Polysarcosine-Vitamin E Derivative

Abstract

The present invention relates to polymers comprising repeating sarcosine-based units covalently linked to vitamin E-based moieties directly or via a linker, their acceptable salts, stereoisomers and mixtures, and conjugates of formula (II) comprising these polymers. Also provided are nutraceutical, pharmaceutical, diagnostic and cosmetic compositions comprising the polymers and / or the conjugates of formula (II) together with acceptable excipients or carriers, and self-assembled particles comprising the polymers and / or the conjugates of formula (II) and optionally a drug encapsulated within the self-assembled particles. The present invention also relates to the use of polysarcosine-vitamin E derivatives and / or their conjugates in medicine and diagnosis, and as solubilizers, absorption and penetration enhancers, emulsifiers or surface stabilizers. [Formula 1] JPEG2025501519000092.jpg39159

Description

[Technical field]

[0001] This application claims the benefit of European Patent Application No. 21383149.8, filed December 17, 2021.

[0002] The present invention relates to polysarcosine-vitamin E derivatives and complexes comprising them, where the polysarcosine-vitamin E derivatives are covalently bound to other moieties, such as diagnostic or therapeutic agents. The present invention also relates to compositions comprising the polysarcosine-vitamin E derivatives and / or their complexes, self-assembled particles formed therefrom that can encapsulate various agents, and their use in pharmaceutical, cosmetic or food applications. [Background technology]

[0003] The vitamin E family is a group of fat-soluble compounds that includes tocopherols and tocotrienols. Both tocopherols and tocotrienols contain a chroman ring and a 16-carbon side chain in their structure. The difference between them is that the carbon side chain of tocopherols is saturated, while the side chain of tocotrienols is unsaturated. Each tocopherol and tocotrienol exists in four different forms, namely α, β, γ, and δ, which differ in the number and position of methyl groups on the ring, as shown below. The most common and biologically active form is α-tocopherol, often referred to as vitamin E. [ka]

[0004] Vitamin E is an essential dietary component. It has been suggested to be an essential factor for reproduction. It has antioxidant, antithrombolytic and other therapeutic effects. The antioxidant properties of vitamin E derivatives are associated with the 6-hydroxychroman ring in their chemical structure.

[0005] Low blood levels of vitamin E have been linked to an increased risk of developing degenerative diseases. This has led researchers to study vitamin E's ability to prevent chronic diseases associated with oxidative stress, including cardiovascular and neurodegenerative diseases, atherosclerosis and cancer. In addition, the involvement of vitamin E in cell signaling and gene expression has also been reported. Furthermore, there has been renewed interest in the use of vitamin E derivatives as drug delivery systems to increase cell permeability and access to desired targets, as well as for medical imaging as contrast agents or fluorescent probes.

[0006] Vitamin E tends to be an unstable molecule. Moreover, its poor water solubility greatly limits its applications. To increase its shelf life, vitamin E has been provided in the form of derivatives in which the 6-hydroxyl moiety attached to the chroman ring is esterified with an acetate or succinate moiety to give vitamin E acetate or succinate derivatives.

[0007] Alpha-tocopherol succinate was the first reported vitamin E derivative that demonstrated its activity in inhibiting cancer cell proliferation. However, this derivative is highly hydrophobic and toxic. Efforts to overcome the poor aqueous solubility of vitamin E led to the preparation of tocopherol polyethylene glycol succinate (TPGS), also called tocophersolan, which is obtained by esterification of vitamin E succinate with poly(ethylene glycol) (PEG). TPGS has the following properties: [ka] It has the chemical structure:

[0008] TPGS has been approved by the US FDA as a nutritional supplement and drug delivery vehicle. It can be used as a solubilizer, absorption and penetration enhancer, emulsifier and surface stabilizer in drug delivery. TPGS can act as an anticancer agent against many cancer types. In this regard, complexes of TPGS with, for example, doxorubicin, paclitaxel or cisplatin have been reported. Furthermore, TPGS-based polymers can enhance drug encapsulation efficiency, intracellular uptake and therapeutic efficacy.

[0009] Notwithstanding the above, TPGS has some drawbacks associated with the inclusion of PEG within its structure. PEG has been widely used in drug delivery and nanotechnology due to its stealth and biocompatibility, which allows particle delivery systems and biomaterials to evade the immune system, thereby having a long circulation time within biological systems. However, it has been reported that PEG can cause an unexpected immunogenic response, known as the accelerated blood clearance (ABC) phenomenon, resulting in increased clearance and reduced efficacy of PEG-conjugated substances. Furthermore, PEG conjugates exhibit poor degradability.

[0010] Therefore, there remains a need to develop other vitamin E derivatives that overcome the problems of the prior art. Summary of the Invention

[0011] The present inventors have developed new polysarcosine (PSar)-based vitamin E derivatives that are biodegradable, non-immunogenic, and exhibit excellent shelf life, unlike PEG-containing derivatives such as TPGS. The polysarcosine-vitamin E derivatives of the present invention are amphiphilic. They contain a hydrophilic polar head, i.e., a PSar-based moiety, and a hydrophobic moiety, i.e., a vitamin E-based moiety (sometimes referred to as the "vitamin E-based moiety"). As hybrid compounds, they have the properties of both components. Thus, on the one hand, they exhibit excellent solubility in water and organic solvents thanks to the PSar-based moiety, and on the other hand, they have antioxidant properties due to the vitamin E-based moiety.

[0012] As shown in the following examples, the polysarcosine-vitamin E derivative of the present invention can form self-assembled particles such as micelles in a solvent and encapsulate molecules such as active agents or imaging contrast agents.Compared to the analog TPGS, the polysarcosine-vitamin E derivative shows higher accumulation of delivered agents in the epidermis layer, demonstrating that PSar-based materials can be more advantageous than TPGS for skin delivery applications while avoiding the disadvantages associated with PEG.

[0013] Accordingly, a first aspect of the present invention relates to a polymer comprising a repeating sarcosine-based unit covalently attached directly or via a linker to a vitamin E based moiety, or a pharma- ceutical, nutraceutical or cosmetically acceptable salt thereof, or any stereoisomer or mixture of stereoisomers of either of the present polymers or any of the salts thereof, wherein the repeating sarcosine-based unit has the formula (XXIII): [ka] having wherein R5 is selected from the group consisting of methyl, -CH2F, -CHF2, and -CF3, R6 and R7 are independently selected from the group consisting of hydrogen and fluorine, and n is an integer from 5 to 500, and the vitamin E base moiety has the formula (XXIV): [ka] having wherein R2, R3 and R4 are independently selected from the group consisting of hydrogen, fluorine, methyl, -CH2F, -CHF2 and -CF3, and the dashed bonds ----- are each independently a single bond or alternatively a double bond. In the polymers of the invention, the repeating sarcosine-based units are referred to herein as " *The vitamin E based moiety is covalently attached to the vitamin E based moiety directly or through a linker by any of the attachment points shown in the figure. The vitamin E based moiety is represented herein by a wavy line crossing the bond. [ka] The repeating sarcosine-based units are covalently attached to the repeating sarcosine-based units either directly or via a linker by attachment points indicated by

[0014] More particularly, the polymer comprising repeating sarcosine-based units covalently attached to a vitamin E-based moiety directly or via a linker has the formula (I): [ka] is a polymer of During the ceremony, PAA is represented by the formula (XXI) and the formula (XXII): [ka] is a repeating sarcosine-based unit selected from During the ceremony, `` *1 " indicates the point of attachment of the repeating sarcosine-based unit PAA to X or R1 (when z is 0), *2 " indicates the point of attachment of the repeating sarcosine-based unit PAA to the linker L or to the oxygen atom (when m is 0) of the vitamin E-based moiety, m is 0 or 1, with the proviso that m is 1 when the repeating sarcosine-based unit PAA has the formula (XXI), z is 0 or 1, with the proviso that when the repeating sarcosine-based unit PAA has the formula (XXI), z is 1, and when the repeating sarcosine-based unit PAA has the formula (XXII), z is 0; R1 is -(C1~C 12 )Alkyl, -(C1-C 12) alkylphenyl, -(C1-C6) alkyl-O-(C1-C6) alkyl, -CO-(C1-C 12 )Alkyl, -CO-(C1-C 12 ) alkylphenyl and -CO-(C1-C6) alkyl-O-(C1-C6) alkyl, where R1 is optionally selected from the group consisting of halogen, -OH, -NR a R b , -SH, -NHNH2, -COOR c , -CF3, and -OCF3; R2, R3 and R4 are independently selected from the group consisting of hydrogen, fluorine, methyl, -CH2F, -CHF2 and -CF3; R5 is selected from the group consisting of methyl, -CH2F, -CHF2, and -CF3; R6 and R7 are independently selected from the group consisting of hydrogen and fluorine; n is an integer from 5 to 500; X is -O- or -NH-, and L is a biradical chain comprising one or more moieties selected from the group consisting of -CH=CH-, -C≡C-, -CH2-, -N=CH-, -CH=NH-, -NH-, -NH-NH-, -NH-N=CH-, -O-, -O(CH2)O-, -CO-, -O(CO)-, -COO-, -C(=CH2)-, -C(=NH)-, -CONH-, -NHCO-, -NH(CO)NH-, -S-, -SS-, -SO-, -SO2-, -SON2NH2- and -phenylene-, wherein L is optionally selected from halogen, -OH, -NR a R b , -SH, -NHNH2, -COOR c , -CF3, -OCF3, [ka] wherein when L contains a -CH2- moiety, the two hydrogen atoms attached to that carbon atom are optionally substituted with one or more substituents selected from the group consisting of: [ka] when PAA is a repeating sarcosine-based unit of formula (XXI), L is bonded to the nitrogen atom of PAA by a chemically feasible bond selected from the group consisting of an amide bond, a carbamate bond, a urea bond and an amine bond, and when PAA is a repeating sarcosine-based unit of formula (XXII) and m is 1, L is bonded to the carbonyl group of PAA by a chemically feasible bond selected from the group consisting of an amide bond and an ester bond; L is bonded to an oxygen atom of the vitamin E base moiety by a chemically feasible bond selected from the group consisting of an ester bond, a carbamate bond and an ether bond; and each dashed bond ----- is independently a single bond or alternatively a double bond; and R a , R b and R c is independently a radical selected from the group consisting of H, -phenyl, -(C1-C6)alkyl, -(C2-C6)alkenyl, -(C1-C6)alkylphenyl and -phenyl(C1-C6)alkyl.

[0015] The polysarcosine-vitamin E derivatives of the present invention may be covalently bonded to other molecules. Thus, another aspect of the present invention is a compound represented by the formula (II): [ka] or a pharma- ceutically, nutraceutical or cosmetically acceptable salt thereof, or any stereoisomer or mixture of stereoisomers of any of the complexes of formula (II) or any of their salts, During the ceremony, m, PAA, X, n, L, R2, R3, R4 and the dashed bond are as defined herein; s is 0 or 1, z' is 0 or 1, with the proviso that when the repeating sarcosine-based unit PAA has the formula (XXII), z' is 0; Z is an agent selected from the group consisting of a nutraceutical active agent, a medicamentously active agent, a cell targeting agent, a diagnostically active agent and a cosmetically active agent; L' is a biradical chain comprising one or more moieties selected from the group consisting of -CH=CH-, -C≡C-, -CH2-, -N=CH-, -CH=NH-, -NH-, -NH-NH-, -NH-N=CH-, -O-, -O(CH2)O-, -CO-, -O(CO)-, -COO-, -C(=CH2)-, -C(=NH)-, -CONH-, -NHCO-, -NH(CO)NH-, -S-, -SS-, -SO-, -SO2-, -SON2NH2- and -phenylene-, wherein L' is optionally selected from halogen, -OH, -NR a R b , -SH, -NHNH2, -COOR c , -CF3, -OCF3, [ka] and is substituted with one or more substituents selected from the group consisting of R a , R b and R c is independently a radical selected from the group consisting of H, -phenyl, -(C1-C6)alkyl, -(C2-C6)alkenyl, -(C1-C6)alkylphenyl and -phenyl(C1-C6)alkyl, and When L' contains a -CH2- moiety, the two hydrogen atoms attached to that carbon atom can optionally be joined to one of the following rings: [ka] and when s is 0, Z is directly bonded to the X or PAA sarcosine repeat unit by a chemically feasible bond selected from the group consisting of an amide bond, a carbamate bond, an amine bond, a urea bond, an ether bond and an ester bond; When S is 1, L' is bonded to Z by a chemically feasible bond selected from the group consisting of an amide bond, a carbamate bond, an amine bond, a urea bond, an ether bond, and an ester bond, and L' is bonded to X or the PAA sarcosine repeat unit by a chemically feasible bond selected from the group consisting of an amide bond, a carbamate bond, an amine bond, a urea bond, an ether bond, and an ester bond.

[0016] Due to their amphiphilicity as mentioned above, the polysarcosine-vitamin E derivatives of the present invention may form self-assembled particles in solution, such as micelles or lipid nanoparticles, which can be used to encapsulate and deliver molecules of different nature. Therefore, another aspect of the present invention is (a) a polymer as defined herein, or alternatively (b) a complex of formula (II) as defined herein, or alternatively (c) a combination of a polymer as defined herein with a conjugate of formula (II); an agent encapsulated within the self-assembled particles, optionally selected from the group consisting of a nutraceutical active agent, a medicament active agent, a cell targeting agent, a diagnostically active agent and a cosmetically active agent; The present invention relates to a self-assembled particle comprising:

[0017] The polysarcosine-vitamin E derivatives of the present invention as well as the complexes of formula (II) as defined herein may be formulated into various compositions, such as dietary supplement compositions, pharmaceutical compositions, diagnostic compositions or cosmetic compositions. Accordingly, another aspect of the present invention is to provide an effective amount of polysarcosine-vitamin E derivatives of the present invention, together with one or more acceptable excipients or carriers. (a) a polymer as defined herein, or alternatively, (b) a complex of formula (II) as defined herein, or alternatively, (c) a combination of a polymer as defined herein with a conjugate of formula (II), or alternatively: (d) a self-assembled particle as defined herein The present invention relates to a composition comprising:

[0018] The polysarcosine-vitamin E derivatives, their complexes, self-assembled particles and compositions thereof of the present invention may be used in pharmaceutical, cosmetic or food applications. Thus, another aspect of the present invention is a method for the preparation of polysarcosine-vitamin E derivatives for use in pharmaceutical applications. (i) a polymer as defined herein, or alternatively, (ii) a conjugate of formula (II) as defined herein, or alternatively, (iii) a self-assembled particle as defined herein, or alternatively, (iv) a pharmaceutical composition as defined herein. wherein the agent encapsulated in the self-assembled particle, when present, is a pharma- ceutical active agent or cell targeting agent as defined herein, and Z, when present in the complex of formula (II), is a pharma- ceutical active agent or cell targeting agent.

[0019] Another aspect of the invention is a method for the diagnosis of (i) a conjugate of formula (II) as defined herein, or alternatively, (ii) a self-assembled particle as defined herein, provided that the encapsulated agent is present in the self-assembled particle when the self-assembled particle comprises a polymer as defined herein in the absence of the complex of formula (II), or alternatively, (iii) a diagnostic composition as defined herein; wherein the agent encapsulated in the self-assembled particle, when present, is a diagnostically active agent, and Z, when present in the complex of formula (II), is a diagnostically active agent.

[0020] According to another aspect, the present invention relates to the use of a polymer as defined herein as a carrier, solubilizer, absorption and penetration enhancer, emulsifier or surface stabilizer. [Brief description of the drawings]

[0021] [Figure 1] Cell viability by MTS assay of Vit E (dotted line), TPGS (dashed line) and TPSS (solid line) in HaCaT cells (A) and fibroblasts (B) after 72 hours of treatment (n=3). [Diagram 2] ImageJ quantification of Dil fluorescence intensity (pixels) of confocal microscopy images of Dil-labeled micelles of TPGS and TPSS at 10 mg / mL after 8 h of permeation using Franz diffusion cells. Original magnification shown for each image was 40x. Asterisks indicate statistically significant differences after ANOVA analysis followed by Bonferroni post-hoc test. Mean ± SEM. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0022] All terms used herein in this application are to be understood in their ordinary sense as known in the art, unless otherwise specified. Other more specific definitions for certain terms used in this application are set forth below and are intended to be applied throughout the specification and claims.

[0023] As used herein, the term "about" or "around" refers to a range of values ​​of ±10% of the specified value. For example, the expression "about 10" or "around 10" includes ±10% of 10, i.e., 9 to 11.

[0024] As used herein, the indefinite articles "a" and "an" are synonymous with "at least one" or "one or more." Unless otherwise specified, definite articles used herein, such as "the," also include plural nouns.

[0025] (C1~C xThe term alkyl refers to a saturated straight or branched hydrocarbon chain containing 1 to x carbon atoms and only single bonds. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, neopentyl, n-hexyl, decyl, and undecyl. (C2 to C x The term alkenyl refers to an unsaturated branched or straight chain hydrocarbon chain containing 2 to x carbon atoms and at least one double bond. Examples of alkenyl groups include, but are not limited to, ethenyl (i.e., vinyl), allyl, propenyl, butenyl, pentenyl, and hexenyl.

[0026] The phrase "biradical chain comprising one or more moieties" is intended to encompass a biradical, as defined herein, which may be optionally substituted as indicated throughout the specification.

[0027] The term "-(C1-C6)alkyl-O-(C1-C6)alkyl" refers to an alkyl chain as defined above in which one of the hydrogen atoms has been replaced by an -O-(C1-C6)alkyl moiety, i.e., an alkoxy group. Examples of this radical include, but are not limited to, 2-methoxyethyl, 3-methoxypropyl, 4-methoxybutyl, 2-ethoxyethyl, 3-ethoxypropyl, and 4-ethoxybutyl.

[0028] "-(C1~C 12 The term "alkylphenyl" refers to an alkyl chain as defined above in which one of the hydrogen atoms is replaced by a phenyl moiety. Examples of this radical include, but are not limited to, benzyl, 2-phenethyl, and 3-phenylpropyl.

[0029] The term "-phenyl(C1-C6)alkyl" refers to a phenyl radical in which one of the hydrogen atoms is replaced by an alkyl group as defined above. Examples of this radical include, but are not limited to, (2-methyl)phenyl, (4-methyl)phenyl, and (3-ethyl)phenyl.

[0030] The terms "alkylene" or "phenylene" refer to a divalent radical.

[0031] "(C6~C 12 The term "aryl" refers to an aromatic carbocyclic monocyclic or bicyclic ring system containing 6 to 12 carbon ring atoms. Examples of aryl moieties include, but are not limited to, phenyl and naphthyl.

[0032] The term "halogen" or "halo" as used herein means fluorine, chlorine, bromine and iodine, preferably fluorine, chlorine and bromine, more preferably fluorine and chlorine.

[0033] The phrase "substituted with one or more" means that the group can be substituted with one or more, preferably 1, 2, 3, 4, 5 or 6, substituents, so long as the group has enough positions available for substitution.

[0034] As used herein, the term "chemically feasible" refers to an atomic connectivity that satisfies the chemical valences of each atom and is expected to be stable by those of skill in the art.

[0035] In any chemical structure disclosed herein, the wavy line crossing a bond as used herein: [ka] and " * " represents the point of attachment to the remainder of the molecule. The wavy line and asterisk are used interchangeably.

[0036] Polymers containing sarcosine and vitamin E based moieties A first aspect of the present invention refers to a polymer comprising repeating sarcosine-based units of formula (XXIII) covalently attached directly or via a linker to a vitamin E-based moiety of formula (XXIV), or a pharma- ceutical, nutraceutical or cosmetically acceptable salt thereof, or any stereoisomer or mixture of stereoisomers of either the polymer or any of the salts thereof.

[0037] The repeating polysarcosine-based units in the polymers of the present invention may be arranged in any order. Thus, the repeating sarcosine-based units of formula (XXIII) may be attached to the vitamin E-based moiety by either the carbonyl group or the amino group, either directly or via a linker.

[0038] This different orientation of the repeating polysarcosine-based moieties does not affect the amphiphilic behavior of the polymers described herein, and therefore the demonstrated activity is maintained.

[0039] There is no limit to the type of salt of the polymer of the present invention that can be used, as long as it is medicamentarily, nutraceutical or cosmetically acceptable when used for pharmaceutical, nutraceutical or cosmetic purposes, respectively. The term "pharmaceutical, nutraceutical or cosmetically acceptable salt" includes commonly used non-toxic salts. The preparation of medicamentarily, nutraceutical or cosmetically acceptable salts of the polymer of the present invention can be carried out by methods well known in the art. In general, such salts can be prepared by reacting the free acid or base form of the polymer of the present invention with a stoichiometric amount of a suitable base or acid, respectively, in a suitable solvent, such as water, an organic solvent or a mixture thereof. The polymer of the present invention and their salts may differ in some physical properties, but they are equivalent for the purposes of the present invention.

[0040] Some polymers of the invention may have chiral centers that can give rise to various stereoisomers. As used herein, the term "stereoisomer" refers to all isomers of individual polymers that differ only in the orientation of their atoms in space. The term stereoisomer includes mirror image isomers (enantiomers), mixtures of mirror image isomers (racemates, racemic mixtures), geometric (cis / trans or syn / anti or E / Z) isomers, as well as isomers of polymers with two or more chiral centers that are not mirror images of one another (diastereomers). The invention also relates to each of these stereoisomers and mixtures thereof. Diastereomers and enantiomers can be separated by conventional techniques such as chromatography or fractional crystallization. Optical isomers may be obtained using enantiospecific synthesis. Alternatively, optical isomers can be resolved by conventional techniques to obtain optically pure isomers. This resolution can be carried out on any chiral synthetic intermediate or on the polymers of the invention.

[0041] In all embodiments of the present invention, reference to polymers comprising repeating sarcosine-based units and vitamin E-based moieties, their pharma- ceutical, nutraceutical or cosmetically acceptable salts, and any stereoisomer or mixture of stereoisomers of any of the present polymers or any of their pharma- ceutical, nutraceutical or cosmetically acceptable salts is always intended, even if they are not specifically mentioned.

[0042] The polymer of the present invention may be in crystalline form, either as a solvated polymer or as a solvate (e.g., hydrate).It is intended that all these forms are within the scope of the present invention.The method of solvation is generally known in the art.For the purpose of the present invention, the solvated form with pharmaceutical, nutraceutical or cosmetically acceptable solvents such as water and ethanol is equivalent to the unsolvated form.

[0043] Unless otherwise specified, the polymers of the present disclosure also include polymers that differ only in the presence of one or more isotopically enriched atoms. Examples of isotopically enriched atoms include, but are not limited to, deuterium, tritium, 13 C or 14 C or 15 Nitrogen atoms enriched in N or 18 F is concentrated fluorine atom.

[0044] The polymers of the present invention are structures that contain polysarcosine-based moieties as repeating units. These polymers are characterized by their molecular weight (which may be average molecular weight (MW) or number average molecular weight (Mn)), degree of polymerization and polydispersity index. Molecular weight can be determined, for example, by size exclusion chromatography (SEC) (also called gel permeation chromatography (GPC)), matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS) or by the use of a molecular weight detector. 1 This can be measured by methods well known in the art, such as H-NMR spectroscopy, some of which are illustrated in more detail in the Examples below.

[0045] The term "repeating unit" as used herein refers to a monomeric sarcosine-based unit and is defined by the brackets shown around it. The number at the bottom right of the bracket (represented by the letter "n") refers to the degree of polymerization (DP) of each monomeric unit as a statistical number. DP is calculated by dividing the molecular weight of the polymer given by the SEC-MALS technique by the molecular weight of the monomeric unit. DP values ​​are reported as the center value of a Gaussian distribution that includes polymers of variable DP (due to inherent polydispersity). DP values ​​are subject to reasonable uncertainty due to the ring-opening polymerization mechanism, which may be considered in the context of the present invention to be within the range of ±20%, preferably ±15%, more preferably ±10%, even more preferably ±5%, and particularly preferably ±2%.

[0046] The term "polydispersity index" (PDI) is used as a measure of the broadness of the molecular weight distribution. The higher the PDI, the broader the molecular weight. The PDI of a polymer is calculated as the ratio of the weight average (MW) / number average (Mn) molecular weight. Polydispersity index=Mw / Mn

[0047] In one embodiment, optionally in combination with one or more features of the various embodiments described above or below, the polymer of the invention comprising recurring sarcosine-based units and a vitamin E-based moiety has formula (I): [ka] having In the formula, R1-R4, X, PAA, L, m, n, and z are as defined herein.

[0048] The polymer of formula (I) comprises a polysarcosine-based moiety PAA (depicted on the left side of the formula) and a vitamin E-based moiety (depicted on the right side of the formula) covalently attached either directly or via a linker L.

[0049] In one embodiment, optionally in combination with one or more features of the various embodiments described above or below, a polymer comprising repeating sarcosine-based units and a vitamin E-based moiety, in particular a polymer of formula (I), in particular the SEC or 1 The degree of polymerization or n of the polymer as measured by H-NMR spectroscopy is 5-400, 5-300, 5-200, 5-100, 5-50, 5-40, 5-35, 5-25, and more particularly about 6 or 15 or 20.

[0050] According to another embodiment, optionally in combination with one or more features of the various embodiments described above or below, the polymers comprising recurring sarcosine-based units and vitamin E-based moieties, in particular polymers of formula (I), have an average molecular weight (Mw) of 700-50000 Da, more particularly 1000-20000 Da, even more particularly 1000-5000 Da or 1000-3000 Da, measured by SEC as disclosed in the examples.

[0051] In another embodiment, optionally in combination with one or more features of the various embodiments described above or below, the polydispersity index of the polymers comprising recurring sarcosine-based units and vitamin E-based moieties, in particular the polymers of formula (I), as disclosed in the examples, measured by SEC, is between 1.01 and 1.80, between 1.01 and 1.50, between 1.01 and 1.30, between 1.01 and 1.20, between 1.01 and 1.10.

[0052] In the polymers comprising repeating sarcosine-based units and vitamin E-based moieties, particularly polymers of formula (I), R5 is selected from the group consisting of methyl, -CH2F, -CHF2 and -CF3. According to one embodiment, optionally in combination with one or more features of the various embodiments described above or below, R5 is methyl.

[0053] In the polymers comprising repeating sarcosine-based units and vitamin E-based moieties, particularly polymers of formula (I), R6 and R7 are independently selected from the group consisting of hydrogen and fluorine. According to one embodiment, optionally in combination with one or more features of the various embodiments described above or below, R6 and R7 are hydrogen.

[0054] In the polymers comprising repeating sarcosine-based units and vitamin E-based moieties, particularly polymers of formula (I), R2, R3 and R4 are independently selected from the group consisting of hydrogen, fluorine, methyl, -CH2F, -CHF2 and -CF3. According to one embodiment, optionally in combination with one or more features of the various embodiments described above or below, R2, R3 and R4 are independently selected from the group consisting of hydrogen and methyl.

[0055] According to one embodiment, the polymer comprising repeating sarcosine-based units and vitamin E-based moieties, particularly in polymers of formula (I), contain vitamin E moieties that can include any of the eight possible different forms of vitamin E (α, β, γ, δ tocopherol and α, β, γ, δ tocotrienol).

[0056] Thus, in one embodiment, optionally in combination with one or more features of the various embodiments described above or below, in the polymers of the present invention, particularly in the polymers of formula (I), the broken bonds of the alkyl chains attached to the chroman ring are each single bonds, and R2, R3 and R4 are selected from the following meanings: (i) R2, R3 and R4 are methyl, (ii) R2, R4 are methyl and R3 is hydrogen, (iii) R3 and R4 are methyl and R2 is hydrogen, and (iv) R4 is methyl and R2 and R3 are hydrogen.In a more particular embodiment, the broken bonds of the alkyl chains attached to the chroman ring are each single bonds, and R2, R3 and R4 are methyl.Even more particularly, the vitamin E-based moiety of the polymers of the present invention, particularly in the polymers of formula (I), is represented by the formula (XXIV'): [ka] has.

[0057] In another embodiment, optionally in combination with one or more features of the various embodiments described above or below, in the polymer of formula (I), each of the dashed bonds of the alkyl chains attached to the chroman ring is a double bond, and R2, R3 and R4 are selected from the following meanings: (i) R2, R3 and R4 are methyl, (ii) R2, R4 are methyl and R3 is hydrogen, (iii) R3 and R4 are methyl and R2 is hydrogen, and (iv) R4 is methyl and R2 and R3 are hydrogen. In a more particular embodiment, each of the dashed bonds of the alkyl chains attached to the chroman ring is a double bond, and R2, R3 and R4 are methyl.

[0058] In the polymer of formula (I), R1 is -(C1-C 12 )Alkyl, -(C1-C 12 ) alkylphenyl, -(C1-C6) alkyl-O-(C1-C6) alkyl, -CO-(C1-C 12 )Alkyl, -CO-(C1-C 12 )alkylphenyl and -CO-(C1-C6)alkyl-O-(C1-C6)alkyl, where the alkyl group may be optionally substituted as defined herein. More particularly, when PAA is a repeating sarcosine-based unit of formula (XXI) and z is 1, R1 is selected from the group consisting of -(C1-C 12 )Alkyl, -(C1-C 12 When PAA is a repeating sarcosine-based unit of formula (XXII) and z is 0, R1 is selected from the group consisting of -CO-(C1-C6)alkylphenyl and -(C1-C6)alkyl-O-(C1-C6)alkyl. 12 )Alkyl, -CO-(C1-C 12 )alkylphenyl and -CO-(C1-C6)alkyl-O-(C1-C6)alkyl, wherein all alkyl groups may be optionally substituted as defined herein.

[0059] In one embodiment, optionally in combination with one or more features of the various embodiments described above or below, in the polymer of formula (I), particularly when PAA is a repeating sarcosine-based unit of formula (XXI) and z is 1, R1 is selected from the group consisting of -(C1-C6)alkyl, -(C1-C3)alkyl-O-(C1-C3)alkyl and -(C1-C6)alkylphenyl, where the alkyl group may be optionally substituted as defined herein. More particularly, R1 is selected from the group consisting of isopropyl, 2-methoxyethyl, n-propyl, n-butyl, neopentyl, benzyl and 2-(2-methoxyethoxy)ethyl, and even more particularly R1 is isopropyl.

[0060] In another embodiment, optionally in combination with one or more features of the various embodiments described above or below, in the polymer of formula (I), particularly when PAA is a repeating sarcosine-based unit of formula (XXII) and z is 0, R1 is selected from the group consisting of -CO-(C1-C6)alkyl, -CO-(C1-C6)alkyl-O-C1-C3)alkyl and -CO-(C1-C6)alkylphenyl, wherein the alkyl group may be optionally substituted as defined herein. More particularly, R1 is acetyl.

[0061] In the polymers of the present invention, the polysarcosine-based repeat units may be arranged in any order. Thus, in the polymer of formula (I), the repeat sarcosine-based unit PAA may be represented by the formula (XXI) and the formula (XXII): [ka] is selected from In the formula, R5, R6, R7 and n are as defined herein. *1 " indicates the attachment point of the repeating sarcosine-based unit PAA to X or R1, *2" indicates the point of attachment of the repeating sarcosine-based unit PAA to the linker L or oxygen atom of the vitamin E-based moiety.

[0062] This different arrangement of the repeating polysarcosine-based moieties does not affect the amphiphilic behavior of the polymers described herein, and therefore the demonstrated activity is maintained.

[0063] In the polymer of formula (I), the linker L is a biradical chain comprising one or more moieties selected from the group consisting of -CH=CH-, -C≡C-, -CH2-, -N=CH-, -CH=NH-, -NH-, -NH-NH-, -NH-N=CH-, -O-, -O(CH2)O-, -CO-, -O(CO)-, -COO-, -C(=CH2)-, -C(=NH)-, -CONH-, -NHCO-, -NH(CO)NH-, -S-, -SS-, -SO-, -SO2-, -SONH2- and -phenylene-, where L is optionally substituted as defined herein.

[0064] As a biradical, one end of L is bonded to the polysarcosine-based moiety and the other end of L is bonded to the oxygen atom of the vitamin E-based moiety. When the repeating sarcosine-based unit PAA has formula (XXI), L is bonded to the nitrogen atom of PAA by a chemically feasible bond selected from the group consisting of amide bond, carbamate bond, urea bond and amine bond, more particularly this bond is formed between the -CO-, -COO-, -(CO)NH- or -CH2- moiety on the left side of the linker L and the nitrogen atom of the polysarcosine-based moiety. When the repeating sarcosine-based unit has formula (XXII) and m is 1, L is bonded to the carbonyl group of PAA by a chemically feasible bond selected from the group consisting of amide bond and ester bond, more particularly this bond is formed between the -(O)- or -(N)- moiety on the left side of the linker L and the carbonyl moiety of the polysarcosine-based moiety.

[0065] Furthermore, L is linked to the oxygen atom of the vitamin E-based moiety by a chemically feasible bond selected from the group consisting of an ester bond, a carbamate bond and an ether bond, more particularly this bond is formed between the -CO-, -N(CO)- or -CH2- moiety on the right side of the linker L and an oxygen of the vitamin E derivative.

[0066] In one embodiment, optionally in combination with one or more features of the various embodiments described above or below, in the polymer of formula (I), L is a biradical chain comprising 1 to 50 moieties, more particularly 2 to 30 or 2 to 20 or 2 to 15 moieties, as defined above, insofar as L can be linked to the remainder of the molecule by any chemically feasible bond.

[0067] According to one embodiment, optionally in combination with one or more features of the various embodiments described above or below, in the polymer of formula (I), PAA is a repeating sarcosine-based unit of formula (XXI), z is 1 and m is 1, i.e. the polymer of formula (I) has the formula (Ia): [ka] is a polymer of wherein R1-R7, X, L and n are as defined herein, and L is bonded to the nitrogen atom of the sarcosine-based unit by a chemically feasible bond selected from the group consisting of an amide bond, a carbamate bond, a urea bond and an amine bond. More specifically, in the polymer of formula (Ia), the sarcosine-based unit is bonded to X by a chemically feasible bond selected from the group consisting of an ester bond and an amide bond.

[0068] In the polymer of formula (Ia), X is -O- or -NH-. In one or more particular embodiments, optionally in combination with one or more features of the various embodiments described above or below, in the polymer of formula (Ia), X is -O-. In another more particular embodiment, optionally in combination with one or more features of the various embodiments described above or below, in the polymer of formula (Ia), X is -NH-.

[0069] In a more particular embodiment, the polymer of formula (Ia) has formula (Ia'): [ka] is a polymer of wherein n, R1, X and L are as defined herein, and even more particularly the polymer of formula (Ia) has the formula (Ia″): [ka] is a polymer of wherein R1 and n are as defined herein.

[0070] According to certain embodiments, optionally in combination with any of the embodiments provided above or below, in the polymer of formula (Ia), the linker L is optionally halogen, -OH, -NR a R b , -SH, -NHNH2, -COOR c , -CF3 and -OCF3 (wherein R a , R b and R c are independently a radical selected from the group consisting of H, -phenyl, -(C1-C6)alkyl, -(C2-C6)alkenyl, -(C1-C6)alkylphenyl and -phenyl(C1-C6)alkyl) substituted with one or more substituents selected from the group consisting of 12) alkylene-, -(C1-C6) alkyl-CO-, -CO-(C1-C6) alkyl- and the formula (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI) (XII) (XIII), (XIV), (XV), (XVI), (XVII), (XVIII) or (XIX): [ka] a biradical selected from the group consisting of the biradicals of JPEG2025501519000022.jpg165159, During the ceremony, " * " indicates the point of attachment of the biradical L to the nitrogen atom of the repeating sarcosine-based unit or to the oxygen atom of the vitamin E-based moiety, *3 " indicates the point of attachment of the biradical L to the nitrogen atom of the repeating sarcosine-based unit, and " *4 " indicates the attachment point of the biradical to the oxygen atom of the vitamin E base moiety, a, c, d, e, f, h, j and k are independently integers from 0 to 10, in particular from 0 to 6, and b and g are independently integers from 0 to 1, with the proviso that if b is 0 then at least one of a or c is other than 0, and if g is 0 then at least one of f or h is other than 0; X' is -O- or -NH-; p is 0 or 1, The dashed bonds ----- are each independently a single bond or alternatively a double bond.

[0071] When drawn, the attachment points are referred to herein as " * ". Unless a specific bond is specified, it is meant that the linker may be attached to the remainder of the molecule interchangeably in any orientation.

[0072] In one embodiment, optionally in combination with one or more features of the various embodiments described above or below, in the polymer of formula (Ia), L is -(C1-C 12) alkylene-, more specifically -(C1-C6) alkyl-, and is optionally substituted as defined herein.

[0073] In another embodiment, optionally in combination with one or more features of the various embodiments described above or below, in the polymer of formula (Ia), L is -(C1-C6)alkyl-CO- or -CO-(C1-C6)alkyl-, and is optionally substituted as defined herein.

[0074] In another embodiment, optionally in combination with one or more features of the various embodiments described above or below, in the polymer of formula (Ia), L is a biradical of formula (III), more particularly a biradical of formula (III) where b is 0 and a+c are selected from 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12, and even more particularly, L is a biradical of formula (III) where b is 0 and a and c are 1, i.e. formula (IIIa): [ka] It is a biradical.

[0075] In another embodiment, optionally in combination with one or more features of the various embodiments described above or below, in the polymer of formula (Ia), L is a biradical selected from formulas (IV), (V) and (VI), more particularly in the biradical of formula (IV), a is 1 and the dashed bond is a double bond, i.e. the biradical of formula (IV) has formula (IVa), and in the biradical of formula (V), the dashed bond is more particularly a double bond, i.e. the biradical of formula (V) has formula (Va). [ka]

[0076] In another embodiment, optionally in combination with one or more features of the various embodiments described above or below, in the polymer of formula (Ia), L is a biradical selected from formulas (VII) and (VIII), more particularly in the biradical of formula (VIII), a is 1.

[0077] In another embodiment, optionally in combination with one or more features of the various embodiments described above or below, in the polymer of formula (Ia), L is a biradical of formula (IX), more particularly of formula (IX) in which b and g are 0 and a, c, d, e, f and h are 1, i.e. of formula (IXa): [ka] It is a biradical.

[0078] In another embodiment, optionally in combination with one or more features of the various embodiments described above or below, in the polymer of formula (Ia), L is a biradical selected from formulae (X) and (XI), more particularly in the biradicals of formulae (X) and (XI), b and g are 0 and a, c, d, e, f and h are 1, i.e. the biradicals of formulae (Xa) and (XIa), respectively, are represented by the formulae (Xa) and (XIa): [ka] has.

[0079] In another embodiment, optionally in combination with one or more features of the various embodiments described above or below, in the polymer of formula (Ia), L is a biradical selected from formulae (XII) and (XIII), more particularly in the biradical of formulae (XII) and (XIII), b is 0 and a, c and d are 1.

[0080] In another embodiment, optionally in combination with one or more features of the various embodiments described above or below, in the polymer of formula (Ia), L is a biradical selected from formulae (XIV), (XV), (XVI), (XVII) and (XVIII), more particularly in the biradicals of formulae (XIV), (XV), (XVI), (XVII) and (XVIII), b is 0 and a and c are 1.

[0081] In another embodiment, optionally in combination with one or more features of the various embodiments described above or below, in the polymer of formula (Ia), L is a biradical of formula (XIX) where p is 0 and j and k are 1. In another embodiment, optionally in combination with one or more features of the various embodiments described above or below, in the polymer of formula (Ia), L is a biradical of formula (XIX) where p is 1, X' is -NH-, and j and k are 1. In another embodiment, optionally in combination with one or more features of the various embodiments described above or below, in the polymer of formula (Ia), L is a selected biradical of formula (XIX) where p is 1, X' is -O-, and j and k are 1.

[0082] According to a more particular embodiment, optionally in combination with one or more features of the various embodiments described above or below, in the polymer of formula (Ia), L is [ka] is a biradical of formula (III) selected from the group consisting of:

[0083] According to another embodiment, optionally in combination with one or more features of the various embodiments described above or below, in the polymer of formula (I), the PAA is a repeating sarcosine-based unit of formula (XXII) and z is 0, i.e. the polymer of formula (I) has the formula (Ib): [ka] is a polymer of wherein R1-R7, L, m and n are as defined herein, and when m is 1, L is bonded to the carbonyl group of PAA through a chemically possible bond selected from the group consisting of an amide bond and an ester bond, and when m is 0, PAA is bonded to the oxygen atom of the vitamin E-based moiety through an ester bond. More specifically, in the polymer of formula (Ib), PAA is bonded to R1 through an amine bond.

[0084] In one particular embodiment, optionally in combination with any of the embodiments provided above or below, in the polymer of Formula (Ib), m is 0.

[0085] According to certain embodiments, optionally in combination with any of the embodiments provided above or below, in the polymer of formula (Ib), m is 1 and the linker L is optionally halogen, -OH, -NR a R b , -SH, -NHNH2, -COOR c , -CF3 and -OCF3 (wherein R a , R b and R c is independently a radical selected from the group consisting of H, -phenyl, -(C1-C6)alkyl, -(C2-C6)alkenyl, -(C1-C6)alkylphenyl and -phenyl(C1-C6)alkyl; 12 ) alkylene-, -X'-(C1-C6) alkyl-CO- and the formula (III'), (IV'), (V'), (VI'), (VII), (VIII), (IX'), (X'), (XI'), (XII') (XIII'), (XIV'), (XV'), (XVI'), (XVII'), (XVIII') or (XIX'): [ka] a biradical selected from the group consisting of the biradicals of JPEG2025501519000030.jpg109159, During the ceremony, " * " indicates the point of attachment of the biradical L to the carbonyl group of the repeating sarcosine-based unit or to the oxygen atom of the vitamin E-based moiety, and " *3 " indicates the point of attachment of the biradical L to the carbonyl group, and " *4 " indicates the point of attachment of the biradical to the oxygen atom of the vitamin E base moiety, a, c, d, e, f, h, j and k are independently integers from 0 to 10, in particular from 0 to 6, and b and g are independently integers from 0 to 1, provided that when b is 0, at least one of a or c is non-zero, and when g is 0, at least one of f or h is non-zero; X' is -O- or -NH-; The dashed bonds ----- are each independently a single bond or alternatively a double bond.

[0086] When drawn, the attachment points are referred to herein as " * ". Unless a specific bond is specified, it is meant that the linker may be attached interchangeably to the remainder of the molecule.

[0087] In one embodiment, optionally in combination with one or more features of the various embodiments described above or below, in the polymer of formula (Ib), L is -X'-(C1-C 12 ) alkylene-, more particularly -X'-(C1-C6) alkyl-, and is optionally substituted as defined herein.

[0088] In another embodiment, optionally in combination with one or more features of the various embodiments described above or below, in the polymer of formula (Ib), L is -X'-(C1-C6)alkyl-CO- or -X'-(C1-C6)alkyl-, and is optionally substituted as defined herein.

[0089] In another embodiment, optionally in combination with one or more features of the various embodiments described above or below, in the polymer of formula (Ib), L is a biradical of formula (III'), more particularly a biradical of formula (III') where b is 0 and a+c is selected from 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12, and even more particularly, L is a biradical of formula (III') where b is 0, a and c are 1 and X' is -NH-, i.e. formula (IIIa'): [ka] It is a biradical.

[0090] In another embodiment, optionally in combination with one or more features of the various embodiments described above or below, in the polymer of formula (Ib), L is a biradical selected from formulas (IV'), (V') and (VI'), more particularly X' is -NH-, even more particularly in the biradical of formula (IV'), a is 1 and the dashed bond is a double bond, i.e. the biradical of formula (IV') has formula (IVa'), and in the biradical of formula (V'), the dashed bond is more particularly a double bond and X' is -NH-, i.e. the biradical of formula (V') has formula (Va'). [ka]

[0091] In another embodiment, optionally in combination with one or more features of the various embodiments described above or below, in the polymer of formula (Ib), L is a biradical selected from formulas (VII) and (VIII), more particularly in the biradical of formula (VIII), a is 1.

[0092] In another embodiment, optionally in combination with one or more features of the various embodiments described above or below, in the polymer of formula (Ib), L is a biradical of formula (IX'), more particularly a biradical of formula (IX') in which b and g are 0, a, c, d, e, f and h are 1 and X' is -NH-, i.e. of formula (IXa'): [ka] It is a biradical.

[0093] In another embodiment, optionally in combination with one or more features of the various embodiments described above or below, in the polymer of formula (Ib), L is a biradical selected from formulae (X') and (XI'), more particularly in the biradicals of formulae (X') and (XI'), b and g are 0, a, c, d, e, f and h are 1, and X' is -NH-, i.e. the biradicals of formulae (X') and (XI') are respectively represented by the formulae (Xa') and (XIa'): [ka] has.

[0094] In another embodiment, optionally in combination with one or more features of the various embodiments described above or below, in the polymer of formula (Ib), L is a biradical selected from formulae (XII') and (XIII'), more particularly in the biradical of formulae (XII') and (XIII'), b is 0, a, c and d are 1 and X' is -NH-.

[0095] In another embodiment, optionally in combination with one or more features of the various embodiments described above or below, in the polymer of formula (Ib), L is a biradical selected from formulae (XIV'), (XV'), (XVI'), (XVII') and (XVIII'), more particularly in the biradicals of formulae (XIV'), (XV'), (XVI'), (XVII') and (XVIII'), b is 0, a and c are 1 and X' is -NH-.

[0096] In another embodiment, optionally in combination with one or more features of the various embodiments described above or below, in the polymer of formula (Ib), L is a biradical selected from formula (XIX') where X' is -NH- and j and k are 1. In another embodiment, optionally in combination with one or more features of the various embodiments described above or below, in the polymer of formula (Ib), L is a biradical selected from formula (XIX') where X' is -O- and j and k are 1.

[0097] According to a more particular embodiment, optionally in combination with one or more features of the various embodiments described above or below, in the polymer of formula (Ib), L is [ka] is a biradical of formula (III') selected from the group consisting of:

[0098] For completeness, the following numbered embodiments also form part of the invention:

[0099] Embodiment 1: A polymer comprising repeating sarcosine-based units covalently attached directly or via a linker to a vitamin E-based moiety, or a pharma- ceutically, nutraceutical or cosmetically acceptable salt thereof, or any stereoisomer or mixture of stereoisomers of either of the polymers or any of the salts thereof. (wherein the repeating sarcosine-based unit has the formula (XXIII): [ka] having wherein R5 is selected from the group consisting of methyl, -CH2F, -CHF2, and -CF3, R6 and R7 are independently selected from the group consisting of hydrogen and fluorine, and n is an integer from 5 to 500, and the vitamin E base moiety has the formula (XXIV): [ka] having wherein R2, R3 and R4 are independently selected from the group consisting of hydrogen, fluorine, methyl, -CH2F, -CHF2 and -CF3, and the dashed bonds ----- are each independently a single bond or alternatively a double bond.

[0100] Embodiment 2: The repeating sarcosine-based unit has an attachment point " * " or " is covalently attached to the vitamin E based moiety directly or through a linker, and the vitamin E based moiety is linked to the vitamin E based moiety by a wavy line [ka] 2. The polymer of embodiment 1, wherein the repeating sarcosine-based unit is covalently attached, either directly or via a linker, to the repeating sarcosine-based unit by the attachment point indicated.

[0101] Embodiment 3: Formula (I): [ka] The polymer according to any one of embodiments 1 to 2, (In the formula, PAA is represented by the formula (XXI) and the formula (XXII): [ka] is a repeating sarcosine-based unit selected from During the ceremony, `` *1 " indicates the attachment point of the repeating sarcosine-based unit PAA to X or R1, *2 " indicates the point of attachment of the repeating sarcosine-based unit PAA to the linker L or oxygen atom of the vitamin E-based moiety, m is 0 or 1, with the proviso that m is 1 when the repeating sarcosine-based unit PAA has the formula (XXI), z is 0 or 1, with the proviso that when the repeating sarcosine-based unit PAA has the formula (XXI), z is 1, and when the repeating sarcosine-based unit PAA has the formula (XXII), z is 0; R1 is H, -(C1~C 12 )Alkyl, -(C1-C 12 ) alkylphenyl, -(C1-C6) alkyl-O-(C1-C6) alkyl, -CO-(C1-C 12 )Alkyl, -CO-(C1-C 12 ) alkylphenyl and -CO-(C1-C6) alkyl-O-(C1-C6) alkyl, where R1 is optionally selected from the group consisting of halogen, -OH, -NR a R b , -SH, -NHNH2, -COOR c , -CF3, and -OCF3; R2, R3 and R4 are independently selected from the group consisting of hydrogen, fluorine, methyl, -CH2F, -CHF2 and -CF3; R5 is selected from the group consisting of methyl, -CH2F, -CHF2, and -CF3; R6 and R7 are independently selected from the group consisting of hydrogen and fluorine; n is an integer from 5 to 500; X is -O- or -NH-, and L is a biradical chain comprising one or more moieties selected from the group consisting of -CH=CH-, -C≡C-, -CH2-, -N=CH-, -CH=NH-, -NH-, -NH-NH-, -NH-N=CH-, -O-, -O(CH2)O-, -CO-, -O(CO)-, -(CO)O-, -C(=CH2)-, -C(=NH)-, -CONH-, -NHCO-, -NH(CO)NH-, -S-, -SS-, -SO-, -SO2-, -SON2NH2- and -phenylene-, wherein L is optionally selected from halogen, -OH, -NR a R b , -SH, -NHNH2, -COOR c , -CF3, -OCF3, [ka] and is substituted with one or more substituents selected from the group consisting of As used herein, when L contains a -CH2- moiety, the two hydrogen atoms attached to that carbon atom may optionally be joined to the following ring: [ka] is replaced by when PAA is a repeating sarcosine-based unit of formula (XXI), L is bonded to a nitrogen atom of PAA by a chemically feasible bond, and when PAA is a repeating sarcosine-based unit of formula (XXII) and m is 1, L is bonded to a carbonyl group of PAA by a chemically feasible bond; L is attached to an oxygen atom of the vitamin E base moiety by any chemically feasible bond; and each dashed bond ----- is independently a single bond or alternatively a double bond; and R a , R b and R c is independently a radical selected from the group consisting of H, -phenyl, -(C1-C6)alkyl, -(C2-C6)alkenyl, -(C1-C6)alkylphenyl and -phenyl(C1-C6)alkyl).

[0102] Embodiment 4: R1 is -(C1-C 12 )Alkyl, -(C1-C 12 ) alkylphenyl, -(C1-C6) alkyl-O-(C1-C6) alkyl, -CO-(C1-C 12 )Alkyl, -CO-(C1-C 12 ) alkylphenyl and -CO-(C1-C6) alkyl-O-(C1-C6) alkyl, where R1 is optionally selected from the group consisting of halogen, -OH, -NR a R b , -SH, -NHNH2, -COOR c , -CF3, and -OCF3; A polymer according to any of the embodiments 1-3, wherein when PAA is a repeating sarcosine-based unit of formula (XXI), L is bonded to the nitrogen atom of PAA by a chemically feasible bond selected from the group consisting of an amide bond, a carbamate bond, a urea bond and an amine bond, and when PAA is a repeating sarcosine-based unit of formula (XXII) and m is 1, L is bonded to the carbonyl group of PAA by a chemically feasible bond selected from the group consisting of an amide bond and an ester bond, and L is bonded to the oxygen atom of the vitamin E-based moiety by a chemically feasible bond selected from the group consisting of an ester bond, a carbamate bond and an ether bond.

[0103] Embodiment 5: SECs or 1 5. The polymer according to any of the preceding embodiments, wherein n is from 5 to 400, from 5 to 300, from 5 to 200, from 5 to 100, from 5 to 50, from 5 to 40, from 5 to 35 or from 5 to 25, more particularly n is about 6, or about 15 or about 20, as measured by H-NMR spectroscopy.

[0104] Embodiment 6: A polymer according to any of the embodiments 1 to 5, having an average molecular weight (Mw) measured by SEC as disclosed in the examples of 700 to 50000 Da, more particularly 1000 to 20000 Da, even more particularly 1000 to 5000 Da or 1000 to 3000 Da.

[0105] Embodiment 7: A polymer according to any of the embodiments 1 to 6 having a polydispersity index of 1.01 to 1.80, 1.01 to 1.50, 1.01 to 1.30, 1.01 to 1.20 or 1.01 to 1.10 as measured by SEC as disclosed in the examples.

[0106] Embodiment 8: A polymer according to any one of embodiments 1 to 7, wherein R5 is methyl.

[0107] Embodiment 9: A polymer according to any one of embodiments 1 to 8, wherein R6 and R7 are hydrogen.

[0108] Embodiment 10: A polymer according to any of embodiments 1 to 9, wherein R2, R3 and R4 are independently selected from the group consisting of hydrogen and methyl.

[0109] Embodiment 11: A polymer according to any of embodiments 1 to 10, wherein the dashed bonds of the alkyl chain attached to the chroman ring are each a single bond, and R2, R3 and R4 have the following meanings: (i) R2, R3 and R4 are methyl, (ii) R2, R4 are methyl and R3 is hydrogen, (iii) R3 and R4 are methyl and R2 is hydrogen, and (iv) R4 is methyl and R2 and R3 are hydrogen.

[0110] Embodiment 12: A polymer according to embodiment 11, wherein the dashed bonds of the alkyl chain attached to the chroman ring are each a single bond, and R2, R3 and R4 are methyl, more particularly, the vitamin E-based portion of the polymer has formula (XXIV').

[0111] Embodiment 13: A polymer according to any of embodiments 1 to 10, wherein the dashed bonds of the alkyl chain attached to the chroman ring are each a double bond, and R2, R3 and R4 have the following meanings: (i) R2, R3 and R4 are methyl, (ii) R2, R4 are methyl and R3 is hydrogen, (iii) R3 and R4 are methyl and R2 is hydrogen, and (iv) R4 is methyl and R2 and R3 are hydrogen.

[0112] Embodiment 14: A polymer according to embodiment 13, wherein the dashed bonds of the alkyl chain attached to the chroman ring are each single bonds, and R2, R3 and R4 are methyl.

[0113] Embodiment 15: R1 is -(C1 to C 12 )Alkyl, -(C1-C 12 ) alkylphenyl, -(C1-C6) alkyl-O-(C1-C6) alkyl, -CO-(C1-C 12 )Alkyl, -CO-(C1-C 12R1 is selected from the group consisting of -(C1-C6)alkylphenyl and -CO-(C1-C6)alkyl-O-(C1-C6)alkyl, where the alkyl group may be optionally substituted as defined herein, more particularly, when PAA is a repeating sarcosine-based unit of formula (XXI) and z is 1, ... 12 )Alkyl, -(C1-C 12 and when PAA is a repeating sarcosine-based unit of formula (XXII) and z is 0, R1 is selected from the group consisting of -CO-(C1-C6)alkylphenyl and -(C1-C6)alkyl-O-(C1-C6)alkyl. 12 )Alkyl, -CO-(C1-C 12 15. The polymer of any of embodiments 3 or 5-14, wherein the alkyl group is selected from the group consisting of -CO-(C1-C6)alkyl-O-(C1-C6)alkyl, and -CO-(C1-C6)alkylphenyl, wherein all alkyl groups may be optionally substituted as defined herein.

[0114] Embodiment 16: A polymer according to any of embodiments 3 or 5-15, particularly when PAA is a repeating sarcosine-based unit of formula (XXI) and z is 1, wherein R1 is selected from the group consisting of -(C1-C6)alkyl, -(C1-C3)alkyl-O-(C1-C3)alkyl and -(C1-C6)alkylphenyl, wherein the alkyl group may be optionally substituted as defined herein.

[0115] Embodiment 17: A polymer according to embodiment 16, in particular when PAA is a repeating sarcosine-based unit of formula (XXI) and z is 1, R1 is selected from the group consisting of isopropyl, 2-methoxyethyl, n-propyl, n-butyl, neopentyl, benzyl and 2-(2-methoxyethoxy)ethyl, more particularly R1 is isopropyl.

[0116] Embodiment 18: A polymer according to any of embodiments 3 or 5-15, particularly when PAA is a repeating sarcosine-based unit of formula (XXII) and z is 0, wherein R1 is selected from the group consisting of -CO-(C1-C6)alkyl, -CO-(C1-C6)alkyl-O-C1-C3)alkyl and -CO-(C1-C6)alkylphenyl, wherein the alkyl group may be optionally substituted as defined herein.

[0117] Embodiment 19: A polymer according to embodiment 18, wherein R1 is acetyl, in particular when PAA is a repeating sarcosine-based unit of formula (XXII) and z is 0.

[0118] Embodiment 20: A polymer according to any one of embodiments 3 to 14, wherein R1 is H.

[0119] Embodiment 21: A polymer according to any of embodiments 3 to 20, wherein the repeating sarcosine-based unit PAA has formula (XXI).

[0120] Embodiment 22: A polymer according to embodiment 21, wherein z is 1 and m is 1, i.e. the polymer of formula (I) is a polymer of formula (Ia), wherein R1-R7, X, L and n are as defined herein, and L is bonded to the nitrogen atom of the sarcosine-based unit by a chemically feasible bond selected from the group consisting of an amide bond, a carbamate bond, a urea bond and an amine bond.

[0121] Embodiment 23: A polymer according to embodiment 22, wherein the sarcosine-based unit is linked to X by a chemically feasible bond selected from the group consisting of an ester bond and an amide bond.

[0122] Embodiment 24: A polymer according to any of embodiments 21-22, wherein X is -NH-.

[0123] Embodiment 25: A polymer according to any of embodiments 21-22, wherein X is -O-.

[0124] Embodiment 26: A polymer according to any of embodiments 21-22, having formula (Ia'), more particularly formula (Ia'').

[0125] Embodiment 27: The linker L is optionally halogen, -OH, -NR a R b , -SH, -NHNH2, -COOR c , -CF3 and -OCF3 (wherein R a , R b and R c are independently a radical selected from the group consisting of H, -phenyl, -(C1-C6)alkyl, -(C2-C6)alkenyl, -(C1-C6)alkylphenyl and -phenyl(C1-C6)alkyl) substituted with one or more substituents selected from the group consisting of 12 27. The polymer according to any of embodiments 21 to 26, wherein the biradical is selected from the group consisting of alkylene-, -(C1-C6)alkyl-CO-, -CO-(C1-C6)alkyl- and biradicals of formula (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI) (XII) (XIII), (XIV), (XV), (XVI), (XVII), (XVIII) or (XIX).

[0126] Embodiment 28: The linker L is -(C 12 28. The polymer of embodiment 27, wherein the aryl group is -(C1-C6)alkylene-, more particularly -(C1-C6)alkyl-, and is optionally substituted as defined herein.

[0127] Embodiment 29: A polymer according to embodiment 27, wherein the linker L is -(C1-C6)alkyl-CO- or -CO-(C1-C6)alkyl-, and is optionally substituted as defined herein.

[0128] Embodiment 30: A polymer according to embodiment 27, wherein the linker L is a biradical of formula (III), more particularly a biradical of formula (III) in which b is 0 and a+c are selected from 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12, and even more particularly L is a biradical of formula (III) in which b is 0 and a and c are 1, i.e. a biradical of formula (IIIa).

[0129] Embodiment 31: A polymer according to embodiment 27, in which the linker L is a biradical selected from formulae (IV), (V) and (VI), more particularly in which in the biradical of formula (IV), a is 1 and the dashed bond is a double bond, i.e. the biradical of formula (IV) has formula (IVa), and in the biradical of formula (V), the dashed bond is more particularly a double bond, i.e. the biradical of formula (V) has formula (Va).

[0130] Embodiment 32: A polymer according to embodiment 27, wherein the linker L is a biradical selected from formulae (VII) and (VIII), more particularly in the biradical of formula (VIII) a is 1.

[0131] Embodiment 33: A polymer according to embodiment 27, wherein the linker L is a biradical of formula (IX), more particularly a biradical of formula (IX) in which b and g are 0 and a, c, d, e, f and h are 1, i.e. a biradical of formula (IXa).

[0132] Embodiment 34: A polymer according to embodiment 27, wherein the linker L is a biradical selected from formulae (X) and (XI), more particularly in the biradicals of formulae (X) and (XI), b and g are 0 and a, c, d, e, f and h are 1, i.e. the biradicals of formulae (X) and (XI) have the formulae (Xa) and (XIa), respectively.

[0133] Embodiment 35: A polymer according to embodiment 27, wherein the linker L is a biradical selected from formulae (XII) and (XIII), more particularly in the biradicals of formulae (XII) and (XIII), b is 0 and a, c and d are 1.

[0134] Embodiment 36: A polymer according to embodiment 27, wherein the linker L is a biradical selected from formulae (XIV), (XV), (XVI), (XVII) and (XVIII), more particularly in the biradicals of formulae (XIV), (XV), (XVI), (XVII) and (XVIII), b is 0 and a and c are 1.

[0135] Embodiment 37: A polymer according to embodiment 27, wherein the linker L is a biradical of formula (XIX), in which p is 0 and j and k are 1, or alternatively p is 1, X' is -NH- and j and k are 1, or alternatively p is 1, X' is -O- and j and k are 1.

[0136] Embodiment 38: The linker L is [ka] 28. The polymer according to embodiment 27, wherein the biradical of formula (III) is selected from the group consisting of:

[0137] Embodiment 39: The linker L has the formula (XVa) and (XVIIa): [ka] is a biradical selected from the group consisting of *" indicates the point of attachment of the biradical L to the nitrogen atom of the repeating sarcosine-based unit or to the oxygen atom of the vitamin E-based moiety, a and c are independently integers 0-10, in particular 0-6, b is an integer 0-1, with the proviso that when b is 0 then at least one of a or c is other than 0, more particularly in the biradicals of formulae (XVa) and (XVIIa) b is 0 and a and c are 1.

[0138] Embodiment 40: A polymer according to any of embodiments 3 to 20, wherein the repeating sarcosine-based unit PAA has the formula (XXII).

[0139] Embodiment 41: A polymer according to embodiment 40, wherein z is 0, i.e. the polymer of formula (I) is a polymer of formula (Ib), wherein R1-R7, L, m, and n are as defined herein, and wherein when m is 1, L is bonded to the carbonyl group of the PAA by a chemically feasible bond selected from the group consisting of an amide bond and an ester bond, and when m is 0, the PAA is bonded to the oxygen atom of the vitamin E-based moiety by an ester bond.

[0140] Embodiment 42: A polymer according to embodiment 41, wherein the PAA is linked to R1 via an amine bond.

[0141] Embodiment 43: m is 1 and the linker L is optionally halogen, -OH, -NR a R b , -SH, -NHNH2, -COOR c , -CF3 and -OCF3, -X'-(C1 to C 12 ) alkylene-(wherein R a , R b and R care independently selected from the group consisting of H, -phenyl, -(C1-C6)alkyl, -(C2-C6)alkenyl, -(C1-C6)alkylphenyl and -phenyl(C1-C6)alkyl; -X'-(C1-C6)alkyl-CO-; and a biradical of formula (III'), (IV'), (V'), (VI'), (VII), (VIII), (IX'), (X'), (XI'), (XII'), (XIII'), (XIV'), (XV'), (XVI'), (XVII'), (XVIII') or (XIX').

[0142] Embodiment 44: The linker L is -X'-(C 12 44. The polymer of embodiment 43, wherein the alkylene is -X'-(C1-C6)alkyl-, more particularly -X'-(C1-C6)alkyl-, and is optionally substituted as defined herein.

[0143] Embodiment 45: A polymer according to embodiment 43, wherein the linker L is -X'-(C1-C6)alkyl-CO- or -X'-(C1-C6)alkyl-, and is optionally substituted as defined herein.

[0144] Embodiment 46: A polymer according to embodiment 43, wherein the linker L is a biradical of formula (III'), more particularly a biradical of formula (III') in which b is 0 and a+c is selected from 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12, and even more particularly L is a biradical of formula (III') in which b is 0, a is 1, c is 0 or 1 and X' is -NH-, i.e. a biradical of formula (IIIa').

[0145] Embodiment 47: A polymer according to embodiment 43, in which the linker L is a biradical selected from the formulae (IV'), (V') and (VI'), more particularly X' is -NH-, even more particularly in which in the biradical of formula (IV'), a is 1 and the dashed bond is a double bond, i.e. the biradical of formula (IV') has formula (IVa'), and in the biradical of formula (V'), the dashed bond is more particularly a double bond and X' is -NH-, i.e. the biradical of formula (V') has formula (Va').

[0146] Embodiment 48: A polymer according to embodiment 47, wherein the linker L is a biradical selected from formulae (VII) and (VIII), more particularly in the biradical of formula (VIII), a is 1.

[0147] Embodiment 49: A polymer according to embodiment 43, wherein the linker L is a biradical of formula (IX'), more particularly a biradical of formula (IX') in which b and g are 0, a, c, d, e, f and h are 1 and X' is -NH-, i.e. a biradical of formula (IXa').

[0148] Embodiment 50: A polymer according to embodiment 43, wherein the linker L is a biradical selected from the formulae (X') and (XI'), more particularly in the biradicals of the formulae (X') and (XI'), b and g are 0, a, c, d, e, f and h are 1 and X' is -NH-, i.e. the biradicals of the formulae (X') and (XI') have the formulae (Xa') and (XIa'), respectively.

[0149] Embodiment 51: A polymer according to embodiment 43, wherein the linker L is a biradical selected from formulae (XII') and (XIII'), more particularly in the biradicals of formulae (XII') and (XIII'), b is 0, a, c and d are 1 and X' is -NH-.

[0150] Embodiment 52: A polymer according to embodiment 43, wherein the linker L is a biradical selected from formulae (XIV'), (XV'), (XVI'), (XVII') and (XVIII'), more particularly in the biradicals of formulae (XIV'), (XV'), (XVI'), (XVII') and (XVIII'), b is 0, a and c are 1 and X' is -NH-.

[0151] Embodiment 53: A polymer according to embodiment 43, wherein the linker L is a biradical selected from formula (XIX'), where X' is -NH- and j and k are 1. In another embodiment, optionally in combination with one or more features of the various embodiments described above or below, in the polymer of formula (Ib), L is a biradical selected from formula (XIX), where X' is -O- and j and k are 1.

[0152] Embodiment 54: The linker L is [ka] JPEG2025501519000046.jpg48159.

[0153] Embodiment 55: Formula (IIIa″): [ka] The linker L is a biradical, *3 " indicates the point of attachment of the biradical L to the carbonyl group, and " * A polymer according to any of embodiments 41-42, wherein "4" indicates the point of attachment of the biradical to the oxygen atom of the vitamin E based moiety.

[0154] Embodiment 56: The polymer according to any one of embodiments 40 to 42, wherein m is 0.

[0155] Processes for the preparation of the polymers of formula (I) are also part of the invention. The polymers of formula (I) may be prepared by synthetic processes well known in the art.

[0156] For example, a polymer of formula (I) in which the repeating sarcosine-based unit PAA has the formula (XXI) (i.e., a polymer of formula (Ia)) can be synthesized according to the following scheme: [ka] The polymer may be prepared by reacting a polymer of formula (A) with a polymer of formula (B) as shown in A is selected from -L1-(CO)-Y or -L2-OH or -L-LG, where -L1-(CO)- is a linker L terminating in a -CO- moiety, -L2-O- is a linker L terminating in a -O- moiety, and Y is an OH or halogen atom, LG is a leaving group, and n, X, R1, R2, R3, R4, R5, R6, R7 and L are as defined herein.

[0157] R A When is -L1-(CO)-Y and Y is OH, an amide bond is formed between compounds (A) and (B). This reaction may be carried out in the presence of an activating agent such as 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium tetrafluoroborate (DMTMMBF4), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC·HCl) or hydroxybenzo-triazole (HOBt), preferably in the presence of a base such as triethylamine (TEA), N-methylmorpholine (NMM) or N,N-diisopropylethylamine (DIPEA), in a suitable solvent such as dimethylformamide, dichloromethane or chloroform, at a temperature comprised between room temperature and the boiling point of the solvent, preferably at room temperature.

[0158] R AWhen is -L1-(CO)-Y and Y is a halogen atom, the reaction may be carried out in the presence of a base such as triethylamine, in a suitable solvent such as tetrahydrofuran, at a temperature comprised between room temperature and the reflux temperature of the solvent. Compounds of formula (A), when X is a halogen atom, may be prepared from the corresponding carboxylic acid by methods well known in the art.

[0159] R A When is -L2-OH, the reaction may be carried out in the presence of a carbonyl source such as 1,1'-carbonyldiimidazole (CDI), N,N'-disuccinimidyl carbonate (DSC) or bis(trichloromethyl) carbonate (BTC), in a suitable solvent such as acetonitrile or 1,4-dioxane, at a temperature comprised between room temperature and the reflux temperature of the solvent.

[0160] R A When is -L-LG, the reaction may be carried out in the presence of a base such as triethylamine (TEA), N-methylmorpholine (NMM) or N,N-diisopropylethylamine (DIPEA), in a suitable solvent such as acetonitrile, tetrahydrofuran, dimethylformamide, dichloromethane or chloroform, at a temperature comprised between room temperature and the boiling point of the solvent, preferably at room temperature. Non-limiting examples of leaving groups include halogen, -OSOR and -OCOR, where R is (C1-C4) alkyl optionally substituted with one or more halogen atoms, and (C6-C10) alkyl optionally substituted with (C1-C4) alkyl or (C1-C4) alkyl optionally substituted with one or more halogen atoms. 12 )aryl. More particularly, LG is selected from the group consisting of halogen, -OSO2CH3 (-OMs), -OSO2C7H7 (-OTs), -OSO2CF3 (-OTf), -OCOCH3 (-OAc), -OCOPh (-OBz) and -OCOCF3 (-TFA).

[0161] R ACompounds of formula (A) where is -L1-(CO)-Y and Y is OH, i.e., compounds of formula (A1), are commercially available or may be prepared by reacting a compound of formula (C), which is a vitamin E derivative, with a compound of formula (D). [ka] where R2, R3 and R4 are as defined herein, and L3 is a linker L terminating in two -COOH moieties. This reaction may be carried out under conditions similar to those disclosed above for the formation of an ester bond.

[0162] R A Compounds of formula (A) where is -L-LG, i.e. compounds of formula (A2), may be prepared by reacting compounds of formula (C) with compounds of formula (E) under conditions similar to those disclosed above for the formation of an ether bond. [ka] wherein R' is -COOH or an anhydride or ester derivative thereof or a leaving group.

[0163] Compounds of formula (B) may be prepared by ring-opening polymerization (ROP) of N-carboxyanhydrides (NCAs), particularly 3-alkyloxazolidine-2,5-diones (compounds of formula (F)). Linear polysarcosine polymers (R1-X-PSar n An amine or alcohol of formula (G) is used as an initiator to obtain the product (III). The reaction is carried out in a suitable solvent, such as dimethylformamide, at a temperature comprised between 4° C. and room temperature, preferably at about 10° C. [ka]

[0164] The degree of polymerization (DP) can be controlled by the monomer (NCA) / initiator (alcohol / amine) ratio. Polymers of formula (I) in which the repeating sarcosine-based unit PAA has formula (XXII) (i.e., polymers of formula (Ib)) may be prepared by synthetic processes well known in the art. For example, compounds of formula (XXII) in which m is 1 may be prepared by ring-opening polymerization (ROP) of N-carboxyanhydrides of formula (F) by using amines or alcohols of formula (H) as initiators. [ka] where -L4-X'- is a linker L that terminates in an X' moiety, where X' is -NH- or -O-.

[0165] When M is 0, the compound of formula (XXII) may be prepared by ring-opening polymerization (ROP) of an N-carboxyanhydride of formula (F) by using an amine or alcohol of formula (K) as an initiator. [ka]

[0166] The resulting intermediates of formula (J) and (J') may be reacted with a compound of formula R1-LG, where LG is a leaving group, to provide a compound of formula (I).

[0167] The complex of formula (II) Using appropriate surface functionalities, the polymers of the invention may be further modified with other molecules that can actively target cells and aid in cell entry, thereby resulting in conjugates with improved cell-specific delivery.

[0168] The present invention therefore also relates to conjugates of the polysarcosine vitamin E derivatives of the present invention with other molecules, either covalently linked directly or via a linker. [ka] or a pharma- ceutically, nutraceutical or cosmetically acceptable salt thereof, or any stereoisomer or mixture of stereoisomers of any of the complexes of formula (II) or any of their salts, wherein m, PAA, X, n, L, R2, R3, R4 and the dashed bond are as defined herein; Z is an agent selected from the group consisting of a nutraceutical active agent, a medicamentously active agent, a cell targeting agent, a diagnostically active agent and a cosmetically active agent; s is 0 or 1, and z' is 0 or 1, with the proviso that when the repeating sarcosine-based unit PAA has the formula (XXII), z' is 0; L' is a biradical chain containing one or more moieties selected from the group consisting of -CH=CH-, -C≡C-, -CH2-, -N=CH-, -CH=NH-, -NH-, -NH-NH-, -NH-N=CH-, -O-, -O(CH2)O-, -CO-, -O(CO)-, -COO-, -C(=CH2)-, -C(=NH)-, -CONH-, -NHCO-, -NH(CO)NH-, -S-, -SS-, -SO-, -SO2-, -SON2NH2-, and -phenylene-, where L' is optionally substituted as defined herein.

[0169] According to one embodiment, optionally in combination with one or more features of the various embodiments described above or below, in the conjugate of formula (II), the PAA is a repeating sarcosine-based unit of formula (XXI), i.e. the conjugate of formula (II) has the formula (IIa): [ka] It is a complex of wherein n, X, L, L', Z, z', s, R2-R7 and the dashed bonds are as defined herein.

[0170] According to another embodiment, optionally in combination with one or more features of the various embodiments described above or below, in the conjugate of formula (II), the PAA is a repeating sarcosine-based unit of formula (XXII), i.e. the conjugate of formula (II) is of formula (IIb): [ka] It is a complex of wherein n, L, L', Z, s, m, R2-R7 and the dashed bonds are as defined herein.

[0171] In one embodiment, optionally combined with any of the embodiments provided above or below, Z is a cell targeting agent.The term "cell targeting agent" used herein refers to any molecule, macromolecule or biopolymer, such as nutraceutical active agent, medicament active agent, diagnostic active agent and cosmetic active agent, that selectively binds to receptors that are expressed or overexpressed in specific cell types.Cell targeting groups are well known in the art.

[0172] Examples of cell targeting groups include, but are not limited to, galactosamine, folate, Her-2 binding peptides, TLR agonists, β-D-glucose, Asn-Gly-Arg peptides, angiopep-2, folic acid, aptamers (A-9, A10, anti-gp120, TTA1, sgc8, anti-MUC-1, AS1411), primaquine, zidovudine, superoxide dismutase, prednisolone, platinum, cisplatin, sulfamethoxazole, amoxicillin, riboflavin ... Cirrhin, etoposide, mesalazine, doxorubicin, paclitaxel, 5-aminosalicylic acid, denosumab, docetaxel, calcitonin, proanthocyanidins, methotrexate, camptothecin, galactose, glycyrrhetinic acid, lactose, hyaluronic acid, octreotide, lactobionic acid, β-galactosyl moieties, arabinogalactan, chitosan, azo-based polyphosphazenes, azo groups and 4-amino-benzyl-carbamate, succinate, 4,4'-Dihydroxyazobenzene-3-carboxylic acid, cyclic RGD penta-peptide, aspartic acid octapeptide, alendronate, transferrin, bisphosphonate alendronate, monosialoganglioside GM1, glutathione, E-selectin thioaptamer, poloxamer-407, urokinase-type plasminogen activator receptor (uPAR) antagonist, CXCR4 chemokine receptor antagonist, GRP78 peptide antagonist, RGD peptide, RGD cyclic peptide, luteinizing hormone releasing hormone (LHRH) antagonist peptide, aminopeptidase targeting peptide, brain homing peptide, kidney homing peptide, heart homing peptide, gut homing peptide, integrin homing peptide, angiogenic tumor endothelial homing peptide homing peptides, ovary homing peptides, uterus homing peptides, sperm homing peptides, microglia homing peptides, synovium homing peptides, urothelium homing peptides, prostate homing peptides, lung homing peptides (e.g., RCPLSHSLICY), laminin receptor binding peptides (e.g., YIGSR), skin homing peptides, retina homing peptides, pancreas homing peptides, liver homing peptides, lymph node homing peptides, adrenal gland homing peptides, thyroid homing peptides, bladder homing peptides, breast homing peptides, neuroblastoma homing peptides, lymphoma homing peptides, muscle homing peptides, wound vasculature homing peptides, adipose tissue homing peptides, virus binding peptides, or fusion peptides.

[0173] According to another embodiment, optionally in combination with one or more features of the various embodiments described above or below, in the conjugate of formula (II), Z is an anticancer drug. Non-limiting examples of anticancer drugs include, but are not limited to, cisplatin, paclitaxel, 5-fluorouracil, gemcitabine, herceptin, mitoxantrone, cantharidin, docetaxel, anthracycline drugs (doxorubicin, epirubicin, daunorubicin, idarubicin, irinotecan or camptothecin.

[0174] According to certain embodiments, optionally in combination with any of the embodiments provided above or below, Z is selected from the group consisting of a low molecular weight drug, a peptide, an antibody, a hormone, an enzyme, a nucleic acid, a protein, and combinations thereof.

[0175] The term "nucleic acid" as used herein refers to DNA or RNA. In certain embodiments, optionally in combination with any of the embodiments provided above or below, the nucleic acid is a DNA / RNA hybrid, small interfering RNA (siRNA), microRNA (miRNA), single guide RNA (sgRNA), donor DNA, self-amplifying / replicating RNA, circular RNA (oRNA), plasmid DNA (pDNA), closed linear DNA (clDNA), small hairpin RNA (shRNA), messenger RNA (mRNA), antisense RNA (aRNA), messenger RNA (mRNA), CRISPR guide RNA, antisense nucleic acid, decoy nucleic acid, aptamer and ribozyme, to name a few, encompassing both nucleotide sequences and any structural embodiment thereof, such as double-stranded, single-stranded, helical, hairpin, and may contain modified or unmodified bases. When separate nucleic acids are provided, they may be all DNA molecules or all RNA molecules, or may be mixtures of DNA and RNA molecules or molecules comprising associations of DNA and RNA strands.

[0176] The nucleic acid may be a poly or oligonucleotide, such as an oligo or poly double-stranded RNA, an oligo or poly double-stranded DNA, an oligo or poly single-stranded RNA, or an oligo or poly single-stranded DNA. Each of the nucleotides contained in the nucleic acid may be a naturally occurring nucleotide or a chemically modified non-naturally occurring nucleotide. The length of the nucleic acid is not particularly limited, and the nucleic acid may have a short chain in the range of 10 to 200 bases, preferably 20 to 180 bases, preferably 25 to 100 bases, preferably 30 to 50 bases, or the nucleic acid may have a relatively long chain of 200 to 20,000 bases, more preferably 250 to about 15,000 bases.

[0177] According to certain embodiments, optionally in combination with any of the embodiments provided above or below, the nucleic acid is a closed linear DNA (clDNA), i.e. a molecule in which a double-stranded region is flanked and protected by two single-stranded loops, thereby generating a dumbbell-shaped molecule.

[0178] In a more particular embodiment, optionally in combination with any of the embodiments provided above or below, the clDNA consists of a stem region comprising a double-stranded DNA sequence of interest covalently closed at both ends by hairpin loops, and the clDNA comprises at least two modified nucleotides.

[0179] The term "closed linear DNA" or "clDNA" as used herein refers to a single-stranded, covalently closed DNA molecule that forms a "dumbbell" or "dogbone" shaped structure under conditions that allow nucleotide hybridization. Thus, clDNA is formed by a single-stranded DNA molecule, but the formation of a "dumbbell" structure by hybridization of two complementary sequences within the same molecule generates a structure consisting of a double-stranded middle segment flanked by two single-stranded loops. Those skilled in the art know how to generate clDNA from open or closed double-stranded DNA using routine molecular biology techniques. For example, those skilled in the art know that clDNA can be generated by attaching a hairpin DNA adapter to both ends of an open double-stranded DNA, for example by the action of a ligase. A "hairpin DNA adapter" refers to a single-stranded DNA that forms a stem-loop structure by hybridization of two complementary sequences, where the stem region formed is closed at one end by a single-stranded loop and open at the other end.

[0180] A "modified nucleotide" is any nucleotide (e.g., adenosine, guanosine, cytidine, uracil, and thymidine) that has been chemically modified by modification of the base, sugar, or phosphate group, or that has incorporated a non-natural moiety into its structure. Thus, modified nucleotides can be naturally or non-naturally occurring, depending on the modification.

[0181] The expression "diagnostically active agent", also referred to as "label or imaging agent" in the context of this disclosure, refers to any substance that is used as a label or enhances a specific structure in any imaging technique. Thus, imaging agents include optical imaging agents, magnetic resonance imaging agents, radioisotopes and contrast agents. Imaging agents or labeling agents are well known in the art. Specific examples of imaging agents or labeling agents are gases such as sterile air, oxygen, argon, nitrogen, fluorescent, perfluorocarbons, carbon dioxide, nitrogen dioxide, sulfur hexafluoride, xenon and helium, as well as commercially available agents used in positron emission tomography (PET), computed tomography (CAT), single photon emission computed tomography, X-ray, fluoroscopy and magnetic resonance imaging (MRI). Examples of materials suitable for use as imaging agents in MRI include currently available gadolinium chelates such as diethylenetriaminepentaacetic acid (DTPA) and gadopentetate dimeglumine, as well as iron, magnesium, manganese, copper and chromium. Examples of materials useful for CAT and X-ray include iodine-based materials for intravenous administration, such as ionic monomers typified by diatrizoate and iothalamic acid, non-ionic monomers such as iopamidol, iohexol and ioversol, non-ionic dimers such as iotrol and iodixanol, and ionic dimers, such as ioxaglic acid. Other useful materials include insoluble salts such as barium and zinc acetate for oral use. In some molecules, the imaging agent is a dye. In some molecules, the imaging agent is a fluorescent moiety. In some molecules, the fluorescent moiety is selected from a fluorescent protein, a fluorescent peptide, a fluorescent dye, a fluorescent substance, or a combination thereof.Examples of fluorescent dyes include, but are not limited to, xanthenes (e.g., rhodamine, rhodol, fluorescein and their derivatives), bimanes, coumarins and their derivatives (e.g., umbelliferone and aminomethylcoumarin), aromatic amines (e.g., dansyl, squaric acid dyes), benzofurans, fluorescent cyanines, indocarbocyanines, carbazoles, dicyanomethylenepyrans, polymethines, oxabenzanthrans, xanthenes, pyryliums, carbostyryls, perylenes, acridones, quinacridones, rubrenes, anthracenes, coronenes, phenanthrenes, pyrenes, butadienes, stilbenes, porphyrins, phthalocyanines, lanthanide metal chelate complexes, rare earth metal chelate complexes and derivatives of such dyes. Examples of fluorescein dyes include, but are not limited to, 5-carboxyfluorescein, fluorescein-5-isothiocyanate, fluorescein-6-isothiocyanate and 6-carboxyfluorescein. Examples of rhodamine dyes include, but are not limited to, tetramethylrhodamine-6-isothiocyanate, 5-carboxytetramethylrhodamine, 5-carboxyrhodol derivatives, tetramethyl, tetraethylrhodamine, diphenyldimethyl, diphenyldiethylrhodamine, dinaphthylrhodamine, rhodamine 101 sulfonyl chloride (sold under the trade name TEXAS RED®). Examples of cyanine dyes include, but are not limited to, Cy3, Cy3B, Cy3.5, Cy5, Cy5.5, Cy7, IRDYE680, Alexa Fluor 750, IRDye800CW, ICG. Examples of fluorescent peptides include GFP (green fluorescent protein) or derivatives of GFP (e.g., EBFP, EBFP2, Azurite, mKalama1, ECFP, Cerulean, CyPet, YFP, Citrine, Venus, YPet). The fluorescent label is detected by any suitable method.For example, fluorescent labels may be detected by exciting the fluorochrome with light of an appropriate wavelength and detecting the resulting fluorescence, for example, by microscopy, visual inspection, or by using electronic detectors such as photographic film, charge-coupled device (CCD), photomultiplier tubes, etc. In some molecules, imaging agents are labeled with positron-emitting isotopes (e.g., 18F) for positron emission tomography (PET), gamma-emitting isotopes (e.g., 99mTc) for single-photon emission computed tomography (SPECT), or paramagnetic molecules or nanoparticles (e.g., Gd3+ chelates or coated magnetite nanoparticles) for magnetic resonance imaging (MRI). In some molecules, imaging agents are labeled with gadolinium chelates, iron oxide particles, superparamagnetic iron oxide particles, ultrasmall paramagnetic particles, manganese chelates, or gallium-containing agents. Examples of gadolinium chelates include, but are not limited to, diethylenetriaminepentaacetic acid (DTPA), 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) and 1,4,7-triazacyclononane-N,N',N''-triacetic acid (NOTA). In some molecules the imaging agent is a near-infrared fluorophore for near-IR imaging, luciferase (firefly, bacteria or coelenterate) or other luminescent molecules for bioluminescence imaging or perfluorocarbon-filled self-assembled particles for ultrasound. In some molecules the imaging agent is a nuclear probe. In some molecules the imaging agent is a SPECT or PET radionuclide probe. In some molecules the radionuclide probe is selected from technetium chelates, copper chelates, radioactive fluorine, radioactive iodine, indium chelates. Examples of Tc chelates include, but are not limited to, HYNIC, DTPA and DOTA. In some molecules the imaging agent is a radioactive moiety, e.g. 211 At, 131 I, 125 I, 90 Y, 186 Re, 188 Re, 153 Sm, 212 Bi, 32 P,64 It contains radioactive isotopes such as Cu and Lu.

[0182] All embodiments given herein for the polymers of formula (I) also apply to the conjugates of formula (II) for all their general structure, and also the embodiments referring to the salts and stereoisomers given for the polymers of formula (I) also apply to the conjugates of formula (II).

[0183] In the complex of formula (II), when s is 0, Z is directly bonded to X or the PAA sarcosine repeat unit by a chemically feasible bond selected from the group consisting of an amide bond, a carbamate bond, an amine bond, a urea bond, an ether bond and an ester bond.

[0184] More specifically, when s is 0, the sarcosine repeat unit PAA has formula (XXI) and z' is 0, Z is directly bonded to the PAA sarcosine repeat unit by a chemically feasible bond selected from the group consisting of an amide bond and an ester bond, and even more specifically, the bond between Z and the PAA sarcosine repeat unit may be formed between the -(O)- or -(N)- moiety of Z and the carbonyl group of the PAA sarcosine repeat unit.

[0185] When s is 0, the sarcosine repeat unit PAA has the formula (XXI) and z' is 1, Z is directly bonded to X by a chemically feasible bond selected from the group consisting of an amide bond, a carbamate bond, an ester bond, an amine bond, a urea bond and an ether bond, and even more particularly, the bond between Z and X may be formed between the -(O)- or -(N)- moiety of X and the -CO-, -COO-, -CONH- or -CH2- moiety of Z.

[0186] When s is 0, the sarcosine repeat unit PAA has formula (XXII) and z' is 0, Z is directly bonded to the PAA sarcosine repeat unit by a chemically feasible bond selected from the group consisting of an amide bond, a carbamate bond, a urea bond and an amine bond, and even more specifically, the bond between Z and PAA may be formed between the -N- moiety of PAA and the -CO-, -COO-, -CONH- or -CH2- moiety of Z.

[0187] When s is 1, L' is bonded to Z by a chemically feasible bond selected from the group consisting of an amide bond, a carbamate bond, an amine bond, a urea bond, an ether bond, and an ester bond, and L' is bonded to X or the PAA sarcosine repeat unit by a chemically feasible bond selected from the group consisting of an amide bond, a carbamate bond, an amine bond, a urea bond, an ether bond, and an ester bond.

[0188] More specifically, when s is 1, the sarcosine repeat unit PAA has formula (XXI) and z' is 0, L' is directly bonded to the PAA sarcosine repeat unit by a chemically feasible bond selected from the group consisting of an amide bond and an ester bond, and even more specifically, the bond between L' and the PAA sarcosine repeat unit may be formed between the -(O)- or -(N)- moiety of L' and the carbonyl group of the PAA sarcosine repeat unit.

[0189] More specifically, when s is 1, the sarcosine repeat unit PAA has the formula (XXI), and z' is 1, L' is bonded to X by a chemically possible bond selected from the group consisting of an amide bond, a carbamate bond, an ester bond, a urea bond, an amine bond, and an ether bond, and more specifically, the bond between L' and X may be formed between the -(O)- or -(N)- moiety of X and the -CO-, -OCO-, -NHCO-, or -CH2- moiety of L'.

[0190] When s is 1, the sarcosine repeat unit PAA has formula (XXII), and z' is 0, L' is directly bonded to the PAA sarcosine repeat unit by a chemically feasible bond selected from the group consisting of an amide bond, a carbamate bond, a urea bond, and an amine bond, and more particularly, the bond between L' and PAA may be formed between the -N- portion of PAA and the -CO-, -COO-, -CONH-, or -CH2- portion of L'.

[0191] In one embodiment, optionally in combination with one or more features of the various embodiments described above or below, in the conjugate of formula (II), L' is a biradical chain comprising 1 to 50 moieties, more particularly 2 to 30 or 2 to 20 or 2 to 15 moieties, as defined above, as long as L' can be linked to the remainder of the molecule by any chemically feasible bond.

[0192] According to a more particular embodiment, optionally in combination with any of the embodiments provided above or below, in the complex of formula (II), when the sarcosine repeat unit PAA has formula (XXI), z' is 1 and s is 1, the linker L' is optionally halogen, -OH, -NR a R b , -SH, -NHNH2, -COOR c , -CF3 and -OCF3 (wherein R a , R b and R c are independently a radical selected from the group consisting of H, -phenyl, -(C1-C6)alkyl, -(C2-C6)alkenyl, -(C1-C6)alkylphenyl and -phenyl(C1-C6)alkyl) substituted with one or more substituents selected from the group consisting of 12) alkylene-, -(C1-C6) alkyl-CO-, -CO-(C1-C6) alkyl- and biradicals of formula (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI) (XII) (XIII), (XIV), (XV), (XVI), (XVII), (XVIII) or (XIX) as previously defined.

[0193] According to another more particular embodiment, optionally in combination with any of the embodiments provided above or below, in the conjugate of formula (II), when the sarcosine repeat unit PAA has formula (XXII), z' is 0 and s is 1, the linker L' is optionally halogen, -OH, -NR a R b , -SH, -NHNH2, -COOR c , -CF3 and -OCF3 (wherein R a , R b and R c are independently a radical selected from the group consisting of H, -phenyl, -(C1-C6)alkyl, -(C2-C6)alkenyl, -(C1-C6)alkylphenyl and -phenyl(C1-C6)alkyl) substituted with one or more substituents selected from the group consisting of 12 ) alkylene-, -(C1-C6) alkyl-CO-, -CO-(C1-C6) alkyl- and biradicals of formula (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI) (XII) (XIII), (XIV), (XV), (XVI), (XVII), (XVIII) or (XIX) as previously defined.

[0194] According to a more particular embodiment, optionally in combination with any of the embodiments provided above or below, in the complex of formula (II), when the sarcosine repeat unit PAA has formula (XXI), z' is 0 and s is 1, the linker L' is optionally halogen, -OH, -NR a R b , -SH, -NHNH2, -COORc , -CF3 and -OCF3 (wherein R a , R b and R c is independently a radical selected from the group consisting of H, -phenyl, -(C1-C6)alkyl, -(C2-C6)alkenyl, -(C1-C6)alkylphenyl and -phenyl(C1-C6)alkyl; 12 ) alkylene-, -X'-(C1-C6)alkyl-CO-, -X'-CO-(C1-C6)alkyl- and biradicals of formula (III'), (IV'), (V'), (VI'), (VII), (VIII), (IX'), (X'), (XI'), (XII')(XIII'), (XIV'), (XV'), (XVI'), (XVII'), (XVIII') or (XIX') as previously defined.

[0195] In one embodiment, optionally in combination with one or more features of the various embodiments described above or below, Z has the formula (XX): [ka] A portion having In the formula, R8, R9 and R 10 are independently selected from the group consisting of hydrogen, fluorine, methyl, -CH2F, -CHF2 and -CF3, and the dashed bonds ----- are each independently a single bond or alternatively a double bond.

[0196] According to one embodiment, optionally in combination with one or more features of the various embodiments described above or below, R8, R9 and R 10 is independently selected from the group consisting of hydrogen and methyl.

[0197] In another embodiment, optionally in combination with any of the embodiments provided above or below, in the complex of formula (II), Z is a radical of formula (XX), in which the dashed bonds of the alkyl chain attached to the chroman ring are each a single bond, and R8, R9 and R 10 (i) R8, R9 and R 10 is methyl; (ii) R, R 10 is methyl and R is hydrogen; (iii) R and R 10 is methyl and R is hydrogen, and (iv) R 10 is methyl, and R and R are hydrogen. More particularly, in the above embodiment, R, R and R 10 is methyl.

[0198] In a more particular embodiment of the above embodiment, R8, R9 and R 10 is methyl. More particularly, in the complex of formula (II), Z is a group of formula (XXa): [ka] and even more particularly Z is a radical of formula (XXb): [ka] is a radical.

[0199] The conjugate of formula (II) may be prepared by processes well known in the art. These processes also form part of the present invention. For example, if the repeating sarcosine-based unit PAA has formula (XXI), s is 0, and X is an amine or alcohol group, Z may be prepared according to the following scheme: [ka] It can be used as an initiator in ROP for the preparation of polysarcosine-based moieties as shown in.

[0200] This reaction can be carried out under the conditions mentioned above for the preparation of polymer (B).

[0201] The resulting polysarcosine derivative (B') may be attached to a vitamin E derivative via a linker L' by any of the processes disclosed for the preparation of the polymer of formula (I).

[0202] When S is 1 and X is an amine or alcohol group, Z is represented by the following scheme: [ka] It can be used as an initiator in ROP for the preparation of polysarcosine-based moieties as shown in.

[0203] This reaction can be carried out under the conditions mentioned above for the preparation of polymer (B).

[0204] The resulting polysarcosine derivative (B″) may be attached to a vitamin E derivative via a linker L by any of the processes disclosed for the preparation of the polymer of formula (I).

[0205] Conjugates of formula (II) in which the repeating sarcosine-based unit PAA has the formula (XXII) may be prepared by the procedures described above for compounds of formula (Ib).

[0206] self-assembled particles Another aspect of the present invention is a method for producing a (a) a polymer as defined herein, or alternatively (b) a complex of formula (II) as defined herein, or alternatively (c) a combination of a polymer as defined herein with a conjugate of formula (II); Optionally, a drug encapsulated within the self-assembled particles of the self-assembled nano / microparticles selected from the group consisting of a nutraceutical active agent, a medicament active agent, a cell targeting agent, a diagnostically active agent and a cosmetically active agent. The present invention relates to a self-assembled particle comprising:

[0207] The term "self-assembled particles" as used herein refers to small enclosed structures of any shape, typically spherical and / or tubular. It is intended to encompass any of the many structures known in the art formed from amphiphilic polymers. Non-limiting examples of self-assembled particles include micelles (also referred to herein interchangeably as micellar worms or simply "worms"), reverse micelles, planar bilayers, crystalline nanoparticles, liposomes, microbubbles or lipid nanoparticles. Self-assembled nanoparticles and microparticles can also form gels.

[0208] The self-assembled particles may be self-assembled nanoparticles or self-assembled microparticles. A "nanoparticle" as defined herein is any particle having a minimum end-to-end diameter in the size range of 1-100 nm. A "microparticle" as defined herein is typically any particle having a minimum end-to-end diameter in the size range of 0.1-100 μm. Typically, in compositions containing multiple particles, the relevant diameter is the number average diameter.

[0209] In the above case a), the polymer forms the outer shell of the self-assembled particle, and the drug is encapsulated or loaded in the inner core. In the above case b), the complex of formula (II) forms the outer shell of the self-assembled particle, and the drug is optionally encapsulated, i.e. loaded, in the inner core. In the above case c), both the polymer as defined herein and the complex of formula (II) form the outer shell of the self-assembled particle, and the drug is optionally encapsulated or loaded on the inner core or on the outer shell surface.

[0210] In one embodiment, optionally in combination with one or more features of the various embodiments described above or below, the self-assembled particle is selected from the group consisting of micelles, reverse micelles, planar bilayers, crystalline nanoparticles, liposomes and lipid nanoparticles.

[0211] For the purposes of the present invention, the term "micelle" refers to the arrangement of the polysarcosine vitamin E derivatives of the present invention in a solvent, with the non-polar tail (hydrophobic part) facing inward and the polar head facing outward. Typically, micelles exhibit a spherical or tubular shape. In particular, micelles are core-shell structures that include an inner core and an outer shell.

[0212] According to one embodiment, optionally in combination with one or more features of the various embodiments described above or below, the present invention provides (a) a polymer as defined herein, or alternatively, (b) a complex of formula (II) as defined herein, or alternatively, (c) a combination of a polymer as defined herein with a conjugate of formula (II); an agent encapsulated within the micelle, optionally selected from the group consisting of a nutraceutical active agent, a medicament active agent, a cell targeting agent, a diagnostically active agent and a cosmetically active agent; The present invention relates to a micelle comprising:

[0213] In one embodiment, optionally in combination with one or more features of the various embodiments described above or below, the micelles are formed in water.

[0214] In another embodiment, optionally in combination with one or more features of the various embodiments described above or below, the micelles are formed in an organic solvent. More particularly, the organic solvent is selected from the group consisting of acetone, tetrahydrofuran, methanol, ethanol, acetonitrile, and mixtures thereof.

[0215] In one embodiment, optionally in combination with one or more features of the various embodiments described above or below, the micelles have a hydrodynamic diameter (Dh) in water of 5 to 500 nm, as measured by diffusion-ordered NMR spectroscopy (DOSY) or alternatively dynamic light scattering (DLS).

[0216] According to another embodiment, optionally in combination with one or more features of the various embodiments described above or below, the micelles have a critical micelle concentration (CMC) of 0.01 to 10 mg / mL in water at 25° C. and atmospheric pressure.

[0217] According to another embodiment, optionally in combination with one or more features of the various embodiments described above or below, the encapsulation efficiency of the polymer of formula (I) is between 0.1 and 100 wt%, more particularly between 15 and 60 wt%. The encapsulation efficiency is expressed by the following formula: Encapsulation efficiency (wt%)=(total drug added−free unencapsulated drug)(wt%) / total drug added(wt%) It is calculated by:

[0218] Micelles may be prepared by different methods well known to those skilled in the art, such as, for example, direct formulation, co-solvent formulation, thin film formulation and formulation in supercritical CO2.

[0219] It also forms part of the present invention a process for the preparation of micelles as defined herein, comprising either a) dissolving the polymer of the present invention as defined herein, the complex of formula (II) or a combination thereof and, optionally, the drug to be encapsulated in the micelles in water, or alternatively b) dissolving the polymer of the present invention as defined herein, the complex of formula (II) or a combination thereof and, optionally, the drug to be encapsulated in the micelles in an organic solvent to obtain a solution, adding this solution to water and evaporating the organic solvent, or alternatively c) dissolving the polymer of the present invention as defined herein, the complex of formula (II) or a combination thereof and, optionally, the drug to be encapsulated in the micelles in an organic solvent to obtain a solution, evaporating the organic solvent to obtain a film and dissolving the film obtained with water. The present invention also relates to micelles obtainable by the above process.

[0220] The term "obtainable" is used herein to define the micelles by their preparation process. For the purposes of the present invention, the terms "obtainable", "obtained" and similar equivalent terms are used interchangeably, and in each case, the term "obtainable" encompasses the term "obtained".

[0221] According to one embodiment, optionally in combination with one or more features of the various embodiments described above or below, the present invention provides (a) a polymer as defined herein, or alternatively, (b) a complex of formula (II) as defined herein, or alternatively, (c) a combination of a polymer as defined herein with a conjugate of formula (II); Optionally, an agent encapsulated within the micelle selected from the group consisting of a nutraceutical active agent, a medicament active agent, a cell targeting agent, a diagnostically active agent and a cosmetically active agent. The present invention relates to a liposome comprising:

[0222] According to one embodiment, optionally in combination with one or more features of the various embodiments described above or below, the present invention provides (a) a polymer as defined herein, or alternatively, (b) a complex of formula (II) as defined herein, or alternatively, (c) a combination of a polymer as defined herein with a conjugate of formula (II); Optionally, an agent encapsulated within the micelle selected from the group consisting of a nutraceutical active agent, a medicament active agent, a cell targeting agent, a diagnostically active agent and a cosmetically active agent. The present invention relates to a lipid nanoparticle (LNP) comprising:

[0223] For purposes of the present invention, the term "liposome" refers to an artificially prepared self-assembled particle consisting of concentric lipid bilayers encapsulating one or more aqueous compartments. Non-limiting examples of liposomes include unilamellar liposomes, multilamellar liposomes, multivesicular liposomes, and polymer-coated liposomes.

[0224] The term "lipid nanoparticle" refers to typically spherical particles on the order of nanometers (eg, 1-1000 nm) that comprise lipids that are stable and dispersible in aqueous media.

[0225] According to one embodiment, optionally in combination with one or more features of the various embodiments described above or below, the present invention provides (a) a polymer as defined herein, or alternatively, (b) a complex of formula (II) as defined herein, or alternatively, (c) a combination of a polymer as defined herein with a conjugate of formula (II); Optionally, an agent encapsulated within the micelle selected from the group consisting of a nutraceutical active agent, a medicament active agent, a cell targeting agent, a diagnostically active agent and a cosmetically active agent. The present invention relates to crystalline nanoparticles comprising:

[0226] For purposes of the present invention, the term "crystalline nanoparticles" refers to artificially prepared crystals consisting of solid lipids encapsulating one or more hydrophobic compartments.

[0227] The term "crystalline nanoparticles" refers to particles of different shapes on the order of nanometers (eg, 1-1000 nm) that contain lipids that are stable and dispersible in aqueous media.

[0228] The liposomes and lipid nanoparticles disclosed herein may comprise any suitable lipid, including ionizable lipids, cationic lipids, zwitterionic lipids, neutral lipids, or anionic lipids.

[0229] Suitable ionizable lipids include, but are not limited to, (2S)-2,5-bis(3-aminopropylamino)-N-[2-(dioctadecylamino)acetyl]pentanamide (DOGS), N1-[2-((1S)-1-[(3-aminopropyl)amino]-4-[di(3-aminopropyl)amino]butylcarboxamido)ethyl]-3,4-di[oleyloxy]-benzamide (MVL5), 3β-[N-(N′,N′-dimethylaminoethane)-carbamoyl]cholesterol (DC-cholesterol), (1,2-distearyloxy)-1,2-dimethylaminoethane (DMSO ... 1,2-Dilinoleyloxy-N,N-dimethyl-3-aminopropane (DSDMA), 1,2-Dilinoleyloxy-N,N-dimethyl-3-aminopropane (DLin-DMA), 1,2-Dilinolenyloxy-N,N-dimethyl-3-aminopropane (DLenDMA), 1,2-Di-y-linolenyloxy-N,N-dimethylaminopropane (γ-DLenDMA), 2-Dilinoleyl-4-dimethylaminomethyl-[1,3]-dioxolane (DLin-K-DMA), 2,2-Dilinoleyl-4-dimethylaminoethyl-[1,3]-dioxolane (DLin- Also known as KC2-DMA, DLin-C2K-DMA, XTC2 and C2K), 2,2-Dilinoleyl-4-(3-dimethylaminopropyl)-[1,3]-dioxolane (DLin-KC3-DMA), 2,2-Dilinoleyl-4-(4-dimethylaminopropyl)-[1,3]-dioxolane (DLin-KC4-DMA), 1,2-Dilinoleyloxy-4-(2-dimethylaminoethyl)-1,3-dioxolane (DLen-C2K-DMA), 1,2-Di-y-linolen ... 3-Dioxolane (y-DLen-C2K-DMA), (6Z,9Z,28Z,31Z)-3-(dimethylamino)propanoic acid heptatriaconta-6,9,28,31-tetraen-19-yl (DLin-M-C2-DMA, also known as MC2), (6Z,9Z,28Z,31Z)-4-(dimethylamino)butanoic acid heptatriaconta-6,9,28,31-tetraen-19-yl (DLin-M-C3-DMA, also known as MC3) and 3-((6Z,9Z,28Z,31Z)-heptatriaconta-6,9,28,31-tetraen-19-yloxy)-N,N-dimethylpropan-1-amine (DLin-MP-DMA, also known as 1-B11).

[0230] Suitable cationic lipids include, but are not limited to, N,N-dioleyl-N,N-dimethylammonium chloride (DODAC), N,N-distearyl-N,N-dimethylammonium bromide (DDA13), N-(1-(2,3-dioleoyloxy)propyl)-N,N,N-trimethylammonium chloride (DOTAP), N-(1-(2,3-dioleyloxy)propyl)-N,N,N-trimethylammonium chloride (DOTMA), N-[1-(2,3-ditetradecyloxy)propyl]-N,N-dimethyl-N-hydroxyethylammonium bromide (DMRIE), N-[1-(2,3,dioleyloxy)propyl]-N,N-dimethyl-N-hydroxyethylammonium bromide (DORIE), 3β-[N-(N',N'-dimethylamino-ethane)-carbamoyl]cholesterol (DC-Chol), dimethyldioctadecylammonium (DDAB), 2,3-dioleyloxy-N-[2-(sperminecarboxamido)ethyl]-N,N-dimethyl-1-propanaminium trifluoroacetate (DOSPA), ethylphosphatidylcholine (ePC), and N,N-dimethyl-2,3-dioleyloxy)propylamine (DODMA).

[0231] Examples of anionic lipids include, but are not limited to, phosphatidylglycerol, diacylphosphatidylserine, diacylphosphatidic acid, N-succinylphosphatidylethanolamine, N-glutarylphosphatidylethanolamine cholesterol hemisuccinate (CHEMS), lysylphosphatidylglycerol, N-dodecanoylphosphatidylethanolamine, cardiolipin, and combinations thereof.

[0232] Suitable neutral lipids may be uncharged or zwitterionic lipids, and include, but are not limited to, steroids, phospholipids, and combinations thereof.

[0233] Examples of steroids include, but are not limited to, cholesterol, progesterone, cortisone, aldosterone, estradiol, testosterone, and combinations thereof.Examples of phospholipids include, but are not limited to, phosphatidylcholine (PC), phosphatidic acid (PA), phosphatidylethanolamine (PE), phosphatidylglycerol (PG), phosphatidylserine (PS) and phosphatidylinositol (PI), dimyristoylphosphatidylcholine (DMPC), distearoylphosphatidylcholine (DSPC), dioleoylphosphatidylcholine (DOPC), dipalmitoylphosphatidylcholine (DPPC), dimyristoylphosphatidylglycerol (DM ... G), distearoylphosphatidylglycerol (DSPG), dioleoylphosphatidylglycerol (DOPG), dipalmitoylphosphatidylglycerol (DPPG), dimyristoylphosphatidylserine (DMPS), distearoylphosphatidylserine (DSPS), dioleoylphosphatidylserine (DOPS), dipalmitoylphosphatidylserine (DPPS), dioleoylphosphatidylethanolamine (DOPE), palmitoyloleoylphosphatidylcholine (POPC), palmitoyloleoyl Dioleoyl-phosphatidylethanolamine (POPE) and dioleoyl-phosphatidylethanolamine 4-(N-maleimidomethyl-cyclohexane-1-carboxylate (DOPE-mal), dipalmitoylphosphatidylethanolamine (DPPE), dimyristoylphosphoethanolamine (DMPE), distearoylphosphatidylethanolamine (DSPE), lysophosphatidylcholine, lysophosphatidylethanolamine, 1,2-distearoyl-sn-glycero-3-phosphocholine (DAPC), dilauroyl-phosphatidylethanolamine (DOPE-mal), dilauroyl-phosphatidylethanolamine (DOPE-mal), dilauroyl-phosphatidylethanolamine (DOPE-mal), dilauroyl-phosphatidylethanolamine (DOPE-mal), dilauroyl-phosphatidylethanolamine (DOPE-mal), dilauroyl-phosphatidylethanolamine (DOPE-mal), dilauroyl-phosphatidylethanolamine (DOPE-mal), dilauroyl-phosphatidylethanolamine (DPE ... 1,2-diarachidoyl-sn-glycero-3-phosphocholine (DBPC), 1-stearoyl-sn-glycero-3-phosphocholine (SPPC), 1,2-dieicosenoyl-sn-glycero-3-phosphocholine (DEPC), and combinations thereof.

[0234] The polymers of the present invention as well as their conjugates may be used as stealth lipids in lipid nanoparticles.

[0235] According to one embodiment, optionally in combination with one or more features of the various embodiments described above or below, the present invention relates to a lipid nanoparticle (LNP) or liposome comprising the polymer, the complex of formula (II) or a combination of both, further comprising one or more of an ionizable lipid, a cationic lipid, a neutral lipid and an anionic lipid. More particularly, the LNP further comprises one or more nucleic acids as defined above.

[0236] composition The present invention also relates to a composition comprising an effective amount of (a) a polymer of the present invention as defined herein, or alternatively, (b) a conjugate of formula (II) as defined herein, or alternatively, (c) a combination of a polymer of the present invention and a conjugate of formula (II), or alternatively, (d) a self-assembled particle as defined herein, together with one or more acceptable excipients or carriers.

[0237] The term "effective amount" as used herein refers to the amount of each one of the components of the compositions of the present invention that provides a beneficial effect following its application.

[0238] In one embodiment, optionally in combination with one or more features of the various embodiments described above or below, the composition is a nutraceutical comprising a nutraceutically effective amount of (a) a polymer of the invention as defined herein, or alternatively, (b) a complex of formula (II) as defined herein, or alternatively, (c) a combination of a polymer and a complex of formula (II) as defined herein, or alternatively, (d) a self-assembled particle as defined herein, together with one or more nutraceutically acceptable excipients or carriers, wherein the agent encapsulated in the self-assembled particle, if present, is a nutraceutically active agent, and Z, if present in the complex of formula (II), is a nutraceutically active agent.

[0239] In the context of the present invention, the terms "nutraceutical supplement", "food supplement", "dietary supplement" or "nutritional supplement", as used interchangeably herein, refer to preparations intended to be added to the diet to provide nutrients that are lacking or cannot be consumed in sufficient amounts in a person's diet. The term "nutraceutical acceptable excipient or carrier" refers to ingredients that may be ingested by humans without causing significant adverse health effects.

[0240] In another embodiment, optionally in combination with one or more features of the various embodiments described above or below, the composition is a pharmaceutical composition comprising a therapeutically effective amount of (a) a polymer as defined herein, or alternatively, (b) a conjugate of formula (II) as defined herein, or alternatively, (c) a combination of a polymer and a conjugate of formula (II) as defined herein, or alternatively, (d) a self-assembled particle as defined herein, together with one or more pharma- ceutically acceptable excipients or carriers, wherein the agent encapsulated in the self-assembled particle, if present, is a pharma- ceutical active agent or cell targeting agent, and Z, if present in the conjugate of formula (II), is a pharma- ceutical active agent or cell targeting agent.

[0241] The term "therapeutically effective amount" as used herein refers to an amount of polymer that is sufficient to prevent or alleviate to some extent the onset of one or more symptoms of the disease being addressed when administered. The specific dosage of the polymer of the present invention to obtain a therapeutic effect may vary depending on the specific circumstances of each individual patient, including, inter alia, the size, weight, age and sex of the patient, the nature and stage of the disease, the aggressiveness of the disease and the route of administration.

[0242] For purposes of this invention, the term "pharmaceutical acceptable" excipient or carrier refers to ingredients suitable for use in pharmaceutical techniques for preparing compositions for medical use. Each ingredient must be "acceptable" in the sense of being compatible with the other ingredients of the composition, and must be free of excessive toxicity, irritation, allergic response, immunogenicity or other problems or complications when used in contact with human and animal tissues or organs, commensurate with a reasonable benefit / risk ratio.

[0243] In one embodiment, optionally in combination with one or more features of the various embodiments described above or below, the composition is a diagnostic composition comprising a diagnostically effective amount of (a) a complex of formula (II) as defined herein, or alternatively, (b) a self-assembled particle as defined herein, together with one or more diagnostically acceptable excipients or carriers, with the proviso that when the self-assembled particle comprises a polymer of the invention in the absence of the complex of formula (II), an encapsulated agent is present in the self-assembled particle, wherein the agent encapsulated in the self-assembled particle, if present, is a diagnostically active agent, and Z, if present in the complex of formula (II), is a diagnostically active agent.

[0244] The term "diagnostic composition" refers to a composition suitable for use in diagnosis, particularly in imaging diagnostic techniques. The term "diagnostically effective amount" as used herein refers to an effective amount of the detection polymer sufficient for the diagnosis of a disease or disorder, particularly when administered as a diagnostic imaging contrast agent for imaging diagnostic applications. The dose of the detection polymer administered will of course be determined by the particular circumstances surrounding the case, including the polymer administered, the route of administration, the particular condition being diagnosed, and similar considerations. The diagnostic composition of the present invention includes one or more diagnostically acceptable excipients or carriers. The term "diagnostically acceptable" refers to an excipient or carrier suitable for use in diagnostic techniques, particularly imaging diagnostic applications, to prepare a composition having diagnostic use. Detection of these diagnostic agents in the patient's body can be achieved by well-known techniques such as those used in magnetic resonance imaging (MRI) and X-ray imaging diagnostics.

[0245] In one embodiment, optionally in combination with one or more features of the various embodiments described above or below, the composition is a cosmetic composition comprising a cosmetically effective amount of (a) a polymer of formula (I) as defined herein, or alternatively, (b) a complex of formula (II) as defined herein, or alternatively, (c) a combination of a polymer of formula (I) and a complex of formula (II), or alternatively, (d) a self-assembled particle as defined herein, together with one or more cosmetically acceptable excipients or carriers, wherein the agent encapsulated in the self-assembled particle, if present, is a cosmetically active agent, and Z, if present in the complex of formula (II), is a cosmetically active agent.

[0246] The term "cosmetically effective amount" as used herein refers to an effective amount of a cosmetically active agent intended to improve the appearance or to beautify, preserve, condition, cleanse, color or protect the skin, nails or hair that has no non-medical use when administered. The terms "cosmetically acceptable" or "dermatologically acceptable" excipients or carriers are used interchangeably herein and refer to ingredients that are suitable for use in contact with human skin, particularly without toxicity, incompatibility, instability or undue allergic reaction.

[0247] The composition of the present invention may be in solid or liquid form. Depending on the desired purpose, a person skilled in the art knows the most suitable formulation and excipient to use. Examples of excipients or carriers include, but are not limited to, diluents, binders, glidants, disintegrants, lubricants, colorants, mixtures thereof and other components known in the state of the art. Any route of administration may be used, such as oral, topical, rectal or parenteral routes (including subcutaneous, intraperitoneal, intradermal, intramuscular, intravenous routes, etc.).

[0248] The nutraceutical active agent, medicament active agent, cell targeting agent present in the self-assembled particles and compositions of the present invention are defined in the context of the complex of formula (II).Therefore, all the embodiments shown for the complex of formula (II) with respect to the active agent also apply to the self-assembled particles and compositions.

[0249] use Another aspect of the present invention relates to (i) a polymer of formula (I) as defined herein, or alternatively, (ii) a conjugate of formula (II) as defined herein, or alternatively, (iii) a self-assembled particle as defined herein, or alternatively, (iv) a pharmaceutical composition as defined herein, for use in medicine, wherein the agent encapsulated in the self-assembled particle, if present, is a pharma- ceutical active agent or cell targeting agent as defined herein, and Z, when present in the conjugate of formula (II), is a pharma-ceutical active agent or cell targeting agent.

[0250] Non-limiting examples of diseases that can be treated and / or prevented by the derivatives of the present invention include neurodegenerative diseases, neurological diseases, cancer, infectious diseases, age-related diseases, neuroinflammation, demyelinating diseases, multiple sclerosis, ischemic diseases, ischemia-reperfusion injury, amyloid diseases, cardiomyopathy, spinal cord injury, immune deficiencies, inflammatory diseases, rare diseases, wound healing, skin-related diseases and lysosomal storage diseases.

[0251] Non-limiting examples of neurodegenerative diseases include Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, ischemia, postencephalitic parkinsonism, dystonia, Tourette's disorder, periodic limb movement disorder, restless legs syndrome, attention deficit hyperactivity disorder, Huntington's disease, progressive supranuclear palsy, Pick's disease, frontotemporal dementia and neuromuscular diseases.

[0252] The term "disorder" as used herein is intended to be generally synonymous with, and is used interchangeably with, the terms "disease," "syndrome," and "condition (as in medical condition)," in that all reflect an abnormal condition of one of the human or animal bodies or parts thereof that impairs normal functioning, typically made clear by a distinction between signs and symptoms.

[0253] For example, a complex of formula (II) where Z is an anti-cancer drug or a self-assembled particle comprising an anti-cancer drug encapsulated within the self-assembled particle may be used for the treatment of cancer. Thus, in one embodiment, the present invention provides a complex of formula (II) for use in the treatment and / or prevention of cancer. (i) a conjugate of formula (II) as defined herein, or alternatively, (ii) a self-assembled particle as defined herein, provided that the encapsulated agent is present in the self-assembled particle when the self-assembled particle comprises a polymer of formula (I) in the absence of a complex of formula (II), or alternatively, (iii) a pharmaceutical composition as defined herein. wherein the drug encapsulated in the self-assembled particle, when present, is an anti-cancer drug, and Z, when present in the complex of formula (II), is an anti-cancer drug.

[0254] This aspect of the invention therefore provides a method for the manufacture of a medicament for the treatment and / or prevention of cancer, comprising: (i) a conjugate of formula (II) as defined herein, or alternatively, (ii) a self-assembled particle as defined herein, provided that the encapsulated agent is present in the self-assembled particle when the self-assembled particle comprises a polymer of formula (I) in the absence of a complex of formula (II), or alternatively, (iii) a pharmaceutical composition as defined herein. wherein the drug encapsulated in the self-assembled particle, when present, is an anti-cancer drug, and Z, when present in the complex of formula (II), is an anti-cancer drug.

[0255] The present invention provides a method for the preparation of a compound comprising administering to a subject, including a human, an effective amount of (i) a conjugate of formula (II) as defined herein, or alternatively, (ii) a self-assembled particle as defined herein, provided that the encapsulated agent is present in the self-assembled particle when the self-assembled particle comprises a polymer of formula (I) in the absence of a complex of formula (II), or alternatively, (iii) a pharmaceutical composition as defined herein. wherein the drug encapsulated in the self-assembled particle, when present, is an anti-cancer drug, and Z, when present in the complex of formula (II), is an anti-cancer drug.

[0256] As used herein, the terms "treat," "treating," and "treatment" refer to ameliorating the symptoms associated with a disease or disorder, including preventing or delaying the onset of a disease or disorder symptom and / or reducing the severity or frequency of a disease or disorder symptom.

[0257] Another aspect of the invention is a method for the diagnosis of (i) a conjugate of formula (II) as defined herein, or alternatively, (ii) a self-assembled particle as defined herein, provided that the encapsulated agent is present in the self-assembled particle when the self-assembled particle comprises a polymer of formula (I) in the absence of a complex of formula (II), or alternatively, (iii) a diagnostic composition as defined herein; wherein the agent encapsulated in the self-assembled particle, when present, is a diagnostically active agent, and Z, when present in the complex of formula (II), is a diagnostically active agent.

[0258] This aspect of the invention is directed to (i) a complex of formula (II) or alternatively, (ii) a self-assembled particle as defined herein, provided that the encapsulated agent is present in the self-assembled particle when the self-assembled particle comprises a polymer of formula (I) in the absence of a complex of formula (II), or alternatively, (iii) a diagnostic composition as defined herein; wherein the agent encapsulated in the self-assembled particle, when present, is a diagnostically active agent, and Z, when present in the complex of formula (II), is a diagnostically active agent. The present invention relates to the use of (i) a complex of formula (II) or alternatively, (ii) a self-assembled particle as defined herein, provided that the encapsulated agent is present in the self-assembled particle when the self-assembled particle comprises a polymer of formula (I) in the absence of a complex of formula (II), or alternatively, (iii) a diagnostic composition as defined herein; wherein the agent encapsulated in the self-assembled particle, when present, is a diagnostically active agent, and Z, when present in the complex of formula (II), is a diagnostically active agent.

[0259] Detection of these imaging agents can be performed by well-known techniques, such as diagnostic imaging techniques, examples of diagnostic imaging techniques suitable for the present disclosure include, but are not limited to, magnetic resonance imaging (MRI), X-ray, positron emission tomography (PET), single photon emission computed tomography (SPECT), fluorescence microscopy, and in vivo fluorescence.

[0260] Another aspect of the present invention relates to the use of the polymer of formula (I) as defined herein as a carrier, solubilizer, absorption and penetration enhancer, emulsifier or surface stabilizer.When used as a carrier, the polymer of formula (I) may be in the form of self-assembled particles.Therefore, the use of self-assembled particles comprising the polymer of formula (I) as a carrier, solubilizer, absorption and penetration enhancer, emulsifier or surface stabilizer also forms part of the present invention.

[0261] Throughout the specification and claims, the word "comprises" and variations of that word are not intended to exclude other technical features, additives, ingredients, or steps. Furthermore, the word "comprises" encompasses the case of "consisting of." Additional objects, advantages, and features of the present invention will become apparent to those skilled in the art upon consideration of the specification or may be learned by practice of the present invention. The following examples and figures are given by way of illustration and are not intended to limit the present invention. Furthermore, the present invention encompasses all possible combinations of the specific preferred embodiments described herein. EXAMPLES

[0262] Analysis method NMR spectroscopy NMR spectra were recorded at 27 °C (300 K) using a 300 Ultrashield™ from Bruker (Billerica, MA, USA). Data were processed with the software Topspin (Bruker, Karlsruhe, Germany). Samples were prepared at concentrations of approximately 20–10 mg / mL in the required solvent.

[0263] Diffusion Experiment Using pulsed field gradient NMR spectroscopy, the integral or intensity of the NMR signal is calculated according to the Stejskal-Tanner equation (Fieber W. et al., Macromolecules 2007, 40(15), 5372-5378): I = I0exp[-Dγ 2 g 2 δ 2 The translational diffusion was measured by fitting the NMR spectroscopy to the NMR spectrum of the observed intensity, δ(Δ-δ / 3)], where I is the observed intensity, I0 is the reference intensity (unattenuated signal intensity), D is the diffusion coefficient, γ is the gyromagnetic ratio of the observed nuclei, g is the gradient strength, δ is the gradient length, and Δ is the diffusion time. Two-dimensional diffusion-ordered NMR spectroscopy (DOSY) was performed by stimulated echo sequence using bipolar gradient pulses. The delay length was kept constant at Δ=100 ms, and 32 spectra of 64 scans each were acquired while varying the diffusion gradient strength from 5% to 95%. The diffusion gradient length and stimulated echo were optimized for each sample. For the analysis of the physically mixed species and cross-linked materials at 15 mg / mL, a typical value δ was 5 ms. Furthermore, the Stokes-Einstein equation: Rh=(KB·T) / (6π·η·D), where KB is the Boltzman constant (1.3806488·10 -23 m 2 Kg / s 2 η is the dynamic viscosity (1.095 10 for DO at 298.15 K and 0.1 MPa), T is the temperature (K), and -3 The hydrodynamic radius (Rh) (unit: nm) was obtained from the diffusion coefficient using the σ (kg / m s) (Duro-Castano A. et al., Advanced Materials 2017,29(39),12).

[0264] Size Exclusion Chromatography (SEC) For SEC measurements in dimethylformamide (DMF) containing 0.1% (w / w) lithium bromide as additive, a GPC max (Malvern Instruments) autosampler was used as the integrated instrument, a TSKgel Alpha-4000 from Tosoh at a flow rate of 0.7 mL / min and 60°C. A Viscoteck TDATM 302 was used as the integrated detection system (refractive index). The system was calibrated with polymethylmethacrylate (PMMA) (Mw=65 kDa; PDI=1.05) from PSS. For the Mw determination, an integrated triple detection system [refractive index, light scattering (two angles: 7 and 90°) and differential pressure viscometer] was used. An additional SEC detector of UV-Vis was used to measure the α-tocopherol absorption at 230 nm.

[0265] Size Distribution Dynamic light scattering (DLS) measurements were performed using a Malvern Zetasizer NanoZS instrument equipped with a 532 nm laser at a fixed scattering angle of 173°. Polymer solutions were prepared under different conditions (MilliQ or KCl (1 mM) at different concentrations and temperatures), the solutions were sonicated for 10 min, aged for the required time, filtered through a 0.45 μm cellulose membrane filter and measured. The size distribution of each polymer was measured (diameter: nm) in triplicates for n>3 measurements, and automatic optimization of beam focusing and attenuation was applied to each sample.

[0266] Zeta potential measurement Zeta potential measurements were performed at 20 °C using a Malvern Zetasizer NanoZS instrument equipped with a 532 nm laser using disposable folded capillary cells provided by Malvern Instruments (Worcestershire, UK). Polymer solutions were prepared in 1 mM KCl in MilliQ water. The solutions were filtered through 0.45 μm cellulose membrane filters. The zeta potential of each sample was measured in triplicate with n > 3 measurements.

[0267] Example 1A Preparation of polysarcosine-vitamin E derivatives Coupling reagent for aqueous conjugation: 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (DMTMMCl) 2-Chloro-4,6-dimethoxy-1,3,5-triazine (CDMT, 50 g, 0.28 mol, 1 equiv.) was dissolved in tetrahydrofuran (THF, 150 mL) at room temperature for 30 min. N-methylmorpholine (NMM, 28.8 g, 0.28 mol, 1 equiv.) was then slowly added into the reaction mixture to precipitate a white solid. The reaction mixture was left for 30 min, and the product (DMTMMCl) was filtered under vacuum and washed with 3×100 mL of THF. The white product was dried under vacuum and air flow for 16 h. Yield: 80-90%. 1 H NMR(300MHz,D2O)δ4.70(d,J=11.4Hz,2H),4.22(d,J=8.7Hz,8H),4.06-3.87(m,4H),3.63(s,3H).

[0268] Coupling Reagent for Organic Bonding: 4-(4,6-Dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium Tetrafluoroborate (DMTMMBF4) DMTMMCl (25 g, 0.09 mol, 1 equiv.) was dissolved in water (50 mL) at room temperature for 10 min. In parallel, sodium tetrafluoroborate (NaBF4, 9.84 g, 0.09 mol, 1 equiv.) was also dissolved in water (20 mL). Then, the NaBF4 solution was added dropwise into the DMTMMCl solution to precipitate DMTMMBF4. The white product (DMTMMBF4) was filtered under vacuum and washed with 3 × 20 mL of water. To remove the water, the wet product was freeze-dried. Yield: 80-90%. 1 H NMR(300MHz,D2O)δ4.58-4.44(m,2H),4.11-3.89(m,8H),3.89-3.63(m,4H),3.49-3.33(m,3H). 19 F NMR(282MHz,D2O)δ-150.52(d,J=14.3Hz).

[0269] 1.1. Isopropyl-poly(sarcosine) derivatives (iPr-PSar6, iPr-PSar12, iPr-PSar20) [ka] Sarcosine-N-carboxyanhydride (3-methyl-2,5-oxazolidinedione, NCA-Sar (5 g, 43.47 mmol) was added to a round-bottom flask equipped with a stir bar and stopper, purged with three cycles of vacuum / N2, and dissolved in anhydrous DMF (20 mL). Isopropylamine (DP6: 746.51 μL, 513.5 mg, 8.7 mmol, DP12: 311.05 μL, 213.9 mg, 4.5 mmol, DP20: 186.63 μL, 128.39 mg, 2.17 mmol) was then dissolved in DMF (4 mL) and added to the reaction mixture under nitrogen atmosphere. Once the initiator was added, the round-bottom flask was immediately connected to an airlock, allowing CO2 to escape. The reaction mixture was cooled to room temperature until the total consumption of NCA-Sar was confirmed by Fourier transform infrared (FTIR) spectroscopy (at 1853 and 1786 cm). -1 After 10 min, the NCA signal disappeared (disappearance of NCA signal at 10° C.) and the mixture was stirred at 10° C. Upon completion, the reaction mixture turned slightly yellow. The reaction mixture was poured into diethyl ether (1:10 DMF:diethyl ether) to precipitate the product. The precipitate was isolated by centrifugation (3750 rpm, 4 min), washed twice with diethyl ether, and dried in vacuum. For further purification, the resulting solid was redissolved in methanol at 500 mg / mL, and then this solution was poured again into diethyl ether (1:10 methanol:diethyl ether), washed twice with diethyl ether, and dried in vacuum for at least 2 h. Finally, the solid was redissolved in distilled water, frozen, and lyophilized. iPrPSar n was isolated as an off-white solid. Yield: 70-90%. 1 H NMR (MeOD): δ = 1.16 (m, 6H, CH3), 2.40 (broad s, 3H, terminal N-CH3), 2.89-3.11 (broad m, 65H, polymeric N-CH3), 3.50 (broad s, 2H, terminal -CH2-) & 3.88-4.42 (broad m, 43H, -CH2-).

[0270] The resulting product was analyzed by SEC and 1 It was analyzed for Mn distribution and DP by H NMR, and the results are shown in Table 1 below. [Table 1]

[0271] 1.2. α-Tocopherol succinate-poly(sarcosine) (iPrPSar(6)-succ-VitE, iPrPSar(12)-succ-VitE, iPrPSar(20)-succ-VitE) [ka] Tocopherol succinate (DP6: 4.925 g, 9.28 mmol; DP12: 2.621 g, 4.94 mmol; DP20: 2.239 g, 4.22 mmol) was added to a round-bottom flask equipped with a stir bar and stopper, purged with three cycles of vacuum / N2, dissolved in anhydrous DMF (mL) and covered with a lid to avoid direct light contact. Then, DMTMM·BF4 coupling agent was added to a round-bottom flask equipped with a stir bar and stopper, purged with three cycles of vacuum / N2 and dissolved in anhydrous DMF (mL). The DMTMM·BF4 solution was added on top of the tocopherol succinate solution under inert atmosphere and allowed to react at room temperature for 30 min with stirring. A few drops of N,N-diisopropylethylamine (DIPEA) were added until the pH rose to 6-7. Then, iPrPSar (6) (3 g, 6.19 mmol), iPrPSar (12) (3 g, 3.29 mmol) or iPrPSar (20) (4 g, 2.81 mmol) was added to a round-bottom flask equipped with a stir bar and stopper, purged with three cycles of vacuum / N2, and dissolved in anhydrous DMF (mL). After 30 min, the iPrPSar solution was added on top of the reaction mixture under inert atmosphere. pH adjustment to 8-9 was performed by addition of DIPEA. The mixture was stirred at room temperature for 48 h, avoiding direct light contact. The amphiphilic polymer was poured into diethyl ether (1:10 DMF:diethyl ether) to precipitate the product. The precipitate was isolated by centrifugation (3750 rpm, 4 min), washed twice with diethyl ether, and dried in vacuum. For further purification, the resulting solid was redissolved in methanol at 500 mg / mL, then the solution was poured again into diethyl ether (1:10 methanol:diethyl ether), washed twice with diethyl ether, and dried under vacuum for at least 2 h. Finally, the solid was dissolved in distilled water and diafiltered in a tangential flow filtration system with the addition of a few drops of HCl for total DIPEA purification. The solution was frozen and lyophilized to obtain an off-white solid. Yield: 70-90%. 1H NMR(MeOD): δ=0.90(m,12H,CH-CH3),1.04-1.63(wide m,30H),1.83(m,2H,-CH2-CH2-CCO),1.98(s,3H,CH3-),2. 02(s,CH3-),2.09(s,CH3-),2.63(t,2H,-CH2-CH2-C=C),2.86-3.15(wide s,71H,N-CH3),3.92-4.55(wide s,46H).

[0272] The resulting product was analyzed by SEC and 1 It was analyzed for Mn distribution and DP by H NMR, and the results are shown in Table 2 below. [Table 2]

[0273] Example 1B 1.1. Functionalized poly(sarcosine) derivative (TLR-7,8-PSar20) [ka] Sarcosine-N-carboxyanhydride (3-methyl-2,5-oxazolidinedione, NCA-Sar (0.5 g, 4.34 mmol) was added to a round-bottom flask equipped with a stir bar and stopper, purged with three cycles of vacuum / N2, and dissolved in anhydrous DMSO (3 mL). 1-[[4-(aminomethyl)phenyl]methyl]-2-butyl-imidazo[4,5-C]quinolin-4-amine (DP20: 93.99 mg, 0.22 mmol) was then dissolved in DMSO (1 mL), treated with N,N-diisopropylethylamine (75.67 μL, 56.14 mg, 0.43 mmol) and added to the reaction mixture under nitrogen atmosphere. Once the initiator was added, the round-bottom flask was immediately connected to an airlock, allowing CO2 to escape. The total consumption of NCA-Sar was confirmed by Fourier transform infrared (FTIR) spectroscopy (at 1853 and 1786 cm -1The mixture was stirred at room temperature until the reaction temperature reached 100° C. (disappearance of the NCA signal at 100° C.). Upon completion, the reaction mixture turned slightly yellow. The reaction mixture was poured into tetrahydrofuran (1:10 DMSO:tetrahydrofuran) to precipitate the product. The precipitate was isolated by centrifugation (3750 rpm, 4 min), washed twice with tetrahydrofuran, and dried in vacuum. For further purification, the resulting solid was redissolved in methanol at 200 mg / mL, and then the solution was poured again into diethyl ether (1:10 methanol:diethyl ether), washed twice with diethyl ether, and dried in vacuum for at least 2 h. Finally, the solid was redissolved in distilled water, frozen, and lyophilized. TLR-7,8PSar 20 was isolated as an off-white solid. Yield: 70-90%. 1 H NMR(MeOD): δ=0.95(t,3H,CH3-),1.46(m,2H,-CH2-),1.84(m,2H,-CH2-),2.72(broad t,5H, terminal N-CH3&-CH2-),2.82-3.13(broad m,71H,terminal N-CH3),3.89(broad s,2H,terminal N-CH3), end -CH2-), 3.98-4.50 (wide m, 50H, -CH2-&-CH2-), 5.93 (s, 2H, -CH2-), 7.05 (wide d ,2H,H-),7.30(wide m,3H,H-),7.60(t,1H,H-)7.75(d,1H,H-)&7.95(d,1H,H-).

[0274] The resulting product was analyzed by SEC and 1 It was analyzed for Mn distribution and DP by H NMR, and the results are shown in Table 3 below. [Table 3]

[0275] 1.2. α-Tocopherol succinate-functionalized poly(sarcosine) (TLR-7,8-PSar(20)-succ-tocopherol) [ka] Tocopherol succinate (67.22 mg, 0.13 mmol) was added to a round-bottom flask equipped with a stir bar and stopper, purged with three cycles of vacuum / N2, dissolved in anhydrous DMF (1 mL), and covered with a lid to avoid direct light contact. Then, DMTMM·BF4 (41.55 mg, 0.13 mmol) coupling agent was added to a round-bottom flask equipped with a stir bar and stopper, purged with three cycles of vacuum / N2, and dissolved in anhydrous DMF (1 mL). The DMTMM·BF4 solution was added on top of the tocopherol succinate solution under inert atmosphere and allowed to react at room temperature for 30 min with stirring. A few drops of N,N-diisopropylethylamine (DIPEA) were added until the pH rose to 6-7. Then, TLR-7,8-PSar (20) (0.15 g, 0.08 mmol) was added to a round-bottom flask equipped with a stir bar and stopper, purged with three cycles of vacuum / N2, and dissolved in anhydrous DMF (2 mL). After 30 min, the iPrPSar solution was added on top of the reaction mixture under inert atmosphere. pH adjustment to 8-9 was performed by addition of DIPEA. The mixture was stirred at room temperature for 48 h, avoiding direct light contact. The amphiphilic polymer was poured into diethyl ether (1:10 DMF:diethyl ether) to precipitate the product. The precipitate was isolated by centrifugation (3750 rpm, 4 min), washed twice with diethyl ether, and dried under vacuum. For further purification, the resulting solid was redissolved in methanol at 500 mg / mL, and then the solution was poured again into diethyl ether (1:10 methanol:diethyl ether), washed twice with diethyl ether, and dried under vacuum for at least 2 h. Finally, the solid was dissolved in distilled water and purified in an ultrafiltration unit with the addition of a few drops of HCl to remove all DIPEA. The solution was frozen and lyophilized to give an off-white solid. Yield: 70-90%. 1 H NMR(MeOD): δ=0.87(m,12H,CH-CH3),0.94(t,3H,CH3-),1.02-1.60(wide m,32H),1.80(m,4H,-CH2-) ,1.98(s,3H,CH3-),2.02(s,3H,CH3-),2.09(s,3H,CH3-),2.59(wide s,2H,-CH2-),2.76-3.15(wide m,84H,terminal N-CH3),3.80-4.57(wide m ,57H,-CH2-&-CH2-),5.89(s,2H,-CH2-),7.03(broad d,2H,H-),7.27(broad m,3H,H-),7.55(t,1H,H-)7.70(d,1H,H-)&7.91(d,1H,H-).

[0276] The resulting product was analyzed by SEC and 1 It was analyzed for Mn distribution and DP by H NMR, and the results are shown in Table 4 below. [Table 4]

[0277] Example 1C Preparation of VitE-Gly-OtBu [ka] α-Tocopherol (2000 mg, 4.64 mmol), Boc-Gly-OH (813 mg, 4.64 mmol) and DMAP (58.48 mg, 0.48 mmol) were added to a round bottom flask equipped with a stir bar and stopper, purged with three cycles of vacuum / N2 and dissolved in anhydrous dichloromethane (16 mL). DCC (958.09 mg, 4.64 mmol) was then dissolved in 4 mL of anhydrous dichloromethane and added on top of the mixture solution. The solution turned from a yellow clear solution to a white cloudy appearance. The reaction mixture was left stirring at room temperature for 16 h.

[0278] The resulting solution was left at -20°C for 45 min, after which it was filtered and the dichloromethane was removed by evaporation. The resulting oil was then purified by silica gel column chromatography using hexane:ethyl acetate (95:5). The product Boc-Gly-VitE fraction was collected, concentrated, and finally dried in vacuum. Yield: 90%. 1 H NMR(MeOD): δ=0.90(m,12H,CH-CH3),1.04-1.63(wide m,24H),1.45(s,9H,(CH3)3-C-),1.83(m,2H,-CH2-CH2-CCO) ,1.98(s,3H,CH3-),2.02(s,3H,CH3-),2.09(s,3H,CH3-),2.63(t,2H,-CH2-CH2-C=C),4.08(s,2H,NH-CH2-CCO).

[0279] 1.2. Deprotection of VitE-Gly [ka] Boc-Gly-VitE (3000 mg, 5.1 mmol) was dissolved in 15.5 mL of dichloromethane, followed by 5.1 mL of dichloromethane:TFA (1:1). The reaction mixture was left stirring at 4° C. for 30 min and then at room temperature for 1 h. The solvent was then removed by evaporation to give a brownish oil, which was left at −20° C. for 24 h. This oil was dissolved in MeOH at a concentration of 250 mg / mL and precipitated in 150 mL of H2O. Finally, the product was lyophilized to give a white powder. Yield: 56%. 1 H NMR(MeOD): δ= 1 H NMR(MeOD): δ=0.90(m,12H,CH-CH3),1.04-1.63(wide m,24H),1.83(m,2H,-CH2-CH2-CCO),1.98(s,3H ,CH3-),2.02(s,3H,CH3-),2.09(s,3H,CH3-),2.63(t,2H,-CH2-CH2-C=C),4.14(s,2H,NH-CH2-CCO).

[0280] 1.3. ROP Polymerization to Obtain VitE-Gly-PSar(x) [ka] VitE-Gly-NH2 (x=20:529.7 mg for DP; x=50:423.8 mg for DP) was purged with three vacuum / N2 cycles and dissolved in anhydrous DMF (x=20:3 mL for DP; x=50:2 mL for DP).

[0281] Sarcosine-N-carboxyanhydride (3-methyl-2,5-oxazolidinedione, NCA-Sar (x = 20: 2500 mg, 21.72 mmol for DP; x = 50: 5000 mg, 43.44 mmol) was added to a round-bottom flask equipped with a stir bar and stopper, purged with three cycles of vacuum / N2, and dissolved in anhydrous DMF (x = 20: 7 mL for DP; x = 50: 18 mL). The corresponding initiator VitE-Gly-NH2 was then added to the reaction mixture at 10 °C under nitrogen atmosphere. Once the initiator was added, the round-bottom flask was immediately connected to an airlock to allow CO2 to escape. The reaction mixture was cooled to 10 °C until the total consumption of NCA-Sar was confirmed by Fourier transform infrared (FTIR) spectroscopy (at 1853 and 1786 cm -1 After 2 min, the NCA signal disappeared at 37° C., and the mixture was stirred at 10° C. Upon completion, the reaction mixture turned slightly yellow. The amphiphilic polymer was poured into diethyl ether (1:10 DMF:diethyl ether) to precipitate the product, and for further purification, the resulting solid was redissolved in methanol at 500 mg / mL, and then the solution was poured again into diethyl ether (1:10 methanol:diethyl ether). The solid was vacuum dried and lyophilized to give a white powder as the product.

[0282] VitE-Gly-PSar(20): 1 H NMR(MeOD): δ=0.90(m,12H,CH-CH3),1.04-1.63(wide m,25H),1.83(m,2H,-CH2-CH2-CCO),1.98(s,3H,CH3-),2.02( s,3H,CH3-),2.09(s,3H,CH3-),2.63(t,2H,-CH2-CH2-C=C),2.86-3.15(wide s,81H,N-CH3),3.92-4.55(wide s,57H). Yield: 75%

[0283] VitE-Gly-PSar(50): 1 H NMR(MeOD): δ=0.90(m,12H,CH-CH3),1.04-1.63(wide m,25H),1.83(m,2H,-CH2-CH2-CCO),1.98(s,3H,CH3-),2.0 2(s,CH3-),2.09(s,CH3-),2.63(t,2H,-CH2-CH2-C=C),2.86-3.15(broad s,214H,N-CH3),3.92-4.55(broad s,144H). Yield: 75%

[0284] The resulting product was analyzed by SEC and 1 It was analyzed for Mn distribution and DP by H NMR, and the results are shown in Table 5 below. [Table 5]

[0285] Determination of CMC The fluorescent dye Nile Red was used to determine the critical micelle concentration of the iPrPSar(x)-VitE polymer. Nile Red is a hydrophobic and solvatochromic dye with poor solubility and fluorescence in aqueous media. Excitation-mediated emission was observed when Nile Red was attached to hydrophobic regions, and thus Nile Red fluoresces when the concentration of the polymer in water exceeds the CMC and polymer micelles are formed.

[0286] A stock solution of Nile Red at a concentration of 500 μM was prepared in acetone. 10 μL of the prepared stock solution was then added to a microcentrifuge tube, which was left in the dark to allow the acetone to evaporate. Various concentrations (1 × 10 -4 500 μL of polymer solution (range ∼2 mg / mL) was added to the microcentrifuge tubes and allowed to sit overnight.

[0287] The samples were analyzed in a JASCO spectrofluorometer FP-8300 equipped with a xenon lamp. The samples were excited at 550 nm and the emission spectra were recorded from 575 to 740 nm. The maximum emission intensity recorded was plotted against the logarithm of the polymer concentration. The CMC was determined as the intersection of the two major linear curves that were adjusted and plotted, and the data are appended in Table 6. [Table 6]

[0288] Solubilizer and Encapsulation Properties The solubilizer properties and encapsulation ability of iPrPSar-VitE polymer were tested and demonstrated using carbamazepine (logP=2.67) as a hydrophobic drug by encapsulation of solid suspensions in aqueous micellar formulations.

[0289] The iPrPSar(X)-succ-VitE polymer was solubilized in ddH2O at 10 mg / mL. Solid carbamazepine was then added on top of the aqueous polymer solution at a ratio of 15% (w / w) to obtain a saturated solution. The micellar solution was allowed to stir at room temperature for 24 h, avoiding direct light contact. The solution was then centrifuged at 13,300 rpm for 2 min. The supernatant was isolated and filtered through 0.22 μm nylon. The resulting solution was diluted 100 times in a MeOH / H2O (1 / 1) mixture, and the carbamazepine content was determined by UV spectroscopy at 285 nm. [Table 7]

[0290] The polymers of the present invention showed comparable or even better encapsulation efficiency relative to TPGS.

[0291] Polymeric Micelle Formulations Empty and Dil-loaded micelles of polysarcosine-vitamin E derivatives were prepared to study their physicochemical properties such as size, electrostatic charge, diffusion coefficient and morphology. Dil dye fluorophore (1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate, Dil C18, ThermoFisher) was used as a hydrophobic active drug model at 1% w / w. Micelles prepared from polysarcosine-vitamin E derivatives were compared with TPGS micelles. TPGS used in these experiments was commercially available (PMC Isochem) and had the following properties, which are shown in Table 8 below: [Table 8]

[0292] Micelles were formulated by three different approaches (direct, thin film and cosolvent methods) adapted from a previously described procedure by Gaucher et al. (Gaucher G. et al., Journal of Controlled Release 2005, 109(1-3), 169-188).

[0293] Common methods of direct formulation The block copolymer iPrPSar(20)-succ-VitE (TPSS) or TPGS (10 mg / mL) prepared in Example 1 was directly dissolved in distilled water with continuous stirring at room temperature until the solution was homogenized. The formulation was equilibrated at room temperature for 24 hours. After equilibrating at room temperature for 24 hours, the formulation was centrifuged at 1000 rpm for 10 minutes. No sediment was observed during the centrifugation step for both TPGS and TPSS. The solution was lyophilized to obtain a powder solid directly. For the preparation of fluorescently labeled micelles, the same procedure was followed with the difference that a loading of 1% w / w Dil was added directly in distilled water along with the block copolymer.

[0294] General Methodology for Co-Solvent Formulation The block copolymer iPrPSar(20)-succ-VitE (TPSS) or TPGS (100mg / mL) prepared in Example 1 was dissolved in MeOH and dropped into distilled water with continuous stirring at room temperature until the organic solvent evaporated. The formulation was equilibrated at room temperature for 24 hours and then centrifuged at 1000 rpm for 10 minutes. No precipitation was observed during the centrifugation step for both TPGS and TPSS. The solution was lyophilized to obtain a powder solid directly. For the preparation of fluorescently labeled micelles, the same procedure was followed with the difference that the block copolypeptide and dye were dissolved in THF / MeOH and the same procedure as above was followed to aim for a loading of 1% w / w Dil.

[0295] General method for thin film formulation In a round-bottom flask with an appropriate size, the block copolymer iPrPSar(20)-succ-VitE (TPSS) or TPGS (100 mg / mL) prepared in Example 1 was dissolved in MeOH. Then, MeOH was slowly removed by rotary evaporator to form a thin layer in the round-bottom flask. The product was dissolved in distilled water (10 mg / mL). The solution was equilibrated at room temperature for 24 hours and then centrifuged at 1000 rpm for 10 minutes. For both TPGS and TPSS, no sediment was observed during the centrifugation step. The solution was lyophilized to obtain a powder solid directly. For the preparation of fluorescently labeled micelles, 1% w / w Dil loading was prepared by dissolving the block copolypeptide and dye in THF / MeOH while following the same procedure as above.

[0296] The properties of empty and Dil-loaded micelles were analyzed, including size by DLS and DOSY NMR, electrostatic charge by zeta potential measurements, diffusion coefficient by DOSY NMR, and morphology by TEM. Regardless of the Dil C18 loading and encapsulation efficiency, Dil C18 encapsulation could be estimated to be quantitative in micelles prepared by all three different routes as an indirect method, since no sediment appeared during the centrifugation step.

[0297] Size by DLS and electrostatic charge by zeta potential The resulting micelles with and without Dil at different concentrations were examined by DLS for size and electrostatic charge, and the results are shown in Table 9 below. [Table 9]

[0298] All micelles were examined at 10 and 1 mg / mL to determine if that concentration induced aggregation, and this was not observed. Since TPGS and TPSS are completely water soluble, empty micelles were formulated using the direct method. Micelle formulation with and without Dil does not appear to affect the hydrodynamic diameter (Dh) by strength or number, as all values ​​are between 6 and 19 nm. Importantly, TPGS+Dil prepared by the thin film method and TPSS+Dil prepared by the direct method gave rise to a bimodal Dh distribution by strength calculation. Regardless of the zeta potential, the determined electrostatic charge was neutral as predicted for TPGS and TPSS at both concentrations examined. Thus, no significant differences are observed in the micellar Dh of TPGS compared to TPSS.

[0299] Size based on diffusion coefficients obtained by DOSY NMR Diffusion ordering spectroscopy by NMR (DOSY NMR) is a powerful tool to study binary and hybrid materials. By applying an electromagnetic field gradient, the diffusion coefficient (DC) of the molecule can be calculated (Avram, L. et al., Chemical Society Reviews 2015, 44(2), 586-602, Groves P., polymer Chemistry 2017, 8(44), 6700-6708). Moreover, using the Stejskal-Tanner equation, intensity retardation profiles can be obtained for different moieties in the complex molecule. The DC and Dh results in D2O for TPGS and TPSS are shown in Table 10 below. [Table 10]

[0300] The Dh values ​​obtained in deuterated water (14.49 nm for TPGS and 14.54 nm for TPSS) are in good agreement with the Dh determined by DLS using the intensity method (14.1 nm for TPGS empty micelles at 10 mg / mL and 14.2 nm for TPSS under the same conditions) and are in good agreement with data previously obtained by different techniques. Regarding a direct comparison between both micelles, the DC and Dh values ​​are very close between them and no obvious differences exist for DC and Dh.

[0301] Lipid Nanoparticle (LNP) Formulations In the following examples, the oligonucleotides used were pDNA purchased from PlasmidFactory, together with the reference PF461 (pCMV-luc) containing 6233 bp expressing luciferase. Any other oligonucleotides with the properties shown above could be used to carry out the following experiments. The ionizable lipid (6Z,9Z,28Z,31Z)-4-(dimethylamino)butanoic acid heptatriaconta-6,9,28,31-tetraen-19-yl (DLin-MC3-DMA or simply MC3) was purchased from Nanosoft Polymers. The shielding lipid 1,2-dimyristoyl-rac-glycero-3-methoxypolyethylene glycol-2000 (DMG-PEG2000) was purchased from Avanti Polar Lipids. Both polymers were used to form the reference LNPs. The structural lipids used to form the LNPs were 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC, Avanti Polar Lipids, 850365P) and cholesterol (Chol, Sigma-Aldrich, C8667).

[0302] For the LNP formulations in Table 11, a microfluidic Herringbone Mixer from Darwing Microfluidics was used. This reactor provides two inlet channels, one for DNA in the aqueous phase and one for the lipid mixture in ethanol, and one outlet channel. The specifications of this mixer are: Slide format: 25×75m Channel depth: 0.08mm Channel width: 0.1~0.5mm Volume: 3.3μL Mixer volume: 0.47μL Blender length: 28.7mm Material: Glass Connector: 1 / 4''-28 fitting It is.

[0303] Additionally, two programmable pumps control the fluid flow rate of the syringes (NE-1000 Programmable Single Syringe Pump, Syringe Pump, USA). The system accepts injection rates from 0.73 μL / h (1 mL syringe) to 2100 mL / h (60 mL syringe).

[0304] This method offers reproducibility of the formation of LNPs as well as the potential to scale up the process.

[0305] The reference LNPs in Table 11 were formulated as follows. Dissolve lipids in ethanol at a molar ratio of 50 / 10 / 38.5 / 1.5 (MC3 / DSPC / cholesterol / DMG-PEG) · pDNA was diluted in 25 mM acetate buffer at pH 4, Amine:phosphate ratio (N / P) is 4, The flow ratio is 3:1 (ethanol:H2O), The total flow rate is 2 mL / min. The inner diameter of the tube was 0.5 mm.

[0306] After formulation, the LNPs were diluted in 10 mM phosphate buffered saline (PBS) at pH 7.4 and concentrated in a centrifugal concentrator (Vivaspin™ 500, Sigma) to remove ethanol. Formulations containing the polymers of the invention were similarly prepared, with the difference that the polymer of formula (I) was used instead of DMG-PEG and the lipid ratios were different (shown in Table 11 below).

[0307] The reference LNPs in Table 12 were formulated using a NanoScaler (KNAUER) as follows. Lipids were dissolved in ethanol in a molar ratio of 46.3 / 9.4 / 42.7 / 1.6 (ALC-0315 / DSPC / cholesterol / ALC-0159). The mRNA was diluted in 25 mM acetate buffer at pH 4. The amine:phosphate ratio (N / P) is 6.2 The flow ratio is 1:3 (ethanol:H2O), · Total flow rate of LNP was 4.5mL / min (3mL / min undiluted LNP + 1.5mL / min in-line dilution with PBS).

[0308] After formulation, the LNPs were further diluted with 10 mM phosphate buffered saline (PBS), pH 7.4 to reduce the ethanol concentration and purified with a centrifugal concentrator (Vivaspin™ 500, Sigma) to remove the ethanol. Formulations containing the polymers of the invention were similarly prepared, with the difference that the polymer of formula (I) was used instead of the shielding lipid ALC-0159 and the lipid ratios were different (shown in Table 12 below).

[0309] Characterization of LNPs Size and polydispersity Measurements of size and polydispersity (PDI) of formulated LNPs containing mRNA or pDNA with different N / P ratios (positively chargeable polymeric amine (N = nitrogen) groups: negatively charged nucleic acid phosphate (P)), different molar ratios and shielding polymers were performed using a Malvern Zetasizer NanoZS instrument equipped with a 532 nm laser at a fixed scattering angle of 173°. 50 μl samples were measured using a quartz glass high performance cuvette (Hellma Analytics). Size distributions (diameter, nm) were measured with n > 3 measurements.

[0310] A reference LNP containing MC3 as the ionizable lipid, DMG-PEG as the shielding lipid and pDNA as the cargo was formulated at a molar ratio of 50 / 10 / 38.5 / 1.5 for MC3 / DSPC / cholesterol / DMG-PEG with the following results: [Table 11]

[0311] The presence of DMG-PEG at 1.5% is sufficient to stabilize the LNPs and obtain good size and PDI as well as reproducible formulations.

[0312] Table 11 shows the results obtained for iPrPSar(20)-succ-VitE formulated at a molar ratio of 5% containing pDNA as cargo. [Table 12]

[0313] The results suggest that with 5% iPrPSar(20)-succ-VitE, LNPs exhibiting low PDI and appropriate size can be obtained.

[0314] The reference LNP containing ALC-0315 as ionizable lipid, ALC-0159 as shielding lipid and mRNA as cargo was formulated with a molar ratio of 46.3 / 9.4 / 42.7 / 1.6 for ALC-0315 / DSPC / cholesterol / ALC-0159, and the results were obtained with iPrPSar(x)-succ-VitE containing mRNA as cargo, formulated with a molar ratio of 5%.The results are shown in Table 12 below: [Table 13]

[0315] The results suggest that with 5% different iPrPSar(x)-succ-VitE, LNPs with low PDI and suitable size and encapsulation efficiency (EE%) >90% can be obtained.

[0316] Biological Evaluation Method cell viability To perform the in vitro cytotoxicity studies, two cell lines were used: human immortalized non-tumorous keratinocytes (HaCaT cells) provided by the CLS Cell Lines Service (Germany) and human fibroblasts provided by Hospital La Fe (Valencia, Spain). High glucose Dulbecco's Modified Eagle Medium (DMEM Glutamax, Fisher, Spain) was used for keratinocyte culture, and DMEM (Gibco, Spain) for fibroblast culture, both supplemented with 2% penicillin / streptomycin and 50 mL fetal bovine serum (FBS) in a humidified incubator (Hucoa-Erloss, Spain) at 5% CO2 and 37°C.

[0317] For cell viability assays, 50 μL of cells were seeded in 96-well plates at a concentration of 4,000 cells / well for HaCaT cells and 2,000 cells / well for human fibroblasts. After 24 h, 50 μL of each treatment was added to reach a final volume of 100 μL. Cells were incubated with samples or controls for 72 h before performing the MTS assay. For this assay, 20 μL of a phenazine methosulfate (PMS) and 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt (MTS) (1:20) solution was added. After 3 h of incubation, Victor 2 Absorbance values ​​were obtained at 490 nm using a Wallac™ plate reader (Perkin Elmer, Spain). Absorbance values ​​were expressed as percentage of cell viability relative to 100% cell viability of untreated control cells. TPGS and iPrPSar(20)-succ-VitE (TPSS) in the form of micelles prepared by direct formulation method as well as free vitamin E were tested. The concentrations of TPGS, iPrPSar(20)-succ-tocopherol (TPSS) and free vitamin E ranged from 0.1 to 2.57 μg / mL equivalent vitamin E.

[0318] Figure 1 shows the in vitro cytotoxicity studies in two cell lines, HaCaT cells and human fibroblasts. The concentration range of TPGS, TPSS and free vitamin E ranged from 0.1 to 2.57 μg / mL equivalent vitamin E, and the results show that no cytotoxic effect was observed in the studied cell lines for any of the samples and any of the tested cell lines.

[0319] Skin permeation research To demonstrate the properties of the present invention as a skin permeation enhancer, skin permeation studies were carried out using Franz diffusion cells on human skin, where the permeation capabilities of both amphiphilic micelles based on vitamin E derivatives were investigated.

[0320] Breast skin samples were obtained from healthy women undergoing plastic surgery after written informed consent (kindly donated by Hospital La Fe, Valencia, Spain). Immediately after excision, subcutaneous adipose tissue was carefully removed using a scalpel. The skin was removed in sections of 4 cm 2 The skin was cut into small pieces, wrapped in aluminum foil, and stored at -20°C until use. To reduce inter-individual variability and obtain better comparative results, skin from only one donor was used in all experiments. Before starting each experiment, the skin was left to equilibrate at room temperature (rt).

[0321] In transmission studies, 0.95 cm 2 A modified Franz diffusion cell (Logan Instruments, USA) with a diffusion area of ​​100 μL was used. The skin was carefully fixed between the donor and receptor chambers with the stratum corneum facing upwards. The receptor chamber was filled with 8 mL of 0.01 M phosphate buffered saline (PBS) (pH=7.4) and stirred at 600 rpm with a magnetic stirrer with a thermostat temperature of 37° C. After an equilibration time of 30 minutes, 100 μL of formulations (TPGS-Dil and TPSS-Dil prepared by the direct formulation method) with a fixed concentration (10 mg / mL) were introduced into the donor chamber with a standard pipette. The donor chamber was then sealed with Parafilm® and aluminum foil, and the experiments were carried out for 8 hours.

[0322] After the permeation study, the skin samples were washed twice with 0.1% phosphate buffered saline containing bovine serum albumin (PBS-BSA) and kept in 4% paraformaldehyde (PFA) for 24 hours at room temperature. The samples were then washed with 30% sucrose in PBS and kept at 4° C. for 24 hours. Finally, the skin samples were washed twice with PBS and kept in a cryopreservation solution (40% 0.1 M phosphate buffer PB, 30% ethylene glycol and 30% glycerol) at 4° C. until use.

[0323] Finally, the samples were placed in an optimal cutting temperature (OCT) containing medium, 5 μm slides were generated by a cryostat (version CM1850UV, Leica, Germany) and the samples were analyzed by confocal microscopy.

[0324] Images were acquired with an inverted DM IRE2 microscope equipped with a λ-blue 40× oil immersion objective and handled by a TCS SP2 system equipped with an Acoustic Optical Beam Splitter (AOBS). Dil C18(3) was excited at 549 nm and DAPI at 405 nm. Images were acquired in 8-bit greyscale and processed with LCS software (version 2.5.1347a, Leica, Germany) including multicolor, macro and 3D components. Control tissues following the same incubation times with MilliQ water were also analyzed to establish autofluorescence. Dil intensity was quantified five times per sample using ImageJ software.

[0325] Confocal microscopy (not shown) and pixel quantification by ImageJ (Figure 2) were performed. It was observed that Dil accumulation in the epidermal layer was higher when applied to TPSS micelles than to TPGS. By pixel quantification using ImageJ, it was observed that both systems accumulated mainly in the stratum corneum (SC), but TPSS micelles showed higher accumulation in the epidermal layer than TPGS Dil micelles. In both cases, all Dil was found in the receptor chamber. These preliminary results validate the use of PSar-based materials for dermal delivery applications, as TPSS showed higher accumulation in deeper layers than PEGylated materials.

[0326] Immunogenicity assays The activation of the complement cascade was analyzed by determining the SC5b-9 (protein S-linked terminal complement complex c5b-9) levels using the immunoassay kit MicroVue SC5b-9 Plus. Serum of three healthy individuals was used for further testing. The concentration used was 0.2 mg / mL VitE equivalent. Hepes-buffered saline (HBS) was used as a negative control and zymosan (0.25 mg / mL) as a positive control. All samples were incubated for 1 hour at 37°C with constant agitation by mixing one part of the polymer suspension with four parts of human serum. After incubation, the samples were diluted 100-fold (700-fold for zymosan) with the manufacturer's dilution buffer and the assay was performed as described in the manufacturer's protocol. Table 13 shows the amount of SC5b-9 and the standard error of the mean (SEM). [Table 14]

[0327] iPrPSar(20)-succ-VitE elicits a 10-fold lower immunogenic response than the positive control zymosan and comparable results to the negative control HBS, thus indicating that iPrPSar(20)-succ-VitE has no immunogenic response under these conditions.

[0328] Prior art documents Fieber W. et al., "NMR diffusion and relaxation studies of the encapsulation of fragrances by amphiphilic multiarm star block copolymers", Macromolecules 2007, 40(15), 5372-5378 ·Duro-Castano A. et al., “Extraordinary” Soft-Assembled ChargE Polypeptides as a Strategy for Nanocarrier Design”, Advanced Materials 2017, 29(39), 12 Gaucher G., et al., "Block copolymer micelles: preparation, characterization and application in drug delivery", Journal of Controlled Release 2005,109(1-3),169-188 Avram, L. et al., "Diffusion NMR of molecular cages and capsules", Chemical Society Reviews 2015, 44(2), 586-602 Groves P., "Diffusion ordered spectroscopy (DOSY) as applied to polymers", Polymer Chemistry 2017, 8(44), 6700-6708

Claims

1. A polymer comprising repeating sarcosine-based units covalently attached directly or via a linker to a vitamin E-based moiety, or a pharma- ceutically, nutraceutical or cosmetically acceptable salt thereof, or any stereoisomer or mixture of stereoisomers of any of said polymers or any of their salts. wherein the repeating sarcosine-based unit has formula (XXIII): 【Chemistry 1】 having During the ceremony, R ５ is methyl, -CH ２ F, -CHF ２ and -CF ３ R ６ and R ７ is independently selected from the group consisting of hydrogen and fluorine, and n is an integer from 5 to 500, and the Vitamin E based moiety has the formula (XXIV): 【Chemistry 2】 wherein R ２ , R ３ and R ４ are independently hydrogen, fluorine, methyl, -CH ２ F, -CHF ２ and -CF ３ and each dashed bond --- is independently a single bond or alternatively a double bond.

2. Formula (I): 【Chemistry 3】 having During the ceremony, PAA has the formula (XXI) and the formula (XXII): 【Chemistry 4】 is a repeating sarcosine-based unit selected from During the ceremony, " ＊１ " is X or R １ " indicates the point of attachment of the repeating sarcosine-based unit PAA to ＊２ " indicates the point of attachment of the repeating sarcosine-based unit PAA to a linker L or oxygen atom of the vitamin E-based moiety, m is 0 or 1, with the proviso that when the repeating sarcosine-based unit PAA has formula (XXI), m is 1; z is 0 or 1, with the proviso that when the repeating sarcosine-based unit PAA has formula (XXI), z is 1, and when the repeating sarcosine-based unit PAA has formula (XXII), z is 0; R １ is -(C １ ~C １２ ) alkyl, -(C １ ~C １２ ) alkylphenyl, -(C １ ~C ６ ) alkyl-O-(C １ ~C ６ ) alkyl, —CO—(C １ ~C １２ ) alkyl, —CO—(C １ ~C １２ ) alkylphenyl and —CO—(C １ ~C ６ ) alkyl-O-(C １ ~C ６ ) alkyl, where R １ is optionally a halogen, —OH, —NR ａ R ｂ , -SH, -NHNH ２ , -COOR ｃ , -CF ３ and -OCF ３ and is substituted with one or more substituents selected from the group consisting of R ２ , R ３ and R ４ are independently hydrogen, fluorine, methyl, -CH ２ F, -CHF ２ and -CF ３ is selected from the group consisting of R ５ is methyl, -CH ２ F, -CHF ２ and -CF ３ is selected from the group consisting of R ６ and R ７ is independently selected from the group consisting of hydrogen and fluorine; n is an integer from 5 to 500; X is -O- or -NH-, and L is -CH=CH-, -C≡C-, -CH ２ -, -N=CH-, -CH=NH-, -NH-, -NH-NH-, -NH-N=CH-, -O-, -O(CH ２ )O-, -CO-, -O(CO)-, -(CO)O-, -C(=CH ２ )-, -C(=NH)-, -CONH-, -NHCO-, -NH(CO)NH-, -S-, -S-S-, -SO-, -SO ２ -, -SO ２ N.H. ２ -phenylene-, ... ａ R ｂ , -SH, -NHNH ２ , -COOR ｃ , -CF ３ , -OCF ３ , 【Chemistry 5】 and is substituted with one or more substituents selected from the group consisting of In the formula, L is -CH ２ - moiety, the two hydrogen atoms bonded to that carbon atom may optionally be joined to one of the following rings: 【Chemistry 6】 is replaced by When PAA is a repeating sarcosine-based unit of formula (XXI), L is bonded to the nitrogen atom of said PAA by a chemically feasible bond selected from the group consisting of an amide bond, a carbamate bond, a urea bond and an amine bond; and when PAA is a repeating sarcosine-based unit of formula (XXII) and m is 1, L is bonded to the carbonyl group of said PAA by a chemically feasible bond selected from the group consisting of an amide bond and an ester bond; L is bonded to an oxygen atom of the vitamin E-based moiety by a chemically feasible bond selected from the group consisting of an ester bond, a carbamate bond, and an ether bond; and each of the dashed bonds --- is independently a single bond or alternatively a double bond; and R ａ , R ｂ and R ｃ are independently H, -phenyl, -(C １ ~C ６ ) alkyl, -(C ２ ~C ６ ) alkenyl, -(C １ ~C ６ ) alkylphenyl and -phenyl(C １ ~C ６ 2. The polymer of claim 1, wherein the radical is selected from the group consisting of: ) alkyl.

3. The polymer according to any one of claims 1 to 2, wherein n is an integer from 5 to 50.

4. R ５ is methyl, and R ６ and R ７ The polymer of claims 1 to 3, wherein is hydrogen.

5. R ２ , R ３ and R ４ The polymer of any of claims 1 to 4, wherein: is methyl and each of the dashed bonds --- is a single bond.

6. 6. The polymer of any of claims 2 to 5, wherein the repeating sarcosine-based unit PAA has the formula (XXI), wherein z is 1 and m is 1.

7. 7. The polymer of claim 6, wherein z is 1 and X is -NH-.

8. 6. The polymer of any one of claims 2 to 5, wherein the repeating sarcosine-based unit PAA has the formula (XXII) and z is 0.

9. Formula (II): 【Chemistry 7】 (II) or a pharma- ceutically, nutraceutical or cosmetically acceptable salt thereof, or any stereoisomer or mixture of stereoisomers of any of the complexes of formula (II) or any of the salts thereof. (In the formula, m, PAA, X, n, L, R ２ , R ３ , R ４ and the dashed bond is as defined in any one of claims 1 to 8, s is 0 or 1; z' is 0 or 1, with the proviso that when the repeating sarcosine-based unit PAA has formula (XXII), z' is 0; Z is an agent selected from the group consisting of a nutraceutical active agent, a medicamentously active agent, a cell targeting agent, a diagnostically active agent and a cosmetically active agent; L' is -CH=CH-, -C≡C-, -CH ２ -, -N=CH-, -CH=NH-, -NH-, -NH-NH-, -NH-N=CH-, -O-, -O(CH ２ )O-, -CO-, -O(CO)-, -COO-, -C(=CH ２ )-, -C(=NH)-, -CONH-, -NHCO-, -NH(CO)NH-, -S-, -S-S-, -SO-, -SO ２ -, -SO ２ N.H. ２ -phenylene-, ... ａ R ｂ , -SH, -NHNH ２ , -COOR ｃ , -CF ３ , -OCF ３ , 【Chemistry 8】 and is substituted with one or more substituents selected from the group consisting of R ａ , R ｂ and R ｃ are independently H, -phenyl, -(C １ ~C ６ ) alkyl, -(C ２ ~C ６ ) alkenyl, -(C １ ~C ６ ) alkylphenyl and -phenyl(C １ ~C ６ ) alkyl, and L' is -CH ２ - moiety, the two hydrogen atoms bonded to that carbon atom may optionally be joined to one of the following rings: 【Chemistry 9】 is replaced by When s is 0, Z is directly bonded to X or to the PAA sarcosine repeat unit by a chemically feasible bond selected from the group consisting of an amide bond, a carbamate bond, an amine bond, a urea bond, an ether bond and an ester bond; When S is 1, L' is bonded to Z by a chemically feasible bond selected from the group consisting of an amide bond, a carbamate bond, an amine bond, a urea bond, an ether bond, and an ester bond, and L' is bonded to X or said PAA sarcosine repeat unit by a chemically feasible bond selected from the group consisting of an amide bond, a carbamate bond, an amine bond, a urea bond, an ether bond, and an ester bond.

10. (a) a polymer as defined in any one of claims 1 to 8, or alternatively (b) a conjugate of formula (II) as defined in claim 9, or alternatively (c) a combination of a polymer as defined in any one of claims 1 to 8 with a conjugate of formula (II) as defined in claim 9; an agent encapsulated within the self-assembled particles, optionally selected from the group consisting of a nutraceutical active agent, a medicament active agent, a cell targeting agent, a diagnostically active agent and a cosmetically active agent; Self-assembled particles comprising:

11. 11. The self-assembled nanoparticle of claim 10, selected from the group consisting of micelles, reverse micelles, planar bilayers, crystalline nanoparticles, liposomes, microbubbles and lipid nanoparticles.

12. An effective amount of (a) a polymer as defined in any one of claims 1 to 8, or alternatively (b) a conjugate of formula (II) as defined in claim 9, or alternatively (c) a combination or alternative of a polymer as defined in any one of claims 1 to 8 with a conjugate of formula (II) as defined in claim 9, (d) Self-assembled particles as defined in claim 10. A composition comprising:

13. A polymer as defined in any of claims 1 to 8 for use in medicine, or alternatively a conjugate of formula (II) as defined in claim 9, or alternatively a self-assembled particle as defined in claim 10, or alternatively a pharmaceutical composition as defined in claim 12, wherein the encapsulated drug in the self-assembled particle, if present, is a pharma- ceutical active drug or a cell targeting agent, and Z, when present in the conjugate of formula (II), is a pharma- ceutical active drug or a cell targeting agent.

14. A complex of formula (II) as defined in claim 9 for use in diagnosis, wherein the encapsulated agent in the self-assembled particle, if present, is a diagnostically active agent, and Z, when present in the complex of formula (II), is a diagnostically active agent; or alternatively a self-assembled particle as defined in claim 10, with the proviso that an encapsulated agent is present in the self-assembled particle when the self-assembled particle comprises a polymer as defined in any of claims 1 to 8 in the absence of the complex of formula (II), or alternatively a diagnostic composition as defined in claim 12.

15. 10. Use of a polymer as defined in any of claims 1 to 8 as a carrier, solubilizer, absorption and penetration enhancer, emulsifier or surface stabilizer.

Images