose, mannose, gulose, idose, galactose, talose, psicose, fructose, sorbose, and tagatose; pentoses (such as D - pentoses and / or L - pentoses), such as arabinose, lyxose, xylose, ribose, ribulose, and xylulose; and hexose derivatives, such as glucuronic acid, iduronic acid, mannuronic acid, guluronic acid, glucosamine and its N - alkyl derivatives, galactosamine and its - N - alkyl derivatives, N - acetylglucosamine, N - acetylgalactosamine, and mono - sulfated and di - sulfated N - acetylgalactosamine, glucuronic acid, and iduronic acid.

[0704] As used herein, the term "glycosidic bond" refers to a bond between the hemiacetal group of one compound (such as a monosaccharide monomer) and the hydroxyl group of another compound (such as another monosaccharide monomer).

[0705] Examples of ionic polysaccharides include, but are not limited to, hyaluronic acid, chondroitin sulfate, alginic acid, xanthan gum, chitosan, and N-alkyl chitosan derivatives.

[0706] Hyaluronic acid is an anionic polysaccharide that contains anionic glucuronic acid monomer units and nonionic N-acetylglucosamine monomer units. Hyaluronic acid is an exemplary ionic (e.g., anionic) polymer.

[0707] Chondroitin sulfate is an anionic polysaccharide that contains anionic sulfated (e.g., monosulfated and / or disulfated) N-acetylgalactosamine, glucuronic acid, and / or iduronic acid monomer units and anionic glucuronic acid and / or iduronic acid monomer units, as well as nonionic N-acetylgalactosamine monomer units.

[0708] Alginic acid is an anionic polysaccharide that contains anionic mannuronic acid and guluronic acid monomer units.

[0709] Xanthan gum is an anionic polysaccharide that contains anionic glucuronic acid monomer units, as well as nonionic glucose and mannose monomer units (including their acetyl and / or pyruvyl derivatives).

[0710] Chitosan is a cationic polysaccharide that contains cationic glucosamine monomer units, optionally together with nonionic N-acetylglucosamine monomer units. In N-alkyl chitosan derivatives, at least a portion of the glucosamine units contain 1, 2, or 3 alkyl groups, preferably C 1-4 alkyl groups, attached to the nitrogen atom. In some embodiments of any of the embodiments described herein in this regard, the alkyl groups attached to the nitrogen atom are each independently methyl or ethyl. In some embodiments, the alkyl group is methyl. In some embodiments, the N-alkylated monomer unit is N-trimethylglucosamine.

[0711] As used herein, the terms "hyaluronic acid", "chondroitin sulfate", "alginic acid", "xanthan gum", "chitosan", "N-alkyl chitosan derivatives", and any other ionic compound named herein include all salts and nonionic forms of the named compounds (e.g., the acid form of an anionic polysaccharide and the free base form of a cationic polysaccharide).

[0712] In some embodiments of any of the embodiments described herein in this regard, the polysaccharide is in the form of a salt. In some embodiments, the salt is a pharmaceutically acceptable salt (e.g., an ophthalmically acceptable salt for ophthalmic administration as described herein, a parenterally acceptable salt suitable for parenteral administration for the parenteral applications described herein).

[0713] In some embodiments of any of the embodiments described herein in this regard, the polysaccharide has 0.2 - 1 charged group per monosaccharide moiety. In some embodiments, the polysaccharide has 0.2 - 0.9 charged groups per monosaccharide moiety. In some embodiments, the polysaccharide has 0.3 - 0.7 charged groups per monosaccharide moiety. In some embodiments, the polysaccharide has 0.4 - 0.6 charged groups per monosaccharide moiety. In some embodiments, the polysaccharide has approximately 0.5 charged groups per monosaccharide moiety.

[0714] It should be understood that the monosaccharide moiety as described herein can contain more than one charged group (such as sulfate groups and carboxylate groups).

[0715] In some embodiments of any of the embodiments described herein in this regard, the monosaccharide moiety contains no more than one charged group, i.e., 0 or 1 charged group.

[0716] In some embodiments of any of the embodiments described herein in this regard, the polysaccharide is characterized by a net charge of 0.2 - 1 charge per monosaccharide moiety (i.e., the difference between the number of cationic groups and the number of anionic groups). In some embodiments, the net charge is 0.2 - 0.9 charges per monosaccharide moiety. In some embodiments, the net charge is 0.3 - 0.7 charges per monosaccharide moiety. In some embodiments, the net charge is 0.4 - 0.6 charges per monosaccharide moiety. In some embodiments, the net charge is approximately 0.5 charges per monosaccharide moiety.

[0717] In some embodiments of any of the embodiments described herein, the water-soluble polymer comprises one or more biopolymers.

[0718] As used herein, the term "biopolymer" refers to polymers that occur naturally in living organisms. Examples of biopolymers include, but are not limited to, polynucleotides (such as RNA and DNA), polypeptides, polysaccharides, and their conjugates (such as glycoproteins and proteoglycans containing polypeptide and polysaccharide moieties). It should be understood that a biopolymer can optionally contain many different kinds of related monomer units (such as about 20 different types of amino acid residues and / or multiple types of monosaccharide moieties), with little or no repetition of a particular kind of monomer unit, but is considered a polymer because at least some of the monomer units are structurally related (such as being amino acid residues or monosaccharide moieties).

[0719] In some embodiments of any of the embodiments described herein, the biopolymer comprises a polypeptide (optionally linked to one or more sugar moieties) and / or a polysaccharide.

[0720] Examples of suitable biopolymers containing polypeptides include, but are not limited to, mucin and lubricin.

[0721] As used herein, the term "lubricin" refers to a proteoglycan of approximately 345 kDa (also referred to in the art as "proteoglycan 4"). Human lubricin is encoded by the PRG4 gene. Lubricin optionally comprises the polypeptide sequences of isoform A and / or isoform B of lubricin, e.g., according to NCBI reference sequence NP_001121180.

[0722] As used herein, the term "mucin" refers to a family of high molecular weight glycosylated proteins produced by many animals and includes human mucins such as mucin 1 (e.g., according to NCBI reference sequence NP_001018016), mucin 2 (e.g., according to NCBI reference sequence NP_002448), mucin 3A (e.g., according to NCBI reference sequence NP_005951), mucin 3B, mucin 4 (e.g., according to NCBI reference sequence NP_004523), mucin 5AC, mucin 5B (e.g., according to NCBI reference sequence NP_002449), mucin 6 (e.g., according to NCBI reference sequence NP_005952), mucin 7 (e.g., according to NCBI reference sequence NP_001138478), mucin 8, mucin 12, mucin 13, mucin 15, mucin 16 (e.g., according to NCBI reference sequence NP_078966), mucin 17 (e.g., according to NCBI reference sequence NP_001035194), mucin 19, and mucin 20 (e.g., according to NCBI reference sequence NP_001269435).

[0723] The polysaccharide as described herein in this regard can be a nonionic polymer (as defined herein) or an ionic polymer (as defined herein), e.g., according to any one of the embodiments described herein regarding ionic polysaccharides.

[0724] Hyaluronic acid (e.g., according to any one of the corresponding embodiments described herein) is a non-limiting example of a suitable polysaccharide and a non-limiting example of a suitable ionic (e.g., anionic) polymer.

[0725] In some embodiments of this aspect, the ionic polymer is hyaluronic acid or a salt thereof.

[0726] The term "at least one water-soluble polymer" throughout this document refers to a formulation or solution that contains a water-soluble polymer or a mixture of two or more water-soluble polymers. In some embodiments of any one of the embodiments described herein, the formulation or solution as described herein in this regard contains one water-soluble polymer.

[0727] In some embodiments of any of the embodiments described in this regard, the water-soluble polymers described herein comprise at least two water-soluble polymers of any of the corresponding embodiments described herein. In some embodiments, the water-soluble polymer comprises at least three water-soluble polymers of any of the corresponding embodiments described herein.

[0728] In some embodiments of any of the embodiments described in this regard herein, the molecular weight of the water-soluble polymer (i.e., the average molecular weight or Mw, as known in the art) ranges from 3 kDa to 10 MDa, including any intermediate values and sub-ranges therebetween. In some embodiments, the molecular weight is from 10 kDa to 10 MDa, including any intermediate values and sub-ranges therebetween. In some embodiments, the molecular weight is from 20 kDa to 5 MDa, including any intermediate values and sub-ranges therebetween. In some embodiments, the molecular weight Mw is from 30 kDa to 2.5 MDa, including any intermediate values and sub-ranges therebetween.

[0729] In some embodiments of any of the embodiments described in this regard herein, the molecular weight of the water-soluble polymer (i.e., the average molecular weight or Mw) ranges from 10 kDa to 1 MDa, including any intermediate values and sub-ranges therebetween. In some embodiments, the molecular weight Mw is from 20 kDa to 500 MDa, including any intermediate values and sub-ranges therebetween. In some embodiments, the molecular weight Mw is from 30 kDa to 250 MDa, including any intermediate values and sub-ranges therebetween.

[0730] In some embodiments of any of the embodiments described in this regard herein, the molecular weight of the water-soluble polymer (i.e., the average molecular weight or Mw) ranges from 0.05 to 10 MDa, including any intermediate values and sub-ranges therebetween. In some embodiments, the molecular weight Mw is from 0.05 to 5 MDa, including any intermediate values and sub-ranges therebetween. In some embodiments, the molecular weight Mw is from 0.5 to 10 MDa, including any intermediate values and sub-ranges therebetween. In some embodiments, the molecular weight Mw is from 0.5 to 5 MDa, including any intermediate values and sub-ranges therebetween. In some embodiments, the water-soluble polymer comprises an ionomer (any of the corresponding embodiments described herein), optionally an ionic polysaccharide, having the above molecular weight. In some embodiments, the ionomer is hyaluronic acid having the above molecular weight. In some embodiments of this aspect, the water-soluble polymer comprises a mixture of one or more water-soluble polymers (e.g., anionic), each polymer having a different Mw within the ranges shown herein.

[0731] In some embodiments, the concentration of the water-soluble polymer in the solution (according to any of the corresponding embodiments described in this aspect) ranges from 0.01 to 10 mg / mL, including any intermediate value and sub-range therebetween. In some embodiments, the concentration ranges from 0.03 to 10 mg / mL, including any intermediate value and sub-range therebetween. In some embodiments of this aspect, the concentration ranges from 0.1 to 10 mg / mL, including any intermediate value and sub-range therebetween. In some embodiments, the concentration ranges from 0.3 to 10 mg / mL, including any intermediate value and sub-range therebetween.

[0732] In some embodiments, the total concentration of the water-soluble polymer in the solution (according to any of the corresponding embodiments described in this aspect) ranges from 0.01 to 20 mg / mL. In some embodiments, the total concentration ranges from 0.03 to 20 mg / mL. In some embodiments, the total concentration ranges from 0.1 to 10 mg / mL. In some embodiments, the total concentration ranges from 0.3 to 10 mg / mL.

[0733] In some embodiments of this aspect of the present embodiment, the concentration of the water-soluble polymer (any of the corresponding embodiments described herein) in the solution ranges from 0.01 to 1 mg / mL. In some embodiments, the concentration ranges from 0.03 to 1 mg / mL. In some embodiments, the concentration ranges from 0.1 to 1 mg / mL. In some embodiments, the concentration ranges from 0.3 to 1 mg / mL. In some embodiments, the water-soluble polymer is an ionic polymer and / or a polysaccharide (such as described in any of the corresponding embodiments in this aspect herein), optionally hyaluronic acid.

[0734] In some embodiments of this aspect of the present embodiment, the concentration of each water-soluble polymer (any of the corresponding embodiments described herein) in the solution ranges from 0.01 to 1 mg / mL. In some embodiments of this aspect, the concentration ranges from 0.03 to 1 mg / mL. In some embodiments of this aspect, the concentration ranges from 0.1 to 1 mg / mL. In some embodiments of this aspect, the concentration ranges from 0.3 to 1 mg / mL. In some embodiments, the water-soluble polymer is hyaluronic acid.

[0735] In some embodiments of this aspect of the present embodiment, the total concentration of the water-soluble polymer (any of the corresponding embodiments described herein) in the solution ranges from 0.01 to 2 mg / mL. In some embodiments of this aspect, the total concentration ranges from 0.03 to 2 mg / mL. In some embodiments of this aspect, the total concentration ranges from 0.1 to 1 mg / mL. In some embodiments of this aspect, the total concentration ranges from 0.3 to 1 mg / mL.

[0736] In some embodiments of any of the embodiments described herein in this regard, the water-soluble polymer comprises hyaluronic acid at a concentration of less than 3 mg / mL. In some embodiments, the hyaluronic acid concentration is at least 0.01 mg / mL. In some embodiments of this aspect, the hyaluronic acid concentration is at least 0.03 mg / mL. In some embodiments of this aspect, the hyaluronic acid concentration is at least 0.1 mg / mL. In some embodiments of this aspect, the hyaluronic acid concentration is at least 0.3 mg / mL.

[0737] In some embodiments of any of the embodiments described herein in this regard, the water-soluble polymer comprises hyaluronic acid at a concentration of less than 0.75 mg / mL. In some embodiments of this aspect, the hyaluronic acid concentration is at least 0.01 mg / mL. In some embodiments of this aspect, the hyaluronic acid concentration is at least 0.03 mg / mL. In some embodiments, the hyaluronic acid concentration is at least 0.1 mg / mL. In some embodiments of this aspect, the hyaluronic acid concentration is at least 0.3 mg / mL.

[0738] In some embodiments of any of the embodiments described herein in this regard, the water-soluble polymer comprises hyaluronic acid at a concentration of less than 0.5 mg / mL. In some embodiments of this aspect, the hyaluronic acid concentration is at least 0.01 mg / mL. In some embodiments of this aspect, the hyaluronic acid concentration is at least 0.03 mg / mL. In some embodiments of this aspect, the hyaluronic acid concentration is at least 0.1 mg / mL. In some embodiments of this aspect, the hyaluronic acid concentration is at least 0.3 mg / mL.

[0739] In some embodiments of any of the embodiments described herein in this regard, the water-soluble polymer comprises hyaluronic acid at a concentration of less than 0.25 mg / mL. In some embodiments of this aspect, the hyaluronic acid concentration is at least 0.01 mg / mL. In some embodiments of this aspect, the hyaluronic acid concentration is at least 0.03 mg / mL. In some embodiments of this aspect, the hyaluronic acid concentration is at least 0.1 mg / mL.

[0740] In some embodiments of any of the embodiments described herein in this regard, the water-soluble polymer comprises hyaluronic acid at a concentration of less than 0.1 mg / mL. In some embodiments of this aspect, the hyaluronic acid concentration is at least 0.01 mg / mL. In some embodiments of this aspect, the hyaluronic acid concentration is at least 0.03 mg / mL.

[0741] In some embodiments of any of the embodiments described herein in this regard, the viscosity of the solution, which can at least partially reflect the concentration of the water-soluble polymer therein, is no greater than 1000 cP (centipoise). In some embodiments of this aspect, the viscosity is no greater than 500 cP. In some embodiments of this aspect, the viscosity is no greater than 200 cP. In some embodiments of this aspect, the viscosity is no greater than 100 cP. In some embodiments of this aspect, the viscosity is no greater than 50 cP. In some embodiments of this aspect, the viscosity is no greater than 20 cP. In some embodiments of this aspect, the viscosity is no greater than 10 cP. In some embodiments of this aspect, the viscosity is no greater than 5 cP. In some embodiments of this aspect, the viscosity is no greater than 3 cP. In some embodiments of this aspect, the viscosity is no greater than 2 cP. In some embodiments of this aspect, the solution is an aqueous solution having the viscosity described herein.

[0742] In this aspect, the viscosity of the solution is determined at a temperature of 20 °C and a shear rate of 1 second -1 (unless otherwise indicated).

[0743] According to some of any of the embodiments described in this aspect, the composition or formulation or solution as described herein comprises one or more sugars, which are not the polysaccharides described herein, and can be, for example, monosaccharides, disaccharides (composed of two monosaccharides linked thereto as described herein), or oligosaccharides composed of 3-10, or 3-8, or 3-6 monosaccharide units linked to each other as described herein.

[0744] An exemplary sugar in the composition or formulation as described in this aspect is trehalose.

[0745] In some of any of the embodiments described in this aspect, the amount of the sugar ranges from 0.1-10% by weight, or 0.1-5%, or 1-10%, or 1-5% by weight of the total weight of the composition / formulation / solution, including any intermediate values and sub-ranges therebetween.

[0746] In some embodiments of this aspect, the ratio of the water-soluble polymer described herein to the sugar described herein ranges from 100:1-1:100, or 20:1-1:20, including any intermediate values and sub-ranges therebetween.

[0747] Thus, the compositions (e.g., solutions) or formulations used according to the present invention can be formulated in a conventional manner using one or more ophthalmically acceptable carriers that facilitate the processing of the water-soluble polymer and / or liposomes into a formulation that can be used as described herein. The water-soluble polymer and / or liposomes described herein can be formulated as an aqueous solution per se. Additionally, the solution can be in the form of a suspension and / or an emulsion (e.g., the aqueous phase of a suspension or a water-in-oil, oil-in-water, or oil-in-water-in-oil emulsion), for example, in order to increase the viscosity of the formulation.

[0748] In some of any of the embodiments described herein, the composition or formulation as described in this aspect of the present embodiment is used for treating ocular discomfort.

[0749] In some of any of the embodiments described herein, a method for treating ocular discomfort is provided, which is carried out by ocular or ophthalmic administration of the composition or formulation as described in this aspect of the present embodiment.

[0750] In some embodiments of any of the embodiments related to ocular discomfort described herein, the ocular discomfort is related to contact lenses. The correlation between contact lenses and ocular discomfort can be based on the observations of contact lens wearers, for example, when wearing contact lenses and / or based on the diagnosis by a clinician (e.g., an ophthalmologist), discomfort occurs, e.g., ocular discomfort (e.g., chronic discomfort) is caused by contact lenses.

[0751] According to another aspect of the embodiments of the present invention, a method for treating ocular discomfort in an individual in need thereof is provided, the method comprising administering to the individual's eye an effective amount of a composition or formulation (e.g., a solution) comprising liposomes and a water-soluble polymer as described in any of the corresponding embodiments herein. According to another aspect of the embodiments of the present invention, the use of a composition or formulation (e.g., a solution) comprising liposomes and a water-soluble polymer as described in any of the corresponding embodiments herein in the preparation of a medicament for treating ocular discomfort is provided.

[0752] Drug delivery:

[0753] In some embodiments of the present invention, liposomes are provided, which comprise at least one bilayer-forming lipid, a polymeric compound of any of the corresponding embodiments described herein, and a therapeutic active agent incorporated into the liposomes and / or on the liposomes as described herein. In some embodiments, the liposomes are used for delivering the therapeutic active agent to an individual in need thereof (e.g., a body part of the individual).

[0754] According to one aspect of some embodiments of the present invention, there is provided the use of liposomes comprising at least one bilayer-forming lipid, a polymeric compound of any one of the corresponding embodiments described herein, and a therapeutic agent incorporated into and / or on the liposomes in the preparation of a medicament for delivering the therapeutic agent to an individual in need thereof (e.g., a body part of the individual).

[0755] According to one aspect of some embodiments of the present invention, there is provided a method for delivering a therapeutic agent to an individual in need thereof (e.g., a body part of the individual), the method comprising administering to the individual liposomes comprising at least one bilayer-forming lipid, a polymeric compound of any one of the corresponding embodiments described herein, and a therapeutic agent incorporated into and / or on the liposomes, thereby delivering the therapeutic agent to the individual in need thereof.

[0756] According to any one of the aspects described herein, in some embodiments of any one of the embodiments, the use of the liposomes and / or methods described herein is for treating a medical condition of an individual treatable with a therapeutic agent (any one of the corresponding embodiments described herein).

[0757] According to any one of the aspects described herein, in some embodiments of any one of the embodiments, delivering the therapeutic agent comprises sustained release of the therapeutic agent of any one of the corresponding embodiments described herein.

[0758] According to any one of the aspects described herein, in some embodiments of any one of the embodiments, the liposomes are selected such that they are capable of sustained release of the therapeutic agent of any one of the corresponding embodiments described herein.

[0759] As used herein, "delivery" of a therapeutic agent or medicament (the terms are used interchangeably herein) means administering the therapeutic agent to an individual while controlling the duration and / or proportion of the agent at a desired body part according to the condition of the individual (e.g., the body part where the agent ideally exerts its therapeutic effect). Thus, the term "delivery" (and its grammatical variations) includes targeting the therapeutic agent to a specific body part such that a higher proportion of the agent reaches said body part (e.g., using a suitable targeting moiety); and / or controlling the duration of such agent's presence in the body (e.g., in the blood) - e.g., by sustained release - which may be related to the duration of such agent at the desired body part (even in the absence of specific targeting to the body part).

[0760] As used herein, "sustained release" refers to a formulation of an active agent that provides a gradual / or delayed ("sustained") release of the active agent (e.g., from a reservoir such as a liposome of any of the corresponding embodiments described herein), which results in the active agent being present in a body site (e.g., in the blood upon systemic administration or in the body site where the active agent is topically administered) for a longer period of time and / or at a later time (relative to administration) than the active agent itself (administered by the same route of administration).

[0761] For example, in the context of an embodiment of the present invention, administering the active agent itself (as opposed to a sustained release formulation) optionally refers to a liposome-free formulation of the active agent according to an embodiment of the present invention and which contains the same carrier (if any) as the sustained release formulation.

[0762] In some embodiments, sustained release is characterized in that the concentration of the therapeutic active agent (e.g., in the blood upon systemic administration or in the body site where the active agent is topically administered) is at least half of the maximum concentration (Cmax), and the duration period is at least 50% higher than the corresponding time period of the therapeutic active agent itself (e.g., as defined herein) when administered to produce the same maximum concentration (i.e., the concentration of the active agent is at least half of the maximum concentration during this process). In some such embodiments, the time period (for sustained release) is at least 100% higher than the corresponding time period (for the active agent itself) (i.e., 2-fold). In some embodiments, the time period (for sustained release) is at least 200% higher than the corresponding time period (for the active agent itself) (i.e., 3-fold). In some embodiments, the time period (for sustained release) is at least 400% higher than the corresponding time period (for the active agent itself) (i.e., 5-fold).

[0763] In some embodiments, sustained release is characterized in that the concentration of the therapeutic active agent (e.g., in the blood upon systemic administration or in the body site where the active agent is topically administered) is at least half of the maximum concentration (Cmax), and the duration is at least 6 hours. In some such embodiments, the time period is at least 12 hours. In some embodiments, the time period is at least 24 hours. In some embodiments, the time period is at least 2 days. In some embodiments, the time period is at least 4 days. In some embodiments, the time period is at least 1 week. In some embodiments, the time period is at least 2 weeks. In some embodiments, the time period is at least 4 weeks.

[0764] Sustained release (of any of the corresponding embodiments described herein) can permit, for example, a regimen characterized by a lower frequency of administration and / or a higher efficacy of any given administration. One skilled in the art can readily determine the suitable frequency of administration of a given therapeutic agent, as well as the ratio between the desired maximum concentration and the minimum effective concentration of a given agent (e.g., the “therapeutic window” of the agent), based on the duration of the sustained release (e.g., the time period during which the concentration of the active agent is at least half the maximum concentration, and / or at least the minimum effective concentration, according to any of the corresponding embodiments described herein).

[0765] In some such embodiments, the therapeutic agent is an analgesic and / or an anti-inflammatory agent. In some such embodiments, the therapeutic agent can be used alone or in combination with additional therapeutic agents to treat osteoarthritis.

[0766] In some of any of the embodiments described herein, the liposomes of the present embodiment are administered to an individual in need thereof in combination with additional therapeutic agents or pharmaceutical compositions containing them that can be used to treat a given medical condition. The additional therapeutic agents can be incorporated into the liposomes of the present embodiment, or into other liposomes, which can have the same or different active agent retention times, or can simply be mixed with a suitable lipid-free carrier.

[0767] According to some embodiments of the present invention, the therapeutically effective agent is selected from analgesics, anti-inflammatory agents, anti-proliferative agents, anti-microbial agents, and vaccine antigens.

[0768] In some such embodiments, the therapeutic agent is an analgesic and / or an anti-inflammatory agent. In some such embodiments, the therapeutic agent can be used alone or in combination with additional therapeutic agents to treat osteoarthritis.

[0769] According to some embodiments of the present invention, delivery is effected by parenteral systemic administration.

[0770] According to some embodiments of the present invention, delivery is effected by intra-articular administration.

[0771] According to some embodiments of the present invention, the liposomes are used to treat synovial joint disorders.

[0772] According to some embodiments of the present invention, synovial joint disorders are selected from arthritis, bursitis, carpal tunnel syndrome, fibromyalgia, gout, joint locking, tendonitis, traumatic joint injury, and surgery-related joint injury.

[0773] According to some embodiments of the present invention, the therapeutic agent is an analgesic and / or an anti-inflammatory agent.

[0774] According to some embodiments of the present invention, the liposomes are formulated as part of a pharmaceutical composition, which further comprises a pharmaceutically acceptable carrier.

[0775] According to some embodiments of the present invention, the carrier comprises an aqueous liquid.

[0776] According to some embodiments of the present invention, the pharmaceutical composition further comprises a water-soluble biopolymer.

[0777] According to some embodiments of the present invention, the biopolymer comprises hyaluronic acid.

[0778] One skilled in the art can readily determine which medical conditions can be treated by a given therapeutic agent, and which therapeutic agent may be suitable for treating a designated medical condition.

[0779] In some embodiments of any of the embodiments described herein, the liposomes are used for treating a proliferative disease or disorder (such as cancer), and the therapeutic agent is an anti-proliferative agent of any of the corresponding embodiments described herein.

[0780] In some embodiments of any of the embodiments described herein, the liposomes are used for treating an inflammatory disease or disorder (such as cancer), and the therapeutic agent is an analgesic and / or anti-inflammatory agent of any of the corresponding embodiments described herein.

[0781] In some embodiments of any of the embodiments described herein, the liposomes are used for treating synovial joint disorders (such as by systemic and / or intra-articular administration), optionally inflammatory synovial joint disorders. Examples of synovial joint disorders that can be treated according to the embodiments of the present invention include, but are not limited to, arthritis (such as osteoarthritis, rheumatoid arthritis, and / or psoriatic arthritis), bursitis, carpal tunnel syndrome, fibromyalgia, gout, joint locking (such as joint locking associated with osteochondritis dissecans and / or synovial osteochondromatosis), tendinitis, traumatic joint injuries, and joint injuries associated with surgery.

[0782] Joint injuries associated with surgery can optionally be associated with surgery that directly damages the joint surface (such as by incision) and / or surgery that only indirectly damages the joint surface. For example, surgery to repair or affect tissues near the joint (such as ligaments and / or menisci) may be associated with joint injuries caused by mechanical changes in the joint.

[0783] Traumatic joint injuries can optionally be injuries directly caused by trauma (such as those caused at the time of trauma) and / or injuries caused by a previous trauma (such as post-traumatic injuries occurring some time after the trauma).

[0784] Methods and intermediates:

[0785] In one aspect of some embodiments according to the present invention, a method for preparing a polymeric compound as described in any one of the corresponding embodiments herein is provided. As described herein, the method is selected to allow control of the composition of the polymeric moiety of the polymeric compound.

[0786] According to some of any of the embodiments described herein, the method comprises contacting an initiator compound having Formula V:

[0787]

[0788] wherein:

[0789] F1, F2, F3, F4, J, K, M and Q are as defined for Formula IV; and

[0790] Ri is an electron transfer functional group,

[0791] with a plurality of monomers forming a -[Y-L-Z]n-[Y]m- polymer backbone under conditions that promote atom transfer radical polymerization (ATRP), wherein Y, L, Z, n and m are as described herein for Formula I.

[0792] According to some of any of the embodiments described herein, Ri can be any functional group suitable for electron transfer radical polymerization and is generally a group capable of autonomously forming a stable radical. Exemplary such groups include halogens (halo), preferably chlorine or bromine, more preferably bromine, although any other suitable group is also contemplated.

[0793] As used herein, the term "stable radical" includes any chemical species that contains an unpaired electron within its molecular or atomic structure but has a relatively longer lifetime and lower reactivity compared to a typical radical. Generally, a stable radical is a radical that is capable of stabilizing the unpaired electron energetically.

[0794] The conditions that promote ATRP include any conditions known in the art, generally in the presence of a radical forming reagent, such as CuX' or CuX'2, where X' is generally a halogen and a suitable ligand.

[0795] As described herein, the inventors have revealed that when ATRP is ARGET-ATRP, better control of the polymerization process is achieved.

[0796] In some of any of the embodiments described herein, the method is carried out under conditions that promote ARGET-ATRP. Exemplary such conditions include any conditions known in the art, typically in the presence of CuX’2, where X’ is typically a halogen, a suitable ligand, and a reducing agent. Exemplary reducing agents and ligands suitable for the context of these embodiments are described in the Examples section below. Suitable solvents for carrying out the ATRP or ARGET-ATRP method include, but are not limited to, polar solvents such as alcohols (e.g., methanol and / or ethanol).

[0797] In some of any of the embodiments described herein, the method is carried out by ATRP, and M is not an amido group.

[0798] In some of any of the embodiments described herein, the method is carried out by ATRP, and when M is an amido group, Q contains an aryl as described herein.

[0799] In some of any of the embodiments described herein, when M is an amido group, the method is carried out by ARGET-ATRP.

[0800] In some of any of the embodiments described herein, the method is carried out at a temperature of 10 °C - 50 °C, or 15 °C - 50 °C, or 15 °C - 30 °C, including any intermediate values and subranges therebetween. In some of any of the embodiments described herein, the method is carried out at room temperature (i.e., ambient temperature; about 20 °C - about 25 °C).

[0801] In some of any of the embodiments described herein, the initiator compound is contacted with a plurality of monomers for a time period of about 1 - about 48 hours, or about 3 - about 48 hours, or about 3 - about 36 hours, or about 3 - about 24 hours, about 4 - about 48 hours, or about 4 - about 36 hours, or about 4 - about 24 hours, about 6 - about 48 hours, or about 6 - about 36 hours, or about 6 - about 24 hours, including any intermediate values and subranges therebetween.

[0802] Exemplary methods for carrying out the ATRP method and the ARGET-ATRP method are described in the Examples section below. If desired, these methods can be controlled by selecting the initiator compound, the molar ratio of the plurality of monomers to the initiator, by controlling the catalyst solution, the ligand, and / or the reduction, and by selecting the synthetic schemes exemplified for Methods 1, 2, and 3.

[0803] In some of any of the embodiments described herein, the method is carried out by contacting a catalyst solution comprising a catalyst and a ligand with a solution comprising an initiator compound, preferably in an inert atmosphere (such as argon), and with a solution of a plurality of monomers, in a molar ratio of the selected initiator compound to provide a desired length (number of repeating backbone units) of the resulting LPC.

[0804] In some of any of the embodiments described herein, the molar ratio of the catalyst to the initiator is about 1:1.

[0805] In some of any of the embodiments described herein, the method is carried out by ATRP, using methods well known in the art. In an exemplary method (such as Method 1), the initiator compound as described herein is dissolved in a solvent (preferably a polar solvent such as dichloromethane, DCM), and a solution comprising a catalyst and a ligand in a polar solvent such as a protic solvent such as an alcohol such as ethanol or methanol or even water is added, followed by addition of a solution of a plurality of monomers also in the polar solvent as described. Optionally, the reaction is carried out at a temperature of 20 - 50, or 20 - 40, or 30 - 50, or 30 - 40 °C.

[0806] In some of any of the embodiments described herein, the method is carried out by ARGET - ATRP, using methods well known in the art. In some of these embodiments, a catalyst solution is prepared by dissolving a catalyst and a ligand in a polar solvent (such as an alcohol solvent such as MeOH or EtOH, preferably EtOH). In an exemplary method (such as Method 2), the catalyst solution is added to a mixture of an initiator compound, a reducing agent, and a plurality of monomers in a polar solvent (such as an alcohol solvent) as described herein. In another exemplary method (such as Method 3), the catalyst solution is added to a mixture of an initiator compound and a plurality of monomers in a polar solvent (such as an alcohol solvent) as described herein, and thereafter a reducing agent is added.

[0807] In some of any of the embodiments described herein, the molar ratio of the monomer(s) as described in any of the corresponding embodiments and any combination thereof to the initiator compound as described herein ranges from 5:1 - 200:1, or 10:1 - 150:1, or 20:1 - 100:1, or 30:1 - 75:1, including any intermediate value and sub - range therebetween. This molar ratio determines the number of repeating units in the resulting polymer compound (LPC).

[0808] In some embodiments, a molar ratio of 50:1 or less (e.g., about 30:1 or about 25:1) provides a short LPC as described herein in the corresponding embodiments, which contains less than 100 or less than 80 repeating units in the polymer portion (as shown by the variable n in Formula I herein).

[0809] In some embodiments, a molar ratio of 60:1 or more (e.g., about 60:1 - about 80:1) provides a longer LPC as described herein in the corresponding embodiments, which contains at least 80 repeating units in the polymer portion (as shown by the variable n in Formula I herein).

[0810] In some of any of the embodiments described herein, the method further includes separating the polymeric compound.

[0811] The separated polymeric compound (e.g., a polymeric compound having Formula I as described in any of the corresponding embodiments herein and any combination thereof) can be carried out by any post-treatment method known in the art, preferably in the context of the ATRP method, including for example TFF, column chromatography, and / or precipitation. Exemplary such methods are described in the Examples section below.

[0812] In some of any of the embodiments described herein, separating the polymeric compound does not involve acidification, even if the polymeric compound is exposed to an acidic environment.

[0813] In some of any of the embodiments described herein, separating the polymeric compound is carried out by precipitation, i.e., by contacting the mixture with an anti-solvent to precipitate the polymeric compound from the polymerization reaction mixture, wherein the polymeric compound is not soluble at a ratio of anti-solvent:reaction mixture in the range of 2:1 - 50:1, including any intermediate values and sub-ranges therebetween.

[0814] Exemplary anti-solvents include but are not limited to ketones such as acetone, dimethoxyethane (DME), chloroform (CHCl3), dichloromethane (DCM), tetrachloroethylene (C2Cl4), dimethyl carbonate (DMC), diethyl carbonate (DEC), and methyl tert-butyl ether (MTBE). In an exemplary embodiment, the anti-solvent is a ketone, such as acetone.

[0815] In some of any of the embodiments described herein, separating the polymeric compound further includes performing column chromatography before and / or subsequent to precipitation.

[0816] In some of any of the embodiments described herein, there is provided a compound represented by Formula V as described in any of the corresponding embodiments herein and any combination thereof.

[0817] In some of any of the embodiments described herein, a compound represented by Formula V as described herein in any of the corresponding embodiments and any combination thereof is provided, which is used as an intermediate in the preparation of a polymer compound as described herein in any of the corresponding embodiments and any combination thereof.

[0818] Exemplary compounds of Formula V and their preparation are described in the Examples section below, and Figure 4A , 5A and 6A show some.

[0819] Additional definitions:

[0820] As used herein, the term "hydrocarbon" describes an organic moiety that includes, as its basic backbone, a chain of carbon atoms that are predominantly substituted with hydrogen atoms. The hydrocarbon can be saturated or unsaturated, composed of aliphatic, alicyclic, or aromatic moieties, and can optionally be substituted with one or more substituents (other than hydrogen). A substituted hydrocarbon can have one or more substituents, where each substituent can independently be, for example, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycloaliphatic, amine, halide, sulfonate, sulfoxide, phosphonate, hydroxy, alkoxy, aryloxy, mercapto, thioalkoxy, thioaryloxy, oxo, cyano, nitro, azo, azide, sulfonamide, carboxy, thiocarbamate, urea, thiourea, carbamate, amide, and hydrazine. The hydrocarbon can be a terminal group or a linking group, where these terms are defined herein. The hydrocarbon moiety is optionally interrupted by one or more heteroatoms, including but not limited to one or more oxygen, nitrogen, and / or sulfur atoms. In some embodiments of any of the embodiments described herein, the hydrocarbon involved is not interrupted by any heteroatoms.

[0821] Preferably, the hydrocarbon moiety has 1 to 20 carbon atoms. Regardless of how a numerical range is described herein; for example, "1-20", it means that in the case of an alkyl group, this group can contain 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 20 carbon atoms.

[0822] As used herein, the term "alkyl" describes saturated aliphatic hydrocarbon end groups, as defined herein, including straight-chain and branched groups. Preferably, the alkyl group has 1 to 20 carbon atoms. More preferably, the alkyl group is a medium-sized alkyl group having 1 to 10 carbon atoms. Most preferably, unless otherwise specified, the alkyl group is a lower alkyl group having 1 to 4 carbon atoms. The alkyl group may be substituted or unsubstituted. Substituted alkyl groups may have one or more substituents, where each substituent may independently be, for example, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycloalkyl, amine, halide, sulfonate, sulfoxide, phosphonate, hydroxy, alkoxy, aryloxy, mercapto, thioalkoxy, thioaryloxy, cyano, nitro, azo, azide, sulfonamide, carboxy, thiocarbamate, urea, thiourea, carbamate, amide, and hydrazine.

[0823] The term "alkylene" describes a saturated aliphatic hydrocarbon linking group, as defined herein, which differs from the alkyl group defined herein only in that the alkylene group is a linking group rather than an end group.

[0824] As used herein, the term "alkenyl" describes an unsaturated aliphatic hydrocarbon end group containing at least one carbon-carbon double bond, including straight-chain and branched groups. Preferably, the alkenyl group has 2 to 20 carbon atoms. More preferably, the alkenyl group is a medium-sized alkenyl group having 2 to 10 carbon atoms. Most preferably, unless otherwise indicated, the alkenyl group is a lower alkenyl group having 2 to 4 carbon atoms. The alkenyl group may be substituted or unsubstituted. Substituted alkenyl groups may have one or more substituents, where each substituent may independently be, for example, cycloalkyl, alkynyl, aryl, heteroaryl, heterocycloalkyl, amine, halide, sulfonate, sulfoxide, phosphonate, hydroxy, alkoxy, aryloxy, mercapto, thioalkoxy, thioaryloxy, cyano, nitro, azo, azide, sulfonamide, carboxy, thiocarbamate, urea, thiourea, carbamate, amide, and hydrazine.

[0825] As used herein, the term "alkynyl" describes an unsaturated aliphatic hydrocarbon end group containing at least one carbon-carbon triple bond, including straight-chain and branched groups. Preferably, the alkynyl group has 2 to 20 carbon atoms. More preferably, the alkynyl group is a medium-sized alkynyl group having 2 to 10 carbon atoms. Most preferably, unless otherwise indicated, the alkynyl group is a lower alkynyl group having 2 to 4 carbon atoms. The alkynyl group may be substituted or unsubstituted. Substituted alkynyl groups may have one or more substituents, where each substituent may independently be, for example, cycloalkyl, alkenyl, aryl, heteroaryl, heterocycloalkyl, amine, halide, sulfonate, sulfoxide, phosphonate, hydroxy, alkoxy, aryloxy, mercapto, thioalkoxy, thioaryloxy, cyano, nitro, azo, azide, sulfonamide, carboxy, thiocarbamate, urea, thiourea, carbamate, amide, and hydrazine.

[0826] The term "cycloalkyl" describes a fully carbon monocyclic or polycyclic (i.e., rings sharing a pair of adjacent carbon atoms) group in which one or more of the rings do not have a fully conjugated π - electron system. The cycloalkyl can be substituted or unsubstituted. A substituted cycloalkyl can have one or more substituents, where each substituent can independently be, for example, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, amine, halide, sulfonate, sulfoxide, phosphonate, hydroxy, alkoxy, aryloxy, mercapto, thioalkoxy, thioaryloxy, cyano, nitro, azo, azide, sulfonamide, carboxy, thiocarbamate, urea, thiourea, carbamate, amide, and hydrazine. The cycloalkyl can be a terminal group, as defined herein, where it is attached to a single adjacent atom or a linking group, as defined herein, that links two or more moieties.

[0827] The term "aryl" describes a fully carbon monocyclic or polycyclic (i.e., rings sharing a pair of adjacent carbon atoms) terminal group (as defined herein) having a fully conjugated π - electron system. The aryl can be substituted or unsubstituted. A substituted aryl can have one or more substituents, where each substituent can independently be, for example, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, amine, halide, sulfonate, sulfoxide, phosphonate, hydroxy, alkoxy, aryloxy, mercapto, thioalkoxy, thioaryloxy, cyano, nitro, azo, azide, sulfonamide, carboxy, thiocarbamate, urea, thiourea, carbamate, amide, and hydrazine. Phenyl and naphthyl are representative aryl terminal groups.

[0828] The term "heteroaryl" describes a monocyclic or polycyclic (i.e., rings sharing a pair of adjacent atoms) group having one or more atoms such as nitrogen, oxygen, and sulfur in the ring, and in addition, having a fully conjugated π - electron system. Examples of heteroaryl include, but are not limited to, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrimidine, quinoline, isoquinoline, and purine. The heteroaryl can be substituted or unsubstituted. A substituted heteroaryl can have one or more substituents, where each substituent can independently be, for example, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, amine, halide, sulfonate, sulfoxide, phosphonate, hydroxy, alkoxy, aryloxy, mercapto, thioalkoxy, thioaryloxy, cyano, nitro, azo, azide, sulfonamide, carboxy, thiocarbamate, urea, thiourea, carbamate, amide, and hydrazine. The heteroaryl can be a terminal group, as defined herein, where it is attached to a single adjacent atom or a linking group, as defined herein, that links two or more moieties. Representative examples are pyridine, pyrazole, oxazole, indole, purine, etc.

[0829] The term "arylene" describes a monocyclic or fused polycyclic linking group, as defined herein, and includes linking groups different from aryl or heteroaryl, as defined herein, except that the arylene is a linking group rather than a terminal group.

[0830] The term "heterocycloalkyl" describes a monocyclic or fused polycyclic group having one or more atoms such as nitrogen, oxygen, and sulfur in the ring. The ring may also have one or more double bonds. However, these rings do not have a fully conjugated π - electron system. The heterocycloalkyl can be substituted or unsubstituted. The substituted heterocycloalkyl can have one or more substituents, where each substituent can independently be, for example, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, amine, halide, sulfonate, sulfoxide, phosphonate, hydroxy, alkoxy, aryloxy, thiol, thioalkoxy, thioaryloxy, cyano, nitro, azo, azide, sulfonamide, carboxyl, thiocarbamate, urea, thiourea, carbamate, amide, and hydrazine. The heterocycloalkyl can be a terminal group, as defined herein, where it is attached to a single adjacent atom or linking group, as defined herein, which links two or more moieties. Representative examples are piperidine, piperazine, tetrahydrofuran, tetrahydropyran, morpholine, and the like.

[0831] As used herein, the terms "amine" and "amino" describe -NRxRy terminal groups and -NRx - linking groups, where Rx and Ry are each independently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, or heterocycloalkyl, as defined herein. When Rx or Ry is heteroaryl or heterocycloalkyl, the amine nitrogen atom is bonded to a carbon atom of the heteroaryl or heterocycloalkyl. The carbon atom attached to the amine nitrogen atom is not substituted with =O or =S, and in some embodiments, is not substituted with any heteroatom.

[0832] Thus, the amino group can be a primary amine (where Rx and Ry are hydrogen), a secondary amine (where Rx is hydrogen and Ry is alkyl, cycloalkyl, aryl, heteroaryl, or heterocycloalkyl), or a tertiary amine (where Rx and Ry are each independently alkyl, cycloalkyl, aryl, heteroaryl, or heterocycloalkyl).

[0833] The ...

Claims

1. A polymer compound represented by Formula I: Wherein: m is 0 or a positive integer; n is an integer, which is at least 2, at least 5, preferably at least 10 (e.g., an integer from 10 to 200); Y is a main chain unit of a polymer main chain forming a polymer compound; L is absent or is a linking moiety; and Z has the general formula II: Wherein: The dashed (curved) line represents the point of attachment to the corresponding Y main chain unit, or if a linking moiety L is present, represents the point of attachment to the linking moiety L; A is a substituted or unsubstituted hydrocarbon; B is an oxygen atom or is absent; R1 - R3 are each independently selected from hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; X is a lipid moiety represented by formula IV: Wherein: The dashed (curved) line represents the point of attachment to the polymer main chain; F1, F2, F3, and F4 are each independently selected from hydrogen, alkyl, alkenyl, alkynyl, acyl, alkoxy, thioalkoxy, carboxyl, thio-carboxyl, wherein at least one of F1, F2, F3, and F4 is not hydrogen, and is at least 10 carbon atoms in length; J is -O-P(=O)(OH)-O- or is absent; K is a substituted or unsubstituted hydrocarbon having 1 - 10 carbon atoms in length or is absent; M is a linking group, which is selected from -O-, -S-, amino, sulfinyl, sulfonyl, phosphate, phosphonyl, phosphino, carbonyl, thiocarbonyl, urea, thiourea, carbamoyl, thiocarbamoyl, acylamino, carboxyl, and sulfonamide, or is absent; and Q is a substituted or unsubstituted hydrocarbon having 1 - 10 carbon atoms in length or is absent, wherein when M is absent, Q is also absent, and when J is absent, M is not absent, Provided that: when J is -O-P(=O)(OH)-O-, M is not acylamino and / or Q contains an aryl moiety.

2. The polymer compound of claim 1, wherein at least one of F1, F2, F3, and F4 is an alkoxy group, a thioalkoxy group, an acyl group, or a carboxyl group having a carbon atom length of at least 10.

3. The polymer compound of claim 1 or 2, wherein at least one of F1, F2, F3, and F4 is derived from a fatty acid selected from lauroyl, myristoyl, palmitoyl, stearoyl, palmitoleoyl, oleoyl, and linoleoyl.

4. The polymer compound of any one of claims 1-3, wherein M is a carboxyl group.

5. The polymer compound of any one of claims 1-4, wherein K is an alkyl group.

6. The polymer compound of claim 1 or 2, wherein J is -P(=O)(OH)-O-; M is an amide group; and Q is a hydrocarbon substituted by at least one aryl group (such as a phenyl group).

7. The polymeric compound according to any one of claims 1-6, wherein Q is a methylene group substituted by at least one aryl group.

8. The polymeric compound according to any one of claims 1-7, wherein J is absent.

9. The polymeric compound according to any one of claims 1-7, wherein both J and K are absent.

10. The polymeric compound according to any one of claims 1-7, wherein both J and K are absent and M is a carboxyl group.

11. The polymeric compound according to any one of claims 1-10, wherein at least one or at least two of F1, F2, F3 and F4 are independently the thioalkoxy group.

12. The polymeric compound according to any one of claims 1-10, wherein at least one or at least two of F1, F2, F3 and F4 are independently the carboxyl group.

13. The polymeric compound according to claim 12, wherein at least one or two of F1 and F2 are the carboxyl group, and at least one of F3 and F4 is an alkyl group.

14. The polymeric compound according to any one of claims 8-13, wherein Q is -C(CH3)2-.

15. The polymeric compound according to any one of claims 1-14, wherein Y is a substituted or unsubstituted alkylene unit.

16. The polymeric compound according to claim 15, wherein Y is a substituted or unsubstituted ethylene unit.

17. The polymeric compound according to any one of claims 1-16, wherein B is an oxygen atom.

18. The polymeric compound according to any one of claims 1-17, wherein A is a substituted or unsubstituted hydrocarbon having 1-4 carbon atoms in length.

19. The polymeric compound according to any one of claims 1-18, wherein each of R1-R3 is independently hydrogen or C 1-4 -alkyl.

20. The polymeric compound according to any one of claims 1-19, wherein n ranges from 10 to 200.

21. The polymeric compound according to any one of claims 1-20, wherein n is at least 30.

22. The polymeric compound according to any one of claims 1-20, wherein n ranges from 30 to 70.

23. The polymeric compound according to any one of claims 1-20, wherein n is at least 50.

24. The polymeric compound according to any one of claims 1-20, wherein n ranges from 50 to 150 or 50 to 80.

25. The polymeric compound according to any one of claims 1-20, wherein n is at least 80.

26. The polymeric compound according to any one of claims 1-20, wherein n ranges from 80 to 120.

27. The polymeric compound according to any one of claims 1-26, wherein m ranges from 0 to 50.

28. The polymeric compound according to any one of claims 1-27, wherein at least a part of the main chain unit Y, the L and / or the Z comprises at least one targeting moiety.

29. A lipid bilayer comprising at least one bilayer-forming lipid and the polymeric compound according to any one of claims 1-28.

30. The lipid bilayer according to claim 29, wherein the molar ratio of the at least one bilayer-forming lipid to the polymeric compound ranges from 5:1 to 5000:1, or 10:1 to 1000:1, or 10:1 to 100:1, or 10:1 to 50:1 (e.g., 30:1 to 40:1), or 100:1 to 200:

1.

31. The lipid bilayer according to claim 29 or 30, wherein the at least one bilayer-forming lipid comprises at least one zwitterionic glycerophospholipid.

32. The lipid bilayer according to claim 31, wherein the at least one bilayer-forming lipid further comprises a negatively charged bilayer-forming lipid (e.g., DPPG).

33. A liposome comprising at least one lipid bilayer according to any one of claims 29-32.

34. A composition comprising the liposome according to claim 33 and a carrier, preferably an aqueous carrier.

35. The composition according to claim 34, which is a sterile composition.

36. The composition according to claim 34 or 35, which is a lubricant composition.

37. The lubricant composition according to claim 36, which further comprises a water-soluble polymer.

38. The lubricant composition according to claim 36 or 37, which is used for lubricating a physiological surface, wherein the carrier is a physiologically acceptable carrier.

39. A method for reducing the surface friction coefficient, the method comprising contacting a surface with the liposome according to claim 33.

40. The method according to claim 39, which is carried out by contacting the surface with a composition comprising the liposome and a carrier, preferably an aqueous carrier.

41. The method according to claim 39 or 40, which further comprises contacting the surface with a water-soluble polymer.

42. The method according to claim 40 or 41, wherein the surface is a physiological surface and the carrier is a physiologically acceptable carrier.

43. The method according to claim 42, wherein the surface is the articular surface of a synovial joint.

44. The liposome of claim 33, which is used for treating synovial joint disorders associated with an increased coefficient of friction of the joint surface in a synovial joint.

45. A method for inhibiting biofilm formation on a substrate surface, the method comprising contacting the substrate with a composition comprising the liposome of claim 33.

46. An article, which comprises a substance composition, the substance composition comprising a substrate, and the substrate is coated with a lipid bilayer according to any one of claims 29 - 32 or a liposome of claim 33 on at least a part of its surface.

47. A lipid bilayer according to any one of claims 29 - 32, a liposome of claim 33, or a composition according to any one of claims 34 - 36, which is used for treating synovial joint disorders.

48. The lipid bilayer, liposome or composition of claim 47, wherein the treatment comprises intra - articular administration of the lipid bilayer, liposome or composition.

49. The liposome of claim 33 or the composition of claim 34 or 19, wherein the liposome has a therapeutic active agent associated therewith, and the liposome or composition is used for delivering the therapeutic active agent to a body part of an individual.

50. The liposome or composition of claim 49, which is used for treating a medical condition of an individual that can be treated by the therapeutic active agent.

51. A method for preparing a polymeric compound according to any one of claims 1 - 28, the method comprising using an initiator compound having formula V: wherein: F1, F2, F3, F4, J, K, M, and Q are as defined for formula IV; and Ri is an electron transfer functional group, Contacting a plurality of monomers under conditions that promote atom transfer radical polymerization (ATRP), wherein the monomers form the -[Y-L-Z]n-[Y]m- polymer main chain.

52. The method of claim 51, wherein the ATRP is ARGET - ATRP.

53. The method of claim 51 or 52, which further comprises separating the polymeric compound.

54. The method of claim 53, wherein the separation is by precipitation.

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