Compositions comprising polymeric lipid analogs for reducing wear of implantable devices or of materials forming such devices

Abstract

A composition comprising a polymeric compound as described and defined in the instant specification and claims or a lipid bilayer (e.g., a liposome) formed thereby, for use in combination with an implantable device for treating a subject in need of the implantable device, and / or for use in a pin-on-disk system, for determining wear resistance of an implantable device, is provided.

Description

[0001] COMPOSITIONS COMPRISING POLYMERIC LIPID ANALOGS FOR REDUCING WEAR OF IMPLANTABLE DEVICES OR OF MATERIALS FORMING SUCH DEVICES

[0002] RELATED APPLICATION / S

[0003] This application claims the benefit of priority under 35 USC § 119(e) of U.S. Provisional Patent Application No. 63 / 622,121 filed on 18 January 2024, the contents of which are incorporated herein by reference in their entirety.

[0004] FIELD AND BACKGROUND OF THE INVENTION

[0005] The present invention, in some embodiments thereof, relates to therapy, and more particularly, but not exclusively, to methods employing liposomes or bilayer lipids made of a lipid- containing polymeric material, in combination with implantable devices, particularly wearable implantable devices such as prosthetic and / or orthopedic implants, when treating medical conditions that require implantation of such devices and / or when evaluating the wear resistance of materials used for forming implantable devices.

[0006] Osteoarthritis (OA) is a group of degenerative joint disorders characterized by the progressive loss of normal cartilage structure and function. The structural changes in the knee joint are accompanied by symptoms of joint pain, restriction of motion, crepitus with motion, deformity, etc. Osteoarthritis is associated with the loss of the cartilage to lubricate and reduce the wear efficiently. Wear is a process of the removal and deformation of a surface’s material due to mechanical interaction between contacting surfaces in movement, and accordingly, an efficient lubricant is such that inhibits wear by reducing friction forces [Affatato S ., Tribological interactions of modem biomaterials used in total hip arthroplasty (THA), Ed. Saverio Affatato, Perspectives in Total Hip Arthroplasty, Woodhead Publishing, 2014, pages 99-116, ISBN 9781782420316].

[0007] Conventional treatments include analgesics and anti-inflammatory drugs, and surgical operations such as bone fusion (e.g., in ankle arthritis) and joint replacement.

[0008] In early osteoarthritis, no clear cartilage lesions or combined abnormalities are observed which need to be addressed surgically. Several treatments have been proposed and are currently used in clinical practice for patients without clear osteoarthritis signs but ascribable to the phase defined as early osteoarthritis [Luyten et al., Knee Surg Sports Traumatol Arthrosc 2012, 20:401- 406]. Available non-surgical treatments for management of early osteoarthritis include the use of non-pharmacological modalities, such as lifestyle adaptations, exercise, and physical therapy, dietary supplements and pharmacological therapies, such as pain, anti-inflammatory, or slow- acting drugs, as well as the local delivery of various substances through a minimally invasive injective approach [Kon et al., Knee Surg Sports Traumatol Arthrosc 2012, 20:436-449].

[0009] Viscosupplementation involves intra- articular injections of hyaluronic acid (HA), a glycosaminoglycan that provides joint lubrication and shock absorbance, and acts as the backbone for the proteoglycans of the extracellular matrix. In normal adult knees, HA concentration ranges from 2.5 to 4.0 mg / ml, whereas in osteoarthritis, the HA concentration decreases by 33-50 % [Kon et al., Knee Surg Sports Traumatol Arthrosc 2012, 20:436-449]. However, there is no evidence which clearly shows that viscosupplementation influences the natural progression of OA; whereas some reports show serum and urine biomarker changes, others show no changes in cartilage structural composition [Conrozier et al., J Orthop Res 2012, 30:679-685].

[0010] Total joint replacement therapy, abbreviated as TJR, and also known as total joint arthroplasty, is a surgical procedure in which a damaged or diseased joint is replaced with a prosthetic implant. TJR is commonly performed on major weight-bearing joints such as the hip and knee, but other joints such as the shoulder, elbow, and ankle may also be candidates for replacement.

[0011] The most common reason for TJR is osteoarthritis, yet, other conditions may also necessitate total joint replacement, including, for example, inflammatory joint disorders such Rheumatoid Arthritis (RA), severe joint injuries, fractures or other damages as a result of trauma, and other degenerative joint diseases such as avascular necrosis.

[0012] Joint replacement surgery is now a common and highly effective treatment for conditions like osteoarthritis, rheumatoid arthritis, and other degenerative joint diseases. Modern joint replacement procedures are often minimally invasive, resulting in shorter recovery times and improved outcomes. The field continues to evolve with ongoing research, technological innovations, and a focus on optimizing patient outcomes and satisfaction.

[0013] Pin-on-disc (POD) wear tester is a widely useful knee simulator that mimics clinical conditions for total joint replacement (TJR) implants. TJR typically utilizes different biomaterial combinations of ceramic, metallic and / or polymeric substances for forming an artificial joint prosthesis.

[0014] An ultra-high molecular weight polyethylene (UHMWPE) is the most popular bearing polymer for artificial joint prostheses, due to good tribological characteristics, low friction and low wear, and good biocompatibility [Zdero et al., Chapter 19 - Pin-on-Disk Wear Testing of Biomaterials Used for Total Joint Replacements, Ed. R. Zdero, Experimental Methods in Orthopedic Biomechanics, Academic Press, 2017, Pages 299-311, ISBN 9780128038024]. UHMWPE has been utilized in orthopedics for the past 45 years, however, together with UHMWPE, moderately cross-linked UHMWPE (like Marathon and XLK) is presented in the market as a second generation of the orthopedic polymer [S. M. Kurtz, 25 - Compendium of HXLPEs, Eds. Steven M. Kurtz, UHMWPE Biomaterials Handbook (Third Edition), William Andrew Publishing, 2016, Pages 449-466, ISBN 9780323354011].

[0015] Commonly used metal components of TJR include cobalt-chrome (CoCr), titanium alloys, and / or stainless steel. An artificial joint model can thus be assembled from a metal circular plate (disc) and a polymeric cylindrical rod (pin).

[0016] An exemplary pin-on-disc system is presented in Background Art FIG. 1A (taken from Sui- Lai Wong, The effect of lubricant composition on the wear behavior of polyethylene for orthopedic applications, Thesis, University of Manitoba, 2013). A UHMWPE pin and CoCr disc are placed together in an acrylic pool filled with a standard or tested lubricant and covered with an acrylic lid to prevent lubricant evaporation during testing.

[0017] POD measurements are carried out under cyclic interfacial motion for a certain number of cycles and under contact stress applied to the POD, as schematically illustrated in Background Art FIG. IB (taken from Zdero et al., 2017, supra). The wear parameter is determined gravimetrically as the weight loss of the pin during the experiment. After testing, each pin is cleaned, dried in a desiccator to remove the absorbed lubricant during the experiment and weighed [Zdero et al., 2017, supra] .

[0018] Polyethylene-based pins tend to absorb liquid [Brandt et al. Proc. Inst. Meeh. Eng. H. 2011, 225(3), 324-331], which may affect wear measurements. To avoid this effect, PE pins are often subjected to pre-soaking in distilled water at 37 °C for several weeks or months, prior to POD measurements, so as to reach a saturation level of absorption, as it has been understood that fluid absorption models in vivo knee conditions in a better manner and can provide the best reproducibility due to minimizing lubricant uptake and eliminating the results of weight change measurement artifacts [Brandt et al., 2011, supra]. However, other reports describe that the hydration of pins led to increased mass losses and wear rates in comparison to non-soaked pins [Yao et al., Wear, Volume 255, Issues 7-12, 2003, Pages 1113-1120, ISSN 0043-1648].

[0019] In POD wear testing, the use of original synovial fluid (SF) as the wear testing lubricant would be ideal; however, among ethical concerns, large volumes of SF obtained from a single source cannot be obtained due to physiological limitations [Sui-Lai Wong, The effect of lubricant composition on the wear behavior of polyethylene for orthopedic applications, Thesis, University of Manitoba, 2013] . Patient-to-patient variability may also introduce confusing variables into the test. Bovine calf sera (BCS)-based solutions are therefore currently the most widely used lubricants in orthopedic material testing to reproduce the composition and mimic the action of human SF [Chang, Effect of select fluids on the friction of metal-on-polyethylene joint replacement surfaces, Thesis, Massachusetts Institute of Technology, 2005].

[0020] A few parameters dictate the wear value using a POD system. Similar parameters and conditions must be used to make the correct comparison between POD tests.

[0021] In various biological systems, it is known that the wear value steeply increases, reaches a peak at 20 mg / ml of protein, and then slowly decreases [Saikko, ASME. J. Tribol. July 2003, 125(3), Pages 638-642]. Moreover, the wear increases with increasing lipid concentrations if the protein concentration is within the physiological level. Increased interactions between protein and lipid molecules and lipid diffusion to the polyethylene surface might be responsible for the increased wear [Saikko, 2013, supra]. Bacterial contamination of protein-containing lubricant can increase wear due to protein cleavage [Wimmer et al., Wear, Volume 301, Issues 1-2, 2013, Pages 264-270, ISSN 0043-1648],

[0022] WO 2015 / 193888 describes a method of reducing a friction coefficient of a surface by attaching a water-soluble polymer to the surface, and contacting the water-soluble polymer with liposomes, thereby coating the surface with an amphiphilic lipid; as well as a method for treating a synovial joint disorder associated with increased articular friction.

[0023] WO 2015 / 193887 describes formulations for use in rinsing, and / or immersing therein, a contact lens, and / or in the treatment of ocular discomfort (e.g., ocular discomfort associated with a contact lens), the formulations comprising at least one water-soluble polymer, liposomes, and an aqueous carrier.

[0024] WO 2017 / 109784 describes polymeric compounds comprising a lipid moiety and an ionic polymeric moiety, such as a pMPC (poly((9-(2-methacryloyloxyethyl)phosphorylcholine)) moiety, as well as bilayers and liposomes formed of such a polymeric compound in combination with a bilayer-forming lipid. The bilayers and / or liposomes formed of, and comprising, such polymeric compounds are described as being useful for reducing a friction coefficient of a surface and / or for inhibiting biofilm formation.

[0025] WO 2023 / 031928 describes stable sterile compositions comprising an aqueous carrier and liposomes which comprise a bilayer forming material and lipid-polymer conjugates such as described in WO 2017 / 109784, and sterile articles-of-manufacturing formed thereby. The sterile compositions were used as a lubricant in pin-on-disc measurements and were shown to substantially reduce wear.

[0026] WO 2024 / 047647, by the present assignee, describes newly designed polymeric compounds that comprise a lipid moiety (lipid-polymer conjugates), which are usable for forming lipid bilayers and liposomes that exhibit an improved performance. Additional background art includes International Patent Application publications WO 2016 / 051413 and WO 2018 / 150429.

[0027] SUMMARY OF THE INVENTION

[0028] According to an aspect of some embodiments of the present invention there is provided a composition (e.g., a sterile composition) for use in combination with an implantable device, the composition comprising an aqueous carrier and polymeric compound represented by Formula I:

[0029] Formula I wherein: m is zero or a positive integer; n is an integer which is at least 2, at least 5, preferably at least 10 (e.g., of from 10 to 200);

[0030] Y is a backbone unit which forms a polymeric backbone of the polymeric compound;

[0031] L is absent or is a linking moiety; and

[0032] Z has the general Formula II:

[0033] Formula II wherein: the dashed (curved) line denotes an attachment point to the respective Y backbone unit or to the linking moiety L, if present;

[0034] A is a substituted or unsubstituted hydrocarbon;

[0035] B is an oxygen atom or is absent; R1-R3 are each independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, heteroalicyclic, aryl and heteroaryl;

[0036] X is a lipid moiety represented by Formula IV :

[0037] Formula IV wherein: the dashed (curved) line denotes an attachment point to the polymeric backbone;

[0038] Fi, F2, F3 and F4 are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, acyl, alkoxy, thioalkoxy, carboxy, thiocarboxy, wherein at least one of Fi, F2, F3 and F4 is not hydrogen and is of at least 10 carbon atoms in length;

[0039] J is -O-P(=O)(OH)-O- or absent;

[0040] K is a substituted or unsubstituted hydrocarbon from 1 to 10 carbon atoms in length or absent;

[0041] M is a linking group selected from the group consisting of -O-, -S-, amino, sulfinyl, sulfonyl, phosphate, phosphonyl, phosphinyl, carbonyl, thiocarbonyl, urea, thiourea, carbamyl, thiocarbamyl, amido, carboxy, and sulfonamide, or absent; and

[0042] Q is a substituted or unsubstituted hydrocarbon from 1 to 10 carbon atoms in length, or 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 other than amido and / or Q comprises an aryl moiety.

[0043] According to some embodiments of any of the embodiments described herein, the composition is a sterile composition, as described herein.

[0044] According to some embodiments of any of the embodiments described herein, at least one of Fi, F2, F3 and F4 is an alkoxy, thioalkoxy, acyl or carboxy of at least 10 carbon atoms in length.

[0045] According to some embodiments of any of the embodiments described herein, at least one of Fi, F2, F3 and F4 is derived from a fatty acid selected from the group consisting of lauroyl, myristoyl, palmitoyl, stearoyl, palmitoleoyl, oleoyl, and linoleoyl.

[0046] According to some embodiments of any of the embodiments described herein, M is carboxy. According to some embodiments of any of the embodiments described herein, K is an alkyl.

[0047] According to some embodiments of any of the embodiments described herein, J is — P(=O)(OH)-O-; M is amido; and Q is a hydrocarbon substituted by at least one aryl (e.g., phenyl).

[0048] According to some embodiments of any of the embodiments described herein, Q is a methylene substituted by at least one aryl.

[0049] According to some embodiments of any of the embodiments described herein, J is absent.

[0050] According to some embodiments of any of the embodiments described herein, J and K are each absent.

[0051] According to some embodiments of any of the embodiments described herein, J and K are each absent and M is carboxy.

[0052] According to some embodiments of any of the embodiments described herein, at least one, or at least two, of Fi, F2, F3 and F4 is independently the thioalkoxy.

[0053] According to some embodiments of any of the embodiments described herein, at least one, or at least two, of Fi, F2, F3 and F4 is independently the carboxy.

[0054] According to some embodiments of any of the embodiments described herein, at least one or both of Fi and F2 is the carboxy and at least one of F3 and F4 is an alkyl.

[0055] According to some embodiments of any of the embodiments described herein, Q is - C(CH3)2-.

[0056] According to some embodiments of any of the embodiments described herein, Y is a substituted or unsubstituted alkylene unit.

[0057] According to some embodiments of any of the embodiments described herein, Y is a substituted or unsubstituted ethylene unit.

[0058] According to some embodiments of any of the embodiments described herein, B is an oxygen atom.

[0059] According to some embodiments of any of the embodiments described herein, A is a substituted or unsubstituted hydrocarbon from 1 to 4 carbon atoms in length.

[0060] According to some embodiments of any of the embodiments described herein, R1-R3 are each independently hydrogen or Ci-4-alkyl.

[0061] According to some embodiments of any of the embodiments described herein, n ranges from 10 to 200.

[0062] According to some embodiments of any of the embodiments described herein, n is at least 30.

[0063] According to some embodiments of any of the embodiments described herein, n ranges from 30 to 70. According to some embodiments of any of the embodiments described herein, n is at least 50.

[0064] According to some embodiments of any of the embodiments described herein, n ranges from 50 to 150, or from 50 to 80.

[0065] According to some embodiments of any of the embodiments described herein, n is at least 80.

[0066] According to some embodiments of any of the embodiments described herein, n ranges from 80 to 120.

[0067] According to some embodiments of any of the embodiments described herein, m ranges from 0 to 50.

[0068] According to some embodiments of any of the embodiments described herein, at least a portion of the backbone units Y, the L and / or the Z comprise at least one targeting moiety.

[0069] According to some embodiments of any of the embodiments described herein, the composition further comprises at least one bilayer-forming lipid.

[0070] According to some embodiments of any of the embodiments described herein, a mol ratio of the at least one bilayer- forming lipid and the polymeric compound is in a range of from 5:1 to 5,000:1, or from 10:1 to 1,000:1, or 10:1 to 100:1 or from 10:1 to 50:1, or from 100:1 to 500:1.

[0071] According to some embodiments of any of the embodiments described herein, the at least one bilayer-forming lipid comprises at least one zwitterionic glycerophospholipid (e.g., DSPC).

[0072] According to some embodiments of any of the embodiments described herein, the at least one bilayer- forming lipid further comprises a negatively charged bilayer-forming lipid (e.g., DPPG).

[0073] According to some embodiments of any of the embodiments described herein, the polymeric compound and the at least one bilay er- forming lipid form a lipid bilayer, e.g., a liposome.

[0074] According to some embodiments of any of the embodiments described herein, the composition further comprises at least one water-soluble polymer.

[0075] According to some embodiments of any of the embodiments described herein, the composition is used in combination with at least one water-soluble polymer (co-administered to the subject prior to, concomitant with or subsequent to administered the composition).

[0076] According to some embodiments of any of the embodiments described herein, the at least one water-soluble polymer comprises hyaluronic acid. According to some embodiments of any of the embodiments described herein, a weight ratio of the lipid bilayer and the water-soluble polymer ranges from 100:1 to 1:100, or from 50:1 to 1:50, or from 20:1 to 1:20, or from 10:1 to 1:10, or from 5:1 to 1:5, or from 2:1 to 1:2.

[0077] According to some embodiments of any of the embodiments described herein, a concentration of the lipid bilayer ranges from 0.1 to 100 mM by weight of the total weight of the composition.

[0078] According to some embodiments of any of the embodiments described herein, the composition is for reducing wear of the implantable device, upon implantation.

[0079] According to some embodiments of any of the embodiments described herein, the composition is administered to a subject in need thereof prior to, concomitant with or subsequent to implanting the implantable device.

[0080] According to some embodiments of any of the embodiments described herein, the implantable device is a joint replacement implantable device, the composition being for use in a total joint replacement procedure.

[0081] According to some embodiments of any of the embodiments described herein, the implantable device is a prosthetic implant.

[0082] According to some embodiments of any of the embodiments described herein, the implantable device is a solid device or a liquid device (e.g., a curable device, which is hardened upon implantation).

[0083] According to some embodiments of any of the embodiments described herein, the implantable device is made of a polymeric material, a biological material (e.g., a proteinaceous material, an ECM component), a metallic material and / or a ceramic material.

[0084] According to some embodiments of any of the embodiments described herein, the polymeric material is selected from polyethylene (e.g., ultrahigh molecular weight polyethylene), polyurethane, polyurethaneurea, a biodegradable polyester amide, and any other biodegradable polymer, for example, such polymers that exhibit one or more of the mechanical properties as described herein.

[0085] According to some embodiments of any of the embodiments described herein, the biological material comprises an ECM material, for example, collagen.

[0086] According to some embodiments of any of the embodiments described herein, the ceramic material is selected from resorbable and non-resorbable ceramic materials. According to an aspect of some embodiments of the present invention there is provided a pin-on-disk system, comprising the composition as described herein in any of the respective embodiments and any combination thereof.

[0087] According to some embodiments of any of the embodiments described herein, the pin is made of a material as described herein, for example, of a polymeric material, a biological material (e.g., a proteinaceous material, an ECM component), a metallic material and / or a ceramic material.

[0088] According to an aspect of some embodiments of the present invention there is provided a method of determining wear resistance of an implantable device, the method comprising performing wear resistance (e.g., pin-on-disk) measurements using the system as described herein in any of the respective embodiments or using the composition as described herein in any of the respective embodiments and any combination thereof.

[0089] 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 the invention pertains. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of embodiments of the invention, exemplary methods and / or materials are described below. In case of conflict, the patent specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and are not intended to be necessarily limiting.

[0090] Implementation of the method and / or system of embodiments of the invention can involve performing or completing selected tasks manually, automatically, or a combination thereof. Moreover, according to actual instrumentation and equipment of embodiments of the method and / or system of the invention, several selected tasks could be implemented by hardware, by software or by firmware or by a combination thereof using an operating system.

[0091] For example, hardware for performing selected tasks according to embodiments of the invention could be implemented as a chip or a circuit. As software, selected tasks according to embodiments of the invention could be implemented as a plurality of software instructions being executed by a computer using any suitable operating system. In an exemplary embodiment of the invention, one or more tasks according to exemplary embodiments of method and / or system as described herein are performed by a data processor, such as a computing platform for executing a plurality of instructions. Optionally, the data processor includes a volatile memory for storing instructions and / or data and / or a non-volatile storage, for example, a magnetic hard-disk and / or removable media, for storing instructions and / or data. Optionally, a network connection is provided as well. A display and / or a user input device such as a keyboard or mouse are optionally provided as well. BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS

[0092] Some embodiments of the invention are herein described, by way of example only, with reference to the accompanying drawings. With specific reference now to the drawings in detail, it is stressed that the particulars shown are by way of example and for purposes of illustrative discussion of embodiments of the invention. In this regard, the description taken with the drawings makes apparent to those skilled in the art how embodiments of the invention may be practiced.

[0093] In the drawings:

[0094] FIGs. 1 A-B (Background Art) present a photograph of an exemplary pin-on-disk set up, as taken from Sui-Lai Wong, Thesis, 2013 supra) (FIG. 1A) and a schematic illustration of POD measurements carried out under cyclic interfacial motion and under contact stress applied to the POD, as taken from Zdero et al., 2017, supra (FIG. IB).

[0095] FIGs. 2A-B (Background Art) are bar graphs showing the average wear rates, as measured in a POD system as described in Examples 1 and 2, using BCS or AJ after 0.5Mc cycles (FIG. 2A), and during 2.0 Me cycles (FIG. 2B; taken from WO 2023 / 031928).

[0096] FIG. 3 is a bar graph showing the average wear rates, as measured in a POD system as described in Examples 1 and 3, using BCS, or AJ* at various concentrations, after 0.5 Me cycles.

[0097] FIG. 4 is a bar graph showing the average wear rates, as measured in a POD system as described in Examples 1 and 3, using BCS, AJ* 50%, HA 50 % or AJ* 25 % + HA 25 %, during 2.0 Me cycles.

[0098] DESCRIPTION OF SPECIFIC EMBODIMENTS OF THE INVENTION

[0099] The present invention, in some embodiments thereof, relates to therapy, and more particularly, but not exclusively, to methods employing liposomes or bilayer lipids made of a lipid- containing polymeric material, in combination with implantable devices, particularly wearable implantable devices such as prosthetic and / or orthopedic implants, when treating medical conditions that require implantation of such devices and / or when evaluating the wear resistance of materials used for forming implantable devices.

[0100] Before explaining at least one embodiment of the invention in detail, it is to be understood that the invention is not necessarily limited in its application to the details set forth in the following description or exemplified by the Examples. The invention is capable of other embodiments or of being practiced or carried out in various ways.

[0101] Before explaining at least one embodiment of the invention in detail, it is to be understood that the invention is not necessarily limited in its application to the details of construction and the arrangement of the components and / or methods set forth in the following description and / or illustrated in the drawings and / or the Examples. The invention is capable of other embodiments or of being practiced or carried out in various ways.

[0102] As described in the Background section hereinabove, WO 2017 / 109784 describes the design and preparation of polymeric compounds which bear phosphocholine analogs as pendant groups and are conjugated to a lipid moiety, which are capable of stabilizing lipid layers such as those of liposomes, while exhibiting considerably enhanced stability and effective lubrication between sliding surfaces, particularly in a saline environment (e.g., a physiological environment) and / or at high pressures.

[0103] As further described hereinabove, WO 2023 / 031928 describes stable sterile compositions comprising an aqueous carrier and liposomes which comprise a bilayer forming material and lipidpolymer conjugates such as described in WO 2017 / 109784, and sterile articles of manufacturing comprising same or formed thereby. WO 2023 / 031928 describes that these sterile compositions, when used as lubricants in pin-on-disc measurements, were shown to substantially reduce the wear.

[0104] The present inventors have now designed additional polymeric compounds that comprise a lipid moiety (lipid-polymer conjugates), and which are usable for forming lipid bilayers and liposomes, and have shown that the performance of the formed lipid bilayers and liposomes is improved. See, PCT / IL2023 / 050927, published as WO 2024 / 047647.

[0105] While further exploring the performance exhibited by lipid bilayers and liposomes formed of the newly designed lipid-polymer conjugates described in WO 2024 / 047647, the present inventors have uncovered that compositions (e.g., aqueous solutions) containing such lipid bilayers and liposomes, even at very low concentrations, substantially reduce the wear of materials used for forming implantable devices such as joint replacement implants, when tested for their wear resistance in pin-on-disk measurements. See, for example, FIGs. 3 and 4, which show an improved wear resistance in the presence of these compositions compared to compositions described in WO 2023 / 031928 (see, FIGs. 2A-B). This improved performance renders these compositions highly suitable for both, inclusion when practicing POD tests, and, importantly, use in combination with implantable medical devices, particularly joint replacement devices, in treating conditions that require implantation.

[0106] Embodiments of the present invention therefore relate to employing compositions that comprise the newly designed lipid-polymer conjugates described in WO 2024 / 047647, and optionally a bilayer-forming lipid, in combination with an implantable device, for reducing wear of the implantable device upon implantation, and hence for improved treatment of conditions that require implantation, such as osteoarthritis and other synovial joint disorders. Embodiments of the present invention further relate to the use of these compositions in pin-on-disk systems used for assessing the wear resistance of materials used for forming implantable devices. Polymeric Compounds:

[0107] The newly designed polymeric compounds according to the present embodiments bear phosphocholine analogs as pendant groups and are conjugated to a lipid (e.g., phospholipid) moiety. Exemplary such polymeric compounds are represented by Formula I. These polymeric compounds are also referred to herein as “lipid-containing polymeric compounds” or simply as “polymeric compounds”, or as “lipid-polymer conjugates” or by the abbreviation “LPCs”.

[0108] According to some embodiments of any of the embodiments of the invention, the polymeric compounds are collectively represented by Formula I:

[0109] Formula I wherein: m is zero or a positive integer; n is an integer which is at least 2, at least 5, preferably at least 10 (e.g., of from 10 to 200);

[0110] Y is a backbone unit which forms a polymeric backbone of the polymeric compound; X is a lipid moiety as described herein in any of the respective embodiments;

[0111] E is absent or is a linking moiety; and

[0112] Z has the general Formula II:

[0113] Formula II wherein: the dashed (curved) line denotes an attachment point to the respective Y backbone unit or to the linking moiety L, if present;

[0114] A is a substituted or unsubstituted hydrocarbon;

[0115] B is an oxygen atom or is absent; and

[0116] R1-R3 are each independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, heteroalicyclic, aryl and heteroaryl, as described in more detail herein below.

[0117] Formula I may also be described herein simply as:

[0118] X-[Y(-L-Z)]n[Y]m- which is to be regarded as interchangeable with the schematic depiction hereinabove, wherein X is a lipid moiety conjugated to the -[Y(-L-Z)]n[Y]m- polymeric moiety.

[0119] Polymeric moiety:

[0120] Herein, the term "polymeric" refers to a compound having at least 2 repeating units (and more preferably at least 3 repeating units), the repeating units being identical or similar. It is to be appreciated that the compound of general Formula I is by definition polymeric when n is at least 2, as it comprises at least 2 of the backbone units represented by Y.

[0121] Herein, the phrase "polymeric moiety" refers to the portion of the polymeric compound (according to any of the embodiments described herein relating to general Formula I) which has the general Formula la:

[0122] Formula la wherein m, n, Y, L and Z are as defined herein for general Formula I, and the dashed (curved) line represents an attachment point to the X lipid moiety.

[0123] Formula la may also be described herein simply as:

[0124] -[Y(-L-Z)]n[Y]m- which is to be regarded as interchangeable with the schematic depiction hereinabove. Herein, the phrase "polymeric compound" further encompasses compounds having a "polymeric moiety" as described herein having at least one unit (e.g., according to Formula la wherein n is at least 1), provided that the lipid moiety described herein (e.g., the lipid moiety represented by X) has a similar unit. For example, when the lipid moiety comprises 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 may be regarded as repeating units.

[0125] In preferred embodiments, however, n is at least 2, such that the polymeric moiety per se has at least two units. In some embodiments, n is at least 3.

[0126] As used herein, the term "backbone unit" refers to a repeating unit, wherein linkage of a plurality of the repeating unit (e.g., sequential linkage) forms a polymeric backbone. A plurality of linked repeating units per se is also referred to herein as a "polymeric backbone". A polymeric moiety as described herein can comprise a plurality of repeating backbone units which identical to one another, and thereby form a homopolymeric moiety, or, alternatively, can comprise two or more types of repeating backbone units, which can be linked to one another randomly or in a certain order (e.g., as two or more blocks, or in alternating order), and thereby form a copolymer moiety.

[0127] As shown in Formulae I and la, L and Z together form a pendant group of at least a portion of the backbone units, which group is referred to herein for brevity simply as the "pendant group".

[0128] Each backbone unit Y with a pendant group (i.e., a unit represented by Y (-L-Z), the number of which is represented by the variable n) and each backbone unit Y without a pendant group (the number of which is represented by the variable m) is also referred to herein as a "monomeric unit".

[0129] A backbone unit may optionally be a unit of a polymerizable monomer or polymerizable moiety of a monomer. A wide variety of polymerizable monomers and moieties will be known to the skilled person, and the structure of the units of such monomers which result upon polymerization (e.g., monomeric units) will also be known to the skilled person.

[0130] A "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.

[0131] A portion of a polymerizable monomer may be formed, for example, by a condensation reaction, e.g., wherein at least one atom or group (e.g., a hydrogen atom or hydroxyl group) in the monomer, and optionally at least two atoms or groups (e.g., a hydrogen atom and a hydroxyl group) in the monomer, is replaced with a covalent bond with another polymerizable monomer.

[0132] A modified form of a polymerizable monomer may be formed, for example, by ringopening (wherein a covalent bond between two atoms in a ring is broken, and each of the two atoms optionally becomes linked to another polymerizable monomer); and / or by adding to an unsaturated bond, wherein an unsaturated bond between two adjacent atoms is broken (e.g., conversion of an unsaturated double bond to a saturated bond, or conversion of an unsaturated triple bond to an unsaturated double bond) and the two atoms optionally each become linked to another polymerizable monomer.

[0133] A modified form of a polymerizable monomer may consist essentially of the same atoms as the original monomer, for example, different merely in the rearrangement of covalent bonds, or alternatively, may have a different atomic composition, for example, wherein polymerization includes a condensation reaction (e.g., as described herein).

[0134] Examples of backbone units include, without limitation, substituted or unsubstituted hydrocarbons (which may form a substituted or unsubstituted hydrocarbon backbone), such as alkylene units; hydroxycarboxylic acid units (which may form a polyester backbone), e.g., glycolate, lactate, hydroxybutyrate, hydroxyvalerate, hydroxycaproate and hydroxybenzoate units; dicarboxylic acid units (which may form a polyester backbone in combination with a diol and / or a polyamide in combination with a diamine), e.g., adipate, succinate, terephthalate and naphthalene dicarboxylic acid units; diol units (which may form a polyether backbone, or form a polyester backbone in combination with a dicarboxylic acid), e.g., ethylene glycol, 1,2- propanediol, 1,3 -propanediol, 1,4-butanediol, and bisphenol A units; diamine units (which may form a polyamide backbone in combination with a dicarboxylic acid), e.g., para-phenylene diamine and alkylene diamines such hexylene diamine; carbamate units (which may form a polyurethane backbone); amino acid residues (which may form a polypeptide backbone); and saccharide moieties (which may form a polysaccharide backbone).

[0135] In some embodiments of any of the embodiments described herein, Y is a substituted or unsubstituted alkylene unit.

[0136] In some embodiments, Y is a substituted or unsubstituted ethylene unit, that is, an alkylene unit 2 atoms in length.

[0137] Polymeric backbones wherein Y is a substituted or unsubstituted ethylene unit may optionally be a polymeric backbone such as formed by polymerizing ethylene (CH2=CH2) and / or substituted derivatives thereof (also referred to herein as "vinyl monomers"). Such polymerization is a very well-studied procedure, and one of ordinary skill in the art will be aware of numerous techniques for effecting such polymerization.

[0138] It is to be understood that any embodiments described herein relating to a polymeric backbone formed by a polymerization encompass any polymeric backbone having a structure which can be formed by such polymerization, regardless of whether the polymeric backbone was formed in practice by such polymerization (or any other type of polymerization). As is well known in the art, the unsaturated bond of ethylene and substituted ethylene derivatives becomes saturated upon polymerization, such that the backbone units in a polymeric backbone formed by the polymerization are saturated, although they may be referred to as units of an unsaturated compound (e.g., a "vinyl monomer" or “olefin monomer”) to which they are analogous.

[0139] Polymers which can be formed from unsaturated monomers such as vinyl monomers and olefin monomers are also referred to by the terms "polyvinyl" and "polyolefin", respectively.

[0140] Herein, an "unsubstituted" alkylene unit (e.g., ethylene unit) refers to an alkylene unit which does not have any substituent other than the pendant group discussed herein (represented as (-L-Z)). That is, an alkylene unit attached to the aforementioned pendant group is considered unsubstituted if there are no substituents at any other positions on the alkylene unit.

[0141] In some embodiments of any of the embodiments described herein, Y has the formula - CR4R5-CR6D-.

[0142] When Y is a backbone unit which is not attached to L or Z (i.e., to a pendant group as described herein), D is R7 (an end group, as defined herein); and when Y is a backbone unit which is attached to L or Z, D is a covalent bond or a linking group attaching Y to L or Z. The linking group may optionally be -O-, -S-, arylene, sulfinyl, sulfonyl, phosphate, phosphonyl, phosphinyl, carbonyl, thiocarbonyl, urea, thiourea, O-carbamyl, N-carbamyl, O-thiocarbamyl, N- thiocarbamyl, C-amido, N-amido, C-carboxy, O-carboxy, sulfonamido, or amino.

[0143] R4-R7 are each independently hydrogen, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heteroalicyclic, halo, hydroxy, alkoxy, aryloxy, thiohydroxy, thioalkoxy, thioaryloxy, sulfinyl, sulfonyl, cyano, nitro, azide, azo, phosphate phosphonyl, phosphinyl, oxo, carbonyl, thiocarbonyl, urea, thiourea, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, C- carboxy, O-carboxy, sulfonamido, or amino.

[0144] Herein throughout, the phrase “linking group” describes a group (e.g., a substituent) that is attached to two or more moieties in the compound.

[0145] Herein throughput, the phrase “end group” describes a group (e.g., a substituent) that is attached to a single moiety in the compound via one atom thereof.

[0146] When each of R4-R6 is hydrogen, and D is a covalent bond or linking group, Y is an unsubstituted ethylene group attached (via D) to a pendant group described herein.

[0147] When each of R4-R7 is hydrogen (and D is R7), Y is an unsubstituted ethylene group which is not attached to a pendant group described herein.

[0148] In some embodiments of any of the embodiments described herein, R4 and R5 are each hydrogen. Such embodiments include polymeric backbones formed from many widely used vinyl monomers (including ethylene), including, for example, olefins (e.g., ethylene, propylene, 1- butylene, isobutylene, 4-methyl-l -pentene), vinyl chloride, styrene, vinyl acetate, acrylonitrile, acrylate and derivatives thereof (e.g., acrylate esters, acrylamides), and methacrylate and derivatives thereof (e.g., methacrylate esters, methacrylamides).

[0149] In some embodiments of any of the embodiments described herein, Re is hydrogen. In some such embodiments, R4 and R5 are each hydrogen.

[0150] In some embodiments of any of the embodiments described herein, Re 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 a derivative thereof (e.g., methacrylate ester, methacrylamide).

[0151] 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 exemplary embodiments, D is -C(=O)O-.

[0152] For example, the backbone unit may optionally be a vinyl alcohol derivative (e.g., an ester or ether of a vinyl alcohol unit) when D is -O-; an acrylate or methacrylate derivative (e.g., an ester of an acrylate or methacrylate unit) when D is -C(=O)O-; an acrylamide or methacrylamide unit when D is -C(=O)NH-; and / or a styrene derivative (e.g., a substituted styrene unit) when D is phenylene.

[0153] In some embodiments of any of the embodiments described herein, L is a substituted or unsubstituted hydrocarbon from 1 to 10 carbon atoms in length. In some embodiments, the hydrocarbon is unsubstituted. In some embodiments, the hydrocarbon is a linear, unsubstituted hydrocarbon, that is, -(CH2 - wherein i is an integer from 1 to 10.

[0154] 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-).

[0155] In some embodiments of any of the embodiments described herein, B is an oxygen atom. In some such embodiments, L is a hydrocarbon according to any of the respective embodiments described herein (i.e., L is not absent), and Z is a phosphate group attached to L.

[0156] In some embodiments of any of the embodiments described herein, B is absent. In some such embodiments, L is a hydrocarbon according to any of the respective 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 attached directly to Y.

[0157] In some embodiments of any of the embodiments described herein, A is a substituted or unsubstituted hydrocarbon from 1 to 4 carbon atoms in length. In some embodiments of any of the embodiments described herein, A is an unsubstituted hydrocarbon. In some such embodiments, the unsubstituted hydrocarbon is from 1 to 4 carbon atoms in length. In some embodiments, the hydrocarbon is a linear, unsubstituted hydrocarbon, that is, -(CH2)j- wherein j is an integer from 1 to 4.

[0158] In some embodiments of any of the embodiments described herein, A is a substituted or unsubstituted ethylene group.

[0159] In some embodiments of any of the embodiments described herein, A is an unsubstituted ethylene group (-CH2CH2-). In such embodiments, the moiety having general Formula II (represented by the variable Z) is similar or identical to a phosphoethanolamine or phosphocholine moiety. Phosphoethanolamine and phosphocholine moieties are present in many naturally occurring compounds (e.g., phosphatidylcholines, phosphatidylethanolamines).

[0160] In some embodiments of any of the embodiments described herein, A is an ethylene group substituted by a C-carboxy group. In some embodiments, the C-carboxy is attached to the carbon atom adjacent to the nitrogen atom depicted in Formula II (rather than the carbon atom attached to the depicted oxygen atom). In such embodiments, the moiety having general Formula II (represented by the variable Z) is similar or identical to a phosphoserine moiety. Phosphoserine is present in many naturally occurring compounds (e.g., phosphatidylserines).

[0161] 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.

[0162] In some embodiments of any of the embodiments described herein, R1-R3 (the substituents of the nitrogen atom depicted in general Formula II) are each independently hydrogen or C1-4- 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.

[0163] The variable n may be regarded as representing a number of backbone units (represented by the variable Y) which are substituted by the pendant group represented by (-L-Z), and the variable m may be regarded as representing a number of backbone units which are not substituted by such a pendant group. The sum n+m may be regarded as representing the total number of backbone units in the polymeric backbone. The ratio n / (n+m) may be regarded as representing the fraction of backbone units which are substituted by the pendant group represented by (-L-Z). In some embodiments of any of the embodiments described herein, the percentage of backbone units (represented by the variable Y) which are substituted by the pendant group represented by (- L-Z) (as represented by the formula 100%*n / (n+m)) is at least 20 %. In some embodiments, the percentage of backbone units substituted by the aforementioned pendant group is at least 30 %. In some embodiments, the percentage of backbone units substituted by the aforementioned pendant group is at least 40 %. In some embodiments, the percentage of backbone units substituted by the aforementioned pendant group is at least 50 %. In some embodiments, the percentage of backbone units substituted by the aforementioned pendant group is at least 60 %. In some embodiments, the percentage of backbone units substituted by the aforementioned pendant group is at least 70 %. In some embodiments, the percentage of backbone units substituted by the aforementioned pendant group is at least 80 %. In some embodiments, the percentage of backbone units substituted by the aforementioned pendant group is at least 90 %. In some embodiments, the percentage of backbone units substituted by the aforementioned pendant group is at least 95 %. In some embodiments, the percentage of backbone units substituted by the aforementioned pendant group is at least 98 %.

[0164] In some embodiments of any of the embodiments described herein, m is 0, such that each of the backbone units (represented by the variable Y) is substituted by the pendant group represented by (-L-Z).

[0165] 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.

[0166] In some embodiments of any of the embodiments described herein, n is in a range of from

[0167] 2 to 1,000, including any intermediate value and subranges therebetween. In some embodiments of any of the embodiments described herein, n is in a range of from 2 to 500, including any intermediate value and subranges therebetween. In some embodiments of any of the embodiments described herein, n is in a range of from 2 to 200, including any intermediate value and subranges therebetween. In some embodiments of any of the embodiments described herein, n is in a range of from 2 to 100, including any intermediate value and subranges therebetween. In some embodiments of any of the embodiments described herein, n is in a range of from 2 to 50, including any intermediate value and subranges therebetween. In some such embodiments, m is 0.

[0168] In some embodiments of any of the embodiments described herein, n is in a range of from

[0169] 3 to 1,000, including any intermediate value and subranges therebetween. In some embodiments of any of the embodiments described herein, n is in a range of from 3 to 500, including any intermediate value and subranges therebetween. In some embodiments of any of the embodiments described herein, n is in a range of from 3 to 200, including any intermediate value and subranges therebetween. In some embodiments of any of the embodiments described herein, n is in a range of from 3 to 100, including any intermediate value and subranges therebetween. In some embodiments of any of the embodiments described herein, n is in a range of from 3 to 50, including any intermediate value and subranges therebetween. In some embodiments of any of the embodiments described herein, n is in a range of from 5 to 50, including any intermediate value and subranges therebetween. In some embodiments of any of the embodiments described herein, n is in a range of from 10 to 50, including any intermediate value and subranges therebetween. In some embodiments of any of the embodiments described herein, n is in a range of from 10 to 25, including any intermediate value and subranges therebetween. In some such embodiments, m is 0.

[0170] In some embodiments of any of the embodiments described herein, n is in a range of from 10 to 200, including any intermediate value and subranges therebetween. In some embodiments of any of the embodiments described herein, n is in a range of from 10 to 180, including any intermediate value and subranges therebetween. In some embodiments of any of the embodiments described herein, n is in a range of from 10 to 150, including any intermediate value and subranges therebetween. In some embodiments of any of the embodiments described herein, n is in a range of from 10 to 120, including any intermediate value and subranges therebetween 0. In some such embodiments, m is 0.

[0171] In some embodiments of any of the embodiments described herein, n is at least 30.

[0172] In some embodiments of any of the embodiments described herein, n is in a range of from 30 to 200, including any intermediate value and subranges therebetween. In some embodiments of any of the embodiments described herein, n is in a range of from 30 to 180, including any intermediate value and subranges therebetween. In some embodiments of any of the embodiments described herein, n is in a range of from 30 to 150, including any intermediate value and subranges therebetween. In some embodiments of any of the embodiments described herein, n is in a range of from 30 to 120, including any intermediate value and subranges therebetween 0. In some such embodiments, m is 0.

[0173] In some embodiments of any of the embodiments described herein, n is in a range of from 30 to 70, including any intermediate value and subranges therebetween. In some embodiments of any of the embodiments described herein, n is in a range of from 35 to 65, including any intermediate value and subranges therebetween. In some such embodiments, m is 0.

[0174] In some embodiments of any of the embodiments described herein, n is at least 50, or at least 60, or at least 80.

[0175] In some embodiments of any of the embodiments described herein, n is in a range of from 50 to 200, including any intermediate value and subranges therebetween. In some embodiments of any of the embodiments described herein, n is in a range of from 50 to 180, including any intermediate value and subranges therebetween. In some embodiments of any of the embodiments described herein, n is in a range of from 50 to 150, including any intermediate value and subranges therebetween. In some embodiments of any of the embodiments described herein, n is in a range of from 50 to 120, including any intermediate value and subranges therebetween. In some embodiments of any of the embodiments described herein, n is in a range of from 80 to 120, including any intermediate value and subranges therebetween. In some embodiments of any of the embodiments described herein, n is in a range of from 50 to 100, including any intermediate value and subranges therebetween. In some embodiments of any of the embodiments described herein, n is in a range of from 50 to 80, including any intermediate value and subranges therebetween. In some such embodiments, m is 0.

[0176] In some embodiments of any of the embodiments described herein, when n is lower than 80, or lower than 70, or lower than 50, or lower than 30, or is in a range of from 10 to 50, or from 30 to 60, or from 30 to 80, or from 30 to 70, or from 50 to 80, as described herein in any of the respective embodiments, the polymeric compound is referred to herein as “short” or “S”.

[0177] In some embodiments of any of the embodiments described herein, when n is higher than 80, or is higher than 100, or is in a range of from 50 to 150, or from 50 to 120, or from 80 to 150, or from 80 to 120, as described herein in any of the respective embodiments, the polymeric compound is referred to herein as “long” or “L”.

[0178] In some embodiments of any of the embodiments described herein, n is in a range of from 10 to 50, including any intermediate value and subranges therebetween. In some such embodiments, m is 0.

[0179] In some embodiments of any of the embodiments described herein, n is in a range of from 50 to 80, including any intermediate value and subranges therebetween. In some such embodiments, m is 0.

[0180] In some embodiments of any of the embodiments described herein, n is in a range of from 80 to 120, including any intermediate value and subranges therebetween. In some such embodiments, m is 0.

[0181] In some embodiments of any of the embodiments described herein, m is in a range of from 0 to 1,000, including any intermediate value and subranges therebetween. In some such embodiments, n is in a range of from 2 to 1,000, including any intermediate value and subranges therebetween, such that the total number of backbone units is in a range of from 2 to 2,000, including any intermediate value and subranges therebetween. In some such embodiments, n is in a range of from 3 to 1,000, including any intermediate value and subranges therebetween. In some embodiments, n is in a range of from 3 to 500, including any intermediate value and subranges therebetween. In some embodiments, n is in a range of from 3 to 200, including any intermediate value and subranges therebetween. In some embodiments, n is in a range of from 3 to 100, including any intermediate value and subranges therebetween. In some embodiments, n is in a range of from 3 to 50, including any intermediate value and subranges therebetween. In some embodiments, n is in a range of from 5 to 50, including any intermediate value and subranges therebetween. In some embodiments, n is in a range of from 10 to 50, including any intermediate value and subranges therebetween. In some embodiments, n is in a range of from 50 to 80, including any intermediate value and subranges therebetween. In some embodiments, n is in a range of from 80 to 120, including any intermediate value and subranges therebetween.

[0182] In some embodiments of any of the embodiments described herein, m is in a range of from 0 to 500, including any intermediate value and subranges therebetween. In some such embodiments, n is in a range of from 2 to 1,000, including any intermediate value and subranges therebetween. In some such embodiments, n is in a range of from 3 to 1,000, including any intermediate value and subranges therebetween. In some embodiments, n is in a range of from 3 to 500, including any intermediate value and subranges therebetween. In some embodiments, n is in a range of from 3 to 200, including any intermediate value and subranges therebetween. In some embodiments, n is in a range of from 3 to 100, including any intermediate value and subranges therebetween. In some embodiments, n is in a range of from 3 to 50, including any intermediate value and subranges therebetween. In some embodiments, n is in a range of from 5 to 50, including any intermediate value and subranges therebetween. In some embodiments, n is in a range of from 10 to 50, including any intermediate value and subranges therebetween. In some embodiments, n is in a range of from 50 to 80, including any intermediate value and subranges therebetween. In some embodiments, n is in a range of from 80 to 120, including any intermediate value and subranges therebetween.

[0183] In some embodiments of any of the embodiments described herein, m is in a range of from 0 to 200, including any intermediate value and subranges therebetween. In some such embodiments, n is in a range of from 2 to 1,000, including any intermediate value and subranges therebetween. In some such embodiments, n is in a range of from 3 to 1,000, including any intermediate value and subranges therebetween. In some embodiments, n is in a range of from 3 to 500, including any intermediate value and subranges therebetween. In some embodiments, n is in a range of from 3 to 200, including any intermediate value and subranges therebetween. In some embodiments, n is in a range of from 3 to 100, including any intermediate value and subranges therebetween. In some embodiments, n is in a range of from 3 to 50, including any intermediate value and subranges therebetween. In some embodiments, n is in a range of from 5 to 50, including any intermediate value and subranges therebetween. In some embodiments, n is in a range of from 10 to 50, including any intermediate value and subranges therebetween. In some embodiments, n is in a range of from 50 to 80, including any intermediate value and subranges therebetween. In some embodiments, n is in a range of from 80 to 120, including any intermediate value and subranges therebetween.

[0184] In some embodiments of any of the embodiments described herein, m is in a range of from 0 to 100, including any intermediate value and subranges therebetween. In some such embodiments, n is in a range of from 2 to 1,000, including any intermediate value and subranges therebetween. In some such embodiments, n is in a range of from 3 to 1,000, including any intermediate value and subranges therebetween. In some embodiments, n is in a range of from 3 to 500. In some embodiments, n is in a range of from 3 to 200, including any intermediate value and subranges therebetween. In some embodiments, n is in a range of from 3 to 100, including any intermediate value and subranges therebetween. In some embodiments, n is in a range of from 3 to 50. In some embodiments, n is in a range of from 5 to 50, including any intermediate value and subranges therebetween. In some embodiments, n is in a range of from 10 to 50, including any intermediate value and subranges therebetween. In some embodiments, n is in a range of from 50 to 80, including any intermediate value and subranges therebetween. In some embodiments, n is in a range of from 80 to 120, including any intermediate value and subranges therebetween. In some embodiments of any of the embodiments described herein, m is in a range of from 0 to 50, including any intermediate value and subranges therebetween. In some such embodiments, n is in a range of from 2 to 1,000, including any intermediate value and subranges therebetween. In some such embodiments, n is in a range of from 3 to 1,000, including any intermediate value and subranges therebetween. In some embodiments, n is in a range of from 3 to 500, including any intermediate value and subranges therebetween. In some embodiments, n is in a range of from 3 to 200, including any intermediate value and subranges therebetween. In some embodiments, n is in a range of from 3 to 100, including any intermediate value and subranges therebetween. In some embodiments, n is in a range of from 3 to 50, including any intermediate value and subranges therebetween. In some embodiments, n is in a range of from 5 to 50, including any intermediate value and subranges therebetween. In some embodiments, n is in a range of from 10 to 50, including any intermediate value and subranges therebetween. In some embodiments, n is in a range of from 50 to 80, including any intermediate value and subranges therebetween. In some embodiments, n is in a range of from 80 to 120, including any intermediate value and subranges therebetween.

[0185] In some embodiments of any of the embodiments described herein, m is in a range of from 0 to 20, including any intermediate value and subranges therebetween. In some such embodiments, n is in a range of from 2 to 1,000, including any intermediate value and subranges therebetween. In some such embodiments, n is in a range of from 3 to 1,000, including any intermediate value and subranges therebetween. In some embodiments, n is in a range of from 3 to 500, including any intermediate value and subranges therebetween. In some embodiments, n is in a range of from 3 to 200, including any intermediate value and subranges therebetween. In some embodiments, n is in a range of from 3 to 100, including any intermediate value and subranges therebetween. In some embodiments, n is in a range of from 3 to 50, including any intermediate value and subranges therebetween. In some embodiments, n is in a range of from 5 to 50, including any intermediate value and subranges therebetween. In some embodiments, n is in a range of from 10 to 50, including any intermediate value and subranges therebetween. In some embodiments, n is in a range of from 50 to 80, including any intermediate value and subranges therebetween. In some embodiments, n is in a range of from 80 to 120, including any intermediate value and subranges therebetween.

[0186] In some embodiments of any of the embodiments described herein, m is in a range of from 0 to 10, including any intermediate value and subranges therebetween. In some such embodiments, n is in a range of from 2 to 1,000, including any intermediate value and subranges therebetween. In some such embodiments, n is in a range of from 3 to 1,000, including any intermediate value and subranges therebetween. In some embodiments, n is in a range of from 3 to 500, including any intermediate value and subranges therebetween. In some embodiments, n is in a range of from 3 to 200, including any intermediate value and subranges therebetween. In some embodiments, n is in a range of from 3 to 100, including any intermediate value and subranges therebetween. In some embodiments, n is in a range of from 3 to 50, including any intermediate value and subranges therebetween. In some embodiments, n is in a range of from 5 to 50, including any intermediate value and subranges therebetween. In some embodiments, n is in a range of from 10 to 50, including any intermediate value and subranges therebetween. In some of any of the embodiments described herein for m, n is in a range of from 30 to 70, as described herein in any of the respective embodiments, or represents a short polymeric moiety, as described herein. In some such embodiments, n is in a range of from 50 to 80, including any intermediate value and subranges therebetween.

[0187] In some of any of the embodiments described herein for m, n is in a range of from 80 to 120, as described herein in any of the respective embodiments, or represents a long polymeric moiety, as described herein.

[0188] In some embodiments of any of the embodiments described herein, the backbone unit Y which is substituted by the pendant group represented by (-L-Z) is the same as the backbone unit Y which is not substituted by the pendant group (e.g., when m is at least 1). In alternative embodiments, at least a portion of the backbone units Y which are substituted by the pendant group are different than a portion of the backbone unit Y which is not substituted by the pendant group (e.g., when m is at least 1).

[0189] In some embodiments of any of the embodiments described herein, the plurality (indicated by the variable n) of backbone units Y which are substituted by the pendant group represented by (-L-Z) are the same as each other. In alternative embodiments, at least a portion of the plurality of backbone units Y which are substituted by the pendant group represented by (-L-Z) are different from a second portion of the plurality of backbone units Y which are substituted by the pendant group.

[0190] In some embodiments of any of the embodiments described herein, the plurality (indicated by the variable n) of pendant groups (-L-Z) attached to the plurality of backbone units Y are the same as each other. In alternative embodiments, at least a portion of the pendant groups (-L-Z) attached to the plurality of backbone units Y are different from each other (e.g., differ in the identity of any one or more of A, B, Ri, R2, R3 and L).

[0191] In any of the embodiments described herein wherein more than one backbone unit Y is not substituted by the pendant group described herein (i.e., when m is greater than 1), the plurality (indicated by the variable m) of backbone units Y which are not substituted by the pendant group are the same as each other. In alternative embodiments wherein m is larger than 1 , at least a portion of the backbone units Y which are not substituted by the pendant group described herein, are different from at least a second portion of the plurality of backbone units Y which are not substituted by the pendant group.

[0192] The number of types of backbone units substituted by the pendant group, the number of types of backbone units not substituted by the pendant group (if any such units are present), and / or the number of types of pendant group in the polymeric moiety may each independently be any number (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more).

[0193] In some embodiments of any of the embodiments described herein, the polymeric moiety is a copolymer moiety, that is, the polymeric moiety comprises at least two different types of monomeric unit. In some such embodiments, the different types of monomeric units differ in whether they comprise the pendant group (-L-Z) according to any of the respective embodiments described herein (e.g., when m is at least 1), and / or the different types of monomeric units differ in the type of backbone unit Y, and / or the different types of monomeric units differ in the type of pendant group (-L-Z).

[0194] For example, in some embodiments of any of the embodiments described herein the backbone unit Y in each of the Y(-L-Z) units may optionally be the same or different, while the L and Z moieties are the same among the Y(-L-Z) units. In some such embodiments, backbone units not substituted by the pendant group (if any such units are present) may optionally be the same as backbone unit Y in each of the Y(-L-Z) units. Alternatively, backbone units not substituted by the pendant group (if any such units are present) may optionally be different than backbone unit Y in each of the Y(-L-Z) units (while optionally being the same among all backbone units not substituted by the pendant group).

[0195] In some embodiments of any of the embodiments described herein the L moiety in each of the Y(-L-Z) units may optionally be the same or different, while the backbone units Y and the Z moieties are the same among the Y(-L-Z) units. In some such embodiments, backbone units not substituted by the pendant group (if any such units are present) may optionally be the same as backbone unit Y in each of the Y(-L-Z) units. Alternatively, backbone units not substituted by the pendant group (if any such units are present) may optionally be different than backbone unit Y in each of the Y(-L-Z) units (while optionally being the same among all backbone units not substituted by the pendant group).

[0196] In some embodiments of any of the embodiments described herein the Z moiety in each of the Y(-L-Z) units may optionally be the same or different, while the backbone units Y and the Z moieties are the same among the Y(-L-Z) units. In some such embodiments, backbone units not substituted by the pendant group (if any such units are present) may optionally be the same as backbone unit Y in each of the Y(-L-Z) units. Alternatively, backbone units not substituted by the pendant group (if any such units are present) may optionally be different than backbone unit Y in each of the Y(-L-Z) units (while optionally being the same among all backbone units not substituted by the pendant group).

[0197] In any of the embodiments described herein wherein the polymeric moiety is a copolymer moiety, any two or more different types of monomeric unit may be distributed randomly or non- randomly throughout the polymeric moiety. When different types of monomeric unit are distributed non-randomly, the copolymer may be one characterized by any non-random distribution, for example, an alternating copolymer, a periodic copolymer, and / or a block copolymer.

[0198] In some of any of the embodiments described herein, the polymeric moiety, which is attached at one of its termini to the lipid moiety X, can have various terminal groups at the other terminus (i.e., at the terminus near the backbone unit Y without a pendant group, wherein m is at least 1 ; or at the other terminus near the backbone unit Y with a pendant group, wherein m is zero). The terminal group can be an intrinsic terminal group, derived from the monomers used to form the polymeric compound and / or from the process used to polymerize the monomers, or can be otherwise conjugated to, or generated within, the terminus of the polymeric moiety. For example, the terminal group can be hydrogen, halo, alkyl, hydroxy, carboxy and the like, or can be a targeting moiety, as described in further detail hereinafter. In some of any of the embodiments described herein, the terminal group is hydrogen or halo. In some of any of the embodiments described herein the terminal group is derived from the initiator used to form the polymeric compound as described herein in any of the respective embodiments and exemplified in the Examples section that follows, and in some of these embodiments the terminal group is a halo (e.g., chloro or bromo).

[0199] In some of any of the embodiments described herein, the terminal group is a functional group that is suitable for electron transfer radical polymerization, e.g., variable Ri in Formula V, as described herein in any of the respective embodiments.

[0200] Lipid moiety:

[0201] The lipid moiety (represented by the variable X in Formula I herein) according to any of the embodiments in this section may be attached to a polymeric moiety according to any of the embodiments described in the section herein relating to the polymeric moiety.

[0202] The lipid moiety may optionally be derived from any lipid known in the art (including, but not limited to, a naturally occurring lipid). Derivation of the lipid moiety from the lipid may optionally consist of substituting a hydrogen atom at any position of the lipid with the polymeric moiety represented in general Formula I by [Y(-E-Z)]n[Y]m (i.e., the polymeric moiety represented by general Formula la).

[0203] In some embodiments of any of the embodiments described herein, the lipid moiety (according to any of the respective embodiments described herein) is attached to a Y(-E-Z) unit (according to any of the embodiments described herein relating to Y, E and / or Z), that is, backbone unit substituted by the pendant group described herein (e.g., rather than a backbone unit not substituted by the pendant group).

[0204] Alternatively or additionally, in some embodiments of any of the embodiments described herein wherein m is at least 1, the lipid moiety (according to any of the respective embodiments described herein) may optionally be attached to a backbone unit (Y) which is not substituted by a pendant group described herein (e.g., rather than attached to a backbone unit substituted by the pendant group). For example, the polymeric moiety may optionally be a copolymer wherein the identity of the backbone unit attached to the lipid moiety varies randomly between molecules. Thus, the depiction of X in Formula I as being attached to a backbone unit substituted by a pendant group (i.e., Y-(L-Z)) rather than to an unsubstituted backbone unit Y is arbitrary, and is not intended to be limiting. In some embodiments of any of the embodiments described herein, the lipid moiety is a moiety of a lipid which is a fatty acid, a monoglyceride, a diglyceride, a triglyceride, a glycerophospholipid, a sphingolipid, or a sterol. In some embodiments, the lipid is a glyceropho spholipid .

[0205] In some embodiments of any of the embodiments described herein, the lipid moiety comprises 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 comprising one fatty acid moiety, a diglyceride moiety comprising two fatty acid moieties, or a triglyceride moiety comprising three fatty acid moieties.

[0206] Examples of fatty acid moieties which may optionally be comprised by the lipid moiety include, without limitation, lauroyl, myristoyl, palmitoyl, stearoyl, palmitoleoyl, oleoyl, and linoleoyl.

[0207] Suitable examples of glycerophospholipids include, without limitation, a phosphatidyl ethanolamine, a phosphatidyl serine, a phosphatidyl glycerol and a phosphatidyl inositol.

[0208] In some embodiments of any of the embodiments described herein, the lipid moiety represented by the variable X has the general Formula I is represented by Formula IV :

[0209] Formula IV wherein: the dashed (curved) line denotes an attachment point to the polymeric backbone (i.e., via the respective Y backbone unit);

[0210] Fi, F2, F3 and F4 are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, acyl, alkoxy, thioalkoxy, carboxy, thiocarboxy, wherein at least one of Fi, F2, F3 and F4 is not hydrogen and is of at least 10 carbon atoms in length;

[0211] J is -O-P(=O)(OH)-O- or absent;

[0212] K is a substituted or unsubstituted hydrocarbon from 1 to 10 carbon atoms in length or absent; M is a linking group selected from the group consisting of -O-, -S-, amino, sulfinyl, sulfonyl, phosphate, phosphonyl, phosphinyl, carbonyl, thiocarbonyl, urea, thiourea, carbamyl, thiocarbamyl, amido, carboxy, and sulfonamide, or absent; and

[0213] Q is a substituted or unsubstituted hydrocarbon from 1 to 10 carbon atoms in length, or absent, wherein when M is absent, Q is also absent.

[0214] Q is attached to a backbone unit of the polymeric backbone according to any of the respective embodiments described herein, or alternatively, when Q is absent, M is attached to the aforementioned backbone unit.

[0215] When M is absent, Q is also absent, and K is attached to a backbone unit of the polymeric backbone according to any of the respective embodiments described herein.

[0216] In some embodiments of any of the embodiments described herein for Formula IV, when J is absent, M is not absent.

[0217] In some embodiments of any of the embodiments described herein for Formula IV, when J is -O-P(=O)(OH)-O-, M is other than amido and / or Q comprises an aryl moiety.

[0218] In some embodiments of any of the embodiments described herein for Formula IV, at least one of Fi, F2, F3 and F4 is an alkoxy, thioalkoxy, acyl or carboxy, preferably of at least 10 carbon atoms in length, for example, of from 8 to 40, or of from 10 to 40, or of from 10 to 30, carbon atoms in length.

[0219] In some such embodiments, the alkoxy, thioalkoxy, acyl and / or carboxy has an alkyl moiety that is derived from a fatty acid acyl, as described herein, and is, for example, lauroyl, myristoyl, palmitoyl, stearoyl, palmitoleoyl, oleoyl, and linoleoyl.

[0220] In some embodiments of any of the embodiments described herein for Formula IV, at least one, or at least two, of Fi, F2, F3 and F4 is independently a thioalkoxy. In some of these embodiments, the thioalkoxy is of at least 10 carbon atoms in length, for example, of from 8 to 40, or of from 10 to 40, or of from 10 to 30, carbon atoms in length. In exemplary embodiments, the alkyl is 15 carbon atoms in length and is derived from palmitic acid. In some of these embodiments, the thioalkoxy has an alkyl group that is of lauric acid, myristic acid, palmitic acid, stearic acid, oleic acid or linoleic acid. In some of these embodiments, each of Fi and F2 is independently a thioalkoxy as described herein, and can be the same or different, preferably the same. In some of these embodiments, F3 and F4 are each hydrogen.

[0221] In some embodiments of any of the embodiments described herein, at least one, or at least two, of Fi, F2, F3 and F4 is independently a carboxy. In some of these embodiments, the carboxy is of at least 10 carbon atoms in length, for example, of from 8 to 40, or of from 10 to 40, or of from 10 to 30, carbon atoms in length. In exemplary embodiments, the carboxy is 16 carbon atoms in length and is derived from palmitic acid. In some of these embodiments, the carboxy has an alkyl group that is of lauric acid, myristic acid, palmitic acid, stearic acid, oleic acid or linoleic acid. In some of these embodiments, at least one or both of Fi and F2 is a carboxy as described herein in any of the respective embodiments. In some of these embodiments, both of Fi and F2 is a carboxy as described herein in any of the respective embodiments, which can be the same or different and is preferably the same. In some of any of these embodiments, at least one of F3 and F4 is an alkyl, which can be the same or different. In some such embodiments, the alkyl is a short alkyl of 1 to 6, or 1 to 4 carbon atoms in length, for example, methyl. Alternatively, each of F3 and F4 is hydrogen.

[0222] According to some of any of the embodiments described herein, M is other than amido.

[0223] According to some of any of the embodiments described herein, M is carboxy.

[0224] According to some of any of the embodiments described herein, M is carboxy and at least one, or at least two, of Fi, F2, F3 and F4 is independently a thioalkoxy. In some of these embodiments, the thioalkoxy is of at least 10 carbon atoms in length, for example, of from 8 to 40, or of from 10 to 40, or of from 10 to 30, carbon atoms in length. In exemplary embodiments, the alkyl is 15 carbon atoms in length and is derived from palmitic acid. In some of these embodiments, the thioalkoxy has an alkyl group that is of lauric acid, myristic acid, palmitic acid, stearic acid, oleic acid or linoleic acid. In some of these embodiments, each of Fi and F2 is independently a thioalkoxy as described herein, and can be the same or different, preferably the same. In some of these embodiments, F3 and F4 are each hydrogen.

[0225] According to some of any of the embodiments described herein, M is carboxy and at least one, or at least two, of Fi, F2, F3 and F4 is independently a carboxy. In some of these embodiments, the carboxy is of at least 10 carbon atoms in length, for example, of from 8 to 40, or of from 10 to 40, or of from 10 to 30, carbon atoms in length. In exemplary embodiments, the carboxy is 16 carbon atoms in length and is derived from palmitic acid. In some of these embodiments, the carboxy has an alkyl group that is of lauric acid, myristic acid, palmitic acid, stearic acid, oleic acid or linoleic acid. In some of these embodiments, at least one or both of Fi and F2 is a carboxy as described herein in any of the respective embodiments. In some of these embodiments, both of Fi and F2 is a carboxy as described herein in any of the respective embodiments, which can be the same or different and is preferably the same. In some of any of these embodiments, at least one of F3 and F4 is an alkyl, which can be the same or different. In some such embodiments, the alkyl is a short alkyl of 1 to 6, or 1 to 4 carbon atoms in length, for example, methyl. Alternatively, each of F3 and F4 is hydrogen. According to some of any of the embodiments described herein, J is absent.

[0226] According to some of any of the embodiments described herein, J is absent and M is other than amido.

[0227] According to some of any of the embodiments described herein, J is absent and M is carboxy.

[0228] According to some of any of the embodiments described herein, J is absent, and at least one, or at least two, of Fi, F2, F3 and F4 is independently a thioalkoxy. In some of these embodiments, the thioalkoxy is of at least 10 carbon atoms in length, for example, of from 8 to 40, or of from 10 to 40, or of from 10 to 30, carbon atoms in length. In exemplary embodiments, the alkyl is 15 carbon atoms in length and is derived from palmitic acid. In some of these embodiments, the thioalkoxy has an alkyl group that is of lauric acid, myristic acid, palmitic acid, stearic acid, oleic acid or linoleic acid. In some of these embodiments, each of Fi and F2 is independently a thioalkoxy as described herein, and can be the same or different, preferably the same. In some of these embodiments, F3 and F4 are each hydrogen.

[0229] According to some of any of the embodiments described herein, J is absent, M is carboxy, and at least one, or at least two, of Fi, F2, F3 and F4 is independently a thioalkoxy. In some of these embodiments, the thioalkoxy is of at least 10 carbon atoms in length, for example, of from 8 to 40, or of from 10 to 40, or of from 10 to 30, carbon atoms in length. In exemplary embodiments, the alkyl is 15 carbon atoms in length and is derived from palmitic acid. In some of these embodiments, the thioalkoxy has an alkyl group that is of lauric acid, myristic acid, palmitic acid, stearic acid, oleic acid or linoleic acid. In some of these embodiments, each of Fi and F2 is independently a thioalkoxy as described herein, and can be the same or different, preferably the same. In some of these embodiments, F3 and F4 are each hydrogen.

[0230] According to some of any of the embodiments described herein, J is absent, and at least one, or at least two, of Fi, F2, F3 and F4 is independently a carboxy. In some of these embodiments, the carboxy is of at least 10 carbon atoms in length, for example, of from 8 to 40, or of from 10 to 40, or of from 10 to 30, carbon atoms in length. In exemplary embodiments, the carboxy is 16 carbon atoms in length and is derived from palmitic acid. In some of these embodiments, the carboxy has an alkyl group that is of lauric acid, myristic acid, palmitic acid, stearic acid, oleic acid or linoleic acid. In some of these embodiments, at least one or both of Fi and F2 is a carboxy as described herein in any of the respective embodiments. In some of these embodiments, both of Fi and F2 is a carboxy as described herein in any of the respective embodiments, which can be the same or different and is preferably the same. In some of any of these embodiments, at least one of F3 and F4 is an alkyl, which can be the same or different. In some such embodiments, the alkyl is a short alkyl of 1 to 6, or 1 to 4 carbon atoms in length, for example, methyl. Alternatively, each of F3 and F4 is hydrogen.

[0231] According to some of any of the embodiments described herein, J is absent, M is carboxy, and at least one, or at least two, of Fi, F2, F3 and F4 is independently a carboxy. In some of these embodiments, the carboxy is of at least 10 carbon atoms in length, for example, of from 8 to 40, or of from 10 to 40, or of from 10 to 30, carbon atoms in length. In exemplary embodiments, the carboxy is 16 carbon atoms in length and is derived from palmitic acid. In some of these embodiments, the carboxy has an alkyl group that is of lauric acid, myristic acid, palmitic acid, stearic acid, oleic acid or linoleic acid. In some of these embodiments, at least one or both of Fi and F2 is a carboxy as described herein in any of the respective embodiments. In some of these embodiments, both of Fi and F2 is a carboxy as described herein in any of the respective embodiments, which can be the same or different and is preferably the same. In some of any of these embodiments, at least one of F3 and F4 is an alkyl, which can be the same or different. In some such embodiments, the alkyl is a short alkyl of 1 to 6, or 1 to 4 carbon atoms in length, for example, methyl. Alternatively, each of F3 and F4 is hydrogen.

[0232] According to some of any of the embodiments described herein for Formula IV when J is absent, Q is -C(CH3)2-.

[0233] According to some of any of the embodiments described herein for Formula IV when J is absent and M is carboxy, Q is -C(CH3)2-.

[0234] Herein, 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 depicted in Formula IV, in cases when J is not absent, or the number of atoms separating M and the lipid skeleton formed of Fi, F2, F3 and F4.

[0235] When K is a substituted hydrocarbon, M may be attached to a carbon atom of the hydrocarbon per se, or be attached to a substituent of the hydrocarbon.

[0236] In some embodiments, K is an all-carbon hydrocarbon.

[0237] In some embodiments, K is an unsubstituted hydrocarbon.

[0238] In some embodiments, K is an unsubstituted all-carbon hydrocarbon.

[0239] In some of any of these embodiments, K is an alkyl (an alkylene chain or linking group), preferably unsubstituted, and optionally being a short alkyl or alkylene of 1 to 6, or 1 to 4, or 1 to 2, carbon atoms in length.

[0240] According to some of any of the embodiments described herein, K is absent. According to some of any of the embodiments described herein, J is absent, as described herein in any of the respective embodiments, and K is absent. In some of these embodiments, M is carboxy.

[0241] According to some of any of the embodiments described herein, Q is a hydrocarbon substituted by at least one aryl (e.g., phenyl).

[0242] In some of these embodiments, Q is a hydrocarbon which is an all-carbon hydrocarbon, and is some of these embodiments the hydrocarbon is alkyl (an alkylene linking group), preferably a short alkyl (or alkylene) of from 1 to 6, or from 1 to 4, preferably 1 or 2, carbon atoms in length, substituted by at least one aryl (e.g., phenyl).

[0243] According to some of any of the embodiments described herein, Q is a methylene substituted by at least one aryl (e.g., phenyl).

[0244] According to some of any of the embodiments described herein, J is -P(=O)(OH)-O-; M is amido; and Q is a hydrocarbon substituted by at least one aryl (e.g., phenyl), as described herein in any of the respective embodiments and any combination thereof.

[0245] According to some of any of the embodiments described herein, J is -P(=O)(OH)-O-; M is amido; and Q is a methylene substituted by at least one aryl (e.g., phenyl).

[0246] In some embodiments of any of the embodiments described herein for Formula I, the lipid moiety represented by the variable X has the general Formula III:

[0247] Formula III wherein: the dashed (curved) line denotes an attachment point to the respective Y backbone unit;

[0248] Wi and W2 are each independently hydrogen, alkyl, alkenyl, alkynyl or acyl, wherein at least one of Wi and W2 is not hydrogen;

[0249] J is -P(=O)(OH)-O-, or J is absent (such that K is attached directly to the depicted oxygen atom of a glycerol moiety);

[0250] K is a substituted or unsubstituted hydrocarbon from 1 to 10 carbon atoms in length; M is a linking group which is -0-, -S-, amino, sulfinyl, sulfonyl, phosphate, phosphonyl, phosphinyl, carbonyl, thiocarbonyl, urea, thiourea, carbamyl, thiocarbamyl, amido, carboxy, or sulfonamide, or M is absent (such that K is attached directly to Q); and

[0251] Q is a substituted or unsubstituted hydrocarbon from 1 to 10 carbon atoms in length, or Q is absent.

[0252] Q is attached to a backbone unit of the polymeric backbone according to any of the respective embodiments described herein, or alternatively, when Q is absent, M is attached to the aforementioned backbone unit.

[0253] When M is absent, Q is also absent, and K is attached to a backbone unit of the polymeric backbone according to any of the respective embodiments described herein.

[0254] In some embodiments of any of the embodiments described herein for Formula III, one of Wi and W2 is hydrogen and the other is not hydrogen.

[0255] In some embodiments of any of the embodiments described herein for Formula III, neither Wi nor W2 is hydrogen.

[0256] In some embodiments of any of the embodiments described herein for Formula III, at least one of Wi and W2 is an alkyl, alkenyl, alkynyl or acyl, which is from 10 to 30 carbon atoms in length. In some embodiments, each of Wi and W2 is from 10 to 30 carbon atoms in length.

[0257] Examples of acyl groups which may optionally serve independently as Wi and / or W2 include, without limitation, lauroyl, myristoyl, palmitoyl, stearoyl, palmitoleoyl, oleoyl, and linoleoyl.

[0258] In some embodiments of any of the embodiments described herein for Formula III, J is — P(=O)(OH)-O- (e.g., the lipid moiety is a glycerophospholipid).

[0259] Herein, 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 depicted in Formula III.

[0260] When K is a substituted hydrocarbon, M may be attached to a carbon atom of the hydrocarbon per se, or be attached to a substituent of the hydrocarbon.

[0261] In some embodiments of any of the embodiments described herein for Formula III, K is an acyl moiety (e.g., -C(=O)-C(CH3)2-). In some such embodiments, J is absent, such that K is attached directly to the depicted oxygen atom of a glycerol moiety. In some such embodiments, K comprises a carbonyl linking group (-C(=O)-), which attaches to the oxygen atom of a glycerol moiety via an ester bond.

[0262] In some embodiments of any of the embodiments described herein for Formula III, 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-.

[0263] In some embodiments of any of the embodiments described herein for Formula III, M is amido, optionally -C(=O)NH-.

[0264] In some embodiments, the nitrogen atom of the amido is attached to K. In some such embodiments, K is an ethanolamine or serine moiety described herein.

[0265] In some embodiments of any of the embodiments described herein for Formula III, Q is a substituted alkylene (e.g., of 1 to 6 or 1 to 4 or 1 to 2 carbon atoms in length, for example, a methylene group). In some such embodiments, M is amido or carboxy. In some embodiments, the C(=O) of the amido or the carboxy is attached to Q.

[0266] In some embodiments of any of the embodiments described herein for Formula III, Q is an alkylene group as described herein, and the methylene group substituted by one or two substituents, and at least one of these substituents is or comprises an aryl (e.g., phenyl). In some such embodiments, M is amido. In some embodiments, the C(=O) of the amido is attached to Q. Alternatively, M is carboxy and the C(=O) of the carboxy is attached to Q.

[0267] In some embodiments of any of the embodiments described herein for Formula III, Q is a methylene group substituted by two substituents, at least one being or comprising an aryl (e.g. phenyl), and the other can be, for example, an aryl (e.g., phenyl) or alkyl (e.g., of 1 to 6 or 1 to 4, carbon atoms in length). In some embodiments, the methylene group is substituted by an alkyl groups (e.g., Ci-4-alkyl) and an aryl (e.g., phenyl). In some such embodiments, M is amido. In some such embodiments, M is carboxy.

[0268] In some embodiments of any of the embodiments described herein for Formula III, Q is a substituted alkylene (e.g., of 1 to 6 or 1 to 4 or 1 to 2 carbon atoms in length, for example, a methylene group). In some such embodiments, M is amido or carboxy. In some embodiments, the C(=O) of the amido or the carboxy is attached to Q.

[0269] In some embodiments of any of the embodiments described herein for Formula III, Q is an alkylene group as described herein, and the methylene group substituted by one or two substituents. In some embodiments, the methylene group is substituted by one or two alkyl groups (e.g., Ci-4-alkyl). In some such embodiments, M is other than amido. In some such embodiments, M is carboxy.

[0270] In some embodiments of any of the embodiments described herein for Formula III, Q is a methylene group substituted by two substituents. In some embodiments, the methylene group is substituted by two alkyl groups (e.g., Ci-4-alkyl). In some embodiments, the alkyl groups are methyl, such that Q is dimethylmethylene (-C(CH3)2-). In some such embodiments, M is other than amido. In some such embodiments, M is carboxy.

[0271] According to some of any of the embodiments described herein for Formula III, when M is amido, Q is an alkylene that is substituted by at least one aryl as described herein in any of the respective embodiments.

[0272] According to some of any of the embodiments described herein, M is other than amido, and Q is as described herein in any of the respective embodiments.

[0273] In some embodiments of any of the embodiments described herein for Formula III, M and Q are each absent, and K is terminated by a substituted or unsubstituted methylene group, according to any of the respective embodiments described herein with respect to Q, for example, a methylene group substituted by two substituents (e.g., dimethylmethylene (-C(CH3)2-)). In some embodiments, K further comprises a carbonyl group according to any of the respective embodiments described herein.

[0274] 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)-) attached directly to the depicted oxygen atom of a glycerol moiety (via an ester bond), and further comprises a substituted or unsubstituted methylene group (e.g., dimethylmethylene). In some embodiment, K consists of a carbonyl linking group attached directly to the depicted oxygen atom of a glycerol moiety (via an ester bond), and a substituted or unsubstituted methylene group, for example, K is -C(=O)-C(CH3)2-.

[0275] According to some of any of the embodiments described herein for Formula IV, Fi is as described herein for OWi. According to some of these embodiments, F3 and F4 are each hydrogen. According to some of these embodiments, J is absent. According to some of these embodiments, M is other than amido.

[0276] According to some of any of the embodiments described herein for Formula IV, F2 is as described herein for OW2. According to some of these embodiments, F3 and F4 are each hydrogen. According to some of these embodiments, J is absent. According to some of these embodiments, M is other than amido.

[0277] According to some of any of the embodiments described herein for Formula IV, Fi is as described herein for OWi and F2 is as described herein for OW2. According to some of these embodiments, F3 and F4 are each hydrogen. According to some of these embodiments, J is absent. According to some of these embodiments, M is other than amido.

[0278] According to some of any of the embodiments described herein, the lipid moiety does not include a moiety of Formula III as described herein. According to some of any of the embodiments described herein, the lipid moiety has a moiety of Formula III as described herein, provided that M is other than amido (e.g., M is carboxy) and / or that Q comprises an aryl substituent, as described herein.

[0279] According to some of any of the embodiments described herein for Formula IV, excluded from the scope of the present embodiments are polymeric compounds in which the lipid moiety X is as described in WO 2017 / 109784 or in WO 2023 / 031928.

[0280] Targeting moiety:

[0281] In some embodiments of any of the embodiments described herein, at least a portion of the monomeric units of the polymeric moiety comprise a targeting moiety (according to any of the embodiments described herein relating to a targeting moiety).

[0282] Herein, a “targeting moiety” refers to a moiety which is capable of bringing a compound (e.g., a compound according to some embodiments of the invention) into proximity with a selected substance and / or material (which is referred to herein as a "target"). The target is optionally a cell (e.g., a proliferating cell associated with the proliferative disease or disorder), wherein the proximity is such that the targeting moiety facilitates attachment and / or internalization of the compound into a target cell, and such that the compound may exert a therapeutic effect.

[0283] In some of any of the embodiments described herein, a targeting moiety comprises a backbone unit Y according to any of the respective embodiments described herein, and optionally a linking moiety L according to any of the respective embodiments described herein and / or moiety Z according to any of the respective embodiments described herein, for example, wherein a substituent according to any of the respective embodiments described herein comprises (and optionally consists of) the targeting moiety.

[0284] For example, in some embodiments wherein at least a portion of backbone units Y have the formula -CR4R5-CR6D- (as described herein in any of the respective embodiments), any one or more of R4-R6 and D (optionally wherein D is R7 as described herein) comprises a targeting moiety according to any of the respective embodiments described herein (e.g., wherein any one or more of R4-R6 and D is a substituted group, comprising a substituent which is a targeting moiety), and optionally any one or more R4-R6 and D is a targeting moiety. However, many other structures of monomeric units comprising a substituent which comprises (and optionally consist of) a targeting moiety are also encompassed by embodiments of the invention.

[0285] In some embodiments, the polymeric moiety is a copolymer moiety as described herein in any of the respective embodiments, wherein at least one monomeric unit as described herein comprises a targeting moiety (according to any of the respective embodiments described herein) and at least one other monomeric unit does not comprise such a targeting moiety. The distribution of a monomeric unit comprising a targeting moiety may be in accordance with any distribution described herein of a monomeric unit in a copolymer moiety (e.g., random, alternating, periodic copolymer, and / or block copolymer). In any of the embodiments described herein wherein m is at least 1, at least a portion of the monomeric units comprising a targeting moiety according to any of the respective embodiments described herein. In some such embodiments, the at least a portion of the monomeric units which comprising a targeting moiety according to any of the respective embodiments described herein, are monomeric units which do not comprise a pendant group represented by (-L-Z) as described herein in any of the respective embodiments. In some such embodiments, the number of the monomeric units comprising the targeting moiety according to any of the respective embodiments is represented by the variable m according to any of the respective embodiments described herein. In some such embodiments, none of the monomeric units comprising the pendant group represented by (-L-Z) comprise the aforementioned targeting moiety.

[0286] In any of the embodiments described herein wherein m is at least 1, each of the monomeric units which do not comprise the pendant group represented by (-L-Z) (the number of which is represented by the variable m) comprises a targeting moiety (according to any of the respective embodiments described herein). In some such embodiments, each of the monomeric units comprising a targeting moiety (according to any of the respective embodiments described herein) is a monomeric unit which does not comprise the pendant group represented by (-L-Z), that is, none of the monomeric units comprising the pendant group represented by (-L-Z) comprise the aforementioned targeting moiety, and each of the monomeric units which does not comprise the pendant group represented by (-L-Z) comprises the aforementioned targeting moiety.

[0287] In any of the embodiments described herein wherein m is at least 1, a monomeric unit comprising a targeting moiety may consist essentially of a backbone unit Y (according to any of the respective embodiments described herein) substituted by one or more targeting moieties (according to any of the respective embodiments described herein).

[0288] In some of any of the embodiments described herein, the at least a portion of the monomeric units which comprising a targeting moiety according to any of the respective embodiments described herein, are monomeric units which comprise a pendant group represented by (-L-Z) as described herein in any of the respective embodiments. In some such embodiments, the number of the monomeric units comprising the targeting moiety according to any of the respective embodiments is represented by the variable n according to any of the respective embodiments described herein (i.e., each of the monomeric units comprising a targeting moiety according to any of the respective embodiments described herein is a monomeric unit which comprises the pendant group). In some such embodiments, none of the monomeric units which do not comprise the pendant group represented by (-L-Z) comprise the aforementioned targeting moiety.

[0289] In some of any of the embodiments described herein, monomeric unit comprising a targeting moiety may optionally be different (optionally considerably different) in structure (i.e., in the structure of Y and / or L and / or Z, if present, as defined in any of the embodiments described herein) than another monomeric unit comprising a targeting moiety. For example, the backbone unit Y of a monomeric unit comprising a targeting moiety may optionally be different in structure than a backbone unit Y of other monomeric units in the polymeric moiety (according to any of the respective embodiments described herein).

[0290] In any of the embodiments described herein wherein m is at least 1, the polymeric moiety comprises a monomeric unit which comprises a targeting moiety, and the monomeric unit is at a terminus of the polymeric moiety distal to the lipid moiety. In such embodiments, the compound represented by general Formula I has the Formula lb: wherein:

[0291] T is a monomeric unit comprising a targeting moiety (according to any of the respective embodiments described herein);

[0292] X and T are attached to distal termini of the moiety represented by [Y(-L-Z)]n[Y]m-l; and

[0293] X, Y, L, Z, n and m are defined in accordance with any of the embodiments described herein relating to Formula I, with the proviso that m is at least 1.

[0294] It is to be understood that T in Formula lb is a type of monomeric unit represented by Y (i.e., without the pendant group represented by (-L-Z)) in formulas I and la, and the number of monomeric units represented by Y (i.e., without the pendant group represented by (-L-Z)) other than T is represented by the value m-1, such that the total number of monomeric units without the pendant group represented by (-L-Z)), including T, is represented by the variable m, as in formulas I and la. In some embodiments, m is 1, such that m-1 is zero, and the compound represented by Formula lb consequently has the formula: X-[Y(-L-Z)]n-T, wherein L, T, X, Y, Z and n are defined in accordance with any of the embodiments described herein.

[0295] A monomeric unit comprising a targeting moiety according to any of the respective embodiments described herein may optionally be prepared by preparing a monomer comprising a targeting moiety, and using the monomer to prepare a polymeric moiety described herein (e.g., by polymerization of monomers according to any of the respective embodiments described herein) and / or by modifying a monomeric unit in a polymeric moiety subsequently to preparation of a polymeric moiety (e.g., by polymerization of monomers according to any of the respective embodiments described herein), using any suitable technique known in the art, including, but not limited to, techniques for conjugation.

[0296] In some embodiments of any of the embodiments described herein relating to a targeting moiety, the targeting moiety does not comprise a moiety having general Formula II (according to any of the respective embodiments described herein). For example, even if a moiety represented by Formula II is capable of forming a bond with a target as described herein, the phrase "targeting moiety", in some embodiments, is to be understood as relating to a moiety distinct from a moiety represented by variable Z (having general Formula II).

[0297] In some embodiments of any one of the embodiments described herein, the pendant group represented by (-L-Z) is selected so as not to form a bond with the target and / or so as not to include a structure and / or property of a targeting moiety as described herein in any one of the respective embodiments. For example, in embodiments wherein a targeting moiety comprising a nucleophilic group (according to any of the respective embodiments described herein) - for example, an amine group - is capable of forming a bond (e.g., covalent bond) with a target, the variable Z (having general Formula II) is optionally selected such that the depicted amine / ammonium group is a tertiary amine / ammonium (i.e., no more than one of R1-R3 is hydrogen) or quaternary ammonium (i.e., none of R1-R3 is hydrogen), preferably a quaternary ammonium (e.g., comprising a trimethylamino group, such as in phosphocholine). Tertiary amine groups, and especially quaternary ammonium groups, may be significantly less reactive nucleophilic groups than primary and secondary amine groups.

[0298] In some embodiments of any of the embodiments described herein relating to a targeting moiety, the targeting moiety comprises (and optionally consists of) at least one functional group capable of forming a covalent bond or non-covalent bond (preferably a selective non-covalent bond) with a substance and / or material (which is referred to herein as a "target"), e.g., at a surface of the target (e.g., a surface of a cell and / or tissue). Herein, the phrase “functional group” encompasses chemical groups and moieties of any size and any functionality described herein (for example, any functionality capable of forming a covalent bond or non-co valent bond with a target).

[0299] A non-covalent bond according to any of the respective embodiments described herein may optionally be effected by non-covalent interactions such as, without limitation, electrostatic attraction, hydrophobic bonds, hydrogen bonds, and aromatic interactions.

[0300] In some embodiments, the targeting moiety comprises a functional group capable of forming a non-covalent bond which is selective for the target, e.g., an affinity (e.g., as determined based on a dissociation constant) of the targeting moiety and / or functional group to the target is greater than an affinity of the of the targeting moiety and / or functional group to most (or all) other compounds capable of forming a non-covalent bond with the targeting moiety.

[0301] In some embodiments of any one of the embodiments described herein, the functional group(s) are capable of forming a covalent bond with one or more specific functional groups (e.g., hydroxy, amine, thiohydroxy and / or oxo groups) which are present on the target (e.g., a target according to any of the respective embodiments described herein).

[0302] Examples of functional groups (in a targeting moiety) capable of forming a covalent bond with a target (according to any of the respective embodiments described herein) and the type of covalent bonds they are capable of forming, include, without limitation: nucleophilic groups such as thiohydroxy, amine (e.g., primary or secondary amine) and hydroxy, which may form covalent bonds with, e.g., a nucleophilic leaving group (e.g., any nucleophilic group described herein), Michael acceptor (e.g., any Michael acceptor described herein), acyl halide, isocyanate and / or isothiocyanate (e.g., as described herein) in a target; nucleophilic leaving groups such as halo, azide (-N3), sulfate, phosphate, sulfonyl (e.g. mesyl, tosyl), A- hydroxy succinimide (NHS) (e.g. NHS esters), sulfo-A-hydroxysuccinimide, and anhydride, which may form covalent bonds with, e.g., a nucleophilic group (e.g., as described herein) in a target;

[0303] Michael acceptors such as enones (e.g., maleimide, acrylate, methacrylate, acrylamide, methacrylamide), nitro groups and vinyl sulfone, which may form covalent bonds with, e.g., a nucleophilic group (e.g., as described herein) in a target, optionally thiohydroxy; dihydroxyphenyl groups (according to any of the respective embodiments described herein), which may form covalent bonds with, e.g., a nucleophilic group (e.g., as described herein) and / or a substituted or unsubstituted phenyl group (e.g., another dihydroxyphenyl group) in a target, as described herein; an acyl halide (-C(=O)-halogen), isocyanate (-NCO) and isothiocyanate (-N=C=S) group, which may form covalent bonds with, e.g., a nucleophilic group (e.g., as described herein) in a target; a carboxylate (-C(=O)OH) group, which may form a covalent bond with, e.g., a hydroxyl group in a target to form an ester bond and / or an amine group (e.g., primary amine) in a target to form an amide bond (optionally by reaction with a coupling reagent such as a carbodiimide); and / or a carboxylate group is in a target and may form an amide or ester bond with an amine or hydroxyl group, respectively, in the targeting moiety; an oxo group (optionally in an aldehyde group (-C(=0)H)), which may form a covalent imine bond with an amine group (e.g., a primary amine) in a target; and / or an oxo group (optionally in an aldehyde group) is in a target and may form a covalent imine bond with an amine groups in the targeting moiety; and / or thiohydroxy groups, which may form covalent disulfide (-S-S-) bonds with a thiohydroxy group in a target.

[0304] Modification of a monomer (e.g., prior to polymerization) or a monomeric unit of a polymeric moiety (e.g., subsequent to polymerization) to comprise any of the functional groups described herein may optionally be performed using any suitable technique for conjugation known in the art. The skilled person will be readily capable of selecting a suitable technique for any given molecule to be modified.

[0305] Herein, the term "dihydroxyphenyl" refers to an aryl group (as defined herein) which is a phenyl substituted by two hydroxyl groups at any positions thereof. The phenyl may optionally be substituted by additional substituents (which may optionally comprise additional hydroxyl groups), to thereby form a substituted dihydroxyphenyl group; or alternatively, the phenyl comprises no substituents other than the two hydroxyl groups, such that the dihydroxyphenyl group is an unsubstituted dihydroxyphenyl group.

[0306] In some embodiments of any one of the embodiments described herein, the dihydroxyphenyl group is an ortho-dihydroxyphenyl (wherein the hydroxyl groups are attached to the phenyl at adjacent positions) or a para-dihydroxyphenyl (wherein the hydroxyl groups are attached to opposite sides of the phenyl ring), each being a substituted or unsubstituted dihydroxyphenyl. In some such embodiments, the ortho-dihydroxyphenyl or para- dihydroxyphenyl is an unsubstituted dihydroxyphenyl.

[0307] A dihydroxyphenyl group according to any of the respective embodiments described herein may optionally bond covalently and / or non-covalently to a target according to any one or more attachment mechanism described for dihydroxyphenyl (catechol) groups in 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).

[0308] In some embodiments of any one of the embodiments described herein, the functional group capable of forming a bond to a target is a functional group capable of forming a covalent bond with an amine group, optionally a primary amine group. In some such embodiments, the target comprises on or more amino acids or amino acid residues, for example, a peptide or polypeptide of any length (e.g., at least two amino acid residues, for example, proteins), and the amine groups may optionally be lysine side chain amine groups and / or N-terminal amine groups. In some embodiments, the target comprises an extracellular matrix protein, for example, collagen. In some embodiments, the target comprises cartilage (e.g., articular cartilage).

[0309] In some embodiments of any one of the embodiments described herein, the targeting moiety comprises (and optionally consists of) at least one functional group capable of forming a non-covalent bond with the target (e.g., as described herein in any one of the respective embodiments).

[0310] In some embodiments of any one of the embodiments described herein, a functional group capable of forming a non-covalent bond with the target comprises (and optionally consists of) a polysaccharide and / or polypeptide (e.g., a protein and / or fragment thereof), wherein the target optionally comprises a ligand of the polysaccharide and / or polypeptide; and / or the target comprises a polysaccharide and / or polypeptide (e.g., a protein and / or fragment thereof) and the functional group capable of forming a non-covalent bond with the target is a ligand of the polysaccharide and / or polypeptide.

[0311] Examples of suitable polysaccharides and / or polypeptides, and ligands thereof, include, without limitation: avidin or streptavidin as a polypeptide described herein, and biotin as a ligand thereof; a polysaccharide-binding polypeptide as a polypeptide described therein, and a complementary polysaccharide as a ligand thereof (or a complementary polysaccharide-binding polypeptide as a ligand of a polysaccharide described herein); a collagen-binding polypeptide as a polypeptide described therein, and a complementary collagen as a ligand thereof (or a collagen as a polypeptide described herein and a complementary collagen-binding polypeptide as a ligand thereof); a cell receptor expressed by a cell, and a ligand selectively bound by the receptor; an antibody towards 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 respective antigen as a ligand thereof; and an antibody mimetic towards any antigen (e.g., wherein the target described herein optionally comprises the antigen).

[0312] Examples of cell receptors expressed by a cell include, without limitation, receptors characteristic of a particular type of cell and / or tissue, and receptors overexpressed by a cancer cell. The cell receptor or the cell is optionally a target described herein, and the targeting moiety optionally comprises any ligand of the receptor. Examples of such ligands include, without limitation, transferrin, a ligand of transferrin receptor which may optionally target transferrin receptor overexpressed by some cancer cells; keratinocyte growth factor (KGF or FGF7) which is specific for cells of epithelial origin, and may optionally target KGF receptor such as that overexpressed by an endometrial carcinoma or pancreatic carcinoma [Visco et al., Int J Oncol 1999, 15:431-435; Siegfried et al., Cancer 1997, 79:1166-1171]; and epidermal growth factor (EGF) which may optionally target an EGF receptor, optionally an erbB, such as that overexpressed by gliomas and endometrial carcinomas [Normanno et al., Curr Drug Targets 2005, 6:243-257]).

[0313] As used herein, the term "antibody" encompasses any type of immunoglobin.

[0314] As used herein, the phrase "antibody mimetic" encompasses any type of molecule, optionally a polypeptide, referred as such in the art capable of selectively binding an antigen (e.g., non-covalently). Non-limiting examples of antibody mimetics include affibodies, affilins, affimers, affitins, alphabodies, anticalins, avimers, DARPins, Fynomers, Kunitz domain peptides, and monobodies, e.g., as described in Nygren [FEBS J 2008, 275:2668-2676], Ebersbach et al. [J Mol Biol 2007, 372:172-185], Johnson et al. [Anal Chem 2012, 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 Opin Drug 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 contents of each of which are incorporated in their entirety, and especially contents regarding particular types of antibody mimetics.

[0315] As used herein, the phrase “polysaccharide-binding polypeptide” encompasses any polypeptide or oligopeptide (peptide chains of at least 2, and preferably at least 4 amino acid residues in length) capable of selectively binding (e.g., non-covalently) to a polysaccharide. A wide variety of polysaccharide-binding polypeptides and their binding specificities will be known to the skilled person, and include short peptide sequences (e.g., from 4 to 50, optionally 4 to 20 amino acid residues in length), and longer polypeptides such as proteins or fragments (e.g., carbohydrate-binding modules and / or domains) thereof. In addition, the phrase “polysaccharide- binding polypeptide” encompasses antibodies capable of specifically binding to a polysaccharide. Such antibodies will be available to the skilled person and / or the skilled person will know how to prepare such antibodies, using immunological techniques known in the art.

[0316] Examples of polysaccharide-binding polypeptides which may be used in some of any one of the embodiments of the invention include, without limitation, carbohydrate-binding modules (CBMs); and hyaluronic acid-binding peptides, polypeptides and / or modules (e.g., having a sequence as described in any of International Patent Application publication WO 2013 / 110056; International Patent Application publication 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 in their entirety, and especially contents regarding particular polysaccharide-binding polypeptides), for example, GAHWQFNALTVR (a hyaluronic acidbinding peptide sequence).

[0317] Examples of CBMs which may be used in some of any one of the embodiments of the invention, include, without limitation, CBMs belonging to the families CBM3, CBM4, CBM9, CBM10, CBM17 and / or CBM28 (which may optionally be used to bind cellulose, e.g., in a cellulose-containing target); CBM5, CBM12, CBM14, CBM18, CBM19 and / or CBM33 (which may optionally be used to bind chitin and / or other polysaccharides comprising N- acetylglucosamine, e.g., in a chitin-containing target); CBM15 (which may optionally be used to bind hemicellulose, e.g., in a hemicellulose-containing target); and / or CBM20, CBM21 and / or CBM48 (which may optionally be used to bind starch and / or glycogen, e.g., in a starch-containing and / or glycogen-containing target).

[0318] As used herein, the phrase “collagen-binding polypeptide” encompasses any polypeptide or oligopeptide (peptide chains of at least 2, and preferably at least 4 amino acid residues in length) capable of selectively binding (e.g., non-covalently) to a collagen (e.g., one type of collagen, some types of collagen, all types of collagen), including glycosylated polypeptides and oligopeptides such as peptidoglycans and proteoglycans. A wide variety of collagen-binding polypeptides and their binding specificities will be known to the skilled person, and include short peptide sequences (e.g., from 4 to 50, optionally 4 to 20 amino acid residues in length), and longer polypeptides such as proteins or fragments (e.g., collagen-binding domains) thereof. In addition, the phrase “collagen-binding polypeptide” encompasses antibodies capable of specifically binding to a collagen. Such antibodies will be available to the skilled person and / or the skilled person will know how to prepare such antibodies, using immunological techniques known in the art.

[0319] Examples of collagen-binding polypeptides which may be used in embodiments of the invention include, without limitation, collagen-binding proteins (e.g., decorin), fragments thereof and / or other polypeptides as described in 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. [NatMater 2008, 7:248-254] and Helms et al. [J Am Chem Soc 2009, 131:11683- 11685] (the contents of each of which are incorporated in their entirety, and especially contents regarding particular collagen-binding polypeptides), for example, the sequence WYRGRL.

[0320] It is expected that during the life of a patent maturing from this application many relevant functional groups and moieties for binding will be developed and / or uncovered and the scope of the terms "targeting moiety", "functional group", "cell receptor", "antibody", "antibody mimetic", "collagen-binding polypeptide" and "polysaccharide-binding polypeptide" and the like is intended to include all such new technologies a priori.

[0321] In some embodiments of any of the embodiments described herein, a functional group in a targeting moiety (according to any of the respective embodiments described herein) is attached to a linking group (as defined herein). The linking group may optionally be any linking group or linking moiety described herein, including, without limitation, a substituted or unsubstituted hydrocarbon. In some embodiments, the targeting moiety (optionally a substituent of a backbone unit Y) consists essentially of a functional group attached to the rest of the polymeric moiety via the linking group.

[0322] A functional group may optionally be attached to the linking moiety by a covalent bond obtainable by a reaction between two functional groups, for example, any covalent bond and / or functional groups described herein in the context of forming a covalent bond between a functional group and a target.

[0323] In some embodiments of any of the embodiments described herein relating to a functional group comprising a peptide or polypeptide, an amino acid residue of the peptide or polypeptide is optionally attached to a linking group of the targeting moiety, for example, via an amide bond formed from an amine or carboxylate group in the peptide or polypeptide (e.g., in an N-terminus, a lysine side chain, a C-terminus, a glutamate side chain and / or an aspartate side chain), an ester bond formed from a hydroxyl or carboxylate group in the peptide or polypeptide (e.g., in a serine side chain, a threonine side chain, a C-terminus, a glutamate side chain and / or an aspartate side chain), and / or a disulfide bond formed from a thiohydroxy group in the peptide or polypeptide (e.g., in a cysteine side chain). In some embodiments, an amino acid residue attached to the linking group is an N-terminal and / or C-terminal residue, for example, any amino acid residue attached via an N-terminal amino group or C-terminal carboxylate group, and / or a terminal lysine, glutamate, aspartate, serine, threonine and / or cysteine residue attached via a side chain thereof.

[0324] In some embodiments, an amino acid residue and / or peptide (e.g., from 2 to 20 amino acid residues in length) is added to the N-terminus and / or C-terminus of a peptide or polypeptide sequence of a functional group (according to any of the respective embodiments described herein), and links the aforementioned sequence to a linking group. Examples of such terminal amino acid residues and / or peptides include, without limitation, glycine residues and peptides with a terminal glycine residue, which may be used to attach a linking group to an N-terminus or C-terminus (according to any of the respective embodiments described herein); serine and threonine residues and peptides with a terminal serine or threonine residue, which may be used to attach a linking group to hydroxyl group in a serine or threonine side chain, optionally via an ester bond (according to any of the respective embodiments described herein); and cysteine residues and peptides with a terminal cysteine residue, which may be used to attach a linking group to a peptide via a disulfide bond (according to any of the respective embodiments described herein).

[0325] In some embodiments, attachment of a peptide or polypeptide to a linking group via a terminal amino acid residue minimizes interference (e.g., steric interference) with the functionality of the peptide or polypeptide following attachment to the linking group.

[0326] In some embodiments, attachment of a peptide or polypeptide to a linking group via a terminal glycine facilitates attachment by minimizing interference (e.g., steric interference) of an amino acid side chain (which glycine lacks) with attachment to the linking group.

[0327] In some embodiments of any of the embodiments described herein wherein at least a portion of the monomeric units comprising a targeting moiety, the monomeric units comprising a targeting moiety are, on average, closer to a terminus of the polymeric moiety distal to the lipid moiety, e.g., an average distance (as measured in atoms or backbone units along the backbone of the polymeric moiety) of monomeric units comprising a targeting moiety from the lipid moiety is greater than an average distance of the other monomeric units from the lipid moiety.

[0328] In some embodiments, at least a portion (and optionally all) of the monomeric units comprising a targeting moiety form a block (of one or more monomeric units) near (and optionally at) a terminus of the polymeric moiety distal to the lipid moiety. In some such embodiments, the copolymer moiety contains a single monomeric unit which comprises a targeting moiety, and the monomeric unit is at a terminus of the polymeric moiety distal to the lipid moiety.

[0329] Without being bound by any particular theory, it is assumed that a targeting moiety located distal to the lipid moiety may be more effective as a targeting moiety (e.g., more effective at binding to a target), for example, due to the targeting moiety being less sterically shielded (e.g., by a surface to which the lipid moiety is associated) and therefore more exposed to and thus better able to make contact with targets in an aqueous environment.

[0330] In alternative embodiments, the polymeric moiety does not comprise a targeting moiety as described herein in any of the respective embodiments.

[0331] Lipid layers and liposomes:

[0332] According to an aspect of some embodiments of the invention, there is provided a lipid bilayer (referred to herein interchangeably simply as a "bilayer") comprising a polymeric compound according to any of the respective embodiments described herein. In some such embodiments, the lipid bilayer further comprises at least one bilayer-forming lipid in addition to the polymeric compound. In some of any of the embodiments described herein or in any combination thereof, the at least one bilayer-forming lipid comprises at least one zwitterionic bilayer-forming lipid, as described herein, and optionally further comprises at least one negatively- charged bilayer-forming lipid.

[0333] Herein, the term "bilayer-forming lipid" encompasses any compound in which a bilayer may form from a pure aqueous solution of the compound, the bilayer comprising two parallel layers of molecules of the compound (referred to as a "lipid").

[0334] Typically, the bilayer comprises relatively polar moieties of the lipid at the two surfaces of the bilayer, which may optionally comprise an interface with the aqueous solution and / or an interface with a solid surface; and relatively hydrophobic moieties of the lipid at the interior of the bilayer, at an interface between the two layers of lipid molecules which form the bilayer.

[0335] In some embodiments, a bilayer-forming lipid is an amphiphilic lipid.

[0336] As used herein, the term “amphiphilic lipid” refers to compounds comprising at least one hydrophilic moiety and at least one lipophilic moiety. Examples of amphiphilic lipids include, without limitation, fatty acids (e.g., at least 6 carbon atoms in length) and derivatives thereof such as phospholipids and glycolipids; sterols (e.g., cholesterol) and steroid acids.

[0337] Herein, the term “phospholipid” refers to a compound comprising a substituted or nonsubstituted phosphate group and at least one alkyl chain (optionally at least two alkyl chains) which is optionally at least 5 carbon atoms in length, optionally at least 7 atoms in length and optionally at least 9 atoms in length. The at least one alkyl chain is optionally a part of an acyl group (e.g., a fatty acid moiety) or an alkyl group per se (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 via the oxygen atoms of glycerol. In the context of the present embodiments, the term “phospholipid” encompasses lipids having a (phosphorylated) glycerol backbone (e.g., monoacylglyceride and / or diacylglyceride phospholipids), referred to as glycerophospholipids.

[0338] In some embodiments of any one of the embodiments described herein, the phospholipid is a glycerophospholipid. In some embodiments, the glycerophospholipid is a diacylglyceride, comprising two fatty acyl groups and one phosphate group attached to a glycerol backbone.

[0339] Examples of bilayer-forming lipids include glycerophospholipids (e.g., a glycerophospholipid according to any of the respective embodiments described herein). It is to be appreciated that the polymeric compound described herein may optionally be a bilayer-forming lipid which can form a bilayer per se or in combination with one or more additional bilayerforming lipids.

[0340] In some embodiments of any one of the embodiments described herein, the bilayer-forming lipid comprises at least one charged group (e.g., one or more negatively charged groups and / or one or more positively charged groups).

[0341] In some embodiments, the bilayer-forming lipid is zwitterionic; comprising both (e.g., an equal number of) negatively charged and positively charged groups (e.g., one of each).

[0342] The bilayer according to some of the present embodiments may optionally be closed upon itself (e.g., such that the bilayer has no edges), thereby forming an inner volume separated by the bilayer from the surrounding environment, which is referred to herein and in the art as a "liposome". Alternatively or additionally, the bilayer may be open-faced and / or with edges.

[0343] According to some embodiments of the invention, the composition comprises a liposome comprising at least one lipid bilayer according to any of the respective embodiments described herein.

[0344] According to some embodiments of the invention, the composition comprises a liposome comprising at least one polymeric compound and, optionally and preferably, at least one bilayerforming lipid, according to any of the respective embodiments described herein.

[0345] As used herein and in the art, the term “liposome” refers to an artificially prepared vesicle comprising a bilayer composed of molecules of an amphiphilic lipid. In an aqueous medium, the bilayer is typically configured such that hydrophilic moieties of the amphiphilic lipid are exposed to the medium at both surfaces of the bilayer, whereas lipophilic moieties of the lipid are located in the internal portion of the bilayer, and therefore less exposed to the medium. Examples of liposomes which may be used in any one of the embodiments described herein include, without limitation, small unilamellar vesicles (SUV), large unilamellar vesicles (LUV) and large multilamellar vesicles (MLV). As described herein, the liposome according to the present embodiments comprises, inter alia, at least one bilayer-forming lipid.

[0346] It is to be appreciated that the polymeric compound comprised by a liposome (according to any of the respective embodiments described herein) may optionally be a bilayer-forming lipid which can form a bilayer per se or in combination with one or more additional bilayer-forming lipids.

[0347] A liposome may optionally comprise a single bilayer (e.g., a unilamellar vesicle) or a plurality of bilayers (e.g., a multilamellar vesicle) - wherein each bilayer optionally independently forms a closed vesicle - comprising, for example, concentric bilayer vesicles and / or a plurality of separate bilayer vesicles encompassed by the same bilayer vesicle.

[0348] As used herein, the term “unilamellar” refers to liposomes characterized by a single lipid bilayer, whereas the term “multilamellar” refers to liposomes characterized by a multiple lipid bilayers, for example, concentric bilayers.

[0349] As used herein, the phrase “small unilamellar vesicle” refers to unilamellar liposomes of less than 100 nm in diameter, whereas the phrase “large unilamellar vesicle” refers to unilamellar liposomes at least 100 nm in diameter.

[0350] As used herein, the phrase “small multilamellar vesicle” refers to multilamellar liposomes of less than 100 nm in diameter, whereas the phrase “large multilamellar vesicle”, MLV, refers to multilamellar liposomes at least 100 nm in diameter.

[0351] In some embodiments of any one of the embodiments described herein, the liposomes comprise multilamellar vesicles. In some embodiments, the liposomes are primarily (more than 50 weight percent) multilamellar vesicles, preferably large multilamellar vesicles (MLV).

[0352] In some embodiments of any one of the embodiments described herein, the liposomes comprise small unilamellar vesicles. In some embodiments, the liposomes are primarily (more than 50 weight percent) small unilamellar vesicles.

[0353] In some embodiments of any one of the embodiments described herein, the liposomes comprise large unilamellar vesicles. In some embodiments, the liposomes are primarily (more than 50 weight percent) large unilamellar vesicles.

[0354] A liposome according to any of the respective embodiments described herein may be approximately spherical in shape or may have any alternative shape, such as an elongated tube and / or a flattened (e.g., sheet-like) shape.

[0355] In some embodiments of any of the embodiments described herein, a mol ratio of the bilayer-forming lipid (comprised in addition to the polymeric compound) and the polymeric compound (according to any of the respective embodiments described herein) in the liposome, or on a composition comprising same, is in a range of from 5:1 to 5,000:1 (bilayer-forming lipid: polymeric compound), optionally in a range of from 10:1 to 2,500:1, optionally in a range of from 25: 1 to 1,000: 1, and optionally in a range of from 50: 1 to 500:1, including any intermediate values and subranges therebetween.

[0356] Herein throughout, the terms “mol ratio” and “molar ratio” are used interchangeably, and describe the ratio between the mol % of the indicated components in the lipid bilayer or liposome, or in a composition comprising same.

[0357] In some embodiments of any of the embodiments described herein relating to a bilayer, a mol ratio of the bilayer-forming lipid (comprised in addition to the polymeric compound) and the polymeric compound in the bilayer, or in a composition comprising same, is in a range of from 10:1 to 1,000:1 (bilayer-forming lipid: polymeric compound), optionally in a range of from 10:1 to 500:1, optionally in a range of from 10:1 to 100:1, and optionally in a range of from 10:1 to 50:1, including any intermediate values and subranges therebetween.

[0358] In some embodiments of any of the embodiments described herein relating to a bilayer, a mol ratio of the bilayer-forming lipid (comprised in addition to the polymeric compound) and the polymeric compound in the bilayer, or on a composition comprising same, is in a range of from 10:1 to 100:1 (bilayer-forming lipid: polymeric compound), optionally in a range of from 10:1 to 50:1, optionally in a range of from 30:1 to 40:1, including any intermediate values and subranges therebetween.

[0359] In some embodiments of any of the embodiments described herein relating to a bilayer, a mol ratio of the bilayer-forming lipid (comprised in addition to the polymeric compound) and the polymeric compound in the bilayer, or on a composition comprising same, is in a range of from 10:1 to 1,000:1 (bilayer-forming lipid: polymeric compound), optionally in a range of from 100:1 to 1,000:1, optionally in a range of from 100:1 to 500:1, and optionally in a range of from 100:1 to 300:1 or 100:1 to 200:1, including any intermediate values and subranges therebetween.

[0360] In some embodiments of any of the embodiments described herein, a mol ratio of the bilayer-forming lipid (comprised in addition to the polymeric compound) and the polymeric compound (according to any of the respective embodiments described herein) in the composition is in a range of from 5:1 to 5,000:1 (bilayer- forming lipid: polymeric compound), optionally in a range of from 10:1 to 2,500:1, optionally in a range of from 25:1 to 1,000:1, and optionally in a range of from 50:1 to 500:1, including any intermediate values and subranges therebetween.

[0361] In some embodiments of any one of the embodiments described herein, a concentration of phospholipids in liposomes or in a composition or formulation as described herein is in a range of from 0.1 mM to 500 mM. In some embodiments, the concentration is in a range of from 0.1 mM to 150 mM. In some embodiments, the concentration is in a range of from 0.1 mM to 50 mM. In some embodiments, the concentration is in a range of from 0.1 mM to 10 mM. In some embodiments, the concentration is in a range of from 0.5 mM to 5 mM. In some embodiments, the concentration is in a range of from 1 mM to 10 mM. In some embodiments, the concentration is in a range of from 1 mM to 5 mM (e.g., 3 mM).

[0362] In some of any of the embodiments described herein or in any combination thereof, a total amount of the at least one bilayer-forming lipid in the liposome ranges from 50 to 99 mol %, weight per volume, including any intermediate values and subranges therebetween.

[0363] In some of any of the embodiments described herein, an amount of the (one or more) polymeric compound (LPC) ranges from 0.1 to 10, or from 0.1 to 5, or from 0.1 to 3, or from 0.1 to 1, or from 0.2 to 0.8, or from 0.1 to 0.5, mol % of the total amount of lipids in the liposomes, including any intermediate values and subranges therebetween.

[0364] In some of any of the embodiments described herein, an amount of the polymeric compound (LPC) ranges from 1 to 50, or from 1 to 40, or from 1 to 30, or from 5 to 50, or from 5 to 40, or from 5 to 30, % by weight of the total amount of lipids in the liposomes, including any intermediate values and subranges therebetween, the remaining being the bilayer forming lipid(s).

[0365] In some of any of the embodiments described herein, a total amount of the polymeric compound (LPC) and the bilayer-forming lipid in the composition, which represents the total amount of lipids in the composition, ranges from 0.01 to 10, or from 0.05 to 10, or from 0.05 to 5, or from 0.1 to 10, or from 0.1 to 5, or from 0.05 to 5, or from 1 to 10, or from 1 to 5, or from 0.01 to 3, or from 0.5 to 3, or from 0.1 to 3, or from 1 to 3, % weight per the total volume or the total weight of the composition, including any intermediate values and subranges therebetween.

[0366] In some of any of the embodiments described herein, a concentration of the lipid bilayer or the liposome in the composition, which represents a total concentration of lipids, or the total lipids concentration, in the composition ranges from 0.1 to 100, or from 0.1 to 50, or from 0.1 to 30, or from 0.1 to 10, or from 0.1 to 5, or from 0.1 to 2, or from 1 to 100, or from 1 to 50, or from 1 to 30, or from 1 to 10, or from 1 to 5, mM, including any intermediate values and subranges therebetween.

[0367] In some of any of the embodiments described herein, a concentration of the lipid bilayer or the liposome in the composition, which represents a total concentration of lipids, or the total lipids concentration, in the composition ranges from 10 to 100, or from 10 to 50, or from 10 to 30, or from 10 to 20, or from 20 to 100, or from 20 to 80, or from 20 to 60, or from 20 to 50, or from 20 to 40, or from 20 to 30, mM, including any intermediate values and subranges therebetween. In some of any of the embodiments described herein, a mean diameter of liposomes ranges from about 100 nm to about 2000 nm, or from about 100 nm to about 1000 nm, of from about 100 nm to about 500 nm, or from about 100 nm to about 200 nm, or from about 150 nm to about 200 nm, or from about 150 nm to about 180 nm, including any intermediate values and subranges therebetween.

[0368] The mean diameter according to any of the respective embodiments described herein may optionally be an arithmetic mean (a ratio of a sum of values to the number of values) or a Z-av erage as this term is defined in the art of dynamic light scattering (in brief, an intensity-weighted harmonic mean). In exemplary embodiments, the mean diameter is a Z-average diameter determined by dynamic light scattering.

[0369] The number- average molecular weight (Mn) and / or molecular weight (Mw) and / or number-average degree of polymerization (DPn) of liposomes in a composition may optionally be determined by gel permeation chromatography (GPC) analysis.

[0370] The polydispersity index (PDI) and / or mean diameter of liposomes in a composition may optionally be determined by dynamic light scattering using a two-parameter fit to the data (e.g., according to ISO 13321 and ISO 22412 standards) for determining PDI and Z-average diameter (e.g., using a commercially available instrument).

[0371] In some of any of the embodiments described herein, a PDI of the liposomes is lower than 1.

[0372] In some of any of the embodiments described herein, a zeta potential of the liposomes is in a range of from 10 mV to -50 mV, or from 0 mV to -50 mV, or from 0 mV to -30 mV, or from -5 mV to -25 mV, or from -10 mV to -25 mV, including any intermediate values and subranges therebetween.

[0373] In some of any of the embodiments described herein, a zeta 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.

[0374] In some of any of the embodiments described herein relating to a polymeric compound comprising a negatively-charged bilayer-forming lipid (e.g., DPPG), the zeta potential of the liposomes is in a range of from 10 mV to -10 mV (e.g., from 5 mV to -5 mV), optionally in a range of from 0 to -10 mV (e.g., from 0 to -5 mV, or from -3 mV to -5 mV).

[0375] Zeta potential may optionally be determined using any suitable technique known in the art (e.g., using a commercially available instrument), for example, electrophoretic light scattering. The zeta potential of liposomes may be determined by diluting the liposomes in an aqueous salt (e.g., NaCl) solution with a predetermined salt concentration (e.g., 10 pM). In some of any of the embodiments described herein, the bilayer-forming lipid or the liposome comprises at least one zwitterionic bilayer-forming lipid, for example, a zwitterionic glyceropho spholipid .

[0376] In some of any of the embodiments described herein, the bilayer-forming lipid or the liposome comprises at least one zwitterionic bilayer-forming lipid, for example, a zwitterionic glycerophospholipid, and at least one negatively-charged bilayer-forming lipid, for example, a negatively charged phosphatidyl glycerol, in accordance with any of the embodiments described herein.

[0377] In some of any of the embodiments described herein or in any combination thereof, the at least one negatively-charged bilayer-forming lipid is a phosphatidyl glycerol (e.g., DPPG).

[0378] In some of any of the embodiments described herein or in any combination thereof, the at least one bilayer-forming lipid further comprises at least one zwitterionic glycerophospholipid (e.g., a phosphatidyl choline such as DSPC and / or or a phosphatidyl ethanolamine such as DPPE).

[0379] Herein and in the art, the term “phosphatidylcholine” refers to a glycerophospholipid comprising a phosphocholine group and two fatty acyl groups attached to a glycerol backbone (i.e., a diacylglyceride). The fatty acyl groups can be of from 8 to 30, or from 8 to 20, or from 10 to 30 or from 10 to 20, or from 12 to 30 or from 12 to 30, carbon atoms in length, including any intermediate values and subranges therebetween, and are preferably of at least 12, or at least 14, more preferably at least 16, carbon atoms in length (e.g., of from 16 to 30, or from 16 to 22, carbon atoms in length).

[0380] Herein and in the art, the term “phosphatidylethanolamine” refers to a glycerophospholipid comprising a phosphoethanolamine group and two fatty acyl groups attached to a glycerol backbone (i.e., a diacylglyceride).

[0381] According to some embodiments of any of the embodiments of the invention, the bilayerforming lipid comprises a negatively-charged bilayer- forming lipid (e.g., a phosphatidyl glycerol such as DPPG).

[0382] According to some embodiments of any of the embodiments of the invention, the bilayerforming lipid comprises a zwitterionic glycerophospholipid (e.g., a phosphatidyl choline such as DSPC, or a phosphatidyl ethanolamine such as DPPE) and a negatively-charged glycerophospholipid (e.g., a phosphatidyl glycerol such as DPPG). According to some embodiments of any of the embodiments of the invention, the total amount of the bilayer-forming lipids in the liposomes ranges from 50 to 99 mol %, including any intermediate values and subranges therebetween. According to some embodiments of any of the embodiments of the invention, an amount of the negatively-charged bilayer-forming lipid, if present, ranges from 0.1 to 40 mol %, or from 0.1 to 20 mol %, or from 0.1 to 20 mol %, of the lipids in the liposomes (bilayer-forming lipids, LPC and cholesterol, if present), including any intermediate values and subranges therebetween.

[0383] According to some embodiments of any of the embodiments of the invention, the liposome further comprises a sterol, for example, cholesterol.

[0384] According to some embodiments of any of the embodiments of the invention, the sterol (e.g., cholesterol) is associated with the lipid bilayer (but does not form the lipid bilayer).

[0385] As used herein, the term “sterol” encompasses all sterols derived from any source and includes synthetic sterols, animal-derived sterols, and plant-derived sterols (termed “phytosterols” as known in the art), as well as the saturated forms of sterols thereof (i.e., stands). Thus, the term “sterols” as used herein encompasses both sterols and stands. Sterols are steroids with a hydroxyl group at C3 (steroid alcohol) and most of the skeleton of cholestane (IUPAC Steroid Nomenclature, 1987). Additional carbon atoms may be present in the side chain, usually in the C17 position. In nature, sterols are found as C26-C30 steroid alcohols. The cylcopentanoperhydrophenanthrene ring structure is common to all sterols, while the side chains may vary in structure. In nature, sterols may be found as conjugates (e.g., glycoconjugates, lipo- conjugates, etc.). Thus, the term “sterol” as used herein, is further intended to encompass conjugated sterols, including, but not limited to, phytosteryl fatty-acid esters and phytostanyl fattyacid esters. An exemplary sterol is cholesterol. According to some embodiments of any of the embodiments of the invention, an amount of the sterol (e.g., cholesterol) ranges from 0.1 to 50 mol % of the total lipids in the liposomes, including any intermediate values and subranges therebetween.

[0386] In some of any of the embodiments described herein or in any combination thereof, an amount of the at least one negatively-charged bilayer- forming lipid, if present, ranges from 0.1 to 40 mol %, or from 0.1 to 20 mol %, of the lipids in the liposomes, including any intermediate values and subranges therebetween.

[0387] In some embodiments of any of the embodiments described herein relating to a liposome, the liposome further comprises at least one functional moiety or agent bound to or associated with a surface of the liposome and / or within a lipid bilayer and / or core of the liposome (e.g., within the liposome bilayer and / or enveloped by the liposome bilayer). In exemplary embodiments, a functional moiety is bound to the liposome, for example, it is covalently bound to the liposome by means of, for example, covalent bonding with one or more the lipids. In exemplary embodiments, a functional agent is associated with the liposome either chemically, by means of, for example, covalent or electrostatic bonds, and / or physically, by being entrapped or entangled within the lipid bilayer or the core.

[0388] Examples of functional moieties and agents suitable for inclusion in embodiments described herein include, without limitation, a therapeutically active agent or moiety of a therapeutically active agent (e.g., wherein the active agent is releasable upon cleavage of the moiety), a labeling moiety or agent, and / or a targeting moiety or targeting agent (e.g., a targeting moiety or agent on a surface of the liposome). Any other moiety or agent that may contribute to or improve the indicated use of the liposome is contemplated. According to some embodiments, the liposome further comprises a sterol, for example, cholesterol. According to some of these embodiments, the cholesterol is incorporated in and / or associated with the lipid bilayer.

[0389] According to some of any of the embodiments described herein, the functional moiety or agent is a therapeutically active agent or moiety thereof, a labeling moiety or agent and / or a targeting moiety or agent.

[0390] According to some of any of the embodiments described herein, the functional moiety or agent is a therapeutically active agent or moiety thereof, and in some of these embodiments, the therapeutically active agent or moiety thereof is within the lipid bilayer and / or core of the liposome. According to some of these embodiments, the liposome further comprises a sterol, for example, cholesterol, in an amount of from 0.1 to 50 mol % of the total lipids in the liposome.

[0391] According to some of these embodiments, the polymeric compound is a long polymeric compound, as described and defined herein in any of the respective embodiments.

[0392] According to some embodiments, the liposome comprises a therapeutically active agent, bound to or associated with a surface of the liposome and / or within a lipid bilayer and / or core of the liposome (e.g., within the liposome bilayer and / or enveloped by the liposome bilayer), and cholesterol (e.g., associated within the lipid bilayer).

[0393] In some of any of the embodiments described herein, the liposomes are devoid of a therapeutically active agent.

[0394] In some of any of the embodiments described herein, liposomes comprise a therapeutically active agent, which is optionally incorporated in a liposome and / or on a surface of the liposome. In some such embodiments, the therapeutically active agent is a therapeutically active agent as described in International Patent Application publication WO 2018 / 150429.

[0395] Herein, the phrase “therapeutically active agent” refers to any agent (e.g., compounds) having a therapeutic effect, provided that the compound is not a bilayer- forming lipid or polymeric compound comprised by the liposome (according to any of the respective embodiments described herein), as well as to any portion of an agent (e.g., a moiety of a compound) which generates an agent having a therapeutic effect upon release (e.g., upon cleavage of one or more covalent bonds), including a portion of a bilayer-forming lipid or polymeric compound. Thus, the bilayer-forming lipid and polymeric compound per se are excluded from the definition of a therapeutically active agent, but a bilayer-forming lipid and / or polymeric compound may optionally generate a therapeutically active agent upon release, in which case the portion of the bilayer-forming lipid and / or polymeric compound which generates the therapeutically active agent is also considered to be a therapeutically active agent as defined herein.

[0396] When associated with a liposome, a therapeutically active agent may optionally be attached by a covalent or non-covalent (e.g., electrostatic and / or hydrophobic) bond to a liposome (e.g., to an exterior surface and / or interior surface of a liposome membrane), incorporated within a liposome membrane (e.g., a lipophilic agent which stably partitions to a lipid phase of the liposome), and / or enveloped within a core of a liposome (e.g., a hydrophilic agent in an aqueous compartment of the liposome). The therapeutically active agent may optionally be a moiety covalently attached to a liposome (e.g., attached to a lipid so as to form a lipid-derivative comprising the moiety). Such attachment may be obtained in some embodiments by using techniques known in the art (e.g., amide bond formation).

[0397] In some embodiments, a therapeutically active agent is attached to the liposome via electrostatic interactions, for example, the therapeutically active agent is a positively-charged agent which is attached to, or complexed by, the negatively-charged bilayer-forming lipid as described herein.

[0398] In some embodiments of any of the embodiments described herein, the therapeutically active agent is, for example, an analgesic (e.g., as described herein in any of the respective embodiments), an anti-inflammatory agent (e.g., as described herein in any of the respective embodiments), an anti-proliferative agent (e.g., as described herein in any of the respective embodiments), an anti-microbial agent (including antibacterial, anti-mycobacterial, antiviral, antifungal, anti-protozoal and / or anti-parasitic agents) and / or a vaccine antigen. In some such embodiments, the therapeutically active agent is an analgesic and / or an anti-inflammatory agent. In some such embodiments, the therapeutically active agent is usable in the treatment osteoarthritis, either alone or in combination with an additional therapeutically active agent.

[0399] The phrase “anti-microbial” as used herein, refers to a property of a substance (e.g., a compound or a composition) that can effect a parameter of microorganism, as defined herein, including death, eradication, elimination, reduction in number, reduction of growth rate, inhibition of growth, and change in population distribution of one or more species of microbial life forms. This term encompasses antibacterial agents, which are also referred to herein as antibiotics. Examples of anti-microbial agents include, without limitation, antibacterial, anti-mycobacterial, antiviral, anti-fungal, anti-protozoal and / or anti-parasitic agents, as known in the art.

[0400] The phrase “vaccine antigen” as used herein, refers to an agent within a vaccine that can stimulate the immune system to recognize and respond to a specific pathogen or foreign agent. Upon introduction into a patient’s body, the antigen triggers an immune response which lead to the production of antibodies within the body of the patient. Examples of vaccine antigens include, without limitation, inactivated or subunit vaccines (e.g., influenza vaccine; hepatitis B vaccine), live attenuated vaccines (e.g., yellow fever vaccine), viral vector vaccines (e.g., COVID- 19 vaccines), toxoid vaccines (e.g., tetanus vaccine), and / or conjugate vaccines (Haemophilus influenzae type b (Hib) vaccine).

[0401] Examples of suitable anti-proliferative agents include, without limitation, acivicin; aclarubicin; acodazole (e.g., acodazole hydrochloride); acronine; adriamycin; adozelesin; aldesleukin; altretamine; ambomycin; ametantrone (e.g., ametantrone acetate); aminoglutethimide; amsacrine; anastrozole; anthramycin; asparaginase; asperlin; azacitidine; azetepa; azotomycin; batimastat; benzodepa; bicalutamide; bisantrene (e.g., bisantrene hydrochloride); bisnafide (e.g., bisnafide dimesylate); bizelesin; bleomycin (e.g., bleomycin sulfate); brequinar (e.g., brequinar sodium); bropirimine; busulfan; cactinomycin; calusterone; caracemide; carbetimer; carboplatin; carmustine; carubicin (e.g., carubicin hydrochloride); carzelesin; cedefingol; chlorambucil; cirolemycin; cisplatin; cladribine; combrestatin A-4 phosphate; crisnatol (e.g., crisnatol mesylate); cyclophosphamide; cytarabine; dacarbazine; dactinomycin; daunorubicin (e.g., daunorubicin hydrochloride); decitabine; dexormaplatin; dezaguanine (e.g., dezaguanine mesylate); diaziquone; docetaxel; doxorubicin (e.g., doxorubicin hydrochloride); droloxifene (e.g., droloxifene citrate); dromostanolone (e.g., dromostanolone propionate); duazomycin; edatrexate; eflomithine (e.g., eflomithine hydrochloride); elsamitrucin; enloplatin; enpromate; epipropidine; epirubicin (e.g., epirubicin hydrochloride); erbulozole; esorubicin (e.g., esorubicin hydrochloride); estramustine (e.g., estramustine phosphate sodium); etanidazole; etoposide (e.g., etoposide phosphate); etoprine; fadrozole (e.g., fadrozole hydrochloride); fazarabine; fenretinide; floxuridine; fludarabine (e.g., fludarabine phosphate); fluorouracil; flurocitabine; fosquidone; fostriecin (e.g., fostriecin sodium); gemcitabine (e.g., gemcitabine hydrochloride); hydroxyurea; idarubicin (e.g., idarubicin hydrochloride); ifosfamide; ilmofosine; interferon alfa-2a; interferon alfa-2b; interferon alfa-nl; interferon alfa-n3; interferon beta-la; interferon gamma-Ib; iproplatin; irinotecan (e.g., irinotecan hydrochloride); lanreotide (e.g., lanreotide acetate); letrozole; leuprolide (e.g., leuprolide acetate); liarozole (e.g., liarozole hydrochloride); lometrexol (e.g., lometrexol sodium); lomustine; losoxantrone (e.g., losoxantrone hydrochloride); masoprocol; maytansine; mechlorethamine (e.g., mechlorethamine hydrochloride); megestrol (e.g., megestrol acetate); melengestrol (e.g., melengestrol acetate); melphalan; menogaril; mercaptopurine; methotrexate (e.g., methotrexate sodium); metoprine; meturedepa; mitindomide; mitocarcin; mitocromin; mitogillin; mitomalcin; mitomycin; mitosper; mitotane; mitoxantrone (e.g., mitoxantrone hydrochloride); mycophenolic acid; nocodazole; nogalamycin; ombrabulin; ormaplatin; oxisuran; paclitaxel; pegaspargase; peliomycin; pentamustine; peplomycin (e.g., peplomycin sulfate); perfosfamide; pipobroman; piposulfan; piroxantrone (e.g., piroxantrone hydrochloride); plicamycin; plomestane; porfimer (e.g., porfimer sodium); porfiromycin; prednimustine; procarbazine (e.g., procarbazine hydrochloride); puromycin (e.g., puromycin hydrochloride); pyrazofurin; riboprine; rogletimide; safingol (e.g., safingol hydrochloride); semustine; simtrazene; sparfosate (e.g., sparfosate sodium); sparsomycin; spirogermanium (e.g., spirogermanium hydrochloride); spiromustine; spiroplatin; streptonigrin; streptozocin; sulofenur; talisomycin; tecogalan (e.g., tecogalan sodium); tegafur; teloxantrone (e.g., teloxantrone hydrochloride); temoporfin; teniposide; teroxirone; testolactone; thiamiprine; thioguanine; thiotepa; tiazofurin; tirapazamine; topotecan (e.g., topotecan hydrochloride); toremifene (e.g., toremifene citrate); trestolone (e.g., trestolone acetate); triciribine (e.g., triciribine phosphate); trimetrexate (e.g., trimetrexate glucoronate); triptorelin; tubulozole (e.g., tubulozole hydrochloride); uracil mustard; uredepa; vapreotide; verteporfin; vinblastine; vincristine (e.g., vincristine sulfate); vindesine (e.g., vindesine sulfate); vinepidine; vinglycinate; vinleurosine; vinorelbine (e.g., vinorelbine tartrate); vinrosidine; vinzolidine; vorozole; zeniplatin; zino statin; and zorubicin (e.g., zorubicin hydrochloride). Additional anti-cancer agents include those disclosed in Chapter 52, Antineoplastic Agents (Paul Calabresi and Bruce A. Chabner), and the introduction thereto, 1202-1263, of Goodman and Gilman's "The Pharmacological Basis of Therapeutics", Eighth Edition, 1990, McGraw-Hill, Inc. (Health Professions Division), the contents of which are incorporated herein by reference. In some of any of the embodiments described herein, a sterol, e.g., cholesterol, is included in the lipid bilayer of the liposome, in accordance with any of the embodiments described herein.

[0402] In some of any of the embodiments described herein, an amount of the sterol (e.g., cholesterol) ranges from 0.1 to 50 mol % of the total lipids in the liposomes, including any intermediate values and subranges therebetween. Examples of therapeutically active agents suitable for inclusion in a liposome (e.g., as a molecule or moiety of the agent) include, without limitation, amphotericin B, cisplatin, cytarabine, daunorubicin, doxorubicin, estradiol, influenza virosome, morphine, surfactant protein B, surfactant protein C, verteporfin and vincristine. Examples of a labeling moiety or agent include moieties and compounds which are chromophoric (e.g., absorb visible light), fluorescent, phosphorescent, and / or radioactive. Many such compounds and moieties (and techniques for preparing such moieties) will be known to a skilled person.

[0403] A targeting moiety in a liposome according to any of the respective embodiments described herein may optionally be a targeting moiety according to any of the respective embodiments described herein. A targeting moiety in a liposome may be comprised by a polymeric compound according to some embodiments of the invention (according to any of the respective embodiments described herein), the liposome comprising the polymeric compound. Alternatively or additionally, a targeting moiety in a liposome may optionally be comprised by another compound in the liposome, optionally a bilayer-forming lipid (according to any of the respective embodiments described herein) conjugated to a targeting moiety according to any of the respective embodiments described herein.

[0404] Herein, a “targeting agent” refers to a compound ("agent") comprising (and optionally consisting essentially of) a targeting moiety according to any of the respective embodiments described herein (e.g., in the context of a targeting moiety comprised by a polymeric compound described herein). Typically, the phrase "targeting agent" is used to refer to a compound other than a polymeric compound comprising a targeting moiety, as described herein.

[0405] In some embodiments, a functional moiety (e.g., targeting moiety or labeling moiety) is covalently attached to a liposome. Such attachment may be obtained in some embodiments by using techniques known in the art (e.g., amide bond formation).

[0406] Composition:

[0407] A composition as described herein, comprises one or more polymeric compound(s) as described herein in any of the respective embodiments, and, optionally and preferably, one or more bilayer-forming lipids, as described herein in any of the respective embodiments.

[0408] According to some of any of the respective embodiments, an amount of the polymeric compound(s) and the bilayer-forming lipid(s) and the total amount thereof (the total amount of lipidic compounds or of lipids) in the composition is as described herein in any of the respective embodiments and any combination thereof.

[0409] According to some of any of the respective embodiments, the composition further comprises a carrier, preferably an aqueous carrier, for example, water, saline or a buffer featuring physiological pH. According to these embodiments, the composition is an aqueous composition.

[0410] According some embodiments of any of the embodiments described herein, the composition is a sterile composition. Herein, the term “sterile” refers to an absence of observable microorganism growth upon subjecting composition to conditions (e.g., medium, incubation temperature) for a suitable period of time, e.g., according to any standard protocol for testing sterility. Optionally, sterility is tested in fluid thioglycollate medium, e.g., at a temperature in a range of from 30 to 35 °C for up to 3 days, and / or soybean-casein digest medium (a.k.a. trypticase soy broth or trypticase soy agar), e.g., at a temperature in a range of from 20 to 25 °C for up to 5 days; for example, whereby a composition is sterile if no microbial growth is observable in either medium. The fluid thioglycollate medium and / or soybean-casein digest medium content and / or procedures for testing sterility may optionally be as described in U.S. Pharmacopeia General Chapter 71, the contents of which are incorporated herein by reference.

[0411] In some of any of the embodiments described herein, a sterile composition is further characterized by a concentration of bacterial endotoxins below an acceptable threshold, for example below a threshold of 35 endotoxin units (EU) per ml (e.g., wherein endotoxin units are defined according to the U.S. Pharmacopeia reference standard). Bacterial endotoxin level may be determined by any suitable test known in the art, for example, using horseshoe crab (Limiiliis) amebocyte lysate (e.g., according to Chapter 85 of the U.S. Pharmacopeia, the contents of which are incorporated herein by reference), for example, by comparing with commercially available reference samples containing endotoxins.

[0412] The sterile composition according to any of the respective embodiments described herein may optionally be prepared according to a process as described herein according to any of the respective embodiments.

[0413] In some embodiments, a process of preparing a sterile composition comprises providing an aqueous composition comprising the aqueous carrier and liposomes which comprise at least one bilayer-forming lipid (e.g., according to any of the respective embodiments described herein) and a polymeric compound (e.g., according to any of the respective embodiments described herein); and subjecting the aqueous composition to a temperature of over 100 °C.

[0414] The sterile composition obtained according to the process may optionally be a sterile composition according to any of the respective embodiments described herein.

[0415] In some of any of the respective embodiments described herein, according to any of the aspects described herein, the temperature to which the aqueous composition is subjected is no more than 150 °C, for example, from 110 °C to 150 °C, or from 115 °C to 150 °C, or from 121 °C to 150 °C, or from 130 °C to 150 °C. In some of any of the respective embodiments described herein, the temperature to which the aqueous composition is subjected is no more than 140 °C, for example, from 110 °C to 140 °C, or from 115 °C to 140 °C, or from 121 °C to 140 °C, or from 130 °C to 140 °C.

[0416] In some of any of the respective embodiments described herein, the temperature to which the aqueous composition is subjected is no more than 134 °C, for example, from 110 °C to 134 °C, or from 115 °C to 134 °C, or from 121 °C to 134 °C.

[0417] In some of any of the respective embodiments described herein, the temperature to which the aqueous composition is subjected is no more than 130 °C, for example, from 110 °C to 130 °C, or from 115 °C to 130 °C, or from 121 °C to 130 °C.

[0418] In some of any of the respective embodiments described herein, the temperature to which the aqueous composition is subjected is no more than 125 °C, for example, from 110 °C to 125 °C, or from 115 °C to 125 °C, or from 121 °C to 125 °C.

[0419] In some of any of the respective embodiments described herein, subjecting the aqueous composition to a temperature of over 100 °C is effected at an elevated pressure, i.e., a pressure greater than ambient atmospheric pressure. Such a pressure may be obtained, for example, by heating the aqueous composition in a closed vessel, such that water vapor formed by the heating participates in elevating the pressure. In some such embodiments, the pressure is such that the boiling point of the aqueous composition at that pressure is equal to the temperature or near (e.g., ±10 °C or ±5 °C) the temperature to which the composition is subjected (according to any of the respective embodiments described herein).

[0420] Subjecting the composition to an elevated temperature (and optionally elevated pressure) according to any of the respective embodiments described herein may optionally be effected using a commercial apparatus configured for such use, such as an autoclave.

[0421] According to some of any of the embodiments described herein, the sterile composition is obtained or is obtainable by a process as described herein in any of the respective embodiments and any combination thereof.

[0422] The liposomes (and optionally also a water-soluble polymer described herein) of the present embodiments may optionally be administered as part of a (e.g., sterile) composition (e.g., solution) that comprises a physiologically acceptable carrier, for example an aqueous carrier which is a physiologically acceptable carrier.

[0423] Herein throughout, the term “physiologically acceptable carrier” refers to a carrier or a diluent that does not cause significant irritation to a subject upon administration in the intended manner, and does not abrogate the activity and properties of (e.g., sterile) composition (e.g., the ability of liposomes therein to treat a condition and / or to reduce a friction coefficient of a surface, as described herein in any one of the respective embodiments). Examples, without limitations, of carriers are: propylene glycol, saline, emulsions and mixtures of organic solvents with water (or saline), as well as solid (e.g., powdered) and gaseous carriers.

[0424] Techniques for formulation and administration of compounds (e.g., liposomes) may be found in “Remington’s Pharmaceutical Sciences” Mack Publishing Co., Easton, PA, latest edition, which is incorporated herein by reference.

[0425] The (e.g., sterile) compositions (e.g., solutions) according to any one of the embodiments of the present invention may be manufactured by processes well known in the art, e.g., by means of conventional mixing or dissolving processes.

[0426] The (e.g., sterile) compositions (e.g., solutions) for use in accordance with the present invention thus may be formulated in conventional manner using one or more physiologically acceptable carriers, which facilitate processing of the liposomes (and optionally also a water- soluble polymer described herein) into preparations which can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen.

[0427] For injection, the (e.g., sterile) composition according to any of the respective embodiments described herein or the liposomes described herein (optionally with a water-soluble polymer described herein) may be formulated in aqueous solutions using a suitable aqueous carrier, preferably a physiologically compatible buffers such as Hank’ s solution, Ringer’ s solution, histidine buffer, or physiological saline buffer with or without organic solvents such as propylene glycol, polyethylene glycol.

[0428] The (e.g., sterile) composition according to any of the respective embodiments described herein or the liposomes described herein (optionally with a water-soluble polymer described herein) may be formulated for parenteral administration, e.g., by bolus injection or continuous infusion. Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers with optionally, an added preservative. The (e.g., sterile) compositions may be suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and / or dispersing agents.

[0429] The (e.g., sterile) composition according to any of the respective embodiments described herein or liposomes described herein (optionally with a water-soluble polymer described herein) may be formulated as an aqueous solution per se. Additionally, the (e.g., sterile) composition (e.g., solution) may be in the form of a suspension and / or emulsions (e.g., the aqueous phase of a suspension or water-in-oil, oil-in-water or water-in-oil-in-oil emulsion), for example, in order to increase the viscosity of the formulation. Aqueous injection suspensions may contain substances, which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol or dextran. Optionally, the suspension may also contain suitable stabilizers or agents, which increase the solubility of the liposomes described herein (and / or the optional water-soluble polymer described herein), for example, to allow for the preparation of highly concentrated solutions.

[0430] In some embodiments, the liposomes described herein (optionally with a water-soluble polymer described herein) may be in powder form for constitution with a suitable vehicle, e.g., sterile, pyrogen-free water, before use.

[0431] The (e.g., sterile) composition or solutions according to any of the respective embodiments described herein may be formulated wherein the liposomes are contained in an amount effective to achieve the intended purpose, for example, an amount effective to prevent, alleviate or ameliorate symptoms of a disorder in the subject being treated, or an amount effective to reduce or prevent wear of an implantable device and thereby prevent, alleviate or ameliorate symptoms of a disorder in the subject being treated. Additionally or alternatively, the (e.g., sterile) composition may be in the form of a suspension and / or emulsions (e.g., water-in-oil, oil-in-water or water-in-oil-in-oil emulsion), for example, in order to increase the viscosity of the formulation. Aqueous injection suspensions may contain substances, which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol or dextran. Optionally, the suspension may also contain suitable stabilizers or agents, which increase the solubility and / or stability of the liposomes described herein, for example, to allow for the preparation of highly concentrated solutions.

[0432] The dosage may vary depending upon the dosage form employed, the route of administration utilized, the location of administration (e.g., the volume and / or surface of the region contacted with the liposomes), the judgment of the operating physician or the surgeon, etc.

[0433] The amount of a composition to be administered will, of course, be dependent on the subject being treated, the severity of the affliction, the manner of administration, the judgment of the prescribing physician, etc.

[0434] The (e.g., sterile) compositions (e.g., solutions) according to embodiments of the present invention may, if desired, be presented in a pack or dispenser device, such as an FDA (the U.S. Food and Drug Administration) approved kit, which may contain one or more unit dosage forms containing the active ingredient(s) (e.g., liposomes described herein or a composition comprising same as described herein). The pack may, for example, comprise metal or plastic foil, such as, but not limited to a blister pack. The pack or dispenser device may be accompanied by instructions for administration. The pack or dispenser may also be accompanied by a notice associated with the container in a form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals, which notice is reflective of approval by the agency of the form of the (e.g., sterile) compositions for human or veterinary administration. Such notice, for example, may be of labeling approved by the U.S. Food and Drug Administration for prescription drugs or of an approved product insert. Compositions (e.g., sterile) comprising liposomes (optionally with a water-soluble polymer or an active agent as described herein), as described herein in any one of the respective embodiments, formulated in a physiologically acceptable carrier may also be prepared, placed in an appropriate container, and labeled for treatment of an indicated condition or analysis, as is detailed herein.

[0435] In some embodiments of any of the embodiments described herein, the (e.g., sterile) composition (or any other composition or formulation descried herein comprising liposomes) further comprises a water-soluble polymer, optionally as part of the carrier.

[0436] As used herein, the phrase “water-soluble polymer” encompasses polymers having a solubility of at least 1 gram per liter in an aqueous (e.g., water) environment at pH 7 (at 25 °C).

[0437] 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 abovementioned 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.

[0438] The water-soluble polymer(s) according to any of the embodiments described herein may comprise at least one ionic polymer and / or at least one non-ionic polymer which are water-soluble as defined herein.

[0439] As used herein, the phrase "non-ionic polymer" refers to a polymer which does not have a charged group. Examples of suitable non-ionic water-soluble polymers include, without limitation, polyvinylpyrrolidone (also referred to herein interchangeably as povidone and / or PVP) and polyethylene oxide (also referred to herein interchangeably as PEO, PEG and / or polyethylene glycol).

[0440] As used herein, the phrase “ionic polymer” refers to polymers having at least one charged group, and encompasses polymers having a net negative charge (also referred to herein as “anionic polymers”), polymers having a net positive charge (also referred to herein as “cationic polymers”), and polymers having no net charge (also referred to herein as “zwitterionic polymers”), in an aqueous (e.g., water) environment at pH 7.

[0441] Herein throughout, the phrase “charged group” refers to any functional group (e.g., a functional group described herein) which is ionic (as defined herein), including, for example, amine, carboxylic acid, sulfate, sulfonate, phosphate and phosphonate. Thus, each electric charge in a moiety or molecule is associated with one charged group, although a single charged group (e.g., non-substituted phosphate) may be associated with more than one electric charge of the same sign (e.g., a dianion, a dication).

[0442] Herein throughout, the term “ionic” refers to the presence of an electric charge on at least one atom in a moiety and / or molecule (in at least 50 % of moieties and / or molecules in a population) in an aqueous medium (e.g., water) at pH 7. The electric charge may be negative (anionic) or positive (cationic). If more than one electric charge is present, the electric charges may be negative (anionic) and / or positive (cationic), for example, both a negative and a positive charge may be present (zwitterionic).

[0443] Examples of ionic polymers include, without limitation, ionic polysaccharides, such as hyaluronic acid, chondroitin sulfate, alginic acid, xanthan gum, chitosan and N-alkyl chitosan derivatives.

[0444] According to exemplary embodiments, the water soluble polymer is or comprises hyaluronic acid.

[0445] According to some of any of the embodiments described herein, an amount of the water- soluble polymer (e.g., hyaluronic acid) in the composition is in range of from 0.01 to 10, or from 0.05 to 10, or from 0.1 to 10, or from 0.01 to 5, or from 0.1 to 5, or from 0.1 to 1, or from 0.05 to 1, or from 0.05 to 0.5, or from 0.1 to 0.5, or from % by weight of the total weight or the total volume of the composition, including any intermediate values and subranges therebetween.

[0446] According to some of any of the embodiments described herein, a weight ratio of the water soluble polymer and the liposomes or bilayer lipid in the composition is in a range of from 20: 1 to 1:20, or from 10:1 to 1:10, or from 5:1 to 1:5, or from 3:1 to 1:3, or from 2:1 to 1:2, including any intermediate values and subranges therebetween, or can be about 1:1.

[0447] According to some of any of the embodiments described herein, the water-soluble polymer (e.g., hyaluronic acid) does not form a part of the composition but is rather used in any of the methods and uses described herein in combination with the (e.g., sterile) composition. For example, the water-soluble polymer is co-administered to a subject, along with the composition and with implantation of the implantable device. The water-soluble polymer can be administered prior to, concomitant with or subsequent to administration of the composition of the present embodiments.

[0448] When a composition as described herein in used in treating a medical condition as described herein, the composition can further comprise one or more therapeutically active agent(s) (e.g., according to any of the respective embodiments described herein). Alternatively, a therapeutically active agent does not form a part of the composition but is rather used in any of the methods and uses described herein in combination with the (e.g., sterile) composition. For example, the therapeutically active agent is co-administered to a subject, along with the composition and optionally a water-soluble polymer as described herein, and with implantation of the implantable device. The therapeutically active agent can be administered prior to, concomitant with or subsequent to administration of the composition of the present embodiments.

[0449] Examples of therapeutically active agents suitable in the context of the present embodiments include, without limitation, analgesics and anti-inflammatory agents.

[0450] Examples of suitable analgesics include, without limitation, allylprodine, alphamethylfentanyl, AP-237, bezitramide, butorphanol, buprenorphine, carfentanyl, clonidine, codeine, desmethylprodine, dextromoramide, dexocine, difenoxin, dihydrocodeine, dihydroetorphine, dihydromorphine, diphenoxylate, dipipanone, eluxadoline, ethylmorphine, etorphine, fentanyl, heterocodeine, hydrocone, hydromorphone, ketamine, ketobemidone, lefetamine, levomethadyl (e.g., levomethadyl acetate), levomethorphan, levorphanol, loperamide, meptazinol, methadone, mexiletine, mitragynine, morphine, nalbuphine, ohmefentanyl, oxycodone, oxymorphone, paracetamol, pentazocine, pethidine, phenethylphenylacetoxypiperidine, piritramide, prodine, promedol, propoxyphene, remifentanil, sulfentanil, tapentadol, tilidine, and tramadol.

[0451] Non-steroidal anti-inflammatory agents (e.g., a non-steroidal anti-inflammatory agent described herein), as well as steroidal anti-inflammatory agents, may also be used as an analgesic. Examples of suitable anti-inflammatory agents include, without limitation, alclofenac; alclometasone (e.g., alclometasone dipropionate); algestone (e.g., algestone acetonide); alpha amylase; amcinafal; amcinafide; amfenac (e.g., amfenac sodium); amiprilose (e.g., amiprilose hydrochloride); anakinra; anirolac; anitrazafen; apazone; aspirin; balsalazide disodium; bendazac; benoxaprofen; benzydamine (e.g., benzydamine hydrochloride); bromelains; broperamole; budesonide; carprofen; cicloprofen; cintazone; cliprofen; clobetasol (e.g., clobetasol propionate, clobetasone butyrate); clopirac; cloticasone (cloticasome propionate); cormethasone (cormethasone acetate); cortodoxone; deflazacort; desonide; desoximetasone; dexamethasone (e.g., dexamethasone dipropionate); diclofenac (e.g., diclofenac potassium, diclofenac sodium); diflorasone (e.g., diflorasone diacetate); diflumidone (e.g., diflumidone sodium); difhmisal; difluprednate; diftalone; drocinonide; endrysone; enlimomab; enolicam (e.g., enolicam sodium); epirizole; etodolac; etofenamate; felbinac; fenamole; fenbufen; fenclofenac; fenclorac; fendosal; fenpipalone; fentiazac; flazalone; fluazacort; flufenamic acid; flumizole; fhmisolide (e.g., fhmisolide acetate); flunixin (e.g., fhmixin meglumine); fluocortin (e.g., fluorcortin butyl); fluoromethoIone (e.g., fluoromethoIone acetate); fluquazone; flurbiprofen; fluretofen; fluticasone (e.g., fluticasone propionate); furaprofen; furobufen; halcinonide; halobetasol (e.g., halobetasol propionate); halopredone (e.g., halopredone acetate); ibufenac; ibuprofen (e.g., ibuprofen aluminum, ibuprofen piconol); ilonidap; indomethacin (e.g., indomethacin sodium); indoprofen; indoxole; intrazole; isoflupredone (e.g., isoflupredone acetate); isoxepac; isoxicam; ketoprofen; lofemizole (e.g., lofemizole hydrochloride); lomoxicam; loteprednol (e.g., loteprednol etabonate); meclofenamate (e.g., meclofenamate sodium, meclofenamic acid); meclorisone (e.g., meclorisone dibutyrate); mefenamic acid; mesalamine; meseclazone; methylprednisolone (e.g., methylprednisolone suleptanate); momiflumate; nabumetone; naproxen (e.g., naproxen sodium); naproxol; nimazone; olsalazine (e.g., olsalazine sodium); orgotein; orpanoxin; oxaprozin; oxyphenbutazone; paranyline (e.g., paranyline hydrochloride); pentosan polysulfate (e.g., pentosan polysulfate sodium); phenbutazone (e.g., phenbutazone sodium glycerate); pirfenidone; piroxicam (e.g., piroxicam cinnamate, piroxicam olamine); pirprofen; prednazate; prifelone; prodolic acid; proquazone; proxazole (e.g., proxazole citrate); rimexolone; romazarit; salcolex; salicylate (e.g., salicylic acid); salnacedin; salsalate; sanguinarium (e.g., sanguinarium chloride); seclazone; sermetacin; sudoxicam; sulindac; suprofen; talmetacin; talniflumate; talosalate; tebufelone; tenidap (e.g., tenidap sodium); tenoxicam; tesicam; tesimide; tetrydamine; tiopinac; tixocortol (e.g., tixocortol pivalate); tolmetin (e.g., tolmetin sodium); triclonide; triflumidate; zidometacin; and zomepirac (e.g., zomepirac sodium).

[0452] Alternatively, or in addition, a liposome composition as described herein in any of the respective embodiments is co-administered to the subject with a therapeutically active agent as described herein.

[0453] According to an aspect of some embodiments of the present invention there is provided a kit which comprises a composition as described herein in any of the respective embodiments and any combination, or which comprises components for preparing the composition. The kit may comprise, for example, dehydrated liposomes and a suitable aqueous solution, and optionally a water soluble polymer and / or a therapeutically active agent and / or an additional agent (e.g., sterol), each being individually packaged in the kit, and instructions to prepare the composition by, for example, mixing all ingredients. The kit may alternatively comprise a polymeric compound and a bilayer-forming lipid, and a suitable aqueous solution, and optionally a water soluble polymer and / or a therapeutically active agent and / or an additional agent (e.g., sterol), each being individually packaged in the kit, and instructions to prepare the composition by, for example, mixing all ingredients. The kit may alternatively comprise a ready-to-use composition as described herein in any of the respective embodiments. In cases where the composition further comprises a water-soluble polymer, the water-soluble polymer can be included in the composition or can be packaged individually within the kit, with instructions to mix it with the composition or to co-administer it with the composition, as described herein. Alternatively, the kit may comprise instructions to co-administer the composition and the water-soluble polymer, as described herein. The kit may alternatively comprise a polymeric compound and a bilayer-forming lipid, and optionally a water soluble polymer and / or a therapeutically active agent and / or an additional agent (e.g., sterol), each being individually packaged in the kit, and instructions to prepare the composition by, for example, by mixing all ingredients in the presence of a suitable aqueous solution, either simultaneously or sequentially. For example, the kit may comprise instructions to first form liposomes or lipid bilayers by mixing the polymeric compound and the bilayer-forming lipid with the aqueous solution, and then add to the formed composition an additional component, if so desired. The kit may further comprise instructions to subject a prepared or packaged composition to sterilization, as described herein, before use (in cases other than when a sterilized composition is already packaged in the kit).

[0454] A kit as described herein in any of the respective embodiments may further comprise instructions to use the composition in combination with an implantable device as described herein in any of the respective embodiments, and / or in any of the methods or uses as described herein in any of the respective embodiments, e.g., for reducing wear of the implantable device and / or treating a condition treatable by implanting the device. A kit as described herein in any of the respective embodiments may further comprise an implantable device as described herein, individually packaged within the kit.

[0455] According to an aspect of some embodiments of the present invention there is provided a kit which comprises a composition as described herein in any of the respective embodiments and the implantable device, as described herein in any of the respective embodiments and any combination thereof. In some embodiments, the composition is in contact with the implantable device, for example, as a solution in which the device is dipped.

[0456] Methods and Uses:

[0457] A composition as described herein in any of the respective embodiments is for use in combination with an implantable device (also referred to herein as “an implant”), during the process of implanting the device in a subject in need thereof. According to some of the present embodiments, the composition is for reducing wear of the implantable device, upon implantation.

[0458] The subject may be human or a non-human animal, such that the phrase “medical device” encompasses veterinary devices. According to an aspect of some embodiments of the present invention, there is provided a composition as described herein in any of the respective embodiments and any combination thereof, for use in combination with an implantable device (an implant). According to some embodiments, the composition is used in combination with the device during the implantation of the implantable device in a subject in need thereof. According to some embodiments, the composition is administered to the subject during the implantation of the implantable device in a subject in need thereof. According to some embodiments, the composition forms a part of the implantable device (e.g., is deposited on at least a portion thereof, for example, on at least a portion of a surface thereof).

[0459] According to an aspect of some embodiments of the present invention, there is provided a use of a composition as described herein in any of the respective embodiments in the manufacture of a medicament or a medical device, which is usable or is for use in combination with an implantable device (an implant). According to some embodiments, the composition is used in combination with the implantable device during the implantation of the implantable device in a subject in need thereof. According to some embodiments, the composition is administered to the subject during the implantation of the implantable device in a subject in need thereof. According to some embodiments, the composition forms a part of the implantable device (e.g., is deposited on at least a portion thereof).

[0460] According to an aspect of some embodiments of the present invention, there is provided a method of implanting an implantable device (an implant) in a subject in need thereof, the method comprising co-administering the composition as described herein in any of the respective embodiments and any combination thereof and the implantable device to the subject. According to some embodiments, the composition is used in combination with the implantable device during the implantation of the implantable device in a subject in need thereof. According to some embodiments, the composition is administered to the subject during the implantation of the implantable device in a subject in need thereof. According to some embodiments, the composition forms a part of the implantable device (e.g., is deposited on at least a portion thereof).

[0461] The phrase “during the implantation of the implantable device” as used herein means that composition is administered to the subject prior to, concomitant with and / or subsequent to implanting the implantable device. The composition can be administered during a time period that ranges from 1 minute to 1 day before the implantation, or from 1 minute to 1 day subsequent to the implantation, or can be administered while the device is implanted, during the implantation procedure. The composition can be administered both prior to and subsequent to the implantation, or prior to and concomitant with the implantation, or concomitant with and subsequent to the implantation, or prior to, concomitant with and subsequent to the implantation.

[0462] According to some of any of the embodiments described herein, the composition is administered locally, to the bodily site in which the implantable device is implanted, or in a vicinity thereof.

[0463] According to some of any of the embodiments described herein, the composition is readministered subsequent to the implantation, as needed as long as the implant is in the subject’s body. In exemplary embodiments, the composition is repeatedly re-administered to the subject, subsequent to the implantation, as needed, in time intervals of from 1 week to 1 year, or from 1 month to one year, or from one month to 6 months, from the implantation and between administrations, including any intermediate values and subranges therebetween. The time intervals can be the same or different.

[0464] The implantable device, or implant, can be a permanent implant or a transient implant, including, but not limited to, replacement joints, pacemakers, heart valves, catheters (e.g., urinary catheters, intravascular catheters), catheter access ports, dialysis tubing, gastric bands, shunts, screw plates, artificial spinal disc replacements, internal implantable defibrillators, cardiac resynchronization therapy devices, implantable cardiac monitors, mitral valve ring repair devices, left ventricular assist devices (LVADs), artificial hearts, implantable infusion pumps, implantable insulin pumps, stents, implantable neurostimulators, maxillofacial implants, dental implants, injection ports, intubation equipment, dialysis shunts, wound drain tubes, skin sutures, vascular grafts, implantable meshes, intraocular devices, heart valves, medical devices for drug delivery such, but not limited to, needles, drug delivery skin patches, drug delivery mucosal patches and medical sponges, intrauterine devices (IUDs), diaphragms and condoms.

[0465] In the context of medical devices, it is to be understood that when the medical device is coated by a lipid bilayer as described herein, the lipid bilayer or bilayer-comprising liposome per se is not considered herein to be a medical device.

[0466] Implantable devices that are particularly suitable for use in the context of the present embodiments include, but are not limited to, implants that are intended to be maintained in the bodily site of the subject for a period of at least one week, and / or which are wearable, that is, are susceptible and / or exposed to wear as a result of physical forces during movement or weightbearing and / or which are susceptible chemical decomposition due to protein and / or lipid diffusion and / or cleavage or microbial contamination.

[0467] According to some of any of the embodiments described herein, the implantable device is a wearable implantable device, that is, is a device that upon implantation is exposed to wear as a result of physical forces during movement or weight-bearing. Depending on the bodily site in which the device is implanted, the device is considered wearable if implanted in a bodily site that is typically exposed to compressive forces that range from 1 to 5 times the body weight of the subject, and / or to shear, tensile and / or rotational forces as a results of movement or other activities. The exposure to such forces can be during movement, standing, lifting, and / or any other activity, and / or at rest.

[0468] According to some of any of the embodiments described herein, the implantable device or a material used to form the implantable device is characterized by high rigidity.

[0469] In some embodiments, the implantable device or a material used to form the implantable device is characterized by elastic modulus of at least 0.5 GPa, or least 1 GPa, preferably at least 10 GPa, or at least 20 GPa, or of at least 50 GPa, or of at least 100 GPa, for example, of from 1 to 500, or from 10 to 500, or from 50 to 500, or from 100 to 500, or from 1 to 400, or from 10 to 400, or from 50 to 400, or from 100 to 400, or from 1 to 300, or from 10 to 300, or from 50 to 300, or from 100 to 300, GPa, including any intermediate values and subranges therebetween.

[0470] In some embodiments, the implantable device or a material used to form the implantable device is characterized by tensile strength of at least 20 MPa, or at least 50 MPs, or at least 100 MPa, or at least 200 MPa, or at least 300 MPa, or of at least 400 MPa, or of at least 500 GPa, or of at least 800 MPa, for example, of from 100 to 2000, or from 100 to 1500, or from 500 to 200, or from 500 to 1500, or from 800 to 2000, or from 800 to 1500, MPa, including any intermediate values and subranges therebetween.

[0471] In some embodiments, the implantable device or a material used to form the implantable device is characterized by elastic modulus of at least 0.5 GPa, or least 1 GPa, or at least 10 GPa, or at least 20 GPa, or of at least 50 GPa, or of at least 100 GPa, for example, of from 1 to 500, or from 10 to 500, or from 50 to 500, or from 100 to 500, or from 1 to 400, or from 10 to 400, or from 50 to 400, or from 100 to 400, or from 1 to 300, or from 10 to 300, or from 50 to 300, or from 100 to 300, GPa, including any intermediate values and subranges therebetween, and by tensile strength of at least 20 MPa, or at least 50 MPs, or at least 100 MPa, or at least 200 MPa, or at least 300 MPa, or of at least 400 MPa, or of at least 500 GPa, or of at least 800 MPa, for example, of from 100 to 2000, or from 100 to 1500, or from 500 to 200, or from 500 to 1500, or from 800 to 2000, or from 800 to 1500, MPa, including any intermediate values and subranges therebetween.

[0472] Herein and in the art, the phrase “elastic modulus” refers to Young’s modulus, as determined by response of a material to application of tensile stress.

[0473] The elastic modulus is determined as the gradient of stress as a function of strain over ranges of stress and strain wherein stress is a linear function of strain (e.g., from a stress and strain of zero, to the elastic proportionality limit, and optionally from zero strain to a strain which is no more than 50 % of the elongation at failure). Elastic modulus can be determined, for example, using standard mechanical testing methods such as tensile tests, compression tests, or bending tests, depending on the material and the test conditions. Exemplary standard methods include ASTM D638, which is typically used for plastics and hydrogels; ASTM D624, which is typically used for rubbery, elastomeric materials; ASTM D3039, which is typically used for fiber-reinforced polymer matrix composites; and ASTM El 11, which is typically used for metals and alloys.

[0474] Herein and in the art, the phrase “tensile strength” describes a material’s resistance to tension, or, in other words, its capacity to withstand loads tending to elongate, and is defined as the maximum stress in MPa, applied during stretching of an elastomeric composite before its rupture. Tensile strength is typically measured by a tensile test and is determined as the highest point of a Stress-Strain curve, as described herein and in the art. Tensile strength represents the maximum stress that a material can withstand while being stretched or pulled before breaking. Tensile strength may also be determined, for example, according to ASTM D-638, ASTM D624, ASTM E8, or ASTM D2370, depending on the tested material.

[0475] According to some of any of the embodiments described herein, the implantable device or a material used to form the implantable device is characterized by fatigue resistance of at least 10 MPa, preferably at least 20 MPa, or at least 40 MPa, or at least 50 MPa, or at least 100 MPa, for example, of from 10 to 1000, or from 10 to 500, or from 20 to 1000, or from 20 to 800, or from 20 to 500, MPa, including any intermediate values and subranges therebetween.

[0476] By “fatigue resistance” it is meant the repetitive mechanical stress a device or material can withstand before failure (e.g., crack initiation and propagation due to cyclic stress). It can be measured using pin-on-disk measurements, or according to standard assays such as ISO 7206-4.

[0477] According to some of any of the embodiments described herein, the implantable device is for use in replacement therapy, and is a prosthetic implant such as a joint replacement device or a spinal-disk replacement device, or a prosthetic implant that comprises such a device.

[0478] According to some of any of the embodiments described herein, the implantable device is or comprises a total joint replacement device, such as used, for example, in total joint replacement of a hip, a knee, a shoulder, an elbow, or an ankle. In exemplary embodiments, the total joint replacement is of the major weight-bearing joints - a knee or a hip. According to these embodiments, the composition is used in a total joint replacement therapy, during a total joint replacement procedure. According to some of any of the embodiments described herein, the implantable device is an orthopedic implantable device, for example, implantable screws, plates and pins, and any other devices used in orthopedic procedures.

[0479] According to some of any of the embodiments described herein, the implantable device is a solid implantable device.

[0480] According to some of any of the embodiments described herein, the implantable device is in a liquid state before and during its insertion to the subject’s body, and is hardened upon implantation, for example, as a result of a chemical reaction with biological components and / or as a result of exposure to a condition that affects its hardening. For example, the implantable device can be a liquid that forms a gel when contacting a biological component. For example, the implantable device can be a liquid that polymerizes when contacting a biological component or when contacting components that are administered therewith, via, for example, chemical reactions optionally in combination with an external energy (e.g., heat or irradiation). For example, the implantable device can be a photocurable or thermally-curable liquid or gel, which hardens upon implantation and application or irradiation and / or heat to the implantation site. For example, the implantable device can be made of a thermosetting material or of a reverse-thermal gelating material, which hardens at a physiological temperature. Any other devices which can be implanted in a liquid form (e.g., via injection) and subsequently harden to form in vivo a solid or semi-solid implant are contemplated.

[0481] According to some of any of the embodiments described herein, the implantable device is a biodegradable or bioresorbable device, and in some of these embodiments, the device degrades or resorb in the subject’s body within a time period of from 1 week to several years, or from 1 month to several years, or from 1 year to several years, including any intermediate values and subranges therebetween.

[0482] Any commercially available implantable device is contemplated within the present embodiments.

[0483] Any commercially available joint replacement device is contemplated within the present embodiments.

[0484] Any commercially available knee or hip replacement device is contemplated within the present embodiments.

[0485] According to some of any of the embodiments described herein, the implantable device is made of, or comprises, one or more of a polymeric material, a biological material (e.g., a proteinaceous material, an ECM component), a metallic material and a ceramic material. According to some of any of the embodiments described herein, the implantable device is made of, or comprises, a material that is capable to withstand compression forces as described herein, and / or is characterized by high elastic modulus and / or tensile strength, as described herein.

[0486] Exemplary polymeric materials include, but are not limited to, polyethylene (e.g., ultrahigh molecular weight polyethylene such as described herein), biomedical polyurethanes and / or polyurethaneureas, which can be is a solid or solution form, polyester amides such as degradable polyester amides, and any other biodegradable polymers and / or polymers used in coating of medical devices (e.g., hydrophilic polymers). Any of these materials can be in a form of fibers, films, meshes, and / or membranes, or can be in polymerizable or curable form, which hardens upon implantation, as described herein. Preferably, the polymeric material is such that exhibits mechanical properties as described herein for the implantable device.

[0487] Exemplary biological materials include, but are not limited to, materials used in bone filling or regeneration or in tissue repair or in tissue augmentation or in tissue regeneration, including, for example, proteinaceous materials, preferably extracellular matrix (ECM) components such as, but not limited to collagen, which can be derived from a human, porcine or bovine source, or synthetically or recombinantly prepared. Preferably, the biologic material is such that exhibits mechanical properties as described herein for the implantable device.

[0488] Exemplary ceramic materials include resorbable and non-resorbable materials, curable or non-curable material, including inorganic bone materials. Preferably, the ceramic material is such that exhibits mechanical properties as described herein for the implantable device.

[0489] Exemplary metallic materials include metals such as, but are not limited to, cobalt, chrome cobalt-chrome (CoCr), titanium, platinum, stainless steel and any alloys comprising any of the foregoing. Preferably, the metallic material is such that exhibits mechanical properties as described herein for the implantable device.

[0490] According to some of any of the embodiments described herein, the implantable device comprises polyethylene, preferably a ultrahigh molecular weight polyethylene such as described herein, which can be cross-linked, partially cross-linked or non-cross-linked, and which can be in a form of fibers, films, meshes, and / or membranes, or as a polymerizable or curable material.

[0491] According to some of any of the embodiments described herein, any of the methods and uses described herein are for treating a condition that is treatable by implantation of the implant as described herein. According to these embodiments, the composition as described herein is for reducing wear and improving the performance, stability and / or durability of the implant, and / or for preventing its contamination, and thereby for improving the treatment. According to these embodiments, the composition as described herein is for use in combination with implantable device in treating the condition.

[0492] According to some of any of the embodiments described herein, the composition is used in a total joint replacement procedure, in combination with a joint replacement device, and is for treating a medical condition associated with a joint defect or injury. According to some of these embodiments, the composition is administered via articular administration. Alternatively, or in addition, the composition is administered locally, during surgery, to the implantation site.

[0493] According to some embodiments, a method or use as described herein is for treating a synovial joint disorder.

[0494] Examples of synovial joint disorders treatable according to embodiments of various aspects of the invention, include, without limitation, arthritis (e.g., osteoarthritis, rheumatoid arthritis and / or psoriatic arthritis), bursitis, carpal tunnel syndrome, fibromyositis, gout, locked joint (optionally associated with osteochondritis dissecans and / or synovial osteochondromatosis), tendinitis, traumatic joint injury (optionally caused directly by trauma, e.g., inflicted at the time of the trauma, and / or by previous trauma, e.g., a post-traumatic injury which develops sometime after the trauma), and joint injury associated with surgery (optionally associated with surgery which directly inflicts damage on an articular surface, e.g., by incision, and / or surgery which damages an articular surface only indirectly; for example, surgery which repairs or otherwise affects tissue in the vicinity of the joint, such as ligaments and / or menisci, may be associated with joint injury due to altered mechanics in the joint). Osteoarthritis is an exemplary synovial joint disorder treatable according to some embodiments of the invention.

[0495] According to an aspect of some embodiments of the invention, there is provided a method of treating a synovial joint disorder in a subject in need thereof, the method comprising administering to the subject a sterile composition according to any of the respective embodiments described herein, in combination with implanting a joint replacement device in the subject, as described herein in any of the respective embodiments and any combination thereof.

[0496] In some of any of the respective embodiments, treatment of a synovial joint disorder (e.g., osteoarthritis) is characterized by an improvement in articular physiology.

[0497] In some of any of the respective embodiments, improvement in articular physiology is determined by range of motion of an afflicted joint (e.g., wherein the improvement is characterized as an increase in range of motion of the joint), optionally in addition to being characterized as a reduction in severity according to a Kellgren-Lawrence scale. In some such embodiments, the treatment is further characterized by a reduction in pain. In some of any of the respective embodiments, improvement in articular physiology is characterized by an increase in physical activity (e.g., activity involving the afflicted joint), optionally in addition to being characterized as a reduction in severity according to a Kellgren- Lawrence scale and / or as an increase in range of motion (e.g., according to any of the respective embodiments described herein). In some such embodiments, the treatment is further characterized by a reduction in pain.

[0498] In some of any of the respective embodiments, improvement in articular physiology is characterized by an increase in quality of life, optionally in addition to being characterized as a reduction in severity according to a Kellgren-Lawrence scale, an increase in range of motion and / or an increase in physical activity (e.g., according to any of the respective embodiments described herein). In some such embodiments, the treatment is further characterized by a reduction in pain.

[0499] In some of any of the respective embodiments, improvement in articular physiology is determined by at least one, or at least two, or at least three or all four of a Kellgren-Lawrence scale of radiological severity, range of motion of joint, physical activity, and quality of life (according to any of the respective embodiments described herein). In some such embodiments, the treatment is further characterized by a reduction in pain.

[0500] In any of the methods and uses described herein, the implantation procedure can be accompanied by administration of a water-soluble polymer and / or a therapeutically active agent, as described herein in any of the respective embodiments. These can be administered prior to, concomitant with and / or subsequent to the implantation and / or prior to, concomitant with and / or subsequent to administration of the composition of the present embodiments.

[0501] According to an aspect of some embodiments of the present invention, there is provided a method of reducing wear of an implantable device, as described herein in any of the respective embodiments, which comprises or is effected by a combined use of the composition as described herein and the device, for example, by co-administering the composition during implantation of the device, as described herein in any of the respective embodiments and any combination thereof.

[0502] According to some embodiments of the present invention, there are provided kits, which comprise a composition as described herein, optionally in combination with a water-soluble polymer and / or a therapeutically active agent, as these are described herein. The kit can be identified for use in combination with an implantable device, or can comprise the device and / or a material used for forming the device. Such kits can also be identified for use in pin-on-disk measurements, as described herein. Pin-on-disk:

[0503] A composition as described herein in any of the respective embodiments can be used as the testing fluid in wear measurement systems such as pin-on-disk, or any other acceptable, standard-recognized method for evaluating the wear resistance of an implantable device.

[0504] According to some embodiments of the present invention, there is provided a composition as described herein in any of the respective embodiments, or a kit comprising same, as described herein, for use in wear measurements of an implantable device, as described herein. In some embodiments, the wear measurements are pin-on-disk measurements.

[0505] According to some embodiments of the present invention, there is provided pin-on-disk system, comprising the composition as described herein in any of the respective embodiments and any combination thereof.

[0506] Any pin-on-disk system or set up are contemplated.

[0507] In some embodiments, the pin in the pin-on-disk system comprises one or more of the materials used for forming the implantable device or the implant, as described herein in any of the respective embodiments and any combination thereof.

[0508] In some embodiments, such a pin is assembled with a suitable disk to provide a pin-on- disk system as is well-known in the art and is exemplified in FIGs. 1A-B.

[0509] Generally, a pin-on-disk system tribological testing system comprises a disk mounted on a rotational drive mechanism; a pin held in a fixture and pressed against the surface of the disk with a controlled normal force; and a load mechanism for applying the controlled normal force to the pin.

[0510] A pin-on-disk system tribological testing system typically further comprises means for measuring the frictional force between the pin and the disk; and optionally a data collection system for recording frictional force, wear measurements, and other parameters measured during the test. The system may further comprise an environmental control chamber configured to control temperature and humidity during testing.

[0511] When a pin-on-disk system is operated, the disk is rotated by a motor at a controlled speed. The rotation direction can be adjusted as desired.

[0512] The disk is typically a flat, rotating surface made of a material as described herein. The disk is mounted onto a rotating assembly driven by a motor or similar rotational mechanism. The disk's surface is typically smooth and polished, although variations in surface texture or coatings may be used based on the testing requirements. The disk is typically positioned horizontally, although alternative orientations may be used depending on specific testing conditions. The pin is a cylindrical or other geometric ally- shaped test specimen, typically made of a material similar to or representative of the material being tested (a potential material for forming an implantable device or an implant as described herein). The pin is held in a fixture above the rotating disk and pressed into contact with the surface of the disk under a controlled normal load. The pin may be oriented perpendicular to the disk surface, although variations in alignment may be made to test different wear scenarios. The pin is typically of smaller diameter compared to the disk, creating a localized contact region.

[0513] The load mechanism is typically a device configured to apply a controlled, adjustable normal force to the pin, so as to press the pin against the disk surface. The load mechanism may include a spring-loaded assembly, pneumatic actuator, or other force-generating systems capable of providing precise force control. The load is typically maintained constant throughout the duration of the test or may be varied to simulate different operating conditions.

[0514] The disk is rotated by a motor or other drive assembly, enabling controlled rotation of the disk surface in contact with the pin. The rotational speed of the disk can be adjusted to simulate different speeds of wear and friction.

[0515] Wear can be quantified by measuring the volume or mass loss of the pin and / or disk after a predetermined number of test cycles. High-precision devices, such as laser scanning or optical profilometers, may be employed to measure wear scar depth, surface roughness, or other relevant wear metrics.

[0516] A computer-based control system can be employed to coordinate the movement of the disk, the application of load, the environmental conditions and the data collection. The system may also include software for analyzing wear patterns, calculating wear rates, and determining the relationship between friction and wear under different testing conditions. The control system can store test data and generate reports on the performance of the tested materials.

[0517] As used herein, the term “subject” includes mammals, preferably human beings at any age which suffer from the pathology. Preferably, this term encompasses individuals who are at risk to develop the pathology.

[0518] It is expected that during the life of a patent maturing from this application many relevant implantable devices, material comprised by implantable devices and systems and method for wear measurements of implantable devices will be developed and the scope of the respective terms and phrases is intended to include all such new technologies a priori.

[0519] As used herein the term “about” refers to ± 10 % or ± 5 %.

[0520] The terms “comprises”, “comprising”, “includes”, “including”, “having” and their conjugates mean “including but not limited to”. The term “consisting of’ means “including and limited to”.

[0521] The term “consisting essentially of’ means that the composition, method or structure may include additional ingredients, steps and / or parts, but only if the additional ingredients, steps and / or parts do not materially alter the basic and novel characteristics of the claimed composition, method or structure.

[0522] As used herein, the singular form “a”, “an” and “the” include plural references unless the context clearly dictates otherwise. For example, the term “a compound” or “at least one compound” may include a plurality of compounds, including mixtures thereof.

[0523] Throughout this application, various embodiments of this invention may be presented in a range format. It should be understood that the description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the invention. Accordingly, the description of a range should be considered to have specifically disclosed all the possible subranges as well as individual numerical values within that range. For example, description of a range such as from 1 to 6 should be considered to have specifically disclosed subranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual numbers within that range, for example, 1, 2, 3, 4, 5, and 6. This applies regardless of the breadth of the range.

[0524] Whenever a numerical range is indicated herein, it is meant to include any cited numeral (fractional or integral) within the indicated range. The phrases “ranging / ranges between” a first indicate number and a second indicate number and “ranging / ranges from” a first indicate number “to” a second indicate number are used herein interchangeably and are meant to include the first and second indicated numbers and all the fractional and integral numerals therebetween.

[0525] As used herein the term “method” refers to manners, means, techniques and procedures for accomplishing a given task including, but not limited to, those manners, means, techniques and procedures either known to, or readily developed from known manners, means, techniques and procedures by practitioners of the chemical, pharmacological, biological, biochemical and medical arts.

[0526] The term “treating” refers to inhibiting, preventing or arresting the development of a pathology (disease, disorder or condition) and / or causing the reduction, remission, or regression of a pathology. Those of skill in the art will understand that various methodologies and assays can be used to assess the development of a pathology, and similarly, various methodologies and assays may be used to assess the reduction, remission or regression of a pathology. As used herein, the term “preventing” refers to keeping a disease, disorder or condition from occurring in a subject who may be at risk for the disease, but has not yet been diagnosed as having the disease.

[0527] Herein, the term “hydrocarbon” describes an organic moiety that includes, as its basic skeleton, a chain of carbon atoms, substituted mainly by hydrogen atoms. The hydrocarbon can be saturated or non- saturated, be comprised of aliphatic, alicyclic or aromatic moieties, and can optionally be substituted by one or more substituents (other than hydrogen). A substituted hydrocarbon may have one or more substituents, whereby each substituent group can independently be, for example, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroalicyclic, amine, halide, sulfonate, sulfoxide, phosphonate, hydroxy, alkoxy, aryloxy, thiohydroxy, thioalkoxy, thioaryloxy, oxo, cyano, nitro, azo, azide, sulfonamide, carboxy, thiocarbamate, urea, thiourea, carbamate, amide, and hydrazine. The hydrocarbon can be an end group or a linking group, as these terms are defined herein. The hydrocarbon moiety is optionally interrupted by one or more heteroatoms, including, without limitation, one or more oxygen, nitrogen and / or sulfur atoms. In some embodiments of any of the embodiments described herein relating to a hydrocarbon, the hydrocarbon is not interrupted by any heteroatoms.

[0528] Preferably, the hydrocarbon moiety has 1 to 20 carbon atoms. Whenever a numerical range; e.g., “1 to 20”, is stated herein, it implies that the group, in this case the alkyl group, may contain 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 20 carbon atoms.

[0529] Herein, the term “alkyl” describes a saturated aliphatic hydrocarbon end group, as defined herein, including straight chain and branched chain groups. Preferably, the alkyl group has 1 to 20 carbon atoms. More preferably, the alkyl is a medium size alkyl having 1 to 10 carbon atoms. Most preferably, unless otherwise indicated, the alkyl is a lower alkyl having 1 to 4 carbon atoms. The alkyl group may be substituted or non-substituted. Substituted alkyl may have one or more substituents, whereby each substituent group can independently be, for example, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroalicyclic, amine, halide, sulfonate, sulfoxide, phosphonate, hydroxy, alkoxy, aryloxy, thiohydroxy, thioalkoxy, thioaryloxy, cyano, nitro, azo, azide, sulfonamide, carboxy, thiocarbamate, urea, thiourea, carbamate, amide, and hydrazine.

[0530] The term "alkylene" describes a saturated aliphatic hydrocarbon linking group, as this term is defined herein, which differs from an alkyl group, as defined herein, only in that alkylene is a linking group rather than an end group.

[0531] Herein, the term “alkenyl” describes an unsaturated aliphatic hydrocarbon end group which comprises at least one carbon-carbon double bond, including straight chain and branched chain groups. Preferably, the alkenyl group has 2 to 20 carbon atoms. More preferably, the alkenyl is a medium size alkenyl having 2 to 10 carbon atoms. Most preferably, unless otherwise indicated, the alkenyl is a lower alkenyl having 2 to 4 carbon atoms. The alkenyl group may be substituted or non-substituted. Substituted alkenyl may have one or more substituents, whereby each substituent group can independently be, for example, cycloalkyl, alkynyl, aryl, heteroaryl, heteroalicyclic, amine, halide, sulfonate, sulfoxide, phosphonate, hydroxy, alkoxy, aryloxy, thiohydroxy, thioalkoxy, thioaryloxy, cyano, nitro, azo, azide, sulfonamide, carboxy, thiocarbamate, urea, thiourea, carbamate, amide, and hydrazine.

[0532] Herein, the term “alkynyl” describes an unsaturated aliphatic hydrocarbon end group which comprises at least one carbon-carbon triple bond, including straight chain and branched chain groups. Preferably, the alkynyl group has 2 to 20 carbon atoms. More preferably, the alkynyl is a medium size alkynyl having 2 to 10 carbon atoms. Most preferably, unless otherwise indicated, the alkynyl is a lower alkynyl having 2 to 4 carbon atoms. The alkynyl group may be substituted or non-substituted. Substituted alkynyl may have one or more substituents, whereby each substituent group can independently be, for example, cycloalkyl, alkenyl, aryl, heteroaryl, heteroalicyclic, amine, halide, sulfonate, sulfoxide, phosphonate, hydroxy, alkoxy, aryloxy, thiohydroxy, thioalkoxy, thioaryloxy, cyano, nitro, azo, azide, sulfonamide, carboxy, thiocarbamate, urea, thiourea, carbamate, amide, and hydrazine.

[0533] The term “cycloalkyl” describes an all-carbon monocyclic or fused ring (i.e., rings which share an adjacent pair of carbon atoms) group where one or more of the rings does not have a completely conjugated pi-electron system. The cycloalkyl group may be substituted or nonsubstituted. Substituted cycloalkyl may have one or more substituents, whereby each substituent group can independently be, for example, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heteroalicyclic, amine, halide, sulfonate, sulfoxide, phosphonate, hydroxy, alkoxy, aryloxy, thiohydroxy, thioalkoxy, thioaryloxy, cyano, nitro, azo, azide, sulfonamide, carboxy, thiocarbamate, urea, thiourea, carbamate, amide, and hydrazine. The cycloalkyl group can be an end group, as this phrase is defined herein, wherein it is attached to a single adjacent atom, or a linking group, as this phrase is defined herein, connecting two or more moieties.

[0534] The term “aryl” describes an all-carbon monocyclic or fused-ring polycyclic (i.e., rings which share adjacent pairs of carbon atoms) end group (as this term is defined herein) having a completely conjugated pi-electron system. The aryl group may be substituted or non-substituted. Substituted aryl may have one or more substituents, whereby each substituent group can independently be, for example, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heteroalicyclic, amine, halide, sulfonate, sulfoxide, phosphonate, hydroxy, alkoxy, aryloxy, thiohydroxy, thioalkoxy, thioaryloxy, cyano, nitro, azo, azide, sulfonamide, carboxy, thiocarbamate, urea, thiourea, carbamate, amide, and hydrazine. Phenyl and naphthyl are representative aryl end groups.

[0535] The term “heteroaryl” describes a monocyclic or fused ring (i.e., rings which share an adjacent pair of atoms) group having in the ring(s) one or more atoms, such as, for example, nitrogen, oxygen and sulfur and, in addition, having a completely conjugated pi-electron system. Examples, without limitation, of heteroaryl groups include pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrimidine, quinoline, isoquinoline and purine. The heteroaryl group may be substituted or non-substituted. Substituted heteroaryl may have one or more substituents, whereby each substituent group can independently be, for example, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heteroalicyclic, amine, halide, sulfonate, sulfoxide, phosphonate, hydroxy, alkoxy, aryloxy, thiohydroxy, thioalkoxy, thioaryloxy, cyano, nitro, azo, azide, sulfonamide, carboxy, thiocarbamate, urea, thiourea, carbamate, amide, and hydrazine. The heteroaryl group can be an end group, as this phrase is defined herein, where it is attached to a single adjacent atom, or a linking group, as this phrase is defined herein, connecting two or more moieties. Representative examples are pyridine, pyrrole, oxazole, indole, purine and the like.

[0536] The term "arylene" describes a monocyclic or fused-ring polycyclic linking group, as this term is defined herein, and encompasses linking groups which differ from an aryl or heteroaryl group, as these groups are defined herein, only in that arylene is a linking group rather than an end group.

[0537] The term “heteroalicyclic” describes a monocyclic or fused ring group having in the ring(s) one or more atoms such as nitrogen, oxygen and sulfur. The rings may also have one or more double bonds. However, the rings do not have a completely conjugated pi-electron system. The heteroalicyclic may be substituted or non-substituted. Substituted heteroalicyclic may have one or more substituents, whereby each substituent group can independently be, for example, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heteroalicyclic, amine, halide, sulfonate, sulfoxide, phosphonate, hydroxy, alkoxy, aryloxy, thiohydroxy, thioalkoxy, thioaryloxy, cyano, nitro, azo, azide, sulfonamide, carboxy, thiocarbamate, urea, thiourea, carbamate, amide, and hydrazine. The heteroalicyclic group can be an end group, as this phrase is defined herein, where it is attached to a single adjacent atom, or a linking group, as this phrase is defined herein, connecting two or more moieties. Representative examples are piperidine, piperazine, tetrahydrofuran, tetrahydropyran, morpholine and the like.

[0538] As used herein, the terms “amine” and “amino” describe both a -NRxRy end group and a -NRx- linking group, wherein Rx and Ry are each independently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl or heteroalicyclic, as these terms are defined herein. When Rx or Ry is heteroaryl or heteroalicyclic, the amine nitrogen atom is bound to a carbon atom of the heteroaryl or heteroalicyclic ring. A carbon atom attached to the nitrogen atom of an amine is not substituted by =0 or =S, and in some embodiments, is not substituted by any heteroatom.

[0539] The amine group can therefore be a primary amine, where both Rx and Ry are hydrogen, a secondary amine, where Rx is hydrogen and Ry is alkyl, cycloalkyl, aryl, heteroaryl or heteroalicyclic, or a tertiary amine, where each of Rx and Ry is independently alkyl, cycloalkyl, aryl, heteroaryl or heteroalicyclic.

[0540] The terms “hydroxy” and “hydroxyl” describe a -OH group.

[0541] The term “alkoxy” describes both an -O-alkyl and an -O-cycloalkyl end group, or -O- alkylene or -O-cycloalkyl linking group, as defined herein.

[0542] The term “aryloxy” describes both an -O-aryl and an -O-heteroaryl end group, or an -O- arylene- linking group, as defined herein.

[0543] The term “thiohydroxy” describes a -SH group.

[0544] The term “thioalkoxy” describes both an -S-alkyl and an -S-cycloalkyl end group, or -S- alkylene or -S-cycloalkyl linking group, as defined herein.

[0545] The term “thioaryloxy” describes both an -S-aryl and an -S-heteroaryl end group, or an - S- arylene- linking group, as defined herein.

[0546] The terms “cyano” and “nitrile” describe a -C=N group.

[0547] The term “nitro” describes an -NO2 group.

[0548] The term “oxo” describes a =0 group.

[0549] The term “azide” describes an -N=N+=N“ group.

[0550] The term “azo” describes an -N=N-Rx end group or -N=N= linking group, with Rx as defined herein.

[0551] The terms “halide” and “halo” refer to fluorine, chlorine, bromine or iodine.

[0552] The term “phosphate” refers to a -0-P(=0)(0RX)-0RY end group, or to a -0-P(=0)(0Rx)- O- linking group, where Rx and Ry are as defined herein.

[0553] The terms "phosphonyl" and "phosphonate" refer to an -P(=0)(0Rx)-0Ry end group, or to a -P(=0)(0Rx)-0- linking group, where Rx and Ry are as defined herein. The term “phosphinyl” refers to a -PRxRy group, where Rx and Ry are as defined hereinabove.

[0554] The term “sulfoxide” or “sulfinyl” describes a -S(=0)-Rx end group or -S(=0)- linking group, where Rx is as defined herein.

[0555] The terms “sulfonate” and “sulfonyl” describe a -S(=0)2-Rx end group or -S(=0)2- linking group, where Rx is as defined herein. The terms “sulfonamide” and "sulfonamido", as used herein, encompass both S- sulfonamide and N-sulfonamide end groups, and a -S(=O)2-NRx- linking group.

[0556] The term “S-sulfonamide” describes a -S(=0)2-NRXRY end group, with Rx and Ry as defined herein.

[0557] The term “N-sulfonamide” describes an RxS(=0)2-NRy- end group, where Rx and Ry are as defined herein.

[0558] The term “carbonyl” as used herein, describes a -C(=O)-Rx end group or -C(=O)- linking group, with Rx as defined herein.

[0559] The term “acyl” as used herein, describes a -C(=O)-Rx end group, with Rx as defined herein.

[0560] The term “thiocarbonyl” as used herein, describes a -C(=S)-Rx end group or -C(=S)- linking group, with Rx as defined herein.

[0561] The terms “carboxy” and “carboxyl”, as used herein, encompasses both C-carboxy and O- carboxy end groups, and a -C(=O)-O- linking group.

[0562] The term “C-carboxy” describes a -C(=O)-ORx end group, where Rx is as defined herein.

[0563] The term “O-carboxy” describes a -OC(=O)-Rx end group, where Rx is as defined herein.

[0564] The term “urea” describes a -NRxC(=O)-NRyRw end group or -NRxC(=O)-NRy- linking group, where Rx and Ry are as defined herein and Rw is as defined herein for Rx and Ry.

[0565] The term “thiourea” describes a -NRx-C(=S)-NRyRw end group or a -NRx-C(=S)-NRy- linking group, with Rx, Ry and Ry as defined herein.

[0566] The terms “amide” and "amido", as used herein, encompasses both C-amide and N-amide end groups, and a -C(=O)-NRx- linking group.

[0567] The term “C-amide” describes a -C(=O)-NRxRy end group, where Rx and Ry are as defined herein.

[0568] The term “N-amide” describes a RxC(=O)-NRy- end group, where Rx and Ry are as defined herein.

[0569] The term “carbamyl” or “carbamate”, as used herein, encompasses N-carbamate and O- carbamate end groups, and a -OC(=O)-NRx- linking group.

[0570] The term “N-carbamate” describes a RyOC(=O)-NRx- end group, with Rx and Ry as defined herein.

[0571] The term “O-carbamate” describes an -OC(=O)-NRxRy end group, with Rx and Ry as defined herein. The term “thiocarbamyl” or “thiocarbamate”, as used herein, encompasses O- thiocarbamate, S -thiocarbamate and N-thiocarbamate end groups, and a -OC(=S)-NRx- or - SC(=O)-NRx- linking group.

[0572] The terms “O-thiocarbamate” and "O-thiocarbamyl" describe a -OC(=S)-NRxRy end group, with Rx and Ry as defined herein.

[0573] The terms “S -thiocarbamate” and "S -thiocarbamyl" describe a -SC(=O)-NRxRy end group, with Rx and Ry as defined herein.

[0574] The terms “N-thiocarbamate” and "N-thiocarbamyl" describe a RyOC(=S)NRx- or RySC(=O)NRx- end group, with Rx and Ry as defined herein.

[0575] The term “guanidine” describes a -RxNC(=N)-NRyRw end group or -RxNC(=N)-NRy- linking group, where Rx, Ry and Rw are as defined herein.

[0576] The term “hydrazine”, as used herein, describes a -NRx-NRyRw end group or -NRx-NRy- linking group, with Rx, Ry, and Rw as defined herein.

[0577] It is appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination or as suitable in any other described embodiment of the invention. Certain features described in the context of various embodiments are not to be considered essential features of those embodiments, unless the embodiment is inoperative without those elements.

[0578] Various embodiments and aspects of the present invention as delineated hereinabove and as claimed in the claims section below find experimental support in the following examples.

[0579] EXAMPLES

[0580] Reference is now made to the following examples, which together with the above descriptions illustrate some embodiments of the invention in a non-limiting fashion.

[0581] EXAMPLE 1

[0582] Design, Materials and Experimental Methods

[0583] Studies were conducted in order to assess the effect of aqueous compositions comprising lipid-polymeric conjugates on the wear in a pin-on-disk (POD) system.

[0584] POD measurements were performed on an OrthoPOD, model PD-05-06, developed and manufactured by the Advanced Mechanical Technology Inc. (AMTI). The POD station used was assembled with a cross-linked UHMWPE pin (GUR 1020 medical grade of UHMWPE, MW = 2- 4 Mg / mol, in Examples 2 and 3, and GUR 1050 UHMWPE, MW = 4-6 Mg / mol, in Example 4) and CoCr disc, immersed inside an acrylic pool with an acrylic cover to prevent lubricant evaporation, such as shown in FIG. 1A. All discs were polished to an average roughness Ra < 0.05±0.006 pm. The disc surface was visually inspected pre- and post-test.

[0585] The wear stations were programmed to run under a constant load of 250N at a 1.0 Hz frequency with the rectangle pin path. The temperature was maintained at 37 ± 2 °C during measurements.

[0586] Parameters such as load regime, sliding distance, contact area, frequency and temperature were kept constant in all measurements. A constant load of 250 N at a 1.0 Hz frequency was applied, with a rectangle pin path 10 mm x 15 mm. The temperature in all experiments was maintained at 37 ± 2°C. The volume of liquid-containing well in each station was 20 mL.

[0587] The measurement duration was 0.5 or 2.0 Me (Million cycles), which correspond to a patient’s activity during 3 months or one year, respectively.

[0588] In the experiment with 2.0 Me, following each 0.5 Me interval, all pins were removed, cleaned, and weighed to document the wear of the PE pin, and a fresh lubricant was added. Changing the lubricant every 0.5 Me allows for limiting the effect of protein degradation on wear.

[0589] The known wear rates of cross-linked UHMWPE pins used under similar conditions with Bovine Calf Serum (BCS) are between 4.987 mg / Mc and 6.008 mg / Mc, depending on the exact material composing the pins [Sui-Lai Wong, Thesis, 2013, supra].

[0590] As a reference medium, Bovine Calf Serum (BCS) was used. BCS defrosted, obtained from Cytiva Hyclone, was used.

[0591] A standard BCS solution was diluted with deionized water to a final protein concentration of 20.0 grams / Liter. A 0.2 % wt. solution of sodium azide was added as an antibacterial agent to eliminate the effect of microbiological contamination on wear.

[0592] The solution was prepared as follows: Deionized water (DIW) was place in a beaker, and heated to 37.4 °C while stirring. EDTA was added to a final concentration of 20 mM, followed by addition of sodium azide to a final concentration of 0.2 % by weight. The pH was adjusted to 6-8, to match the pH of BCS, using sodium hydroxide. BCS was then added to obtain a final protein concentration of 20.0 grams / Liter the beaker and the solution was stirred until a homogeneous mixture was obtained. EXAMPLE 2

[0593] A pin-on-disc (POD) test aimed at evaluating the wear performance of polyethylene (PE) test pins (cross-linked UHMWPE), when using a liposome-containing exemplary sterile composition prepared as described in WO 2023 / 031928 (also referred to herein as “Aqueous Joint”, or “AJ”), was performed. DPPE-dm-pMPC (an average of 55 MPC units per LPC) was used as the lipid-polymer conjugate, and DSPC (distearylphosphocholine) was used as a glycerophospholipid bilayer forming lipid, at a mol ratio of the LPC :bilay er- forming lipid of 0.5:99.5, in physiological (e.g., PBS) buffer.

[0594] A joint simulator that imitates cartilage wear in knee articulation is used in such a set-up.

[0595] Testing was effected according to ASTM F732-00 / ASTM F2025-06 / ISO 14243-2 (2009). Prior to test initiation, all discs were polished to an average roughness (Ra) < 0.05 ± 0.006 pm. Pins were weighed pre-testing and post-testing.

[0596] AJ formulated at a total lipid concentration of 30 mM is denoted as a 100 % (v / v) solution. AJ formulation diluted to 10 mM total lipid concentration is denoted as 33 % (v / v) AJ. AJ formulation diluted to 5 mM total lipid concentration is denoted as 17 % (v / v) AJ.

[0597] In preliminary feasibility tests, 500,000 cycles (0.5 Me) were selected as the test duration.

[0598] Two POD stations were prepared using BCS as a substitute of Synovial Fluid; and two stations were prepared using a 1:1 BCS:AJ solution (a 17 % (v / v), corresponding to a 10 mM solution diluted at a 1:1 volume ratio in BCS to provide a 5 mM AJ solution).

[0599] The obtained results are presented in FIG. 2A and show that stations with 17 % (v / v) AJ (5 mM total lipids), presented close to 5-fold wear reduction compared to BCS alone.

[0600] Further experiments were performed using the 1:1 BCS:AJ solution, while evaluating its effect on the wear during 2.0 Me. Six POD stations were prepared, three with BCS and three with 17 % AJ.

[0601] Every 0.5 Me interval, the pins were removed, cleaned and weighed, and the lubricant solutions in the pools were replaced by new ones. The stations were then reassembled, and the experiment was allowed to continue to 2.0 Me.

[0602] The results are presented in FIG. 2B, and confirmed that stations with 17 % (v / v) AJ present close to 5-fold wear reduction compared to BCS alone throughout the test.

[0603] EXAMPLE 3

[0604] A formulation comprising newly designed lipid-polymer conjugates, such as described in WO 2024 / 047647 (the contents of which are incorporated herein by reference as if fully set forth herein) was tested, using the POD system described in the preceding examples. The tested aqueous formulation is also referred to herein as “AqueousJoint*”, or “AJ*”, and comprises liposomes made of DPPE-Ph-pMPC and DSPC, at a mol ratio of 0.7:99.3 LPC:DSPC, in a physiological buffer (e.g., PBS).

[0605] Tests were performed as described in Example 2 hereinabove, for a duration of 2.0 Me, in 0.5 Me intervals. Six types of stations were prepared, each in duplicate (a total of 12 stations), as follows:

[0606] Two stations used AqueousJoint* (30 mM total lipids concentration) as a lubricating medium, denoted as 100 %; Two stations used 1:1 AJ*:BCS (15 mM total lipids concentration, denoted as 50 %); Two stations used 1:3 AJ*:BCS (7.5 mM total lipids concentration, denoted as 25 %; Two stations used 1:7 AJ*:BCS (3.75 mM total lipids concentration, denoted as 13 %); Two stations used 1:15 AJ*:BCS (1.875 mM total lipids concentration , denoted as 6 %); and two stations 1:31 AJ*:BCS (about 0.94 mM total lipids concentration, denoted as 3 %).

[0607] The obtained data are presented in FIG. 3, and show a concentration-dependent reduction in wear, compared to BCS alone, wherein for 100 %-50 % volume fraction of AJ*, wear is within the range of 0.12-0.29 mg, which is a decrease of about 27-fold in wear compared to the standard BCS solution, and for the 25 %-3 % volume fraction range of AJ*, wear is within the range of 1.07-1.74 mg, which is a decrease of about 4-fold in wear compared to the standard BCS solution.

[0608] The obtained data further show that a significant reduction in wear, compared to BCS alone, is observed already at the lowest AJ*:BCS ratio (denoted as 3 %), indicating that also at low lipid concentrations, AJ* provides effective wear protection of the pin, and accordingly of the cartilage.

[0609] Data shown in FIG. 3 for BCS alone and for 17 % volume fraction AJ* are taken from different sets of measurements performed under the same conditions, for comparison.

[0610] EXAMPLE 4

[0611] In a further set of experiments, the performance of the AJ* formulation described in Example 3 hereinabove, in combination with hyaluronic acid (HA) was tested, in order to evaluate its effect on the wear characteristic during 2.0 Me, and to further evaluate the effect of HA as a natural synovial joint component on the lubricating properties of AJ*.

[0612] In these experiments, the same POD system as in Examples 2 and 3 was used, but the pin was GUR 1050 UHMWPE.

[0613] GUR 1050 and GUR 1020 are two commercial polymer types used in orthopedics. The main difference between these polymeric materials is the molecular weight. Additionally, GUR1020 is formed by compression molding, while GUR1050 is made by the RAM extrusion method. The GUR1050 polymeric pins have been reported to exhibit higher wear-resistant compared to the GUR1020 polymeric pins [Brandt et al. Journal of the Mechanical Behavior of Biomedical Materials, Volume 34, 2014, Pages 208-216, ISSN 1751-6161]. For example, it was reported that the wear of GUR1020 in knee wear testing was 23 + 6 mm3 / Mc while the wear of GUR1050 wear was 13 + 4 mm3 / Mc [Fisher et al., Clin Orthop Relat Res. 2004, (428), Pages 114- 119],

[0614] The general POD test parameters in this set of experiments were the same as in Examples 1-3. A hyaluronic acid, 1 % (w / v) solution in saline was used. Four solutions were tested in triplicate, as follows: Three stations were prepared with BCS only, denoted as BCS 100 %; Three stations were prepared with a 1:1 (v / v) mixture of BCS and AJ*, resulting in a liposome solution with a final concentration of 15 mM total lipids, denoted as 50 % AJ*; three stations were prepared with a 2:1:1 (v / v / v) mixture of BCS:AJ*:HA, resulting in a liposome solution with a final concentration of 7.5 mM total lipids and 0.25 % (w / v) HA, denoted as 25 % AJ* + 25 % HA; and three stations prepared with a 1:1 (v / v) mixture of BCS:HA, resulting in 0.5 % (w / v) HA, denoted as 50 % HA.

[0615] Wear values were calculated as the average of three measurements for each dilution and after every 0.5 Me. The results are presented in FIG. 4, and clearly show that AJ* provides a 3- fold greater reduction in wear compared to hyaluronic acid, the commonly used treatment for osteoarthritis, when tested at the same dilution concentration (50 %). Further, the cumulative wear of pins immersed in HA increased faster than in AJ* solution as the number of cycles increased, further indicating that AJ* provides a more effective and long-lasting protective effect.

[0616] The lowest cumulative wear values were observed for the 25 % AJ* + 25 % HA mixture, even though the tested lubricants were more diluted, suggesting a synergistic effect, which allows using lower concentrations.

[0617] Due to the change in the use of pins made of different types of polymeric materials, the wear values are not consistent with those shown in Examples 2 and 3. However, the lower values for BCS obtained in these experiments with GUR1050 (4.3 mg / Mc) compared with those obtained with GUR1020 (12 mg / Mc) as shown in FIG. 2B, are in line with literature data [see, e.g., Fisher et al., 2004, supra].

[0618] Although the invention has been described in conjunction with specific embodiments thereof, it is evident that many alternatives, modifications and variations will be apparent to those skilled in the art. Accordingly, it is intended to embrace all such alternatives, modifications and variations that fall within the spirit and broad scope of the appended claims. It is the intent of the applicant(s) that all publications, patents and patent applications referred to in this specification are to be incorporated in their entirety by reference into the specification, as if each individual publication, patent or patent application was specifically and individually noted when referenced that it is to be incorporated herein by reference. In addition, citation or identification of any reference in this application shall not be construed as an admission that such reference is available as prior art to the present invention. To the extent that section headings are used, they should not be construed as necessarily limiting. In addition, any priority document(s) of this application is / are hereby incorporated herein by reference in its / their entirety.

Claims

WHAT IS CLAIMED IS:

1. A composition for use in combination with an implantable device, the composition comprising an aqueous carrier and polymeric compound represented by Formula I:Formula I wherein: m is zero or a positive integer; n is an integer which is at least 2, at least 5, preferably at least 10 (e.g., of from 10 to 200);Y is a backbone unit which forms a polymeric backbone of the polymeric compound;L is absent or is a linking moiety; andZ has the general Formula II:Formula II wherein: the dashed (curved) line denotes an attachment point to the respective Y backbone unit or to the linking moiety L, if present;A is a substituted or unsubstituted hydrocarbon;B is an oxygen atom or is absent;R1-R3 are each independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, heteroalicyclic, aryl and heteroaryl;X is a lipid moiety represented by Formula IV :Formula IV wherein: the dashed (curved) line denotes an attachment point to said polymeric backbone;Fi, F2, F3 and F4 are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, acyl, alkoxy, thioalkoxy, carboxy, thiocarboxy, wherein at least one of Fi, F2, F3 and F4 is not hydrogen and is of at least 10 carbon atoms in length;J is -O-P(=O)(OH)-O- or absent;K is a substituted or unsubstituted hydrocarbon from 1 to 10 carbon atoms in length or absent; M is a linking group selected from the group consisting of -O-, -S-, amino, sulfinyl, sulfonyl, phosphate, phosphonyl, phosphinyl, carbonyl, thiocarbonyl, urea, thiourea, carbamyl, thiocarbamyl, amido, carboxy, and sulfonamide, or absent; andQ is a substituted or unsubstituted hydrocarbon from 1 to 10 carbon atoms in length, or 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 other than amido and / or Q comprises an aryl moiety.

2. The composition for use of claim 1, wherein at least one of Fi, F2, F3 and F4 is an alkoxy, thioalkoxy, acyl or carboxy of at least 10 carbon atoms in length.

3. The composition for use of claim 1 or 2, wherein at least one of Fi, F2, F3 and F4 is derived from a fatty acid selected from the group consisting of lauroyl, myristoyl, palmitoyl, stearoyl, palmitoleoyl, oleoyl, and linoleoyl.

4. The composition for use of any one of claims 1 to 3, wherein M is carboxy.

5. The composition for use of any one of claims 1 to 4, wherein K is an alkyl.

6. The composition for use of claim 1 or 2, wherein J is -P(=O)(OH)-O-; M is amido; and Q is a hydrocarbon substituted by at least one aryl.

7. The composition for use of any one of claims 1 to 6, wherein Q is a methylene substituted by at least one aryl.

8. The composition for use of any one of claims 1 to 7, wherein J is absent.

9. The composition for use of any one of claims 1 to 7, wherein J and K are each absent.

10. The composition for use of any one of claims 1 to 7, wherein J and K are each absent and M is carboxy.

11. The composition for use of any one of claims 1 to 10, wherein at least one, or at least two, of Fi, F2, F3 and F4 is independently said thioalkoxy.

12. The composition for use of any one of claims 1 to 10, wherein at least one, or at least two, of Fi, F2, F3 and F4 is independently said carboxy.

13. The composition for use of claim 12, wherein at least one or both of Fi and F2 is said carboxy and at least one of F3 and F4 is an alkyl.

14. The composition for use of any one of claims 8 to 13, wherein Q is -C(CH3)2-.

15. The composition for use of any one of claims 1 to 14, wherein Y is a substituted or unsubstituted alkylene unit.

16. The composition for use of claim 15, wherein Y is a substituted or unsubstituted ethylene unit.

17. The composition for use of any one of claims 1 to 16, wherein B is an oxygen atom.

18. The composition for use of any one of claims 1 to 17, wherein A is a substituted or unsubstituted hydrocarbon from 1 to 4 carbon atoms in length.

19. The composition for use of any one of claims 1 to 18, wherein R1-R3 are each independently hydrogen or Ci-4-alkyl.

20. The composition for use of any one of claims 1 to 19, wherein n ranges from 10 to 200.

21. The composition for use of any one of claims 1 to 20, wherein n is at least 30.

22. The composition for use of any one of claims 1 to 20, wherein n ranges from 30 to 70.

23. The composition for use of any one of claims 1 to 20, wherein n is at least 50.

24. The composition for use of any one of claims 1 to 20, wherein n ranges from 50 to150, or from 50 to 80.

25. The composition for use of any one of claims 1 to 20, wherein n is at least 80.

26. The composition for use of any one of claims 1 to 20, wherein n ranges from 80 to120.

27. The composition for use of any one of claims 1 to 26, wherein m ranges from 0 to 50.

28. The composition for use of any one of claims 1 to 27, wherein at least a portion of said backbone units Y, said L and / or said Z comprise at least one targeting moiety.

29. The composition for use of any one of claims 1 to 28, further comprising at least one bilayer-forming lipid.

30. The composition for use of any one of claims 1 to 29, wherein a mol ratio of said at least one bilayer- forming lipid and said polymeric compound is in a range of from 5: 1 to 5,000: 1 , or from 10:1 to 1,000:1, or 10:1 to 100:1 or from 10:1 to 50:1, or from 100:1 to 500:1.

31. The composition for use of claim 29 or 30, wherein said at least one bilayer-forming lipid comprises at least one zwitterionic glycerophospholipid.

32. The composition for use of claim 31 , wherein said at least one bilayer- forming lipid further comprises a negatively charged bilayer-forming lipid.

33. The composition for use of any one of claims 29 to 32, wherein said polymeric compound and said at least one bilayer-forming lipid form a lipid bilayer.

34. The composition for use of any one of claims 1 to 33, further comprising at least one water-soluble polymer.

35. The composition for use of claim 34, wherein said at least one water-soluble polymer comprises hyaluronic acid.

36. The composition for use of any one of claims 33 to 35, wherein a weight ratio of said lipid bilayer and said water-soluble polymer ranges from 100: 1 to 1 : 100, or from 50: 1 to 1 :50, or from 20:1 to 1:20, or from 10:1 to 1:10, or from 5:1 to 1:5, or from 2:1 to 1:2.

37. The composition for use of any one of claims 33 to 36, wherein a concentration of said lipid bilayer ranges from 0.1 to 100 mM by weight of the total weight of the composition.

38. The composition for use of any one of claims 1 to 37, being for reducing wear of the implantable device, upon implantation.

39. The composition for use of any one of claims 1 to 38, wherein the composition is administered to a subject in need thereof prior to, concomitant with or subsequent to implanting said implantable device.

40. The composition for use of any one of claims 1 to 39, wherein said implantable device is a joint replacement implantable device, the composition being for use in a total joint replacement procedure.

41. The composition for use of any one of claims 1 to 39, wherein the implantable device is a prosthetic implant.

42. A pin-on-disk system, comprising the composition as defined in any one of claims 1 to 37.

43. A method of determining wear resistance of an implantable device, the method comprising performing pin-on-disk measurements using the system of claim 42.