Stealth-stabilized sulfur-containing lipo / polyamino acids

Abstract

It relates to sulfur-containing lipo-polyamino acid conjugates of formula (I), and acceptable salts, stereoisomers and mixtures thereof. It also relates to self-assembled particles comprising these lipo / polyamino acid conjugates and optionally active agents, and to compositions comprising the lipo-polyamino acid conjugates or the self-assembled particles comprising them. It relates as well to the use of the lipo-polyamino acid conjugates, self-assembled particles, or compositions comprising them in medicine, cosmetics and diagnostics, and to the use of the lipo-polyamino acid conjugates of formula (I) as carriers.

Description

[0001] Stealth-stabilized sulfur-containing lipo-polyamino acids

[0002] This application claims the benefit of the European Patent Application EP23382821 .9 filed on 04.08.2023.

[0003] Technical Field

[0004] The present disclosure relates to lipo-polyamino acid conjugates which comprise a sulfur-containing polyamino acid (PAA) moiety conjugated to a lipid-like moiety. These lipo-polyamino acid conjugates may form self-assembled nanoparticles, such as for example lipid nanoparticles (LNPs), and can be used as non- viral vectors for delivery of active ingredients, including nucleic acids, to cells.

[0005] Background Art

[0006] Nucleic acids have emerged in recent years to yield promising drug candidates for a wide range of diseases, including, among others, cancer, infectious diseases, and cardiovascular, inflammatory, and neurodegenerative diseases. Nucleic acids exert their action via gene inhibition, addition, replacement or editing. However, their clinical efficacy is very much limited because of their inability to cross physiological barriers. The negative charge and hydrophilicity of nucleic acids hinder their passive diffusion across plasma membranes. Moreover, the association of nucleic acids with serum proteins as well as their susceptibility to enzymatic degradation by endogenous nucleases also interferes with their efficient translation to functional response.

[0007] Non-viral vectors such as LNPs are known to permeate plasma membranes and thus to be able to deliver nucleic acids to cells. LNPs are vesicles composed of mixtures of lipids that are physically associated with each other by intermolecular forces forming a micellar structure. LNPs typically have a small diameter of less than 200 nm. LNPs are used as drug delivery system thanks to their ability to encapsulate biologically active agents and deliver them to specific locations within the body at a desired time. The lipid components of LNPs may include ionizable or cationic lipids, helper lipids such as phospholipids and structural lipids such as sterols or cholesterol. lonizable / cationic lipids, which have either a permanent or ionizable positively charged head group followed by a hydrophobic tail, can form complexes with negatively charged nucleic acids by means of electrostatic bonds.

[0008] One of the potential problems of LNPs is that once they are injected, they may be recognised by the immune system as foreign particles and subsequently cleared from the bloodstream by phagocytes. In order to overcome this problem, different strategies may be used including decreasing the particle size of the vesicles or modifying their surface. For example, the LNP surface may be modified by conjugating the hydrophilic polymer polyethylene glycol (PEG) to lipids such as phospholipids or long-chain fatty acids to form PEG-lipids. PEG is a hydrophilic polymer widely used in drug delivery and nanotechnology because of its stealth properties and biocompatibility. Thanks to these properties, particulate delivery systems containing PEG are able to evade the immune system, and, as a result, have a prolonged circulation time within the body.

[0009] Despite the above, it has been recently reported that the presence of covalently bonded PEG also significantly reduces the transfection efficiency because the neutral surface of the nanoparticles can decrease the cellular uptake efficiency. Also, it is well known that the PEG also generates anti-PEG antibodies that may cause immunogenicity and allergic reactions.

[0010] While other hydrophilic polymers such as poly (vinylpyrrolidones), poly (acryloyl-morpholines) or polyoxazolines have been reported as alternatives to PEG-lipids, no LNP containing such polymers have been marketed yet.

[0011] Polysarcosine (pSar) is a polypeptoid based on the endogenous amino acid sarcosine (N-methylated glycine), which has previously shown potent stealth properties. Lipid nanoparticles (LNPs) for therapeutic application of messenger RNA assembled using pSarcosinylated lipids have been reported as a promising tool for particle engineering (ACS Appl. Nano Mater., 2020, 3, 10634—10645) but this is still under development and no clinical data including this polymer into LNPs is presented yet.

[0012] Therefore, from what it is known in the field, there is still the need to develop alternative LNPs which overcome the disadvantages of the prior art.

[0013] Summary of Invention

[0014] The inventors have developed new lipo-polyamino acid conjugates which comprise a sulfur-containing polyamino acid (PAA) moiety conjugated to at least one lipid-like moiety. These conjugates may form selfassembled nanoparticles, such as for example lipid nanoparticles (LNPs), and can be effectively used as non- viral vectors for delivery of active ingredients, including nucleic acids, to cells, thanks to their stealth properties and consequent improved plasma half-life time.

[0015] Furthermore, the sulfur-containing lipo-polyamino acid conjugates show low cytotoxicity, high biodegradability and may confer to the final nanosystem enhanced efficiency, high stability due to limited or even completely suppressed aggregation issues in the bloodstream and potential different cell and tissue tropism.

[0016] Therefore, a first aspect of the invention relates to a lipo-polyamino acid conjugate of formula (I), a salt thereof, or any stereoisomer or mixtures of stereoisomers, either of the compound of formula (I), or of any of its salts, wherein:

[0017] PAAi is a repetitive unit of formula (II)

[0018] PAA2 is a repetitive unit of formula (III) wherein though the repeating units PAA1 and PAA2 are shown in a particular order for convenience of description, the repeating units may be present in any order and may be block or randomly present; and wherein each of the repeating units PAA1 and PAA2 may comprise blocks of monomer units which may be the same or different between each other; n is an integer from 5 to 250; m is an integer from 0 to 250; p is 0 or 1; s Is O or 1 ;

[0019] X is selected from the group consisting of CH, N, S, and 0;

[0020] X' is selected from the group consisting of N and 0;

[0021] R1 and R1' are independently selected from the group consisting of H, -(Ci-Ci8)alkyl, and -(C2-Ci8)alkenyl, with the condition that R1 is absent when X is 0 or S, and R is absent when X' is 0;

[0022] R2 is a radical selected from the group consisting of (IV), (V) and (VI)

[0023] (IV) (V) (VI) wherein a, b and c are independently an integer from 0 to 3; R is -(Ci-Cejalkyl, and R' is selected from the group consisting of -(Ci-CeJalkyl-SOr and -(Ci-C6)alkyl-CO2-;

[0024] R3 and R5 are independently selected from the group consisting of H and -(Ci-Cejalky I;

[0025] R4 is any amino acid side chain optionally functionalized with an active moiety;

[0026] A is selected from the group consisting of

[0027] H, -(Ci-C6)alkyl, -C0(Ci-C6)alkyl, -(Ci-C6)alkyl-CO-N[(Ci-Ci8)alkyl]2, -(C5-Cio)aryl, -(C5-Cio)heteroaryl, -(C6-Cio)aralkyl, -(Ci-C6)alkyl-0-(C5-Cio)aryl, -(C5-Cio)heterocycloalkyl, a radical (IV), a radical (V), a radical (VI), a protective group, a lipid-like moiety R7, and an active moiety;

[0028] A1 is selected from the group consisting of H, -OH, -(Ci-Cejalkyl, -(C5-Cio)aryl, -(C5-Cio)heteroaryl, -(C6-Cio)aralkyl, -(Ci-C6)alkyl-0-(C5-Cio)aryl, -(C5-Cio)heterocycloalkyl, -(C1-C10) alkoxy, -(C6-Cio)aryloxy, -(C6-Cio)aralkoxy, -(C5-Cio)heteroaralkoxy, -(Ci-Cio)alkyl-0-(C6-Cio)aryloxy, an amino protective group, a lipid- like moiety R , an amino acid-like moiety Rs, and an active moiety; with the condition that:

[0029] I) when p is 0, s is 0, and A1 is selected from the group consisting of H, -(Ci-Cejalkyl, -(C5-Cio)aryl, -(C5-Cio)heteroaryl, -(C6-Cio)aralkyl, -(Ci-C6)alkyl-0-(C5-Cio)aryl, -(C5-Cio)heterocycloalkyl, an amino protective group, a lipid-like moiety R , an amino acid-like moiety Rs, and an active moiety; ii) when p is 1 and s is 0, A1 is selected from the group consisting of H, -OH, -(Ci-Cejalkyl, -(C5-Cio)aryl, -(C5-Cio)heteroaryl, -(C6-Cio)aralkyl, -(Ci-C6)alkyl-0-(C5-Cio)aryl, -(C5-Cio)heterocycloalkyl, -(C1-C10) alkoxy, -(C6-Cio)aryloxy, -(C6-Cio)aralkoxy, -(C5-Cio)heteroaralkoxy, -(Ci-Cio)alkyl-0-(C6-Cio)aryloxy, a lipid-like moiety R , and an active moiety; ill) when p is 1 and s is 1 , A1 is selected from the group consisting of H, -(Ci-Cejalkyl, -(C5-Cio)aryl, -(C5-Cio)heteroaryl, -(C6-Cio)aralkyl, -(Ci-C6)alkyl-0-(C5-Cio)aryl, -(C5-Cio)heterocycloalkyl, -(C1-C10) alkoxy, -(C6-Cio)aryloxy, -(C6-Cio)aralkoxy, -(C5-Cio)heteroaralkoxy, -(Ci-Cio)alkyl-0-(C6-Cio)aryloxy, a lipid-like moiety R , and an active moiety; and iv) at least one of A and A1 is a lipid-like moiety R? or R ; wherein A and Ai are independently optionally substituted by one or more groups selected from the group consisting of -OH, halogen, -CF3, -NH2, -NH-(Ci-C4)alkyl, -NH-CO-(Ci-C6)alkyl, -(Ci-Cejalkyl, -NO2, -N3, -CO-(Ci-C6)alkyl, -CO-O-(Ci-C6)alkyl, -SO3H, -SO2NH2, -SO2-N((Ci-C6)alkyl)2, -COOH, CONH2, and -CON((Ci-C6)alkyl)2; each lipid-like moiety Rz is independently selected from the group consisting of -(Ci-C2o)alkyl, -(C2-C2o)alkenyl, each Rz' is independently selected from the group consisting of -(Ci-C2o)alkyl, -(C2-C2o)al keny I , and a radical of formula (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), or (XVIII’) wherein:

[0030] Y and Y' are independently selected from -OH, -OCORx and -COORx;

[0031] Q and Q' are independently selected from -OCORy and -COORy;

[0032] Z and Z' are independently selected from -O-, -OCO-, -COO-, -NRz'CO-, and -CONRz'-; each Rz' is H or Rz; each Rx, Ry, and Rz is independently -(Ci-Ci8)alkyl or -(C2-Ci8)alkenyl; each g is independently an integer from 0 to 18; each h is independently an integer from 1 to 18;

[0033] I is an integer from 0 to 18; each j is independently an integer from 0 to 18; t is 0 or 1 , with the condition that t is 0 when X= 0, and t is 1 when X is other than 0; t' is 0 or 1 ; with the condition that t' is 1 when p is 0 and s is 0, and t' is 1 when p is 1 and s is 1;

[0034] R22, R33 and R44 are independently selected from the group consisting of hydrogen, fluorine, methyl, -CH2F, -CHF2, and -CF3; each of the dashed bonds — is independently a single bond or, alternatively, a double bond;

[0035] L is a biradical chain which comprises 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-, -0-, -O(CH2)O-, -CO-, -0(00)-, -(CO)O-, -C(=CH2)-, -C(=NH)-, -CONH-, -NHCO-, -NH(CO)NH-, -S-, -S-S-, -SO-, -S02-, -SO2NH2- and -phenylene-, wherein L is optionally substituted with one or more substituents selected from the group consisting of halogen, -OH, -NRaRb, -SH, -NHNH2, -C00Rc, -CF3, -OCF3, wherein when L comprises a -CH2- moiety, the two hydrogen atoms attached to the carbon atom are optionally replaced by the ring: and each Rs is a radical independently selected from the group consisting of (XX), (XXI) and (XXII) wherein each a', each b', and each c' are independently an integer from 0 to 3, each Rg is independently -(Ci-Ce)alkyl, and Rw is selected from the group consisting of -(Ci-CeJalkyl-SOr and -(Ci-C6)alkyl-CO2_; denote the attaching points; and each active moiety is independently selected from the group consisting of a pharmaceutically active agent, a penetration enhancing agent, a cell-targeting agent, a cosmetically active agent, and a diagnostically active agent.

[0036] A second aspect of the invention relates to a lipo-polyamino acid conjugate of formula (I), a salt thereof, or any stereoisomer or mixtures of stereoisomers, either of the compound of formula (I), or of any of its salts, wherein the lipo-polyamino acid conjugate of formula (I) is as defined in the first aspect wherein:

[0037] A and Ai may also be independently optionally substituted by one or more groups selected from the group consisting of -(CHg -SO-CHg, and NH(Ci-Ce)alkyl; and

[0038] - when Ai is H, p is 0, s is 0, X is N, and Ri is H, then A is other than butyl;

[0039] - when Ai is H, p is 0, s is 0, X is N, and A is H, then Ri is other than butyl; and

[0040] - when A is methyl, X is N, Ri is H, p is 1 , and s is 0, then Ai is other than a lipid-like moiety Rz of formula (XVII) wherein each j is16 and i is 2.

[0041] Using appropriate surface functionality, the lipo-polyamino acid conjugates of the present disclosure may be decorated with cell-targeting groups in any of A, Ai, A2 or A3 that can actively target cells and aid in cellular entry, resulting in a conjugate which has improved cell-specific delivery. The lipo-polyamino acid conjugates may also be decorated with penetration enhancing agents when an increased cell or skin penetration is desired, Further, the lipo-polyamino acid conjugates can also be used for delivering pharmaceutically, cosmetically or diagnostically active agents attached to the backbone of the conjugate in any of A, Ai, A2 or A3.

[0042] Additionally, thanks to their amphiphilic nature, the lipo-polyamino acid conjugates of the invention may form self-assembled particles in solution such as for example liposomes or lipid nanoparticles which may be used to encapsulate and deliver molecules of a different nature. Thus, the lipo-polyamino acid conjugates of the invention allow carrying and / or delivering different active agents at the same time, not only bonded to the structure of the conjugate but also contained in self-assembled particles formed from the conjugated. Accordingly, another aspect of the invention relates to a self-assembled particle comprising the lipo-polyamino acid conjugate of formula (I) as defined herein, and optionally one or more active agents selected from the group consisting of pharmaceutically active agents, cell-targeting agents, penetration enhancing agents, cosmetically active agents, diagnostically active agents, nucleic acids, peptides, proteins, and mixtures thereof.

[0043] The lipo-polyamino acid conjugates of the invention may be formulated in a variety of compositions, including pharmaceutical, cosmetic and diagnostic compositions, with excipients and carriers. Thus, another aspect of the invention relates to a composition comprising the lipo-polyamino acid conjugate as defined herein; or alternatively, the self-assembled particle containing them, together with one or more appropriate excipients or carriers.

[0044] The lipo-polyamino acid conjugates of the invention, self-assembled particles, and compositions thereof may be used in medicinal, cosmetic and diagnostic applications.

[0045] Thus, another aspect of the invention relates to a therapeutic product which is or comprises: a) a lipo- polyamino acid conjugate of formula (I) as defined herein, wherein at least one of A, A1, A2 or A3 is a pharmaceutically active agent; or alternatively, b) a self-assembled particle containing the lipo-polyamino acid conjugate a); or alternatively, c) a composition containing the lipo-polyamino acid conjugate a) or the selfassembled particle b); or alternatively, d) a self-assembled particle which comprises the lipo-polyamino acid conjugate as defined herein and one or more active agents selected from the group consisting of pharmaceutically active agents, nucleic acids, peptides, proteins, and mixtures thereof; or alternatively, e) a composition containing the self-assembled particle d), for use in medicine.

[0046] According to another aspect, the invention relates to a diagnostic product which is or comprises: a') a lipo- polyamino acid conjugate as defined herein, wherein at least one of A, A1, A2 or A3 is a diagnostically active agent; or alternatively, b') a self-assembled particle containing the lipo-polyamino acid conjugate a'); or alternatively, c') a composition containing the lipo-polyamino acid conjugate a') or the self-assembled particle b'); or alternatively, d) a self-assembled particle which comprises the lipo-polyamino acid conjugate as defined herein and one or more diagnostically active agents; or alternatively, e') a composition containing the self- assembled particle d'), for use in diagnostics.

[0047] According to another aspect, the invention relates to the use in cosmetics of a cosmetic product which is or comprises: a”) a lipo-polyamino acid conjugate as defined herein, wherein at least one of A, Ai, A2 or A3 is a cosmetically active agent; or alternatively, b”) a self-assembled particle containing the lipo-polyamino acid conjugate a'); or alternatively, c”) a composition containing a”) or the self-assembled particle b”); or alternatively, d”) a self-assembled particle which comprises the lipo-polyamino acid conjugate as defined herein and one or more cosmetically active agents; or alternatively, e”) a composition containing the selfassembled particle d”).

[0048] Another aspect of the invention relates to the use of the lipo-polyamino acid conjugate of formula (I) as defined herein, wherein A, A1, A2 and A3 are other than an active moiety, as a carrier.

[0049] Brief Description of Drawings

[0050] FIG. 1 shows an agarose gel (2%) for the detection of free mRNA from different LNPs formulations: M) free mRNA; 1) benchmark LNPs formulation; 2) benchmark LNPs formulation + 1% triton X-100; 3) PMetO5 LNPs formulation; 4) PMetO5 LNPs formulation + 1% triton X-100.

[0051] FIG 2 shows an agarose gel (2%) for the detection of free mRNA from different LNPs formulations: M) free mRNA; 1) benchmark LNPs formulation; 2) benchmark LNPs formulation + 1% triton X-100; 3) PMetOI LNPs formulation; 4) PMetOI LNPs formulation + 1% triton X-100.

[0052] Detailed description of the invention

[0053] All terms as used herein in this application, unless otherwise stated, shall be understood in their ordinary meaning as known in the art. Other more specific definitions for certain terms as used in the present application are as set forth below and are intended to apply throughout the description and claims.

[0054] The term "about" or "around” as used herein refers to a range of values ± 10% of a specified value. For example, the expression "about 10" or "around 10” includes ± 10% of 10, i.e. from 9 to 11.

[0055] As used herein, the indefinite articles "a” and "an” are synonymous with "at least one” or "one or more.” Unless indicated otherwise, definite articles used herein, such as "the” also include the plural of the noun.

[0056] The term "moiety” refers to a specific segment or functional group of a molecule or compound.

[0057] As used herein, the term "subject" refers to any mammal, including both human and other mammals. The term -(Ci-Cx)alkyl refers to a saturated linear or branched hydrocarbon chain which contains from 1 to x carbon atoms and only single bonds. Examples of alkyl groups may include without limitation methyl, ethyl, n- propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, neopentyl, n-hexyl, decyl, undecyl, dodecyl, tetradecyl and hexadecyl. The term -(C2-Cx)alkenyl refers to an unsaturated branched or linear hydrocarbon chain which comprises from 2 to x carbon atoms and at least one or more double bonds. Examples of alkenyl groups may include without limitation ethenyl (i.e. vinyl), allyl, propenyl, butenyl, pentenyl and hexenyl, dodecenyl, tetradecenyl and hexadecenyl.

[0058] The term “-(Ci-Cio)alkoxy” refers to an alkyl group as defined herein comprising 1 to 10 carbon atoms which is connected to the rest of the molecule via an oxygen atom. Examples of alkoxy groups may include without limitation methoxy, ethoxy, 1 -propoxy, and 2-propoxy.

[0059] The term “-(C5-Cio)aryl” refers to an aromatic carbocyclic mono- or bicyclic ring system comprising 5 to 10 carbon ring atoms. Examples of aryl groups may include without limitation phenyl, biphenyl, and naphthyl.

[0060] The term "-(C6-Cio)aryloxy” refers to an aryl group as defined herein comprising 6 to 10 carbon ring atoms, which is connected to the rest of the molecule via an oxygen atom. Examples of aryloxy groups may include without limitation phenoxy and biphenyloxy.

[0061] The term "-(C5-Cio)heteroaryl” refers to an aromatic carbocyclic mono- or bicyclic ring system comprising 5 to 10 ring atoms, wherin at least one aromatic ring containing one, two, or three ring heteroatoms selected from N, O, and S, the remaining ring atoms being carbon atoms. Examples of heteroaryl groups may include without limitation pyridyl, azetidinyl, furyl, pyrrolyl, thienyl, thiazolyl, oxazolyl, imidazolyl, tetrazolyl, benzofuryl, isoquinolinyl, benzthiazolyl, benzimidazolyl, benzthiazolyl, quinolyl, and quinazolyl.

[0062] The term "-(C6-Cio)aralkyl” refers to a lower alkyl group as defined herein (e.g. -(Ci-Ce)alkyl) which is substituted by an aryl group (e.g. “-(C5-Cio)aryl) as defined herein. Examples of aralkyl groups may include without limitation benzyl, phenethyl, and methylbenzyl.

[0063] The term "-(C6-Cio)aralkoxy” refers to a lower alkoxy group as defined herein (e.g. -(Ci-Ce)alkoxy) which is substituted by an aryl group (e.g. “-(C5-Cio)aryl) as defined herein. Examples of aralkoxy groups may include without limitation benzyloxy, phenethoxy, and methylbenzyloxy.

[0064] The term "-(C5-Cio)heteroaralkoxy” refers to a lower alkoxy group as defined herein (e.g. -(Ci-Ce) alkoxy) which is substituted by an heteroaryl group (e.g. "-(C5-Cio)heteroaryl) as defined herein. Examples of heteroaralkoxy groups may include without limitation furyloxy, pyridyloxy, and azetidinyloxy.

[0065] The term "-(C5-Cio)heterocycloalkyl” refers to a 5-10 membered mono- or bicylic (fused or bridged) saturated o unsaturated ring structure, in which one or more of the ring atoms is a heteroatom selected from N, O, and S. Examples of a heterocycloalkyl groups may include without limitation include piperidyl, piperazyl, tetrahydropyranyl, tetrahydrofuryl, 1,4-dioxolanyl, oxazolidyl, isoxazolidyl, morpholinyl, thiomorpholyl.

[0066] As used herein, the term "protective group" refers to a grouping of atoms that when attached to a reactive group in a molecule masks, reduces or prevents that reactivity.

[0067] Protective groups for carboxyl and amino groups are described for example in T. W. Green and P.G. M. Wuts, Protective Groups in Organic Chemistry (Wiley, 3rd ed. 1999) in Chapter 5 (pp. 369-451) and Chapter 7 (pp. 495-653), respectively.

[0068] The term "substituted" means that one or more hydrogen atoms on the designated atom or group are replaced with a selection from the indicated group, provided that the designated atom's normal valency under the existing circumstances is not exceeded. Combinations of substituents and / or variables are permissible.

[0069] The term "optionally substituted" means that the number of substituents can be equal to or different from zero. Unless otherwise indicated, it is possible that optionally substituted groups are substituted with as many optional substituents as can be accommodated by replacing a hydrogen atom with a non-hydrogen substituent on any available carbon or nitrogen atom. It is possible that groups in the conjugates according to the invention are substituted with one, two, three, four or five identical or different substituents, particularly with one, two or three substituents.

[0070] In the embodiments of the invention where the substitution or unsubstitution of a certain group is not specified, i.e. , a certain substitution for that group is not indicated, nor is it indicated that the group is unsubstituted, it has to be understood that the possible substitution of this group is the broadest one as defined herein.

[0071] Lipo-polyamino acid conjugates

[0072] A first aspect of the invention refers to a lipo-polyamino acid conjugate of formula (I), a salt thereof, or any stereoisomer or mixtures of stereoisomers, either of the compound of formula (I), or of any of its salts. wherein A, X, X', Ri, R / , n, m, p, s and Ai are as defined herein, and PAAi and PAA2 are repetitive units of formulas (II) and (III), respectively

[0073] Although the repeating units PAAi and PAA2 are shown in a particular order for convenience of description, the repeating units may be present in any order and may be block or randomly present; and wherein each of the repeating units PAA1 and PAA2 may comprise blocks of monomer units which may be the same or different between each other.

[0074] The symbols denote the attaching points of the PAA-based moieties to the rest of the molecule as drawn, i.e., the moiety of formula (II) is attached by the carbonyl moiety to X, and by the N atom to the carbonyl moiety of PAA2; and the moiety of formula (III) is attached by the carbonyl moiety to the N atom of PAA1, and by the N atom to the carbonyl PAA2.

[0075] For the purposes of the invention, the term “I ipo-poly amino acid conjugate” refers to a molecule which comprises a) at least one polyamino acid-based moiety and b) at least one lipid-like moiety. The term "lipid- like moiety" refers to a moiety which, while it cannot be considered to be a lipid as such, structurally and / or functionally resembles a lipid. The term lipid-like moiety is intended to include moieties that are able to form amphiphilic layers. The term "lipid" refers to a group of organic compounds such as fatty acids, glycerolipids, glycerophospholipids, sphingolipids, saccharolipids, sterols, and the like, which are insoluble in water.

[0076] The lipid-like moiety can be placed on any of the terminal ends of the (PAAi)n-(PAA2)m-based moiety. It is also possible that the lipo-polyamino acid conjugates of the invention comprise a lipid-like moiety at both ends of the molecule. For example, the lipid like moiety can be placed at the left side of the drawn molecule of formula (I) when A is R7, or at the right side when A1 is R , or at both ends when A is R7, and A is R . In any case, at least one of A and A1 must be a lipid-like moiety (R7 in the case of A or R in the case of A1) .

[0077] There is no limitation on the type of salt of the lipo-polyamino acid conjugates that can be used, provided that these are pharmaceutically, cosmetically or diagnostically acceptable when they are used for pharmaceutical, cosmetic or diagnostic purposes, respectively. The term "pharmaceutically, cosmetically or diagnostically acceptable salts", embraces non-toxic salts commonly used. The preparation of pharmaceutically, cosmetically or diagnostically acceptable salts of the lipo-polyamino acid conjugates of the invention can be carried out by methods well-known in the art. Generally, such salts can be prepared by reacting the free acid or base form of a lipo-polyamino acid conjugate of the invention with a stoichiometric amount of an appropriate base or acid, respectively, in a suitable solvent such as water, an organic solvent or a mixture of them. Examples of pharmaceutically, cosmetically or diagnostically acceptable salts include acid addition salts formed with inorganic acids e.g. hydrochloric, hydrobromic, sulfuric, nitric, hydroiodic, metaphosphoric, or phosphoric acid; and organic acids e.g. succinic, maleic, acetic, fumaric, citric, tartaric, benzoic, trifluoroacetic, malic, lactic, formic, propionic, glycolic, gluconic, camphorsulfuric, isothionic, mucic, gentisic, isonicotinic, saccharic, glucuronic, furoic, glutamic, ascorbic, anthranilic, salicylic, phenylacetic, mandelic, embonic (pamoic), ethanesulfonic, pantothenic, stearic, sulfinilic, alginic and galacturonic acid; and arylsulfonic, for example benzenesulfonic, p-toluenesulfonic, oxalic, methanesulfonic or naphthalenesulfonic acid; and base addition salts formed with alkali metals and alkaline earth metals and organic bases such as N,N- dibenzylethylene-diamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N- methylglucamine), lysine and procaine; and internally formed salts. The lipo-polyamino acid conjugates of the invention and their salts may differ in some physical properties, but they are equivalent for the purposes of the present invention.

[0078] Some of the lipo-polyamino acid conjugates of the invention can have chiral centres that can give rise to various stereoisomers. As used herein, the term "stereoisomer" refers to all isomers of individual lipo- polyamino acid conjugates 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, and isomers of lipo-polyamino acid conjugates with more than one chiral center that are not mirror images of one another (diastereoisomers). The present invention relates to each of these stereoisomers and also mixtures thereof. Hence, the definition of the lipo- polyamino acid conjugates of formula (I) is also intended to encompass all R- and S-isomers of a chemical structure in any ratio, e.g. with enrichment (i.e. enantiomeric excess or diastereomeric excess) of one of the possible isomers and corresponding smaller ratios of other isomers. In the particular case of amino acids, they may acquire L-configuration or D-configuration.

[0079] Diastereoisomers 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 give optically pure isomers. The resolution can be carried out on any chiral synthetic intermediates or on the polymers of the invention.

[0080] In all embodiments of the invention referring to the lipo-polyamino acid conjugates, the pharmaceutically, cosmetically or diagnostically acceptable salts thereof and the stereoisomers or mixtures of stereoisomers, either of any of the lipo-polyamino acid conjugates or of any of their pharmaceutically, cosmetically or diagnostically acceptable salts are always contemplated even if they are not specifically mentioned.

[0081] The lipo-polyamino acid conjugates of the invention may be in crystalline form either as free solvation lipo- polyamino acid conjugates or as solvates (e.g. hydrates). It is intended that all these forms are within the scope of the present invention. Methods of solvation are generally known within the art. For the purposes of the invention, the solvated forms with pharmaceutically, cosmetically or diagnostically acceptable solvents such as water, ethanol and the like are equivalent to the unsolvated form.

[0082] Except as otherwise specified, the lipo-polyamino acid conjugates of the present disclosure also include lipo- polyamino acid conjugates that differ only in the presence of one or more isotope-enriched atoms. Examples of isotope-enriched atoms, without limitation, are deuterium, tritium,13C or14C, or a nitrogen atom enriched in15N or a fluorine atom enriched in18F.

[0083] The lipo-polyamino acid conjugate of formula (I) comprise “n” PAAi repetitive units of formula (II) and optionally “m” PAA2 repetitive units of formula (III). According to one embodiment, optionally in combination with any of the embodiments provided above or below, the weight ratio of the PAA1 monomer to the PAA2 monomer in the conjugate is from 100 / 0 to 50 / 50, more particularly from 100 / 0 to 75 / 25. Thus, when the lipo- polyamino acid conjugate of formula (I) only comprises PAA1 repetitive units, the conjugate is a homopolymer, whereas when the lipo-polyamino acid conjugate of formula (I) only comprises both PAA1 and PAA2 repetitive units, the conjugate is a copolymer.

[0084] For the purposes of the invention, the term "homopolymer” refers to a polymer derived from a single monomer. The term "copolymer” as used herein refers to a polymer derived from more than one monomer. The copolymer may be a random or a block copolymer. The term "random copolymer” as used herein refers to a copolymer in which the monomer units are located randomly in the polymer molecule. The term "block copolymer” as used herein refers to a copolymer that comprises at least two different monomer units that upon polymerization form at least two chemically distinct regions, segments or blocks that are chemically distinguishable from one another. The term block copolymer includes linear block copolymers, multiblock copolymers and star shaped block copolymers.

[0085] The lipo-polyamino acid conjugates of the invention are characterized by a molecular weight, which can be average molecular weight (MW) or number average molecular weight (Mn), a degree of polymerization, and a polydispersity index. The molecular weight can be measured by methods well-known in the art such as size exclusion chromatography (SEC) (also referred to as gel permeation chromatography (GPC)) matrix assisted laser desorption ionization-time-of-flight mass spectrometry (MALDI-TOF MS). Composition and ratios are characterized by1H-NMR spectroscopy among other techniques, for example. Some of these methods are indicated in more detail in the examples below.

[0086] As used herein, the term "repeating unit”, refers to the monomeric amino acid-based unit and is defined by square brackets ("[ ]”) depicted around it. The number on the lower right of the brackets (represented by letters “n” or “m”) refers to the degree of polymerization (DP) for each monomeric unit as a statistical number. The DP is calculated by dividing the corrected molecular weight (subtracting the initiator MW) of the polymer determined by SEC-MALS technique by the molecular weight of the monomer unit. The DP value is reported as the central value of a gaussian distribution which comprises polymers of variable DP (depending on intrinsic polydispersity). The DP value is subject to a reasonable uncertainty, due to the ring-opening polymerization mechanism, which, in the context of the present invention, may be considered within the range ±20%, preferably ±15%, more preferably ±10%, even more preferably ±5%, being particularly preferred ±2%.

[0087] The term "polydispersity index” (PD I ) is used as a measure of broadness of molecular weight distribution. The larger the PDI, the broader the molecular weight. PDI of a polymer is calculated as the ratio of weight average (MW) by number average (Mn) molecular weight.

[0088] Mw Polydispersity index = -

[0089] Mn

[0090] According to one embodiment, optionally in combination with any of the embodiments provided above or below, the lipo-polyamino acid conjugate of formula (I) is a copolymer comprising “n” PAAi repetitive units of formula (II) and “m” PAA2 repetitive units of formula (III), more particularly wherein the weight ratio of the PAA1 monomer to the PAA2 monomer in the conjugate is from 95 / 5 to 50 / 50, for example about 10 / 5, about 20 / 5, about 30 / 5, about 40 / 5, about 50 / 5, about 60 / 5, about 70 / 5 or about 80 / 5, particularly measured1H-NMR spectroscopy. More particularly, the copolymer is a random or a block copolymer. In this embodiment, the lipo-polyamino acid conjugate has the formula (IB): wherein A, A1, X, X', R1, R / , R2, R3, R4, R5, n, m, p and s are as defined herein.

[0091] In another embodiment, optionally in combination with any of the embodiments provided above or below, the lipo-polyamino acid conjugate of formula (I) is a homopolymer comprising “n” PAA1 repetitive units of formula (II), i.e., wherein PAA2 repetitive units of formula (III) are absent. In this embodiment, the lipo-polyamino acid conjugate according has the formula (IA) wherein A, A1, X, X', R1, R / , R2, R3, n, and p and s are as defined herein. According to one embodiment, optionally in combination with any of the embodiments provided above or below, the lipo-polyamino acid conjugate of formula (I) has the formula (IA'): wherein A, Ai, X, X', Ri, R / , R2, R3, n, and p and s are as defined herein.

[0092] In the lipo-polyamino acid conjugate of formula (I), n and m are independently an integer from 5 to 250, particularly measured by1H-NMR spectroscopy.

[0093] In one embodiment, optionally in combination with any of the embodiments provided above or below, n is an integer from 5 to 150, more particularly from 5 to 100, even more particularly from 5 to 50, and even more particularly from 5 to 30 or from 5 to 25. In another embodiment, optionally in combination with any of the embodiments provided above or below, n is a value from 5 to 200, from 10 to 200, from 10 to 150, or from 10 to 100.

[0094] In another embodiment, optionally in combination with any of the embodiments provided above or below, m is an integer from 5 to 150, more particularly from 5 to 100, even more particularly from 5 to 50, and even more particularly from 5 to 30 or from 5 to 25. In another embodiment, optionally in combination with any of the embodiments provided above or below, n is a value from 5 to 200, from 5 to 80, from 10 to 80, from 5 to 70, from 10 to 70, from 5 to 60 or from 10 to 60.

[0095] In another embodiment, optionally in combination with any of the embodiments provided above or below, n and m are independently about 5, about 6, about 7, about 8, about 9, about 10, about 15, about 10, about 25, about 30, about 35, about 40, about 45, about 50, about 55, about 60, about 65, about 70, about 75, about 80, about 85, about 90, about 95, about 100, about 110, about 120, about 130, about 140, about 150, about 160, about 170, about 180, about 190, about 200, about 210, about 220, about 230, about 240, or about 250, particularly measured by1H-NMR spectroscopy.

[0096] In the lipo-polyamino acid conjugate of formula (I), X is selected from CH, N, S, and O. In one embodiment, optionally in combination with any of the embodiments provided above or below, X is N and R1 is H. In another embodiment, optionally in combination with any of the embodiments provided above or below, X is N and R1 is -(Ci-Cisjalkyl, more particularly -(Ci-Ci2)alkyl, even more particularly -(Ci-Cejalkyl. In another embodiment, optionally in combination with any of the embodiments provided above or below, X is N and R1 is -(C2-Ci8)alkenyl, more particularly -(C2-Ci2)alkenyl, even more particularly -(C2-C6)alkenyl. According to another embodiment, optionally in combination with any of the embodiments provided above or below, in the lipo-polyamino acid conjugate of formula (I), X is 0 and Ri is absent. In another embodiment, optionally in combination with any of the embodiments provided above or below, X is S and Ri is absent. In another embodiment, optionally in combination with any of the embodiments provided above or below, X is CH and Ri is H.

[0097] In the lipo-polyamino acid conjugate of formula (I), p and s are 0 or 1 depending on the meaning of Ai. In one embodiment, optionally in combination with any of the embodiments provided above or below, p is 0 and s is 0, and Ai is selected from the group consisting of H, -(Ci-Cejalkyl, -(Cs-C jaryl, -(Cs-Ciojheteroaryl, -(Ce-Ciojaralkyl, -(Ci-C6)alkyl-0-(C5-Cio)aryl, -(Cs-Ciojheterocycloalkyl, an amino protective group, a lipid-like moiety R , an amino acid-like moiety Rs, and an active moiety, wherein and Ai is as defined herein. In another embodiment, optionally in combination with any of the embodiments provided above or below, p is 1 and s is 0, and Ai is selected from the group consisting of H, -OH, -(Ci-Cejalkyl, -(Cs-C jaryl, -(Cs-Ciojheteroaryl, -(Ce-Ciojaralkyl, -(Ci-C6)alkyl-0-(C5-Cio)aryl, -(Cs-Ciojheterocycloalkyl, -(Ci-C jalkoxy, -(Ce-Cwjaryloxy, -(C6-Cio)aralkoxy, -(C5-Cio)heteroaralkoxy, -(Ci-Cio)alkyl-0-(C6-Cio)aryloxy, a lipid-like moiety R , and an active moiety, wherein and Ai is as defined herein. In another embodiment, optionally in combination with any of the embodiments provided above or below, p is 1 and s is 1, and Ai is selected from the group consisting of H, -(Ci-Cejalkyl, -(Cs-C jaryl, -(Cs-Ciojheteroaryl, -(Ce-Ciojaralkyl, -(Ci-C6)alkyl-0-(C5-Cio)aryl, -(Cs-Ciojheterocycloalkyl, -(Ci-Cio)alkoxy, -(Ce-Cwjaryloxy, -(Ce-Cwjaralkoxy, -(C5-Cio)heteroaralkoxy, -(Ci-Cio)alkyl-0-(C6-Cio)aryloxy, a lipid-like moiety R , and an active moiety, wherein and Ai is as defined herein.

[0098] In the lipo-polyamino acid conjugate of formula (I), when s is 1, X' is selected from N and 0. In one embodiment, optionally in combination with any of the embodiments provided above or below, s is 1, X' is N and Ri' is H. In another embodiment, optionally in combination with any of the embodiments provided above or below, s is 1, X' is N and R / is -(Ci-Cisjalkyl, more particularly -(Ci-Cejalkyl even more particularly -(Ci-Cejalkyl. In another embodiment, optionally in combination with any of the embodiments provided above or below, X' is N and R / is -(C2-Ci8)alkenyl, more particularly -(C2-Ci2)alkenyl, even more particularly -(C2-C6)alkenyl.

[0099] According to another embodiment, optionally in combination with any of the embodiments provided above or below, in the lipo-polyamino acid conjugate of formula (I), s is 1, X' is 0 and R / is absent.

[0100] In the lipo-polyamino acid conjugate of formula (I), R2 is a radical selected from the group consisting of (IV) and (V), wherein a and b are independently an integer from 0 to 3; and R is -(Ci-C6)alkyl.

[0101] In one embodiment, optionally in combination with any of the embodiments provided above or below, in the lipo-polyamino acid conjugate of formula (I), R2 is a radical of formula (IV) and a is 0. In another embodiment, optionally in combination with any of the embodiments provided above or below, in the lipo-polyamino acid conjugate of formula (I), R2 is a radical of formula (IV) and a is 1. In another embodiment, optionally in combination with any of the embodiments provided above or below, in the lipo-polyamino acid conjugate of formula (I), R2 is a radical of formula (IV) and a is 2. In another embodiment, optionally in combination with any of the embodiments provided above or below, in the lipo-polyamino acid conjugate of formula (I), R2 is a radical of formula (IV) and a is 3.

[0102] More particularly, the radical of formula (IV) is selected from the formulas (iv1)-(iv24): In another embodiment, optionally in combination with any of the embodiments provided above or below, in the lipo-polyamino acid conjugate of formula (I), R2 is a radical of formula (V) and b is 0. In another embodiment, optionally in combination with any of the embodiments provided above or below, in the lipo- polyamino acid conjugate of formula (I), R2 is a radical of formula (V) and b is 1. In another embodiment, optionally in combination with any of the embodiments provided above or below, in the lipo-polyamino acid conjugate of formula (I), R2 is a radical of formula (V) and b is 2. In another embodiment, optionally in combination with any of the embodiments provided above or below, in the lipo-polyamino acid conjugate of formula (I), R2 is a radical of formula (V) and b is 3.

[0103] (v21) (v22) (v24) In another embodiment, optionally in combination with any of the embodiments provided above or below, in the lipo-polyamino acid conjugate of formula (I), R2 is a radical of formula (VI) and c is 0. In another embodiment, optionally in combination with any of the embodiments provided above or below, in the lipo- polyamino acid conjugate of formula (I), R2 is a radical of formula (VI) and c is 1 . In another embodiment, optionally in combination with any of the embodiments provided above or below, in the lipo-polyamino acid conjugate of formula (I), R2 is a radical of formula (VI) and c is 2. In another embodiment, optionally in combination with any of the embodiments provided above or below, in the lipo-polyamino acid conjugate of formula (I), R2 is a radical of formula (VI) and c is 3.

[0104] More particularly, the radical of formula (VI) is selected from the formulas (vi1)-(vi72):

[0105]

[0106] (vi49) (vi50) (vi51) (vi52)

[0107] (vi69) (vi70) (vi71) (vi72)

[0108] In the lipo-polyamino acid conjugate of formula (I), R3 is H or -(Ci-Cejalkyl. In one embodiment, optionally in combination with any of the embodiments provided above or below, in the lipo-polyamino acid conjugate of formula (I), R3 is H. According to another embodiment, optionally in combination with any of the embodiments provided above or below, in the lipo-polyamino acid conjugate of formula (I), R3 is -(Ci-Cejalkyl, more particularly R3 is -CH3.

[0109] In the PAA2 repetitive units of formula (III), R4 is any amino acid side chain optionally functionalized with an active moiety. According to another embodiment, optionally in combination with any of the embodiments provided above or below, R4 is any amino acid side chain. For the purposes of the invention, the term "amino acid” refers to a molecule containing both an amino group and a carboxyl group attached through a carbon atom to which a side chain is attached.

[0110] Suitable amino acid side chains in R4 include, without limitation, the side chains of alpha amino acids, such as the L-isomers of alpha-amino acids of the 20 common naturally occurring alpha-amino acids: alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine; natural betaamino acids (e.g., beta-alanine); and unnatural amino acids.

[0111] The term "unnatural amino acid” comprises D-isomers of the 20 common naturally occurring alpha-amino acids as defined above or other amino acids as defined in Table A.

[0112] Table A

[0113] Further illustrative non-limitative examples of unnatural amino acids include 2-Aminoadipic acid (Aad), 3- Aminoadipic acid (bAad), beta-Alanine, beta-Aminopropionic acid (bAla), 2-Aminobutyric acid (Abu), 4- Aminobutyric acid, piperidinic acid (4Abu), 6-Aminocaproic acid (Acp), 2-Aminoheptanoic acid (Ahe), 2- Aminoisobutyric acid (Aib), 3-Aminoisobutyric acid (bAib), 2-Aminopimelic acid (Apm), 2,4 Diaminobutyric acid (Dbu), Desmosine (Des), 2,2’-Diaminopimelic acid (Dpm), 2,3-Diaminopropionic acid (Dpr), N-Ethylglycine (EtGly), N-Ethylasparagine (EtAsn), Hydroxylysine (Hyl), allo-Hydroxylysine (aHyl), 3-Hydroxyproline (3Hyp), 4-Hydroxyproline (4Hyp), Isodesmosine (Ide), allo-lsoleucine (alle), Norvaline (Nva), Norleucine (Nle), or Ornithine (Orn).

[0114] Each one of the amino acids forming the peptide of the invention can have, independently from the others, L- or D-configuration.

[0115] Amino acids used in the preparation of the peptides of the present invention may be prepared by organic synthesis, or obtained by other routes, such as, for example, degradation of or isolation from a natural source. According to one embodiment, optionally in combination with any of the embodiments provided above or below, R4 corresponds to the amino acid the side chains of phenylalanine, alanine, leucine, glycine, isoleucine, or valine, more particularly R4 corresponds to the amino acid the side chain of alanine.

[0116] In the PAA2 repetitive units of formula (III), R5 is H or -(Ci-Ce) alkyl. In one embodiment, optionally in combination with any of the embodiments provided above or below, R5 is H. According to another embodiment, optionally in combination with any of the embodiments provided above or below, R5 is -(Ci-C6)alkyl, more particularly R5 is -CH3.

[0117] In the lipo-polyamino acid conjugate of formula (I), A is selected from the group consisting of H, -(Ci-C6)alkyl, -CO(Ci-C6)alkyl, -(Ci-C6)alkyl-CO-N[(Ci-Ci8)alkyl]2, -(C5-Cio)aryl, -(C5-Cio)heteroaryl, -(Ce-

[0118] Cio)aralkyl, -(Ci-C6)alkyl-0-(C5-Cio)aryl, -(C5-Cio)heterocycloalkyl, a radical (IV), a radical (V), a radical (VI), a protective group, a lipid-like moiety R7, and an active moiety; and A1 is selected from the group consisting of H, -OH, -(Ci-Cejalkyl, -(Cs-Ciojaryl, -(Cs-Ciojheteroaryl, -(C6-Cio)aralkyl, -(Ci-C6)alkyl-0-(C5-Cio)aryl, -(C5-Cio)heterocycloalkyl, -(Ci-Cio)alkoxy, -(Ce-Cwjaryloxy, -(Ce-Cwjaralkoxy, -(C5-Cio)heteroaralkoxy, -(Ci-Cio)alkyl-0-(C6-Cio)aryloxy, an amino protective group, a lipid-like moiety R , an amino acid-like moiety Rs, and an active moiety; being A and A1 optionally substituted as defined herein; with the condition that:

[0119] I) when p is 0, s is 0, and A1 is selected from the group consisting of H, -(Ci-Cejalkyl, -(Cs-Ciojaryl, -(Cs-Ciojheteroaryl, -(C6-Cio)aralkyl, -(Ci-C6)alkyl-0-(C5-Cio)aryl, -(C5-Cio)heterocycloalkyl, an amino protective group, a lipid-like moiety R , an amino acid-like moiety Rs, and an active moiety; ii) when p is 1 and s is 0, A1 is selected from the group consisting of H, -OH, -(Ci-Cejalkyl, -(Cs-Ciojaryl, -(Cs-Ciojheteroaryl, -(C6-Cio)aralkyl, -(Ci-C6)alkyl-0-(C5-Cio)aryl, -(C5-Cio)heterocycloalkyl, -(C1-C10) alkoxy, -(C6-Cio)aryloxy, -(C6-Cio)aralkoxy, -(Cs-Ciojheteroaralkoxy, -(Ci-Cio)alkyl-0-(C6-Cio)aryloxy, a lipid-like moiety R , and an active moiety; ill) when p is 1 and s is 1 , A1 is selected from the group consisting of H, -(Ci-Cejalkyl, -(Cs-Cwjaryl, -(Cs-Ciojheteroaryl, -(C6-Cio)aralkyl, -(Ci-C6)alkyl-0-(C5-Cio)aryl, -(C5-Cio)heterocycloalkyl, -(C1-C10) alkoxy, -(C6-Cio)aryloxy, -(C6-Cio)aralkoxy, -(Cs-Ciojheteroaralkoxy, -(Ci-Cio)alkyl-0-(C6-Cio)aryloxy, a lipid-like moiety R , and an active moiety; and ii) at least one of A and A1 is a lipid-like moiety Rz or R ;

[0120] In accordance with one embodiment, optionally in combination with any of the embodiments provided above or below, in the lipo-polyamino acid conjugate of formula (I), one of A and A1 is a lipid-like moiety Rz or Rz' as defined herein, and the other one of A and A1 is other than a lipid-like moiety Rz or R , respectively.

[0121] In another embodiment, optionally in combination with any of the embodiments provided above or below, in the lipo-polyamino acid conjugate of formula (I), A is a lipid-like moiety Rz, and A1 is other than a lipid-like moiety R ; more particularly, A1 is selected from the group consisting of H, -OH, -(Ci-Cejalkyl, -(Cs-Ciojaryl, -(C5-Cio)heteroaryl, -(C6-Cio)aralkyl, -(Ci-C6)alkyl-0-(C5-Cio)aryl, -(C5-Cio)heterocycloalkyl, -(C1-C10) alkoxy, -(C6-Cio)aryloxy, -(C6-Cio)aralkoxy, -(C5-Cio)heteroaralkoxy, -(Ci-Cio)alkyl-0-(C6-Cio)aryloxy, an amino protective group, an amino acid-like moiety Rs, and an active moiety; being A and A1 optionally substituted as defined herein.

[0122] In another embodiment, optionally in combination with any of the embodiments provided above or below, in the lipo-polyamino acid conjugate of formula (I), A1 is a lipid-like moiety Rz', and A is other than a lipid-like moiety Rz; more particularly, A is selected from the group consisting of A is selected from the group consisting of H, -(Ci-Cejalkyl, -CO(Ci-C6)alkyl, -(Ci-C6)alkyl-CO-N[(Ci-Ci8)alkyl]2, -(C5-Cio)aryl, -(C5-Cio)heteroaryl, -(Ce- Cio)aralkyl,

[0123] -(Ci-C6)alkyl-0-(C5-Cio)aryl, -(C5-Cio)heterocycloalkyl, a radical (IV), a radical (V), a radical (VI), a protective group, and an active moiety; being A and A1 optionally substituted as defined herein.

[0124] The lipid-like moiety Rz in A in the lipo-polyamino acid conjugate of formula (I) is selected from the group consisting of -(Ci-C2o)alkyl, -(C2-C2o)alkenyl, and a radical of formula (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), or (XVIII).

[0125] In one embodiment, optionally in combination with any of the embodiments provided above or below, the lipid- like moiety Rz is -(Ci-C2o)alkyl, more particularly -(Ce-Cisjalkyl, and even more particularly -(Ci2-Cis)alkyl.

[0126] More particularly, the lipid-like moiety Rz has the formula (XXIII):

[0127] (XXIII) wherein k is an integer from 1 to 16, more particularly k is 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, or 16.

[0128] In another embodiment, optionally in combination with any of the embodiments provided above or below, the lipid-like moiety Rz is -(C2-C2o)alkenyl, more particularly -(Ce-Cisjalkenyl, and even more particularly -(Ci2-Cis)alkenyl. Even more particularly, the lipid-like moiety Rz has the formula (XXIV): wherein k is an integer from 1 to 16, more particularly k is 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, or 16, and q is an integer from 0 to 18, more particularly q is 0, 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, or 18. Even more particularly, the lipid-like moiety Rz has the formula (XXIV), wherein k is an integer from 10 to 16, and q is an integer from 0 to 18.

[0129] In another embodiment, optionally in combination with any of the embodiments provided above or below, the lipid-like moiety Rz has the formula (XXV): wherein p is an integer from 1 to 6, more particularly k is 1, 2, 3, 4, 5, 6.

[0130] In another embodiment, optionally in combination with any of the embodiments provided above or below, the lipid-like moiety Rz has the formula (XXVI): wherein k is an integer from 1 to 16, more particularly k is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16, and p is an integer from 1 to 6. More particularly, the lipid-like moiety R7 has the formula (XXVI) wherein k is an integer from 12 to 16, and p is an integer from 1 to 6.

[0131] In another embodiment, optionally in combination with any of the embodiments provided above or below, the lipid-like moiety Rz has the formula (IX), wherein g is an integer from 0 to 16, more particularly, g is from 0 to 12, and even more particularly g is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12; and each I is independently an integer from 0 to 18, more particularly, each I is independently from 0 to 12, and even more particularly, each I is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12. Even more particularly, the lipid-like moiety Rz has the formula (IX), wherein g is an integer from 10 to 16; and each I is independently an integer from 0 to 18.

[0132] In another embodiment, optionally in combination with any of the embodiments provided above or below, the lipid-like moiety Rz has the formula (X), wherein each g is independently an integer from 0 to 16, more particularly, each g is independently from 0 to 12, and even more particularly each g is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12, and I is an integer from 0 to 18, more particularly, I is from 0 to 12, and even more particularly, I is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12. Even more particularly, the lipid-like moiety Rz has the formula (X), wherein each is independently from 8 to 12; and I is from 0 to 12

[0133] In another embodiment, optionally in combination with any of the embodiments provided above or below, the lipid-like moiety Rz has the formula (XI), wherein I is an integer from 0 to 18, more particularly, I is from 0 to 12, and even more particularly, I is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12; Y and Y' are independently selected from -OH, -COORx, and -OCORx; and each Rx is independently -(Ci-Ci8)alkyl or -(C2-Ci8)alkenyl. More particularly, the lipid-like moiety Rz has the formula (XI), wherein I is an integer from 0 to 18; Y and Y' are independently selected from -OH, -COORx, and -OCORx; and each Rx is independently -(Cio-Ci8)alkyl or -(Cio-Ci8)alkenyl. Even more particularly, in the lipid- like moiety Rz of formula (XI), each Rx is a radical independently selected from formula (xia) and (xib):

[0134] (xia) (xib) wherein the wavy bonds mean that the stereochemistry of the double bonds is undefined (i.e. it includes cis and trans isomers), k is an integer from 1 to 16, more particularly k is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16; p and q are independently an integer from 0 to 18, more particularly p and q are independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18; and r is an integer from 0 to 6, more particularly r is 0, 1, 2, 3, 4, 5, or 6. Even more particularly, in the lipid-like moiety Rz of formula (XI), each Rx is a radical selected from formula (xia) and (xib) :

[0135] (xia) (xib) wherein the wavy bonds mean that the stereochemistry of the double bonds is undefined (i.e. it includes cis and trans isomers), k is an integer from 12 to 16, p is an integer from 12 to 18, q is an integer from 0 to 18; and r is an integer from 0 to 6.

[0136] In one particular embodiment, optionally in combination with any of the embodiments provided above or below, in the lipid-like moiety Rz of formula (XI), Y and Y' are the same. In another particular embodiment, optionally in combination with any of the embodiments provided above or below, in the lipid-like moiety R?of formula (IX), Y and Y' are different.

[0137] In another particular embodiment, optionally in combination with any of the embodiments provided above or below, the lipid-like moiety Rz of formula (XI) is selected from the formulas (xi1), (xi2), (xi3), (xi4), (xi5), (xi6), wherein each k is independently an integer from 1 to 16, more particularly each k is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16; I is an integer from 0 to 18, more particularly, I is from 0 to 12, and even more particularly, I Is O, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12; each p and each q are independently an integer from 0 to 18, more particularly each p and each q are independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18; and each r is independently an integer from 0 to 6, more particularly each r is independently 0, 1, 2, 3, 4, 5, or 6. More particularly, the lipid-like moiety Rz of formula (XI) is selected from the formulas (xi1), (xi2), (xi3), (xi4), (xi5), (xi6), (xi7) and (xi8), wherein each k is independently an integer from 12 to 16, 1 is an integer from 0 to 18, p is an integer from 12 to 18, q is an integer from 0 to 18, and r is an integer from 0 to 6.

[0138] According to a particular embodiment, optionally in combination with any of the embodiments provided above or below, in the lipid-like moiety Rz of formula (xi5), each k has the same meaning. According to another particular embodiment, optionally in combination with any of the embodiments provided above or below, in the lipid-like moiety Rz of formulas (xi6) and (xi7), each p has the same meaning, each r has the same meaning, and each q has the same meaning.

[0139] In another embodiment, optionally in combination with any of the embodiments provided above or below, the lipid-like moiety Rz has the formula (XII), wherein Q and Q' are independently selected from -OCORy and -COORy; each Ry is independently -(Ci-Ci8)alkyl or -(C2-Ci8)alkenyl; each h is independently an integer from 1 to 18, more particularly, each h is independently from 1 to 12, and even more particularly each h is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12; and I is an integer from 0 to 18, more particularly, I is from 0 to 12, and even more particularly, I Is O, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12. Even more particularly, the lipid-like moiety Rz has the formula (XII), wherein Q and Q' are independently selected from -OCORy and -COORy; each Ry is independently -(Cio-Ci8)alkyl or -(Cio-Ci8)alkenyl; each h is independently an integer from 1 to 18, and I is an integer from 0 to 18. Even more particularly, in the lipid-like moiety Rz of formula (X), each Ry is a radical independently selected from formula (xiia), (xiib), and (xiic):

[0140] (xiia) (xiib) (xiic) wherein the wavy bonds mean that the stereochemistry of the double bonds is undefined (i.e. it includes cis and trans isomers), k is an integer from 1 to 16, more particularly k is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16; p and q are independently an integer from 0 to 18, more particularly p and q are independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18; and r is an integer from 0 to 6, more particularly r is 0, 1, 2, 3, 4, 5, or 6. Even more particularly, in the lipid-like moiety Rz of formula (XII), each Ry is a radical independently selected from formula (xiia), (xiib), and (xiic), wherein the wavy bonds mean that the stereochemistry of the double bonds is undefined (i.e. it includes cis and trans isomers), k is an integer from 12 to 16, p is an integer from 12 to 18, q is an integer from 0 to 18, and r is an integer from 0 to 6.

[0141] In one particular embodiment, optionally in combination with any of the embodiments provided above or below, in the lipid-like moiety Rz of formula (XII), Q and Q' are both -OCORy. In another particular embodiment, optionally in combination with any of the embodiments provided above or below, in the lipid-like moiety Rz of formula (XII), Q and Q' are both -COORy.

[0142] In another particular embodiment, optionally in combination with any of the embodiments provided above or below, the lipid-like moiety Rz of formula (XII) is selected from the formulas (xii1), (xii2), (xii3), and (xii4): wherein k is an integer from 1 to 16, more particularly k is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16; each p and each q are independently an integer from 0 to 18, more particularly each p and each q are independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18; each h is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12; and i is an integer from 0 to 18, more particularly, i is from 0 to 12, and even more particularly, i is O, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12. Even more particularly, the lipid-like moiety Rzof formula (XII) is selected from the formulas (xii 1 ), (xii2), (xii3), and (xii4), wherein k is an integer from 12 to 16, each h is independently an integer from 1 to 18, i is an integer from 0 to 18, p is an integer from 12 to 18, q is an integer from 0 to 18, and r is an integer from 0 to 6.

[0143] In another embodiment, optionally in combination with any of the embodiments provided above or below, the lipid-like moiety Rz has the formula (XIII), wherein Q and Q' are independently selected from -OCORy and -COORy; each Ry is independently -(Ci-Cis)alkyl or -(C2-Cis)alkenyl; each h is independently an integer from 1 to 18, more particularly, each h is independently from 1 to 12, and even more particularly each h is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12; and i is an integer from 0 to 18, more particularly, i is from 0 to 12, and even more particularly, i is O, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12. Even more particularly, the lipid-like moiety Rz has the formula (XIII), wherein Q and Q' are independently selected from -OCORy and -COORy; each Ry is independently -(Cio-Ci8)alkyl or -(Cio-Ci8)alkenyl; each h is independently an integer from 1 to 18, and i is an integer from 0 to 18. Even more particularly, in the lipid-like moiety Rz of formula (XIII), each Ry is a radical independently selected from formula (xiiia), (xiiib), and (xiiic):

[0144] (xiiia) (xiiib) (xiiic) wherein the wavy bonds mean that the stereochemistry of the double bonds is undefined (i.e. it includes cis and trans isomers), k is an integer from 1 to 16, more particularly k is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16; p and q are independently an integer from 0 to 18, more particularly p and q are independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18; and r is an integer from 0 to 6, more particularly r is 0, 1, 2, 3, 4, 5, or 6. Even more particularly, in the lipid-like moiety Rz of formula (XIII), each Ry is a radical independently selected from formula (xiiia), (xiiib), and (xiiic), wherein the wavy bonds mean that the stereochemistry of the double bonds is undefined (i.e. it includes cis and trans isomers), k is an integer from 12 to 16, p is an integer from 12 to 18, q is an integer from 0 to 18, and r is an integer from 0 to 6.

[0145] In one particular embodiment, optionally in combination with any of the embodiments provided above or below, in the lipid-like moiety Rz of formula (XIII), Q and Q' are both -OCORy. In another particular embodiment, optionally in combination with any of the embodiments provided above or below, in the lipid-like moiety Rz of formula (XIII), Q and Q' are both -COORy.

[0146] In another particular embodiment, optionally in combination with any of the embodiments provided above or below, the lipid-like moiety Rz of formula (XIII) has the formula (xiiil):

[0147] (xiiil) wherein each p and each q are independently an integer from 0 to 18, more particularly each p and each q are independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18; r is an integer from 0 to 6, more particularly each r is independently 0, 1, 2, 3, 4, 5, or 6; each h is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12; and i is an integer from 0 to 18, more particularly, i is from 0 to 12, and even more particularly, i is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12. Even more particularly, the lipid-like moiety Rz of formula (XIII) is has the formula (xiiil), each h is independently an integer from 1 to 18, i is an integer from 0 to 18, p is an integer from 12 to 18, q is an integer from 0 to 18, and r is an integer from 0 to 6.

[0148] In another embodiment, optionally in combination with any of the embodiments provided above or below, the lipid-like moiety Rz has the formula (XIV), wherein i is an integer from 0 to 18, more particularly, i is from 0 to 12, and even more particularly, i is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12; and each j is independently an integer from 0 to 18, more particularly, each j is independently selected from 0 to 12, and even more particularly each j is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12. More particularly, the lipid-like moiety Rz has the formula (XIV), wherein i is an integer from 0 to 18, and each j is independently an integer from 10 to 18.

[0149] In another embodiment, optionally in combination with any of the embodiments provided above or below, the lipid-like moiety Rz has the formula (XV), wherein i is an integer from 0 to 18; more particularly, i is from 0 to 12, and even more particularly i is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12; and each j is independently an integer from 0 to 18, more particularly, each j is independently selected from 0 to 12, and even more particularly each j is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12. More particularly, the lipid-like moiety Rz has the formula (XV), wherein i is an integer from 0 to 18, and each j is independently an integer from 10 to 18.

[0150] In another embodiment, optionally in combination with any of the embodiments provided above or below, the lipid-like moiety Rz has the formula (XVI), wherein Q and Q' are independently selected from -OCORy and -COORy; Z is selected from -O-, -OCO-, -COO-, -NRz'CO-, and -CONRz'-; each Rz' is H or Rz; each Ry and Rz is independently -(Ci-Cis)alkyl or -(C2-Cis)alkenyl; and i is an integer from 0 to 18, more particularly, i is from 0 to 12, and even more particularly i is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12. More particularly, the lipid-like moiety Rz has the formula (XVI), wherein Q and Q' are independently selected from -OCORy and -COORy; Z is selected from -O-, -OCO-, -COO-, -NRz'CO-, and -CONRz'-; each Rz' is H or Rz; each Ry is independently -(Cio-Ci8)alkyl or -(Cio-Ci8)alkenyl; each Rz is independently -(Ci-Ci8)alkyl or -(C2-Ci8)alkenyl, and i is an integer from 0 to 18. Even more particularly, in the lipid-like moiety Rz of formula (XVI), each Ry is a radical independently selected from formula (xvia) and (xvib):

[0151] (xvia) (xvib) wherein the wavy bonds mean that the stereochemistry of the double bonds is undefined (i.e. it includes cis and trans isomers), k is an integer from 1 to 16, more particularly k is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16; p and q are independently an integer from 0 to 18, more particularly p and q are independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18; and r is an integer from 0 to 6, more particularly r is 0, 1, 2, 3, 4, 5, or 6. Even more particularly, in the lipid-like moiety Rz of formula (XVI), each Ry is a radical independently selected from formula (xvia) and (xvib), wherein the wavy bonds mean that the stereochemistry of the double bonds is undefined (i.e. it includes cis and trans isomers), k is an integer from 12 to 16, p is an integer from 12 to 18, q is an integer from 0 to 18, and r is an integer from 0 to 6. In one particular embodiment, optionally in combination with any of the embodiments provided above or below, in the lipid-like moiety Rz of formula (XVI), Q and Q' are both -OCORy. In another particular embodiment, optionally in combination with any of the embodiments provided above or below, in the lipid-like moiety Rz of formula (XVI), Q and Q' are both -COORy. . In another particular embodiment, optionally in combination with any of the embodiments provided above or below, in the lipid-like moiety Rz of formula (XVI), Z is -O-. In another particular embodiment, optionally in combination with any of the embodiments provided above or below, in the lipid-like moiety Rz of formula (XVI), Z is -OCO-. In another particular embodiment, optionally in combination with any of the embodiments provided above or below, in the lipid-like moiety Rzof formula (XVI), Z is -CONRz’.

[0152] In another particular embodiment, optionally in combination with any of the embodiments provided above or below, the lipid-like moiety Rz of formula (XVI) is selected from the formulas (xvi1), (xvi2), (xvi3), and (xvi4):

[0153] (xvi3)(xvi4)wherein each k is independently an integer from 1 to 16, more particularly each k is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16; and i is an integer from 0 to 18, more particularly, i is from 0 to 12, and even more particularly, i is O, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12. Even more particularly, the lipid-like moiety Rz of formula (XVI) is selected from the formulas (xvi1), (xvi2), (xvi3), and (xvi4), wherein each k is an integer from 12 to 16, and i is an integer from 0 to 18.

[0154] In another embodiment, optionally in combination with any of the embodiments provided above or below, the lipid-like moiety Rz has the formula (XVII), wherein I is an integer from 0 to 18, more particularly, i is from 0 to 12, and even more particularly, i is 0, 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , or 12; and each j is independently an integer from 0 to 18, more particularly, each j is independently selected from 0 to 12, and even more particularly each j is independently 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , or 12. More particularly, the lipid-like moiety Rz has the formula (XVII), wherein i is an integer from 0 to 18, and each j is independently an integer from 10 to 18.

[0155] In one particular embodiment, optionally in combination with any of the embodiments provided above or below, the lipid-like moiety Rz of formula (XVII) has the formula (xviil):

[0156] (xviil) wherein i is an integer from 0 to 18, more particularly, i is from 0 to 12, and even more particularly, i is 0, 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , or 12.

[0157] In another embodiment, optionally in combination with any of the embodiments provided above or below, the lipid-like moiety Rz has the formula (XVIII),

[0158] (XVIII) wherein t, R22, R33, R44, the dashed bonds — , and L are as defined herein.

[0159] In a more particular embodiment, in the radical of the formula (XVIII), each of the dashed bonds of the alkyl chain attached to the chroman ring is a single bond, and R22, R33 and R44 are selected from the following meanings: (i) R22, R33 and R44 are methyl, (ii) R22, R44 are methyl and R33 is hydrogen, (iii) R33 and R44 are methyl and R22 is hydrogen, and (iv) R44 is methyl and R22 and R33 are hydrogen. Even more particularly, each of the dashed bonds of the alkyl chain attached to the chroman ring is a single bond and R22, R33 and R44 are methyl. Even more particularly, the formula (XVIII) has the formula (xviiil):

[0160] (xviiil) wherein t, the dashed bonds — , and L are as defined herein.

[0161] In another more particular embodiment, in the radical of the formula (XVIII), each of the dashed bonds of the alkyl chain attached to the chroman ring is a double bond, and R22, R33 and R44 are selected from the following meanings: (I) R22, R33 and R44 are methyl, (II) R22, R44 are methyl and R33 is hydrogen, (ill) R33 and R44 are methyl and R22 is hydrogen, and (iv) R44 is methyl and R22 and R33 are hydrogen. In a more particular embodiment, each of the dashed bonds of the alkyl chain attached to the chroman ring is a double bond and R22, R33 and R44 are methyl.

[0162] According to a particular embodiment, optionally in combination with any of the embodiments provided above or below, in the radical of formula (XVIII) the linker L is a biradical selected from the group consisting of -(Ci-Ci2)alkylene- optionally substituted with one or more substituents selected from the group consisting of halogen, -OH, -NRaaRbb, -SH, -NHNH2, -OOORCc, -CF3, and -OCF3, wherein Raa, Rbb and Rccare radicals independently selected from the group consisting of H, -phenyl, -(Ci-C6)alkyl, -(C2-C6)alkenyl, -(Ci-Cejalkylphenyl, and -phenyl(Ci-Ce)alkyl; -(Ci-Ce)alkyl-CO-; -CO-(Ci-Ce)alkyl-; and a biradical of formula (HID), (IVD), (VD), (VID), (VIID), (VIIID), (IXD), (XD), (XID) (XIID) (XIIID), (XIVD), (XVD), (XVID), (XVIID),

[0163] (XVIIID) or (XIXD),

[0164]

[0165] (XVI ID)

[0166] (XVI D) wherein the “*” denote the attaching points of the biradical L to X or the oxygen atom of the vitamin E-based moiety, "*3” denotes the attaching point of the biradical L to X, and "*4” denotes the attaching point of the biradical to the oxygen atom of the vitamin E-based moiety, a1 , d , d1 , e1 , f1 , hi, j1, and k1 are independently an integer from 0 to 10, particularly from 0 to 6; b1 and g1 are independently an integer from 0 to 1 ; with the condition that when b1 is 0, then at least one of a1 or d is other than 0, and when g1 is 0, then at least one of f1 or hi is other than 0; xr is -O- or -NH-; p1 Is O or 1 ; each of the dashed bonds — is independently a single bond or, alternatively, a double bond.

[0167] When drawn, the attachments points are indicated herein with an As long as the specific attachment is not specified, it means that the linker may be attached to the rest of the molecule interchangeably in any direction.

[0168] In one embodiment, optionally in combination with one or more features of the various embodiments described above or below, in the radical of formula (XVIII), L is a -(Ci-Ci2)alkylene-, more particularly a -(Ci-C6)alkyl-, and is optionally substituted as defined herein.

[0169] In another embodiment, optionally in combination with one or more features of the various embodiments described above or below, in the radical of formula (XVIII), L is -(Ci-Ce)alkyl-CO- or -CO-(Ci-Ce)alkyl- and is optionally substituted as defined herein.

[0170] In another embodiment, optionally in combination with one or more features of the various embodiments described above or below, in the radical of formula (XVIII), L is a biradical of formula (HID), more particularly a biradical of formula (HID) wherein b1 Is O, and a1 + c1 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 (HID) selected from the group consisting of formula (IIIDa), formula (IIIDb), and formula (lllDc):

[0171] In another embodiment, optionally in combination with one or more features of the various embodiments described above or below, in the radical of formula (XVIII), L is a biradical selected from the formulas (IVD), (VD), and (VID), more particularly, in the biradical of formula (IVD), a1 is 1 and the dashed bond is a double bond, i.e., the biradical of formula (IVD) has the formula (IVDa), and in the biradical of formula (VD), the dashed bond is more particularly a double bond, i.e., the biradical of formula (VD) has the formula (VDa).

[0172] (IVDa) (VDa)

[0173] In another embodiment, optionally in combination with one or more features of the various embodiments described above or below, in the radical of formula (XVIII), L is a biradical selected from the formulas (VID), (VIID), and (VIIID), more particularly, in the biradical of formula (VIIID), a1 is 1.

[0174] In another embodiment, optionally in combination with one or more features of the various embodiments described above or below, in the radical of formula (XVIII), L is a biradical of formula (IXD), more particularly a biradical of formula (IXD) wherein b1 and g1 are 0; and a1, d, d1, e1, f1 and hi are 1, i.e., a biradical of formula (IXDa).

[0175] In another embodiment, optionally in combination with one or more features of the various embodiments described above or below, in the radical of formula (XVIII), L is a biradical selected from the formulas (XD) and (XID), more particularly in the biradicals of formula (XD) and (XID), b1 and g1 are 0; and a1, d, d1, e1, f1 and hi are 1, i.e. the biradicals of formula (XD), and (XID) have the formulas (XDa), and (XIDa), respectively.

[0176] (XI Da)

[0177] In another embodiment, optionally in combination with one or more features of the various embodiments described above or below, in the radical of formula (XVIII), L is a biradical selected from the formulas (XIID) and (XIIID), more particularly in the biradicals of formula (XIID) and (XIIID), b1 is O; and a1, d and d1 are 1.

[0178] In another embodiment, optionally in combination with one or more features of the various embodiments described above or below, in the radical of formula (XVIII), L is a biradical selected from the formulas (XIVD), (XVD), (XVID), (XVIID), and (XVIIID), more particularly in the biradicals of formula (XIVD), (XVD), (XVID), (XVIID), and (XVIIID), b1 Is O; and a1, and d are 1.

[0179] In another embodiment, optionally in combination with one or more features of the various embodiments described above or below, in the radical of formula (XVIII), L is a biradical of formula (XIXD), wherein p1 is 0, and j1 and k1 are 1. In another embodiment, optionally in combination with one or more features of the various embodiments described above or below, in the radical of formula (XVIII), L is a biradical of formula (XIXD), wherein p1 is 1, X1' is -NH-, and j1 and k1 are 1. In another embodiment, optionally in combination with one or more features of the various embodiments described above or below, in the radical of formula (XVIII), L is a biradical selected of formula (XIXD), wherein p1 is 1, X1' is -O-, and j1 and k1 are 1.

[0180] In another embodiment, optionally in combination with any of the embodiments provided above or below, A is a lipid-like moiety Rz which has the formula (XVIII), t is 0, X is 0 and Ri is absent, i.e., the lipo-polyamino acid conjugate of formula (I) has the formula (Ih): wherein Ai, PAAi, PAA2, n, m, p, R22, R33, R44, and the dashed bonds — are as defined herein. In another embodiment, optionally in combination with any of the embodiments provided above or below, A is a lipid-like moiety Rz which has the formula (XVIII), wherein t is 1 , i.e., the lipo-polyamino acid conjugate of formula (I) has the formula (Ij): wherein Ai, PAAi, PAA2, X, R1, L, n, m, p, R22, R33, R44, and the dashed bonds — are as defined herein.

[0181] In another embodiment, optionally in combination with any of the embodiments provided above or below, in the lipo-polyamino acid conjugate of formula (I) has the formula (Ij) L is -CO-(Ci-C6)alkyl, X is N and R1 is H.

[0182] In another embodiment, optionally in combination with any of the embodiments provided above or below, in the lipo-polyamino acid conjugate of formula (I) has the formula (Ij) L is a biradical of formula (HID).

[0183] According to one embodiment, optionally in combination with any of the embodiments provided above or below, in the lipo-polyamino acid conjugate of formula (I) A is a lipid-like moiety Rz selected from the group consisting of: a) -(Ci-Ci8)alkyl, more particularly -(Ce-C jalkyl, and even more particularly, a radical of the formula (XXIII) as previously defined; b) -(C2-Ci8)alkenyl, more particularly -(Ce-C jalkenyl, and even more particularly, a radical of the formula (XXIV) as previously defined; c) a radical of formula (XXV) as defined herein; d) a radical of formula (XXVI) as defined herein; e) a radical of formula (IX) as defined herein; f) a radical of formula (X) as defined herein; g) a radical of formula (XI) as defined herein, more particularly, a radical selected from the formulas (xi1), (xi2), (xi3), (xi4), (xi5), (xi6), (xi7) and (xi8) as previously defined; h) a radical of formula (XII) as defined herein, more particularly, a radical selected from the formulas (xii1), (xii2), (xii3), and (xii4) as previously defined; i) a radical of formula (XIII) as defined herein, more particularly, a radical of the formula (xiiil) as previously defined; j) a radical of formula (XIV) as defined herein; k) a radical of formula (XV) as defined herein; l) a radical of formula (XVI) as defined herein, more particularly, a radical selected from the formulas (xvi1), (xvi2), (xvi3), and (xvi4) as previously defined; m) a radical of formula (XVII) as defined herein, more particularly, a radical of the formula (xvlH) as previously defined; n) a radical of formula (XVIII) as defined herein, more particularly, a radical of the formula (xvilH) as previously defined.

[0184] In another embodiment, optionally in combination with any of the embodiments provided above or below, in the lipo-polyamino acid conjugate of formula (I) A and Ri are the same and are -(Ci-Ci8)alkyl, and X is N. More particularly, in this embodiment, the lipo-polyamino acid conjugate of formula (I) has the formula (IC), wherein Ai, PAAi, PAA2, m, n, and p are as defined herein, and each k is independently an integer from 1 to 16, more particularly each k is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16. Even more particularly, each k is independently an integer from 12 to 16. Even more particularly, in the lipo-polyamino acid conjugate of formula (IC), each k has the same meaning.

[0185] In accordance with one embodiment, optionally in combination with any of the embodiments provided above or below, in the lipo-polyamino acid conjugate of formula (I), A is a lipid-like moiety Rz as defined herein, p is 0, and A1 is H.

[0186] In accordance with another embodiment, optionally in combination with any of the embodiments provided above or below, in the lipo-polyamino acid conjugate of formula (I), A is a lipid-like moiety Rz as defined herein, p is 0, and A1 is an amino protective group. Suitable amino protective groups known in the art may be used without limitation. Non-limiting examples of amino protective groups include acyl-based groups, carbamate-based groups, imide-based groups, sulfonamide-based groups, and the like. In a particular embodiment, the amino protective group is selected from the group consisting of acetyl, methyloxycarbonyl, benzyloxycarbonyl (Cbz), p-methoxybenzyloxycarbonyl, t-butyloxycarbonyl (Boc), 9-fluorenyl methyloxycarbonyl (Fmoc), allyloxycarbonyl (Alloc), 2,2,2-trichloroethoxycarbonyl group (Troc), benzoyl (Bz), benzyl (Bn), p-methoxybenzyl (PMB), 3,4-dimethoxybenzyl (DMPM), p-methoxyphenyl (PMP), tosyl (Ts), trimethylsilylethoxycarbonyl (Teoc), benzhydryl, triphenylmethyl (Trityl), (4-methoxyphenyl)diphenylmethyl (MMT), dimethoxytrityl (DMT), and diphenylphosphino, and even more particularly the amino protective group is acetyl.

[0187] Introduction and removal of amino protective groups can be carried out by standard methods such as the ones described in T. W. Green and P.G. M. Wuts, Protective Groups in Organic Chemistry, Wiley, 3rd ed. 1999, Chapter / (pp. 495-653). In accordance with another embodiment, optionally in combination with any of the embodiments provided above or below, in the lipo-polyamino acid conjugate of formula (I), A is a lipid-like moiety Rz as defined herein, p is 0, and Ai is an amino acid-like moiety Rs, being Rs a radical independently selected from the group consisting of (XX), (XXI) and (XXII)

[0188] (XX) (XXI) (XXII) wherein each a', each b', and each c' are independently an integer from 0 to 3, each Rg is independently -(Ci-Cejalkyl, and Rw is selected from the group consisting of -(Ci-Cejalkyl-SOs- and -(Ci-Cejalkyl-COg-; and

[0189] In another more particular embodiment, in the lipo-polyamino acid conjugate of formula (I), A is a lipid-like moiety Rz as defined herein, p is 0, and Ai is selected from the group consisting of H, -(Ci-Cejalkyl, -(C5-Cio)aryl, -(C5-Cio)heteroaryl, -(Cs-C jaralkyl, -(Ci-C6)alkyl-0-(C5-Cio)aryl, and -(C5-Cio)heterocycloalkyl; being Ai optionally substituted as defined herein, more particularly Ai is methyl.

[0190] In another more particular embodiment, in the lipo-polyamino acid conjugate of formula (I) A is a lipid-like moiety Rz as defined herein, p is 1 , Ai is selected from the group consisting of H, -OH, -(Ci-Cejalkyl, -(C5-Cio)aryl, -(C5-Cio)heteroaryl, -(Ce-C jaralkyl, -(Ci-C6)alkyl-0-(C5-Cio)aryl, -(C5-Cio)heterocycloalkyl, -(C1-C10) alkoxy, -(Ce-Cwjaryloxy, -(Ce-Cwjaralkoxy, -(C5-Cio)heteroaralkoxy, -(Ci-Cio)alkyl-0-(C6-Cio)aryloxy; being Ai optionally substituted as defined herein, more particularly Ai is 0, and Ai is -(Ci-Cejalkyl, even more particularly Ai is methyl.

[0191] In accordance with another embodiment, optionally in combination with any of the embodiments provided above or below, in the lipo-polyamino acid conjugate of formula (I), p is 1 , A is a lipid-like moiety Rz and Ai is a lipid-like moiety Rz' as defined herein.

[0192] In accordance with another embodiment, optionally in combination with any of the embodiments provided above or below, in the lipo-polyamino acid conjugate of formula (I), p is 0, A is a lipid-like moiety Rz and Ai is a lipid-like moiety Rz' as defined herein. In another embodiment, optionally in combination with any of the embodiments provided above or below, in the lipo-polyamino acid conjugate of formula (I), A is a lipid-like moiety Rz as defined herein, p is 1 , and Ai is an active moiety selected from the group consisting of a pharmaceutically active agent, a cell-targeting agent, a penetration enhancing agent, a cosmetically active agent, and a diagnostically active agent.

[0193] The active moiety in Ai may be directly bound to the nitrogen atom of the lipo-polyamino acid conjugate or, alternatively, it may be bound through a linker. There is no limitation in the nature of the linker provided that it can be attached to the rest of the molecule by chemically feasible bonds. For example, the linker may be a a biradical chain which comprises 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)-, -C00-, -C(=CH2)-, -C(=NH)-, -CONH-, -NHCO-, -NH(CO)NH-, -S-, -S-S-, -SO-, -S02-, -SO2NH2-, -phenylene-, and the like. The linker may contain from 1-50 moieties, more particularly from 2 to 30 or from 2 to 20 or from 2 to 15 moieties as defined above, and may be attached to the nitrogen atom of the PAA by a chemically feasible bond which is selected from the group consisting of an amine bond, an amide bond, a carbamate bond or a urea bond.

[0194] The lipid-like moiety Rz' in Ai in the lipo-polyamino acid conjugate of formula (I) is selected from the group consisting of -(Ci-C2o)alkyl, -(C2-C2o)alkenyl, and a radical of formula (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), or (XVIII’).

[0195] In one embodiment, optionally in combination with any of the embodiments provided above or below, the lipid- like moiety Rz' is -(Ci-C2o)alkyl, more particularly -(Ce-C jalkyl. More particularly, the lipid-like moiety Rz' has the formula (XXIII) as defined herein.

[0196] In another embodiment, optionally in combination with any of the embodiments provided above or below, the lipid-like moiety Rz' is -(C2-C2o)alkenyl, more particularly -(Ce-Cisjalkenyl. Even more particularly, the lipid-like moiety Rz' has the formula (XXIV) as defined herein.

[0197] In another embodiment, optionally in combination with any of the embodiments provided above or below, the lipid-like moiety Rz' has the formula (XXV) as defined herein.

[0198] In another embodiment, optionally in combination with any of the embodiments provided above or below, the lipid-like moiety Rz' has the formula (XXVI) as defined herein.

[0199] In another embodiment, optionally in combination with any of the embodiments provided above or below, the lipid-like moiety Rz' has the formula (IX) as defined herein.

[0200] In another embodiment, optionally in combination with any of the embodiments provided above or below, the lipid-like moiety Rz' has the formula (X) as defined herein. In another embodiment, optionally in combination with any of the embodiments provided above or below, the lipid-like moiety R has the formula (XI) as defined herein.

[0201] In one particular embodiment, optionally in combination with any of the embodiments provided above or below, in the lipid-like moiety R of formula (XI), Y and Y' are the same. In another particular embodiment, optionally in combination with any of the embodiments provided above or below, in the lipid-like moiety R of formula (XI), Y and Y' are different.

[0202] In another particular embodiment, optionally in combination with any of the embodiments provided above or below, the lipid-like moiety R of formula (XI) is selected from the formulas (xi 1 ), (xi2), (xi3), (xi4), (xi5), (xi6), (xi7) and (xi8) as defined herein. According to a particular embodiment, optionally in combination with any of the embodiments provided above or below, in the lipid-like moiety R of formula (xi5'), each k has the same meaning. According to another particular embodiment, optionally in combination with any of the embodiments provided above or below, in the lipid-like moiety R of formulas (xi6') and (xi7'), each p has the same meaning, each r has the same meaning, and each q has the same meaning.

[0203] In one embodiment, optionally in combination with any of the embodiments provided above or below, the lipid- like moiety R has the formula (XII) as defined herein.

[0204] In one particular embodiment, optionally in combination with any of the embodiments provided above or below, in the lipid-like moiety R of formula (XII), Q and Q' are both -OCORy. In another particular embodiment, optionally in combination with any of the embodiments provided above or below, in the lipid-like moiety R of formula (XII), Q and Q' are both -COORy.

[0205] In another particular embodiment, optionally in combination with any of the embodiments provided above or below, the lipid-like moiety R of formula (XII) is selected from the formulas (xii1), (xii2), (xii3), and (xii4) as defined herein.

[0206] In one embodiment, optionally in combination with any of the embodiments provided above or below, the lipid- like moiety R has the formula (XIII) as defined herein. In one particular embodiment, optionally in combination with any of the embodiments provided above or below, in the lipid-like moiety R of formula (XIII), Q and Q' are both -OCORy. In another particular embodiment, optionally in combination with any of the embodiments provided above or below, in the lipid-like moiety R of formula (XIII), Q and Q' are both -COORy. In another particular embodiment, optionally in combination with any of the embodiments provided above or below, the lipid-like moiety R of formula (XIII) has the formula (xiiil) as defined herein.

[0207] In one embodiment, optionally in combination with any of the embodiments provided above or below, the lipid- like moiety R has the formula (XIV) as defined herein. In one embodiment, optionally in combination with any of the embodiments provided above or below, the lipid- like moiety R has the formula (XV) as defined herein.

[0208] In another embodiment, optionally in combination with any of the embodiments provided above or below, the lipid-like moiety R has the formula (XVI) as defined herein.

[0209] In one particular embodiment, optionally in combination with any of the embodiments provided above or below, in the lipid-like moiety R of formula (XVI), Q and Q' are both -OCORy. In another particular embodiment, optionally in combination with any of the embodiments provided above or below, in the lipid-like moiety R of formula (XVI), Q and Q' are both -COORy. In another particular embodiment, optionally in combination with any of the embodiments provided above or below, in the lipid-like moiety R of formula (XVI), Z' is -O-. In another particular embodiment, optionally in combination with any of the embodiments provided above or below, in the lipid-like moiety R of formula (XVI), Z' is -OCO-. In another particular embodiment, optionally in combination with any of the embodiments provided above or below, in the lipid-like moiety R of formula (XVI), Z' is -CONRz'. In another particular embodiment, optionally in combination with any of the embodiments provided above or below, the lipid-like moiety R of formula (XVI) is selected from the formulas (xvi1), (xvi2), (xvi3), and (xvi4) as defined herein.

[0210] In another embodiment, optionally in combination with any of the embodiments provided above or below, the lipid-like moiety R has the formula (XVII) as defined herein. In one particular embodiment, optionally in combination with any of the embodiments provided above or below, the lipid-like moiety R of formula (XVII) has the formula (xviil) as defined herein.

[0211] In another embodiment, optionally in combination with any of the embodiments provided above or below, the lipid-like moiety R has the formula (XVIII'), wherein t', R22, R33, R44, the dashed bonds — , and L are as defined herein.

[0212] In a more particular embodiment, in the radical of the formula (XVII'), each of the dashed bonds of the alkyl chain attached to the chroman ring is a single bond, and R22, R33 and R44 are selected from the following meanings: (i) R22, R33 and R44 are methyl, (ii) R22, R44 are methyl and R33 is hydrogen, (iii) R33 and R44 are methyl and R22 is hydrogen, and (iv) R44 is methyl and R22 and R33 are hydrogen. Even more particularly, each of the dashed bonds of the alkyl chain attached to the chroman ring is a single bond and R22, R33 and R44 are methyl. Even more particularly, the formula (XVIII') has the formula (xviiil '): wherein t', the dashed bonds — , and L are as defined herein.

[0213] In another more particular embodiment, in the radical of the formula (XVI 11'), each of the dashed bonds of the alkyl chain attached to the chroman ring is a double bond, and R22, R33 and R44 are selected from the following meanings: (I) R22, R33 and R44 are methyl, (II) R22, R44 are methyl and R33 is hydrogen, (ill) R33 and R44 are methyl and R22 is hydrogen, and (iv) R44 is methyl and R22 and R33 are hydrogen. In a more particular embodiment, each of the dashed bonds of the alkyl chain attached to the chroman ring is a double bond and R22, R33 and R44 are methyl.

[0214] According to a particular embodiment, optionally in combination with any of the embodiments provided above or below, in the radical of formula (XVIII'), the linker L is a biradical selected from the group consisting of -(Ci-Ci2)alkylene- optionally substituted with one or more substituents selected from the group consisting of halogen, -OH, -NRaaRbb, -SH, -NHNH2, -OOORCc, -CF3, and -OCF3, wherein Raa, Rbb and Rccare radicals independently selected from the group consisting of H, -phenyl, -(Ci-C6)alkyl, -(C2-C6)alkenyl, -(Ci-Cejalkylphenyl, and -phenyl(Ci-C6)alkyl; -(Ci-C6)alkyl-CO-; and a biradical of formula (HID), (IVD), (VD), (VID), (VIID), (VIIID), (IXD), (XD), (XID), (XIID) (XIIID), (XIVD), (XVD), (XVID), (XVIID), (XVIIID), or (XIXD) as defined herein.

[0215] In one embodiment, optionally in combination with one or more features of the various embodiments described above or below, in the radical of formula (XVIII'), L is a -(Ci-Ci2)alkylene-, more particularly a -(Ci-Cejalkyl-, and is optionally substituted as defined herein.

[0216] In another embodiment, optionally in combination with one or more features of the various embodiments described above or below, in the radical of formula (XVIII'), L is -(Ci-Ce)alkyl-CO- or -(Ci-Ce)alkyl- and is optionally substituted as defined herein.

[0217] In another embodiment, optionally in combination with one or more features of the various embodiments described above or below, in the radical of formula (XVIII'), L is a biradical of formula (HID), L is a biradical of formula (HID), more particularly a biradical of formula (HID) wherein b1 is 0, and a1 + c1 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 (HID) selected from the group consisting of formula (IIIDa), formula (IIIDb), and formula (IHDc): In another embodiment, optionally in combination with one or more features of the various embodiments described above or below, in the radical of formula (XVIII'), L is a biradical selected from the formulas formulas (IVD), (VD), and (VID), more particularly, in the biradical of formula (IVD), a1 is 1 and the dashed bond is a double bond, i.e., the biradical of formula (IVD) has the formula (IVDa), and in the biradical of formula (VD), the dashed bond is more particularly a double bond, i.e., the biradical of formula (VD) has the formula (VDa) as defined herein.

[0218] In another embodiment, optionally in combination with one or more features of the various embodiments described above or below, in the radical of formula (XVIII'), L is a biradical selected from the formulas (VID), (VIID), and (VIIID) as defined herein, more particularly, in the biradical of formula (VIIID), a1 is 1.

[0219] In another embodiment, optionally in combination with one or more features of the various embodiments described above or below, in the radical of formula (XIX), L is a biradical of formula (IXD), more particularly a biradical of formula (IXD) wherein b1 and g1 are 0; a1, d, d1, e1, f1 and hi are 1, i.e. a biradical of formula (IXDa) as defined herein.

[0220] In another embodiment, optionally in combination with one or more features of the various embodiments described above or below, in the radical of formula (XVIII'), L is a biradical selected from the formulas (XD') and (XID'), more particularly in the biradicals of formula (XD) and (XID), b1 and g1 are 0; and a1, d, d1, e1, f1 and hi are 1, i.e. the biradicals of formula (XD), and (XID) have the formulas (XDa), and (XIDa), respectively, as defined herein.

[0221] In another embodiment, optionally in combination with one or more features of the various embodiments described above or below, in the radical of formula (XVIII'), L is a biradical selected from the formulas (XIID) and (XIIID), more particularly in the biradicals of formula (XIID) and (XIIID) as defined herein, b1 is 0; a1, d and d1 are 1.

[0222] In another embodiment, optionally in combination with one or more features of the various embodiments described above or below, in the radical of formula (XVIII'), L is a biradical selected from the formulas (XIVD), (XVD), (XVID), (XVIID), and (XVIIID), as defined herein, more particularly in the biradicals of formula (XIVD), (XVD), (XVID), (XVIID), and (XVIIID), b1 is O; and a1, and d are 1.

[0223] In another embodiment, optionally in combination with one or more features of the various embodiments described above or below, in the radical of formula (XVIII'), L is a biradical selected from the formulas (XIXD), wherein p1 is 0, and j1 and k1 are 1. In another embodiment, optionally in combination with one or more features of the various embodiments described above or below, in the radical of formula (XVIII), L is a biradical of formula (XIXD) as defined herein, wherein p1 is 1, X1' is -NH-, and j1 and k1 are 1. In another embodiment, optionally in combination with one or more features of the various embodiments described above or below, in the radical of formula (XVIII), L is a biradical selected of formula (XIXD), wherein p1 is 1 , X1’ is -O-, and j1 and k1 are 1.

[0224] In another embodiment, optionally in combination with any of the embodiments provided above or below, Ai is a lipid-like moiety R which has the formula (XVIII'), p is 0, s is 0, and t' is 1 , i.e., the lipo-polyamino acid conjugate of formula (I) has the formula (Ih'): wherein A, X, Ri, PAAi, PAA2, n, m, R22, R33, R44, L, and the dashed bonds — are as defined herein.

[0225] In another embodiment, optionally in combination with any of the embodiments provided above or below, A1 is a lipid-like moiety R which has the formula (XVIII'), wherein p is 1 , i.e., the lipo-polyamino acid conjugate of formula (I) has the formula (lj'): wherein A, X, R1, PAA1, PAA2, n, m, R22, R33, R44, L, t', and the dashed bonds — are as defined herein

[0226] In another embodiment, optionally in combination with any of the embodiments provided above or below, in the lipo-polyamino acid conjugate of formula (I) has the formula (Ih') L is -(Ci-Ce)alkyl-CO- or a biradical of formula (HID).

[0227] In another embodiment, optionally in combination with any of the embodiments provided above or below, the lipid-like moiety R has the formula (XVIII”):

[0228] (XVIII”) wherein a1, b1, d, R22, R33, R44, L, t', and the dashed bonds — are as defined herein. More particularly, the lipid-like moiety R has the formula (XVIII”), wherein b1 is 0, and a1 and d are independently selected from 2 to 6.

[0229] According to one embodiment, optionally in combination with any of the embodiments provided above or below, in the lipo-polyamino acid conjugate of formula (I) A1 is a lipid-like moiety R selected from the group consisting of: a) -(Ci-Ci8)alkyl, more particularly -(Ce-Cisjalkyl, and even more particularly, a radical of the formula (XXIII) as previously defined; b) -(C2-Ci8)alkenyl, more particularly -(Ce-Cisjalkenyl, and even more particularly, a radical of the formula (XXIV) as previously defined; c) a radical of formula (XXV) as defined herein; d) a radical of formula (XXVI) as defined herein; e) a radical of formula (IX) as defined herein; f) a radical of formula (X) as defined herein; g) a radical of formula (XI) as defined herein, more particularly, a radical selected from the formulas (xi1), (xi2), (xi3), (xi4), (xi5), (xi6), (xi7) and (xi8) as previously defined; h) a radical of formula (XII) as defined herein, more particularly, a radical selected from the formulas (xii1), (xii2), (xii3), and (xii4) as previously defined;

[0230] I) a radical of formula (XIII) as defined herein, more particularly, a radical of the formula (xiiil) as previously defined; j) a radical of formula (XIV) as defined herein; k) a radical of formula (XV) as defined herein; l) a radical of formula (XVI) as defined herein, more particularly, a radical selected from the formulas (xvi1), (xvi2), (xvi3), and (xvi4) as previously defined; m) a radical of formula (XVII) as defined herein, more particularly, a radical of the formula (xviil) as previously defined; n) a radical of formula (XVIII') as defined herein, more particularly, a radical of the formula (xviiiT) as previously defined;

[0231] 0) a radical of formula (XVIII”) as defined herein, more particularly, a radical of the formula (xviiiT) as previously defined.

[0232] In accordance with another embodiment, optionally in combination with any of the embodiments provided above or below, in the lipo-polyamino acid conjugate of formula (I), A1 is a lipid-like moiety R as defined herein, p is 1, and A is H.

[0233] In accordance with another embodiment, optionally in combination with any of the embodiments provided above or below, in the lipo-polyamino acid conjugate of formula (I), A1 is a lipid-like moiety R as defined herein, p is 1, and A is a protective group. In a more particular embodiment, in the lipo-polyamino acid conjugate of formula (I), Ai is a lipid-like moiety R as defined herein, p is 1, X is N, and A is an amino protective group; more particularly the amino protective group is selected from the group consisting of acetyl, methyloxycarbonyl, benzyloxycarbonyl, p-methoxybenzyloxycarbonyl, t-butyloxycarbonyl (Boc), 9- fluorenylmethyloxycarbonyl (Fmoc), allyloxycarbonyl (Alloc), 2,2,2-trichloro-ethoxycarbonyl group (Troc), benzoyl (Bz), benzyl (Bn), p-methoxybenzyl (PMB), 3,4-dimethoxybenzyl (DMPM), p-methoxyphenyl (PMP), tosyl (Ts), trimethylsilylethoxy-carbonyl (Teoc), benzhydryl, triphenylmethyl (Trityl), (4-methoxyphenyl- )diphenylmethyl (MMT), dimethoxytrityl (DMT), and diphenylphosphino, and even more particularly the amino protective group is acetyl.

[0234] In another more particular embodiment, in the lipo-polyamino acid conjugate of formula (I), Ai is a lipid-like moiety R as defined herein, p is 1, X is 0, and A is a carboxy protective group. Suitable carboxy protective groups known in the art may be used without limitation. Representative carboxy protective groups include alkyl, aryl or benzyl esters, silyl esters, amides or hydrazides. In a particular embodiment, the carboxy protective group is selected from the group consisting of -(Ci-Cejalkyl, benzyl, p-methoxyphenyl, trimethylsilyl and [2-(trimethylsilyl)ethoxy]methyl (SEM).

[0235] Introduction and removal of these protective groups can be carried out by standard methods such as the ones described in T. W. Green and P.G. M. Wuts, Protective Groups in Organic Chemistry, Wiley, 3rd ed. 1999, Chapter 5 (pp. 369-451).

[0236] In another more particular embodiment, in the lipo-polyamino acid conjugate of formula (I), Ai is a lipid-like moiety R as defined herein, p is 1, X is S, and A is selected from the group consisting of -(Ci-Cejalkyl, benzyl, p-methoxyphenyl, trimethylsilyl and [2-(trimethylsilyl)ethoxy] methyl (SEM).

[0237] In accordance with another embodiment, optionally in combination with any of the embodiments provided above or below, in the lipo-polyamino acid conjugate of formula (I), Ai is a lipid-like moiety R as defined herein, p is 1, and A is selected from the group consisting of H, -(Ci-Cejalkyl, -CO(Ci-C6)alkyl, -(Ci-C6)alkyl-CO-N[(Ci-Ci8)alkyl]2, -(C5-Cio)aryl, -(C5-Cio)heteroaryl, -(Ce-C jaralkyl, -(Ci-C6)alkyl-0-(C5-Cio)aryl, -(C5-Cio)heterocycloalkyl, a radical (IV), a radical (V), a radical (VI), a protective group, a lipid-like moiety Rz, an active moiety; being A optionally substituted as defined herein.

[0238] In accordance with another embodiment, optionally in combination with any of the embodiments provided above or below, in the lipo-polyamino acid conjugate of formula (I), Ai is a lipid-like moiety Rz' as defined herein, p is 1, and A is an active moiety selected from the group consisting of a pharmaceutically active agent, a cell-targeting agent, a penetration enhancing agent, a cosmetically active agent, and a diagnostically active agent.

[0239] The active moiety in A may be directly bound to X or, alternatively, it may be bound through a linker. There is no limitation in the nature of the linker provided that it can be attached to the rest of the molecule by chemically feasible bonds. For example, the linker may be a biradical chain which comprises 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-, -S-S-, -SO-, -SO2-, -SO2NH2-, -phenylene-, and the like. The linker may contain from 1-50 moieties, more particularly from 2 to 30 or from 2 to 20 or from 2 to 15 moieties as defined above and may be attached to X by a chemically feasible bond such as an ether bond, a thioether bond, or an amide bond.

[0240] It also forms part of the invention the lipo-polyamino acid conjugate of formula (ID), wherein A, X, Ri, PAAi, PAA2, n, m, are as defined herein;

[0241] PAA1” is a repetitive unit of formula (II”) wherein though the repeating units PAA1” and PAA2” are shown in a particular order for convenience of description, the repeating units may be present in any order and may be block or randomly present; and wherein each of the repeating units PAA1” and PAA2” may comprise blocks of monomer units which may be the same or different between each other; n' is an integer from 5 to 250; m' is an integer from 5 to 250;

[0242] Xi is selected from the group consisting of CH, N, S, and 0;

[0243] Ria is a radical which has any of the meanings of R1, with the condition that Riais absent when Xi is 0 or S; R2' is a radical which has any of the meanings of R2; R3' is a radical which has any of the meanings of R3; R4' is a radical which has any of the meanings of R4;

[0244] R5' is a radical which has any of the meanings of R5; B and B’ are independently S or CH2; e and f are independently an integer from 1 to 18;

[0245] A3 is selected from the group consisting of H, -(Ci-C6)alkyl, -CO(Ci-C6)alkyl, -(Ci-C6)alkyl-CO-N[(Ci-Ci8)alkyl]2, -(C5-Cio)aryl, -(C5-Cio)heteroaryl, -(C6-Cio)aralkyl, -(Ci-C6)alkyl-0-(C5-Cio)aryl, -(C5-Cio)heterocycloalkyl, a radical (IV), a radical (V), a radical (VI), a protective group, a lipid-like moiety Rz, and an active moiety; wherein is optionally substituted by one or more groups selected from the group consisting of -OH, halogen, -CF3, -NH2, -NH-(Ci-C4)alkyl, -NH-CO-(Ci- C6)alkyl, -(Ci-C6)alkyl, -NO2, -N3, -CO-(Ci-C6)alkyl, -CO-O-(Ci-C6)alkyl, -SO3H, -SO2NH2, -SO2-N((Ci-C6)alkyl)2, -COOH, CONH2, and -CON((Ci-C6)alkyl)2.

[0246] All embodiments indicated herein related to the meanings of A, X, R1, PAA1, PAA2, n, and m in the lipo- polyamino acid conjugate of formula (I) also apply to the meanings of A3, Xi, Ria, PAA1”, PAA2”, n', and m', respectively, in the lipo-polyamino acid conjugate of formula (ID).

[0247] In one particular embodiment, the lipo-polyamino acid conjugate of formula (ID) is a dimer wherein A and A3 have the same meaning, X and Xi have the same meaning, R1 and Riahave the same meaning, R2and R2' have the same meaning, R3 and R3' have the same meaning, R4 and R4’ have the same meaning, R5 and R5’ have the same meaning, B and B’ have the same meaning, e and f have the same meaning, n and n' have the same meaning, and m and m' have the same meaning, respectively.

[0248] It also forms part of the invention the lipo-polyamino acid of formula (ID'), wherein A1, X, Xi, X‘, PAA1, PAA2, R1, R', Ria, n, n', m, m', p, s, e, f, B, and B’ are as defined herein;

[0249] PAA / is a repetitive unit of formula (II')

[0250] PAA2' is a repetitive unit of formula (III') wherein R2', R3', R4', and R5' are as defined herein; p' is 0 or 1 ; s' is 0 or 1 ;

[0251] X” is selected from the group consisting of N, and 0;

[0252] Ri” is a radical which has any of the meanings of R1', with the condition that R is absent when X” is 0;

[0253] A2 is selected from the group consisting of H, -OH, -(Ci-Cejalkyl,

[0254] -(C5-Cio)aryl, -(C5-Cio)heteroaryl,

[0255] -(C6-Cio)aralkyl, -(Ci-C6)alkyl-0-(C5-Cio)aryl, -(C5-Cio)heterocycloalkyl, -(Ci-Cio)alkoxy, -(C6-Cio)aryloxy, -(C6-Cio)aralkoxy, -(C5-Cio)heteroaralkoxy, -(Ci-Cio)alkyl-0-(C6-Cio)aryloxy, an amino protective group, a lipid-like moiety R , an amino acid-like moiety Rs, and an active moiety; with the condition that: when p' is 0 and s' is 0, A2 is selected from the group consisting of H, -(Ci-C6)alkyl, -(C5-Cio)aryl, -(C5-Cio)heteroaryl, -(C6-Cio)aralkyl, -(Ci-C6)alkyl-0-(C5-Cio)aryl, -(C5-Cio)heterocycloalkyl, an amino protective group, an amino acid-like moiety Rs, a lipid-like moiety R , and an active moiety; and when p' is 1 and s' is 0, A2 is selected from the group consisting of H, -OH, -(Ci-Cejalkyl, -(C5-Cio)aryl, -(C5-Cio)heteroaryl, -(C6-Cio)aralkyl, -(Ci-C6)alkyl-0-(C5-Cio)aryl, -(C5-Cio)heterocycloalkyl, -(C1-C10) alkoxy, -(C6-Cio)aryloxy, -(C6-Cio)aralkoxy, -(C5-Cio)heteroaralkoxy, -(Ci-Cio)alkyl-0-(C6-Cio)aryloxy, a lipid-like moiety R , and an active moiety; and when p' is 1 and s' is 1 , A2 is selected from the group consisting of H, -(Ci-C6)alkyl, -(C5-Cio)aryl, -(C5-Cio)heteroaryl, -(C6-Cio)aralkyl, -(Ci-C6)alkyl-0-(C5-Cio)aryl, -(C5-Cio)heterocycloalkyl, -(C1-C10) alkoxy, -(C6-Cio)aryloxy, -(C6-Cio)aralkoxy, -(C5-Cio)heteroaralkoxy, -(Ci-Cio)alkyl-0-(C6-Cio)aryloxy, a lipid-like moiety R , and an active moiety. All embodiments indicated herein related to the meanings of Ai, X', R / , X, Ri, PAAi, PAA2, n, m, p, and s in the lipo-polyamino acid conjugate of formula (I) also apply to the meanings of A2, X”, R1”, Xi, Ria, PAAi’, PAA2', n', m', p', and s', respectively, in the lipo-polyamino acid conjugate of formula (ID').

[0256] In one particular embodiment, the lipo-polyamino acid conjugate of formula (ID') is a dimer wherein A1 and A2 have the same meaning, X and Xi have the same meaning, X' and X” have the same meaning, R / and R1” have the same meaning, R1 and Riahave the same meaning, R2 and R2' have the same meaning, Rs and R3' have the same meaning, R4 and R4' have the same meaning, Rs and R5' have the same meaning, B and B’ have the same meaning, e and f have the same meaning, n and n' have the same meaning, and m and m' have the same meaning, p and p' have the same meaning, and s and s' have the same meaning, respectively.

[0257] In another embodiment, optionally in combination with any of the embodiments provided above or below, the lipo-polyamino acid conjugate of formula (I) has the formula (IA) wherein: n is an integer from 5 to 100; X is N; R1 is selected from the group consisting of H, and -(Ci-Ce)alkyl;

[0258] R2 is a radical selected from the group consisting of (IV) and (VI); R3 is H; p is 0 or 1 ; s is 0 or 1 ; X' is N;

[0259] R1' is selected from the group consisting of H, and -(Ci-Ce)alkyl; A is H, -(Ci-C6)alkyl-CO-N[(Ci-Ci8)alkyl]2, or a lipid-like moiety Rz which is selected from the group consisting of H, -(Ci-C2o)alkyl, -(C2-C2o)alkenyl, and a radical of formula (XI), (XII), (XIV), (XV), (XVI), (XVII) or (XVIII); and A1 is H or a lipid-like moiety Rz' which is selected from the group consisting of -(Ci-C2o)alkyl, -(C2-C2o)alkenyl, and a radical of formula (XI), (XII), (XIV), (XV), (XVI), (XVII) or (XVIII'). More particularly in this embodiment, when A1 is H, p is 0, s is 0, X is N, and R1 is H, then A is other than butyl; when A1 is H, p is 0, s is 0, X is N, and A is H, then R1 is other than butyl; and when A is methyl, X is N, R1 is H, p is 1 , and s is 0, then A1 is other than a lipid-like moiety Rz of formula (XVII) wherein each j is16 and i is 2.

[0260] In another embodiment, optionally in combination with any of the embodiments provided above or below, the lipo-polyamino acid conjugate of formula (I) has the formula (IB) (IB) wherein: n is an integer from 5 to 100; m is an integer from 5 to 100; X is N; Ri is selected from the group consisting of H, and -(Ci-Ce)alkyl; R2 is a radical selected from the group consisting of (IV) and (VI); R3 is H; R4 corresponds to the amino acid the side chain of phenylalanine, alanine, leucine, glycine, isoleucine, or valine; R5 is H; p is 0 or 1 ; s is 0 or 1 ; X' is N; R / is selected from the group consisting of H, and -(Ci-Cejalkyl; A is H, -(Ci-Ce)alkyl- CO-N[(Ci-Ci8)alkyl]2, or a lipid-like moiety Rz which is selected from the group consisting of H, -(Ci-C2o)alkyl, - (C2-C2o)alkenyl, and a radical of formula (XI), (XII), (XIV), (XV), (XVI), (XVII) or (XVIII); and A1 is H or a lipid-like moiety Rz' which is selected from the group consisting of -(Ci-C2o)alkyl, -(C2-C2o)alkenyl, and a radical of formula (XI), (XII), (XIV), (XV), (XVI), (XVII) or (XVIII’).

[0261] More particularly, in the above two embodiments, the lipid-like moiety Rz is -(Ci-C2o)alkyl, a radical of formula (XI), or a radical of formula (XVIII); and the lipid-like moiety Rz’ is -(Ci-C2o)alkyl, a radical of formula (XI), or a radical of formula (XVIII'). Even more particularly, in the radical of formula (XVIII), t is 1 , and L is -CO-(Ci-C6)alkyl, or a biradical of formula (HID), and in the radical of formula (XVIII'), t is 1 , and L is -(Ci-CeJalkyl-CO-, or a biradical of formula (HID).

[0262] In another embodiment, optionally in combination with any of the embodiments provided above or below, the lipo-polyamino acid conjugate of formula (I) has the formula (IB'): wherein:

[0263] X is N or CH;

[0264] A is selected from the group consisting of butyl, (Ci2-Ci8)alkyl, a radical of formula (XXV), and a radical of formula (XXVI);

[0265] R1 is selected from the group consisting of H and (Ci-Cis)alkyl;

[0266] R” is selected from the group consisting of H, -CO(Ci-C6)alkyl, a radical of formula (XVIII”), and -CONH(Ci-Ci8)alkyl; R2 is as defined herein, particularly R2 is a radical of formula (VI) or a radical of formula (VI), wherein more particularly in the radical of formula (VI), c is an integer from 0 to 3; R is -(Ci-C6)alkyl, and R' is -(Ci-Ce)alkyl- CO2-.

[0267] R4 is selected from the group consisting of H, methyl; isopropyl, isobutyl, and sec-butyl; n is a value from 5 to 200, or from 5 to 150, or from 10 to 150, particularly measured by 1 H-NMR spectroscopy; and m is 0 or a value from 5 to 150, or from 5 to 100, or from 5 to 80, or from 10 to 80, particularly measured by 1 H-NMR spectroscopy.

[0268] Preparation processes

[0269] Processes for the preparation of the lipo-polyamino acid conjugates of formula (I) are also part of the invention. The conjugates may be prepared by synthetic processes which are well-known in the art.

[0270] As mentioned above, the lipo-polyamino acid conjugates of formula (I) must contain at least one lipid-like moiety, which may be either a lipid-like moiety Rz in A, a lipid-like moiety R / in A1, or both.

[0271] The process for the preparation of the lipo-polyamino acid conjugates of formula (I) generally comprises polymerizing N-carboxy anhydrides (NCA) of protected or non-protected amino acids, to produce a poly(amino acid), or protected poly amino acid ester, carbamate, S-alkylsulfonyl, or trifluoroacetyl derivative. Then a deprotection step or thiol exchange should be carried out by methods well known for a person skilled in the art. The different radicals present in the repeating units may be introduced at desired ratios by changing the ratios of the respective block or random copolymers.

[0272] In accordance with another embodiment, optionally in combination with any of the embodiments provided above or below, the process comprises: i) reacting an amine or tetrafluoroborate or trifluoroacetate ammonium salt form of an initiator i.1) with an appropriate N-carboxyanhydride (NCA); alternatively, reacting the amine or tetrafluoroborate or trifluoroacetate ammonium salt form of initiator of step i) with an appropriate N- carboxyanhydrides in a sequential manner to obtain a block co-polymer; or alternatively, i.2) reacting the amine or tetrafluoroborate or trifluoroacetate ammonium salt form of initiator of step i) with an appropriate NCA mixture in a statistical manner to obtain random co-polymers; ii) optionally, reacting the amine group at the N-terminal position with an amine reactive group to introduce R1; iii) optionally, orthogonally removing amino acid side chain protecting groups; iv) optionally, reacting the amine, thiol, disulfide, S-alkylsulfonyl group or carboxilic acid group at side chain terminal position with an amine or carboxilic acid reactive group to introduce architectural extension, conjugation, labelling or shielding in R2 v) purifying the product obtained in step i), ii) or iii), optionally by fractionation, precipitation, ultrafiltration, dialysis, size-exclusion chromatography, affinity chromatography or tangential flow filtration.

[0273] Step I) above may include: a) ring opening polymerization of amino acids N-carboxyanydride (NCA) monomer by reacting the amine or tetrafluoroborate or trifluoroacetate ammonium salt form of initiator with the selected NCA, wherein the ratio of monomer / initiator allows the control of the degree of polymerization (DP); b) a sequential polymerization, wherein block co-polypeptides are prepared following the polymerization reaction a') in a sequential manner, allowing the first NCA monomer to be consumed and the resulting product may be purified or not before adding the next monomer to build the following polypeptidic block; or c) a statistical polymerization a') wherein random copolypeptides are prepared following the polymerization reactionin a statistical manner, mixing all the NCA monomers before starting the polymerization by the addition of an amine or tetrafluoroborate or trifluoroacetate ammonium salt form of initiator.

[0274] Step II) above corresponds to the end-capping, wherein the amine group at the N-terminal position is reacted with an amine reactive group to introduce Ri.

[0275] Step iii) above corresponds to the exchange reaction or deprotection, wherein amino acid side chains are removed orthogonally depending on the protecting group.

[0276] Step iv) corresponds to the conjugation, reacting the amine or carboxylic acid group at side chain terminal position to achieve a shielding moiety, by chloracetylation, methylation, thiol exchange, nucleophilic substitution or peptide coupling reactions in a sequential manner if needed.

[0277] In accordance with another embodiment, optionally in combination with any of the embodiments provided above or below, there is provided a process for preparing a compound which is structurally different from a compound of formula I as defined herein, comprising the following steps:

[0278] I. using a compound of formula I as defined herein as starting compound; ii. making structural changes to the compound of step (I) to obtain a compound, which is structurally different from a compound of formula (I).

[0279] Self-assembled particles

[0280] As mentioned above, the lipo-polyamino acid conjugates of the invention have amphiphilic nature since they comprise a polyamino acid-based moiety (hydrophilic part) and at least one lipid-like moiety (hydrophobic part). Thanks to their amphiphilic nature, the lipo-polyamino acid conjugates of the invention may form selfassembled particles in solution.

[0281] Therefore, the present invention also relates to a self-assembled particle comprising the lipo-polyamino acid conjugate of formula (I) as defined herein, and optionally one or more active agents selected from the group consisting of pharmaceutically active agents, penetration enhancing agents, cell-targeting agents, cosmetically active agents, diagnostically active agents, nucleic acids, peptides, proteins, and mixtures thereof.

[0282] 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 self-assembled particle comprising the lipo-polyamino acid conjugate of formula (I) as defined herein, and one or more nucleic acids.

[0283] As used herein, the term "self-assembled particles” refers to the arrangement of the lipo-polyamino acid conjugate molecules in a solvent, in particular, small, self-assembled particle may be enclosed structures of any shape, typically spherical and / or tubular. The term "self-assembled particles” intends to encompass any of a number of structures that are known in the art to be formed from amphiphilic polymers. Non-limiting examples of self-assembled particles include micelles (also being referred to interchangeably herein as micellar worms or simply "worms”), inverted micelles, planar bilayers, crystal nanoparticles, liposomes, microbubbles or lipid nanoparticles. The self-assembled nanoparticles and microparticles can also form gels. The self-assembled particles of the invention are non-viral particles, which means that they are not able to virally infect cells.

[0284] The self-assembled particles may show a variety of sizes, in particular, they can be nanoparticles or microparticles. A "nanoparticle”, as defined herein, is any particle of nanometric size, in particular having smallest end-to-end diameter of between 1 and 900, more particularly, between 1 and 700 nm, between 1 and 500 nm, between 1 and 300 nm, between 1 and 200 nm, and between 1 and 100 nm in size. A "microparticle”, as defined herein, is typically any particle of micrometric size, having a smallest end-to-end between 1 and 100 m in size. Typically, in a composition comprising a plurality of particles, the relevant diameter is the number average diameter.

[0285] As used herein, the term "size" refers to a characteristic physical dimension. For example, in the case of a particle that is substantially spherical, the size of the particle corresponds to the diameter of the particle. In the case of a particle that is substantially rod-shaped with a substantially circular cross-section, such as wire or a tube, the size of the particle is determined by the diameter of the two relevant cross-section dimensions of the particle. In the case of a particle that is substantially box-shaped, such as a cube, a box, or a cage, the size of the nanoparticle corresponds to the maximum edge length. When referring to a set of particles as being of a particular size, it is contemplated that the set of particles can have a distribution of sizes around the specified size. Thus, as used herein, a size of a set of particles can refer to a mode of a distribution of sizes, such as a peak size of the distribution of sizes.

[0286] As used herein, the term "diameter” refers to the average diameter and is also designated as Z-average or Z- ave. The average diameter corresponds to the mean hydrodynamic diameter (Dh) and can be measured by dynamic light scattering (DLS) as shown in the examples below. In one embodiment, optionally in combination with one or more features of the various embodiments described above or below, the self-assembled particles of the invention have a hydrodynamic diameter (Dh) in water from 5 to 1200 nm, more particularly, from 10 to 1100 nm, from 10 to 1000 nm, from 10 to 700, from 20 to 500 nm, from 20 to 400 nm, from 20 to 300 nm, from 30 to 200 nm, or from 50 to 150 nm.

[0287] All embodiments indicated for the lipo-polyamino acid conjugate of formula (I) also apply to the selfassembled particles.

[0288] According to one embodiment, optionally in combination with one or more features of the various embodiments described above or below, in the self-assembled particle comprising the lipo-polyamino acid conjugate of formula (I), the lipid-like moieties (hydrophobic part) face inward and the polar head portion (the PAA) face outward.

[0289] According to another embodiment, optionally in combination with one or more features of the various embodiments described above or below, the self-assembled particle is a core-shell structure comprising an inner core and an external shell. More particularly, the lipo-polyamino acid conjugate of formula (I) forms the external shell of the self-assembled particle, and an agent is optionally encapsulated or loaded in the inner core.

[0290] According to one embodiment, optionally in combination with one or more features of the various embodiments described above or below, the self-assembled particle is a nanoparticle, more particularly selected from the group consisting of a micelle, an inverted micelle, a planar bilayer, a crystal nanoparticle, a liposome, microbubbles, and a lipid nanoparticle, and even more particularly, the self-assembled particle is a lipid nanoparticle or a liposome.

[0291] For the purposes of the invention, the term "liposome” refers to artificially prepared self-assembled particles composed of concentric lipidic bi-layers enclosing one or more aqueous compartments. Non-limiting examples of liposomes include monolamellar liposome, multi-lamellar liposomes, multi-vesicular-liposomes and polymer-coated liposomes.

[0292] The term "lipid nanoparticle” refers to particles typically spherical on the order of nanometers (e.g., 1-1000 nm) that includes lipids and that is stable and dispersible in aqueous media.

[0293] For the purposes of the invention, the term "crystal nanoparticle” refers to artificially prepared crystals composed of solid lipids enclosing one or more hydrophobic compartments. The term "crystal nanoparticle” refers to particles of different shapes on the order of nanometers (e.g., 1-1000 nm) that includes lipids and that is stable and dispersible in aqueous media.

[0294] In another embodiment, optionally in combination with one or more features of the various embodiments described above or below, the invention relates to a lipid nanoparticle (LNP) or a liposome comprising the lipo-polyamino acid conjugate of formula (I) as defined herein in the first or the second aspect, and optionally one or more active agents selected from the group consisting of pharmaceutically active agents, cell-targeting agents, penetration enhancing agents, cosmetically active agents, diagnostically active agents, nucleic acids, peptides, proteins, and mixtures thereof.

[0295] The liposomes and lipid nanoparticles disclosed herein may comprise any suitable lipids, including ionizable lipids, cationic lipids, zwitterionic lipids, neutral lipids, or anionic lipids.

[0296] Suitable ionizable lipids include, without limitation, (2S)-2,5- bis(3-aminopropylamino)- N-[2- (dioctadecylamino)acetyl]pentanamide (DOGS), N1-[2-((1 S)-1-[(3-aminopropyl)amino]-4-[di(3-aminopropyl)- amino]butylcarboxamido)ethyl]-3,4-di[oleyloxy]-benzamide (MVL5), 3|3-[N-(N',N'- dimethylaminoethane)- carbamoyl]cholesterol (DC-Cholesterol), (1 ,2-distearyloxy-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 (y-DLenDMA), 2-dilinoleyl-4-dimethylamino- methyl-[1 ,3]-dioxolane (DLin-K-DMA), 2,2- dilinoleyl-4- dimethylaminoethyl-[1 ,3]- dioxolane (DLin- KC2-DMA, also known as DLin-C2K-DMA, XTC2, and C2K), 2,2-Dilinoleyl-4-(3-dimethylaminopropyl)-[1 ,3]-dioxolane (DLin-KC3-DMA), 2, 2-D 111 noley l-4-(4-d I methy I aminopropy l)-[1 , 3] -dioxol ane (DLin-KC4-DMA), 1 , 2-dili noleny loxy-4-(2-d i methyl aminoethyl)- 1 ,3-dioxolane (DLen-C2K-DMA), 1 ,2-di- y-li noleny loxy-4-(2-d I methy I ami no- ethyl)-1 ,3-dioxolane (y-DLen-C2K-DMA), (6Z,9Z,28Z,31Z)-Heptatriaconta-6,9,28,31-tetraen-19-yl 3- (dimethylamino)propanoate (DLin-M-C2-DMA, also known as MC2), (6Z,9Z,28Z,31 Z)- heptatriaconta- 6,9,28,31- tetraen-19- yl 4-(dimethylamino)-butanoate (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).

[0297] Suitable cationic lipids include, without limitation, 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)propyll-N,N-dimethyl-N-hydroxyethylammonium bromide (DMRIE), N-[1-(2,3,dioleyloxy)- propyl]-N, N-dimethyl-N-hydroxy ethylammonium bromide (DORIE), 3|3-[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) and ([(4- hydroxybutyl)azanediyl]di(hexane-6, 1-diyl) bis(2-hexyldecanoate)) (ALC-0315).

[0298] Examples of anionic lipids include, but are not limited to, phosphatidylglycerol, diacylphosphatidylserine, diacylphosphatidic acid, N-Succinyl phosphatidylethanolamine, N-glutaryl phosphatidylethanolamine cholesterol hemisuccinate (CHEMS), lysylphos-phatidylglycerol, N-dodecanoyl phosphatidyl ethanoloamine, cardiolipin, and combinations thereof. Suitable neutral lipids may be uncharged or zwitterionic lipids and include, without limitation steroids, phospholipids, and combinations thereof.

[0299] Examples of steroids include, without limitation, cholesterol, progesterone, cortisone, aldosterone, estradiol, testosterone, and combinations thereof.

[0300] Examples of phospholipids include, but are not limited to, phosphatidylcholine (PC), phosphatidic acid (PA), phosphatidylethanolamine (PE), phosphatidylglycerol (PG), phosphatidylserine (PS), and phosphatidylinositol (PI), dimyristoyl phosphatidyl choline (DMPC), distearoyl phosphatidyl choline (DSPC), dioleoyl phosphatidyl choline (DOPC), dipalmitoyl phosphatidyl choline (DPPC), dimyristoyl phosphatidyl glycerol (DMPG), distearoyl phosphatidyl glycerol (DSPG), dioleoyl phosphatidyl glycerol (DOPG), dipalmitoyl phosphatidyl glycerol (DPPG), dimyristoyl phosphatidyl serine (DMPS), distearoyl phosphatidyl serine (DSPS), dioleoyl phosphatidyl serine (DOPS), dipalmitoyl phosphatidyl serine (DPPS), dioleoyl phosphatidyl ethanolamine (DOPE), palmitoyloleoylphosphatidylcholine (POPC), palmitoyloleoyl-phosphatidylethanolamine (POPE) and dioleoyl-phosphatidylethanolamine 4-(N-maleimidomethyp-cyclohexane-1-carboxylate (DOPE-mal), dipalmitoyl phosphatidyl ethanolamine (DPPE), dimyristoylphosphoethanolamine (DMPE), distearoylphosphatidyl-ethanolamine (DSPE); lysophosphatidyl choline, lysophosphatidylethanolamine, 1,2- distearoyl-sn-glycero-3-phosphocholine (DAPC), dilauryloylphosphatidylcholine (DLPC), 1 -myristoyl-2- palmitoyl phosphatidylcholine (MPPC), 1 -palmitoyl-2-myristoyl phosphatidylcholine (PMPC), 1-palmitoyl-2- stearoyl phosphatidylcholine (PSPC), 1 ,2-diarachidoyl-sn-glycero-3-phosphocholine (DBPC), 1 -stearoy I-2- palmitoyl phosphatidylcholine (SPPC), 1,2-dieicosenoyl-sn-glycero3-phosphocholine (DEPC), and combinations thereof.

[0301] In the liposomes and lipid nanoparticles disclosed herein the lipo-polyamino acid conjugate advantageously provides stealth properties. As used herein, the term "stealth” refers to the fact that the liposomes or lipid nanoparticles are not detected and sequestered and / or degraded by the immune system of the host to which they are administered, and consequently the length of time for which the liposomes or lipid nanoparticles can exist in vivo is increased.

[0302] In one embodiment, optionally in combination with one or more features of the various embodiments described above or below, the liposomes and lipid nanoparticles disclosed herein lack a polyethyleneglycol (PEG)-lipid conjugate, that is a lipid containing polyethyleneglycol.

[0303] In another embodiment, optionally in combination with one or more features of the various embodiments described above or below, the self-assembled particles of the invention, in particular liposomes and lipid nanoparticles, lack polyethyleneglycol (PEG).

[0304] The liposomes and lipid nanoparticles disclosed herein may also comprise one or more cationic polymers such as cationic amine-containing polymers. Typically, these polymers may carry active ingredients, particularly nucleic acids. Examples of cationic amine-containing polymers include, without limitation, poly-L- lysine, polyamidoamine, polyethyleneimine, chitosan, poly(beta-amino esters), and the like.

[0305] In another embodiment, optionally in combination with one or more features of the various embodiments described above or below, the invention relates to a lipid nanoparticle (LNP) or a liposome comprising the lipo-polyamino acid conjugate of formula (I) as defined herein, and one or more lipids selected from the group consisting of ionisable lipids, cationic lipids, neutral lipids, and anionic lipids. More particularly, the lipid nanoparticle (LNP) or liposome comprises the lipo-polyamino acid conjugate of formula (I) as defined herein, a ionizable lipid or a cationic lipid, a phospholipid, and a sterol. Even more particularly, the lipid nanoparticle (LNP) or liposome comprises: i) the lipo-polyamino acid conjugate of formula (I) as defined herein in an amount from 0.1 to 10 mol%, more particularly from 1 to 5 mol% or from 1 to 6 mol% or from 0.5 to 5 mol%, even more particularly from 2 to 5% mol%; ii) a ionizable lipid or a cationic lipid in an amount from 30 to 70 mol%, more particularly from 40 to 60 mol%; iii) a phospholipid in an amount from 1 to 20 mol%, more particularly from 5 to 15 mol%; and iv) a sterol in an amount from 20 to 60 mol%, more particularly from 30 to 50 mol%; wherein the percentages are expressed with respect to the sum of the mol% of the lipids and the lipo-polyamino acid conjugate of formula (I).

[0306] In another embodiment, optionally in combination with one or more features of the various embodiments described above or below, the invention relates to a lipid nanoparticle (LNP) or a liposome comprising the lipo-polyamino acid conjugate of formula (I) as defined herein, one or more lipids selected from the group consisting of ionisable lipids, cationic lipids, neutral lipids, and anionic lipids, and one or more nucleic acids.

[0307] The lipid nanoparticles and the liposomes containing one or more nucleic acids may be prepared by standard methods. Typically, the process for the preparation of LNPs comprises: i) preparing a first alcoholic mixture comprising one or more lipids and the lipo-polyamino acid conjugate of the invention in a suitable alcohol such as for example ethanol; ii) preparing a second aqueous composition comprising one or more nucleic acids and an aqueous solvent (an acidic buffer); and iii) mixing i) with ii) in a microfluidic mixing device. The microfluidic mixing allows thorough and rapid mixing of the lipid phase and the nucleic acid phase in a microscale device. Depending on the process parameters, and in particular on the total flow rate, the skilled person will be able to modulate the size of the LNPs.

[0308] Active agents

[0309] As mentioned above, the lipo-polyamino acid conjugate of the invention may contain one or more active moieties in its structure in any of A, Ai, A2 or A3. These active moieties are independently selected from the group consisting of a pharmaceutically active agent, a cell-targeting agent, a penetration enhancing agent, a cosmetically active agent, and a diagnostically active agent.

[0310] Additionally, the lipo-polyamino acid conjugate of the invention may form self-assembled particles which may comprise one or more active agents selected from the group consisting of pharmaceutically active agents, cell-targeting agents, penetration enhancing agents, cosmetically active agents, diagnostically active agents, nucleic acids, peptides, proteins, and mixtures thereof.

[0311] As used herein, the term "pharmaceutically active agent” refers to and agent that has pharmacological activity and is used for curing, mitigating, treating or preventing a disease in a mammal, in particular a human. The term "cosmetic active agent” refers to an agent that does not provide any therapy but is used for aesthetic purposes, for example to improve the appearance, preserve, condition, cleanse, color or protect the skin, nails or hair.

[0312] As used herein, the term "cell-targeting agent” refers to any molecule, macromolecule, or biomacromolecule, displaying affinity for a molecule present in the human or animal body, which is able to direct the conjugates or the self-assembled particles thereof by directing them towards the target site for therapeutic treatment since e.g., it selectively binds to receptors that are expressed or over-expressed on specific cell types. Celltargeting groups are well known in the art. The term therefore includes ligands for specific receptors or antigens, such as antibodies for a specific antigen, folic acid for its receptor or sugars such as galactose for its hepatic receptors. The targeting agent may be attached to the lipo-polyamino acid conjugate backbone in any of A, Ai, A2 or A3 and / or may be contained in the self-assembled particles formed from the conjugated.

[0313] Examples of cell-targeting groups include, but are not limited to, galactosamine, folate, a Her-2 binding peptide, TLR agonists, p-D-Glucose, Asn-Gly-Arg peptide, angiopep2, folic acid, aptamers (A-9, A10, Anti- gp120, TTA1, sgc8, Anti MUC-1, AS1411), primaquine, zidovudine, superoxide dismutase, prednisolone, platinum, cisplatin, sulphamethoxazole, amoxicillin, etoposide, mesalzine, doxorubicin, paclitaxel, 5-amino salicylic acid, denosumab, docetaxel, calcitonin, proanthocyanidin, methotrexate, camptothecin, galactose, glycyrrhetinic acid, lactose, hyaluornic acid, octeotride, lactobionic acid, p-galactosyl moiety, arabino-galactan, chitosan, azo-based poly-phosphazene, azo group and 4-amino-benzyl-carbamate, succinate, 4,4'- dihydroxyazo benzene-3-carboxilic acid, cyclic RGD penta-peptide, Aspartic acid octapeptide, alendronate, transferrin, bisphosphonate adendronate, mono sialoganglioside GM1, gluthatione, E-selectin thioaptamer, poloxamer-407, a urokinase-type plasminogen activator receptor (uPAR) antagonist, a CXCRe chemokine receptor antagonist, a GRP78 peptide antagonist, an RGD peptide, an RGD cyclic peptide, a luteinizing hormone-releasing hormone (LHRH) antagonist peptide, an aminopeptidase targeting peptide, a brain homing peptide, a kidney homing peptide, a heart homing peptide, a gut homing peptide, an integrin homing peptide, an angiogenic tumor endothelium homing peptide, an ovary homing peptide, a uterus homing peptide, a sperm homing peptide, a microglia homing peptide, a synovium homing peptide, a urothelium homing peptide, a prostate homing peptide, a lung homing peptide (e.g. RCPLSHSLICY), laminin receptor binding peptide (e.g. YIGSR) a skin homing peptide, a retina homing peptide, a pancreas homing peptide, a liver homing peptide, a lymph node homing peptide, an adrenal gland homing peptide, a thyroid homing peptide, a bladder homing peptide, a breast homing peptide, a neuroblastoma homing peptide, a lymphoma homing peptide, a muscle homing peptide, a wound vasculature homing peptide, an adipose tissue homing peptide, a virus binding peptide, or a fusogenic peptide. The term "penetration enhancing agent" as used herein refers to moiety or compound that increases the permeability of an active agent, in particular selected from a pharmaceutically active agent, a cell-targeting agent, a cosmetically active agent, and a diagnostically active agent. The penetration enhancing agent is also known as permeation enhancer.

[0314] Examples of penetration enhancing agents include, without limitation, cell penetrating peptides, surfactants, terpenes, sulfoxides, pyrrolidones, fatty acids, fatty alcohols, urea, azones, fatty alcohols, fatty acids, fatty esters; such as for example, lauryl sarcosine, octoxynol, phenylsulfonate, pluronic, sodium laurate, sodium oleate, sorbitan dilaurate, sorbitan dioleate, sorbitan trilaurate, sorbitan trioleate, sodium octyl sulfate, alkyl ammonium halides, decanol, dodecanol, linolenyl alcohol, oleyl alcohol, butyl acetate, cetyl lactate, lauryl lactate, myristyl lactate, diethyl sebacate, diethyl succinate, diisopropyl sebacate, glycerol monolaurate, glycerol monooleate, glycerol monolinoleate, isopropyl isostearate, isopropyl linoleate, isopropyl myristate, isopropyl palmitate, methyl caprate, methyl laurate, methyl valerate, octyl acetate, oleyl oleate, sorbitan dilaurate, dodecyl acetate, sorbitan dioleate, sorbitan monolaurate, sorbitan trilaurate, sorbitan trioleate, capric acid, hexanoic acid, lactic acid, lauric acid, linoleic acid, linolenic acid, neodecanoic acid, oleic acid, palmitic acid, lecithin, phospholipids, sodium deoxycholate, and sodium taurocholate.

[0315] For the purposes of the present invention, pharmaceutically active agents include low molecular weight drugs, peptides, antibodies, hormones, enzymes, nucleic acids, proteins, and combinations thereof.

[0316] As used herein, the term "nucleic acid” refers to DNA or RNA. In a particular embodiment, optionally in combination with any of the embodiments provided above or below, the nucleic acid is an DNA / RNA hybrid, a short interfering RNA (siRNA), a microRNA (miRNA), a single guide RNA (sgRNA), a donorDNA, a self- amplyfing / replicating RNA, a circularRNA (oRNA), a plasmid DNA (pDNA), a closed-linear DNA (clDNA), a short hairpin RNA (shRNA), messenger RNA (mRNA), and antisense RNA (aRNA), a messenger RNA (mRNA), a CRISPR guide RNA, an antisense nucleic acid, a decoy nucleic acid, an aptamer, and a ribozyme to name a few, and encompasses both the nucleotide sequence and any structural embodiments thereof, such as double stranded, single stranded, helical, hairpin, etc, and may contain modified or unmodified bases. When distinct 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 an association of DNA and RNA strands.

[0317] The nucleic acid may be a poly- or oligonucleotide, such as oligo- or poly-double stranded RNA, oligo- or polydouble stranded DNA, oligo- or poly-single stranded RNA, 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 strand length of the nucleic acid is not particularly limited and the nucleic acid may have a short strand ranging from 10 to 200 bases, preferably from 20 to 180 bases, preferably from 25 to 100 bases, preferably from 30 to 50 bases; or the nucleic acid may have a relatively long strand of from 200 to 20000 bases, more preferably of from 250 to about 15000 bases. In accordance with a particular embodiment, optionally in combination with any of the embodiments provided above or below, the nucleic acid is closed-linear DNA (clDNA), i.e. molecules wherein the double stranded region is flanked and protected by two single stranded loops thereby generating dumbbell-shaped molecules.

[0318] 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, the clDNA comprising at least two modified nucleotides.

[0319] As used herein, the term "closed linear DNA” or "clDNA” refers to a single stranded covalently closed DNA molecule that forms a "dumbbell” or "doggy-bone” shaped structure under conditions allowing nucleotide hybridization. Therefore, although the clDNA is formed by a single stranded DNA molecule, the formation of the "dumbbell” structure by the hybridization of two complementary sequences within the same molecule generates a structure consisting on a double-stranded middle segment flanked by two single-stranded loops. The skilled in the art know how to generate clDNA from open or closed double stranded DNA using routine molecular biology techniques. For instance, those skilled in the art knows that a clDNA can be generated by attaching hairpin DNA adaptors, for instance, by the action of a ligase, to both ends of an open double stranded DNA. "Hairpin DNA adaptor” refers to a single stranded DNA that forms a stem-loop structure by the hybridization of two complementary sequences, wherein the stem region formed is closed at one end by a single stranded loop and is open at the other end.

[0320] A "modified nucleotide” is any nucleotide (e.g., adenosine, guanosine, cytidine, uracil, and thymidine) that has been chemically modified -by modification of the base, the sugar or the phosphate group- or that incorporates a non-natural moiety in its structure. Thus, the modified nucleotide may be naturally or non-naturally occurring depending on the modification.

[0321] As used herein, the term "peptide" refers to molecules that comprise two or more consecutive amino acids linked to one another via peptide bonds. The term peptide includes oligopeptides and polypeptides. The term "protein" refers to large peptides, in particular peptides having at least about 50 amino acids. For the purposes of the invention, the terms peptide and protein are used interchangeably.

[0322] Examples of proteins of interest include, without limitation cytokines, interleukins, tumor necrosis factor (TNF), interferons, integrins, chimeric antigen receptors (CARs), antibodies, hormones, growth factors, enzymes), collagen, fibrinogen, elastin, tubulin, thrombin, serum albumin, erythropoietin, granulocyte colony stimulating factor (G-CSF), colony stimulating factor (CSF), and the like.

[0323] In the context of the present disclosure the expression, "diagnostically active agent”, also referred to as "labeling or imaging agent", refers to any substance that is used as a label, or that enhances specific structures in any imaging technique. An imaging agent, hence, includes optical imaging agent, magnetic resonance imaging agent, radioisotope, and contrast agent. Imaging or labelling agents are well known in the art. Particular examples or imaging or labelling agents are gases such as sterilized air, oxygen, argon, nitrogen, fluor, perfluorocarbons, carbon dioxide, nitrogen dioxide, sulfur hexafluoride, xenon and helium; commercially available agents used in positron emission tomography (PET), computer assisted tomography (CAT), single photon emission computerized tomography, x-ray, fluoroscopy, and magnetic resonance imaging (MRI). Examples of suitable materials for use as contrast agents in MRI include the gadolinium chelates currently available, such as diethylene triamine pentaacetic acid (DTPA) and gadopentotate dimeglumine, as well as iron, magnesium, manganese, copper and chromium. Examples of materials useful for CAT and x-rays include iodine based materials for intravenous administration, such as ionic monomers typified by diatrizoate and iothalamate, non-ionic monomers such as iopamidol, isohexol, and ioversol, nonionic dimers, such as iotrol and iodixanol, and ionic dimers, for example, ioxagalte. Other useful materials include barium for oral use and non-soluble salts such as zinc acetate. In some molecules, an imaging agent is a dye. In some molecules, an imaging agent is a fluorescent moiety. In some molecules, a fluorescent moiety is selected from: a fluorescent protein, a fluorescent peptide, a fluorescent dye, a fluorescent material or a combination thereof. Examples of fluorescent dyes include, but are not limited to, xanthenes (e.g., rhodamines, rhodols and fluoresceins, and their derivatives); bimanes; coumarins and their derivatives (e.g., umbelliferone and aminomethyl coumarins); aromatic amines (e.g., dansyl; squarate dyes); benzofurans; fluorescent cyanines; indocarbocyanines; carbazoles; dicyanomethylene pyranes; polymethine; oxabenzanthrane; xanthene; pyrylium; carbostyl; perylene; acridone; quinacridone; rubrene; anthracene; coronene; phenanthrecene; pyrene; butadiene; stilbene; porphyrin; pthalocyanine; 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-isothiocy anate, fluorescein-6-isothiocyanate and 6-carboxyfluorescein. Examples of rhodamine dyes include, but are not limited to, tetramethylrhodamine- 6-isothiocyanate, 5-carboxytetramethylrhodamine, 5-carboxy rhodol derivatives, tetramethyl and tetraethyl rhodamine, diphenyldimethyl and diphenyldiethyl rhodamine, dinaphthyl rhodamine, rhodamine 101 sulfonyl chloride (sold under the tradename of TEXAS RED(R)). 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, mKalamal, ECFP, Cerulean, CyPet, YFP, Citrine, Venus, YPet). Fluorescent labels are detected by any suitable method. For example, a fluorescent label may be detected by exciting the fluorochrome with the appropriate wavelength of light and detecting the resulting fluorescence, e.g., by microscopy, visual inspection, via photographic film, by the use of electronic detectors such as charge coupled devices (CCDs), photomultipliers, etc. In some molecules, the imaging agent is labeled with a positron-emitting isotope (e.g.,18F) for positron emission tomography (PET), gamma-ray isotope (e.g., 99mTc) for single photon emission computed tomography (SPECT), or a paramagnetic molecule or nanoparticle (e.g.,Gd3+ chelate or coated magnetite nanoparticle) for magnetic resonance imaging (MRI). In some molecules, the imaging agent is labeled with: a gadolinium chelate, an iron oxide particle, a super paramagnetic iron oxide particle, an ultra small paramagnetic particle, a manganese chelate or gallium containing agent. Examples of gadolinium chelates include, but are not limited to diethylene triamine pentaacetic 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-infra red (near-IR) imaging, a luciferase (firefly, bacterial, or coelenterate) or other luminescent molecule for bioluminescence imaging, or a perfluorocarbon-filled self-assembled particle 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: a technetium chelate, a copper chelate, a radioactive fluorine, a radioactive iodine, a indiuim chelate. Examples of Tc chelates include, but are not limited to HYNIC, DTPA, and DOTA. In some molecules, the imaging agent contains a radioactive moiety, for example a radioactive isotope such as211At,1311,125l,90Y,186Re,188Re,153Sm,212Bi,32P,64Cu radioactive isotopes of Lu, and others. The diagnostically active agents may be attached to the lipo-polyamino acid conjugate backbone in any of A, Ai, A2 or A3 and / or may be contained in the self-assembled particles formed from the conjugated.

[0324] Compositions

[0325] The present invention also relates to a composition comprising the lipo-polyamino acid conjugate, or alternatively, the self-assembled particle as defined herein, together with one or more appropriate excipients or carriers.

[0326] In one 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) the lipo-polyamino acid conjugate as defined herein, wherein at least one of A, A1, A2 or A3 is a pharmaceutically active agent or alternatively, (b) a self-assembled particle containing the lipo- polyamino acid conjugate (a), or alternatively, (c) a self-assembled particle which comprises the lipo- polyamino acid conjugate as defined herein and one or more active agents selected from the group consisting of pharmaceutically active agents, nucleic acids, peptides, proteins, and mixtures thereof, together with one or more pharmaceutically acceptable excipients or carriers.

[0327] The expression "therapeutically effective amount" as used herein, refers to the amount of a polymer that, when administered, is sufficient to prevent development of, or alleviate to some extent, one or more of the symptoms of the disease which is addressed. The specific dose of the polymer of the invention to obtain a therapeutic benefit may vary depending on the particular circumstances of the individual patient including, among others, 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.

[0328] For the purpose of the present invention, the term "pharmaceutically acceptable excipients or carriers” refers to components which are appropriate for use in pharmaceutical technology for the preparation of compositions for medical use. Each component should be "acceptable" in the sense of being compatible with the other ingredients of the composition. When used in contact with the tissue or organ of humans and animals should not have excessive toxicity, irritation, allergic response, immunogenicity, or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0329] The lipo-polyamino acid conjugates described in the present disclosure, and the self-assembled particles and pharmaceutical compositions containing them may be used jointly with other, additional drugs, to provide combined therapy. Said additional drugs may be a part of the same pharmaceutical composition or, alternatively, may be provided in the form of a separate composition for simultaneous or non-simultaneous administration.

[0330] In another 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') the lipo-polyamino acid conjugate as defined herein, wherein at least one of A, Ai, A2 or A3 is a diagnostically active agent or alternatively, (b') a self-assembled particle containing the lipo-polyamino acid conjugate (a'), or alternatively, (c') a self-assembled particle which comprises the lipo-polyamino acid conjugate as defined herein and one or more diagnostically active agents, together with one or more diagnostically acceptable excipients or carriers.

[0331] The term "diagnostic composition” refers to a composition suitable for use in diagnostic, particularly in imaging diagnostic technology. The term "diagnostically effective amount” as used herein, refers to the effective amount of a detection polymer that, when administered, is sufficient for the diagnosis of a disease or disorder; particularly as imaging diagnostic use as contrast imaging agent. 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 diagnosticated, and the similar considerations. The diagnostic composition of the present invention comprises one or more diagnostically acceptable excipients or carriers. The term "diagnostically acceptable” refers to that excipients or carriers suitable for use in the diagnosing technology for preparing compositions with diagnostic use; particularly by imaging diagnostic use. The detection of these diagnostic agents in the body of the patient can be carried out by the well-known techniques used such as in imaging diagnostic with magnetic resonance imaging (MRI) and X-ray.

[0332] In another 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”) the lipo-polyamino acid conjugate as defined herein, wherein at least one of A, A1, A2 or A3 is a cosmetically active agent or alternatively, (b”) a self-assembled particle containing the lipo-polyamino acid conjugate (a”), or alternatively, (c”) a self-assembled particle which comprises the lipo-polyamino acid conjugate as defined herein and one or more cosmetically active agents, together with one or more cosmetically acceptable excipients or carriers. The term "cosmetically effective amount” as used herein, refers to the effective amount of a cosmetically active agent that, when administered, is intended to improve its appearance or to beautify, preserve, condition, cleanse, color or protect the skin, nails or hair without a medical application. The term "cosmetically acceptable" or "dermatologically acceptable" excipients or carriers is used interchangeably in this document and refer to components which are appropriate for use in human skin contact without toxicity, incompatibility, instability, inappropriate allergic response, among others.

[0333] The compositions of the invention may be in solid or liquid form. Non-limiting examples of solid forms include frozen forms, lyophilized forms and spray-dried forms. Depending on the desired purpose, the skilled person will know the most appropriate formulation and excipients to be used. Examples of excipients or carriers include, without limitation, diluents, binders, glidants, disintegrants, lubricants colorants, mixtures thereof, and other components known in the state of the art. Any administration route may be used such as e.g. oral, topical, rectal or parenteral route (including subcutaneous, intraperitoneal, intradermal, intramuscular, intravenous route, etc.).

[0334] Uses

[0335] The lipo-polyamino acid conjugates of the invention, self-assembled particles, and compositions thereof may be used in therapeutic applications. In particular, they may be used as non-viral vectors of general use for biomedical applications, such as vaccines or gene therapy, being effective for transfection of hosts eukaryotic cells in culture, in vivo or ex vivo, monocellular parasites and bacteria, including gene editing using the CRISP / Cas9 methodology. Further, they may be used in protein-based therapy; particularly protein-based vaccine against viral infections or as a therapeutic protein-based vaccine against cancers or infectious diseases.

[0336] Thus, the invention relates to a therapeutic product which is or which comprises: a) a lipo-polyamino acid conjugate of formula (I) as defined herein, wherein at least one of A, Ai, A2 or A3 is a pharmaceutically active agent; or alternatively, b) a self-assembled particle containing the lipo-polyamino acid conjugate a); or alternatively, c) a composition containing the lipo-polyamino acid conjugate a) or the self-assembled particle b); or alternatively, d) a self-assembled particle which comprises the lipo-polyamino acid conjugate as defined herein and one or more active agents selected from the group consisting of pharmaceutically active agents, nucleic acids, peptides, proteins, and mixtures thereof; or alternatively, e) a composition containing the selfassembled particle d), for use in medicine.

[0337] This aspect may also be formulated as a method for treating or preventing a disease or disorder in a subject, more particularly a mammal, and even more particularly a human, comprising administering the therapeutic product as defined herein, and one or more pharmaceutically acceptable excipients or carriers.

[0338] Non-limiting examples of diseases that may be treated and / or prevented by the derivatives of the present invention include neurodegenerative disorders, neurological diseases, cancer, infectious diseases, disorders related to aging, neuro-inflammation, demyelinating disorders, multiple sclerosis, ischemic disorders, ischemia-reperfusion damage, amyloidotic disease, cardiomyopathy, spinal cord injury, immune disorders, inflammatory disorders, rare diseases, wound healing, skin related diseases and lysosomal storage diseases.

[0339] Non-limiting examples of neurodegenerative diseases include Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, cerebral ischaemia, post-encephalitic Parkinsonisms, dystonias, Tourette syndrome, periodic limb movement pathologies, restless legs syndrome, attention deficit hyperactivity disorders, Huntington's disease, progressive supranuclear palsy, Pick's disease, fronto-temporal dementia and neuromuscular diseases.

[0340] In one embodiment, optionally in combination with any of the embodiments provided above or below, the invention relates to a therapeutic product which is or which comprises: a) a lipo-polyamino acid conjugate of formula (I) wherein any of A, Ai, A2 or A2 is an anticancer agent or an anti-infective agent as defined herein; or alternatively, b) a self-assembled particle containing the lipo-polyamino acid conjugate a); or alternatively, c) a composition containing the lipo-polyamino acid conjugate a) or the self-assembled particle b); or alternatively, d) a self-assembled particle which comprises the lipo-polyamino acid conjugate as defined herein and one or more anticancer agents or anti-infective agents; or alternatively, e) a composition containing the selfassembled particle d); for use in the treatment and / or prevention of cancer or an infectious disease, respectively.

[0341] The term "disorder" as used herein is intended to be generally synonymous, and is used interchangeably with, the terms "disease," "syndrome," and "condition" (as in medical condition), in that all reflect an abnormal condition of the human or animal body or of one of its parts that impairs normal functioning, is typically manifested by distinguishing signs and symptoms.

[0342] In the context of the present invention, the terms "treat", "treating" and "treatment", as used herein, refers to ameliorating symptoms associated with a disease or disorder, including preventing or delaying the onset of the disease or disorder symptoms, and / or lessening the severity or frequency of symptoms of the disease or disorder.

[0343] According to one embodiment, optionally in combination with any of the embodiments provided above or below, the invention relates to the therapeutic product as defined herein for use (i) as transfection reagent for transfecting at least one active agent into a cell; (ii) for use in the in vivo or ex vivo production of biologies encoding a recombinant protein, a peptide or an antibody, or in the production of recombinant virus; (iii) for use as a therapeutic or prophylactic vaccine against viral infections or as a therapeutic vaccine against cancers or infectious diseases; or (iv) for use in genome engineering, for cell reprogramming, for differentiating cells or for gene-editing.

[0344] In a particular embodiment, optionally in combination with any of the embodiments provided above or below, the present invention relates to the therapeutic product as defined herein as transfection reagent for delivering one or more nucleic acids (regardless of size and structure, circular and linear nucleic acids) to target cells, in in vivo, in vitro or ex vivo. More particularly, the active agent is selected from the group consisting of low molecular weight drugs, peptides, proteins, antibodies, nucleic acids, aptamers, and combinations thereof.

[0345] The present invention also relates to a method for in vitro, ex vivo and in vivo transferring active agents comprising the therapeutic product as defined herein.

[0346] In a particular embodiment, optionally in combination with any of the embodiments provided above or below, the therapeutic product is a self-assembled particle which comprises the lipo-polyamino acid conjugate as defined herein and one or more nucleic acids, or alternatively, a composition containing the self-assembled particle which comprises the lipo-polyamino acid conjugate as defined herein and one or more nucleic acids.

[0347] The transfection reagents of the invention are also useful for co-transfection of two or more active agents simultaneously, e.g. two or more nucleic acids, simultaneously. Transfection compositions (such as kits), as well as methods of using the transfection reagents to deliver nucleic acid to target cells are also within the scope of the present invention.

[0348] The present invention also provides therapeutic products as defined herein for inducing a regulating effect on the expression of one or more target proteins responsible or involved in genetic hereditary diseases or complex genetic diseases, immune diseases, cancers, viral infections in various tissues / organs or tumors.

[0349] The present invention also relates to the in vitro or ex vivo use of therapeutic products as defined herein in the production of biologies, in particular biologies encoding a recombinant protein, a peptide or an antibody; or in the production of recombinant virus, such as adeno-associated virus (AAV), lentivirus (LV), adenovirus, oncolytic virus, or baculovirus, or viral or virus-like particles, in particular said products comprising the lipo- polyamino acid conjugates of the invention and at least one nucleic acid molecule for transfection. As used herein, the term "biologies” refers to proteins or nucleic acids or combinations thereof, living entities such as cells or viruses, cell compartments, organoids, and tissues.

[0350] The present invention also relates to an in vitro or ex vivo use of the therapeutic products as defined herein, in particular said products comprising the lipo-polyamino acid conjugates of the invention and at least one nucleic acid molecule for transfection, for genome engineering, for cell reprogramming, for differentiating cells or for gene-editing.

[0351] The compositions for transfecting cells comprise the therapeutic products as defined herein, in particular said products comprising the lipo-polyamino acid conjugates of the invention and at least one nucleic acid molecule for transfection, and an acceptable excipient, buffering agent, cell culture medium, or transfection medium. The present invention is also directed to the therapeutic products as defined herein for use as a therapeutic or prophylactic vaccine against viral infections, or a therapeutic vaccine against cancers. Generally, in this aspect, the vaccine is delivered through direct administration such as systemic, intramuscular, intradermal, intraperitoneal, intratumoral, oral, topical, or sub-cutaneous administration, and, in said vaccine, the composition is in association with a pharmaceutically acceptable vehicle. In other words, the vaccine can be injected directly into the body, in particular in a human individual, for inducing a cellular and / or a humoral response.

[0352] The cell targeting is achieved through different mechanisms and depends on the nature and properties of the transfection reagent, method or protocol composition or formulation and the route of administration.

[0353] The lipo-polyamino acid conjugates of the invention, self-assembled particles, and compositions thereof may be used also in cosmetic and diagnostic applications.

[0354] Accordingly, another aspect of the invention relates to a diagnostic product which is or which comprises: a') a lipo-polyamino acid conjugate as defined herein, wherein at least one of A, Ai, A2 or A3 is a diagnostically active agent; or alternatively, b') a self-assembled particle containing the lipo-polyamino acid conjugate i'); or alternatively, c') a composition containing the lipo-polyamino acid conjugate i') or the self-assembled particle ii'); or alternatively, d') a self-assembled particle which comprises the lipo-polyamino acid conjugate as defined herein and one or more diagnostically active agents; or alternatively, e') a composition containing the self-assembled particle iv'), for use in diagnostics.

[0355] This aspect of the invention may also be formulated as the use of a') a lipo-polyamino acid conjugate as defined herein, wherein at least one of A, A1, A2 or A3 is a diagnostically active agent; or alternatively, b') a self-assembled particle containing the lipo-polyamino acid conjugate a'); or alternatively, c') a composition containing the lipo-polyamino acid conjugate a') or the self-assembled particle b'); or alternatively, d') a selfassembled particle which comprises the lipo-polyamino acid conjugate as defined herein and one or more diagnostically active agents; or alternatively, e') a composition containing the self-assembled particle d'), in diagnostics. Further, it may also be formulated as a method for the diagnostic of a disease or condition, comprising administering a') a lipo-polyamino acid conjugate as defined herein, wherein at least one of A, A1, A2 or A3 is a diagnostically active agent; or alternatively, b') a self-assembled particle containing the lipo- polyamino acid conjugate a'); or alternatively, c') a composition containing the lipo-polyamino acid conjugate a') or the self-assembled particle b'); or alternatively, d') a self-assembled particle which comprises the lipo- polyamino acid conjugate as defined herein and one or more diagnostically active agents; or alternatively, e') a composition containing the self-assembled particle d'), in a subject in need thereof, more particularly a mammal, and even more particularly a human.

[0356] In a particular embodiment, the invention relates to microbubbles which comprise the lipo-polyamino acid conjugate as defined herein and one or more diagnostically active agents, in particular contrast agents, for use in diagnostics.

[0357] The detection of these imaging agents can be carried out by well-known techniques such as imaging diagnostic techniques. Examples of imaging diagnostic techniques suitable for the present disclosure include, but not limited to, are magnetic resonance imaging (MRI), X-ray, positron emission tomography (PET), singlephoton emission computed tomography (SPECT), fluorescence microscopy, and in vivo fluorescence.

[0358] According to another aspect, the invention relates to the use in cosmetics of a cosmetic product which is or which comprises: a") a lipo-polyamino acid conjugate as defined herein, wherein at least one of A, Ai, A2 or A3 is a cosmetically active agent; or alternatively, b”) a self-assembled particle containing the lipo-polyamino acid conjugate a'); or alternatively, c”) a composition containing a") or the self-assembled particle b”); or alternatively, d”) a self-assembled particle which comprises the lipo-polyamino acid conjugate as defined herein and one or more cosmetically active agents; or alternatively, e”) a composition containing the selfassembled particle d”).

[0359] Throughout the description and claims the word "comprise" and variations of the word, are not intended to exclude other technical features, additives, components, or steps. Furthermore, the word "comprise” encompasses the case of "consisting of”. Additional objects, advantages and features of the invention will become apparent to those skilled in the art upon examination of the description or may be learned by practice of the invention. The following examples and drawings are provided by way of illustration, and they are not intended to be limiting of the present invention. Furthermore, the present invention covers all possible combinations of particular and preferred embodiments described herein.

[0360] Examples

[0361] Analytical methods

[0362] NMR spectroscopy

[0363] NMR spectra were recorded at 27 °C (300 K) on a 300 UltrashieldTM from Bruker (Billerica MA, USA). Data were processed with the software Topspin (Bruker GmbH, Karlsruhe, Germany). Samples were prepared at a concentration of 20 - 10 mg / mL approx, in the required solvent.

[0364] Size Exclusion Chromato raphy (SEC)

[0365] For SEC measurements in dimethylformamide (DMF) containing 0.1 % (w / w) of lithium bromide as an additive, a GPC max (Malvern Instruments) autosampler was used with a flow rate of 0.7 mL / min at 60 °C with TSKgel Alpha-4000 column from Tosoh Bioscience. Viscotek TDA-302 was used as an integrated detection system. The system was calibrated with polymethyl methacrylate (PMMA) (Mw = 65 kDa; PDI = 1.05) from PSS. For this Mw determination an integrated triple detection system was used [Refractive Index, Light Scattering (two angles: 7 and 90 °) and Ultraviolet-Visible detector]. For SEC measurements in aqueous containing 0.1 M of sodium nitrate and 0.005% of sodium azide as an additive, a GPC max (Malvern Instruments) pump and autosampler was used with a flow rate of 0.7 mL / min at 25 °C with TSKGel PWXL G5000 column from Tosoh Bioscience. Viscotek TDA-305 was used as an integrated detection system. The system was calibrated with polyethylene oxide (PEO) (Mw = 24 kDa; PDI = 1.01) from Malvern Panalytical. For this Mw determination an integrated triple detection system was used [Refractive Index, Light Scattering (two angles: 7 and 90 °) and Ultraviolet-Visible detector].

[0366] Size Distribution

[0367] 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 water or PBS at different concentrations and temperatures), solutions were sonicated for 10 min and allowed to age for the required time, filtered through a 1.20 pm cellulose membrane filter and measured. Size distribution was measured (diameter, nm) for each polymer per triplicate with n > 3 measurements, automatic optimization of beam focusing and attenuation was applied for each sample.

[0368] Example 1. Synthesis of lipo-shielding Cx-PMet(O)

[0369] 1. 1. General procedure for one-pot polymerization and end-cappinci of ln-NH-PMet-C(O)CH3 ln-NH2= Initiator

[0370] Methionine NCA (2 g, 11.4mmol) was added to a Schlenk tube fitted with a stirring bar and a stopper. After 3 cycles of vacuum / N2, the mixture was dissolved in anhydrous THF (100mg reagents per mL THF). Then, the initiator (i.e. Tetradecylamine 96%, TCI EUROPE N.V., 81 mg, 0.381 mmol) was diluted in THF (5 mL) and added to the reaction mixture, which was stirred at RT for 16 hours. Once NCA consumption was confirmed by IR. Then anhydride acetic (0.359 mL, 3.81 mmol) was added to the reaction mixture and the reaction mixture was stirred at 10°C for 2 hours. The reaction mixture was poured into diethyl ether to precipitate the product. The precipitate was isolated by centrifugation (3750 rpm, 4 min) and dried under vacuum. Homopolymer was isolated as a white solid. Yield: 70-90%.

[0371] 1H NMR (300 MHz,TFA-d) 5 5.02-4.88 (m, CH), 3.15 (s, CH3), 2.76 (m, CH2), 2.35-2.19 (m, CH2+ CH3), 1.33 (brs, CH2), 0.93 (f, J = 6.3 Hz, CH3).

[0372] Table 1. Polymers based on -In-NH-PMet: (PMet) determined by NMR. determined by GPC, wherein the cited DP numbers are subject to a reasonable uncertainty within the range ±20%.

[0373] 1.2 General procedure for oxidation of capped In-NH-PMetO

[0374] Cx-PMet dissolved in water (50 mg / mL) containing Camphorsulfonic Acid (CSA) (0.2 eq per Methionine unit). Then, tert-butylHydroperoxide 70% (TBHP) (16 eq per Methionine unit) was added to the reaction mixture gradually (4eq / hour) and stirred for 16 minutes at room temperature. After this time, Na2S2O3'5H2O 1 M (10% of the total volume) was added to stop the oxidation. The mixture was dialyzed against 10% methanol (aq) (Mw cutt of 3000 Da) during 24h and lyophilized. The final product was isolated as a white solid. Yield: 40-501H NMR (300 MHz, D2O) 5 5.47 (brs, CH), 4.05 - 3.72 (m, CH2), 3.52 (s, CH3), 3.23 - 3.03 (m, CH2), 1 .88 (brs, CH2), 1.43 (t, J = 6.8 Hz, CH3).

[0375] Table 2. Polymers based on capped Cx-PMet oxidated (PMet(O))n determined by NMR. determined by GPC, wherein the cited DP numbers are subject to a reasonable uncertainty within the range ±20%>. Example 2. General procedure for the synthesis of Polymethionine Oxides from a urethane derivative: N-

[0376] (phenoxycarbonyl)-L-methionine

[0377] 2.1. Synthesis of Urethane Derivative: N-(phenoxycarbonyl)-Lmethionine (L-Met):

[0378] To a stirred suspension of L-methionine (30 g, 0.201 mol) in methanol 240 mL, tetrabutylammonium hydroxide (37% in methanol) (52.2 g, 0.201 mmol) was slowly added at room temperature. After stirring for thirty minutes, the reaction mixture was concentrated under reduced pressure. The resulting residue was dissolved into acetonitrile (240 mL), and then the resulting solution added dropwise to a stirred solution of diphenyl carbonate (DPC) (43 g, 0.201 mmol) in acetonitrile (240 mL) at room temperature. After stirring the solution for an hour, the distilled water (500 mL) was added into the resulting mixture.

[0379] The resulting mixture was acidified to pH 2-3 with 1 M HCI aqueous solution, and then extracted with ethyl acetate (3 x 500 mL). The combined organic layer was dried over Na2SO4, filtrated, and concentrated under reduced pressure. The crude products were purified by column chromatography (eluting with a gradient from 30-70% ethyl acetate in n-hexane), and then concentrated to give a urethane derivative, L-Met, as a colorless oil which crystallized. Yield: 60%.

[0380] 1H NMR (500 MHz, CDCI3, 5, ppm): 2.00-2.17 (m, 4H), 2.25 (m, 1 H), 2.62 (m, 2H), 4.59 (m, 1 H), 5.83 (d, 1 H, J = 8.0 Hz), 7.07-7.16 (m, 2H), 7.17-7.24 (m, 1 H), 7.31-7.40 (m, 2H).

[0381] 2.2. Synthesis of polypeptide through polycondensation of urethane derivative (L-PMet). Urethane derivative of L-methionine, L-Met (3 g, 0.011 mol) was dissolved in DMA:Chloroform 1 :1 and initiator solution was added. Depending on the initiator used, the reagent will dissolve in DMA (N-butylamine and N-tetradecylamine) or solvent mixtures will be necessary due to the solubility of the initiator: for lipidic initiators such as 1 ,2-dimyristoyl-sn-glycerol-3-phosphoethanol amine, N-ditetradecylamine or ditetradecyl-N- glycine-amine it was necessary to dissolve the initiator in chloroform at a ratio of 1 :3 with respect to the DMA concentration. The mixture was placed into flame-dried Schlenk tube and heated at 60°C for 24 h. The reaction mixture was cooled to room temperature and poured into diethyl ether. The resulting precipitates were collected by filtration given rise a white product. Yield: 50-60% nBu-PMet,1H NMR (500 MHz, TFA, 5, ppm): 0.90 (t, J=7.4 Hz, CH3), 1.34 (dd, J= 15.1, 7.5 Hz, CH2), 1.55 (dd, J= 14.1 , 7.4 Hz, CH2), 2.12 (brs, CH3), 2.15-2.28 (m, CH2), 2.65 (m, CH2), 4.84 (brs, CH).

[0382] N-Tetradecyl-PMet,1H NMR (500 MHz, TFA, 5, ppm): 0.82 (t, J=6.8 Hz, CH3), 1.28 (m, CH2), 1.58 (brs, CH2), 2.12 (brs, CH3), 2.15-2.28 (m, CH2), 2.65 (m, CH2), 4.82 (brs, CH).

[0383] 1 ,2-dimyristoyl-sn-glycerol-3-phosphoethanol amine -PMet,1H NMR (500 MHz, TFA, 5, ppm): 0.78 (t, J=6.4 Hz, CH3), 1.25 (m, CH2), 1.64 (brs, CH2), 2.07 (brs, CH3), 2.12-2.19 (m, CH2), 2.60 (m, CH2), 3.66 (d, J= 17.7 Hz, CH2), 4.82 (brs, CH).

[0384] N-Ditetradecyl-PMet,1H NMR (500 MHz, TFA, 5, ppm): 0.82 (t, J=6.8 Hz, CH3), 1.28 (m, CH2), 1.58 (brs, CH2), 2.12 (brs, CH3), 2.15-2.28 (m, CH2), 2.65 (m, CH2), 4.80 (brs, CH).

[0385] N-Ditetradecylamine-N-glycine-PMet,1H NMR (500 MHz, TFA, 5, ppm): 0.82 (t, J=6.8 Hz, CH3), 1.28 (m, CH2), 1.58 (brs, CH2), 2.12 (brs, CH3), 2.15-2.28 (m, CH2), 2.65 (m, CH2), 3.72 (m, CH2), 4.80 (brs, CH).

[0386] Synthesis of L-PMet(O):

[0387] The experimental procedure for the oxidation step is described above. nBu-PMet(O),1H NMR (500 MHz, TFA, 5, ppm): 0.99 (t, J=7.4 Hz, CH3), 1.42 (dd, J= 15.0, 7.5 Hz, CH2), 1.63 (m, CH2), 1.50-1.70 (m, CH2), 2.98 (s, CH3), 3.17-3.48 (m, CH2), 4.92 (brs, CH).

[0388] N-Tetradecyl-PMet,1H NMR (500 MHz, TFA, 5, ppm): 0.93 (t, J=6.7 Hz, CH3), 1.38 (brs, CH2), 1.66 (m, CH2), 1.50-1.70 (m, CH2), 3.00 (s, CH3), 3.17-3.48 (m, CH2), 4.96 (brs, CH).

[0389] 1 ,2-dimyristoyl-sn-glycerol-3-phosphoethanol amine -PMet,1H NMR (500 MHz, TFA, 5, ppm): 0.93 (t, J=6.7 Hz, CH3), 1.40 (brs, CH2), 1.78 (m, CH2), 1.50-1.70 (m, CH2), 2.99 (s, CH3), 3.17-3.48 (m, CH2),3.83 (m, CH2), 4.95 (brs, CH).

[0390] N-Ditetradecyl-PMet,1H NMR (500 MHz, TFA, 5, ppm): 0.91 (t, J=6.7 Hz, CH3), 1.37 (brs, CH2), 1.66 (m, CH2), 1.50-1.70 (m, CH2), 2.99 (s, CH3), 3.17-3.48 (m, CH2), 4.95 (brs, CH).

[0391] N-Ditetradecylamine-N-glycine-PMet1H NMR (500 MHz, TFA, 5, ppm): 0.89 (t, J=6.9 Hz, CH3), 1.36 (brs, CH2), 1.75 (m, CH2), 1.50-1.70 (m, CH2), 2.96 (s, CH3), 3.17-3.48 (m, CH2), 4.92 (brs, CH).

[0392] Table 3. Polymers based on capped PMetO with different initiators: determined by NMR. determined by SEC, wherein the cited DP numbers are subject to a reasonable uncertainty within the range ±20%.

[0393] 2.3. End capping of polymer of formula PMetO9 with Tocopherol succinate:

[0394] PMetO9-VitE

[0395] Tocopherol succinate (4.22 mmol) was added to a round bottom flask with a stirrer bar, a stopper and purged with 3 cycles of vacuum / N2, dissolved in DMSCkFW (mL). Then, DMTMM'BF4 coupling agent was added to a round bottom flask with a stirrer bar, a stopper and purged with 3 cycles of vacuum / N2, and dissolved in anhydrous DMSCkFW (mL). DMTMM'BF4 solution was added over tocopherol succinate solution under inert atmosphere and let to react at r.t. for 30 min with stirring. A few drops of N, N-diisopropy lethy I amine (DIPEA) were added until pH rising to 6-7. Afterwards, PMetO9 (6.19 mmol) was added to a round bottom flask with a stirrer bar, a stopper and purged with 3 cycles of vacuum / N2, and dissolved in anhydrous DMF (mL). After the 30-minutes, the PMetO9 solution was added over the reaction mixture under inert atmosphere. pH adjustment to 8-9 was performed with DIPEA addition. The mixture was stirred at r.t. for 48 hours at r.t avoiding direct light contact. The amphiphile 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 two times with diethyl ether and dried under vacuum. For further purification, the obtained solid was redissolved in methanol at 500 mg / mL and then the solution was poured again into diethyl ether (1 :10 to methanokdiethyl ether), washed two times with diethyl ether and dried under vacuum at least for 2 hours. Finally, the solid was dissolved in distilled water and diafiltrated in a tangential flow filtration system with the addition of some drops of HCI for total DIPEA purification. The solution was freezed and lyophilized to obtain an off-white solid. Conjugation % = 87%

[0396] PMetO9-VitE, 1H NMR (500 MHz, MeOD, 5, ppm): 0.90 (t, J=8.3 Hz, CH3), 0.97 (t, J=7.3Hz, CH3), 1.06-1.69 (m, CH2), 2.03 (m CH2), 2.12 (brs, CH3), 2.28-2.60 (m, CH2), 2.69 (s, CH3), 2.80-3.31 (m, CH2), 4.39 (brs, CH)

[0397] Table 4. Polymers based on capped In-PMet oxidated end capped with VitE PMetO9-VitE: determined by NMR. determined by GPC, wherein the cited DP numbers are subject to a reasonable uncertainty within the range ±20%.

[0398] Example 3. General procedure of random copolypeptides containing alanine of formula Ci4-(PMet(O)c-co-

[0399] PAIad):

[0400] PMetOPAIa 1 -3

[0401] The following random copolymers were first synthesized via ROP polymerization by including Alanine-NCA to Methionine-NCA mixture solution, and followed as described in Example 1.1. The initiator employed in these polymerizations was tetradecylamine. After the polymerization, the methionine units of the compounds of formula Ci4-(PMetx-co-PAIay) were oxidized as described in Example 1.2. to obtain the following compounds disclosed in table 4:

[0402] Table 5. Polymers based on capped Ci4-(PMet(O)x-co-PAIay): determined by NMR. determined by GPC, wherein the cited DP numbers are subject to a reasonable uncertainty within the range ±20%>. Example 4. General procedure for the Ni and Co initiated PMet polymerizations.

[0403] The following polymers were synthesized according to the synthetic protocol described in reference J. Am. Chem. Soc. 2000, 122, 5710-5717 by Deming T. et al., via Cobalt and Nickel-mediated living polymerization of NCAs for polypeptide synthesis.

[0404] After the polymerization, the compounds of formula PMet obtained by polymerization initiated by Nickel or Cobalt, were oxidized as described in Example 1.2.

[0405] Table 6. Polymers based on PMetO: determined by NMR.

[0406] Example 5. General procedure for the synthesis of zwitterionic Ci4-PMetc

[0407] The following compounds were first polymerized by the general protocol described in Example 1.1. Then, the carbonyl functionalization aiming the zwitterionics C14-PMetc, were obtained as described in the reference A. R. Rodriguez, U.-J. Choe, D. T. Kamei, T. J. Deming, "Use of Methionine Alkylation to Prepare Cationic and Zwitterionic Block Copolypeptide Vesicles”, Isr. J. Chem. 2016, 56, 607.

[0408] Table 7. Polymers based on Ci4-PMetc(PMetCn): determined by NMR.

[0409] Example 6. Lipid nanoparticles formulation

[0410] In the following examples the oligonucleotides used were: a mRNA purchased from Trilink, with reference L- 1201-1000 CleanCap Flue mRNA (5moU) expressing luciferase as reporter gene. Any other oligonucleotide with the characteristics above indicated could be used to carry out the experiments below.

[0411] The ionizable lipid (6Z,9Z,28Z,31Z)-heptatriacont-6,9,28,31-tetraene-19-yl 4-(dimethylamino)butanoate (DLin- MC3-DMA) was purchased from Nanosoft Polymers, or [(4-Hydroxybutyl)azanediyl]di(hexane-6, 1-diyl) bis(2- hexyldecanoate) (ALC-0315) was purchased from BroadPharmShielding lipid 1 ,2-Dimyristoyl-rac-glycero-3- methoxypolyethylene glycol-2000 (DMG-PEG2000) was purchased from Avanti Polar Lipids. Both polymers were used to form benchmark LNPs. Structural lipids used to form LNPs were: 1 ,2-distearoyl-sn-glycero-3- phosphocholine (DSPC, from Avanti Polar Lipids, 850365P) and Cholesterol (Sigma-Aldrich, C8667).

[0412] Formulation of LNPs were performed by following two different protocols:

[0413] A) A microfluidic HerringboneMixer from Darwing Microfluidics was used for the formulations of LNPs 1-2. The reactor presents 2 inlet-channels (one for the DNA in aqueous phase and the other for the lipid mixture in ethanol) and 1 outlet-channel. The specifications of the mixer are the following:

[0414] • Slide format: 25 x 75 m

[0415] • Channel depth: 0.08 mm

[0416] • Channel width: 0.1 to 0.5 mm

[0417] • Volume: 3.3 piL

[0418] • Volume Mixer: 0.47 piL

[0419] • Length Mixer: 28.7 mm

[0420] • Material: Glass

[0421] • Connectors: 1 / 4"-28 Fittings

[0422] In addition, two programmable pumps control the fluid flow rates of the syringes (NE-1000 Programmable Single Syringe Pump, Syringe Pump, USA). The system accepts infusion rates from 0.73 piL / h (1 mL syringe) to 2100 mL / h (60 mL syringe). This methodology provides reproducibility to the formation of LNPs as well as the possibility of scaling up the process.

[0423] Benchmark LNPs were formulated as follows: • Lipids were disolved in ethanol at 50 / 10 / 38.5 / 1.5 molar ratio (MC3 / DSPC / Cholesterol / DMG-PEG)

[0424] • pDNA was diluted in acetat buffer 25 mM at pH 4

[0425] • Amine to phosphate ratio (N / P) was 4

[0426] • Flow ratio was 3:1 (ethanol: H2O)

[0427] • Total flow was 2 mL / min

[0428] • Tubing internal diameter was 0.5 mm

[0429] • After formulation, LNPs were diluted in 10 mM Phosphate buffer saline (PBS) pH 7.4 and concentrated with centrifugal concentrators (Vivaspin™ 500, Sigma) to remove ethanol

[0430] The formulations containing the lipo-polyamino acid conjugates of formula (I) were prepared analogously with the difference that lipo-polyamino acid conjugates of formula (I) were used instead of DMG-PEG and the lipid ratio was different (shown below in Example 7).

[0431] B) LNPs 3 to 7 formulated with Nanoscaler (KNAUER).

[0432] LNPs 3 to 7 were formulated with NanoScaler (KNAUER) as follows:

[0433] • Lipids were dissolved in ethanol at 46.3 / 9.4 / 42.7 / 1.6 molar ratio (ALC-0315 / DSPC / Cholesterol / DMG- PEG).

[0434] • mRNA was diluted in acetate buffer 25 mM at pH 4

[0435] • Amine to phosphate ratio (N / P) was 6.2

[0436] • Flow ratio was 1 :3 (ethanol: H2O)

[0437] • Total flow rate for LNPs was 4.5 mL / min (3mL / min undiluted LNPs + 1 .5mL / min in -line dilution with PBS)

[0438] After formulation, LNPs 3 to 7 were further diluted in 10 mM Phosphate buffer saline (PBS) pH 7.4 to decrease ethanol concentration and purified with centrifugal concentrators (Vivaspin™ 500, Sigma) to remove ethanol. The formulation containing the polymer of the invention was prepared analogously with the difference that different polymers was used instead of shielding lipid DMG-PEG and the lipid ratio was different (shown below in Example 7).

[0439] Example 7. LNPs characterization

[0440] 7.1 Size and polydispersity

[0441] Size and polydispersity (PDI) of the formulated LNPs containing mRNA at N / P= 6.17 (positively chargeable polymer amine (N = nitrogen) groups to negatively-charged nucleic acid phosphate (P)), were performed using a Stunner instrument, equipped with a combination of UV / Vis for RNA concentration determination and dynamic light scattering (DLS). DLS is equipped with a 660 nm laser diode and 2 piL of the samples were added in a Stunner plate with a microfluidic circuit, which has two fixed pathlengths that cover a wide dynamic range of 0.03-275 OD. Size distribution was measured (diameter, nm) with n > 3 measurements. Benchmark LNPs containing MC3 as ionizable lipid, DMG-PEG as shielding lipid and mRNA as cargo, were formulated at 50 / 10 / 38.5 / 1.5 molar ratios for MC3 / DSPC / Cholesterol / DMG-PEG obtaining the following results:

[0442] Table 8. Size and PDI of comparative benchmark LNPs containing mRNA

[0443] The presence of DMG-PEG at 1 .5% is enough to stabilize the LNPs obtaining a good size (expressed as Z- average) and PDI and reproducible formulations.

[0444] Table 9 shows the results obtained of PMetOI formulated at molar ratio of 5% containing pDNA as cargo.

[0445] Table 9. Size and PDI of PMetOI LNPs containing pDNA.

[0446] Results show when using 5% of polymer the results were consistent in all replicates, showing low PDI values and appropriate sizes.

[0447] This composition was also used to formulate LNPs with different mRNA (Firefly luciferase (luc); RBD and GFP) obtaining low PDI values and appropriate sizes (Table 10-13).

[0448] Table 10. Size and Pdl of PMetOI LNPs containing mRNA luc.

[0449] Table 11. Size and Pdl of PMetOI LNPs containing mRNA luc.

[0450] Table 12. Size and Pdl of PMetOI LNPs containing mRNA RBD.

[0451] Table 13. Size and Pdl of PMetOI LNPs containing mRNA GFP.

[0452] Results show when using 2 and 5% of polymer at different compositions the results were consistent in all replicates, showing low PDI values and appropriate sizes.

[0453] Table 14. Size and Pdl of different PMetO LNPs containing mRNA luc.

[0454] 7.2 Free oligonucleotide detection by gel electrophoresis

[0455] The possible presence of free pDNA or mRNA after LNPs formulation were assessed using an electrophoresis gel as first screening method. To perform the electrophoresis, E-gel Power Snap Electrophoresis Device and E-Gel Power Snap Camera (Invitrogen) was used. 2% agarose gels prepared that include the SYBR Gold DNA marker (E-Gel™ EX Agarose Gels, 2%, Invitrogen) were used following manufacturer's instructions. The LNPs (20 l) composed by the different lipo-polypeptide shieldings indicated in Figure 1 were evaluated, and also the disassembly of the LNPs in the presence of 1% triton X-100 (Scharlab.S.L). Once the gel was loaded (300 ng / well), the equipment protocol was selected according to the type of gel used (in our case, protocol approximately 10 min, although the time could be modified according to the samples).

[0456] In all cases, no free mRNA was observed when different lipo-polypeptide shieldings were tested. However, when 1 %Triton X-100 was used, free mRNA signals were observed due to that capacity of Triton X-100, as a surfactant, to disassemble the different components of the LNPs, and thus, release the LNPs cargo (Representative image of the gels can be observed in Figure 1 and 2).

[0457] 7.3 pKa of the formulated LNPs

[0458] The positively charged amino groups in nanoparticles depends on the pH of the medium and the apparent pKa can predict these changes. The influence of lipo-polypeptides on the LNPs surface can alter this apparent pKa, and therefore, affect on the tranfection efficiency. LNPs apparent pKa values were determined by measuring the fluorescence of 2-(p-toluidino)-6-napthalene sulfonic acid (TNS) during titration with different buffer solutions: from pH 4 to 5.5 (0.5 pH unit increments) with 20 mM Acetate buffer; from pH 6 to 7.5 (0.5 pH unit increments) with 20 mM Phosphate buffer; from pH 8 to 9 (0.5 pH unit increments) with 20 mM Borate buffer. The formulation was diluted to 20 piM lipid concentration with different buffer solutions and added to a black 96-well plate. TNS solution (0.3 mM in DMSO) was added to a final concentration of 6 piM. Fluorescence was quantified at Aem= 445 nm, AeX= 321 nm and the pH at half-maximal fluorescence intensity was defined as pKa.

[0459] Table 15. Different parameters of LNPs formulated with lipo-polypeptides. Total flow used was 2mL / min. N / P ratio was 4.

[0460] Table 16. Different parameters of LNP formulated with lipo-polypeptides. Total flow used was 4.5 mL / min. N / P ratio was 6.17.

[0461] Example 8. In vitro biological studies in HEK293 cells.

[0462] 8.1 Cell Culture

[0463] HEK293 cells were cultured in DMEM high glucose with Glutamax (Gibco- Thermo Fisher # 61965-059) supplemented with 10% of Fetal Bovine Serum (Hyclone # SV30160.03HI, provided by GE Healthcare Europe GmbH) and 1 % penicillin / streptomycin. Transfections were carried out on 96-well plates containing 10OOOcells / well in a final volume of 10Opil, and cells were incubated 24 hours at 37°C and 5% CO2. After 24h from cell seeding, the medium was removed and refreshed with 90pil of complete medium. 10pil of each LNPs formulation were added to the cells. In the case of positive control (Lipofectamine™ 2000 Transfection Reagent, I nvitrogen ™), manufacturer guidelines were followed. After 24 hours cells were recovered and processed.

[0464] 8.2 ATP Evaluation for Cell Toxicity evaluation

[0465] After 24h post-incubation with the LNPs formulation, the medium was aspirated and 50 pil / well of ATPLite reagent (ATPLite PerkinElmer #6016731) were added. The plate was incubated 10 minutes at room temperature in the dark. Luminiscence was read spectrophotometrically using VictorNivo (PerkinElmer) following manufacturer's instructions and data was represented as the percentage of cell viability, taken untreated control cells as 100%.

[0466] 8.3 Luciferase Assay for transfection efficiency evaluation

[0467] After 24h post-incubation with the LNPs formulation, 100 l of BrightGlo reagent (Promega # E2620) was added in each well following manufacturer instructions. After 5 minutes of incubation at room temperature luciferase activity was measured using VictorNivo (PerkinElmer). Data was represented as luminescence relative to the percentage of transfection relative to the positive control of transfection.

[0468] 8.4. Biological activity of LNPs in HEK293 cells

[0469] The transfection efficiency and the cell viability of the LNPs formulations in HEK293 cells is reported in the following table. The transfection data is represented as % of the positive control DMG-PEG with the formulation reported 46.3 / 9.4 / 44.3-x / x molar ratios for ALC-0315 / DSPC / Cholesterol / DMG-PEG or PMetOn being x the different molar ratios for each PMetOn employed, and being the positive control 100% after 24h of treatment and cell viability is compared to non-treated (NT) cells, being the ATP content readout of NT (nontreated) cells equal to 100%.

[0470] Table 17. Different parameters of LNPs formulated with lipo-polypeptides. Molar ratio was 46.3 / 9.4 / 44.3-x / x, where x is the lipo-polypeptide. Total flow used was 3+1.5mL / min. N / P ratio was 6.17 and nucleic acid content was 150, 300 and 500 ng mRNA / well. % Transfection is calculated considering the formulation ALC- 0315 / DSPC / Cholesterol / DMG-PEG 46.3 / 9.4 / 42.7 / 1.6 and n=3 for LNP4, n=1 for LNP7, 8 and 9:

[0471] According to the results, the transfection obtained from LNPs containing PMetOI and PMet9 were 1.6-3.2-fold more efficient than the commercial standard DMG-PEG at different concentrations. LNP 8 was 3.2-5.5-fold more efficient than the commercial LNP12 containing DMG-PEG. And LNP9 obtained comparable transfection results to control LNP12.

[0472] Therefore, it can be concluded that by adding different PMetOn into LNPs, the following is obtained: I) stable nanoparticles with acceptable size and polydispersity; II) non-cytotoxic formulation, and ill) high transfection efficiency. These results demonstrate that the PMetOI, PMetO9, PMetOI 0 and PMetOI 2 presented in this application can be alternatives of the actual DMG-PEG compound.

[0473] Example 9. In vivo transfection capacity of LNPs

[0474] 9.1 Experimental details

[0475] All animal experiments were conducted in accordance with the approved animal protocols. For in vivo mRNA transfection, male Balb / c mice aged 6 weeks were intravenously (iv) administered with LNP12 and LNP4 (n=4- 5). At 4 and 24h postinjection of LNP12 (n=4), and LNP4 (n=5), mice were injected subcutaneously Luciferin (15 mg / kg), and after 10 minutes mice were euthanized via CO2 inhalation and organs dissected (blood, liver, spleen, lungs, heart, kidney and ALNs (Axillary lymph nodes)). Image acquisition was obtained by MS Spectrum (settings: Binning factor 8 F / Stop 1 Exp AUTO FOV 22,5 (D)). The weight of the different organs was obtained and then freezed with N2 and -80°C. Image Analysis was performed by Living Image 4.5.4 (settings: ROI (Draw auto, threshold 2%) and data represented in total counts I tissue g.

[0476] 9.2 In vivo transfection results

[0477] Mice after administration of the different formulations were weighted obtaining the following results:

[0478] Table 17. Body and organs weight (g) of mice administered iv with the formulations at time 4 and 24h.

[0479] Mice body weights remained in the range of 20-23 g, showing no significant differences. Same behavior was observed for all the organs, showing no significant differences between non-treated (PBS) and LNP 12 with mice administered with LNP 4.

[0480] The Image analysis by Living Image 4.5.4 of the different organs dissected showed the total counts per g of tissue in Table 18.

[0481] Table 18. Transfection results obtained by Image analysis in total counts / g of mice administered iv with the formulations of LNP7 as control and LNP4 at time 4 and 24h.

[0482] Statistical analysis by ANOVA One Way, multiple comparisons with Kruskal-Wallis test determined no significant differences between LNP12 (containing DMG-PEG) at 4 h with LNP44h and 24h in liver and the other organs. Therefore, transfection capacity between positive control (LNP12) and LNP4 at 4h have comparable results.

[0483] Citation List

[0484] - Nogueira S. et al., “Polysarcosine-Functionalized Lipid Nanoparticles for Therapeutic mRNA Delivery, ACS Appl. Nano Mater., 2020, 3, 10634-10645

[0485] - T. W. Green and P.G. M. Wuts, Protective Groups in Organic Chemistry, Wiley, 3rd ed. 1999, Chapter 5 (pp. 369-451)

[0486] - T. W. Green and P.G. M. Wuts, Protective Groups in Organic Chemistry, Wiley, 3rd ed. 1999, Chapter 7 (pp. 495-653)

[0487] - Deming T. et al., “Chain Initiation Efficiency in Cobalt- and Nickel-Mediated polypeptide synthesis", J. Am. Chem. Soc. 2000, 122, 5710-5717.

[0488] - Deming T. et al., “Functional Modification of Thioether Groups in Peptides, Polypeptides, and Proteins", Bioconjugate Chem. 2017, 28, 3, 691-700.

[0489] - Rodriguez A. et al., "Use of Methionine Alkylation to Prepare Cationic and Zwitterionic Block Copolypeptide Vesicles”, Isr. J. Chem. 2016, 56, 607.

[0490] Clauses

[0491] For reasons of completeness, various aspects of the invention are set out in the following numbered clauses:

[0492] Clause 1 . A lipo-polyamino acid conjugate of formula (I), a salt thereof, or any stereoisomer or mixtures of stereoisomers, either of the compound of formula (I), or of any of its salts, wherein A, X, X', R1, R / , PAA1, PAA2, n, m, p, s, and A1 are as defined in the first aspect.

[0493] Clause 2. A lipo-polyamino acid conjugate of formula (I), a salt thereof, or any stereoisomer or mixtures of stereoisomers, either of the compound of formula (I), or of any of its salts, as defined in the second aspect.

[0494] Clause 3. The lipo-polyamino acid conjugate according to clauses 1 to 2, which is a copolymer comprising n PAAi repetitive units of formula (II) and m PAA2 repetitive units of formula (III), i.e. it has the formula (IB): more particularly wherein the weight ratio of the PAA1 monomer to the PAA2 monomer in the conjugate is from 95 / 5 to 50 / 50.

[0495] Clause 4. The lipo-polyamino acid conjugate according to any of clauses 1 to 3, wherein m is an integer from 5 to 150, more particularly from 5 to 100, even more particularly from 5 to 50, and even more particularly from 5 to 30 or from 5 to 25, particularly wherein m is measured by1H-NMR spectroscopy.

[0496] Clause 5. The lipo-polyamino acid conjugate according to any of clauses 1 to 4, wherein R4 corresponds to the amino acid the side chain of phenylalanine, alanine, leucine, glycine, isoleucine, or valine, more particularly R4 corresponds to the amino acid the side chain of alanine.

[0497] Clause 6. The lipo-polyamino acid conjugate according to any of clauses 1 to 5, wherein in the PAA2 repetitive units of formula (III), R5 is H.

[0498] Clause 7. The lipo-polyamino acid conjugate according to any of clauses 1 to 5, wherein in the PAA2 repetitive units of formula (III), R5 is -(Ci-Cejalkyl, more particularly R5 is -CH3.

[0499] Clause 8. The lipo-polyamino acid conjugate according to any of the clauses 1 to 2, which has formula (IA)

[0500] Clause 9. The lipo-polyamino acid conjugate according to any of clauses 1 to 8, wherein n is an integer from 5 to 150, more particularly from 5 to 100, even more particularly from 5 to 50, and even more particularly from 5 to 30 or from 5 to 25, particularly wherein m is measured by1H-NMR spectroscopy.

[0501] Clause 10. The lipo-polyamino acid conjugate according to any of clauses 1 to 9, wherein p is 0.

[0502] Clause 11. The lipo-polyamino acid conjugate according to any of clauses 1 to 9, wherein p is 1.

[0503] Clause 12. The lipo-polyamino acid conjugate according to any of clauses 1 to 11, wherein s is 0.

[0504] Clause 13. The lipo-polyamino acid conjugate according to any of clauses 1 to 11, wherein s is 1.

[0505] Clause 14. The lipo-polyamino acid conjugate according to any of clauses 1 to 13, wherein X is N and Ri is H.

[0506] Clause 15. The lipo-polyamino acid conjugate according to any of clauses 1 to 13, wherein X is N and Ri is -(Ci-Cisjalkyl, more particularly -(Ci-Ci2)alkyl.

[0507] Clause 16. The lipo-polyamino acid conjugate according to any of clauses 1 to 13, wherein X is N and Ri is -(C2-Ci8)alkenyl, more particularly -(C2-Ci2)alkenyl.

[0508] Clause 17. The lipo-polyamino acid conjugate according to any of clauses 1 to 13, wherein X is O and Ri is absent.

[0509] Clause 18. The lipo-polyamino acid conjugate according to any of clauses 1 to 13, wherein X is S and Ri is absent.

[0510] Clause 19. The lipo-polyamino acid conjugate according to any of clauses 1 to 13, wherein X is CH and Ri is H, -(Ci-Cisjalkyl, or -(C2-Ci8)alkenyl, more particularly X is CH and Ri is H, -(Ci-Ci2)alkyl, or -(C2-Ci2)alkenyl, and even more particularly X is CH and Ri is H.

[0511] Clause 20. The lipo-polyamino acid conjugate according to any of clauses 1 to 19, wherein R2 is a radical of formula (IV), more particularly, the radical of formula (IV) is selected from the formulas (iv1)-(iv24) as defined herein. Clause 21. The lipo-polyamino acid conjugate according to any of clauses 1 to 19, wherein R2 is a radical of formula (V), more particularly, the radical of formula (V) is selected from the formulas (v1)-(v24) as defined herein.

[0512] Clause 22. The lipo-polyamino acid conjugate according to any of clauses 1 to 19, wherein R2 is a radical of formula (VI), more particularly, the radical of formula (VI) is selected from the formulas (vi1)-(vi72) as defined herein.

[0513] Clause 23. The lipo-polyamino acid conjugate according to clause 22, wherein in R2 of formula (VI), c is an integer from 0 to 3; R is -(Ci-Cejalkyl, and R' is -(Ci-Cejalkyl-CO?.

[0514] Clause 24. The lipo-polyamino acid conjugate according to any of clauses 1 to 23, wherein R3 is H.

[0515] Clause 25. The lipo-polyamino acid conjugate according to any of clauses 1 to 23, wherein R3 is -(Ci-Cejalkyl, more particularly R3 is -CH3.

[0516] Clause 26. The lipo-polyamino acid conjugate according to any of clauses 1 to 25, wherein A is a lipid-like moiety R7, and A1 is other than a lipid-like moiety Rz'.

[0517] Clause 27. The lipo-polyamino acid conjugate according to any of clauses 1 to 26, wherein the lipid-like moiety Rz is -(Ci-C2o)alkyl, more particularly -(Ce-C jalkyl, and even more particularly, either -(Ci2-Cis)alkyl or a radical of the formula (XXIII) as defined herein.

[0518] Clause 28. The lipo-polyamino acid conjugate according to any of clauses 1 to 26, wherein the lipid-like moiety Rz is -(C2-C2o)alkenyl, more particularly -(Ce-C jalkenyl, and even more particularly, either - (Ci2-Cis)alkenyl or a radical of the formula (XXIV) as defined herein.

[0519] Clause 29. The lipo-polyamino acid conjugate according to any of clauses 1 to 26, wherein the lipid-like moiety Rz is a radical of formula (XXV) as defined herein.

[0520] Clause 30. The lipo-polyamino acid conjugate according to any of clauses 1 to 26, wherein the lipid-like moiety Rz is a radical of formula (XXVI) as defined herein.

[0521] Clause 31. The lipo-polyamino acid conjugate according to any of clauses 1 to 26, wherein the lipid-like moiety Rz is a radical of formula (IX) as defined herein.

[0522] Clause 32. The lipo-polyamino acid conjugate according to any of clauses 1 to 26, wherein the lipid-like moiety Rz is a radical of formula (X) as defined herein. Clause 33. The lipo-polyamino acid conjugate according to any of clauses 1 to 26, wherein the lipid-like moiety Rz is a radical of formula (XI), more particularly, a radical selected from the formulas (xi1), (xi2), (xi3), (xi4), (xi5), (xi6), (xi7) and (xi8), as defined herein.

[0523] Clause 34. The lipo-polyamino acid conjugate according to any of clauses 1 to 26, wherein the lipid-like moiety Rz is a radical of formula (XII), more particularly, a radical selected from the formulas (xii1), (xii2), (xii3), and (xii4), as defined herein.

[0524] Clause 35. The lipo-polyamino acid conjugate according to any of clauses 1 to 25, wherein the lipid-like moiety Rz is a radical of formula (XIII), more particularly, a radical of the formula (xiiil) as defined herein.

[0525] Clause 36. The lipo-polyamino acid conjugate according to any of clauses 1 to 25, wherein the lipid-like moiety Rz is a radical of formula (XIV) as defined herein.

[0526] Clause 37. The lipo-polyamino acid conjugate according to any of clauses 1 to 25, wherein the lipid-like moiety Rz is a radical of formula (XV) as defined herein.

[0527] Clause 38. The lipo-polyamino acid conjugate according to any of clauses 1 to 25, wherein the lipid-like moiety Rz is a radical of formula (XVI), more particularly, a radical selected from the formulas (xvi1), (xvi2), (xvi3), and (xvi4) as defined herein.

[0528] Clause 39. The lipo-polyamino acid conjugate according to any of clauses 1 to 25, wherein the lipid-like moiety Rz is a radical of formula (XVII), more particularly, a radical of the formula (xviil) as defined herein.

[0529] Clause 40. The lipo-polyamino acid conjugate according to any of clauses 1 to 25, wherein the lipid-like moiety Rz is a radical of formula (XVIII), more particularly, a radical of formula (xviiil) as defined herein.

[0530] Clause 41 . The lipo-polyamino acid conjugate according to any of clauses 1 to 25, wherein Rz is selected from the group consisting of — (Ci-C2o)alkyl, -(C2-C2o)alkenyl, and a radical of formula (XI), (XII), (XIV), (XV), (XVI), (XVII) or (XVIII).

[0531] Clause 42. The lipo-polyamino acid conjugate according to any of clauses 1 to 10 or 12 to 41, wherein p is 0, and Ai is H.

[0532] Clause 43. The lipo-polyamino acid conjugate according to any of clauses 1 to 10 or 12 to 41, wherein p is 0, and Ai is an amino protective group.

[0533] Clause 44. The lipo-polyamino acid conjugate according to any of clauses 1 to 10 or 12 to 41, wherein p is 0, and Ai is an amino acid-like moiety Rs, being Rs a radical independently selected from the group consisting of (XX), (XXI) and (XXII).

[0534] Clause 45. The lipo-polyamino acid conjugate according to any of clauses 1 to 10 or 12 to 41, wherein p is 0, and Ai is selected from the group consisting of H, -(Ci-Cejalkyl, -(Cs-C jaryl, -(C5-Cio)heteroaryl, -(Ce- Cio)aralkyl, -(Ci-C6)alkyl-0-(C5-Cio)aryl, and - (C5-Cio)heterocycloalkyl; being Ai optionally substituted as defined herein.

[0535] Clause 46. The lipo-polyamino acid conjugate according to any of clauses 1 to 9 or 11 to 41, wherein p is 1, and Ai is selected from the group consisting of H, -OH, -(Ci-Cejalkyl, -(Cs-C jaryl, -(C5-Cio)heteroaryl, -(C6-Cio)aralkyl, -(Ci-C6)alkyl-C-(C5-Cio)aryl, -(C5-Cio)heterocycloalkyl, -(C1-C10) alkoxy, -(C6-Cio)aryloxy, -(C6-Cio)aralkoxy, -(Cs-Ciojheteroaralkoxy, -(Ci-Cio)alkyl-C-(C6-Cio)aryloxy; being Ai optionally substituted as defined herein.

[0536] Clause 47. The lipo-polyamino acid conjugate according to any of clauses 1 to 10 or 12 to 41, wherein p is 0, and Ai is a lipid-like moiety R / .

[0537] Clause 48. The lipo-polyamino acid conjugate according to any of clauses 1 to 9 or 11 to 41, wherein p is 1 , and Ai is a lipid-like moiety R / .

[0538] Clause 49. The lipo-polyamino acid conjugate according to any of clauses 1 to 9 or 11 to 41, wherein p is 1, and Ai is an active moiety selected from the group consisting of a pharmaceutically active agent, a celltargeting agent, a penetration enhancing agent, a cosmetically active agent, and a diagnostically active agent.

[0539] Clause 50. The lipo-polyamino acid conjugate according to any of clauses 1 to 25, wherein Ai is a lipid-like moiety R / and A is other than a lipid-like moiety R7.

[0540] Clause 51 . The lipo-polyamino acid conjugate according to any of clauses 1 to 25, 47 to 48 or 50, wherein A and R1 are the same and are - (Ci-C jalkyl, and X is N, more particularly, the lipo-polyamino acid conjugate of formula (I) has the formula (IC), as defined herein.

[0541] Clause 52. The lipo-polyamino acid conjugate according to any of clauses 1 to 25, 47 to 48 or 50, wherein the lipid-like moiety R7' is -(Ci-C2o)alkyl, more particularly -(Ce-Cisjalkyl, and even more particularly, a radical of the formula (XXIII) as defined herein.

[0542] Clause 53. The lipo-polyamino acid conjugate according to any of clauses 1 to 25, 47 to 48 or 50, wherein the lipid-like moiety R7 is -(C2-C2o)alkenyl, more particularly -(Ce-Cisjalkenyl, and even more particularly, a radical of the formula (XXIV) as defined herein. Clause 54. The lipo-polyamino acid conjugate according to any of clauses 1 to 25, 47 to 48 or 50, wherein the lipid-like moiety Rz’ is a radical of formula (XXIV) as defined herein.

[0543] Clause 55. The lipo-polyamino acid conjugate according to any of clauses 1 to 25, 47 to 48 or 50, wherein the lipid-like moiety Rz is a radical of formula (XXV) as defined herein.

[0544] Clause 56. The lipo-polyamino acid conjugate according to any of clauses 1 to 25, 47 to 48 or 50, wherein the lipid-like moiety Rz is a radical of formula (IX) as defined herein.

[0545] Clause 57. The lipo-polyamino acid conjugate according to any of clauses 1 to 25, 47 to 48 or 50, wherein the lipid-like moiety Rz is a radical of formula (X) as defined herein.

[0546] Clause 58. The lipo-polyamino acid conjugate according to any of clauses 1 to 25, 47 to 48 or 50, wherein the lipid-like moiety Rz is a radical of formula (XI), more particularly, a radical selected from the formulas (xi1), (xi2), (xi3), (xi4), (xi5), (xi6), (xi7) and (xi8), as defined herein.

[0547] Clause 59. The lipo-polyamino acid conjugate according to any of clauses 1 to 25, 47 to 48 or 50, wherein the lipid-like moiety Rz is a radical of formula (XII), more particularly, a radical selected from the formulas (xii1), (xii2), (xii3), and (xii4), as defined herein.

[0548] Clause 60. The lipo-polyamino acid conjugate according to any of clauses 1 to 25, 47 to 48 or 50, wherein the lipid-like moiety Rz is a radical of formula (XIII), more particularly, a radical of the formula (xiiil) as defined herein.

[0549] Clause 61 . The lipo-polyamino acid conjugate according to any of clauses 1 to 25, 47 to 48 or 50, wherein the lipid-like moiety Rz is a radical of formula (XIV) as defined herein.

[0550] Clause 62. The lipo-polyamino acid conjugate according to any of clauses 1 to 18, 38 to 39, or 41, wherein the lipid-like moiety Rz is a radical of formula (XV) as defined herein.

[0551] Clause 63. The lipo-polyamino acid conjugate according to any of clauses 1 to 25, 47 to 48 or 50, wherein the lipid-like moiety Rz is a radical of formula (XVI), more particularly, a radical selected from the formulas (xvi1), (xvi2), (xvi3), and (xvi4) as defined herein.

[0552] Clause 64. The lipo-polyamino acid conjugate according to any of clauses 1 to 25, 47 to 48 or 50, wherein the lipid-like moiety Rz is a radical of formula (XVII), more particularly, a radical of the formula (xviil) as defined herein.

[0553] Clause 65. The lipo-polyamino acid conjugate according to any of clauses 1 to 25, 47 to 48 or 50, wherein the lipid-like moiety Rz’ Rz is a radical of formula (XVIII'), more particularly, a radical of formula (XVIII”) as defined herein .

[0554] Clause 66. The lipo-polyamino acid conjugate according to any of clauses 1 to 25, 47 to 48 or 50, wherein the lipid-like moiety Rz is selected from the group consisting of -(Ci-Ci8)alkyl, -(C2-Ci8)alkenyl, and a radical of formula (XI), (XII), (XIV), (XV), (XVI), (XVII) or (XVIII’).

[0555] Clause 67. The lipo-polyamino acid conjugate according to any of clauses 1 to 9, 11 to 25 or 42 to 66, wherein p is 1, and A is H.

[0556] Clause 68. The lipo-polyamino acid conjugate according to any of clauses 1 to 9, 11 to 25 or 42 to 66, wherein p is 1, and A is a protective group.

[0557] Clause 69. The lipo-polyamino acid conjugate according to any of clauses 1 to 9, 11 to 12, 14 to 25 or 42 to 66, wherein p is 1, s is 0 and A is selected from the group consisting of H, -(Ci-Cejalkyl, -CO(Ci- Cejalkyl, -(Ci-C6)alkyl-CO-N[(Ci-Ci8)alkyl]2, -(Cs-C jaryl, -(Cs-Ciojheteroaryl,

[0558] -(C6-Cio)aralkyl, -(Ci-C6)alkyl-0-(C5-Cio)aryl, -(C5-Cio)heterocycloalkyl, a radical (IV), a radical (V), a radical (VI), a protective group, a lipid-like moiety Rz, an active moiety; being A optionally substituted as defined herein, more particularly A is methyl.

[0559] Clause 70. The lipo-polyamino acid conjugate according to any of clauses 1 to 9, 11 to 25 or 42 to 66, wherein p is 1, and A is selected from the group consisting of a pharmaceutically active agent, a cell-targeting agent, a penetration enhancing agent, a cosmetically active agent, and a diagnostically active agent.

[0560] Clause 71 . A lipo-polyamino acid conjugate of formula (I), a salt thereof, or any stereoisomer or mixtures of stereoisomers, either of the compound of formula (I), or of any of its salts, wherein the lipo-polyamino acid conjugate of formula (I) has the formula (IB'):

[0561] OB’) wherein: X is N or CH; A is selected from the group consisting of butyl, (C12-C18) alkyl, a radical of formula (XXV), and a radical of formula (XXVI); Ri is selected from the group consisting of H and (Ci-Cis)alkyl; R” is selected from the group consisting of H, -CO(Ci-C6)alkyl, a radical of formula (XVIII”), and -CONH(Ci-Ci8)alkyl; R2 is as defined herein, particularly R2 is a radical of formula (VI) or a radical of formula (VI), wherein more particularly in the radical of formula (VI), c is an integer from 0 to 3; R is -(Ci- Cejalkyl, and R' is -(Ci-C6)alkyl-CC>2'. R4 is selected from the group consisting of H, methyl; isopropyl, isobutyl, and sec-butyl; n is a value from 5 to 200, or from 5 to 150, or from 10 to 150, particularly measured by 1 H- NMR spectroscopy; and m is 0 or a value from 5 to 150, or from 5 to 100, or from 5 to 80, or from 10 to 80, particularly measured by 1 H-NMR spectroscopy.

[0562] Clause 72. A self-assembled particle comprising the lipo-polyamino acid conjugate of formula (I) as defined in any of clauses 1-71, and optionally one or more active agents selected from the group consisting of pharmaceutically active agents, cell-targeting agents, penetration enhancing agents, cosmetically active agents, diagnostically active agents, nucleic acids, peptides, proteins, and mixtures thereof.

[0563] Clause 73. The self-assembled particle according to clause 72, and one or more nucleic acids.

[0564] Clause 74. The self-assembled particle according to any of the clauses 72 to 73, wherein the self-assembled particle is a nanoparticle, more particularly selected from the group consisting of a micelle, an inverted micelle, a planar bilayer, a crystal nanoparticle, a liposome, microbubbles, and a lipid nanoparticle, and even more particularly, the self-assembled particle is a lipid nanoparticle or a liposome.

[0565] Clause 75. The self-assembled particle according to any of the clauses 72 to 74, which further comprises one or more lipids selected from the group consisting of ionisable lipids, cationic lipids, neutral lipids, and anionic lipids.

[0566] Clause 76. The self-assembled particle according to any of the clauses 72 to 74, which further comprises a ionizable lipid or a cationic lipid, a phospholipid, and a sterol.

[0567] Clause 77. The self-assembled particle according to clause 76, which is particularly a lipid nanoparticle or a liposome and which comprises: i) the lipo-polyamino acid conjugate of formula (I) as defined in any of clauses 1-70, or any stereoisomer or mixtures of stereoisomers, either of the compound of formula (I), or of any of its salts, in an amount from 0.1 to 10 mol%; ii) a ionizable or a cationic lipid in an amount from 30 to 70 mol%; iii) a phospholipid in an amount from 1 to 20 mol%; iv) a sterol in an amount from 20 to 60 mol%; and wherein the percentages are expressed with respect to the sum of the mol% of the lipids and the lipopolyamino acid conjugate of formula (I);

Claims

Claims1 . A lipo-poly amino acid conjugate of formula (I), a salt thereof, or any stereoisomer or mixtures of stereoisomers, either of the compound of formula (I), or of any of its salts,wherein:PAAi is a repetitive unit of formula (II)PAA2 is a repetitive unit of formula (III)wherein though the repeating units PAA1 and PAA2 are shown in a particular order for convenience of description, the repeating units may be present in any order and may be block or randomly present; and wherein each of the repeating units PAA1 and PAA2 may comprise blocks of monomer units which may be the same or different between each other; n is an integer from 5 to 250; m is an integer from 0 to 250; p is 0 or 1; s Is O or 1 ;X is selected from the group consisting of CH, N, S, and 0;X' is selected from the group consisting of N, and 0;R1 and R / are independently selected from the group consisting of H, -(Ci-Ci8)alkyl, and -(C2-Ci8)alkenyl, withthe condition that R1 is absent when X is 0 or S, and R is absent when X' is 0;R2 is a radical selected from the group consisting of (IV), (V) and (VI)wherein a, b and c are independently an integer from 0 to 3; R is -(Ci-C6)alkyl, and R' is selected from the group consisting of -(Ci-CeJalkyl-SOs' and -(Ci-CeJalkyl-CO?;R3 and R5 are independently selected from the group consisting of H and -(Ci-Ce)alky I;R4 is any amino acid side chain optionally functionalized with an active moiety;A is selected from the group consisting ofH, -(Ci-C6)alkyl, -CO(Ci-C6)alkyl, -(Ci-C6)alkyl-CO-N[(Ci-Ci8)alkyl]2, -(C5-Cio)aryl, -(C5-Cio)heteroaryl, -(C6-Cio)aralkyl, -(Ci-C6)alkyl-0-(C5-Cio)aryl, -(C5-Cio)heterocycloalkyl, a radical (IV), a radical (V), a radical (VI), a protective group, a lipid-like moiety R7, and an active moiety;A1 is selected from the group consisting of H, -OH, -(Ci-Cejalkyl, -(C5-Cio)aryl, -(C5-Cio)heteroaryl, -(C6-Cio)aralkyl, -(Ci-C6)alkyl-0-(C5-Cio)aryl, -(C5-Cio)heterocycloalkyl, -(C1-C10) alkoxy, -(C6-Cio)aryloxy, -(C6-Cio)aralkoxy, -(C5-Cio)heteroaralkoxy, -(Ci-Cio)alkyl-0-(C6-Cio)aryloxy, an amino protective group, a lipid- like moiety R , an amino acid-like moiety Rs, and an active moiety; with the condition that: i) when p is 0, s is 0, and A1 is selected from the group consisting of H, -(Ci-Cejalkyl, -(C5-Cio)aryl, -(C5-Cio)heteroaryl, -(C6-Cio)aralkyl, -(Ci-C6)alkyl-0-(C5-Cio)aryl, -(C5-Cio)heterocycloalkyl, an amino protective group, a lipid-like moiety R , an amino acid-like moiety Rs, and an active moiety; ii) when p is 1 and s is 0, A1 is selected from the group consisting of H, -OH, -(Ci-Cejalkyl, -(C5-Cio)aryl, -(C5-Cio)heteroaryl, -(C6-Cio)aralkyl, -(Ci-C6)alkyl-0-(C5-Cio)aryl, -(C5-Cio)heterocycloalkyl, -(C1-C10) alkoxy, -(C6-Cio)aryloxy, -(C6-Cio)aralkoxy, -(C5-Cio)heteroaralkoxy, -(Ci-Cio)alkyl-0-(C6-Cio)aryloxy, a lipid-like moiety R , and an active moiety; iii) when p is 1 and s is 1 , A1 is selected from the group consisting of H, -(Ci-Cejalkyl, -(C5-Cio)aryl, -(C5-Cio)heteroaryl, -(C6-Cio)aralkyl, -(Ci-C6)alkyl-0-(C5-Cio)aryl, -(C5-Cio)heterocycloalkyl, -(C1-C10) alkoxy, -(C6-Cio)aryloxy, -(C6-Cio)aralkoxy, -(C5-Cio)heteroaralkoxy, -(Ci-Cio)alkyl-0-(C6-Cio)aryloxy, a lipid-like moiety R , and an active moiety; iv) at least one of A and A1 is a lipid-like moiety R? or R ;v) when Ai is H, s is 0, p is 0, X is N, Ri is H, then A is other than butyl; vi) when Ai is H, p is 0, s is 0, X is N, and A is H, then Ri is other than butyl; and vii) when A is methyl, X is N, Ri is H, p is 1 , and s is 0, then Ai is other than a lipid-like moiety Rz of formula (XVII) wherein each j is16 and i is 2; wherein A and Ai are independently optionally substituted by one or more groups selected from the group consisting of -OH, halogen, -CF3, -NH2, -NH-(Ci-C4)alkyl, -NH-CO-(Ci-C6)alkyl, -(Ci-Cejalkyl, -NO2, -N3, -CO-(Ci-C6)alkyl, -CO-O-(Ci-C6)alkyl, -SO3H, -SO2NH2, -SO2-N((Ci-C6)alkyl)2, -COOH, CONH2, -CON((Ci- C6)alkyl)2, of -(CH2)2-SO-CH3, and NH(Ci-C6)alkyl; each lipid-like moiety Rz is independently selected from the group consisting of -(Ci-C2o)alkyl, -(C2-C2o)alkenyl, and a radical of formula (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), or (XVIII)(XV) (XVI) (XVII)(XVIII) each R is independently selected from the group consisting of -(Ci-C2o)alkyl, -(C2-C2o)alkenyl, and a radical of formula (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), or (XVIII’)wherein:Y and Y' are independently selected from -OH, -OCORx and -COORx;Q and Q' are independently selected from -OCORy and -COORy;Z and Z' are independently selected from -O-, -OCO-, -COO-, -NRz'CO-, and -CONRz'-; each Rz' is H or Rz; each Rx, Ry, and Rz is independently -(Ci-Ci8)alkyl or -(C2-Ci8)alkenyl; each g is independently an integer from 0 to 18; each h is independently an integer from 1 to 18;I is an integer from 0 to 18; each j is independently an integer from 0 to 18; t is 0 or 1 , with the condition that t is 0 when X= 0, and t is 1 when X is other than 0; t' is 0 or 1 ; with the condition that t' is 1 when p is 0 and s is 0; and t' is 1 when p is 1 and s is 1;R22, R33 and R44 are independently selected from the group consisting of hydrogen, fluorine, methyl, -CH2F, -CHF2, and -CF3; each of the dashed bonds — is independently a single bond or, alternatively, a double bond;L is a biradical chain which comprises 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-, -S-S-, -SO-, -S02-, -SO2NH2- and -phenylene-, wherein L is optionally substituted with one or more substituents selected from the group consisting of halogen, -OH, -NRaRb, -SH, -NHNH2, -C00Rc, -CF3, -OCF3,wherein when L comprises a -CH2- moiety, the two hydrogen atoms attached to the carbon atom are optionally replaced by the ring:and each Rs is a radical independently selected from the group consisting of (XX), (XXI) and (XXII)wherein each a', each b', and each c' are independently an integer from 0 to 3, each Rg is independently -(Ci-Cejalkyl, and Rw is selected from the group consisting of -(Ci-Cejalkyl-SOs- and -(Ci-Cejalkyl-COg-; denote the attaching points; and each active moiety is independently selected from the group consisting of a pharmaceutically active agent, a penetration enhancing agent, a cell-targeting agent, a cosmetically active agent, and a diagnostically active agent.

2. The lipo-polyamino acid conjugate according to claim 1, which has formula (IA)3. The lipo-polyamino acid conjugate according to any of claims 1 to 2, wherein n is an integer from 5 to 100.

4. The lipo-polyamino acid conjugate according to any of claims 1 to 3, wherein R3 is H.

5. The lipo-polyamino acid conjugate according to any of claims 1 to 4, wherein X is N and R1 is selected from the group consisting of H, and -(Ci-Ce)alkyl.

6. The lipo-polyamino acid conjugate according to to any of claims 1 to 5, wherein Rz is selected from the group consisting of -(Ci-C2o)alkyl, -(C2-C2o)alkenyl, and a radical of formula (XI), (XII), (XIV), (XV), (XVI), (XVII) or (XVIII), and Rz' is selected from the group consisting of -(Ci-C2o)alkyl, -(C2-C2o)alkenyl, and a radical of formula (XI), (XII), (XIV), (XV), (XVI), (XVII) or (XVIII').

7. The lipo-polyamino acid conjugate according to any of claims 1 to 6, wherein A is a lipid-like moiety Rz, and A1 is other than a lipid-like moiety Rz'.

8. The lipo-polyamino acid conjugate according to any of claims 1 to 6, wherein A1 is a lipid-like moiety Rz', and A is other than a lipid-like moiety Rz.

9. A self-assembled particle comprising the lipo-polyamino acid conjugate of formula (I) as defined in any of claims 1-8, and optionally one or more active agents selected from the group consisting of pharmaceutically active agents, cell-targeting agents, penetration enhancing agents, cosmetically active agents, diagnostically active agents, nucleic acids, peptides, proteins, and mixtures thereof.

10. A composition comprising the lipo-polyamino acid conjugate of formula (I) as defined in any of the claims 1-8, or alternatively, the self-assembled particle as defined in claim 9, together with one or more appropriate excipients or carriers.11 . A therapeutic product which comprises: a) a lipo-polyamino acid conjugate of formula (I) as defined in any of the claims 1-8, wherein at least one of A, A1, A2 or A3 is a pharmaceutically active agent, or alternatively, b) a self-assembled particle as defined in claim 9 containing the lipo-polyamino acid conjugate a), oralternatively, c) a composition as defined in claim 10 containing the lipo-polyamino acid conjugate a) or the self-assembled particle b), or alternatively, d) a self-assembled particle as defined in claim 9, which comprises one or more active agents selected from the group consisting of pharmaceutically active agents, nucleic acids, peptides, proteins, and mixtures thereof, or alternatively, e) a composition as defined in claim 10 containing the self-assembled particle d), for use in medicine.

12. The therapeutic product for use according to claim 11, for use (i) as transfection reagent for transfecting at least one active agent into a cell; (ii) for use in the in vivo or ex vivo production of biologies encoding a recombinant protein, a peptide or an antibody, or in the production of recombinant virus; (iii) for use as a therapeutic or prophylactic vaccine against viral infections or as a therapeutic vaccine against cancers or infectious diseases; or (v) for use in genome engineering, for cell reprogramming, for differentiating cells or for gene-editing.

13. A diagnostic product which comprises: a') a lipo-polyamino acid conjugate of formula (I) as defined in any of the claims 1-8, wherein at least one of A, Ai, A2 or A3 is a diagnostically active agent, or alternatively, b') a self-assembled particle as defined in claim 9 containing the lipo-polyamino acid conjugate a'), or alternatively, c') a composition as defined in claim 10 containing the lipo-polyamino acid conjugate a') or the self-assembled particle b'), or alternatively, d') a self-assembled particle as defined in claim 9, which comprises one or more diagnostically active agents, or alternatively, e') a composition as defined in claim 10 containing the self-assembled particle d'), for use in diagnostics.

14. Use in cosmetics of a cosmetic product which comprises: a") a lipo-polyamino acid conjugate of formula (I) as defined in any of the claims 1-8, wherein at least one of A, A1, A2 or A3 is a cosmetically active agent, or alternatively, b”) a self-assembled particle as defined in claim 9 containing the lipo-polyamino acid conjugate a”), or alternatively, c”) a composition as defined in claim 10 containing the lipo-polyamino acid conjugate a”) or the selfassembled particle b"), or alternatively, d”) a self-assembled particle as defined in claim 9, which comprises one or more cosmetically active agents, or alternatively, e”) a composition as defined in claim 10 containing the self-assembled particle d”).

15. The lipo-polyamino acid conjugate of formula (I) as defined in any of claims 1-8, wherein A, Ai, A2 and A3 are other than an active moiety, or alternatively, a self-assembled particle as defined in claim 9 containing it, for use as a carrier.

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