Hidden stable lipid polyamino acids

Abstract

The present invention relates to lipid polyamino acid conjugates of formula (I) and acceptable salts, stereoisomers and mixtures thereof. The invention also relates to: a self-assembled particle comprising these lipopolyamino acid conjugates and optionally an active agent; and a composition comprising the lipid polyamino acid conjugate or the self-assembled particle comprising the lipid polyamino acid conjugate. The invention also relates to: the use of said lipid polyamino acid conjugate, self-assembled particle or composition comprising same in medicine, cosmetics and diagnostics; and the use of the lipid polyamino acid conjugate of formula (I) as a carrier. # imgabs0 #

Description

[0001] This application claims the benefit of European patent application 22382135.6 filed on February 18, 2022. Technical Field

[0002] The present disclosure relates to lipo-polyamino acid conjugates, which include a polyamino acid (PAA) portion conjugated to a lipid-like portion. These lipo-polyamino acid conjugates can form self-assembled nanoparticles such as, for example, lipid nanoparticles (LNPs), and can be used as non-viral vectors for delivering active ingredients (including nucleic acids) to cells. Background Art

[0003] Nucleic acids have emerged in recent years to generate promising drug candidates for a variety of diseases, including cancer, infectious diseases, and cardiovascular, inflammatory and neurodegenerative diseases. Nucleic acids exert their effects through gene inhibition, addition, replacement or editing. However, their clinical efficacy is very limited because they cannot cross physiological barriers. The negative charge and hydrophilicity of nucleic acids hinder their passive diffusion across the plasma membrane. In addition, the binding of nucleic acids to serum proteins and their susceptibility to enzymatic degradation by endogenous nucleases also interfere with their efficient translation into functional responses.

[0004] Known non-viral vectors such as LNP permeate plasma membrane, therefore can deliver nucleic acid to cell.LNP is the vesicle that is made up of lipid mixture, and lipid mixture is physically associated with each other by intermolecular force, forms micellar structure.LNP generally has the minor diameter less than 200nm.LNP is used as drug delivery system, and this is because it can encapsulate bioactive agent and deliver bioactive agent to specific position in body at the required time.The lipid component of LNP can comprise ionizable or cationic lipid, auxiliary lipid such as phospholipid and structural lipid such as sterol or cholesterol.

[0005] Ionizable / cationic lipids—which have a permanently or ionizable positively charged head group followed by a hydrophobic tail—can form complexes with negatively charged nucleic acids via electrostatic binding.

[0006] One of the potential problems with LNPs is that once injected, they may be recognized by the immune system as foreign particles and subsequently cleared from the bloodstream by phagocytes. To overcome this problem, different strategies can be used, including reducing the particle size of the vesicles or modifying their surface. For example, the LNP surface can be modified by conjugating the hydrophilic polymer polyethylene glycol (PEG) to lipids such as phospholipids or long-chain fatty acids to form PEG-lipids.

[0007] PEG is a hydrophilic polymer that is widely used in drug delivery and nanotechnology due to its stealth and biocompatibility. Due to these properties, microparticle delivery systems containing PEG are able to evade the immune system and therefore have a prolonged circulation time in the body.

[0008] Nevertheless, it has recently been reported that the presence of covalently bound PEG can also significantly reduce transfection efficiency, as the neutral surface of the nanoparticles can reduce cellular uptake efficiency. In addition, PEG is also known to generate anti-PEG antibodies, which can lead to immunogenicity and allergic reactions.

[0009] Although other hydrophilic polymers such as poly(vinyl pyrrolidone), poly(acryloylmorpholine) or poly( Oxazolines have been proposed as an alternative to PEG-lipids, but no LNPs containing this polymer are commercially available.

[0010] Polyinosinic acid (pSar) is a peptide based on the endogenous amino acid sarcosine (N-methylated glycine) that has previously been shown to have potent stealth properties. Lipid nanoparticles (LNPs) assembled with pSarcosinylated lipids for messenger RNA therapeutic applications have been reported as a promising tool for particle engineering (ACS Appl. NanoMater., 2020, 3, 10634-10645), but this is still under development and there is no clinical data on incorporating this polymer into LNPs.

[0011] Therefore, from what is known in the art, there is still a need to develop alternative LNPs to overcome the shortcomings of the prior art. Summary of the invention

[0012] The present inventors have developed novel lipopolyamino acid conjugates comprising a polyamino acid (PAA) portion conjugated to at least one lipid-like portion. These conjugates can form self-assembling nanoparticles such as, for example, lipid nanoparticles (LNPs), and can be effectively used as non-viral vectors for delivering active ingredients (including nucleic acids) to cells due to their stealth and the resulting increased plasma half-life.

[0013] Furthermore, lipopolyamino acid conjugates show low cytotoxicity, high biodegradability, and can endow the final nanosystem with enhanced efficiency, high stability due to limited or even complete inhibition of aggregation issues in the bloodstream and potential different cell and tissue tropisms.

[0014] Therefore, the first aspect of the present invention relates to a lipopolyamino acid conjugate of formula (I), a salt thereof, or any stereoisomer or mixture of stereoisomers of any one of the compounds of formula (I) or their salts,

[0015]

[0016] in

[0017] n is an integer from 5 to 250; m is 0 or 1;

[0018] X is selected from N, S and O;

[0019] R1 is selected from H, -(C1-C 18 )alkyl and -(C2-C 18 )alkenyl, provided that when X is O or S, R1 is absent;

[0020] R2 is a radical selected from (II), (III), (IV) and (V)

[0021]

[0022] in:

[0023] a, b, c and d are independently integers from 1 to 4;

[0024] R3 is H or -(C1-C6)alkyl;

[0025] A is selected from H, -(C1-C6)alkyl, -CO(C1-C6)alkyl, -(C5-C 10 )aryl, -(C5-C 10 )heteroaryl, -(C6-C 10 )aralkyl, -(C1-C6)alkyl-O-(C5-C 10 )aryl, -(C5-C 10 ) heterocycloalkyl, protecting group, free radical R4, lipid-like part R5 and active part; A is optionally substituted by one or more groups selected from the following: -OH, halogen, -CF3, -NH2, -NH-(C1-C4)alkyl, -NH-CO-(C1-C6)alkyl, -(C1-C6)alkyl, -NO2, -N3, -CO-(C1-C6)alkyl, -CO-O-(C1-C6)alkyl, -SO3H, -SO2NH2, -SO2-N((C1-C6)alkyl)2, -COOH, CONH2 and -CON((C1-C6)alkyl)2;

[0026] A' is selected from H, -OH, -(C1-C6)alkyl, -(C5-C 10 )aryl, -(C5-C 10 )heteroaryl, -(C6-C 10 )aralkyl, -(C1-C6)alkyl-O-(C5-C 10 )aryl, -(C5-C 10 )heterocycloalkyl, -(C1-C10 )alkoxy, -(C6-C 10 ) aryloxy, -(C6-C 10 )aralkyloxy, -(C5-C 10 )heteroaralkyloxy, -(C1-C 10 )alkyl-O-(C6-C 10 ) aryloxy, amino protecting group, free radical R4', lipid-like part R5', amino acid-like part R6 and active part; A' is optionally substituted by one or more groups selected from the following: -OH, halogen, -CF3, -NH2, -NH-(C1-C4) alkyl, -NH-CO-(C1-C6) alkyl, -(C1-C6) alkyl, -NO2, -N3, -CO-(C1-C6) alkyl, -CO-O-(C1-C6) alkyl, -SO3H, -SO2NH2, -SO2-N((C1-C6) alkyl)2, -COOH, CONH2 and -CON((C1-C6) alkyl)2; Provided that:

[0027] i) when m is 0, A' is selected from H, -(C1-C6)alkyl, -(C5-C 10 )aryl, -(C5-C 10 )heteroaryl, -(C6-C 10 )aralkyl, -(C1-C6)alkyl-O-(C5-C 10 )aryl, -(C5-C 10 ) heterocycloalkyl, an amino protecting group, an amino acid-like portion R6 and an active portion; A' is optionally substituted by one or more groups selected from the following: -OH, halogen, -CF3, -NH2, -NH-(C1-C4)alkyl, -NH-CO-(C1-C6)alkyl, -(C1-C6)alkyl, -NO2, -N3, -CO-(C1-C6)alkyl, -CO-O-(C1-C6)alkyl, -SO3H, -SO2NH2, -SO2-N((C1-C6)alkyl)2, -COOH, CONH2 and -CON((C1-C6)alkyl)2; and

[0028] When m is 1, A' is selected from H, -OH, -(C1-C6)alkyl, -(C5-C 10 )aryl, -(C5-C 10 )heteroaryl, -(C6-C 10 )aralkyl, -(C1-C6)alkyl-O-(C5-C 10 )aryl, -(C5-C 10 )heterocycloalkyl, -(C1-C 10 )alkoxy, -(C6-C 10 ) aryloxy, -(C6-C 10)aralkyloxy, -(C5-C 10 )heteroaralkyloxy, -(C1-C 10 )alkyl-O-(C6-C 10 ) aryloxy, free radical R4', lipid-like part R5' and active part; A' is optionally substituted by one or more groups selected from the following: -OH, halogen, -CF3, -NH2, -NH-(C1-C4)alkyl, -NH-CO-(C1-C6)alkyl, -(C1-C6)alkyl, -NO2, -N3, -CO-(C1-C6)alkyl, -CO-O-(C1-C6)alkyl, -SO3H, -SO2NH2, -SO2-N((C1-C6)alkyl)2, -COOH, CONH2 and -CON((C1-C6)alkyl)2; and

[0029] ii) at least one of A and A' is a lipid-like moiety R5 or R5';

[0030] R4 is a free radical of formula (VIa)

[0031]

[0032]

[0033] R4' is a free radical of formula (VIb)

[0034]

[0035] in:

[0036] n' is an integer from 5 to 250;

[0037] m' is 0 or 1;

[0038] X” is selected from N, S and O;

[0039] R1" is a free radical having any of the meanings of R1, provided that when X" is O or S, R1" is absent;

[0040] R2' is a radical having any of the meanings of R2;

[0041] R3' is a radical having any of the meanings of R3;

[0042] B and B' are independently S or CH2;

[0043] e and f are independently an integer from 1 to 18;

[0044] A" is selected from H, -OH, -(C1-C6)alkyl, -(C5-C 10 )aryl, -(C5-C 10)heteroaryl, -(C6-C 10 )aralkyl, -(C1-C6)alkyl-O-(C5-C 10 )aryl, -(C5-C 10 )heterocycloalkyl, -(C1-C 10 )alkoxy, -(C6-C 10 ) aryloxy, -(C6-C 10 )aralkyloxy, -(C5-C 10 )heteroaralkyloxy, -(C1-C 10 )alkyl-O-(C6-C 10 ) aryloxy, amino protecting group, lipid-like part R5 ', amino acid-like part R6 and active part; A "is optionally substituted by one or more groups selected from the following: -OH, halogen, -CF3, -NH2, -NH-(C1-C4) alkyl, -NH-CO-(C1-C6) alkyl, -(C1-C6) alkyl, -NO2, -N3, -CO-(C1-C6) alkyl, -CO-O-(C1-C6) alkyl, -SO3H, -SO2NH2, -SO2-N((C1-C6) alkyl)2, -COOH, CONH2 and -CON((C1-C6)

[0045] Alkyl)2;

[0046] The conditions are:

[0047] When m' is 0, A" is selected from H, -(C1-C6)alkyl, -(C5-C 10 )aryl, -(C5-C 10 )heteroaryl, -(C6-C 10 )aralkyl, -(C1-C6)alkyl-O-(C5-C 10 )aryl, -(C5-C 10 ) heterocycloalkyl, amino protecting group, amino acid-like part R6 and active part; A "is optionally substituted by one or more groups selected from the following: -OH, halogen, -CF3, -NH2, -NH-(C1-C4) alkyl, -NH-CO-(C1-C6) alkyl, -(C1-C6) alkyl, -NO2, -N3, -CO-(C1-C6) alkyl, -CO-O-(C1-C6) alkyl,

[0048] -SO3H, -SO2NH2, -SO2-N((C1-C6)alkyl)2, -COOH, CONH2 and -CON((C1-C6)alkyl)2;

[0049] and

[0050] When m' is 1, A" is selected from H, -OH, -(C1-C6)alkyl, -(C5-C10 )aryl, -(C5-C 10 )heteroaryl, -(C6-C 10 )aralkyl, -(C1-C6)alkyl-O-(C5-C 10 )aryl, -(C5-C 10 )heterocycloalkyl, -(C1-C 10 )alkoxy, -(C6-C 10 ) aryloxy, -(C6-C 10 )aralkyloxy, -(C5-C 10 )heteroaralkyloxy, -(C1-C 10 )alkyl-O-(C6-C 10 ) aryloxy, lipid-like portion R5 'and active portion; A "is optionally substituted by one or more groups selected from the following: -OH, halogen, -CF3, -NH2, -NH-(C1-C4) alkyl, -NH-CO-(C1-C6) alkyl, -(C1-C6) alkyl, -NO2, -N3, -CO-(C1-C6) alkyl, -CO-O-(C1-C6) alkyl,

[0051] -SO3H, -SO2NH2, -SO2-N((C1-C6)alkyl)2, -COOH, CONH2 and -CON((C1-C6)alkyl)2;

[0052] and

[0053] A"' is selected from H, -(C1-C6)alkyl, -CO(C1-C6)alkyl, -(C5-C 10 )aryl, -(C5-C 10 )heteroaryl, -(C6-C 10 )aralkyl, -(C1-C6)alkyl-O-(C5-C 10 )aryl, -(C5-C 10 ) heterocycloalkyl, protecting group, lipid-like part R5 and active part; A "' is optionally substituted by one or more groups selected from the following: -OH, halogen, -CF3, -NH2, -NH-(C1-C4) alkyl, -NH-CO-(C1-C6) alkyl, -(C1-C6) alkyl, -NO2, -N3, -CO-(C1-C6) alkyl, -CO-O-(C1-C6) alkyl,

[0054] -SO3H, -SO2NH2, -SO2-N((C1-C6)alkyl)2, -COOH, CONH2 and -CON((C1-C6)alkyl)2; each R5 is independently selected from -(C1-C 18 )alkyl, -(C2-C 18) alkenyl and a radical of formula (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XXI), (XXII) or (XXIII)

[0055]

[0056]

[0057] Each R5' is independently selected from -X'(R1')-(C1-C 18 )alkyl, -X'(R1')-(C2-C 18 )alkenyl and a radical of formula (VII'), (VIII'), (IX'), (X'), (XI'), (XII'), (XIII'), (XIV'), (XXI'), (XXII') or (XXIII')

[0058]

[0059]

[0060] in:

[0061] Y and Y' are independently selected from -OH, -OCORx and -COORx;

[0062] Q and Q' are independently selected from -OCORy and -COORy;

[0063] Z and Z' are independently selected from -OCO-, -COO-, -NRz'CO- and -CONRz'-;

[0064] Each Rz' is H or Rz;

[0065] Each of Rx, Ry and Rz is independently -(C1-C 18 )alkyl or -(C2-C 18 )alkenyl;

[0066] Each g is independently an integer from 0 to 18;

[0067] Each h is independently an integer from 1 to 18;

[0068] i is an integer from 0 to 18;

[0069] Each j is independently an integer from 0 to 18;

[0070] X' is selected from N, S and O;

[0071] R1′ is a free radical having any of the meanings of R1, provided that when X′ is O or S, R1′ is absent; and

[0072] t is 0 or 1, provided that when X=0, t is 0, and when X is not 0, t is 1;

[0073] t' is 0 or 1; provided that when m is 0, t' is 1;

[0074] R 22 , R 33 and R 44 independently selected from hydrogen, fluorine, methyl, -CH2F, -CHF2 and -CF3;

[0075] Each of the dashed bonds ----- is independently a single bond, or, alternatively, a double bond;

[0076] L is a diradical chain comprising one or more moieties selected from the group consisting of: -CH=CH-, -C≡C-, -CH2-,

[0077] -N=CH-, -CH=NH-, -NH-, -NH-NH-, -NH-N=CH-, -O-, -O(CH2)O-, -CO-, -O(CO)-,

[0078] -(CO)O-, -C(=CH2)-, -C(=NH)-, -CONH-, -NHCO-, -NH(CO)NH-, -S-, -SS-,

[0079] -SO-, -SO2-, -SO2NH2- and -phenylene-, wherein L is optionally substituted with one or more substituents selected from the group consisting of halogen, -OH, -NR a R b 、-SH、-NHNH2、-COOR c , -CF3, -OCF3,

[0080]

[0081] Wherein when L includes a -CH2- moiety, the two hydrogen atoms attached to the carbon atom are optionally replaced by the following ring:

[0082]

[0083] and

[0084] Each R6 is a radical independently selected from (XV), (XVI) and (XVII)

[0085]

[0086] wherein a', b' and c' are independently integers from 1 to 4;

[0087] Each active moiety is independently selected from the group consisting of pharmaceutically active agents, penetration enhancers, cell targeting agents, cosmetic active agents, and diagnostic active agents.

[0088] With appropriate surface functionality, the lipopolyamino acid conjugates of the present disclosure can be modified with cell targeting groups, which can actively target cells and aid cell entry, in any of A, A', A", or A'", thereby producing conjugates with improved cell-specific delivery. When increased cell or skin penetration is desired, the lipopolyamino acid conjugates can also be modified with penetration enhancers. In addition, the lipopolyamino acid conjugates can also be used to deliver pharmaceutically active agents, cosmetic active agents, or diagnostic active agents linked to any of A, A', A", or A'" of the conjugate backbone.

[0089] In addition, due to its amphiphilicity, the lipopolyamino acid conjugates of the present invention can form self-assembled particles in solution, such as, for example, liposomes or lipid nanoparticles, which can be used to encapsulate and deliver molecules of different properties. Therefore, the lipopolyamino acid conjugates of the present invention allow for the simultaneous carrying and / or delivery of different active agents, which are not only bound to the structure of the conjugate, but are also contained in the self-assembled particles formed by the conjugate. Therefore, another aspect of the present invention relates to self-assembled particles, which include the lipopolyamino acid conjugates of formula (I) as defined herein, and optionally one or more active agents, the active agent being selected from pharmaceutically active agents, cell targeting agents, penetration enhancers, cosmetic active agents, diagnostic active agents, nucleic acids, peptides, proteins and mixtures thereof.

[0090] The lipopolyamino acid conjugates of the present invention can be formulated into a variety of compositions together with excipients and carriers, including pharmaceutical compositions, cosmetic compositions and diagnostic compositions. Therefore, another aspect of the present invention relates to a composition comprising a lipopolyamino acid conjugate as defined herein; or alternatively, a self-assembled particle comprising it and one or more suitable excipients or carriers.

[0091] The lipopolyamino acid conjugates, self-assembled particles and compositions thereof of the present invention can be used in medicine, cosmetics and diagnostic applications.

[0092] Therefore, another aspect of the present invention relates to a therapeutic product for medical use, which comprises: a) a lipopolyamino acid conjugate of formula (I) as defined herein, wherein at least one of A, A', A" or A'" is a pharmaceutically active agent; or alternatively, b) a self-assembled particle comprising the lipopolyamino acid conjugate a); or alternatively, c) a composition comprising the lipopolyamino acid conjugate a) or the self-assembled particle b); or alternatively, d) a self-assembled particle comprising the lipopolyamino acid conjugate as defined herein and one or more active agents selected from pharmaceutically active agents, nucleic acids, peptides, proteins and mixtures thereof; or alternatively, e) a composition comprising the self-assembled particle d).

[0093] According to another aspect, the present invention relates to a diagnostic product for diagnostic use, comprising: a') a lipopolyamino acid conjugate as defined herein, wherein at least one of A, A', A" or A'" is a diagnostically active agent; or alternatively, b') a self-assembled particle comprising the lipopolyamino acid conjugate a'); or alternatively, c') a composition comprising the lipopolyamino acid conjugate a') or the self-assembled particle b'); or alternatively, d') a self-assembled particle comprising a lipopolyamino acid conjugate as defined herein and one or more diagnostically active agents; or alternatively, e') a composition comprising the self-assembled particle d').

[0094] According to another aspect, the present invention relates to the use of a cosmetic product in cosmetics, the cosmetic product comprising: a")) a lipopolyamino acid conjugate as defined herein, wherein at least one of A, A', A" or A"' is a pharmaceutically active agent; or alternatively, b")) a self-assembled particle comprising the lipopolyamino acid conjugate a'); or alternatively, c")) a composition comprising a")) or the self-assembled particle b"); or alternatively, d")) a self-assembled particle comprising the lipopolyamino acid conjugate as defined herein and one or more cosmetically active agents; or alternatively, e")) a composition comprising the self-assembled particle d").

[0095] Another aspect of the invention relates to the use of a lipopolyamino acid conjugate of formula (I) as defined herein as a carrier, wherein A, A', A" and A'" are not active moieties. BRIEF DESCRIPTION OF THE DRAWINGS

[0096] Figure 1 Agarose gel (2%) used to detect free mRNA from different LNP formulations is shown: M) free mRNA; 1) benchmark LNP formulation; 2) benchmark LNP formulation + 10% triton X-100 and 2 mg / mL heparin; 3) LNP4 formulation; 4) LNP4 formulation + 10% triton X-100 and 2 mg / mL heparin; 5) LNP9 formulation; 6) LNP9 formulation + 10% triton X-100 and 2 mg / mL heparin; 7) LNP12 formulation; 8) LNP12 formulation + 10% triton X-100 and 2 mg / mL heparin; 9) LNP11 formulation; 10) LNP11 formulation + 10% triton X-100 and 2 mg / mL heparin.

[0097] Figure 2 Shows Including according to the present invention Lipopolyamino acid conjugate LNP(LNP 15) Comparison of LNPs using DMG-PEG as a lipid shielding compound in mice in vivo mRNA Transfection capacity (Total counts / g tissue in liver (A), ALN (B), spleen (C), lung (D)). DETAILED DESCRIPTION

[0098] Unless otherwise stated, all terms used herein in this application should be understood with their ordinary meanings known in the art. Other more specific definitions of certain terms used in this application are set forth below and are intended to apply throughout the specification and claims.

[0099] As used herein, the term "about" or "approximately" refers to a numerical range of ±10% of a particular value. For example, the expression "about 10" or "approximately 10" includes ±10% of 10, ie, 9 to 11.

[0100] As used herein, the indefinite articles "a" and "an" are synonymous with "at least one" or "one or more". Definite articles such as "the" as used herein also include plural nouns unless otherwise stated.

[0101] The term "moiety" refers to a specific segment or functional group of a molecule or compound.

[0102] As used herein, the term "subject" refers to any mammal, including both humans and other mammals.

[0103] Terminology - (C1-C x )alkyl refers to a saturated linear or branched hydrocarbon chain containing 1 to x carbon atoms and having only single bonds. Examples of alkyl may include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, neopentyl, n-hexyl, decyl, undecyl, dodecyl, tetradecyl, and hexadecyl. The term -(C2-C x )Alkenyl refers to an unsaturated branched or linear hydrocarbon chain comprising 2 to x carbon atoms and at least one or more double bonds. Examples of alkenyl may include, but are not limited to, ethenyl (i.e., vinyl), allyl, propenyl, butenyl, pentenyl and hexenyl, dodecenyl, tetradecenyl and hexadecenyl.

[0104] The term "-(C1-C 10 ")alkoxy" refers to an alkyl group as defined herein comprising 1 to 10 carbon atoms, which is attached to the rest of the molecule via an oxygen atom. Examples of alkoxy may include, but are not limited to, methoxy, ethoxy, 1-propoxy and 2-propoxy.

[0105] The term "-(C5-C 10 )Aryl" refers to an aromatic carbocyclic monocyclic or bicyclic ring system comprising 5 to 10 carbon ring atoms. Examples of aryl groups may include, but are not limited to, phenyl, biphenyl and naphthyl.

[0106] The term "-(C6-C 10 )Aryloxy" refers to an aryl group as defined herein comprising 6 to 10 carbon ring atoms, which is attached to the remainder of the molecule via an oxygen atom. Examples of aryloxy may include, but are not limited to, phenoxy and biphenyloxy.

[0107] The term "-(C5-C 10 )Heteroaryl" refers to an aromatic carbocyclic monocyclic or bicyclic ring system comprising 5 to 10 ring atoms, wherein at least one aromatic ring contains one, two or three ring heteroatoms selected from N, O and S, and the remaining ring atoms are carbon atoms. Examples of heteroaryl may include, but are not limited to, pyridyl, azetidinyl, furanyl, pyrrolyl, thienyl, thiazolyl, oxazolyl, imidazolyl, tetrazolyl, benzofuranyl, isoquinolyl, benzothiazolyl, benzimidazolyl, benzothiazolyl, quinolyl and quinazolinyl.

[0108] The term "-(C6-C 10 "(C1-C6) alkyl" refers to a lower alkyl group as defined herein (e.g., "-(C1-C6) alkyl") replaced by an aryl group as defined herein (e.g., "-(C5-C6) alkyl") 10 Examples of aralkyl groups may include, but are not limited to, benzyl, phenethyl, and methylbenzyl.

[0109] The term "-(C6-C 10 "(C1-C6) alkoxy" refers to a lower alkoxy group as defined herein (e.g., "-(C1-C6) alkoxy") replaced by an aryl group as defined herein (e.g., "-(C5-C6) alkoxy"). 10 Examples of the aralkyloxy group may include, but are not limited to, benzyloxy, phenethyloxy, and methylbenzyloxy.

[0110] The term "-(C5-C 10 "(C1-C6) alkoxy" refers to a lower alkoxy group as defined herein (e.g., "-(C1-C6) alkoxy") replaced by a heteroaryl group as defined herein (e.g., "-(C5-C6) alkoxy"). 10 )heteroaryl). Examples of heteroaralkoxy may include, but are not limited to, furanyloxy, pyridyloxy, and azetidinyloxy.

[0111] The term "-(C5-C 10 )Heterocycloalkyl" refers to a 5-10 membered monocyclic or bicyclic (fused or bridged) saturated or unsaturated ring structure, wherein one or more of the ring atoms is a heteroatom selected from N, O and S. Examples of heterocycloalkyl may include, but are not limited to, piperidinyl, piperazinyl, tetrahydropyranyl, tetrahydrofuranyl, 1,4-dioxolanyl, Azolyl, iso Azolyl, morpholinyl, thiomorpholinyl.

[0112] As used herein, the term "protecting group" refers to a group of atoms that mask, reduce or prevent reactivity when attached to a reactive group in a molecule. Protecting groups for carboxyl and amino groups are described in, for example, Chapter 5 (pages 369-451) and Chapter 7 (pages 495-653) of TW Green and PGM Wuts, Protective Groups in Organic Chemistry (Wiley, 3rd ed. 1999), respectively.

[0113] The term "substituted" means that one or more hydrogen atoms on the designated atom or group is replaced with one selected from the indicated group, provided that the designated atom's normal valency in the existing context is not exceeded. Combinations of substituents and / or variables are permissible.

[0114] The term "optionally substituted" means that the number of substituents may be equal to or different from zero. Unless otherwise stated, it is possible that an optionally substituted group is substituted with as many optional substituents as would be accommodated by replacing any available carbon or nitrogen atom with a hydrogen atom by a non-hydrogen substituent. It is possible that a group in the conjugate according to the invention is substituted with one, two, three, four or five identical or different substituents, in particular with one, two or three substituents.

[0115] In the embodiments of the present invention, where it is not specified whether a group is substituted or unsubstituted, i.e., it is not indicated that the group has a certain substitution, nor is it indicated that the group is unsubstituted, it must be understood that the possible substitution of this group is the broadest substitution as defined herein.

[0116] Lipopolyamino acid conjugate

[0117] The first aspect of the present invention relates to a lipopolyamino acid conjugate of formula (I), a salt thereof, or any stereoisomer or mixture of stereoisomers of any one of the compounds of formula (I) or their salts.

[0118]

[0119] wherein A, X, R1, R2, R3, n, m and A' are as defined herein.

[0120] For the purposes of the present invention, the term "lipopolyamino acid conjugate" refers to a molecule comprising a) a polyamino acid-based portion and b) at least one lipid-like portion. The term "lipid-like portion" refers to a portion that, although not considered a lipid, is structurally and / or functionally similar to a lipid. The term lipid-like portion is intended to include portions that are capable of forming an amphiphilic layer. The term "lipid" refers to a group of water-insoluble organic compounds, such as fatty acids, glycerolipids, glycerophospholipids, sphingolipids, glycolipids, sterols, etc.

[0121] There is no limitation on the types of salts of the lipopolyamino acid conjugates that can be used, provided that they are pharmaceutically, cosmetically or diagnostically acceptable when used for pharmaceutical, cosmetic or diagnostic purposes, respectively. The term "pharmaceutically, cosmetically or diagnostically acceptable salts" encompasses commonly used non-toxic salts. The preparation of pharmaceutically, cosmetically or diagnostically acceptable salts of the lipopolyamino acid conjugates of the present 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 the lipopolyamino acid conjugate of the present 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 thereof.

[0122] Examples of pharmaceutically, cosmetically or diagnostically acceptable salts include acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, hydroiodic acid, metaphosphoric acid or phosphoric acid; and organic acids such as succinic acid, maleic acid, acetic acid, fumaric acid, citric acid, tartaric acid, benzoic acid, trifluoroacetic acid, malic acid, lactic acid, formic acid, propionic acid, glycolic acid, gluconic acid, camphorsulfuric acid, isothionic acid, mucic acid, gentisic acid, isonicotinic acid, saccharic acid, glucuronic acid, furanic acid, furoic, glutamic, ascorbic, anthranilic, salicylic, phenylacetic, mandelic, pamoic, ethanesulfonic, pantothenic, stearic, sulfinilic, alginic and galacturonic acid; and arylsulfonic acids, such as 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-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine), lysine and procaine; and internally formed salts. The lipopolyamino acid conjugates and salts thereof of the present invention may differ in certain physical properties, but for the purposes of the present invention, they are equivalent.

[0123] Some of the lipopolyamino acid conjugates of the present invention may have chiral centers, which can produce various stereoisomers. As used herein, the term "stereoisomer" refers to all isomers of a single lipopolyamino acid conjugate, which 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 cis / trans or E / Z) isomers, and isomers (diastereomers) of lipopolyamino acid conjugates with more than one chiral center that are not mirror images of each other. The present invention relates to each of these stereoisomers and mixtures thereof. Therefore, the definition of the lipopolyamino acid conjugate of formula (I) is also intended to cover all R-isomers and S-isomers of the chemical structure in any proportion, such as one possible isomer is enriched (i.e., enantiomeric excess or diastereomeric excess), and the corresponding proportion of the other isomers is less. In the specific case of an amino acid, it can adopt either the L-configuration or the D-configuration.

[0124] Diastereomers and enantiomers can be separated by conventional techniques such as chromatography or fractional crystallization. Optical isomers can be obtained using enantiospecific synthesis. Alternatively, optical isomers can be resolved by conventional techniques to obtain optically pure isomers. The resolution can be performed on any chiral synthetic intermediate or on the polymers of the invention.

[0125] In all embodiments of the present invention relating to lipopolyamino acid conjugates, pharmaceutically, cosmetically or diagnostically acceptable salts thereof, as well as stereoisomers or mixtures of stereoisomers of any of the lipopolyamino acid conjugates or any of its pharmaceutically, cosmetically or diagnostically acceptable salts, are always considered even if they are not specifically mentioned.

[0126] The lipopolyamino acid conjugates of the present invention may be in a crystalline form, or a free solvated lipopolyamino acid conjugate, or a solvate (e.g., a hydrate). All of these forms fall within the scope of the present invention. Solvation methods are well known in the art. For the purposes of the present invention, solvated forms using pharmaceutically, cosmetically, or diagnostically acceptable solvents such as water, ethanol, etc. are equivalent to non-solvated forms.

[0127] Unless otherwise specified, the lipopolyamino acid conjugates of the present disclosure also include lipopolyamino acid conjugates that differ only in the presence of one or more isotopically enriched atoms. Examples of isotopically enriched atoms are, but are not limited to, deuterium, tritium, 13 C or 14 C, or enrichment 15 N nitrogen atoms, or enriched 18 F is a fluorine atom.

[0128] The lipopolyamino acid conjugate of the present invention is a polymer structure comprising a polyamino acid (PAA) moiety of formula (XVIII) as a repeating unit.

[0129]

[0130] Wherein "*" indicates the point of attachment of the PAA-based moiety to the rest of the molecule. The orientation of the PAA-based moiety does not affect the amphiphilic behavior of the polymers described herein, and thus the activity exhibited is maintained.

[0131] According to one embodiment, optionally in combination with any of the embodiments provided above or below, the lipopolyamino acid conjugate of formula (I) has the following formula (I'):

[0132]

[0133] wherein A, A', X, R1, R2, R3, n and m are as defined herein.

[0134] As described above, the lipopolyamino acid conjugate of the present invention further includes at least one lipid-like portion. The lipid-like portion may be located at any end of the PAA-based portion. The lipopolyamino acid conjugate of the present invention may also include lipid-like portions at both ends of the molecule. For example, when A is R5, the lipid-like portion may be located on the left side of the molecule of the drawn formula (I), or when A' is R5', it may be located on the right side, or when A is R5 and A is R5', it may be located at both ends, but at least one of A and A' must be a lipid-like portion (R5 in the case of A, R5' in the case of A').

[0135] The lipopolyamino acid conjugates of the present invention are characterized by molecular weight (which can be an average molecular weight (MW) or a number average molecular weight (Mn)), degree of polymerization and polydispersity index. Molecular weight can be measured by methods known in the art such as size exclusion chromatography (SEC) (also known as gel permeation chromatography (GPC)), matrix assisted laser desorption ionization-time-of-flight mass spectrometry (MALDI-TOF MS). The composition and ratio are determined by, for example 1 Some of these methods are described in more detail in the examples below.

[0136] As used herein, the term "repeat unit" refers to a unit based on monomeric amino acids and is defined by the square brackets ("[ ]") surrounding it. The number in the lower right corner of the bracket (represented by the letter "n") refers to the statistical number of the degree of polymerization (DP) of each monomer unit. The DP is calculated by dividing the corrected molecular weight of the polymer determined by the SEC-MALS technique (minus the initiator MW) by the molecular weight of the monomer unit. The DP value is reported as the center value of a Gaussian distribution that includes polymers of variable DP (depending on the intrinsic polydispersity). Due to the ring-opening polymerization mechanism, the DP value is also subject to reasonable uncertainty, which in the context of the present invention can be considered to be within the range of ±20%, preferably ±15%, more preferably ±10%, even more preferably ±5%, and particularly preferably ±2%.

[0137] The term "polydispersity index" (PDI) is used as a measure of the breadth of the molecular weight distribution. The larger the PDI, the broader the molecular weight. The PDI of a polymer is calculated as the ratio of the weight average molecular weight (MW) to the number average molecular weight (Mn).

[0138]

[0139] In the lipopolyamino acid conjugate of formula (I), n is an integer from 5 to 250. In one embodiment, optionally in combination with any embodiment 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 5 to 25.

[0140] In the lipopolyamino acid conjugate of formula (I), X is selected from 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 -(C1-C 18 )alkyl, more particularly -(C1-C 12 In another embodiment, optionally in combination with any of the embodiments provided above or below, X is N and R1 is -(C2-C 18 )alkenyl, more particularly -(C2-C 12 ) alkenyl.

[0141] According to another embodiment, optionally in combination with any embodiment provided above or below, in the lipopolyamino acid conjugate of formula (I), X is O and R1 is absent. In another embodiment, optionally in combination with any embodiment provided above or below, X is S and R1 is absent.

[0142] In the lipopolyamino acid conjugate of formula (I), m is 0 or 1, depending on the meaning of A'. In one embodiment, optionally in combination with any of the embodiments provided above or below, m is 0 and A' is selected from H, -(C1-C6)alkyl, -(C5-C 10 )aryl, -(C5-C 10 )heteroaryl, -(C6-C 10 )aralkyl, -(C1-C6)alkyl-O-(C5-C 10 )aryl, -(C5-C 10 ) heterocycloalkyl, amino protecting group, amino acid-like part R6 and active part; A' is optionally substituted by one or more groups selected from the following: -OH, halogen, -CF3, -NH2, -NH-(C1-C4) alkyl, -NH-CO-(C1-C6) alkyl, -(C1-C6) alkyl, -NO2, -N3, -CO-(C1-C6) alkyl, -CO-O-(C1-C6) alkyl, -SO3H, -SO2NH2, -SO2-N((C1-C6) alkyl)2, -COOH, CONH2 and -CON((C1-C6) alkyl)2. In another embodiment, optionally in combination with any of the embodiments provided above or below, m is 1 and A' is selected from H, -OH, -(C1-C6) alkyl, -(C5-C 10 )aryl, -(C5-C 10 )heteroaryl, -(C6-C 10 )aralkyl, -(C1-C6)alkyl-O-(C5-C 10 )aryl, -(C5-C 10 )heterocycloalkyl, -(C1-C 10 )alkoxy, -(C6-C 10 ) aryloxy, -(C6-C 10 )aralkyloxy, -(C5-C 10 )heteroaralkyloxy, -(C1-C 10 )alkyl-O-(C6-C 10 ) aryloxy, free radical R4', lipid-like part R5' and active part; A' is optionally substituted by one or more groups selected from the following: -OH, halogen, -CF3, -NH2, -NH-(C1-C4)alkyl, -NH-CO-(C1-C6)alkyl, -(C1-C6)alkyl, -NO2, -N3, -CO-(C1-C6)alkyl, -CO-O-(C1-C6)alkyl, -SO3H, -SO2NH2, -SO2-N((C1-C6)alkyl)2, -COOH, CONH2 and -CON((C1-C6)alkyl)2.

[0143] In the lipopolyamino acid conjugate of formula (I), R2 is a free radical selected from (II), (III), (IV) and (V), wherein a, b, c and d are independently integers of 1 to 4.

[0144] In one embodiment, optionally in combination with any of the embodiments provided above or below, in the lipopolyamino acid conjugate of formula (I), R2 is a free radical of formula (II), more particularly in the free radical of formula (II), a is 1 or 2.

[0145] According to another embodiment, optionally in combination with any embodiment provided above or below, in the lipopolyamino acid conjugate of formula (I), R2 is a free radical of formula (III), more particularly in the free radical of formula (III), b is 1 or 2.

[0146] According to another embodiment, optionally in combination with any embodiment provided above or below, in the lipopolyamino acid conjugate of formula (I), R2 is a free radical of formula (IV), more particularly in the free radical of formula (IV), c is 1 or 2.

[0147] In another embodiment, optionally in combination with any of the embodiments provided above or below, in the lipopolyamino acid conjugate of formula (I), R2 is a free radical of formula (V), more particularly in the free radical of formula (V), d is 1 or 2.

[0148] In the lipopolyamino acid conjugate of formula (I), R3 is H or -(C1-C6) alkyl. In one embodiment, optionally in combination with any embodiment provided above or below, in the lipopolyamino acid conjugate of formula (I), R3 is H. According to another embodiment, optionally in combination with any embodiment provided above or below, in the lipopolyamino acid conjugate of formula (I), R3 is -(C1-C6) alkyl, more particularly R3 is -CH3.

[0149] In the lipid polyamino acid conjugate of formula (I), A is selected from H, -(C1-C6)alkyl, -CO(C1-C6)alkyl, -(C5-C 10 )aryl, -(C5-C 10 )heteroaryl, -(C6-C 10 )aralkyl, -(C1-C6)alkyl-O-(C5-C 10 )aryl, -(C5-C 10 ) heterocycloalkyl, protecting group, free radical R4, lipid-like part R5 and active part; and A' is selected from H, -OH, -(C1-C6)alkyl, -(C5-C 10 )aryl, -(C5-C 10 )heteroaryl, -(C6-C 10)aralkyl, -(C1-C6)alkyl-O-(C5-C 10 )aryl, -(C5-C 10 )heterocycloalkyl, -(C1-C 10 )alkoxy, -(C6-C 10 ) aryloxy, -(C6-C 10 )aralkyloxy, -(C5-C 10 )heteroaralkyloxy, -(C1-C 10 )alkyl-O-(C6-C 10 ) aryloxy, amino protecting group, free radical R4', lipid-like part R5', amino acid-like part R6 and active part; A and A' are optionally substituted by one or more groups selected from the following: -OH, halogen, -CF3, -NH2, -NH-(C1-C4)alkyl, -NH-CO-(C1-C6)alkyl, -(C1-C6)alkyl, -NO2, -N3, -CO-(C1-C6)alkyl, -CO-O-(C1-C6)alkyl, -SO3H, -SO2NH2, -SO2-N((C1-C6)alkyl)2, -COOH, CONH2 and -CON((C1-C6)alkyl)2;

[0150] The conditions are:

[0151] i) when m is 0, A' is selected from H, -(C1-C6)alkyl, -(C5-C 10 )aryl, -(C5-C 10 )heteroaryl, -(C6-C 10 )aralkyl, -(C1-C6)alkyl-O-(C5-C 10 )aryl, -(C5-C 10 ) heterocycloalkyl, amino protecting group, amino acid-like part R6 and active part; A' is optionally substituted by one or more groups selected from the following: -OH, halogen, -CF3, -NH2, -NH-(C1-C4)alkyl, -NH-CO-(C1-C6)alkyl, -(C1-C6)alkyl, -NO2, -N3, -CO-(C1-C6)alkyl, -CO-O-(C1-C6)alkyl, -SO3H, -SO2NH2, -SO2-N((C1-C6)alkyl)2, -COOH, CONH2 and -CON((C1-C6)alkyl)2; and when m is 1, A' is selected from H, -OH, -(C1-C6)alkyl, -(C5-C 10 )aryl, -(C5-C 10 )heteroaryl, -(C6-C 10 )aralkyl, -(C1-C6)alkyl-O-(C5-C 10 )aryl, -(C5-C 10)heterocycloalkyl, -(C1-C 10 )alkoxy, -(C6-C 10 ) aryloxy, -(C6-C 10 )aralkyloxy, -(C5-C 10 )heteroaralkyloxy, -(C1-C 10 )alkyl-O-(C6-C 10 ) aryloxy, free radical R4', lipid-like part R5' and active part; A' is optionally substituted by one or more groups selected from the following: -OH, halogen, -CF3, -NH2, -NH-(C1-C4)alkyl, -NH-CO-(C1-C6)alkyl, -(C1-C6)alkyl, -NO2, -N3, -CO-(C1-C6)alkyl, -CO-O-(C1-C6)alkyl, -SO3H, -SO2NH2, -SO2-N((C1-C6)alkyl)2, -COOH, CONH2 and -CON((C1-C6)alkyl)2; and

[0152] ii) at least one of A and A' is a lipid-like moiety R5 or R5'.

[0153] According to one embodiment, optionally in combination with any of the embodiments provided above or below, in the lipopolyamino acid conjugate of formula (I), one of A and A' is a lipid-like moiety R5 or R5' as defined herein, respectively, and the other of A and A' is not a lipid-like moiety R5 or R5'.

[0154] In another embodiment, optionally in combination with any of the embodiments provided above or below, in the lipopolyamino acid conjugate of formula (I), A is a lipid-like portion R5, and A' is not a lipid-like portion R5'; more particularly, A' is selected from H, -OH, -(C1-C6)alkyl, -(C5-C 10 )aryl, -(C5-C 10 )heteroaryl, -(C6-C 10 )aralkyl, -(C1-C6)alkyl-O-(C5-C 10 )aryl, -(C5-C 10 )heterocycloalkyl, -(C1-C 10 )alkoxy, -(C6-C 10 ) aryloxy, -(C6-C 10 )aralkyloxy, -(C5-C 10 )heteroaralkyloxy, -(C1-C 10 )alkyl-O-(C6-C 10) aryloxy, amino protecting group, free radical R4', amino acid-like part R6 and active part, is A' optionally substituted by one or more groups selected from the following: -OH, halogen, -CF3, -NH2, -NH-(C1-C4)alkyl, -NH-CO-(C1-C6)alkyl, -(C1-C6)alkyl, -NO2, -N3, -CO-(C1-C6)alkyl, -CO-O-(C1-C6)alkyl, -SO3H, -SO2NH2, -SO2-N((C1-C6)alkyl)2, -COOH, CONH2 and -CON((C1-C6)alkyl)2.

[0155] In another embodiment, optionally in combination with any of the embodiments provided above or below, in the lipopolyamino acid conjugate of formula (I), A' is a lipid-like portion R5', and A is not a lipid-like portion R5; more particularly, A is selected from H, -(C1-C6)alkyl, -CO(C1-C6)alkyl, -(C5-C 10 )aryl, -(C5-C 10 )heteroaryl, -(C6-C 10 )aralkyl, -(C1-C6)alkyl-O-(C5-C 10 )aryl, -(C5-C 10 )heterocycloalkyl, protecting group, free radical R4 and active part are A optionally substituted by one or more groups selected from the following: -OH, halogen, -CF3, -NH2, -NH-(C1-C4)alkyl, -NH-CO-(C1-C6)alkyl, -(C1-C6)alkyl, -NO2, -N3, -CO-(C1-C6)alkyl, -CO-O-(C1-C6)alkyl, -SO3H, -SO2NH2, -SO2-N((C1-C6)alkyl)2, -COOH, CONH2 and -CON((C1-C6)alkyl)2.

[0156] The lipid-like part R5 in A of the lipopolyamino acid conjugate of formula (I) and / or the lipid-like part R5 in A"' of the free radical R4' of formula (VIb) are independently selected from -(C1-C 18 )alkyl, -(C2-C 18 ) alkenyl and a radical of formula (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XXI), (XXII) or (XXIII)

[0157]

[0158] Among them Y, Y', Q, Q', Z, g, h, i, j, t, R 22 , R 33 , R 44, the dashed bond ----- and L are as defined herein.

[0159] In one embodiment, optionally in combination with any of the embodiments provided above or below, the lipid-like portion R5 in A of the lipopolyamino acid conjugate of formula (I), and / or the lipid-like portion R5 in A"' of the free radical R4' of formula (VIb) are independently selected from -(C1-C 18 )alkyl, -(C2-C 18 )alkenyl and free radicals of formula (VII), (VIII), (IX), (X), (XI), (XII), (XIII) or (XIV).

[0160] In one embodiment, optionally in combination with any of the embodiments provided above or below, the lipid-like moiety R5 is -(C1-C 18 )alkyl, more particularly -(C6-C 18 ) alkyl. More particularly, the lipid-like moiety R5 has the following formula (XIX):

[0161]

[0162] 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.

[0163] In another embodiment, optionally in combination with any of the embodiments provided above or below, the lipid-like moiety R5 is -(C2-C 18 )alkenyl, more particularly -(C6-C 18 ) alkenyl. Even more particularly, the lipid-like moiety R5 has the following formula (XX):

[0164]

[0165] 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.

[0166] In another embodiment, optionally in combination with any of the embodiments provided above or below, the lipid-like moiety R5 has the following formula (VII),

[0167]

[0168] wherein g is an integer from 0 to 16, more particularly, g is from 0 to 12, even more particularly, g is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12.

[0169] In another embodiment, optionally in combination with any of the embodiments provided above or below, the lipid-like moiety R5 has the following formula (VIII),

[0170]

[0171] wherein each g is independently an integer from 0 to 16, more specifically, each g is independently from 0 to 12, even more specifically, each g is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12.

[0172] In another embodiment, optionally in combination with any of the embodiments provided above or below, the lipid-like moiety R5 has the following formula (IX),

[0173]

[0174] wherein Y and Y' are independently selected from -OH, -COORx and -OCORx; and each Rx is independently -(C1-C 18 )alkyl or -(C2-C 18 More particularly, in the lipid-like moiety R5 of formula (IX), each Rx is a radical independently selected from formula (ixa) and (ixb):

[0175]

[0176] wherein the wavy bond means that the stereochemistry of the double bond 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.

[0177] In one embodiment, optionally in combination with any of the embodiments provided above or below, in the lipid-like portion R5 of formula (IX), Y and Y' are the same. In another embodiment, optionally in combination with any of the embodiments provided above or below, in the lipid-like portion R5 of formula (IX), Y and Y' are different.

[0178] In another specific embodiment, optionally in combination with any of the embodiments provided above or below, the lipid-like portion R5 of formula (IX) is selected from formula (ix1), (ix2), (ix3), (ix4), (ix5), (ix6), (ix7) and (ix8):

[0179]

[0180] 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; 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.

[0181] According to one specific embodiment, optionally in combination with any of the embodiments provided above or below, in the lipid-like moiety R5 of formula (ix5), each k has the same meaning. According to another specific embodiment, optionally in combination with any of the embodiments provided above or below, in the lipid-like moiety R5 of formula (ix6) and (ix7), each p has the same meaning, each r has the same meaning, and each q has the same meaning.

[0182] In another embodiment, optionally in combination with any of the embodiments provided above or below, the lipid-like moiety R5 has the following formula (X):

[0183]

[0184] wherein Q and Q' are independently selected from -OCORy and -COORy; each Ry is independently -(C1-C 18 )alkyl or -(C2-C 18 )alkenyl; each h is independently an integer from 1 to 18, more particularly, each h is independently 1 to 12, even more particularly, each h is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12; and i is an integer from 0 to 12, more particularly, i is 0 to 12, even more particularly i is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12. More particularly, in the lipid-like moiety R5 of formula (X), each Ry is a radical independently selected from formula (xa), (xb) and (xc):

[0185]

[0186] wherein the wavy bond means that the stereochemistry of the double bond 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.

[0187] In one embodiment, optionally in combination with any of the embodiments provided above or below, in the lipid-like portion R5 of formula (X), Q and Q' are both -OCORy. In another embodiment, optionally in combination with any of the embodiments provided above or below, in the lipid-like portion R5 of formula (X), Q and Q' are both -COORy.

[0188] In another specific embodiment, optionally in combination with any of the embodiments provided above or below, the lipid-like moiety R5 of formula (X) is selected from formula (x1), (x2), (x3) and (x4):

[0189]

[0190] 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, 12; and i is an integer from 0 to 12; more particularly i is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12.

[0191] In another embodiment, optionally in combination with any of the embodiments provided above or below, the lipid-like moiety R5 has the following formula (XI),

[0192]

[0193] wherein Q and Q' are independently selected from -OCORy and -COORy; each Ry is independently -(C1-C 18 )alkyl or -(C2-C 18)alkenyl; each h is independently an integer from 1 to 18, more particularly, each h is independently 1 to 12, even more particularly each h is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12; and i is an integer from 0 to 18, more particularly, i is 0 to 12, even more particularly i is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12. More particularly, in the lipid-like moiety R5 of formula (XI), each Ry is a radical independently selected from formula (xia), (xib) and (xic):

[0194]

[0195] wherein the wavy bond means that the stereochemistry of the double bond 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.

[0196] In one embodiment, optionally in combination with any of the embodiments provided above or below, in the lipid-like portion R5 of formula (XI), Q and Q' are both -OCORy. In another embodiment, optionally in combination with any of the embodiments provided above or below, in the lipid-like portion R5 of formula (XI), Q and Q' are both -COORy.

[0197] In another specific embodiment, optionally in combination with any of the embodiments provided above or below, the lipid-like moiety R5 of formula (XI) has the following formula (xi1):

[0198]

[0199] 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, 12; and i is an integer from 0 to 12; more particularly, i is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12.

[0200] In another embodiment, optionally in combination with any of the embodiments provided above or below, the lipid-like moiety R5 has the following formula (XII),

[0201]

[0202] wherein i is an integer from 0 to 18; more particularly i is from 0 to 12, even more particularly i is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12; and each j is independently an integer from 0 to 18, more particularly, each j is independently selected from 0 to 12, even more particularly each j is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12.

[0203] In another embodiment, optionally in combination with any of the embodiments provided above or below, the lipid-like moiety R5 has the following formula (XIII),

[0204]

[0205] wherein i is an integer from 0 to 18; more particularly, i is from 0 to 12, even more particularly i is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12; and each j is independently an integer from 0 to 18, more particularly, each j is independently selected from 0 to 12, even more particularly each j is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12.

[0206] In another embodiment, optionally in combination with any of the embodiments provided above or below, the lipid-like moiety R5 has the following formula (XIV),

[0207]

[0208] wherein Q and Q' are independently selected from -OCORy and -COORy; Z is selected from -OCO-, -COO-, -NRz'CO- and -CONRz'-; each Rz' is H or Rz; each Ry and Rz are independently -(C1-C 18 )alkyl or -(C2-C 18 ) alkenyl; and i is an integer from 0 to 18, more particularly i is from 0 to 12, even more particularly i is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12. More particularly, in the lipid-like moiety R5 of formula (XIV), each Ry is independently selected from the free radicals of formula (xiva) and (xivb):

[0209]

[0210] wherein the wavy bond means that the stereochemistry of the double bond 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.

[0211] In one embodiment, optionally in combination with any of the embodiments provided above or below, in the lipid-like portion R5 of formula (XIV), Q and Q' are both -OCORy. In another embodiment, optionally in combination with any of the embodiments provided above or below, in the lipid-like portion R5 of formula (XIV), Q and Q' are both -COORy. In another embodiment, optionally in combination with any of the embodiments provided above or below, in the lipid-like portion R5 of formula (XIV), Z is -OCO-. In another embodiment, optionally in combination with any of the embodiments provided above or below, in the lipid-like portion R5 of formula (XIV), Z is -CONRz'.

[0212] In another specific embodiment, optionally in combination with any of the embodiments provided above or below, the lipid-like moiety R5 of formula (XIV) is selected from the following formulae (xiv1) and (xiv2):

[0213]

[0214] wherein each k is independently an integer from 1 to 16, more specifically 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 12; more specifically, i is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12.

[0215] In another embodiment, optionally in combination with any of the embodiments provided above or below, the lipid-like moiety R5 has the following formula (XXI),

[0216]

[0217] wherein i is an integer from 0 to 18; more particularly i is from 0 to 12, even more particularly i is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12; and each j is independently an integer from 0 to 18, more particularly each j is independently selected from 0 to 12, even more particularly each j is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12. In a specific embodiment, optionally in combination with any of the embodiments provided above or below, the lipid-like portion R5 of formula (XXI) has the following formula (xxi1):

[0218]

[0219] wherein i is an integer from 0 to 12; more particularly i is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12.

[0220] In another embodiment, optionally in combination with any of the embodiments provided above or below, the lipid-like moiety R5 has the following formula (XXII),

[0221]

[0222] wherein Q and Q' are independently selected from -OCORy and -COORy; each Ry is independently -(C1-C 18 )alkyl or -(C2-C 18 ) alkenyl; and i is an integer from 0 to 18, more particularly, i is from 0 to 12, even more particularly i is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12. More particularly, in the lipid-like moiety R5 of formula (XXII), each Ry is independently selected from the free radicals of the following formulae (xxiia) and (xxiib):

[0223]

[0224] wherein the wavy bond means that the stereochemistry of the double bond 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.

[0225] In one embodiment, optionally in combination with any of the embodiments provided above or below, in the lipid-like portion R5 of formula (XXII), Q and Q' are both -OCORy. In another embodiment, optionally in combination with any of the embodiments provided above or below, in the lipid-like portion R5 of formula (XXII), Q and Q' are both -COORy.

[0226] In another specific embodiment, optionally in combination with any of the embodiments provided above or below, the lipid-like moiety R5 of formula (XXII) is selected from the following formulae (xxii1) and (xxii2):

[0227]

[0228] wherein each k is independently an integer from 1 to 16, more specifically 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 12; more specifically, i is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12.

[0229] In another embodiment, optionally in combination with any of the embodiments provided above or below, the lipid-like moiety R5 has the following formula (XXIII),

[0230]

[0231] Where t, R 22 , R 33 , R 44 , the dashed bond ----- and L are as defined herein.

[0232] In a more specific embodiment, in the free radical of formula (XXIII), each dotted bond of the alkyl chain connected 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, R33 is hydrogen, (III) R33 and R44 are methyl, R22 is hydrogen, and (IV) R44 is methyl, R22 and R33 are hydrogen. Even more particularly, each dotted bond of the alkyl chain connected to the chroman ring is a single bond, and R22, R33 and R44 are methyl. Even more particularly, formula (XXIII) has the following formula (xxiii1):

[0233]

[0234] In another more specific embodiment, in the free radical of formula (XXIII), each dotted bond of the alkyl chain connected to the chroman ring is a double bond, and R 22 , R 33and R 44 Selected from the following meanings: (i) R 22 , R 33 and R 44 is methyl, (ii) R 22 , R 44 is methyl and R 33 is hydrogen, (iii) R 33 and R 44 is methyl and R 22 is hydrogen, and (IV) R 44 is methyl and R 22 and R 33 In a more specific embodiment, each dashed bond of the alkyl chain attached to the chroman ring is a double bond, and R 22 , R 33 and R 44 It's methyl.

[0235] In another embodiment, optionally in combination with any of the embodiments provided above or below, A is a lipid-like moiety R5 having the following formula (XXIII), X is O and R1 is absent, that is, the lipopolyamino acid conjugate of formula (I) has the following formula (Ih):

[0236]

[0237] Where A', R2, R3, m, n, R 22 , R 33 , R 44 and dotted bonds-----as defined herein.

[0238] In another embodiment, optionally in combination with any of the embodiments provided above or below, A is a lipid-like moiety R5 having the following formula (XXIII), wherein t is 1, i.e., the lipopolyamino acid conjugate of formula (I) has the following formula (Ij):

[0239]

[0240] Where A', R2, R3, m, n, R 22 , R 33 , R 44 , L and dotted bond-----as defined herein.

[0241] According to a specific embodiment, optionally in combination with any of the embodiments provided above or below, in the radical of formula (XXIII), the linker L is a diradical selected from the following: -(C1-C 12 ) alkylene-, which is selected from halogen, -OH, -NR aa R bb 、-SH、-NHNH2、-COORcc , -CF3 and -OCF3 are optionally substituted, wherein R aa , R bb and R cc is a radical independently selected from H, -phenyl, -(C1-C6)alkyl, -(C2-C6)alkenyl, -(C1-C6)alkylphenyl and -phenyl(C1-C6)alkyl; -(C1-C6)alkyl-CO-; -CO-(C1-C6)alkyl-; and a diradical of formula (IIID), (IVD), (VD), (VID), (VIID), (VIIID), (IXD), (XD), (XID) (XIID) (XIIID), (XIVD), (XVD), (XVID), (XVIID), (XVIIID) or (XIXD),

[0242]

[0243]

[0244]

[0245] Wherein "*" represents the connection point between the diradical L and the oxygen atom of X or the vitamin E radical part, "* 3 ” represents the connection point of the diradical L and X, and “* 4 " represents the connection point of the diradical to the oxygen atom of the vitamin E radical part,

[0246] a1, c1, d1, e1, f1, h1, j1 and k1 are independently integers from 0 to 10, in particular from 0 to 6; b1 and g1 are independently integers from 0 to 1; provided that when b1 is 0, at least one of a1 or c1 is not 0, and when g1 is 0, at least one of f1 or h1 is not 0;

[0247] X1' is -O- or -NH-;

[0248] p1 is 0 or 1;

[0249] Each dashed bond is independently a single bond, or alternatively, a double bond.

[0250] When drawing, the connection point is indicated herein by "*". Whenever a specific connection is not specified, it is meant that the linker can be connected to the rest of the molecule interchangeably in any orientation.

[0251] In one embodiment, optionally in combination with one or more features of the various embodiments described above or below, in the radical of formula (XXIII), L is -(C1-C 12)alkylene-, more particularly -(C1-C6)alkyl-, and optionally substituted as defined herein.

[0252] In another embodiment, optionally in combination with one or more features of the various embodiments described above or below, in the radical of formula (XXIII), L is -(C1-C6)alkyl-CO- or -CO-(C1-C6)alkyl-, and is optionally substituted as defined herein.

[0253] In another embodiment, optionally in combination with one or more features of the various embodiments described above or below, in the radical of formula (XXIII), L is a diradical of formula (IIID), more particularly a diradical of formula (IIID), wherein b1 is 0, and a1+c1 is selected from 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12, even more particularly, L is a diradical of formula (IIID) selected from:

[0254]

[0255] In another embodiment, optionally in combination with one or more features of the various embodiments described above or below, in the radical of formula (XXIII), L is a diradical selected from formula (IVD), (VD) and (VID), more particularly, in the diradical of formula (IVD), a1 is 1 and the dotted bond is a double bond, i.e. the diradical of formula (IVD) has formula (IVDa), while in the diradical of formula (VD), the dotted bond is more particularly a double bond, i.e. the diradical of formula (VD) has formula (VDa).

[0256]

[0257] In another embodiment, optionally in combination with one or more features of the various embodiments described above or below, in the radical of formula (XXIII), L is a diradical selected from formula (VID), (VIID) and (VIIID), more particularly, in the diradical of formula (VIIID), a1 is 1.

[0258] In another embodiment, optionally in combination with one or more features of the various embodiments described above or below, in the radical of formula (XXIII), L is a diradical of formula (IXD), more particularly a diradical of formula (IXD) wherein b1 and g1 are 0; and a1, c1, d1, e1, f1 and h1 are 1, i.e. a diradical of formula (IXDa).

[0259]

[0260] In another embodiment, optionally in combination with one or more features of the various embodiments described above or below, in the radical of formula (XXIII), L is a diradical selected from the diradicals of formula (XD) and (XID), more particularly in the diradicals of formula (XD) and (XID), b1 and g1 are 0; and a1, c1, d1, e1, f1 and h1 are 1, i.e., the diradicals of formula (XD) and (XID) have the following formulae (XDa) and (XIDa), respectively.

[0261]

[0262] In another embodiment, optionally in combination with one or more features of the various embodiments described above or below, in the radical of formula (XXIII), L is a diradical selected from the diradicals of formulas (XIID) and (XIIID), more particularly in the diradicals of formulas (XIID) and (XIIID), b1 is 0; and a1, c1 and d1 are 1.

[0263] In another embodiment, optionally in combination with one or more features of the various embodiments described above or below, in the radical of formula (XXIII), L is a diradical selected from the group consisting of formulas (XIVD), (XVD), (XVID), (XVIID) and (XVIII), more particularly in the diradicals of formulas (XIVD), (XVD), (XVID), (XVIID) and (XVIII), b1 is 0; a1 and c1 are 1.

[0264] In another embodiment, optionally in combination with one or more features of the various embodiments described above or below, in the radical of formula (XXIII), L is a diradical 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 (XXIII), L is a diradical 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 (XXIII), L is a diradical selected from formula (XIXD), wherein p1 is 1, X1' is -O-, and j1 and k1 are 1.

[0265] According to one embodiment, optionally in combination with any of the embodiments provided above or below, in the lipopolyamino acid conjugate of formula (I), A is a lipid-like portion R selected from the following 5 :

[0266] a)-(C1-C 18 )alkyl, more particularly -(C6-C 18)alkyl, even more particularly a radical of formula (XIX) as defined above;

[0267] b)-(C2-C 18 )alkenyl, more particularly -(C6-C 18 )alkenyl, even more particularly a radical of formula (XX) as defined above;

[0268] c) a radical of formula (VII) as defined herein;

[0269] d) a radical of formula (VIII) as defined herein;

[0270] e) a radical of formula (IX) as defined herein, more particularly selected from radicals of formula (ix1), (ix2), (ix3), (ix4), (ix5), (ix6), (ix7) and (ix8) as defined hereinbefore;

[0271] f) a radical of formula (X) as defined herein, more particularly selected from radicals of formula (x1), (x2), (x3) and (x4) as defined above;

[0272] g) a radical of formula (XI) as defined herein, more particularly a radical of formula (xi1) as defined above;

[0273] h) a radical of formula (XII) as defined herein;

[0274] I) a free radical of formula (XIII) as defined herein;

[0275] j) a radical of formula (XIV) as defined herein, more particularly a radical selected from the group consisting of formulae (xiv1) and (xiv2);

[0276] k) a radical of formula (XXI) as defined herein, more particularly a radical of formula (xxi1) as defined above;

[0277] l) a radical of formula (XXII) as defined herein, more particularly a radical selected from the group consisting of formulae (xxii1) and (xxii2); and

[0278] m) a radical of formula (XXIII) as defined herein.

[0279] In another embodiment, optionally in combination with any of the embodiments provided above or below, in the lipopolyamino acid conjugate of formula (I), A and R1 are the same and are -(C1-C 18 ) alkyl, and X is N. More specifically, in this embodiment, the lipopolyamino acid conjugate of formula (I) has the following formula (Ia),

[0280]

[0281] wherein A', R2, R3, m, n 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, in the lipopolyamino acid conjugate of formula (Ia), each k has the same meaning.

[0282] According to one embodiment, optionally in combination with any of the embodiments provided above or below, in the lipopolyamino acid conjugate of formula (I), A is a lipid-like moiety R5 as defined herein, m is 0, and A′ is H.

[0283] According to another embodiment, optionally in combination with any of the embodiments provided above or below, in the lipopolyamino acid conjugate of formula (I), A is a lipid-like moiety R5 as defined herein, m is 0, and A' is an amino protecting group. Suitable amino protecting groups known in the art can be used without restriction. Non-limiting examples of amino protecting groups include acyl-based groups, carbamate-based groups, imide-based groups, sulfonamide-based groups, and the like. In a particular embodiment, the amino protecting group is selected from acetyl, methoxycarbonyl, benzyloxycarbonyl (Cbz), p-methoxybenzyloxycarbonyl, tert-butoxycarbonyl (Boc), 9-fluorenylmethoxycarbonyl (Fmoc), allyloxycarbonyl (Alloc), 2,2,2-trichloroethoxycarbonyl (Troc), benzoyl (Bz), benzyl (Bn), p-methoxybenzyl (PMB), 3,4-dimethoxybenzyl (DMPM), p-methoxyphenyl (PMP), tosyl (Ts), trimethylsilylethoxycarbonyl (Teoc), diphenylmethyl, triphenylmethyl (Trityl), (4-methoxyphenyl)diphenylmethyl (MMT), dimethoxytrityl (DMT) and diphenylphosphino, and even more particularly the amino protecting group is acetyl.

[0284] Introduction and removal of the amino protecting group can be carried out by standard methods such as those described in TW Green and PGM Wuts, Protective Groups in Organic Chemistry, Wiley, 3rd ed. 1999, Chapter 7 (pp. 495-653).

[0285] According to another embodiment, optionally in combination with any of the embodiments provided above or below, in the lipopolyamino acid conjugate of formula (I), A is a lipid-like portion R5 as defined herein, m is 1, and A' is a free radical R4', which is a free radical R4' of formula (VIb)

[0286]

[0287] in:

[0288] n' is an integer from 5 to 250;

[0289] X” is selected from N, S and O;

[0290] R1″ is a free radical having any of the meanings of R1, provided that when X′ is O or S, R1″ is absent;

[0291] R2' is a radical having any of the meanings of R2;

[0292] R3' is a radical having any of the meanings of R3;

[0293] B and B' are independently S or CH2;

[0294] e and f are independently integers from 1 to 18; and

[0295] A"' is selected from H, -(C1-C6)alkyl, -CO(C1-C6)alkyl, -(C5-C 10 )aryl, -(C5-C 10 )heteroaryl, -(C6-C 10 )

[0296] Aralkyl, -(C1-C6)alkyl-O-(C5-C 10 )aryl, -(C5-C 10 ) heterocycloalkyl, protecting group, lipid-like part R5 and active part; A "' is optionally substituted by one or more groups selected from the following: -OH, halogen, -CF3, -NH2, -NH-(C1-C4) alkyl, -NH-CO-(C1-C6) alkyl, -(C1-C6) alkyl, -NO2, -N3, -CO-(C1-C6) alkyl, -CO-O-(C1-C6) alkyl,

[0297] -SO3H, -SO2NH2, -SO2-N((C1-C6)alkyl)2, -COOH, CONH2 and -CON((C1-C6)alkyl)2;

[0298] That is, the lipid polyamino acid conjugate of formula (I) has the following formula (Ib):

[0299]

[0300] wherein R5, A'", X, X", R1, R1", R2, R2', R3, R3', n, n', e, f, B and B' are as defined herein.

[0301] All embodiments indicated herein regarding the meanings of A, X, R1, R2 and R3 in the lipopolyamino acid conjugate of formula (I) also apply to the meanings of A'', X'', R1'', R2' and R3' in the lipopolyamino acid conjugate of formula (Ib).

[0302] In one embodiment, the lipopolyamino acid conjugate of formula (Ib) is a dimer, wherein, respectively, R5 and A'" have the same meaning, X and X" have the same meaning, R1 and R1" have the same meaning, R2 and R2' have the same meaning, R3 and R3' have the same meaning, B and B' have the same meaning, e and f have the same meaning, and n and n' have the same meaning.

[0303] According to another embodiment, optionally in combination with any of the embodiments provided above or below, in the lipopolyamino acid conjugate of formula (I), A is a lipid-like portion R5 as defined herein, m is 0, and A' is an amino acid-like portion R6, R6 is a free radical selected from (XV), (XVI) and (XVII)

[0304]

[0305] wherein a', b' and c' are independently integers from 1 to 4.

[0306] In a more specific embodiment, in the lipopolyamino acid conjugate of formula (I), R2 is a free radical of formula (II), A is a lipid-like portion R5 as defined herein, m is 0, and A' is an amino acid-like portion R6, R6 is a free radical of formula (XV), that is, the lipopolyamino acid conjugate of formula (I) has the following formula (Ic),

[0307]

[0308] wherein X, R1, R3, R5, n, a and a' are as defined herein. More particularly, in the lipopolyamino acid conjugate of formula (Ic), a and a' have the same meaning, even more particularly a and a' are both 1 or 2.

[0309] In another more specific embodiment, in the lipopolyamino acid conjugate of formula (I), R2 is a free radical of formula (III), A is a lipid-like portion R5 as defined herein, m is 0, and A' is an amino acid-like portion R6, R6 is a free radical of formula (XVI), that is, the lipopolyamino acid conjugate of formula (I) has the following formula (Id),

[0310]

[0311] wherein X, R1, R3, R5, n, b and b' are as defined herein. More particularly, in the lipopolyamino acid conjugate of formula (Id), b and b' have the same meaning, even more particularly, b and b' are both 1 or 2.

[0312] In another more specific embodiment, in the lipopolyamino acid conjugate of formula (I), R2 is a free radical of formula (IV), A is a lipid-like portion R5 as defined herein, m is 0, and A' is an amino acid-like portion R6, R6 is a free radical of formula (XVII), that is, the lipopolyamino acid conjugate of formula (I) has the following formula (Ie),

[0313]

[0314] wherein X, R1, R3, R5, n, c and c' are as defined herein. More particularly, in the lipopolyamino acid conjugate of formula (Ie), c and c' have the same meaning, even more particularly, c and c' are both 1 or 2.

[0315] In another more specific embodiment, in the lipopolyamino acid conjugate of formula (I), R2 is a free radical of formula (IV), A is a lipid-like portion R5 as defined herein, and m is 0, that is, the lipopolyamino acid conjugate of formula (I) has the following formula (Ig),

[0316]

[0317] wherein X, R1, R3, R5, n and c are as defined herein, and A' is selected from H, -(C1-C6)alkyl, -(C5-C 10 )aryl, -(C5-C 10 )heteroaryl, -(C6-C 10 )aralkyl, -(C1-C6)alkyl-O-(C5-C 10 )aryl and -(C5-C 10 )heterocycloalkyl; A' is optionally substituted by one or more groups selected from the group consisting of: -OH, halogen, -CF3, -NH2, -NH-(C1-C4)alkyl, -NH-CO-(C1-C6)alkyl, -(C1-C6)alkyl, -NO2, -N3, -CO-(C1-C6)alkyl, -CO-O-(C1-C6)alkyl, -SO3H, -SO2NH2, -SO2-N((C1-C6)alkyl)2, -COOH, CONH2 and -CON((C1-C6)alkyl)2, more particularly A' is methyl.

[0318] In another more specific embodiment, in the lipopolyamino acid conjugate of formula (I), R2 is a free radical of formula (IV), A is a lipid-like portion R5 as defined herein, and m is 1, that is, the lipopolyamino acid conjugate of formula (I) has the following formula (Ig'),

[0319]

[0320] wherein X, R1, R3, R5, n and c are as defined herein, and A' is selected from H, -OH, -(C1-C6)alkyl, -(C5-C 10 )aryl, -(C5-C 10 )heteroaryl, -(C6-C 10 )aralkyl, -(C1-C6)alkyl-O-(C5-C 10 )aryl, -(C5-C 10 )heterocycloalkyl, -(C1-C 10 )alkoxy, -(C6-C 10 ) aryloxy, -(C6-C 10 )aralkyloxy, -(C5-C 10 )heteroaralkyloxy, -(C1-C 10 )alkyl-O-(C6-C 10 )aryloxy; A' is optionally substituted by one or more groups selected from the group consisting of: -OH, halogen, -CF3, -NH2, -NH-(C1-C4)alkyl, -NH-CO-(C1-C6)alkyl, -(C1-C6)alkyl, -NO2, -N3, -CO-(C1-C6)alkyl, -CO-O-(C1-C6)alkyl, -SO3H, -SO2NH2, -SO2-N((C1-C6)alkyl)2, -COOH, CONH2 and -CON((C1-C6)alkyl)2, more particularly A' is methyl.

[0321] According to another embodiment, optionally in combination with any of the embodiments provided above or below, in the lipopolyamino acid conjugate of formula (I), m is 1, A is the lipid-like moiety R5, and A' is the lipid-like moiety R5' as defined herein.

[0322] In another embodiment, optionally in combination with any of the embodiments provided above or below, in the lipopolyamino acid conjugate of formula (I), A is a lipid-like portion R5 as defined herein, m is 1, and A' is an active portion selected from a pharmaceutically active agent, a cell targeting agent, a penetration enhancer, a cosmetic active agent, and a diagnostic active agent.

[0323] The active part in A' can be directly bound to the nitrogen atom of the lipopolyamino acid conjugate, or alternatively, it can be bound through a linker. There is no restriction on the nature of the linker, as long as it can be connected to the rest of the molecule through a chemically feasible bond. For example, the linker can be a free radical chain, which includes one or more parts selected from the following: -CH=CH-, -C≡C-, -CH2-, -N=CH-, -CH=NH-, -NH-, -NH-NH-, -NH-N=CH-, -O-, -O(CH2)O-, -CO-, -O(CO)-, -COO-, -C(=CH2)-, -C(=NH)-, -CONH-, -NHCO-, -NH(CO)NH-, -S-, -SS-, -SO-, -SO2-, -SO2NH2-, -phenylene-, etc. The linker may comprise 1-50 moieties, more particularly 2 to 30 or 2 to 20 or 2 to 15 moieties as defined above, and may be linked to the nitrogen atom of PAA via a chemically feasible bond selected from an amine bond, an amide bond, a carbamate bond or a urea bond.

[0324] The lipid-like part R5' in A' of the lipopolyamino acid conjugate of formula (I) and / or the lipid-like part R5' in A" of the free radical R4 of formula (VIa) are independently selected from -X'(R1')-(C1-C 18 )alkyl, -X'(R1')-(C2-C 18 )alkenyl and a radical of formula (VII'), (VIII'), (IX'), (X'), (XI'), (XII'), (XIII'), (XIV'), (XXI'), (XXII') or (XXIII'),

[0325]

[0326]

[0327] Among them Y, Y', Q, Q', Z', X', R1', g, h, i, j, t', R 22 , R 33 , R 44 , the dashed bond ----- and L are as defined herein.

[0328] In one embodiment, optionally in combination with any of the embodiments provided above or below, the lipid-like portion R5' in A' of the lipopolyamino acid conjugate of formula (I) and / or the lipid-like portion R5' in A" of the free radical R4 of formula (VIa) is independently selected from -X'(R1')-(C1-C 18 )alkyl, -X'(R1')-(C2-C 18)alkenyl and free radicals of formula (VII'), (VIII'), (IX'), (X'), (XI'), (XII'), (XIII') or (XIV').

[0329] In one embodiment, optionally in combination with any of the embodiments provided above or below, the lipid-like moiety R5′ is -X′(R1′)-(C1-C 18 )alkyl, more particularly -X'(R1')-(C6-C 18 More particularly, the lipid-like moiety R5' has the following formula (XIX'):

[0330]

[0331] wherein X′ and R 1 ′ are as defined herein, and 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.

[0332] In another embodiment, optionally in combination with any of the embodiments provided above or below, the lipid-like moiety R5′ is -X′(R1′)-(C1-C 18 )alkyl, wherein X' is N and R1' is -(C1-C 18 ) alkyl, more particularly, the lipid-like moiety R5' has the following formula (XIX'):

[0333]

[0334] wherein X' and R1' 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 has the same meaning.

[0335] In another embodiment, optionally in combination with any of the embodiments provided above or below, the lipid-like moiety R5′ is -X′(R1′)-(C2-C 18 )alkenyl, more particularly -X'(R1')-(C6-C 18 Even more particularly, the lipid-like moiety R5' has the following formula (XX'):

[0336]

[0337] wherein X′ and R′ are as defined herein and 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.

[0338] In another embodiment, optionally in combination with any of the embodiments provided above or below, the lipid-like moiety R5' has the following formula (VII'),

[0339]

[0340] wherein g is an integer from 0 to 18, more particularly g is from 0 to 12, even more particularly g is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12.

[0341] In another embodiment, optionally in combination with any of the embodiments provided above or below, the lipid-like moiety R5' has the following formula (VIII'),

[0342]

[0343] wherein each g is independently an integer from 0 to 18, more specifically, each g is independently 0 to 12, even more specifically each g is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12.

[0344] In another embodiment, optionally in combination with any of the embodiments provided above or below, the lipid-like moiety R5' has the following formula (IX'),

[0345]

[0346] wherein X' and R1' are as defined herein, Y and Y' are independently selected from -OH, -COORx and -OCORx; and each Rx is independently -(C1-C 18 )alkyl or -(C2-C 18 More particularly, in the lipid-like moiety R5' of formula (IX'), each Rx is a free radical independently selected from formula (ixa') and (ixb'):

[0347]

[0348] wherein X' and R1' are as defined herein, a wavy bond means that the stereochemistry of the double bond 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.

[0349] In one embodiment, optionally in combination with any of the embodiments provided above or below, in the lipid-like portion R5' of formula (IX'), Y and Y' are the same. In another embodiment, optionally in combination with any of the embodiments provided above or below, in the lipid-like portion R5' of formula (IX'), Y and Y' are different.

[0350] In another specific embodiment, optionally in combination with any of the embodiments provided above or below, the lipid-like portion R5' of formula (IX') is selected from formula (ix1'), (ix2'), (ix3'), (ix4'), (ix5'), (ix6'), (ix7') and (ix8'):

[0351]

[0352]

[0353] wherein X' and R1' are as defined herein, 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; 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.

[0354] According to one specific embodiment, optionally in combination with any of the embodiments provided above or below, in the lipid-like moiety R5' of formula (ix5'), each k has the same meaning. According to another specific embodiment, optionally in combination with any of the embodiments provided above or below, in the lipid-like moiety R5' of formula (ix6') and (ix7'), each p has the same meaning, each r has the same meaning, and each q has the same meaning.

[0355] In one embodiment, optionally in combination with any of the embodiments provided above or below, the lipid-like moiety R5' has the following formula (X'),

[0356]

[0357] wherein X' and R1' are as defined herein, Q and Q' are independently selected from -OCORy and -COORy; each Ry is independently -(C1-C 18 )alkyl or -(C2-C 18 )alkenyl; each h is independently an integer from 1 to 18, more particularly, each h is independently 1 to 12, even more particularly each h is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12; and i is an integer from 0 to 18; more particularly, i is 0 to 12, even more particularly i is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12. More particularly, in the lipid-like moiety R5 of formula (X), each Ry is a radical independently selected from formula (xa'), (xb') and (xc'):

[0358]

[0359] wherein X' and R1' are as defined herein, a wavy bond means that the stereochemistry of the double bond 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.

[0360] In one embodiment, optionally in combination with any of the embodiments provided above or below, in the lipid-like moiety R5' of formula (X'), Q and Q' are both -OCORy. In another embodiment, optionally in combination with any of the embodiments provided above or below, in the lipid-like moiety R5' of formula (X'), Q and Q' are both -COORy.

[0361] In another specific embodiment, optionally in combination with any of the embodiments provided above or below, the lipid-like moiety R5' of formula (X') is selected from formula (x1'), (x2'), (x3') and (x4'):

[0362]

[0363] wherein X' and R1' are as defined herein, 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, 12; and i is an integer from 0 to 12; more particularly, i is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12.

[0364] In one embodiment, optionally in combination with any of the embodiments provided above or below, the lipid-like moiety R5' has the following formula (Xi'),

[0365]

[0366] wherein X' and R1' are as defined herein, Q and Q' are independently selected from -OCORy and -COORy; each Ry is independently -(C1-C 18 )alkyl or -(C2-C 18 )alkenyl; each h is independently an integer from 1 to 18, more particularly, each h is independently 1 to 12, even more particularly each h is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12; and i is an integer from 0 to 18, more particularly, i is 0 to 12, even more particularly i is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12. More particularly, in the lipid-like moiety R5' of formula (XI'), each Ry is a radical independently selected from formula (xia'), (xib') and (xic'):

[0367]

[0368] wherein X' and R1' are as defined herein, a wavy bond means that the stereochemistry of the double bond 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.

[0369] In one embodiment, optionally in combination with any of the embodiments provided above or below, in the lipid-like moiety R5' of formula (XI'), Q and Q' are both -OCORy. In another embodiment, optionally in combination with any of the embodiments provided above or below, in the lipid-like moiety R5' of formula (XI'), Q and Q' are both -COORy.

[0370] In another specific embodiment, optionally in combination with any of the embodiments provided above or below, the lipid-like moiety R5' of formula (XI') has the following formula (xi1'):

[0371]

[0372] wherein X' and R1' are as defined herein, 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, 12; and i is an integer from 0 to 12; more particularly, i is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12.

[0373] In one embodiment, optionally in combination with any of the embodiments provided above or below, the lipid-like moiety R5' has the following formula (XII'),

[0374]

[0375] wherein X' and R1' are as defined herein, i is an integer from 0 to 18; more particularly, i is from 0 to 12, even more particularly i is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12; and each j is independently an integer from 0 to 18, more particularly, each j is independently selected from 0 to 12, even more particularly each j is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12.

[0376] In one embodiment, optionally in combination with any of the embodiments provided above or below, the lipid-like moiety R5' has the following formula (XIII'),

[0377]

[0378] wherein X' and R1' are as defined herein, i is an integer from 0 to 18; more particularly, i is from 0 to 12, even more particularly i is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12; and each j is independently an integer from 0 to 18, more particularly, each j is independently selected from 0 to 12, even more particularly each j is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12.

[0379] In another embodiment, optionally in combination with any of the embodiments provided above or below, the lipid-like moiety R5' has the following formula (XIV'),

[0380]

[0381] wherein X' and R1' are as defined herein, Q and Q' are independently selected from -OCORy and -COORy; Z' is selected from -OCO-, -COO-, -NRz'CO- and -CONRz'-; each Rz' is H or Rz; each Ry and Rz are independently -(C1-C 18 )alkyl or -(C2-C 18 ) alkenyl; and i is an integer from 0 to 18, more particularly, i is from 0 to 12, even more particularly i is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12. More particularly, in the lipid-like moiety R5' of formula (XIV'), each Ry is independently selected from the free radicals of formula (xiva) and (xivb):

[0382]

[0383] wherein the wavy bond means that the stereochemistry of the double bond 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.

[0384] In one embodiment, optionally in combination with any of the embodiments provided above or below, in the lipid-like moiety R5' of formula (XIV'), Q and Q' are both -OCORy. In another embodiment, optionally in combination with any of the embodiments provided above or below, in the lipid-like moiety R5' of formula (XIV'), Q and Q' are both -COORy. In another embodiment, optionally in combination with any of the embodiments provided above or below, in the lipid-like moiety R5' of formula (XIV'), Z' is -OCO-. In another embodiment, optionally in combination with any of the embodiments provided above or below, in the lipid-like moiety R5' of formula (XIV'), Z' is -CONRz'.

[0385] In another specific embodiment, optionally in combination with any of the embodiments provided above or below, the lipid-like moiety R5' of formula (XIV') is selected from formula (xiv1') and (xiv2'):

[0386]

[0387] wherein X' and R1' are as defined herein, each k is independently an integer from 1 to 16, more specifically 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 12; more specifically, i is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12.

[0388] In another embodiment, optionally in combination with any of the embodiments provided above or below, the lipid-like moiety R5' has the following formula (XXI'),

[0389]

[0390] wherein X' and R1' are as defined herein; i is an integer from 0 to 18; more particularly, i is from 0 to 12, even more particularly i is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12; and each j is independently an integer from 0 to 18, more particularly, each j is independently selected from 0 to 12, even more particularly each j is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12. In a specific embodiment, optionally in combination with any of the embodiments provided above or below, the lipid-like portion R5' of formula (XXI') has the following formula (xxi1'):

[0391]

[0392] wherein X' and R1' are as defined herein. In another embodiment, optionally in combination with any of the embodiments provided above or below, the lipid-like moiety R5' has the following formula (XXII'),

[0393]

[0394] wherein X' and R1' are as defined herein, Q and Q' are independently selected from -OCORy and -COORy; each Ry is independently -(C1-C 18 )alkyl or -(C2-C 18 ) alkenyl; and i is an integer from 0 to 18, more particularly, i is from 0 to 12, even more particularly i is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12. More particularly, in the lipid-like moiety R5' of formula (XXII'), each Ry is independently selected from the free radicals of formula (xxiia) and (xxiib):

[0395]

[0396] wherein the wavy bond means that the stereochemistry of the double bond 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.

[0397] In one embodiment, optionally in combination with any of the embodiments provided above or below, in the lipid-like portion R5' of formula (XXII'), Q and Q' are both -OCORy. In another embodiment, optionally in combination with any of the embodiments provided above or below, in the lipid-like portion R5' of formula (XXII'), Q and Q' are both -COORy.

[0398] In another specific embodiment, optionally in combination with any of the embodiments provided above or below, the lipid-like moiety R5' of formula (XXII') is selected from formula (xxii1') and (xxii2'):

[0399]

[0400] wherein X' and R1' are as defined herein, each k is independently an integer from 1 to 16, more specifically 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 12; more specifically, i is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12.

[0401] In another embodiment, optionally in combination with any of the embodiments provided above or below, the lipid-like moiety R5 has the following formula (XXIII'),

[0402]

[0403] Among them, t', R 22 , R 33 , R 44 , the dashed bond ----- and L are as defined herein.

[0404] In a more specific embodiment, in the radical of formula (XXIII'), each dashed bond of the alkyl chain connected to the chroman ring is a single bond, and R 22 , R 33 and R 44 Selected from the following meanings: (i) R 22 , R 33 and R 44 is methyl, (ii) R 22 , R 44 is methyl and R 33 is hydrogen, (iii) R 33 and R 44 is methyl and R 22 is hydrogen, and (iv) R 44 is methyl and R 22 and R 33 is hydrogen. Even more particularly, each dotted bond to the alkyl chain of the chroman ring is a single bond and R 22 , R 33 and R 44 is methyl. Even more particularly, formula (XXIII') has the following formula (xxiii1'):

[0405]

[0406] In another more specific embodiment, in the free radical of formula (XXIII'), each dotted bond of the alkyl chain connected to the chroman ring is a double bond, and R 22 , R 33 and R 44 Selected from the following meanings: (i) R 22 , R 33 and R 44is methyl, (ii) R 22 , R 44 is methyl and R 33 is hydrogen, (iii) R 33 and R 44 is methyl and R 22 is hydrogen, and (iv) R 44 is methyl and R 22 and R 33 In a more specific embodiment, each dashed bond to the alkyl chain of the chroman ring is a double bond and R 22 , R 33 and R 44 It's methyl.

[0407] In another embodiment, optionally in combination with any of the embodiments provided above or below, A is a lipid-like moiety R5 having the following formula (XXIII'), m is 0 and t' is 1, that is, the lipopolyamino acid conjugate of formula (I) has the following formula (Ih'):

[0408]

[0409] Where A, X, R1, R2, R3, n, R 22 , R 33 , R 44 , L and dotted bond-----as defined herein.

[0410] In another embodiment, optionally in combination with any of the embodiments provided above or below, A is a lipid-like moiety R5 having the following formula (XXIII'), wherein m is 1, ie, the lipopolyamino acid conjugate of formula (I) has the following formula (Ij'):

[0411]

[0412] Where A', R2, R3, m, n, R 22 , R 33 , R 44 , L and dotted bond-----as defined herein.

[0413] According to a specific embodiment, optionally in combination with any of the embodiments provided above or below, in the radical of formula (XXIII'), the linker L is a diradical selected from the following: -X1'-(C1-C 12 ) alkylene-, which is selected from halogen, -OH, -NR aa R bb 、-SH、-NHNH2、-COOR cc , -CF3 and -OCF3 are optionally substituted, wherein R aa , R bband R cc is a radical independently selected from H, -phenyl, -(C1-C6)alkyl, -(C2-C6)alkenyl, -(C1-C6)alkylphenyl and -phenyl(C1-C6)alkyl; -X'-(C1-C6)alkyl-CO-; and a diradical of formula (IIID'), (IVD'), (VD'), (VID'), (VIID), (VIIID), (IXD'), (XD'), (XID'), (XIID')(XIIID'), (XIVD'), (XVD'), (XVID'), (XVIID'), (XVIIID') or (XIXD'),

[0414]

[0415]

[0416] Wherein "*" represents the connection point between the diradical L and the oxygen atom of the PAA or vitamin E radical part, "* 3 ” indicates the connection point between the diradical L and PAA, and “* 4 ” represents the point of attachment of the diradical to the oxygen atom of the vitamin E radical portion, a1, c1, d1, e1, f1, h1, j1 and k1 are independently integers from 0 to 10, in particular from 0 to 6; b1 and g1 are independently integers from 0 to 1; provided that when b1 is 0, at least one of a1 or c1 is not 0, and when g1 is 0, at least one of f1 or h1 is not 0;

[0417] X1' is -O- or -NH-;

[0418] Each dashed bond is independently a single bond, or alternatively, a double bond.

[0419] When drawing, the connection point is indicated herein with a "*". Whenever a specific connection is not specified, it is intended that the linker can be connected interchangeably to the rest of the molecule.

[0420] In one embodiment, optionally in combination with one or more features of the various embodiments described above or below, in the radical of formula (XXIII'), L is -X1'-(C1-C 12 )alkylene-, more particularly -X1'-(C1-C6)alkyl-, and optionally substituted as defined herein.

[0421] In another embodiment, optionally in combination with one or more features of the various embodiments described above or below, in the radical of formula (XXIII'), L is -X1'-(C1-C6)alkyl-CO- or -X1'-(C1-C6)alkyl-, and is optionally substituted as defined herein.

[0422] In another embodiment, optionally in combination with one or more features of the various embodiments described above or below, in the radical of formula (XXIII'), L is a diradical of formula (IIID'), more particularly a diradical of formula (IIID'), wherein b1 is 0, and a1+c1 is selected from 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12, even more particularly, L is a diradical of formula (IIID') selected from the following:

[0423]

[0424] In another embodiment, optionally in combination with one or more features of the various embodiments described above or below, in the radical of formula (XXIII'), L is a diradical selected from formula (IVD'), (VD') and (VID'), more particularly, X1' is -NH-, even more particularly, in the diradical of formula (IVD'), a1 is 1 and the dotted bond is a double bond, i.e. the diradical of formula (IVD') has formula (IVDa'), while in the diradical of formula (VD'), the dotted bond is more particularly a double bond and X1' is -NH-, i.e. the diradical of formula (VD') has formula (VDa').

[0425]

[0426] In another embodiment, optionally in combination with one or more features of the various embodiments described above or below, in the radical of formula (XXIII'), L is a diradical selected from formula (VID'), (VIID') and (VIIID'), more particularly, in the diradical of formula (VIIID'), a1 is 1.

[0427] In another embodiment, optionally in combination with one or more features of the various embodiments described above or below, in the radical of formula (XXIII'), L is a diradical of formula (IXD'), more particularly a diradical of formula (IXD'), wherein b1 and g1 are 0; a1, c1, d1, e1, f1 and h1 are 1, and X1' is -NH-, i.e. a diradical of formula (IXDa').

[0428]

[0429] In another embodiment, optionally in combination with one or more features of the various embodiments described above or below, in the radical of formula (XXIII'), L is a diradical selected from the diradicals of formula (XD') and (XID'), more particularly in the diradicals of formula (XD') and (XID'), b1 and g1 are 0; a1, c1, d1, e1, f1 and h1 are 1, and X1' is -NH-, i.e., the diradicals of formula (XD') and (XID') have formulas (XDa') and (XIDa'), respectively.

[0430]

[0431] In another embodiment, optionally in combination with one or more features of the various embodiments described above or below, in the radical of formula (XXIII'), L is a diradical selected from the diradicals of formulas (XIID') and (XIIID'), more particularly in the diradicals of formulas (XIID') and (XIIID'), b1 is 0; a1, c1 and d1 are 1; and X1' is -NH-.

[0432] In another embodiment, optionally in combination with one or more features of the various embodiments described above or below, in the radical of formula (XXIII'), L is a diradical selected from the group consisting of formulas (XIVD'), (XVD'), (XVID'), (XVIID') and (XVIIID'), more particularly in the diradicals of formulas (XIVD'), (XVD'), (XVID'), (XVIID') and (XVIIID'), b1 is 0; a1 and c1 are 1; and X1' is -NH-.

[0433] In another embodiment, optionally in combination with one or more features of the various embodiments described above or below, in the radical of formula (XXIII'), L is a diradical selected from formula (XIXD'), wherein 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 (XXIII'), L is a diradical selected from formula (XIXD'), wherein X1' is -O- and j1 and k1 are 1.

[0434] According to one embodiment, optionally in combination with any of the embodiments provided above or below, in the lipopolyamino acid conjugate of formula (I), A' is a lipid-like portion R selected from the following 5 ':

[0435] a)-X'(R1')-(C1-C 18 )alkyl, more particularly -X'(R1')-(C6-C 18)alkyl, even more particularly, a radical of formula (XIX') or formula (XIX") as defined above;

[0436] b)-X'(R1')-(C2-C 18 )alkenyl, more particularly -X'(R1')-(C6-C 18 )alkenyl, even more particularly, a radical of formula (XX') as defined above;

[0437] c) a radical of formula (VII') as defined herein;

[0438] d) a radical of formula (VIII') as defined herein;

[0439] e) a radical of formula (IX') as defined herein, more particularly, selected from the radicals of formula (ix1'), (ix2'), (ix3'), (ix4'), (ix5'), (ix6'), (ix7') and (ix8') as defined hereinbefore;

[0440] f) a radical of formula (X') as defined herein, more particularly selected from radicals of formula (x1'), (x2'), (x3') and (x4') as defined above;

[0441] g) a radical of formula (XI') as defined herein, more particularly a radical of formula (xi1') as defined above;

[0442] h) a radical of formula (XII') as defined herein;

[0443] i) a radical of formula (XIII') as defined herein; and

[0444] j) a radical of formula (XIV') as defined herein, more particularly selected from radicals of formula (xiv1') and (xiv2') as defined above;

[0445] k) a radical of formula (XXI') as defined herein, more particularly selected from a radical of formula (xxi1'),

[0446] l) a radical of formula (XXII') as defined herein, more particularly selected from the radicals of formula (xxii1') and (xxii2') as defined above, and

[0447] m) a radical of formula (XXIII') as defined herein.

[0448] According to another embodiment, optionally in combination with any of the embodiments provided above or below, in the lipopolyamino acid conjugate of formula (I), A' is a lipid-like moiety R5' as defined herein, m is 1, and A is H.

[0449] According to another embodiment, optionally in combination with any of the embodiments provided above or below, in the lipopolyamino acid conjugate of formula (I), A' is a lipid-like moiety R5' as defined herein, m is 1, and A is a protecting group. In a more specific embodiment, in the lipopolyamino acid conjugate of formula (I), A' is a lipid-like moiety R5' as defined herein, m is 1, X is N, and A is an amino protecting group; more particularly, the amino protecting group is selected from acetyl, methoxycarbonyl, benzyloxycarbonyl, p-methoxybenzyloxycarbonyl, tert-butyloxycarbonyl (Boc), 9-fluorenylmethoxycarbonyl (Fmoc), allyloxycarbonyl (Alloc), 2,2,2-trichloroethoxycarbonyl (Troc), benzoyl (Bz), benzyl (Bn), p-methoxybenzyl (PMB), 3,4-dimethoxybenzyl (DMPM), p-methoxyphenyl (PMP), tosyl (Ts), trimethylsilylethoxycarbonyl (Teoc), diphenylmethyl, triphenylmethyl (Trityl), (4-methoxyphenyl)diphenylmethyl (MMT), dimethoxytrityl (DMT) and diphenylphosphino, and even more particularly the amino protecting group is acetyl.

[0450] In another more specific embodiment, in the lipopolyamino acid conjugate of formula (I), A' is a lipid-like portion R5' as defined herein, m is 1, X is O, and A is a carboxyl protecting group. Suitable carboxyl protecting groups known in the art can be used without restriction. Representative carboxyl protecting groups include alkyl, aryl or benzyl esters, silyl esters, amides or hydrazides. In a specific embodiment, the carboxyl protecting group is selected from -(C1-C6) alkyl, benzyl, p-methoxyphenyl, trimethylsilyl and [2-(trimethylsilyl)ethoxy]methyl (SEM).

[0451] Introduction and removal of these protecting groups can be carried out by standard methods such as those described in TW Green and PGM Wuts, Protective Groups in Organic Chemistry, Wiley, 3rd ed. 1999, Chapter 5 (pp. 369-451).

[0452] In another more specific embodiment, in the lipopolyamino acid conjugate of formula (I), A' is a lipid-like moiety R5' as defined herein, m is 1, X is S, and A is selected from -(C1-C6)alkyl, benzyl, p-methoxyphenyl, trimethylsilyl and [2-(trimethylsilyl)ethoxy]methyl (SEM).

[0453] According to another embodiment, optionally in combination with any of the embodiments provided above or below, in the lipopolyamino acid conjugate of formula (I), A' is a lipid-like portion R5' as defined herein, m is 1, and A is a free radical R4, R4 is a free radical of formula (VIa)

[0454]

[0455] in:

[0456] n' is an integer from 5 to 250;

[0457] m' is 0 or 1;

[0458] X” is selected from N, S and O;

[0459] R1" is a radical having any of the meanings of R1, provided that when X' is O or S, R1' is absent;

[0460] R2' is a radical having any of the meanings of R2;

[0461] R3' is a radical having any of the meanings of R3;

[0462] B and B' are independently S or CH2;

[0463] e and f are independently integers from 1 to 18; and

[0464] A" is selected from H, -OH, -(C1-C6)alkyl, -(C5-C 10 )aryl, -(C5-C 10 )heteroaryl, -(C6-C 10 )aralkyl, -(C1-C6)alkyl-O-(C5-C 10 )aryl, -(C5-C 10 )heterocycloalkyl, -(C1-C 10 )alkoxy, -(C6-C 10 ) aryloxy, -(C6-C 10 )aralkyloxy, -(C5-C 10 )heteroaralkyloxy, -(C1-C 10 )alkyl-O-(C6-C 10) aryloxy, amino protecting group, lipid-like part R5 ', amino acid-like part R6 and active part; A "is optionally substituted by one or more groups selected from the following: -OH, halogen, -CF3, -NH2, -NH-(C1-C4) alkyl, -NH-CO-(C1-C6) alkyl, -(C1-C6) alkyl, -NO2, -N3, -CO-(C1-C6) alkyl, -CO-O-(C1-C6) alkyl, -SO3H, -SO2NH2, -SO2-N((C1-C6) alkyl)2, -COOH, CONH2 and -CON((C1-C6) alkyl)2;

[0465] The conditions are:

[0466] When m' is 0, A" is selected from H, -(C1-C6)alkyl, -(C5-C 10 )aryl, -(C5-C 10 )heteroaryl, -(C6-C 10 )aralkyl, -(C1-C6)alkyl-O-(C5-C 10 )aryl, -(C5-C 10 ) heterocycloalkyl, an amino protecting group, an amino acid-like portion R6 and an active portion; A" is optionally substituted by one or more groups selected from the following: -OH, halogen, -CF3, -NH2, -NH-(C1-C4)alkyl, -NH-CO-(C1-C6)alkyl, -(C1-C6)alkyl, -NO2, -N3, -CO-(C1-C6)alkyl, -CO-O-(C1-C6)alkyl, -SO3H, -SO2NH2, -SO2-N((C1-C6)alkyl)2, -COOH, CONH2 and -CON((C1-C6)alkyl)2; and

[0467] When m' is 1, A" is selected from H, -OH, -(C1-C6)alkyl, -(C5-C 10 )aryl, -(C5-C 10 )heteroaryl, -(C6-C 10 )aralkyl, -(C1-C6)alkyl-O-(C5-C 10 )aryl, -(C5-C 10 )heterocycloalkyl, -(C1-C 10 )alkoxy, -(C6-C 10 ) aryloxy, -(C6-C 10 )aralkyloxy, -(C5-C 10 )heteroaralkyloxy, -(C1-C 10 )alkyl-O-(C6-C 10) aryloxy, lipid-like portion R5 'and active portion; A "is optionally substituted by one or more groups selected from the following: -OH, halogen, -CF3, -NH2, -NH-(C1-C4) alkyl, -NH-CO-(C1-C6) alkyl, -(C1-C6)

[0468] Alkyl, -NO2, -N3, -CO-(C1-C6)alkyl, -CO-O-(C1-C6)alkyl,

[0469] -SO3H, -SO2NH2, -SO2-N((C1-C6)alkyl)2, -COOH, CONH2 and -CON((C1-C6)alkyl)2;

[0470] That is, the lipid polyamino acid conjugate of formula (I) has the following formula (Ib'):

[0471]

[0472] wherein R5′, A″, X, X′, R1, R1′, R1″, R2, R2′, R3, R3′, n, n′, m, m′, e, f, B and B′ are as defined herein.

[0473] All embodiments herein regarding the meanings of A', X, R1, R2 and R3 in the lipopolyamino acid conjugate of formula (I) also apply to the meanings of A", X", R1", R2' and R3' in the lipopolyamino acid conjugate of formula (Ib').

[0474] In a more specific embodiment, the lipopolyamino acid conjugate of formula (Ib') is a dimer, wherein, respectively, R5 and A" have the same meaning, m and m' have the same meaning, X and X" have the same meaning, R1 and R1" have the same meaning, R2 and R2' have the same meaning, R3 and R3' have the same meaning, B and B' have the same meaning, e and f have the same meaning, and n and n' have the same meaning.

[0475] According to another embodiment, optionally in combination with any of the embodiments provided above or below, in the lipopolyamino acid conjugate of formula (I), A' is a lipid-like portion R5' as defined herein, m is 1, and A is selected from H, -(C1-C6)alkyl, -CO(C1-C6)alkyl, -(C5-C 10 )aryl, -(C5-C 10 )heteroaryl, -(C6-C 10 )aralkyl, -(C1-C6)alkyl-O-(C5-C 10 )aryl, -(C5-C 10) heterocycloalkyl, protecting group, free radical R4, lipid-like part R5, active part; A is optionally substituted by one or more groups selected from the following: -OH, halogen, -CF3, -NH2, -NH-(C1-C4)alkyl, -NH-CO-(C1-C6)alkyl, -(C1-C6)alkyl, -NO2, -N3, -CO-(C1-C6)alkyl, -CO-O-(C1-C6)alkyl, -SO3H, -SO2NH2, -SO2-N((C1-C6)alkyl)2, -COOH, CONH2 and -CON((C1-C6)alkyl)2, more particularly A is methyl.

[0476] According to another embodiment, optionally in combination with any of the embodiments provided above or below, in the lipopolyamino acid conjugate of formula (I), A' is a lipid-like portion R5' as defined herein, m is 1, and A is an active portion selected from a pharmaceutically active agent, a cell targeting agent, a penetration enhancer, a cosmetic active agent, and a diagnostic active agent.

[0477] The active part in A can be directly combined with X, or alternatively, it is combined through a linker. There is no restriction on the nature of the linker, as long as it can be connected to the rest of the molecule through a chemically feasible bond. For example, the linker can be a diradical chain, which includes one or more parts selected from the following: -CH=CH-, -C≡C-, -CH2-, -N=CH-, -CH=NH-, -NH-, -NH-NH-, -NH-N=CH-, -O-, -O(CH2)O-, -CO-, -O(CO)-, -COO-, -C(=CH2)-, -C(=NH)-, -CONH-, -NHCO-, -NH(CO)NH-, -S-, -SS-, -SO-, -SO2-, -SO2NH2-, -phenylene-, etc. The linker may comprise 1-50 moieties, more particularly 2 to 30 or 2 to 20 or 2 to 15 moieties as defined above, and may be linked to X via a chemically feasible bond such as an ether bond, a thioether bond or an amide bond.

[0478] Preparation process

[0479] The method for preparing the lipopolyamino acid conjugate of formula (I) is also part of the present invention. The conjugate can be prepared by synthetic methods known in the art.

[0480] As mentioned above, the lipopolyamino acid conjugate of formula (I) must contain at least one lipid-like moiety, which can be the lipid-like moiety R5 in A, the lipid-like moiety R5' in A', or both.

[0481] The lipopolyamino acid conjugate of formula (I) wherein A is a lipid-like moiety R5 can be prepared by ring-opening polymerization (ROP) of N-carboxylic anhydride (NCA). The oxazolidine-2,5-dione derivative (compound of formula (A)) can be reacted with an amine, alcohol or thiol of formula (B) which already contains a lipid-like part R5 and acts as an initiator. As a result, a polyamino acid polymer of formula (I) is obtained:

[0482]

[0483] wherein m is 0, A' is H; R1, R2, R3 and n are as defined herein; and A is R5. The reaction is carried out in a suitable solvent such as dimethylformamide at a temperature of 4°C to room temperature, preferably about 10°C. The ratio of monomer (NCA) / initiator (alcohol / amine) allows control of the degree of polymerization (DP).

[0484] Alternatively, the above reaction can also be carried out using NCA containing a precursor of R2 instead of the R2 moiety, and once the polymer is formed, the R2 precursor is later converted into the R2 moiety. For example, NCA compounds derived from natural amino acids such as glutamic acid or lysine, optionally protected with a suitable protecting group, can be polymerized in the presence of compound (B) to obtain a lipopolyamino acid conjugate of formula (If), wherein R2 is the side chain of the natural amino acid used. If necessary, this precursor can be deprotected and further reacted with other reagents to obtain the desired R2 moiety, as shown in the following examples.

[0485] The obtained polyamino acid can optionally be purified by any known method such as fractionation, precipitation, ultrafiltration, dialysis, size exclusion chromatography, affinity chromatography or tangential flow filtration.

[0486] If desired, the polymer conjugate of formula (If) can be converted into other polymer conjugates of formula (I) by reacting the terminal amine with other groups. For example, the terminal amine can be directly reacted with the active agent or connected through a linker. Depending on the chemical groups present in the active agent, the technician will easily determine the appropriate method for connecting the selected active agent to the main chain of the lipopolyamino acid conjugate.

[0487] Alternatively, the polymer conjugate of formula (I) (wherein A' is R5' and m' is 1) may be prepared from a compound of formula (If) as defined above (wherein A may have any meaning as defined herein) by reacting it with a compound of formula R5'-(CO)Z (wherein Z may be OH or halogen).

[0488] When Z is a hydroxyl group, the reaction can be carried out in the presence of an activating agent such as 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholiniumtetrafluoroborate (DMTMMBF4), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC.HCl) or hydroxybenzotriazole (HOBt), preferably in the presence of a base, in a suitable solvent. When Z is a halogen atom, the reaction can be carried out in the presence of a base such as triethylamine in a suitable solvent. When Z is a halogen atom, the compound R5'-(CO)Z can be prepared from the corresponding carboxylic acid by methods known in the art.

[0489] Alternatively, compounds of formula (I) wherein A' is R5' and m' is 1 can also be prepared from compounds of formula (If) as defined above by reacting them with a compound of formula R5'-H. In this case, the reaction can be carried out in the presence of a carbonyl source such as 1,1'-carbonyldiimidazole (CDI), N,N'-disuccinimidyl carbonate (DSC) or bis(trichloromethyl) carbonate (BTC) in a suitable solvent.

[0490] Self-assembled particles

[0491] As described above, the lipopolyamino acid conjugate of the present invention has amphiphilicity because it includes a polyamino acid-based portion (hydrophilic portion) and at least one lipid-like portion (hydrophobic portion). Due to its amphiphilicity, the lipopolyamino acid conjugate of the present invention can form self-assembled particles in solution.

[0492] Therefore, the present invention also relates to self-assembled particles, which include a lipopolyamino acid conjugate of formula (I) as defined herein, and optionally one or more active agents selected from pharmaceutically active agents, penetration enhancers, cell targeting agents, cosmetic active agents, diagnostic active agents, nucleic acids, peptides, proteins and mixtures thereof.

[0493] As used herein, the term "self-assembled particles" refers to the arrangement of lipopolyamino acid conjugate molecules in a solvent, specifically, small self-assembled particles can be closed structures of any shape, generally spherical and / or tubular. The term "self-assembled particles" is intended to encompass any of a variety of structures formed by amphiphilic polymers known in the art. Non-limiting examples of self-assembled particles include micelles (also interchangeably referred to herein as micellar worms or simply "worms"), reverse micelles, planar bilayers, crystalline nanoparticles, liposomes, microbubbles, or lipid nanoparticles. Self-assembled nanoparticles and microparticles can also form gels. The self-assembled particles of the present invention are non-viral particles, which means that they cannot infect cells in a viral manner.

[0494] Self-assembled particles can show a variety of sizes, specifically, they can be nanoparticles or microparticles. "Nanoparticles" as defined herein are any particles of nanometer size, specifically having a minimum end-to-end diameter of 1 to 900, more specifically 1 to 700nm, 1 to 500nm, 1 to 300nm, 1 to 200nm and 1 to 100nm size. "Microparticles" as defined herein are generally particles of any micron size, with a minimum end-to-end dimension of 1 to 100 μm. Generally, in compositions comprising a plurality of particles, the relevant diameter is the number average diameter.

[0495] As used herein, the term "size" refers to a characteristic physical dimension. For example, when the particle is substantially spherical, the size of the particle corresponds to the diameter of the particle. When the particle is substantially rod-shaped (such as a wire or a tube) with a substantially circular cross-section, the size of the particle is determined by the diameter of two relevant cross-sectional dimensions of the particle. When the particle 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 group of particles of a specific size, it is taken into account that this group of particles can have a size distribution near a specified size. Therefore, as used herein, the size of a group of particles can refer to a size distribution pattern, such as the peak size of a size distribution.

[0496] As used herein, the term "diameter" refers to the average diameter, also referred to as the Z-average or Z-ave. The average diameter corresponds to the average hydrodynamic diameter (Dh) and can be measured by dynamic light scattering (DLS), as shown in the following examples. 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 present invention have a hydrodynamic diameter (Dh) of 5 to 1200 nm, more particularly, 10 to 1100 nm, 10 to 1000 nm, 10 to 700 nm, 20 to 500 nm, 20 to 400 nm, 20 to 300 nm, 30 to 200 nm or 50 to 150 nm in water.

[0497] All embodiments indicated with respect to the lipopolyamino acid conjugates of formula (I) also apply to the self-assembling particles.

[0498] According to one embodiment, optionally in combination with one or more features of the various embodiments described above or below, in the self-assembling particle comprising the lipopolyamino acid conjugate of formula (I), the lipid-like part (hydrophobic part) faces inward and the polar head (PAA) faces outward.

[0499] According to another embodiment, optionally with one or more feature combinations of various embodiments described above or below, the self-assembled particle is a core-shell structure comprising a core and an outer shell. More particularly, formula (I) lipopolyamino acid conjugate forms the outer shell of the self-assembled particle, and the agent is optionally encapsulated or loaded in the core.

[0500] According to one embodiment, optionally in combination with one or more features of various embodiments described above or below, the self-assembled particle is a nanoparticle, more particularly selected from micelles, reverse micelles, planar bilayers, crystalline nanoparticles, liposomes, microbubbles and lipid nanoparticles, even more particularly, the self-assembled particle is a lipid nanoparticle or a liposome.

[0501] For the purposes of the present invention, the term "liposome" refers to an artificially prepared self-assembled particle consisting of concentric lipid bilayers enclosing one or more aqueous compartments. Non-limiting examples of liposomes include unilamellar liposomes, multilamellar liposomes, multivesicular liposomes, and polymer-coated liposomes.

[0502] The term "lipid nanoparticle" refers to spherical particles, generally nanometer-sized (eg, 1-1000 nm), which include lipids and are stable and dispersible in aqueous media.

[0503] For purposes of the present invention, the term "crystalline nanoparticle" refers to an artificially prepared crystal consisting of a solid lipid enclosing one or more hydrophobic compartments. The term "crystalline nanoparticle" refers to particles of different shapes of nanometer scale (e.g., 1-1000 nm) that include lipids and are stable and dispersible in aqueous media.

[0504] In another embodiment, optionally in combination with one or more features of the various embodiments described above or below, the present invention relates to a lipid nanoparticle (LNP) or a liposome comprising a lipopolyamino acid conjugate of formula (I) as defined herein, and optionally one or more active agents selected from pharmaceutically active agents, cell targeting agents, penetration enhancers, cosmetic active agents, diagnostic active agents, nucleic acids, peptides, proteins and mixtures thereof.

[0505] The liposomes and lipid nanoparticles disclosed herein may include any suitable lipid, including ionizable lipids, cationic lipids, zwitterionic lipids, neutral lipids, or anionic lipids.

[0506] Suitable ionizable lipids include, but are not limited to, (2S)-2,5-bis(3-aminopropylamino)-N-[2-(dioctadecylamino)acetyl]pentanamide (DOGS), N1-[2-((1S)-1-[(3-aminopropyl)amino]-4-[di(3-aminopropyl)amino]-butylcarboxamido)ethyl]-3,4-di[oleyloxy]-benzamide (N1-[2-((1S)-1-[(3-aminopropyl)amino]-4-[di(3-aminopropyl)amino]-butylcarboxamido)ethyl]-3,4-di[oleyloxy]-benzamide y]-benzamide, MVL5), 3β-[N-(N',N'-dimethylaminoethane)-carbamoyl]cholesterol (DC-cholesterol), (1,2-distearoyloxy-N,N-dimethyl-3-aminopropane (DSDMA), 1,2-dilinoleyloxy-N,N-dimethyl-3-aminopropane (DLin-DMA), 1,2-dilinoleyloxy-N,N-dimethyl-3-aminopropane (DLenDMA), 1,2-di-y-linoleyloxy-N,N-dimethylaminopropane (γ-DLenDMA), 2-dilinoleyl-4-dimethyl-aminomethyl-[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-Dilinoleyl-4-(4-dimethylaminopropyl)-[1,3]-dioxolane (DLin-KC4-DMA), 1,2-Dilinolenoyloxy-4-(2-dimethylaminoethyl)-1,3-dioxolane (DLen-C2K-DMA), 1,2-Di-y-linolenoyloxy-4-(2-dimethylaminoethyl)-1,3-dioxolane )-1,3-dioxolane (y-DLen-C2K-DMA), (6Z,9Z,28Z,31Z)-heptatriacontane-6,9,28,31-tetraen-19-yl 3-(dimethylamino)propanoic acid (DLin-M-C2-DMA, also known as MC2), (6Z,9Z,28Z,31Z)-heptatriacontane-6,9,28,31-tetraen-19-yl 4-(dimethylamino)-butyrate (DLin-M-C3-DMA, also known as MC3) and 3-((6Z,9Z,28Z,31Z)-heptatriacontane-6,9,28,31-tetraen-19-yloxy)-N,N-dimethylpropane-1-amine (DLin-MP DMA, also known as 1-B11).

[0507] Suitable cationic lipids include, but are not limited to, N,N-dioleyl-N,N-dimethylammonium chloride (DODAC), N,N-distearoyl-N,N-dimethylammonium bromide (DDA13), N-(1-(2,3-dioleoyloxy)propyl)-N,N,N-trimethylammonium chloride (DOTAP), N-(1-(2,3-dioleoyloxy)-propyl)-N,N,N-trimethylammonium chloride (DOTMA), N-[1-(2,3,-ditetradecyloxy)propyl-N,N-dimethyl-N-hydroxyethylammonium bromide (DMRIE), N-[1-(2,3, dioleyloxy)-propyl]-N,N-dimethyl-N-hydroxyethylammonium bromide (DORIE), 3β-[N-(N',N'-dimethylamino-ethane)-carbamoyl]cholesterol (DC-Chol), Dimethyldioctadecylammonium (DDAB), 2,3-dioleyloxy-N-[2-(spermine-carboxamido)ethyl]-N,N-dimethyl-1-propanaminiumtrifluoroacetate (DOSPA), ethylphosphatidylcholine (ePC), N,N-dimethyl-2,3-dioleyloxy)propylamine (DODMA) and ([(4-hydroxybutyl)azanediyl]bis(hexane-6,1-diyl)bis(2-hexyldecanoate)) (ALC-0315).

[0508] Examples of anionic lipids include, but are not limited to, phosphatidylglycerol, diacylphosphatidylserine, diacylphosphatidic acid, N-succinylphosphatidylethanolamine, N-glutarylphosphatidylethanolamine cholesterol hemisuccinate (CHEMS), lysylphosphatidylglycerol, N-lauroylphosphatidylethanolamine, cardiolipin, and combinations thereof.

[0509] Suitable neutral lipids may be uncharged or zwitterionic lipids, including but not limited to steroids, phospholipids, and combinations thereof.

[0510] Examples of steroids include, but are not limited to, cholesterol, progesterone, cortisone, aldosterone, estradiol, testosterone, and combinations thereof.

[0511] Examples of phospholipids include, but are not limited to, phosphatidylcholine (PC), phosphatidic acid (PA), phosphatidylethanolamine (PE), phosphatidylglycerol (PG), phosphatidylserine (PS), and phosphatidylinositol (PI), dimyristoylphosphatidylcholine (DMPC), distearoylphosphatidylcholine (DSPC), dioleoylphosphatidylcholine (DOPC), dipalmitoylphosphatidylcholine (DPPC), dimyristoylphosphatidylglycerol (DMPG), distearoylphosphatidylglycerol (DSPG), , dioleoylphosphatidylglycerol (DOPG), dipalmitoylphosphatidylglycerol (DPPG), dimyristoylphosphatidylserine (DMPS), distearoylphosphatidylserine (DSPS), dioleoylphosphatidylserine (DOPS), dipalmitoylphosphatidylserine (DPPS), dioleoylphosphatidylethanolamine (DOPE), palmitoyloleoylphosphatidylcholine (POPC), palmitoyloleoylphosphatidylethanolamine (POPE) and dioleoylphosphatidylethanolamine 4-(N-maleyl)phosphatidylcholine (POPC). iminomethyl-cyclohexane-1-carboxylate (DOPE-mal), dipalmitoylphosphatidylethanolamine (DPPE), dimyristoylphosphoethanolamine (DMPE), distearoylphosphatidylethanolamine (DSPE); lysophosphatidylcholine, lysophosphatidylethanolamine, 1,2-distearoyl-sn-glycero-3-phosphocholine (DAPC), dilauroylphosphatidylcholine (DLPC), 1-myristoyl-2-palmitoylphosphatidylcholine (MPPC), 1-palmitoyl-2 -Myristoylphosphatidylcholine (PMPC), 1-palmitoyl-2-stearoylphosphatidylcholine (PSPC), 1,2-diarachidoyl-sn-glycero-3-phosphocholine (DBPC), 1-stearoyl-2-palmitoylphosphatidylcholine (SPPC), 1,2-diicosenoyl-sn-glycero-phosphocholine (DEPC), and combinations thereof.

[0512] In the liposomes and lipid nanoparticles disclosed herein, the lipid polyamino acid conjugates advantageously provide stealth. As used herein, the term "stealth" refers to that the liposome or lipid nanoparticle is not detected and sequestered and / or degraded by the immune system of the host to which it is administered, so that the length of time that the liposome or lipid nanoparticle can exist in the body is increased.

[0513] 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 do not include (i.e. lack) polyethylene glycol (PEG)-lipid conjugates, i.e. lipids comprising polyethylene glycol.

[0514] In another embodiment, optionally in combination with one or more features of the various embodiments described above or below, the self-assembling particles of the invention, in particular liposomes and lipid nanoparticles, lack polyethylene glycol (PEG).

[0515] Liposomes and lipid nanoparticles disclosed herein may also include one or more cationic polymers, such as cationic amine-containing polymers. Generally, these polymers can carry active ingredients, particularly nucleic acids. Examples of cationic amine-containing polymers include, but are not limited to, poly-L-lysine, polyamidoamine, polyethyleneimine, chitosan, poly(β-amino esters), etc.

[0516] In another embodiment, optionally in combination with one or more features of various embodiments described above or below, the present invention relates to lipid nanoparticles (LNP) or liposomes comprising a lipid polyamino acid conjugate of formula (I) as defined herein, and one or more lipids selected from ionizable lipids, cationic lipids, neutral lipids and anionic lipids. More particularly, lipid nanoparticles (LNP) or liposomes comprise a lipid polyamino acid conjugate of formula (I) as defined herein, ionizable lipids or cationic lipids, phospholipids and sterols. Even more particularly, the lipid nanoparticle (LNP) or liposome comprises: i) a lipopolyamino acid conjugate of formula (I) as defined herein in an amount of 0.1 to 10 mol%, more particularly 1 to 5 mol% or 1 to 6 mol%, even more particularly 2 to 5 mol%; ii) an ionizable lipid or cationic lipid in an amount of 30 to 70 mol%, more particularly 40 to 60 mol%; iii) a phospholipid in an amount of 1 to 20 mol%, more particularly 5 to 15 mol%; and iv) a sterol in an amount of 20 to 60 mol%, more particularly 30 to 50 mol%; wherein the percentages are expressed as the sum of the mol% of the lipid and the lipopolyamino acid conjugate of formula (I).

[0517] In another embodiment, optionally in combination with one or more features of the various embodiments described above or below, the present invention relates to a lipid nanoparticle (LNP) or a liposome comprising a lipopolyamino acid conjugate of formula (I) as defined herein, one or more lipids selected from ionizable lipids, cationic lipids, neutral lipids and anionic lipids, and one or more nucleic acids.

[0518] Lipid nanoparticles and liposomes containing one or more nucleic acids can be prepared by standard methods. Generally, the method for preparing LNP includes: i) preparing a first alcohol mixture including one or more lipids and a lipopolyamino acid conjugate of the present invention in a suitable alcohol such as ethanol; ii) preparing a second aqueous composition including one or more nucleic acids and an aqueous solvent (acidic buffer); and iii) mixing i) with ii) in a microfluidic mixing device. Microfluidic mixing allows the lipid phase and the nucleic acid phase to be thoroughly and quickly mixed in a microdevice. Depending on the process parameters, specifically according to the total flow rate, the technician will be able to adjust the size of the LNP.

[0519] Active Agent

[0520] As described above, the lipopolyamino acid conjugates of the present invention may contain one or more active moieties in their structure, in any of A, A', A" or A'". These active moieties are independently selected from pharmaceutically active agents, cell targeting agents, penetration enhancers, cosmetic active agents and diagnostic active agents.

[0521] In addition, the lipopolyamino acid conjugates of the present invention can also form self-assembled particles, which can include one or more active agents selected from pharmaceutically active agents, cell targeting agents, penetration enhancers, cosmetic active agents, diagnostic active agents, nucleic acids, peptides, proteins and mixtures thereof.

[0522] As used herein, the term "pharmaceutically active agent" refers to an agent that has pharmacological activity and is used to cure, alleviate, treat or prevent a disease in a mammal, particularly a human. The term "cosmetic active agent" refers to an agent that does not provide any treatment but is used for aesthetic purposes, such as to improve the appearance, preserve, condition, cleanse, color or protect the skin, nails or hair.

[0523] As used herein, the term "cell targeting agent" refers to any molecule, macromolecule or biomacromolecule that exhibits affinity for a molecule present in the human or animal body, which is capable of directing a conjugate or its self-assembled particles to a target site for therapeutic treatment, because, for example, it selectively binds to a receptor expressed or overexpressed on a specific cell type. Cell targeting groups are well known in the art. Therefore, the term includes ligands for specific receptors or antigens, such as antibodies for specific antigens, folic acid for its receptors, or sugars such as galactose for liver receptors. The targeting agent may be attached to any of A, A', A" or A"' of the main chain of the lipopolyamino acid conjugate and / or may be included in the self-assembled particles formed by the conjugate.

[0524] Examples of cell targeting groups include, but are not limited to, galactosamine, folate, Her-2 binding peptides, TLR agonists, β-D-glucose, Asn-Gly-Arg peptides, angiopep2, folic acid, aptamers (A-9, A10, anti-gp120, TTA1, sgc8, anti-MUC-1, AS1411), primaquine, zidovudine, superoxide dismutase, prednisolone, platinum, cisplatin, sulfamethoxazole, sulphamethoxazole, amoxicillin, etoposide, mesalazine, doxorubicin, paclitaxel, 5-aminosalicylic acid, denosumab, docetaxel, calcitonin, proanthocyanidins, methotrexate, camptothecin, galactose, glycyrrhetinic acid, lactose, hyaluronic acid, octeotride, lactobionic acid, β-galactosyl moiety, arabinogalactan, chitosan, azo-based poly-phosphazene, azo and 4-amino-benzyl-carbamate moieties, succinate, 4,4'-dihydroxyazobenzene-3-carboxylic acid, cyclicRGD penta-peptide, aspartic acid octapeptide, alendronate, transferrin, bisphosphonate adendronate), monosialoganglioside GM1, glutathione, E-selectin thioaptamer, poloxamer-407, urokinase-type plasminogen activator receptor (uPAR) antagonist, CXCR4 chemokine receptor antagonist, GRP78 peptide antagonist, RGD peptide, RGD cyclic peptide, luteinizing hormone releasing hormone (LHRH) antagonist peptide, aminopeptidase targeting peptide, brain homing peptide, kidney homing peptide, heart homing peptide, intestine homing peptide, integrin homing peptide, angiogencidtumor endothelium homing peptide

[00136] In some embodiments, the peptide may be a homing peptide, an ovary homing peptide, a uterus homing peptide, a sperm homing peptide, a microglia homing peptide, a synovial homing peptide, a urothelial homing peptide, a prostate homing peptide, a lung homing peptide (e.g., RCPLSHSLICY), a 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 lymphocyte homing peptide, a muscle homing peptide, a wound vasculature homing peptide, an adipose tissue homing peptide, a virus binding peptide, or a fusion peptide.

[0525] The term "penetration enhancer" as used herein refers to a moiety or compound that increases the permeability of an active agent, specifically selected from pharmaceutically active agents, cell targeting agents, cosmetic active agents, and diagnostic active agents. A penetration enhancer is also known as a permeation enhancer.

[0526] Examples of penetration enhancers include, but are not limited to, 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, phenyl sulfonate, pluronic, sodium laurate, sodium oleate, sorbitan dilaurate, sorbitan dioleate, sorbitan trilaurate, sorbitan trioleate, sodium octyl sulfate, alkyl ammonium halides, decyl alcohol, dodecanol, linolenic alcohol, oleyl alcohol, butyl acetate, cetyl lactate, lauryl lactate, myristyl lactate, diethyl sebacate Esters, diethyl succinate, diisopropyl sebacate, glyceryl monolaurate, glyceryl monooleate, glyceryl 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, caproic acid, lactic acid, lauric acid, linoleic acid, linolenic acid, neodecanoic acid, oleic acid, palmitic acid, lecithin, phospholipids, sodium deoxycholate and sodium taurocholate.

[0527] For purposes of the present invention, pharmaceutically active agents include low molecular weight drugs, peptides, antibodies, hormones, enzymes, nucleic acids, proteins, and combinations thereof.

[0528] As used herein, the term "nucleic acid" refers to DNA or RNA. In a specific embodiment, optionally in combination with any one of the embodiments provided above or below, the nucleic acid is a DNA / RNA hybrid, a short interfering RNA (siRNA), a microRNA (miRNA), a single guide RNA (sgRNA), a donor DNA, a self-amplification / replication RNA, a circular RNA (oRNA), a plasmid DNA (pDNA), a closed-linear DNA (closed-linear DNA, clDNA), a short hairpin RNA (shRNA), a messenger RNA (mRNA) and an antisense RNA (aRNA), a messenger RNA (mRNA), a CRISPR guide RNA, an antisense nucleic acid, a decoy nucleic acid, an aptamer, and a ribozyme, etc., and covers both nucleotide sequences and any structural embodiments thereof (such as double-stranded, single-stranded, helical, hairpin, etc.), and may contain modified or unmodified bases. When different nucleic acids are provided, they may be all DNA molecules or all RNA molecules, or a mixture of DNA and RNA molecules or molecules comprising DNA and RNA chains associated.

[0529] The nucleic acid can be a poly- or oligonucleotide, such as a poly- or oligo-double-stranded RNA, a poly- or oligo-double-stranded DNA, a poly- or oligo-single-stranded RNA, a poly- or oligo-single-stranded DNA. Each nucleotide contained in the nucleic acid can be a naturally occurring nucleotide or a chemically modified non-naturally occurring nucleotide. The chain length of the nucleic acid is not particularly limited, and the nucleic acid can have a short chain ranging from 10 to 200 bases, preferably 20 to 180 bases, preferably 25 to 100 bases, preferably 30 to 50 bases; or the nucleic acid can have a relatively long chain of 200 to 20,000 bases, more preferably 250 to about 15,000 bases.

[0530] According to a specific embodiment, optionally in combination with any of the embodiments provided above or below, the nucleic acid is a closed-linear DNA (clDNA), ie a molecule in which the double-stranded region is flanked and protected by two single-stranded loops, thereby generating a dumbbell-shaped molecule.

[0531] In a more specific 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, the double-stranded DNA sequence of interest being covalently closed at both ends by hairpin loops, and the clDNA comprises at least two modified nucleotides.

[0532] As used herein, the term "closed linear DNA" or "clDNA" refers to a single-stranded covalently closed DNA molecule that forms a "dumbbell" or "dog bone" shaped structure under conditions that allow nucleotide hybridization. Therefore, although clDNA is formed by a single-stranded DNA molecule, the formation of a "dumbbell" structure by hybridization of two complementary sequences within the same molecule generates a structure consisting of a double-stranded intermediate segment flanked by two single-stranded loops. Those skilled in the art know how to generate clDNA from open or closed double-stranded DNA using conventional molecular biology techniques. For example, those skilled in the art know that clDNA can be generated by connecting a hairpin DNA adapter to both ends of an open double-stranded DNA, for example, by the action of a ligase. "Hairpin DNA adapter" refers to a single-stranded DNA that forms a stem-loop structure by hybridization of two complementary sequences, wherein the stem region formed is closed at one end by a single-stranded loop and open at the other end.

[0533] A "modified nucleotide" is any nucleotide that has been chemically modified - by modification of the base, sugar or phosphate group - or has a non-natural moiety incorporated into its structure (e.g., adenosine, guanosine, cytidine, uracil and thymidine). Thus, depending on the modification, a modified nucleotide may be naturally occurring or non-naturally occurring.

[0534] As used herein, the term "peptide" refers to a molecule comprising two or more consecutive amino acids interconnected by peptide bonds. The term peptide includes oligopeptides and polypeptides. The term "protein" refers to large peptides, specifically peptides having at least about 50 amino acids. For the purposes of the present invention, the terms peptide and protein are used interchangeably.

[0535] Examples of proteins of interest include, but are not limited to, 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), etc.

[0536] In the context of the present disclosure, the expression "diagnostically active agent", also referred to as "labeling or imaging agent", refers to any substance used as a label, or any substance that enhances a specific structure in any imaging technique. Thus, imaging agents include optical imaging agents, magnetic resonance imaging agents, radioisotopes and contrast agents. Imaging or labeling agents are well known in the art. Specific examples of imaging or labeling agents are gases such as sterile air, oxygen, argon, nitrogen, fluorine (fluor), perfluorocarbons, carbon dioxide, nitrogen dioxide, sulfur hexafluoride, xenon and helium; commercially available agents for positron emission tomography (PET), computer-assisted tomography (CAT), single photon emission computed tomography, x-rays, fluoroscopy and magnetic resonance imaging (MRI). Suitable materials for use as contrast agents in MRI include currently available gadolinium chelates, such as diethylenetriamine pentaacetic acid (DTPA) and gadopentotate dimeglumine, as well as iron, magnesium, manganese, copper and chromium. Examples of materials for CAT and x-rays include iodine-based materials for intravenous administration, such as ionic monomers represented by diatrizoate and iothalamate, nonionic monomers such as iopamidol, isohexol and ioversol, nonionic dimers such as iothalamate and iodixanol, and ionic dimers, such as ioxagalte. Other useful materials include oral barium and insoluble salts such as zinc acetate. In some molecules, the imaging agent is a dye. In some molecules, the imaging agent is a fluorescent moiety. In some molecules, the fluorescent moiety is selected from: fluorescent protein, fluorescent peptide, fluorescent dye, fluorescent material or a combination thereof. Examples of fluorescent dyes include, but are not limited to, xanthenes (e.g., rhodamines, rhodols, and fluorescein, and their derivatives); 2,3,5,6-tetramethylpyrazolo[1,2-a]pyrazole-1,7-diones (bimanes); coumarins and their derivatives (e.g., umbelliferone and aminomethylcoumarin); aromatic amines (e.g., dansyl; squaratedyes); benzofurans; fluorescent cyanines; indocarbocyanines; carbazoles; dicyanomethylene pyranes; polymethines; oxabenzanthrane; xanthenes; pyranose; 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-isothiocyanate, fluorescein-6-isothiocyanate, and 6-carboxyfluorescein. Examples of rhodamine dyes include, but are not limited to, tetramethylrhodamine-6-isothiocyanate, 5-carboxytetramethylrhodamine, 5-carboxy-p-aminophenol derivatives, tetramethylrhodamine and tetraethylrhodamine, diphenyldimethylrhodamine and diphenyldiethylrhodamine, dinaphthylrhodamine, and rhodamine 101 sulfonyl chloride (sold under the trade name TEXAS RED(R)). Examples of cyanine dyes include, but are not limited to, Cy3, Cy3B, Cy3.5, Cy5, Cy5.5, Cy7, IRDYE680, AlexaFluor 750, IRDye800CW, ICG. Examples of fluorescent peptides include GFP (green fluorescent protein) or derivatives of GFP (e.g., EBFP, EBFP2, Azurite, mKalama1, ECFP, Cerulean, CyPet, YFP, Citrine, Venus, YPet). Fluorescent labels are detected by any suitable method. For example, fluorescent labels can be detected by exciting fluorescent dyes with appropriate wavelengths of light and detecting the resulting fluorescence (e.g., by microscopic examination, visual observation, by photographic film, by using electronic detectors such as charge coupled devices (CCD), photomultipliers), etc. In some molecules, the imaging agent is labeled with a positron-emitting isotope (e.g., 18F) for positron emission tomography (PET), a 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 magnetic nanoparticle) for magnetic resonance imaging (MRI). In some molecules, the imaging agent is labeled with: gadolinium chelates, iron oxide particles, superparamagnetic iron oxide particles, ultra-small paramagnetic particles, manganese chelates, or gallium-containing agents. Examples of gadolinium chelates include, but are not limited to, diethylenetriaminepentaacetic acid (DTPA), 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), and 1,4,7-triazacyclononane-N,N',N"-triacetic acid (NOTA). In some molecules, the imaging agent is a near-infrared fluorophore for near-infrared (near-IR) imaging, a luciferase (from fireflies, bacteria, or coelenterates) or other luminescent molecules for bioluminescent 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: technetium chelates, copper chelates, radiofluorine, radioiodine, indium chelates. Examples of Tc chelates include, but are not limited to, HYNIC, DTPA, and DOTA. In some molecules, the imaging agent comprises a radioactive portion, such as a radioisotope such as. 211 At 13 1I. 125 I. 90 Y. 186 Re, 188 Re, 153 Sm, 212 Bi, 32 P. 64 Radioisotopes of Cu, etc. The diagnostically active agent may be linked to any of A, A', A", or A'" of the main chain of the lipopolyamino acid conjugate and / or may be contained in the self-assembled particles formed by the conjugate.

[0537] Composition

[0538] The invention also relates to a composition comprising a lipopolyamino acid conjugate, or alternatively, a self-assembling particle as defined herein, and one or more suitable excipients or carriers.

[0539] 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) a lipopolyamino acid conjugate as defined herein, wherein at least one of A, A', A" or A'" is a pharmaceutically active agent, or alternatively, (b) a self-assembling particle comprising the lipopolyamino acid conjugate (a), or alternatively, (c) a self-assembling particle comprising a lipopolyamino acid conjugate as defined herein and one or more active agents selected from pharmaceutically active agents, nucleic acids, peptides, proteins and mixtures thereof, and one or more pharmaceutically acceptable excipients or carriers.

[0540] As used herein, the expression "therapeutically effective amount" refers to an amount of a polymer that, when administered, is sufficient to prevent the development of one or more symptoms of a disease or to alleviate to some extent one or more symptoms of a disease. The specific dosage of the polymer of the present invention to achieve therapeutic benefit may vary depending on the specific circumstances of the individual patient, including the patient's size, weight, age and sex, the nature and stage of the disease, the aggressiveness of the disease, and the route of administration, etc.

[0541] For the purpose of the present invention, the term "pharmaceutically acceptable excipient or carrier" refers to a component of pharmaceutical technology suitable for preparing a pharmaceutical composition. Each component should be "acceptable" in the sense of being compatible with the other ingredients of the composition. When used in contact with human and animal tissues or organs, there should not be excessive toxicity, irritation, allergic reaction, immunogenicity or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0542] The lipopolyamino acid conjugates described in the present disclosure, and the self-assembling particles and pharmaceutical compositions comprising the same can be used in combination with other additional drugs to provide combination therapy. The additional drugs can be part of the same pharmaceutical composition, or alternatively, can be provided in the form of separate compositions for simultaneous or non-simultaneous administration.

[0543] 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') a lipopolyamino acid conjugate as defined herein, wherein at least one of A, A', A" or A'" is a diagnostically active agent, or alternatively, (b') self-assembled particles comprising the lipopolyamino acid conjugate (a'), or alternatively, (c') self-assembled particles comprising a lipopolyamino acid conjugate as defined herein and one or more diagnostically active agents, and one or more diagnostically acceptable excipients or carriers.

[0544] The term "diagnostic composition" refers to a composition suitable for diagnosis, particularly imaging diagnostic techniques. The term "diagnostally effective amount" as used herein refers to an effective amount of a detection polymer sufficient to diagnose a disease or disorder when administered; particularly for use as a contrast imaging agent for imaging diagnosis. The dose of the detection polymer administered will of course be determined by the specific circumstances surrounding the case, including the polymer administered, the route of administration, the specific condition being diagnosed, and similar considerations. The diagnostic composition of the present invention includes one or more diagnostically acceptable excipients or carriers. The term "diagnostably acceptable" refers to an excipient or carrier that is suitable for use in diagnostic techniques and is used to prepare a composition with diagnostic use (particularly by imaging diagnostic use). Detection of these diagnostic agents in a patient's body can be performed by known techniques such as those used in imaging diagnosis using magnetic resonance imaging (MRI) and X-rays.

[0545] 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") a lipopolyamino acid conjugate as defined herein, wherein at least one of A, A', A" or A"' is a cosmetic active agent, or alternatively, (b") self-assembled particles comprising the lipopolyamino acid conjugate (a"), or alternatively, (c') self-assembled particles comprising a lipopolyamino acid conjugate as defined herein and one or more cosmetic active agents, and one or more cosmetically acceptable excipients or carriers.

[0546] As used herein, the term "cosmetically effective amount" refers to an effective amount of a cosmetic active agent that, when applied, is intended to improve its appearance or beautify, preserve, condition, cleanse, color or protect the skin, nails or hair without pharmaceutical applications. The terms "cosmetically acceptable" or "dermatologically acceptable" excipients or carriers are used interchangeably in this document and refer to components that are suitable for contact with human skin without toxicity, incompatibility, instability, undue allergic response, etc.

[0547] The compositions of the present invention can 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 technician will know the most appropriate formulation and excipient to be used. Examples of excipients or carriers include, but are not limited to, diluents, adhesives, glidants, disintegrants, lubricants, colorants, mixtures thereof, and other ingredients known in the art. Any route of administration can be used, such as, for example, oral, topical, rectal or parenteral routes (including subcutaneous, intraperitoneal, intradermal, intramuscular, intravenous routes, etc.).

[0548] use

[0549] The lipopolyamino acid conjugates, self-assembled particles and compositions thereof of the present invention can be used for therapeutic applications. Specifically, they can be used as non-viral vectors generally used for biomedical applications such as vaccines or gene therapy, and are effective for transfecting host eukaryotic cells in culture, in vivo or in vitro, in unicellular parasites and bacteria, including gene editing using the CRISP / Cas9 method. In addition, they can also be used for protein-based therapies; in particular, protein-based vaccines for viral infections or as therapeutic protein-based vaccines for cancer or infectious diseases.

[0550] Therefore, the present invention relates to a therapeutic product for medical use, which is or comprises: a) a lipopolyamino acid conjugate of formula (I) as defined herein, wherein at least one of A, A', A" or A"' is a pharmaceutically active agent; or alternatively, b) a self-assembled particle comprising the lipopolyamino acid conjugate a); or alternatively, c) a composition comprising the lipopolyamino acid conjugate a) or the self-assembled particle b); or alternatively, d) a self-assembled particle comprising the lipopolyamino acid conjugate as defined herein and one or more active agents selected from pharmaceutically active agents, nucleic acids, peptides, proteins and mixtures thereof; or alternatively, e) a composition comprising the self-assembled particle d).

[0551] This aspect may also be formulated as a method for treating or preventing a disease or disorder in a subject, more particularly a mammal, even more particularly a human, comprising administering a therapeutic product as defined herein, together with one or more pharmaceutically acceptable excipients or carriers.

[0552] Non-limiting examples of diseases that can be treated and / or prevented by the derivatives of the present invention include neurodegenerative disorders, neurological diseases, cancer, infectious diseases, disorders associated with aging, neuroinflammation, demyelinating disorders, multiple sclerosis, ischemic disorders, ischemia-reperfusion injury, amyloidotic diseases, cardiomyopathy, spinal cord injury, immune disorders, inflammatory disorders, rare diseases, wound healing, skin-related diseases and lysosomal storage diseases.

[0553] Non-limiting examples of neurodegenerative diseases include Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, cerebral ischemia, post-encephalitic Parkinsonisms, dystonia, Tourette syndrome, periodic limb movement pathologies, restless legs syndrome, attention deficit hyperactivity disorders, Huntington's chorea, progressive supranuclear palsy, Pick's disease, frontotemporal dementia, and neuromuscular diseases.

[0554] In one embodiment, optionally in combination with any embodiment provided above or below, the present invention relates to a therapeutic product for use in the treatment and / or prevention of cancer or infectious diseases, respectively, which is or comprises: a) a lipopolyamino acid conjugate of formula (I) as defined herein, wherein any one of A, A', A" or A"' is an anticancer agent or an anti-infective agent; or alternatively, b) a self-assembled particle comprising the lipopolyamino acid conjugate a); or alternatively, c) a composition comprising the lipopolyamino acid conjugate a) or the self-assembled particle b); or alternatively, d) a self-assembled particle comprising a lipopolyamino acid conjugate as defined herein and one or more anticancer agents or anti-infective agents; or alternatively, e) a composition comprising the self-assembled particle d).

[0555] The term "disorder" as used herein is intended to be generally synonymous and used interchangeably with the terms "disease," "syndrome," and "condition" (as in medical condition), as all reflect an abnormal condition of one of the parts of the human or animal body or of which its normal function is impaired, generally manifested by distinguishing signs and symptoms.

[0556] In the context of the present invention, the terms "treat," "treating," and "treatment" as used herein refer to ameliorating symptoms associated with a disease or disorder, including preventing or delaying the onset of disease or disorder symptoms, and / or lessening the severity or frequency of disease or disorder symptoms.

[0557] According to one embodiment, optionally in combination with any of the embodiments provided above or below, the present invention relates to a therapeutic product as defined herein, which is (i) used as a transfection agent for transfecting at least one active agent into a cell; (ii) for the in vivo or ex vivo production of a biological preparation encoding a recombinant protein, peptide or antibody, or for the production of a recombinant virus; (iii) for use as a therapeutic or prophylactic vaccine against a viral infection, or as a therapeutic vaccine against cancer or an infectious disease; or (iv) for use in genome engineering, for cell reprogramming, for differentiating cells or for gene editing.

[0558] In one embodiment, optionally in combination with any of the embodiments provided above or below, the present invention relates to a therapeutic product as defined herein as a transfection agent for delivering one or more nucleic acids (regardless of size and structure, circular and linear nucleic acids) to a target cell in vivo, in vitro or ex vivo. More particularly, the active agent is selected from a low molecular weight drug, a peptide, a protein, an antibody, a nucleic acid, an aptamer and a combination thereof.

[0559] The present invention also relates to methods for in vitro, ex vivo and in vivo transfer of active agents including therapeutic products as defined herein.

[0560] In one embodiment, optionally in combination with any of the embodiments provided above or below, the therapeutic product is a self-assembling particle comprising a lipopolyamino acid conjugate as defined herein and one or more nucleic acids, or alternatively, is a composition comprising self-assembling particles comprising a lipopolyamino acid conjugate as defined herein and one or more nucleic acids.

[0561] The transfection reagents of the invention are also used to co-transfect two or more active agents simultaneously, such as two or more nucleic acids simultaneously. Transfection compositions (such as kits) and methods of using transfection reagents to deliver nucleic acids to target cells are also within the scope of the invention.

[0562] The present invention also provides a therapeutic product as defined herein for inducing a regulatory effect on the expression of one or more target proteins responsible for or involved in genetic inherited diseases or complex genetic diseases, immune diseases, cancer, viral infections in various tissues / organs or tumors.

[0563] The present invention also relates to the use of therapeutic products as defined herein in the production of biological preparations, specifically biological preparations encoding recombinant proteins, peptides or antibodies; or in vitro or ex vivo use in the production of recombinant viruses, such as adeno-associated viruses (AAV), lentiviruses (LV), adenoviruses, oncolytic viruses or baculoviruses, or viruses or virus-like particles, specifically the products include the lipopolyamino acid conjugates of the present invention and at least one nucleic acid molecule for transfection. As used herein, the term "biological preparation" refers to proteins or nucleic acids or combinations thereof, living entities such as cells or viruses, cell compartments, organelles and tissues.

[0564] The present invention also relates to the in vitro or ex vivo use of a therapeutic product as defined herein, in particular said product comprising the lipopolyamino acid conjugate of the present invention and at least one nucleic acid molecule for transfection, genome engineering, cell reprogramming, cell differentiation or gene editing.

[0565] The composition for transfecting cells comprises the therapeutic product as defined herein, specifically comprising the lipopolyamino acid conjugate of the present invention and at least one nucleic acid molecule for transfection, as well as an acceptable excipient, buffer, cell culture medium or transfection medium.

[0566] The invention also relates to therapeutic products as defined herein, which are used as therapeutic or preventive vaccines against viral infections, or therapeutic vaccines against cancer. In general, in this aspect, the vaccine is delivered by direct administration such as systemic, intramuscular, intradermal, intraperitoneal, intratumoral, oral, topical or subcutaneous administration, and in the vaccine, the composition is combined with a pharmaceutically acceptable vehicle. In other words, the vaccine can be injected directly into the body, specifically into a human individual, for eliciting a cellular and / or humoral response.

[0567] Cell targeting is achieved by different mechanisms and depends on the nature and properties of the transfection reagent, the method or protocol composition or formulation, and the route of administration.

[0568] The lipopolyamino acid conjugates, self-assembled particles and compositions thereof of the present invention may also be used in cosmetic and diagnostic applications.

[0569] Therefore, another aspect of the present invention relates to a diagnostic product for diagnostic use, which is or comprises: a') a lipopolyamino acid conjugate as defined herein, wherein at least one of A, A', A" or A'" is a diagnostically active agent; or alternatively, b') a self-assembled particle comprising the lipopolyamino acid conjugate i'); or alternatively, c') a composition comprising the lipopolyamino acid conjugate i') or the self-assembled particle ii'); or alternatively, d') a self-assembled particle comprising a lipopolyamino acid conjugate as defined herein and one or more diagnostically active agents; or alternatively, e') a composition comprising the self-assembled particle iv').

[0570] This aspect of the invention may also be formulated as a') a lipopolyamino acid conjugate as defined herein, wherein at least one of A, A', A" or A'" is a diagnostically active agent; or alternatively, b') a self-assembled particle comprising the lipopolyamino acid conjugate a'); or alternatively, c') a composition comprising the lipopolyamino acid conjugate a') or the self-assembled particle b'); or alternatively, d') a self-assembled particle comprising a lipopolyamino acid conjugate as defined herein and one or more diagnostically active agents; or alternatively, e') a composition comprising the use of the self-assembled particle d') in diagnosis. In addition, it can also be formulated into a method for diagnosing a disease or condition, comprising administering to a subject in need thereof, more particularly a mammal, and even more particularly a human, a') a lipopolyamino acid conjugate as defined herein, wherein at least one of A, A', A" or A"' is a diagnostically active agent; or alternatively, b') a self-assembled particle comprising the lipopolyamino acid conjugate a'); or alternatively, c') a composition comprising the lipopolyamino acid conjugate a') or the self-assembled particle b'); or alternatively, d') a self-assembled particle comprising a lipopolyamino acid conjugate as defined herein and one or more diagnostically active agents; or alternatively, e') a composition comprising the self-assembled particle d').

[0571] In one embodiment, the invention relates to microvesicles for diagnostic use comprising a lipopolyamino acid conjugate as defined herein and one or more diagnostically active agents, in particular a contrast agent.

[0572] 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 are not limited to, magnetic resonance imaging (MRI), X-rays, positron emission tomography (PET), single photon emission computed tomography (SPECT), fluorescence microscopy, and in vivo fluorescence.

[0573] According to another aspect, the present invention relates to the use of a cosmetic product in cosmetics, which is or comprises: a") a lipopolyamino acid conjugate as defined herein, wherein at least one of A, A', A" or A"' is a cosmetic active agent; or alternatively, b") a self-assembled particle comprising the lipopolyamino acid conjugate a'); or alternatively, c") a composition comprising a") or the self-assembled particle b"); or alternatively, d") a self-assembled particle comprising the lipopolyamino acid conjugate as defined herein and one or more cosmetic active agents; or alternatively, e") a composition comprising the self-assembled particle d").

[0574] Throughout the specification and claims, the word "comprise" and variations of the word are not intended to exclude other technical features, additives, components or steps. In addition, the word "comprise" also covers the situation of "consisting of". Other objects, advantages and features of the present disclosure will become apparent to those skilled in the art after studying the specification, or can be learned by the practice of the present disclosure. The following examples and drawings are provided by way of illustration, and they are not intended to limit the present invention. In addition, the present invention also covers all possible combinations of the specific and preferred embodiments described herein.

[0575] Example

[0576] Analytical methods

[0577] NMR spectroscopy

[0578] NMR spectra were recorded at 27°C (300K) 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 approximately 20-10 mg / mL in the desired solvent.

[0579] Size Exclusion Chromatography (SEC)

[0580] For SEC measurements in dimethylformamide (DMF) containing 0.1% (w / w) lithium bromide as an additive, a GPC max (Malvern Instruments) autosampler was used with a flow rate of 0.7 mL / min, 60°C, and a 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) from PSS (Mw = 65 kDa; PDI = 1.05). For this Mw measurement, an integrated triple detection system [refractive index, light scattering (two angles: 7° and 90°) and UV-visible detector] was used.

[0581] For SEC measurements in aqueous solutions containing 0.1 M sodium nitrate and 0.005% sodium azide as additives, a GPC max (Malvern Instruments) pump and autosampler were used, with a flow rate of 0.7 mL / min, 25° C., using a 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 measurement, an integrated triple detection system [refractive index, light scattering (two angles: 7° and 90°) and UV-visible detector] was used.

[0582] Size distribution

[0583] Dynamic light scattering (DLS) measurements were performed using a Malvern Zetasizer NanoZS instrument equipped with a 532 nm laser and a fixed scattering angle of 173°. Polymer solutions were prepared under different conditions (MilliQ water or PBS at different concentrations and temperatures), sonicated for 10 min, aged for the required time, filtered through a 1.20 μm cellulose membrane filter and measured. The size distribution (diameter, nm) of each polymer was measured in triplicate with n>3 measurements, automatically optimizing beam focus and attenuation for each sample.

[0584] Example 1. Lipid shielding C 14 -Synthesis of PGA(DIOL)

[0585] 1.1C 14- General procedure for PGlu(OBzl) polymerization

[0586]

[0587] Benzyl glutamate NCA (10 g, 40.12 mmol) was added to a Schlenk tube equipped with a stirring bar and a stopper. After 3 vacuum / N2 cycles, the mixture was dissolved in anhydrous DMF (150 mg reagent / mL DMF). Then, the initiator (tetradecamine 96%, TCI EUROPE NV: DP23: 0.392 g, 1.74 mmol, DP8: 1.13 g, 5.02 mmol) was diluted in DMF (5 mL) and added to the reaction mixture, which was stirred at 10 ° C for 16 hours. After confirming the consumption of NCA by IR, the reaction mixture was poured into diethyl ether to precipitate the product. The precipitate was separated by centrifugation (3750 rpm, 4 min) and dried under vacuum. The white solid homopolymer (C 14 -PGluOBzl). Yield: 70-90%. 1H NMR (300MHz, DMSO) δ8.38-7.82 (m, NH amide), 7.48-7.04 (m, CH aryl), 5.42-4.81 (m, CH2 benzyl), 4.01 (m, CH), 2.57-1.79 (m, CH2), 1.20 (s, CH2), 0.82 (t, J = 6.35 Hz, CH3).

[0588] Following the general procedure above, the polymers shown in Table 1 were obtained:

[0589] Table 1. Based on C 14 -PGlu(OBzl) polymer (lipid PGA x )

[0590]

[0591] a Confirmed by NMR. b Determined by GPC, with the quoted DP numbers subject to reasonable uncertainties in the range ±20%.

[0592] 1.2 General procedure for N-terminal capping:

[0593]

[0594] The C obtained in Example 1.1 14 -PGlu(OBzl) (PGADIOL1: 2.0 g, 0.38 mmol, PGADIOL2: 2.0 g, 1.02 mmol) was dissolved in DMF (200 mg / mL DMF), and acetic anhydride (10 eq) and DIPEA (3 eq) were added to the reaction mixture. Then, the mixture was stirred for 1 hour at RT. The reaction mixture was poured into diethyl ether to precipitate the product. The precipitate (C14 -PGlu(OBzl)-COCH3) and dried under vacuum.

[0595] Yield: 60-70%. 1 H NMR (300 MHz, TFA) δ 8.05-7.73 (brs, CH aryl), 5.69 (m, CH 2 benzyl), 5.25 (m, CH ), 3.88 (s, CH 3 ), 3.26-2.36 (m, CH 2 ), 1.83 (brs, CH 2 ), 1.40 (t, J = 6.6 Hz, CH 3 ).

[0596] Following the general procedure above, the polymers shown in Table 2 were obtained:

[0597] Table 2. Based on C 14 -PGlu(OBzl)-COCH3 polymer (lipid PGA x )

[0598]

[0599] a Confirmed by NMR. b Determined by GPC, with the quoted DP numbers subject to reasonable uncertainties in the range ±20%.

[0600] 1.3 General procedure for the deprotection step:

[0601]

[0602] The lipid polymer C obtained in Example 1.2 14 -PGlu(OBzl)-COCH3 (lipid PGA1-4: 6.4 mmol) was dissolved in trifluoroacetic acid (100 mg / mL) and 48% HBr (2 eq / glutamic acid unit) was added. The mixture was stirred at RT for 16 hours. The reaction mixture was poured into diethyl ether to precipitate the product. The precipitate was washed with a mixture of acetonitrile:H2O (8:2) until pH 4-5. The product was then washed with diethyl ether, separated by centrifugation (3750 rpm, 4 min) and dried under vacuum. A white solid polymer (C 14 -PGA).

[0603] Yield: 95%. 1 H NMR(300MHz,D2O)δ4.35(m,CH),3.22(m,CH3),2.69-1.76(m,CH2),1.53(brs,CH2),1.30(s,CH2),0.89(t,J=6.4Hz,CH3).

[0604] Following the general procedure above, the polymers shown in Table 3 were obtained:

[0605] Table 3. Based on C 14 -PGA polymer (lipid PGA x )

[0606] Code Precursor R <![CDATA[DP(n) of Glu(ONa)]]> a > Lipid PGA5 Lipid PGA3 <![CDATA[-COCH3]]> 22 LipoPGA6 Lipid PGA4 <![CDATA[-COCH3]]> 9 Lipid PGA7 Lipid PGA1 -H 11 Lipid PGA8 Lipid PGA2 -H 6

[0607] a Determined by NMR, with the quoted DP numbers subject to reasonable uncertainties in the range ±20%.

[0608] 1.4 Synthesis of C by coupling peptide with CDI 14 -General Procedure for PGA(diol)

[0609]

[0610] The C obtained in Example 1.3 14 -PGA (PGA diol 0.4 g, 3.1 mmol) was dissolved in DMF (50 mg / mL). Then, CDI (1.6 eq / glutamic acid unit) was added to the reaction mixture and stirred at room temperature for 30 minutes. Thereafter, 3-aminopropane-1,2-diol (1.3 eq / glutamic acid unit) dissolved in 2 mL DMF was added. The mixture was stirred at room temperature for 16 hours. The reaction mixture was poured into acetone to precipitate the product. The precipitate was separated by centrifugation (3750 rpm, 4 min) and dried under vacuum. The white solid final product was separated.

[0611] Yield: 50-60%. 1 H NMR(300MHz,D2O)δ4.38(brs,CH),3.83(brs,CH),3.59(ddd,J=18.1,11.8,5.2Hz,CH2),3.32(ddd,J =21.1,14.0,5.8Hz,CH2),2.66-1.82(m,CH2),1.53(brs.CH2),1.29(s,CH2),0.88(t,J=6.5Hz,CH3).

[0612] Following the general procedure above, the polymers shown in Table 4 were obtained:

[0613] Table 4. Based on the end-capping C 14 -PGA(diol) polymer (lipid PGA x )

[0614]

[0615] a Confirmed by NMR. bDetermined by GPC, with the quoted DP numbers subject to reasonable uncertainties in the range ±20%.

[0616] Example 2. Lipid shielding C 14 -PLys(thioglycerol) x Synthesis

[0617] 2.1C 14 General procedure for -PLys(OBzl) polymerization

[0618]

[0619] L-Lysine benzyl ester NCA (10 g, 32.64 mmol) was added to a Schlenk tube equipped with a stirring bar and a stopper. After 3 vacuum / N2 cycles, the mixture was dissolved in anhydrous DMF (150 mg reagent / mL DMF). Then, the initiator (tetradecamine 96%, TCI EUROPE NV: DP23: 0.319 g, 1.42 mmol, DP8: 0.917 g, 1.08 mmol) was diluted in DMF (5 mL) and added to the reaction mixture, which was stirred at 10 °C for 16 hours. After confirming the consumption of NCA by IR, the reaction mixture was poured into diethyl ether to precipitate the product. The precipitate was separated by centrifugation (3750 rpm, 4 min) and dried under vacuum. The white solid homopolymer (C 14 -PLys(OBzl)).

[0620] Yield: 70-90%. 1 H NMR (300 MHz, DMSO) δ 8.31-7.69 (m, NH amide), 7.41-6.98 (m, CH aryl), 4.97 (m, CH 2 benzyl), 2.92 (m, CH 2 ), 2.07-1.09 (m, CH 2 ), 0.83 (t, J = 5.5 Hz, CH 3 ).

[0621] Following the general procedure above, the polymers shown in Table 5 were obtained:

[0622] Table 5. Based on C 14 -PLys(OBzl) polymer (lipid PLys x )

[0623]

[0624] a Confirmed by NMR. b Determined by GPC, with the quoted DP numbers subject to reasonable uncertainties in the range ±20%.

[0625] 2.2 General procedure for N-terminal capping:

[0626]

[0627] According to the above procedure in Example 1.2, the C obtained in Example 2.1 was 14 -PLys(OBzl) (PLysTG1: 1.5g, 0.24mmol, PLysTG2: 1.5g, 0.65mmol) end-capping.

[0628] Yield: 60-70%. 1 H NMR (300 MHz, TFA) δ 8.19-7.75 (m, CH aryl), 5.70 (brs, CH), 5.11 (brs, CH benzyl), 3.81 (brs, CH2), 2.74 (s, CH3), 1.92-2.63 (m, CH2), 1.80 (brs, CH2), 1.37 (t, J = 6.6 Hz, CH3).

[0629] Following this procedure, the polymers shown in Table 6 were obtained:

[0630] Table 6. Based on C 14 -PLys(OBzl)-COCH3 polymer (PLys x )

[0631]

[0632] a Confirmed by NMR. b Determined by GPC, with the quoted DP numbers subject to reasonable uncertainties in the range ±20%.

[0633] 2.3 General procedure for the deprotection step:

[0634]

[0635] The lipid polymer C obtained in Example 2.2 14 -PLys(OBzl)-COCH3 (PLys: 1.25 g, 4.7 mmol) was dissolved in chloroform (50 mg / mL) and 33% HBr (4 eq / lysine unit) was added. The mixture was stirred at RT for 16 hours. An orange solid appeared. The solid was recovered by filtration and washed with diethyl ether. The precipitate was washed with a mixture of acetonitrile:H2O (8:2) until pH 4-5. The product was then washed with diethyl ether, separated by centrifugation (3750 rpm, 4 min) and dried under vacuum. A pale yellow solid polymer was isolated. Final purification was performed by dialysis (cutoff Mw was 2000 Da) to obtain a white solid (C 14 -PLys).

[0636] Yield: 70%. 1H NMR (300 MHz, D2O) δ4.29 (m, CH), 3.04 (m, CH2), 2.07 (s, CH3), 1.93-1.37 (m, CH2), 1.31 (brs, CH2), 0.89 (t, J = 6.7 Hz, CH3).

[0637] Following this procedure, the polymers shown in Table 7 were obtained:

[0638] Table 7. Based on C 14 -PLys polymer (lipid PLys x )

[0639] Code Precursor <![CDATA[DP(n) of Lys a > Lipid PLys5 Lipid PLys3 28 Lipopolysaccharide 6 Lipid PLys4 8

[0640] a Determined by NMR, with the quoted DP numbers subject to reasonable uncertainties in the range ±20%.

[0641] 2.4 General procedure for the synthesis of C14-PLys(ClAc) by coupling peptides with chloroacetic anhydride

[0642]

[0643] The C obtained in Example 2.3 14 -PLys (PLys 0.5 g, 0.1 mmol) was dissolved in cold DMF (50 mg / mL). Then, 2,6-lutidine (0.25 mL / mL DMF) was added to the reaction mixture and stirred at 4°C for 75 minutes. Thereafter, cold chloroacetic anhydride (4 eq / lysine unit) dissolved in DMF (514 mg / mL) was added dropwise. The mixture was stirred at 4°C for 16 hours. The reaction mixture was poured into hot ethanol. The mixture was left at 4°C for 45 minutes to precipitate the product. The precipitate was separated by filtration, washed with ethanol and dried under vacuum. The white solid final product (C 14 -PLys(ClAc)).

[0644] Yield: 80-90%. 1 H NMR (300 MHz, TFA) δ5.19(brs,CH),4.79(s,CH2),3.99(brs,CH2),2.90(s,CH3),2.60-1.98(m,CH2),1.87(brs,CH2),1.41(t,J=6.6 Hz,CH3).

[0645] Following this procedure, the polymers shown in Table 8 were obtained:

[0646] Table 8. Based on C 14 -PLys(ClAc) polymers (lipid PLysx )

[0647] Code Precursor <![CDATA[DP(n) of Lys(ClAc)]]> a > Lipid PLys7 Lipid PLys5 30 Lipopolysaccharide 8 Lipopolysaccharide 6 9

[0648] a Determined by NMR, with the quoted DP numbers subject to reasonable uncertainties in the range ±20%.

[0649] 2.5 Synthesis of C by coupling with thioglycerol 14 - General Procedure for PLys(thioglycerol)

[0650]

[0651] The C obtained in Example 2.4 14 -PLys(ClAc) (PLysTG: 502 mg, 0.1 mmol) was dissolved in DMF (22 mg / mL). Then, thioglycerol (8 eq / lysine unit) and DIPEA (8 eq / lysine unit) were added to the reaction mixture. The reaction mixture was stirred for 16 h at room temperature. Thereafter, the reaction mixture was poured into diethyl ether, the precipitate was isolated by filtration, washed with diethyl ether and dried in vacuo. The product was dissolved in H2O, purified by a sephadex column (PD-10 desalting column) and lyophilized. The white solid final product was isolated.

[0652] Yield: 60-70%. 1 H NMR(300MHz,D2O)δ4.10(brs,CH),3.88(brs,CH),3.64(ddd,J=22.9,12.1,4.6Hz,CH2),3.34(br s,CH2),3.25(brs,CH2),2.75(ddd,J=21.4,13.8,6.1Hz,CH2),2.20-1.14(m,CH2),0.88(m,CH3).

[0653] Following this procedure, the polymers shown in Table 9 were obtained:

[0654] Table 9. Based on the end-capping C 14 -PLys(thioglycerol) polymer (lipid PLys x )

[0655] Code Precursor <![CDATA[DP(n) of Lys(TG)]]> a > Lipid PAA5 Lipid PLys7 33 Lipid PAA6 Lipopolysaccharide 8 10

[0656] a Confirmed by NMR. b Determined by GPC, with the quoted DP numbers subject to reasonable uncertainties in the range ±20%.

[0657] Example 3. Lipid shielding C 14 -Synthesis of PLys (betaine)

[0658] 3.1 C 14 General procedure for -PLys(TFA) polymerization

[0659]

[0660] L-Lysine TFA NCA (10 g, 37.29 mmol, DP 5) was added to a Schlenk tube equipped with a stirring bar and a stopper. After 3 vacuum / N2 cycles, the mixture was dissolved in anhydrous DMF (150 mg reagent / mL DMF). Then, the initiator (1.67 g, 7.45 mmol, tetradecylamine 96%, TCI EUROPE NV) was diluted in DMF (5 mL) and added to the reaction mixture, which was stirred at 10 ° C for 16 hours. After confirming the consumption of NCA by IR, the reaction mixture was poured into diethyl ether to precipitate the product. The precipitate was separated by centrifugation (3750 rpm, 4 min) and dried under vacuum. The white solid homopolymer (C 14 -PLys(TFA)).

[0661] Yield: 70-90%. 1H NMR (300 MHz, TFA) δ 5.35-4.88 (m, CH), 4.4 (m, CH2), 2.77-2.00 (m, CH2), 1.91 (brs, CH2), 1.45 (t, J = 6.7 Hz, CH3).

[0662] Following the general procedure above, the polymers shown in Table 10 were obtained:

[0663] Table 10. Based on C 14 -PLys(TFA) polymer (lipid PBet x )

[0664]

[0665] a Confirmed by NMR. b Determined by GPC, with the quoted DP numbers subject to reasonable uncertainties in the range ±20%.

[0666] 3.2 General procedure for the deprotection step:

[0667]

[0668] The lipid polymer C obtained in Example 3.1 14 -PLys(TFA) was dissolved in cold methanol (300 mg / mL) and cold NaOH was added aq(1.5 eq / lysine unit). The mixture was stirred at RT for 16 hours. The reaction mixture was quenched with 48% HBr until pH 2. The precipitate was washed with an acetone mixture, separated by centrifugation (3750 rpm, 4 min) and dried under vacuum. The product was dissolved in H2O, the pH was adjusted to 4 with 1 M NaOH and lyophilized. A white solid polymer (C 14 -PLys).

[0669] Yield: 1 H NMR (300MHz, TFA) δ5.31(m,CH),3.94(m,CH2),2.92-2.12(m,CH2),1.95(brs,CH2),1.49(t,J=6.7Hz,CH3).

[0670] Following the general procedure above, the polymers shown in Table 11 were obtained:

[0671] Table 11. Based on C 14 -PLys polymer (lipid PBet x )

[0672] Code Precursor <![CDATA[DP(n) of Lys(TFA)]]> a > LipidPBet3 lipidPBet1 5 LipoPBet4 lipidPBet2 36

[0673] a Determined by NMR, with the quoted DP numbers subject to reasonable uncertainties in the range ±20%.

[0674] 3.3C 14 -PLys n General procedure for the dimethylation of amine groups.

[0675]

[0676] The lipid polymer C obtained in Example 3.2 14 -PLys was dissolved in formaldehyde (1 eq / lysine unit) and formic acid (2.3 eq / lysine unit). The mixture was heated to 85°C and stirred for 16 hours. The reaction mixture was concentrated using a rotary evaporator and redissolved in methanol. The mixture was precipitated with diethyl ether, separated by centrifugation (3750 rpm, 4 min) and dried under vacuum. The product was dissolved in H2O, purified by a cross-linked dextran gel column (PD-10 desalting column) and lyophilized. A white solid polymer (C 14 -PLys(Dimet)).

[0677] Yield: 50%. 1H NMR (300MHz, D2O) δ4.49-4.01(m,CH),3.17(brs,CH2),2.86(s,CH3),1.97-1.35(m,CH2),1.26(brs,CH2),0.84(t,J=6.7Hz,CH3).

[0678] Following the general procedure above, the polymers shown in Table 12 were obtained:

[0679] Table 12. Based on C 14 -PLys(Dimet) polymer (lipid PBet x )

[0680] Code Precursor <![CDATA[DP(n) of Lys(TFA)]]> a > LipidPBet5 LipidPBet3 5 LipoPBet6 LipoPBet4 36

[0681] a Determined by NMR, with the quoted DP numbers subject to reasonable uncertainties in the range ±20%.

[0682] 3.4 Incorporation of tert-butyl bromoacetate into C 14 - General Procedure for PLys(Dimet)

[0683]

[0684] The C obtained in Example 3.3 14 -PLys(Dimet) was dissolved in DMF (50 mg / mL). Then, tert-butyl bromoacetate (6 eq / lysine unit) was added to the reaction mixture and stirred at RT for 5 minutes. Thereafter, TBAI (0.5 eq / lysine unit) and DIPEA (3 eq / lysine unit) were added. The mixture was stirred for 16 hours at RT. The reaction mixture was concentrated by rotary evaporator and redissolved in DCM. The mixture was precipitated with diethyl ether, separated by centrifugation (3750 rpm, 4 min) and dried under vacuum. The product was used without further purification or characterization. Yield: 75%.

[0685] 3.5 General procedure for tert-butyl deprotection step:

[0686]

[0687] The protected lipid polymer C obtained in Example 3.4 14 -PBet was dissolved in cold trifluoroacetic acid (50 mg / mL) and stirred at RT for 24 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. The solid was redissolved in H2O, dialyzed with miliQ water (Mw cutoff of 3000 Da) for 24 h and lyophilized. The white solid polymer was isolated.

[0688] Yield: 70%. 1H NMR (300 MHz, D2O) δ 4.31 (m, CH), 4.05 (m, CH2), 3.70 (brs, CH2), 3.27 (s, CH3), 2.09-1.41 (m, CH2), 1.31 (m, CH2), 0.92 (t, J = 6.2 Hz, CH3).

[0689] Following the general procedure above, the polymers shown in Table 13 were obtained:

[0690] Table 13. Based on C 14 -PBet polymer (lipid PBet x )

[0691]

[0692] a Determined by NMR, with the quoted DP numbers subject to reasonable uncertainties in the range ±20%. b Determined by GPC, with the quoted DP numbers subject to reasonable uncertainties in the range ±20%. * Based on precursor.

[0693] Example 4. Synthesis of lipid-shielded DMPE (14:0)-PGA (diol)

[0694] 4.1 General Procedure for DMPE(14:0)-PGluOBzl Polymerization

[0695]

[0696] N-Carboxy-L-glutamic acid-benzyl-anhydride (NCA) was added to a Schlenk tube equipped with a stirring bar and a stopper. After 3 vacuum / N2 cycles, the monomer was dissolved in anhydrous DMF. Then, the initiator (1,2-dimyristoyl-sn-glycero-3-phosphoethanolamine, DMPE (14:0), Avanti Polar Lipids) was diluted in chloroform (5 mL) and added to the reaction mixture and stirred at room temperature for 16 hours. After confirming the consumption of NCA by IR, the reaction mixture was poured into diethyl ether to precipitate the product. The precipitate (DMPE (14:0)-PGlu (OBzl)) was separated by centrifugation (3750rpm, 4min) and dried under vacuum. Yield: 70-90%. 1H NMR (300 MHz, TFA) δ 8.08 (m, CH aryl), 5.93 (m, CH 2 benzyl), 5.49 (brs, CH ), 3.56-2.71 (m, CH 2 ), 2.49 (m, CH 2 ), 2.08 (m, CH 2 ), 1.64 (t, J = 6.6 Hz, CH 3 ).

[0697] Following the general procedure above, the polymers shown in Table 14 were obtained:

[0698] Table 14. Polymers based on DMPE (14:0)-PGlu (OtBu) (lipid PGA x )

[0699]

[0700] a Confirmed by NMR. b Determined by GPC, with the quoted DP numbers subject to reasonable uncertainties in the range ±20%.

[0701] 4.2 General procedure for the deprotection step:

[0702]

[0703] The lipopolymer DMPE (14: 0) -PGlu (OBzl) obtained in Example 4.1 was dissolved in trifluoroacetic acid (100 mg / mL), and HBr 48% (2eq / glutamic acid unit) was added. The mixture was stirred for 16 hours at RT. The reaction mixture was poured into diethyl ether to precipitate the product. The precipitate was washed with a mixture of acetonitrile: H2O (8: 2) until pH 4-5. Then, the product was washed with diethyl ether, separated by centrifugation (3750rpm, 4min) and dried under vacuum.

[0704] The polymer (DMPE (14:0)-PGA) was isolated as a white solid. Yield: 80%.

[0705] 1 H NMR(300MHz,D2O)δ4.47-3.80(m,CH),2.45-1.76(m,CH2),1.57(brs,CH2),1.24(m,CH2),0.83(t,J=6.55Hz,CH3).

[0706] Following the general procedure above, the polymers shown in Table 15 were obtained:

[0707] Table 15. DMPE (14:0)-PGA based polymers (lipid PGA x )

[0708] Code Precursor <![CDATA[DP(n) of Glu(ONa)]]> a > Lipopolysaccharide GABA11 Lipid PGA9 30 Lipid PGA12 Lipid PGA10 21

[0709] a Confirmed by NMR.

[0710] 4.3 General procedure for coupling peptides with CDI to synthesize DMPE(14:0)-PGA(diol)

[0711]

[0712] Following the above procedure in Example 1.4, 3-aminopropane-1,2-diol was introduced into the side chain of DMPE(14:0)-PGA obtained in Example 4.2 to generate the corresponding DMPE(14:0)-PGA(diol).

[0713] Yield: 60-70%. 1 H NMR(300MHz,D2O)δ4.38(brs,CH),3.87(brs,CH),3.63(ddd,J=18.2,12.0,5.5Hz,CH2), 3.35(ddd,J=21.1,14.1,5.7Hz,CH2),2.681.92(m,CH2),1.34(brs,CH2),0.94(s,CH3).

[0714] Following the general procedure above, the polymers shown in Table 16 were obtained:

[0715] Table 16. Polymers based on DMPE (14:0)-PGA (diol) (lipid PGA x )

[0716]

[0717] a Confirmed by NMR. b Determined by GPC, with the quoted DP numbers subject to reasonable uncertainties in the range ±20%.

[0718] Example 5. Lipid shielding of Dimyrist-GABA-PGA(diol) n Synthesis

[0719]

[0720] 5.1 General procedure for the synthesis of initiator (y)

[0721]

[0722] 5.1a. General procedure for the synthesis of tert-butyl (4-(ditetradecylamino)-4-oxobutyl)carbamate.

[0723]

[0724] Boc-GABA-OH (4-(Boc-amino)butyric acid: 400 mg, 1.968 mmol) was dissolved in DCM (9 mL). HOBt (1.1 eq, 2.16 mmol, 292 mg) and dicyclohexylcarbodiimide (DCC) (1.1 eq, 2.16 mmol, 447 mg) were added to the reaction mixture, and the solution was stirred for 30 minutes at rt. Then, Dimyrist (ditetradecylamine: 1.1 eq, 2.16 mmol, 885 mg) was added, and the reaction mixture was stirred for 16 hours at room temperature. The completion of the reaction was monitored by TLC. The reaction was filtered, and the filtrate was concentrated to dryness using rotary evaporation. The crude material of the reaction was then purified by rapid column chromatography using hexane: ethyl acetate (8:2) as eluent. The obtained product was concentrated to dryness, and a light yellow oil was isolated (m obtained: 1.12 g). Yield: 95%.

[0725] 1 H NMR(300MHz,CHCl3)δ4.84(brs,CH),3.27(m,CH2),3.17(dd,J=13.6,6.4Hz,CH2),2.32(t,J=7Hz,CH 2),1.82(p,J=6.6Hz,CH),1.57-1.46(m,CH2),1.42(s,CH3),1.26(brs,CH2),0.87(t,J=6.7Hz,CH3).

[0726] 5.1b. General procedure for the deprotection step.

[0727]

[0728] Tert-butyl (4-(ditetradecylamino)-4-oxobutyl)carbamate was dissolved in DCM (9 mL) and TFA was added dropwise to the reaction mixture at 0°C. The reaction mixture was stirred for 16 h at RT. The crude reaction was then dried using rotary evaporation and used in subsequent reactions without prior purification. Yield: 100%.

[0729] 1 H NMR(300MHz,CHCl3)δ7.80(brs,NH2),3.26-2.93(m,CH2),2.55(brs,CH2),1.93(brs,CH),1.46(m,CH2),1.19(brs,CH2),0.81(t,J=6.7Hz,CH3).

[0730] 5.2 General Procedure for Dimyrist-GABA-PGlu(OBzl) Polymerization

[0731]

[0732] Glutamic acid benzyl ester NCA (1.33 g, 10.29 mmol) was added to a Schlenk tube equipped with a stirring bar and a stopper. After 3 vacuum / N2 cycles, the mixture was dissolved in anhydrous DMF (150 mg reagent / mL DMF). Then, the initiator (Dimyrist-GABA-NH3TFA.:DP20:254 mg, 0.51 mmol) was diluted in DMF (5 mL), and DIPEA (1 eq, 0.51 mmol, 896 μL) was added to the initiator solution. Then, the initiator solution was added to the reaction mixture and stirred at 10 ° C for 16 hours. After confirming the consumption of NCA by IR, the reaction mixture was poured into diethyl ether to precipitate the product. The precipitate was separated by centrifugation (3750 rpm, 4 min) and dried under vacuum. White solid homopolymer (Dimyrist-GABA-PGluOBzl) was isolated. Yield: 70-90%.

[0733] 1 H NMR (300 MHz, TFA) δ 7.36 (m, CH aryl), 5.35 (m, CH 2 benzyl), 4.78 (m, CH ), 3.66 (m, CH 2 ), 2.92-1.98 (m, CH 2 ), 1.84 (d, J = 7.7 Hz, CH 2 ), 1.53-1.30 (m, CH 2 ), 0.82 (t, J = 5.9 Hz, CH 3 ).

[0734] Table 17. Polymers based on Dimyrist GABANH2-PGlu (lipid PGA x )

[0735]

[0736]

[0737] a Confirmed by NMR. b Determined by GPC, with the quoted DP numbers subject to reasonable uncertainties in the range ±20%.

[0738] 5.3 General procedure for the deprotection step:

[0739]

[0740] The lipopolymer Dimyrist-GABA-PGlu(OBzl)-COCH3 (1.g, 4.8mmol) obtained in Example x.2 was dissolved in trifluoroacetic acid (100mg / mL) and HBr 48% (2eq / glutamic acid unit) was added. The mixture was stirred for 16 hours at RT. The reaction mixture was poured into diethyl ether to precipitate the product. The precipitate was washed with a mixture of acetonitrile:H2O (8:2) until pH 4-5. Then, the product was washed with diethyl ether, separated by centrifugation (3750rpm, 4min) and dried under vacuum. A white solid polymer (Dimyrist-GABA-PGA) was isolated.

[0741] Yield: 95%. 1 H NMR(300MHz,D2O)δ4.92(m,CH),3.70(m,CH3),3.13-2.08(m,CH2),1.87(brs,CH2),1.44(m,CH2),0.94(brs,CH3).

[0742] Table 18. Dimyrist GABA-PGA based polymers (lipid PGAn)

[0743] Code Precursor <![CDATA[DP(n) of Glu(ONa)]]> a > Lipid PGA17 Lipid PGA15 15 Lipid PGA18 Lipopolysaccharide GABA16 67

[0744] a Determined by NMR, with the quoted DP numbers subject to reasonable uncertainties in the range ±20%.

[0745] 5.4 Synthesis of C by coupling peptide with CDI 14 -PGA(DIOL) n general procedure.

[0746]

[0747] Dimyrist-GABA-PGA (PGADIOL 0.4 g, 3.3 mmol) obtained in Example 5.3 was dissolved in DMF (50 mg / mL). Then, CDI (1.6 eq / glutamic acid unit) was added to the reaction mixture and stirred at room temperature for 30 minutes. Thereafter, 3-aminopropane-1,2-diol (1.3 eq / glutamic acid unit) dissolved in 2 ml of DMF was added. The mixture was stirred at room temperature for 16 hours. The reaction mixture was poured into acetone to precipitate the product. The precipitate was separated by centrifugation (3750 rpm, 4 min) and dried under vacuum. The white solid final product was isolated. Yield: 50-60%.

[0748] 1H NMR(300MHz,D2O)δ4.33(brs,CH),3.88(brs,CH),3.71-3.49(m,CH2),3.43-3.20(m,CH2),2.98(dd,J= 13.2,3.5Hz,CH2),2.83(dd,J=13.2,8.5Hz,CH2),2.56-1.91(m,CH2),1.30(brs.CH2),0.90(brs,CH3).

[0749] Table 19. Polymers based on end-capped Dimyrist-GABA-PGA(diol) (lipid PGAn)

[0750]

[0751] a Confirmed by NMR. b Determined by GPC, with the quoted DP numbers subject to reasonable uncertainties in the range ±20%.

[0752] Example 6. Lipid Nanoparticle Formulation

[0753] In the following examples, the oligonucleotides used were: pDNA purchased from PlasmidFactory (reference PF461 (pCMV-luc), which contains 6233 bp expressing luciferase) and mRNA purchased from Trilink (reference L-1201-1000CleanCap Fluc mRNA (5moU), which expresses luciferase as a reporter gene). Any other oligonucleotides having the above characteristics can be used to perform the following experiments.

[0754] Ionizable lipids DLin-MC3-DMA, or (6Z,9Z,28Z,31Z)-triacontriacontane-6,9,28,31-tetraen-19-yl 4-(dimethylamino)-butyrate were purchased from Nanosoft Polymers. The shielding lipid 1,2-dimyristoyl-rac-glycero-3-methoxypolyethylene glycol-2000 (DMG-PEG2000) was purchased from Avanti Polar Lipids. Both polymers were used to form benchmark LNPs. The 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).

[0755] LNP 1-12 was prepared using a microfluidic HerringboneMixer from Darwing Microfluidics. The reactor presented two inlet channels (one for DNA in aqueous phase and the other for lipid mixture in ethanol) and one outlet channel. The specifications of the mixer were as follows:

[0756] Slide format: 25 x 75m

[0757] Channel depth: 0.08mm

[0758] Channel width: 0.1 to 0.5 mm

[0759] Volume: 3.3 μL

[0760] Volume mixer: 0.47 μL

[0761] Length mixer: 28.7mm

[0762] Material: Glass

[0763] Connector: 1 / 4″-28 fittings

[0764] In addition, two programmable pumps control the fluid flow rate of the syringe (NE-1000 programmable single syringe pump, SyringePump, USA). The system accepts an infusion rate of 0.73 μL / h (1mL syringe) to 2100mL / h (60mL syringe). This method provides the reproducibility of LNP formation and the possibility of scaling up the process. The benchmark LNP is formulated as follows:

[0765] Dissolve lipids in ethanol at a molar ratio of 50 / 10 / 38.5 / 1.5 (MC3 / DSPC / cholesterol / DMG-PEG)

[0766] Dilute pDNA in 25 mM acetate buffer, pH 4

[0767] The ratio of amine to phosphoric acid (N / P) is 4

[0768] Flow ratio is 3:1 (ethanol: H2O)

[0769] Total flow rate is 2mL / min

[0770] The inner diameter of the tube is 0.5mm

[0771] After formulation, LNPs were diluted in 10 mM phosphate buffered saline (PBS) at pH 7.4 and concentrated using a centrifugal concentrator (Vivaspin TM 500, Sigma) was concentrated to remove ethanol

[0772] Formulations containing the lipopolyamino acid conjugate of formula (I) were prepared similarly, except that the lipopolyamino acid conjugate of formula (I) was used instead of DMG-PEG and the lipid ratio was different (as shown below).

[0773] Benchmark LNP 13-17 was formulated using the NanoScaler (KNAUER) as follows:

[0774] • Lipids were dissolved in ethanol at a molar ratio of 46.3 / 9.4 / 42.7 / 1.6 (ALC-0315 / DSPC / cholesterol / DMG-PEG).

[0775] Dilute mRNA in 25 mM acetate buffer, pH 4

[0776] The ratio of amine to phosphoric acid (N / P) is 6.2

[0777] Flow ratio is 1:3 (ethanol: H2O)

[0778] Total flow rate of LNP is 4.5 mL / min (3 mL / min undiluted LNP + 1.5 mL / min PBS in-line dilution)

[0779] After formulation, LNPs were further diluted in 10 mM phosphate buffered saline (PBS) at pH 7.4 to reduce the ethanol concentration and concentrated using a centrifugal concentrator (Vivaspin TM 500, Sigma) to remove ethanol. Formulations containing polymers of the invention were similarly prepared except that a different lipid PAA was used instead of the shielding lipid DMG-PEG and the lipid ratios were different (as shown in Tables 27 and 28 below).

[0780] Example 7. LNP Characterization

[0781] 7.1 Size and polydispersity

[0782] The size and polydispersity (PDI) of formulated LNPs containing different N / P ratios (positively charged polymer amine (N=nitrogen) groups: negatively charged nucleic acid phosphate (P)), mRNA or pDNA of different molar ratios and shielding polymers were measured using a Malvern ZetasizerNanoZS instrument equipped with a 532 nm laser and a fixed scattering angle of 173°. 50 μl of sample was measured using a quartz glass high performance cuvette (Hellma Analytics). Size distribution (diameter, nm) was measured with n≥3 measurements.

[0783] Benchmark LNPs containing MC3 as ionizable lipid, DMG-PEG as shielding lipid and mRNA as cargo were formulated at a MC3 / DSPC / cholesterol / DMG-PEG molar ratio of 50 / 10 / 38.5 / 1.5 and the following results were obtained:

[0784] Table 20. Size and PDI of comparative benchmark LNPs containing mRNA

[0785]

[0786]

[0787] The presence of 1.5% DMG-PEG was sufficient to stabilize the LNPs, resulting in good size (expressed as Z-average) and PDI as well as reproducible formulations.

[0788] Table 21 shows the results obtained with lipid PAA1 comprising pDNA as cargo formulated at 2% and 5% molar ratios.

[0789] Table 21. Size and PDI of LipoPAA1 LNPs containing pDNA.

[0790]

[0791] The results showed that 2% lipid PAA1 achieved consistent best results in all replicates, showing low PDI values ​​and appropriate size. This composition was also used to formulate LNPs containing mRNA that achieved low PDI values ​​and appropriate size (Table 22).

[0792] Table 22. Size and PDI of LipoPAA1 LNPs containing mRNA.

[0793]

[0794] Table 23 shows the results obtained with lipid PAA2 formulated at 5% molar ratio containing pDNA as cargo.

[0795] Table 23. Size and PDI of LipoPAA2 LNPs containing pDNA.

[0796]

[0797] In this case, the results showed that the best results were achieved at 5% lipid PAA2. In addition, when 5% polymer was used, the results were consistent in all replicates, showing low PDI values ​​and appropriate size. This composition was also used to formulate LNPs containing mRNA that obtained low PDI values ​​and appropriate size (Table 24).

[0798] Table 24. Size and PDI of LipoPAA2 LNPs containing mRNA.

[0799]

[0800] Table 25 shows the results obtained with lipid PAA7 formulated at 5% molar ratio directly containing mRNA as cargo.

[0801] Table 25. Size and PDI of lipopA7 LNPs containing mRNA.

[0802]

[0803] Since lipid PAA9 is similar to lipid PAA1, Table 26 shows the results obtained by directly including mRNA as cargo at a 2% molar ratio.

[0804] Table 26. Size and PDI of LipoPAA9 LNPs containing mRNA.

[0805]

[0806] ALC-0315 / DSPC / cholesterol / DMG-PEG or C 14 Benchmark LNPs containing ALC-0315 as ionizable lipid, DMG-PEG as shielding lipid and mRNA as cargo were formulated with a PSar molar ratio of 46.3 / 9.4 / 44.3-x / x and the following results were obtained:

[0807] Table 27. Comparative benchmark DMG-PEG and C containing mRNA formulated at 1.6 and 5% molar ratios, respectively. 14 -Size and PDI of PSarLNP:

[0808]

[0809] LNPs were obtained with good size (expressed as Z-average) and PDI and reproducible formulation.

[0810] Table 28 shows the results obtained for LipoPAA1, LipoPAA8 and LipoPAA10 formulated at a molar ratio of 2% containing mRNA as cargo:

[0811] Table 28. Size and PDI of lipid PAALNPs containing mRNA.

[0812]

[0813]

[0814] The results showed that at 2% LipoPAA1, LipoPAA8, and LipoPAA10 were consistent in all replicates, showing low PDI values ​​and appropriate sizes.

[0815] 7.2 Detection of free oligonucleotides by gel electrophoresis

[0816] Electrophoresis gel was used as the first screening method to evaluate the possible presence of free pDNA or mRNA after LNP preparation. For electrophoresis, an E-gel Power Snap electrophoresis instrument and an E-Gel Power Snap camera (Invitrogen) were used. According to the manufacturer's instructions, a prepared 2% agarose gel was used, which included a SYBR Gold DNA marker (E-Gel TM EXAgarose Gels, 2%, Invitrogen). Evaluation Figure 1 LNPs (20 μl) composed of different lipopeptide shieldings and the disintegration of LNPs in the presence of 10% triton X-100 (Scharlab, SL) and 2 mg / mL heparin (PanReac AppliChem, Spain) are shown in Figure 1. After gel loading (20 μl / well), the device protocol was selected according to the type of gel used (in our case, the protocol was approximately 10 min, but the time can be modified according to the sample).

[0817] In all cases, no free mRNA was observed when different lipopolypeptide shields were tested. However, when 10% Triton X-100 was used, free mRNA signal was observed due to the ability of Triton X-100 as a surfactant to decompose the different components of the LNP and thus release the LNP cargo (representative images of the gel can be found at Figure 1 observed in ).

[0818] 7.3 pKa of formulated LNPs

[0819] The positively charged amino groups in the nanoparticles depend on the pH of the medium, and the apparent pKa predicts these changes. The impact of lipopeptides on the LNP surface can change this apparent pKa and thus affect the transfection efficiency. The LNP apparent pKa value was determined by measuring the fluorescence of 2-(p-toluidino)-6-naphthalenesulfonic 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; and from pH 8 to 9 (0.5 pH unit increments) with 20 mM borate buffer. The formulations were diluted to 20 μM lipid concentration with different buffer solutions and added to black 96-well plates. TNS solution (0.3 mM in DMSO) was added to a final concentration of 6 μM. At λ em =445nm,λ ex The fluorescence was quantified at 50 nm and the pH at half-maximum fluorescence intensity was defined as pKa.

[0820] Table 29. Different parameters for LNPs formulated with lipopolypeptides. The total flow rate used was 2 mL / min. The N / P ratio was 4.

[0821]

[0822] The pKa of LNPs formulated with lipid PAA1 and lipid PAA2 were similar to the benchmark LNPs, which were comprised between 6.2 and 6.7. This range of pKA is reported to be ideal for obtaining optimal performance of LNPs.

[0823] Example 8. In vitro biological studies of HeLa cells

[0824] 8.1 Cell culture

[0825] HeLa cells were cultured in DMEM high glucose supplemented with 10% fetal bovine serum (Hyclone #SV30160.03HI, provided by GE Healthcare Europe GmbH) and 1% penicillin / streptomycin containing Glutamax (Gibco-Thermo Fisher #61965-059). Transfection was performed on a 96-well plate containing 10,000 cells / well in a final volume of 100 μl, and the cells were incubated for 24 hours at 37°C and 5% CO2. After 24 h from cell inoculation, the medium was removed and replaced with 90 μl complete medium. 10 μl of each LNP formulation was added to the cells. In the positive control (Lipofectamine TM 2000TransfectionReagent,Invitrogen TM ) were followed according to the manufacturer's guidelines. After 24 hours, the cells were recovered and processed.

[0826] 8.2 ATP Assessment for Cytotoxicity Assessment

[0827] After 24 h of incubation with the LNP formulation, the culture medium was aspirated and 50 μl / well of ATPLite reagent (ATPLite PerkinElmer #6016731) was added. The plate was incubated for 10 minutes in the dark at room temperature. Victor Nivo (PerkinElmer) was used according to the manufacturer's instructions, and the luminescence was read spectrophotometrically, and the data were expressed as a percentage of cell viability, with untreated control cells being taken as 100%.

[0828] 8.3 Luciferase Assay for Transfection Efficiency Assessment

[0829] After 24h of incubation with LNP formulations, 100 μl of BrightGlo reagent (Promega # E2620) was added to each well according to the manufacturer's instructions. After incubation for 5 minutes at room temperature, luciferase activity was measured using Victor Nivo (Perkin Elmer). Data are expressed as luminescence relative to the transfection percentage relative to the transfection positive control.

[0830] 8.4 Bioactivity of LNP in HeLa cells

[0831] The following table reports the transfection efficiency and cell viability of LNP formulations in HeLa cells. Transfection data are presented as positive control Lipofectamine after 24 h of treatment. TM 2000 (positive control, 100%), and cell viability was compared to that of untreated (NT) cells (ATP content reading of NT (untreated) cells, equal to 100%).

[0832] Table 30. Different parameters of LNPs formulated with lipopolypeptides. The molar ratio was 50 / 10 / 40-x / x, where x is the lipopolypeptide. The total flow rate used was 2 mL / min. The N / P ratio was 4 and the nucleic acid content was 1 μg mRNA / well.

[0833]

[0834] According to these results, the transfection obtained from the two LNPs containing PGADIOL derivatives was higher than those containing DMG-PEG. In addition, the efficiency of cells transfected by the compound LipoPAA1 was 2.5 times that of the gold standard Lipofectamine. Therefore, it can be concluded that by adding LipoPAA to LNPs, the following results are obtained: i) stable nanoparticles with acceptable size and polydispersity; ii) non-cytotoxic formulation, and iii) high transfection efficiency. These results show that the LipoPAA presented in this application can replace the actual DMG-PEG compound.

[0835] Example 9. In vitro biological studies of HEK293 cells

[0836] 9.1 Cell culture

[0837] HEK293 cells were cultured in DMEM high glucose supplemented with 10% fetal bovine serum (Hyclone #SV30160.03HI, provided by GE Healthcare Europe GmbH) and 1% penicillin / streptomycin containing Glutamax (Gibco-Thermo Fisher #61965-059). Transfection was performed on a 96-well plate containing 30,000 cells / well in a final volume of 100 μl, and the cells were incubated for 24 hours at 37°C and 5% CO2. After 24 hours from cell inoculation, the culture medium was removed and replaced with 90 μl complete culture medium. 10 μl of each LNP preparation was added to the cells. After 24 hours, the cells were recovered and processed.

[0838] 9.2 ATP Assessment for Cytotoxicity Assessment

[0839] After 24 h of incubation with the LNP formulation, the culture medium was aspirated and 50 μl / well of ATPLite reagent (ATPLite PerkinElmer #6016731) was added. The plate was incubated for 10 minutes in the dark at room temperature. Victor Nivo (PerkinElmer) was used according to the manufacturer's instructions, and the luminescence was read spectrophotometrically, and the data were expressed as a percentage of cell viability, with untreated control cells being taken as 100%.

[0840] 9.3 Luciferase Assay for Transfection Efficiency Assessment

[0841] After 24h of incubation with LNP formulations, 100 μl of BrightGlo reagent (Promega # E2620) was added to each well according to the manufacturer's instructions. After incubation for 5 minutes at room temperature, luciferase activity was measured using Victor Nivo (Perkin Elmer). Data are expressed as luminescence relative to the transfection percentage relative to the transfection positive control.

[0842] 9.4 Bioactivity of LNPs in HEK293 cells

[0843] The following table reports the transfection efficiency and cell viability of LNP formulations in HEK293 cells. Transfection data are expressed as a percentage of the positive control DMG-PEG (where formulations, reported as ALC-0315 / DSPC / cholesterol / DMG-PEG or lipid PAA - i.e. x, with a molar ratio of 46.3 / 9.4 / 44.3-x / x, with different molar ratios for each lipid PAA used, and positive control, 100%) after 24 h of treatment, and cell viability is compared to untreated (NT) cells (reading of ATP content of NT (untreated) cells, equal to 100%).

[0844] Table 31. Different parameters of LNPs formulated with lipopolypeptides. The molar ratio was 46.3 / 9.4 / 44.3-x / x, where x is the lipopolypeptide. The total flow rate used was 3+1.5 mL / min. The N / P ratio was 6.17, and the nucleic acid content was 50, 150 and 300 ng mRNA / well. The transfection percentage was calculated considering the formulation ALC-0315 / DSPC / cholesterol / DMG-PEG 46.3 / 9.4 / 42.7 / 1.6:

[0845]

[0846]

[0847] According to these results, the transfection obtained from LNPs containing LipoPAA1 and LipoPAA8 and LipoPAA10 was higher than those containing DMG-PEG and the PEG surrogate C14-PSar. In addition, it is noteworthy that the structurally different conjugates transfected cells 1.9 to 3.3 times (LipoPAA1), 3.1 to 3.3 times (LipoPAA8), and 3.3 to 5.1 times (LipoPAA10) more efficiently than the commercial standard DMG-PEG at different concentrations, while C14PSar showed only comparable transfection to DMG-PEG.

[0848] Therefore, it can be concluded that by adding lipoPAA to LNPs, the following results are obtained: i) stable nanoparticles with acceptable size and polydispersity; ii) non-cytotoxic formulation, and iii) high transfection efficiency. These results demonstrate that the lipoPAA presented in this application can replace the actual DMG-PEG compound as well as C 14 P.S.ar.

[0849] Example 10. In vivo transfection ability of LNP

[0850] 10.1 Experimental Details

[0851] All animal experiments were performed in accordance with approved animal experimental protocols. For in vivo mRNA transfection, Comp.LNP13 and LNP15 (n=3-5) were administered intravenously (IV) to 6-week-old male Balb / c mice. 4h and 24h after injection of Comp.LNP13 (n=4) and LNP15 (n=5), mice were injected subcutaneously with luciferin (15mg / kg), and 10 minutes later, mice were euthanized by CO2 inhalation, and organs (blood, liver, spleen, lung, kidney and ALN (axillary lymph node)) were dissected. Image acquisition was obtained by IVIS Spectrum (settings: Binning factor 8F / Stop 1Exp AUTO FOV 22,5 (D)). The weight of different organs was obtained and then frozen with N2 and -80°C. Image analysis was performed by Living Image 4.5.4 (settings: ROI (automatic drawing, threshold 2%), and data are expressed as total counts / tissue g.

[0852] 10.2 In vivo transfection results

[0853] The mice were weighed after administration of different formulations, and the following results in Table 32 were obtained:

[0854] Table 32. Body weight (g) of mice administered formulations iv at time 4h and 24h.

[0855]

[0856] The body weight of mice was maintained in the range of 20-22 g and showed no significant difference. Image analysis of different organs dissected by Living Image 4.5.4 showed Figure 2 The total counts per g of tissue shown in . Statistical analysis performed by Kruskal-Wallis test determined that Comp.LNP13 (containing DMG-PEG) at 4h had no significant difference with Comp.LNP13 24h and LNP15 4h in liver (A). Organ BD (ALN, spleen and lung, respectively) showed no significant difference between Comp.LNP13 and LNP15. Therefore, the transfection capacity between the positive control (Comp.LNP13) and LNP15 at 4h had comparable results.

[0857] Citation List

[0858] -Nogueira S. et al., "Polysarcosine-Functionalized Lipid Nanoparticles for Therapeutic mRNA Delivery", ACS Appl. Nano Mater., 2020, 3, 10634-10645

[0859] -TWGreen and PGMWuts,Protective Groups in Organic Chemistry,Wiley,3rd ed.1999,Chapter 5(pp.369-451)

[0860] -TWGreen and PGMWuts,Protective Groups in Organic Chemistry,Wiley,3rd ed.1999,Chapter 7(pp.495-653)

[0861] For reasons of completeness, various aspects of the invention are set out in the following numbered clauses:

[0862] Item 1. A lipopolyamino acid conjugate of formula (I), a salt thereof, or any stereoisomer or mixture of stereoisomers of any one of the compounds of formula (I) or their salts,

[0863]

[0864] in

[0865] n is an integer from 5 to 250; m is 0 or 1;

[0866] X is selected from N, S and O;

[0867] R1 is selected from H, -(C1-C 18 )alkyl and -(C2-C 18 )alkenyl, provided that when X is O or S, R1 is absent;

[0868] R2 is a free radical selected from (II), (III), (IV) and (V),

[0869] Wherein: a, b, c and d are independently integers from 1 to 4;

[0870] R3 is H or -(C1-C6)alkyl;

[0871] A is selected from H, -(C1-C6)alkyl, -CO(C1-C6)alkyl, -(C5-C 10)aryl, -(C5-C 10 )heteroaryl, -(C6-C 10 )aralkyl, -(C1-C6)alkyl-O-(C5-C 10 )aryl, -(C5-C 10 ) heterocycloalkyl, protecting group, free radical R4, lipid-like part R5 and active part; A is optionally substituted by one or more groups selected from the following: -OH, halogen, -CF3, -NH2, -NH-(C1-C4) alkyl, -NH-CO-(C1-C6) alkyl, -(C1-C6) alkyl, -NO2, -N3, -CO-(C1-C6) alkyl, -CO-O-(C1-C6) alkyl, -SO3H, -SO2NH2, -SO2-N((C1-C6)

[0872] -CON((C1-C6)alkyl)2;

[0873] A' is selected from H, -OH, -(C1-C6)alkyl, -(C5-C 10 )aryl, -(C5-C 10 )heteroaryl, -(C6-C 10 )aralkyl, -(C1-C6)alkyl-O-(C5-C 10 )aryl, -(C5-C 10 )heterocycloalkyl, -(C1-C 10 )alkoxy, -(C6-C 10 ) aryloxy, -(C6-C 10 )aralkyloxy, -(C5-C 10 )heteroaralkyloxy, -(C1-C 10 )alkyl-O-(C6-C 10 ) aryloxy, amino protecting group, free radical R4', lipid-like part R5', amino acid-like part R6 and active part; A' is optionally substituted by one or more groups selected from the following: -OH, halogen, -CF3, -NH2, -NH-(C1-C4) alkyl, -NH-CO-(C1-C6) alkyl, -(C1-C6) alkyl, -NO2, -N3, -CO-(C1-C6) alkyl, -CO-O-(C1-C6) alkyl, -SO3H, -SO2NH2, -SO2-N((C1-C6) alkyl)2, -COOH, CONH2 and -CON((C1-C6) alkyl)2; Provided that:

[0874] i) when m is 0, A' is selected from H, -(C1-C6)alkyl, -(C5-C 10 )aryl, -(C5-C 10 )heteroaryl, -(C6-C10 )aralkyl, -(C1-C6)alkyl-O-(C5-C 10 )aryl, -(C5-C 10 ) a heterocycloalkyl group, an amino protecting group, an amino acid-like portion R6 and an active portion; and

[0875] When m is 1, A' is selected from H, -OH, -(C1-C6)alkyl, -(C5-C 10 )aryl, -(C5-C 10 )heteroaryl, -(C6-C 10 )aralkyl, -(C1-C6)alkyl-O-(C5-C 10 )aryl, -(C5-C 10 )heterocycloalkyl, -(C1-C 10 )alkoxy, -(C6-C 10 ) aryloxy, -(C6-C 10 )aralkyloxy, -(C5-C 10 )heteroaralkyloxy, -(C1-C 10 )alkyl-O-(C6-C 10 ) an aryloxy group, a free radical R4', a lipid-like portion R5' and an active portion; and

[0876] ii) at least one of A and A' is a lipid-like moiety R5 or R5';

[0877] R4 is a free radical of formula (VIa);

[0878] R4' is a free radical of formula (VIb);

[0879] in:

[0880] n' is an integer from 5 to 250; m' is 0 or 1;

[0881] X” is selected from N, S and O;

[0882] R1" is a free radical having any of the meanings of R1, provided that when X" is O or S, R1" is absent;

[0883] R2' is a radical having any of the meanings of R2;

[0884] R3' is a radical having any of the meanings of R3;

[0885] B and B' are independently S or CH2;

[0886] e and f are independently an integer from 1 to 18;

[0887] A" is selected from H, -OH, -(C1-C6)alkyl, -(C5-C 10)aryl, -(C5-C 10 )heteroaryl, -(C6-C 10 )aralkyl, -(C1-C6)alkyl-O-(C5-C 10 )aryl, -(C5-C 10 )heterocycloalkyl, -(C1-C 10 )alkoxy, -(C6-C 10 ) aryloxy, -(C6-C 10 )aralkyloxy, -(C5-C 10 )heteroaralkyloxy, -(C1-C 10 )alkyl-O-(C6-C 10 ) aryloxy, amino protecting group, lipid-like part R5 ', amino acid-like part R6 and active part; A "is optionally substituted by one or more groups selected from the following: -OH, halogen, -CF3, -NH2, -NH-(C1-C4) alkyl, -NH-CO-(C1-C6) alkyl, -(C1-C6) alkyl, -NO2, -N3, -CO-(C1-C6) alkyl, -CO-O-(C1-C6) alkyl, -SO3H, -SO2NH2, -SO2-N((C1-C6) alkyl)2, -COOH, CONH2 and -CON((C1-C6) alkyl)2;

[0888] The conditions are:

[0889] When m' is 0, A" is selected from H, -(C1-C6)alkyl, -(C5-C 10 )aryl, -(C5-C 10 )heteroaryl, -(C6-C 10 )aralkyl, -(C1-C6)alkyl-O-(C5-C 10 )aryl, -(C5-C 10 ) a heterocycloalkyl group, an amino protecting group, an amino acid-like portion R6 and an active portion; and

[0890] When m' is 1, A" is selected from H, -OH, -(C1-C6)alkyl, -(C5-C 10 )aryl, -(C5-C 10 )heteroaryl, -(C6-C 10 )aralkyl, -(C1-C6)alkyl-O-(C5-C 10 )aryl, -(C5-C 10 )heterocycloalkyl, -(C1-C 10 )alkoxy, -(C6-C 10 ) aryloxy, -(C6-C 10 )aralkyloxy, -(C5-C 10 )heteroaralkyloxy, -(C1-C10 )alkyl-O-(C6-C 10 )Aromatic Oxygen

[0891] A base, a lipid-like portion R5' and an active portion; and

[0892] A"' is selected from H, -(C1-C6)alkyl, -CO(C1-C6)alkyl, -(C5-C 10 )aryl, -(C5-C 10 )heteroaryl, -(C6-C 10 )aralkyl, -(C1-C6)alkyl-O-(C5-C 10 )aryl, -(C5-C 10 ) heterocycloalkyl, protecting group, lipid-like part R5 and active part; A "' is optionally substituted by one or more groups selected from the following: -OH, halogen, -CF3, -NH2, -NH-(C1-C4) alkyl, -NH-CO-(C1-C6) alkyl, -(C1-C6) alkyl, -NO2, -N3, -CO-(C1-C6) alkyl, -CO-O-(C1-C6) alkyl,

[0893] -SO3H, -SO2NH2, -SO2-N((C1-C6)alkyl)2, -COOH, CONH2 and -CON((C1-C6)alkyl)2; each R5 is independently selected from -(C1-C 18 )alkyl, -(C2-C 18 ) alkenyl and a radical of formula (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XXI), (XXII) or (XXIII),

[0894] Each R5' is independently selected from -X'(R1')-(C1-C 18 )alkyl, -X'(R1')-(C2-C 18 )alkenyl and a radical of formula (VII'), (VIII'), (IX'), (X'), (XI'), (XII'), (XIII'), (XIV'), (XXI'), (XXII') or (XXIII'),

[0895] in:

[0896] Y and Y' are independently selected from -OH, -OCORx and -COORx;

[0897] Q and Q' are independently selected from -OCORy and -COORy;

[0898] Z and Z' are independently selected from -OCO-, -COO-, -NRz'CO- and -CONRz'-;

[0899] Each Rz' is H or Rz;

[0900] Each of Rx, Ry and Rz is independently -(C1-C 18 )alkyl or -(C2-C 18 )alkenyl;

[0901] Each g is independently an integer from 0 to 18;

[0902] Each h is independently an integer from 1 to 18;

[0903] i is an integer from 0 to 18;

[0904] Each j is independently an integer from 0 to 18;

[0905] X' is selected from N, S and O;

[0906] R1′ is a free radical having any of the meanings of R1, provided that when X′ is O or S, R1′ is absent;

[0907] t is 0 or 1, provided that when X=0, t is 0, and when X is not 0, t is 1;

[0908] t' is 0 or 1; provided that when m is 0, t' is 1;

[0909] R 22 , R 33 and R 44 independently selected from hydrogen, fluorine, methyl, -CH2F, -CHF2 and -CF3;

[0910] Each of the dashed bonds ----- is independently a single bond, or, alternatively, a double bond;

[0911] L is a diradical chain comprising one or more moieties selected from the group consisting of: -CH=CH-, -C≡C-, -CH2-,

[0912] -N=CH-, -CH=NH-, -NH-, -NH-NH-, -NH-N=CH-, -O-, -O(CH2)O-, -CO-, -O(CO)-,

[0913] -(CO)O-, -C(=CH2)-, -C(=NH)-, -CONH-, -NHCO-, -NH(CO)NH-, -S-, -SS-,

[0914] -SO-, -SO2-, -SO2NH2- and -phenylene-, wherein L is optionally substituted with one or more substituents selected from the group consisting of halogen, -OH, -NR a Rb 、-SH、-NHNH2、-COOR c , -CF3, -OCF3,

[0915]

[0916] Wherein when L includes a -CH2- moiety, the two hydrogen atoms attached to the carbon atom are optionally replaced by the following ring:

[0917]

[0918] and

[0919] Each R6 is a radical independently selected from (XV), (XVI) and (XVII)

[0920] wherein a', b' and c' are independently integers from 1 to 4;

[0921] Each active moiety is independently selected from the group consisting of pharmaceutically active agents, penetration enhancers, cell targeting agents, cosmetic active agents, and diagnostic active agents.

[0922] Item 2. The lipopolyamino acid conjugate according to Item 1, wherein

[0923] When m is 0, A' is selected from H, -(C1-C6)alkyl, -(C5-C 10 )aryl, -(C5-C 10 )heteroaryl, -(C6-C 10 )aralkyl, -(C1-C6)alkyl-O-(C5-C 10 )aryl, -(C5-C 10 ) heterocycloalkyl, amino protecting group, amino acid-like part R6 and active part;

[0924] When m is 1, A' is selected from H, -OH, -(C1-C6)alkyl, -(C5-C 10 )aryl, -(C5-C 10 )heteroaryl, -(C6-C 10 )aralkyl, -(C1-C6)alkyl-O-(C5-C 10 )aryl, -(C5-C 10 )heterocycloalkyl, -(C1-C 10 )alkoxy, -(C6-C 10 ) aryloxy, -(C6-C 10 )aralkyloxy, -(C5-C 10 )heteroaralkyloxy, -(C1-C 10 )alkyl-O-(C6-C 10 ) an aryloxy group, a free radical R4', a lipid-like portion R5' and an active portion;

[0925] When m' is 0, A" is selected from H, -(C1-C6)alkyl, -(C5-C 10 )aryl, -(C5-C 10 )heteroaryl, -(C6-C 10 )aralkyl, -(C1-C6)alkyl-O-(C5-C 10 )aryl, -(C5-C 10 ) a heterocycloalkyl group, an amino protecting group, an amino acid-like portion R6 and an active portion; and

[0926] When m' is 1, A" is selected from H, -OH, -(C1-C6)alkyl, -(C5-C 10 )aryl, -(C5-C 10 )heteroaryl, -(C6-C 10 )aralkyl, -(C1-C6)alkyl-O-(C5-C 10 )aryl, -(C5-C 10 )heterocycloalkyl, -(C1-C 10 )alkoxy, -(C6-C 10 ) aryloxy, -(C6-C 10 )aralkyloxy, -(C5-C 10 )heteroaralkyloxy, -(C1-C 10 )alkyl-O-(C6-C 10 ) an aryloxy group, a lipid-like portion R5' and an active portion;

[0927] Each R5 is independently selected from -(C1-C 18 )alkyl, -(C2-C 18 )alkenyl and a radical of formula (VII), (VIII), (IX), (X), (XI), (XII), (XIII) or (XIV); and

[0928] Each R5' is independently selected from -X'(R1')-(C1-C 18 )alkyl, -X'(R1')-(C2-C 18 )alkenyl and free radicals of formula (VII'), (VIII'), (IX'), (X'), (XI'), (XII'), (XIII') or (XIV').

[0929] Clause 3. The lipopolyamino acid conjugate according to any one of clauses 1 to 2, wherein the lipopolyamino acid conjugate of formula (I) has the following formula (I'):

[0930]

[0931] Clause 4. The lipopolyamino acid conjugate according to any one of clauses 1 to 3, 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.

[0932] Clause 5. The lipopolyamino acid conjugate according to any one of clauses 1 to 4, wherein X is N and R1 is H.

[0933] Clause 6. A lipopolyamino acid conjugate according to any one of clauses 1 to 4, wherein X is N and R1 is -(C1-C 18 )alkyl, more particularly -(C1-C 12 )alkyl.

[0934] Clause 7. A lipopolyamino acid conjugate according to any one of clauses 1 to 4, wherein X is N and R1 is -(C2-C 18 )alkenyl, more particularly -(C2-C 12 ) alkenyl.

[0935] Clause 8. The lipopolyamino acid conjugate according to any one of clauses 1 to 4, wherein X is O and R1 is absent.

[0936] Clause 9. The lipopolyamino acid conjugate according to any one of clauses 1 to 4, wherein X is S and R1 is absent.

[0937] Clause 10. A lipopolyamino acid conjugate according to any one of clauses 1 to 9, wherein m is 0, and A' is selected from H, -(C1-C6)alkyl, -(C5-C 10 )aryl, -(C5-C 10 )heteroaryl, -(C6-C 10 )aralkyl, -(C1-C6)alkyl-O-(C5-C 10 )aryl, -(C5-C 10 )heterocycloalkyl, an amino protecting group, an amino acid-like portion R6 and an active portion; A' is optionally substituted by one or more groups selected from the following: -OH, halogen, -CF3, -NH2, -NH-(C1-C4)alkyl, -NH-CO-(C1-C6)alkyl, -(C1-C6)alkyl, -NO2, -N3, -CO-(C1-C6)alkyl, -CO-O-(C1-C6)alkyl, -SO3H, -SO2NH2, -SO2-N((C1-C6)alkyl)2, -COOH, CONH2 and -CON((C1-C6)alkyl)2.

[0938] Clause 11. A lipopolyamino acid conjugate according to any one of clauses 1 to 9, wherein m is 1, and A' is selected from H, -OH, -(C1-C6)alkyl, -(C5-C10 )aryl, -(C5-C 10 )heteroaryl, -(C6-C 10 )aralkyl, -(C1-C6)alkyl-O-(C5-C 10 )aryl, -(C5-C 10 )heterocycloalkyl, -(C1-C 10 )alkoxy, -(C6-C 10 ) aryloxy, -(C6-C 10 )aralkyloxy, -(C5-C 10 )heteroaralkyloxy, -(C1-C 10 )alkyl-O-(C6-C 10 ) aryloxy, free radical R4', lipid-like part R5' and active part; A' is optionally substituted by one or more groups selected from the following: -OH, halogen, -CF3, -NH2, -NH-(C1-C4)alkyl, -NH-CO-(C1-C6)alkyl, -(C1-C6)alkyl, -NO2, -N3, -CO-(C1-C6)alkyl, -CO-O-(C1-C6)alkyl, -SO3H, -SO2NH2, -SO2-N((C1-C6)alkyl)2, -COOH, CONH2 and -CON((C1-C6)alkyl)2.

[0939] Item 12. The lipopolyamino acid conjugate according to any one of items 1 to 11, wherein R2 is a free radical of formula (II), more particularly in the free radical of formula (II), a is 1 or 2.

[0940] Item 13. The lipopolyamino acid conjugate according to any one of items 1 to 11, wherein R2 is a free radical of formula (III), more particularly in the free radical of formula (III), b is 1 or 2.

[0941] Item 14. The lipopolyamino acid conjugate according to any one of items 1 to 11, wherein R2 is a radical of formula (IV), more particularly in the radical of formula (IV), c is 1 or 2.

[0942] Clause 15. The lipopolyamino acid conjugate according to any one of clauses 1 to 11, wherein R2 is a radical of formula (V), more particularly in the radical of formula (V), d is 1 or 2.

[0943] Clause 16. The lipopolyamino acid conjugate according to any one of clauses 1 to 15, wherein R3 is H.

[0944] Clause 17. The lipopolyamino acid conjugate according to any one of clauses 1 to 15, wherein R3 is -(C1-C6)alkyl, more particularly R3 is -CH3.

[0945] Clause 18. The lipopolyamino acid conjugate according to any one of clauses 1 to 17, wherein A is a lipid-like moiety R5, and A' is not a lipid-like moiety R5', more particularly, A' is selected from H, -OH, -(C1-C6)alkyl, -(C5-C 10 )aryl, -(C5-C 10 )heteroaryl, -(C6-C 10 )aralkyl, -(C1-C6)alkyl-O-(C5-C 10 )aryl, -(C5-C 10 )heterocycloalkyl, -(C1-C 10 )alkoxy, -(C6-C 10 ) aryloxy, -(C6-C 10 )aralkyloxy, -(C5-C 10 )heteroaralkyloxy, -(C1-C 10 )alkyl-O-(C6-C 10 ) aryloxy, amino protecting group, free radical R4', amino acid-like part R6 and active part; A' is optionally substituted by one or more groups selected from the following: -OH, halogen, -CF3, -NH2, -NH-(C1-C4)alkyl, -NH-CO-(C1-C6)alkyl, -(C1-C6)alkyl, -NO2, -N3, -CO-(C1-C6)alkyl, -CO-O-(C1-C6)alkyl, -SO3H, -SO2NH2, -SO2-N((C1-C6)alkyl)2, -COOH, CONH2 and -CON((C1-C6)alkyl)2.

[0946] Clause 19. A lipopolyamino acid conjugate according to any one of clauses 1 to 18, wherein A is a lipid-like moiety R5, which is -(C1-C 18 )alkyl, more particularly -(C6-C 18 ) alkyl radicals, and even more particularly, radicals of formula (XIX).

[0947] Clause 20. A lipopolyamino acid conjugate according to any one of clauses 1 to 18, wherein A is a lipid-like moiety R5, which is -(C2-C 18 )alkenyl, more particularly -(C6-C 18 )alkenyl, and even more particularly, radicals of formula (XX).

[0948] Clause 21. The lipopolyamino acid conjugate according to any one of clauses 1 to 18, wherein A is a lipid-like moiety R5 which is a radical of formula (VII).

[0949] Clause 22. The lipopolyamino acid conjugate according to any one of clauses 1 to 18, wherein A is a lipid-like moiety R5, which is a radical of formula (VIII).

[0950] Item 23. A lipopolyamino acid conjugate according to any one of items 1 to 18, wherein A is a lipid-like portion R5, which is a free radical of formula (IX), more particularly, a free radical selected from formula (ix1), (ix2), (ix3), (ix4), (ix5), (ix6), (ix7) and (ix8).

[0951] Item 24. A lipopolyamino acid conjugate according to any one of items 1 to 18, wherein A is a lipid-like moiety R5, which is a radical of formula (X), more particularly, a radical selected from formula (x1), (x2), (x3) and (x4).

[0952] Clause 25. The lipopolyamino acid conjugate according to any one of clauses 1 to 18, wherein A is a lipid-like moiety R5, which is a radical of formula (XI), more particularly, a radical of formula (xi1).

[0953] Clause 26. The lipopolyamino acid conjugate according to any one of clauses 1 to 18, wherein A is a lipid-like moiety R5, which is a radical of formula (XII).

[0954] Clause 27. The lipopolyamino acid conjugate according to any one of clauses 1 to 18, wherein A is a lipid-like moiety R5, which is a radical of formula (XIII).

[0955] Clause 28. The lipopolyamino acid conjugate according to any one of clauses 1 to 18, wherein A is a lipid-like moiety R5, which is a radical of formula (XIV), more particularly, a radical selected from formula (xiv1) and (xiv2).

[0956] Clause 29. The lipopolyamino acid conjugate according to any one of clauses 1 to 18, wherein A is a lipid-like moiety R5, which is a radical of formula (XXI), more particularly, a radical of formula (xxi1).

[0957] Clause 30. The lipopolyamino acid conjugate according to any one of clauses 1 to 18, wherein A is a lipid-like moiety R5, which is a radical of formula (XXII), more particularly, a radical selected from formula (xxii1) and (xxii2).

[0958] Clause 31. The lipopolyamino acid conjugate according to any one of clauses 1 to 18, wherein A is a lipid-like moiety R5, which is a radical of formula (XXIII).

[0959] Clause 32. The lipopolyamino acid conjugate according to any one of clauses 1 to 31, wherein A is the lipid-like moiety R5, m is 0, and A' is H.

[0960] Clause 33. The lipopolyamino acid conjugate according to any one of clauses 1 to 31, wherein A is the lipid-like moiety R5, m is 0, and A' is an amino protecting group.

[0961] Clause 34. The lipopolyamino acid conjugate according to any one of clauses 1 to 4 or 10 to 17, which has formula (Ia).

[0962] Clause 35. A lipopolyamino acid conjugate according to any one of clauses 1 to 9 or 12 to 17, which has formula (Ib), more particularly the lipopolyamino acid conjugate of formula (Ib) is a dimer, wherein, respectively, R5 and A'' have the same meaning, X and X'' have the same meaning, R1 and R1'' have the same meaning, R2 and R2' have the same meaning, R3 and R3' have the same meaning, B and B' have the same meaning, e and f have the same meaning, and n and n' have the same meaning.

[0963] Clause 36. The lipopolyamino acid conjugate according to any one of clauses 1 to 9 or 16 to 17, which has formula (Ic).

[0964] Clause 37. The lipopolyamino acid conjugate according to any one of clauses 1 to 9 or 16 to 17, which has formula (Id).

[0965] Clause 38. The lipopolyamino acid conjugate according to any one of clauses 1 to 9 or 16 to 17, which has formula (Ie).

[0966] Clause 39. A lipopolyamino acid conjugate according to any one of clauses 1 to 9 or 16 to 17, which has formula (Ig), wherein A' is selected from H, -OH, -(C1-C6)alkyl, -(C5-C 10 )aryl, -(C5-C 10 )heteroaryl, -(C6-C 10 )aralkyl, -(C1-C6)alkyl-O-(C5-C 10 )aryl and -(C5-C 10 )heterocycloalkyl; A' is optionally substituted by one or more groups selected from the group consisting of: -OH, halogen, -CF3, -NH2, -NH-(C1-C4)alkyl, -NH-CO-(C1-C6)alkyl, -(C1-C6)alkyl, -NO2, -N3, -CO-(C1-C6)alkyl, -CO-O-(C1-C6)alkyl, -SO3H, -SO2NH2, -SO2-N((C1-C6)alkyl)2, -COOH, CONH2 and -CON((C1-C6)alkyl)2, more particularly A' is methyl.

[0967] Clause 40. A lipopolyamino acid conjugate according to any one of clauses 1 to 9 or 16 to 17, which has the formula (Ig'), wherein A' is selected from H, -OH, -(C1-C6)alkyl, -(C5-C 10 )aryl, -(C5-C 10 )heteroaryl, -(C6-C 10 )aralkyl, -(C1-C6)alkyl-O-(C5-C 10 )aryl, -(C5-C 10 )heterocycloalkyl, -(C1-C 10 )alkoxy, -(C6-C 10 ) aryloxy, -(C6-C 10 )aralkyloxy, -(C5-C 10 )heteroaralkyloxy, -(C1-C 10 )alkyl-O-(C6-C 10 )aryloxy; A' is optionally substituted by one or more groups selected from the group consisting of: -OH, halogen, -CF3, -NH2, -NH-(C1-C4)alkyl, -NH-CO-(C1-C6)alkyl, -(C1-C6)alkyl, -NO2, -N3, -CO-(C1-C6)alkyl, -CO-O-(C1-C6)alkyl, -SO3H, -SO2NH2, -SO2-N((C1-C6)alkyl)2, -COOH, CONH2 and -CON((C1-C6)alkyl)2, more particularly A' is methyl.

[0968] Clause 41. The lipopolyamino acid conjugate according to any one of clauses 1 to 4 or 10 to 17, which has formula (Ih).

[0969] Clause 42. The lipopolyamino acid conjugate according to any one of clauses 1 to 17, which has formula (Ij).

[0970] Clause 43. The lipopolyamino acid conjugate according to any one of clauses 1 to 9, or 12 to 17, or 19 to 31, which has formula (Ih').

[0971] Clause 44. The lipopolyamino acid conjugate according to any one of clauses 1 to 9, or 12 to 17, or 19 to 31, which has formula (Ij').

[0972] Clause 45. A lipopolyamino acid conjugate according to any one of clauses 1 to 9 or 12 to 17, wherein A is a lipid-like moiety R5, m is 1, and A' is an active moiety selected from a pharmaceutically active agent, a cell targeting agent, a penetration enhancer, a cosmetic active agent, and a diagnostic active agent.

[0973] Clause 46. A lipopolyamino acid conjugate according to any one of clauses 1 to 17, wherein A' is a lipid-like moiety R5', which is -X'(R1')-(C1-C 18 )alkyl, more particularly -X'(R1')-(C6-C 18 ) alkyl, and even more particularly, a radical of the formula (XIX′) or (XIX″).

[0974] Clause 47. A lipopolyamino acid conjugate according to any one of clauses 1 to 17, wherein A' is a lipid-like moiety R5', which is -X'(R1')-(C2-C 18 )alkenyl, more particularly -X'(R1')-(C6-C 18 )alkenyl, and even more particularly, radicals of formula (XX′).

[0975] Clause 48. The lipopolyamino acid conjugate according to any one of clauses 1 to 17, wherein A' is a lipid-like moiety R5' which is a radical of formula (VII').

[0976] Clause 49. The lipopolyamino acid conjugate according to any one of clauses 1 to 17, wherein A' is a lipid-like moiety R5' which is a radical of formula (VIII').

[0977] Article 50. A lipopolyamino acid conjugate according to any one of clauses 1 to 17, wherein A' is a lipid-like portion R5', which is a radical of formula (IX'), more particularly, a radical selected from formula (ix1'), (ix2'), (ix3'), (ix4'), (ix5'), (ix6'), (ix7') and (ix8').

[0978] Item 51. A lipopolyamino acid conjugate according to any one of items 1 to 17, wherein A' is a lipid-like moiety R5', which is a radical of formula (X'), more particularly, a radical selected from formula (x1'), (x2'), (x3') and (x4').

[0979] Clause 52. The lipopolyamino acid conjugate according to any one of clauses 1 to 17, wherein A′ is a lipid-like moiety R5′, which is a radical of formula (XI′), more particularly, a radical of formula (xi1′).

[0980] Clause 53. The lipopolyamino acid conjugate according to any one of clauses 1 to 17, wherein A' is a lipid-like moiety R5' which is a radical of formula (XII').

[0981] Clause 54. The lipopolyamino acid conjugate according to any one of clauses 1 to 17, wherein A' is a lipid-like moiety R5' which is a radical of formula (XIII').

[0982] Clause 55. The lipopolyamino acid conjugate according to any one of clauses 1 to 17, wherein A' is a lipid-like moiety R5' which is a radical of formula (XIV'), more particularly, a radical selected from formula (xiv1') and (xiv2').

[0983] Clause 56. The lipopolyamino acid conjugate according to any one of clauses 1 to 17, wherein A′ is a lipid-like moiety R5′, which is a radical of formula (XXI′), more particularly, a radical of formula (xxi1′).

[0984] Clause 57. The lipopolyamino acid conjugate according to any one of clauses 1 to 17, wherein A' is a lipid-like moiety R5', which is a radical of formula (XXII'), more particularly, a radical selected from formula (xxii1') and (xxii2').

[0985] Clause 58. The lipopolyamino acid conjugate according to any one of clauses 1 to 17, wherein A' is a lipid-like moiety R5' which is a radical of formula (XXIII').

[0986] Clause 59. The lipopolyamino acid conjugate according to any one of clauses 1 to 9, or 12 to 17, or 19 to 31, or 46 to 58, wherein A is the lipid-like moiety R5 and A' is the lipid-like moiety R5'.

[0987] Clause 60. The lipopolyamino acid conjugate according to any one of clauses 1 to 9, or 12 to 17, or 46 to 58, wherein A′ is the lipid-like moiety R5′, m is 1, and A is H.

[0988] Clause 61. The lipopolyamino acid conjugate according to any one of clauses 1 to 9, or 12 to 17, or 46 to 58, wherein A' is the lipid-like moiety R5', m is 1, and A is a protecting group.

[0989] Clause 62. A lipopolyamino acid conjugate according to any one of clauses 1 to 9 or 12 to 17, which has formula (Ib'), more particularly the lipopolyamino acid conjugate of formula (Ib') is a dimer, wherein, respectively, R5' and A" have the same meaning, m and m' have the same meaning, X and X" have the same meaning, R1 and R1" have the same meaning, R2 and R2' have the same meaning, R3 and R3' have the same meaning, B and B' have the same meaning, e and f have the same meaning, and n and n' have the same meaning.

[0990] Clause 63. A lipopolyamino acid conjugate according to any one of clauses 1 to 9, or 12 to 17, or 46 to 58, wherein A' is a lipid-like moiety R5', m is 1, and A is selected from H, -(C1-C6)alkyl, -CO(C1-C6)alkyl, -(C5-C 10 )aryl, -(C5-C 10 )heteroaryl, -(C6-C 10 )aralkyl, -(C1-C6)alkyl-O-(C5-C 10 )aryl, -(C5-C 10 ) heterocycloalkyl, protecting group, free radical R4, lipid-like part R5, active part; A is optionally substituted by one or more groups selected from the following: -OH, halogen, -CF3, -NH2, -NH-(C1-C4)alkyl, -NH-CO-(C1-C6)alkyl, -(C1-C6)alkyl, -NO2, -N3, -CO-(C1-C6)alkyl, -CO-O-(C1-C6)alkyl, -SO3H, -SO2NH2, -SO2-N((C1-C6)alkyl)2, -COOH, CONH2 and -CON((C1-C6)alkyl)2, more particularly A is methyl.

[0991] Clause 64. A lipopolyamino acid conjugate according to any one of clauses 1 to 9, or 12 to 17, or 46 to 58, wherein A' is a lipid-like moiety R5', m is 1, and A is an active moiety selected from a pharmaceutically active agent, a cell targeting agent, a penetration enhancer, a cosmetic active agent, and a diagnostic active agent.

[0992] Item 65. A self-assembled particle comprising a lipopolyamino acid conjugate of formula (I) as defined in any one of Items 1 to 64, and optionally one or more active agents selected from the following: pharmaceutically active agents, cell targeting agents, penetration enhancers, cosmetic active agents, diagnostic active agents, nucleic acids, peptides, proteins and mixtures thereof.

[0993] Item 66. The self-assembled particle according to Item 65, which is a nanoparticle, more particularly selected from micelles, reverse micelles, planar bilayers, crystalline nanoparticles, liposomes, microbubbles and lipid nanoparticles, and even more particularly, the self-assembled particle is a lipid nanoparticle (LNP) or a liposome.

[0994] Clause 67. The self-assembled particle according to any one of clauses 65 to 66, which is a lipid nanoparticle (LNP) and further comprises one or more lipids selected from ionizable lipids, cationic lipids, neutral lipids and anionic lipids.

[0995] Clause 68. The self-assembled particle according to any one of clauses 65 to 67, which is a lipid nanoparticle (LNP) and further comprises an ionizable lipid or a cationic lipid, a phospholipid and a sterol.

[0996] Clause 69. The self-assembled particle according to any one of clauses 65 to 68, which is a lipid nanoparticle comprising:

[0997] i) a lipopolyamino acid conjugate of formula (I) as defined in any one of clauses 1 to 64, in an amount of 0.1 to 10 mol%, more particularly 1 to 6 mol%, even more particularly 2 to 5 mol%;

[0998] ii) ionizable lipids or cationic lipids in an amount of 30 to 70 mol%, more particularly 40 to 60 mol%;

[0999] iii) phospholipids in an amount of 1 to 20 mol%, more particularly 5 to 15 mol%; and

[1000] iv) sterols in an amount ranging from 20 to 60 mol %, more particularly from 30 to 50 mol %;

[1001] The percentages are expressed relative to the sum of the mol % of lipid and the lipopolyamino acid conjugate of formula (I).

[1002] Clause 70. The self-assembled particle according to Clause 69, which is a lipid nanoparticle, further comprising a nucleic acid.

[1003] Clause 71. The self-assembled particle according to any one of clauses 65 to 70, which lacks polyethylene glycol (PEG).

[1004] Clause 72. A composition comprising a lipopolyamino acid conjugate of formula (I) as defined in any one of clauses 1 to 64, or alternatively, a self-assembling particle as defined in any one of clauses 65 to 71, and one or more suitable excipients or carriers.

[1005] Article 73. Therapeutic products for medical use which are:

[1006] a) a lipopolyamino acid conjugate of formula (I) as defined in any one of clauses 1 to 64, wherein at least one of A, A', A" or A'" is a pharmaceutically active agent, or alternatively,

[1007] b) a self-assembling particle as defined in any one of clauses 65 to 71 comprising the lipopolyamino acid conjugate a), or alternatively,

[1008] c) a composition as defined in clause 72, comprising a lipopolyamino acid conjugate a) or a self-assembled particle b), or alternatively,

[1009] d) A self-assembled particle as defined in any one of clauses 65 to 71 comprising one or more active agents selected from pharmaceutically active agents, nucleic acids, peptides, proteins and mixtures thereof, or alternatively,

[1010] e) A composition as defined in clause 72 comprising self-assembled particles d).

[1011] Clause 74. A therapeutic product for use according to clause 73, which is (i) used as a transfection agent for transfecting at least one active agent into a cell; (ii) used for the in vivo or ex vivo production of a biological agent encoding a recombinant protein, peptide or antibody, or for the production of a recombinant virus; (iii) used as a therapeutic or prophylactic vaccine against viral infection, or as a therapeutic vaccine against cancer or an infectious disease; or (v) used for genome engineering, for cell reprogramming, for differentiating cells or for gene editing.

[1012] Article 75. Diagnostic products for diagnostic purposes:

[1013] a') a lipopolyamino acid conjugate of formula (I) as defined in any one of clauses 1 to 64, wherein at least one of A, A', A" or A'" is a diagnostically active agent, or alternatively,

[1014] b') a self-assembling particle as defined in any one of clauses 65 to 71 comprising the lipopolyamino acid conjugate a'), or alternatively,

[1015] c') a composition as defined in clause 72, comprising the lipopolyamino acid conjugate a') or the self-assembled particle b'), or alternatively,

[1016] d') a self-assembled particle as defined in any one of clauses 65 to 71, comprising one or more diagnostically active agents, or alternatively,

[1017] e') A composition as defined in clause 72 comprising self-assembled particles d').

[1018] Article 76. Use of a cosmetic product in a cosmetic product, where the cosmetic product is:

[1019] a”) a lipopolyamino acid conjugate of formula (I) as defined in any one of clauses 1 to 64, wherein at least one of A, A′, A″ or A′″ is a cosmetic active agent, or alternatively,

[1020] b")) a self-assembling particle as defined in any one of clauses 65 to 71 comprising a lipopolyamino acid conjugate a"), or alternatively,

[1021] c")) a composition as defined in clause 72 comprising a lipopolyamino acid conjugate a") or a self-assembled particle b"), or alternatively,

[1022] d") a self-assembled particle as defined in any one of clauses 65 to 71, comprising one or more cosmetic active agents, or, alternatively,

[1023] e")) A composition as defined in clause 72, comprising self-assembled particles d").

[1024] Item 77. A lipopolyamino acid conjugate of formula (I) as defined in any one of items 1 to 64, wherein A, A', A" and A'" are not active moieties, or, alternatively, a self-assembled particle comprising the same as defined in any one of items 59 to 65, for use as a carrier.

Claims

1. A lipopolyamino acid conjugate of formula (I), a salt thereof, or any stereoisomer or mixture of stereoisomers of any one of the compounds of formula (I) or their salts, in n is an integer from 5 to 250; m is 0 or 1; X is selected from N, S and O; R1 is selected from H, -(C1-C 18 )alkyl and -(C2-C 18 )alkenyl, provided that when X is O or S, R1 is absent; R2 is a radical selected from (II), (III), (IV) and (V) in: a, b, c and d are independently integers from 1 to 4; R3 is H or -(C1-C6)alkyl; A is selected from H, -(C1-C6)alkyl, -CO(C1-C6)alkyl, -(C5-C 10 )aryl, -(C5-C 10 )heteroaryl, -(C6-C 10 )aralkyl, -(C1-C6)alkyl-O-(C5-C 10 )aryl, -(C5-C 10 ) heterocycloalkyl, protecting group, free radical R4, lipid-like part R5 and active part; A is optionally substituted by one or more groups selected from the following: -OH, halogen, -CF3, -NH2, -NH-(C1-C4)alkyl, -NH-CO-(C1-C6)alkyl, -(C1-C6)alkyl, -NO2, -N3, -CO-(C1-C6)alkyl, -CO-O-(C1-C6)alkyl, -SO3H, -SO2NH2, -SO2-N((C1-C6)alkyl)2, -COOH, CONH2 and -CON((C1-C6)alkyl)2; A' is selected from H, -OH, -(C1-C6)alkyl, -(C5-C 10 )aryl, -(C5-C 10 )heteroaryl, -(C6-C 10 )aralkyl, -(C1-C6) Alkyl-O-(C5-C 10 )aryl, -(C5-C 10 )heterocycloalkyl, -(C1-C 10 )alkoxy, -(C6-C 10 ) aryloxy, -(C6-C 10 ) Aralkyloxy, -(C5-C 10 )heteroaralkyloxy, -(C1-C 10 )alkyl-O-(C6-C 10 ) aryloxy, amino protecting group, free radical R4', lipid-like part R5', amino acid-like part R6 and active part; A' is optionally substituted by one or more groups selected from the following: -OH, halogen, -CF3, -NH2, -NH-(C1-C4) alkyl, -NH-CO-(C1-C6) alkyl, -(C1-C6) alkyl, -NO2, -N3, -CO-(C1-C6) alkyl, -CO-O-(C1-C6) alkyl, -SO3H, -SO2NH2, -SO2-N((C1-C6) alkyl)2, -COOH, CONH2 and -CON((C1-C6) alkyl)2; The conditions are: i) when m is 0, A' is selected from H, -(C1-C6)alkyl, -(C5-C 10 )aryl, -(C5-C 10 )heteroaryl, -(C6-C 10 )aralkyl, -(C1-C6)alkyl-O-(C5-C 10 )aryl, -(C5-C 10 ) heterocycloalkyl, an amino protecting group, an amino acid-like portion R6 and an active portion; A' is optionally substituted by one or more groups selected from the following: -OH, halogen, -CF3, -NH2, -NH-(C1-C4)alkyl, -NH-CO-(C1-C6)alkyl, -(C1-C6)alkyl, -NO2, -N3, -CO-(C1-C6)alkyl, -CO-O-(C1-C6)alkyl, -SO3H, -SO2NH2, -SO2-N((C1-C6)alkyl)2, -COOH, CONH2 and -CON((C1-C6)alkyl)2; and When m is 1, A' is selected from H, -OH, -(C1-C6)alkyl, -(C5-C 10 )aryl, -(C5-C 10 )heteroaryl, -(C6-C 10 )aralkyl, -(C1-C6)alkyl-O-(C5-C 10 )aryl, -(C5-C 10 )heterocycloalkyl, -(C1-C 10 )alkoxy, -(C6-C 10 ) aryloxy, -(C6-C 10 )aralkyloxy, -(C5-C 10 )heteroaralkyloxy, -(C1-C 10 )alkyl-O-(C6-C 10 ) aryloxy, free radical R4', lipid-like part R5' and active part; A' is optionally substituted by one or more groups selected from the following: -OH, halogen, -CF3, -NH2, -NH-(C1-C4)alkyl, -NH-CO-(C1-C6)alkyl, -(C1-C6)alkyl, -NO2, -N3, -CO-(C1-C6)alkyl, -CO-O-(C1-C6)alkyl, -SO3H, -SO2NH2, -SO2-N((C1-C6)alkyl)2, -COOH, CONH2 and -CON((C1-C6)alkyl)2; and ii) at least one of A and A' is a lipid-like moiety R5 or R5'; R4 is a free radical of formula (VIa) R4' is a free radical of formula (VIb) in: n' is an integer from 5 to 250; m' is 0 or 1; X” is selected from N, S and O; R1" is a free radical having any of the meanings of R1, provided that when X" is O or S, R1" is absent; R2' is a radical having any of the meanings of R2; R3' is a radical having any of the meanings of R3; B and B' are independently S or CH2; e and f are independently an integer from 1 to 18; A" is selected from H, -OH, -(C1-C6)alkyl, -(C5-C 10 )aryl, -(C5-C 10 )heteroaryl, -(C6-C 10 )aralkyl, -(C1-C6) Alkyl-O-(C5-C 10 )aryl, -(C5-C 10 )heterocycloalkyl, -(C1-C 10 )alkoxy, -(C6-C 10 ) aryloxy, -(C6-C 10 ) Aralkyloxy, -(C5-C 10 )heteroaralkyloxy, -(C1-C 10 )alkyl-O-(C6-C 10 ) aryloxy, amino protecting group, lipid-like part R5 ', amino acid-like part R6 and active part; A "is optionally substituted by one or more groups selected from the following: -OH, halogen, -CF3, -NH2, -NH-(C1-C4) alkyl, -NH-CO-(C1-C6) alkyl, -(C1-C6) Alkyl, -NO2, -N3, -CO-(C1-C6)alkyl, -CO-O-(C1-C6)alkyl, -SO3H, -SO2NH2, -SO2-N((C1-C6)alkyl)2, -COOH, CONH2 and -CON((C1-C6)alkyl)2; The conditions are: When m' is 0, A" is selected from H, -(C1-C6)alkyl, -(C5-C 10 )aryl, -(C5-C 10 )heteroaryl, -(C6-C 10 ) Aralkyl, -(C1-C6)alkyl-O-(C5-C 10 )aryl, -(C5-C 10 ) heterocycloalkyl, an amino protecting group, an amino acid-like portion R6 and an active portion; A" is optionally substituted by one or more groups selected from the following: -OH, halogen, -CF3, -NH2, -NH-(C1-C4)alkyl, -NH-CO-(C1-C6)alkyl, -(C1-C6)alkyl, -NO2, -N3, -CO-(C1-C6)alkyl, -CO-O-(C1-C6)alkyl, -SO3H, -SO2NH2, -SO2-N((C1-C6)alkyl)2, -COOH, CONH2 and -CON((C1-C6)alkyl)2; and When m' is 1, A" is selected from H, -OH, -(C1-C6)alkyl, -(C5-C 10 )aryl, -(C5-C 10 )heteroaryl, -(C6-C 10 ) Aralkyl, -(C1-C6)alkyl-O-(C5-C 10 )aryl, -(C5-C 10 )heterocycloalkyl, -(C1-C 10 )alkoxy, -(C6-C 10 ) Aryloxy, -(C6-C 10 )aralkyloxy, -(C5-C 10 )heteroaralkyloxy, -(C1-C 10 )alkyl-O-(C6-C 10 ) aryloxy, lipid-like moiety R5' and active moiety; A" is optionally substituted by one or more groups selected from the following: -OH, halogen, -CF3, -NH2, -NH-(C1-C4)alkyl, -NH-CO-(C1-C6)alkyl, -(C1-C6)alkyl, -NO2, -N3, -CO-(C1-C6)alkyl, -CO-O-(C1-C6)alkyl, -SO3H, -SO2NH2, -SO2-N((C1-C6)alkyl)2, -COOH, CONH2 and -CON((C1-C6)alkyl)2; and A"' is selected from H, -(C1-C6)alkyl, -CO(C1-C6)alkyl, -(C5-C 10 )aryl, -(C5-C 10 )heteroaryl, -(C6-C 10 ) Aralkyl, -(C1-C6)alkyl-O-(C5-C 10 )aryl, -(C5-C 10 ) heterocycloalkyl, protecting group, lipid-like part R5 and active part; A "' is optionally substituted by one or more groups selected from the following: -OH, halogen, -CF3, -NH2, -NH-(C1-C4) alkyl, -NH-CO-(C1-C6) alkyl, -(C1-C6) alkyl, -NO2, -N3, -CO-(C1-C6) alkyl, -CO-O-(C1-C6) alkyl, -SO3H, -SO2NH2, -SO2-N((C1-C6) alkyl)2, -COOH, CONH2 and -CON((C1-C6) alkyl)2; Each R5 is independently selected from -(C1-C 18 )alkyl, -(C2-C 18 )alkenyl and a radical of formula (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XXI), (XXII) or (XXIII) Each R5' is independently selected from -X'(R1')-(C1-C 18 )alkyl, -X'(R1')-(C2-C 18 )alkenyl and a radical of formula (VII'), (VIII'), (IX'), (X'), (XI'), (XII'), (XIII'), (XIV'), (XXI'), (XXII') or (XXIII') in: 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 -OCO-, -COO-, -NRz'CO- and -CONRz'-; Each Rz' is H or Rz; Each of Rx, Ry and Rz is independently -(C1-C 18 )alkyl or -(C2-C 18 )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; X' is selected from N, S and O; R1′ is a free radical having any of the meanings of R1, provided that when X′ is O or S, R1′ is absent; and t is 0 or 1, provided that when X=0, t is 0, and when X is not 0, t is 1; t' is 0 or 1; provided that when m is 0, t' is 1; R 22 , R 33 and R 44 independently selected from 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 diradical chain comprising one or more moieties selected from the group consisting of -CH=CH-, -C≡C-, -CH2-, -N=CH-, -CH=NH-, -NH-, -NH-NH-, -NH-N=CH-, -O-, -O(CH2)O-, -CO-, -O(CO)-, -(CO)O-, -C(=CH2)-, -C(=NH)-, -CONH-, -NHCO-, -NH(CO)NH-, -S-, -SS-, -SO-, -SO2-, -SO2NH2-, and -phenylene-, wherein L is optionally substituted with one or more substituents selected from the group consisting of halogen, -OH, -NR a R b 、-SH、-NHNH2、-COOR c , -CF3, -OCF3, wherein when L comprises a -CH2- moiety, two hydrogen atoms attached to the carbon atom are optionally replaced by the following ring: and Each R6 is a radical independently selected from (XV), (XVI) and (XVII) wherein a', b' and c' are independently integers from 1 to 4; Each active moiety is independently selected from the group consisting of pharmaceutically active agents, penetration enhancers, cell targeting agents, cosmetic active agents, and diagnostic active agents.

2. The lipopolyamino acid conjugate according to claim 1, wherein n is an integer from 5 to 100.

3. The lipopolyamino acid conjugate according to any one of claims 1 to 2, wherein R3 is H.

4. The lipopolyamino acid conjugate according to any one of claims 1 to 3, wherein X is N, and R1 is selected from H and -(C1-C 18 )alkyl. 5 . The lipopolyamino acid conjugate according to claim 1 , wherein A is the lipid-like moiety R5, and A′ is not the lipid-like moiety R5′.

6. The lipopolyamino acid conjugate according to claim 5, wherein R5 is selected from -(C1-C 18 )alkyl, -(C2-C 18 )alkenyl and free radicals of formula (IX), (X), (XII), (XIII), (XIV) or (XXI).

7. The lipopolyamino acid conjugate according to any one of claims 5 to 6, wherein A' is selected from H, -(C1-C6)alkyl, -(C5-C 10 )aryl, -(C5-C 10 )heteroaryl, -(C6-C 10 )aralkyl, -(C1-C6)alkyl-O-(C5-C 10 )aryl, -(C5-C 10 )heterocycloalkyl, -(C1-C 10 )alkoxy, -(C6-C 10 ) aryloxy, -(C6-C 10 )aralkyloxy, -(C5-C 10 )heteroaralkyloxy and -(C1-C 10 )alkyl-O-(C6-C 10 )aryloxy group.

8. The lipopolyamino acid conjugate according to any one of claims 1 to 4, wherein A' is the lipid-like moiety R5', and A is not the lipid-like moiety R5.

9. The lipopolyamino acid conjugate according to claim 8, wherein R5' is selected from -(C1-C 18 )alkyl, -(C2-C 18 )alkenyl and free radicals of formula (IX'), (X'), (XII'), (XIII'), (XIV') or (XXI').

10. Self-assembled particles comprising a lipopolyamino acid conjugate of formula (I) as defined in any one of claims 1 to 9, and optionally one or more active agents selected from pharmaceutically active agents, cell targeting agents, penetration enhancers, cosmetic active agents, diagnostic active agents, nucleic acids, peptides, proteins and mixtures thereof.

11. A composition comprising a lipopolyamino acid conjugate of formula (I) as defined in any one of claims 1 to 9, or alternatively, a self-assembling particle as defined in claim 10, and one or more suitable excipients or carriers.

12. Therapeutic products for medical use, comprising: a) a lipopolyamino acid conjugate of formula (I) as defined in any one of claims 1 to 9, wherein at least one of A, A', A" or A'" is a pharmaceutically active agent, or alternatively, b) a self-assembled particle as defined in claim 10, comprising the lipopolyamino acid conjugate a), or alternatively, c) A composition as defined in claim 11, comprising said lipopolyamino acid conjugate a) or said self-assembled particle b), or alternatively, d) A self-assembled particle as defined in claim 10 comprising 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 11 comprising said self-assembled particles d).

13. The therapeutic product for use according to claim 12, which is (i) used as a transfection agent for transfecting at least one active agent into cells; (ii) used for in vivo or ex vivo production of biological preparations encoding recombinant proteins, peptides or antibodies, or for producing recombinant viruses; (iii) used as a therapeutic or prophylactic vaccine against viral infections, or as a therapeutic vaccine against cancer or infectious diseases; or (v) used for genome engineering, for cell reprogramming, for differentiating cells or for gene editing.

14. Diagnostic products for diagnostic purposes, including: a') a lipopolyamino acid conjugate of formula (I) as defined in any one of claims 1 to 9, wherein at least one of A, A', A" or A'" is a diagnostically active agent, or alternatively, b') a self-assembled particle as defined in claim 10, comprising the lipopolyamino acid conjugate a'), or alternatively, c') a composition as defined in claim 11, comprising said lipopolyamino acid conjugate a') or said self-assembled particle b'), or alternatively, d') A self-assembled particle as defined in claim 10 comprising one or more diagnostically active agents, or alternatively, e') A composition as defined in claim 11 comprising said self-assembled particles d').

15. Use of a cosmetic product in cosmetics, the cosmetic product comprising: a”) a lipopolyamino acid conjugate of formula (I) as defined in any one of claims 1 to 9, wherein at least one of A, A′, A″ or A′″ is a cosmetic active agent, or alternatively, b")) a self-assembled particle as defined in claim 10, comprising the lipopolyamino acid conjugate a"), or alternatively, c")) a composition as defined in claim 11, comprising said lipopolyamino acid conjugate a") or said self-assembled particle b"), or alternatively, d") a self-assembled particle as defined in claim 10 comprising one or more cosmetic active agents, or alternatively, e")) A composition as defined in claim 11 comprising said self-assembled particles d").

16. The lipopolyamino acid conjugate of formula (I) as defined in any one of claims 1 to 9, wherein A, A', A", and A'" are not active moieties, or alternatively, the self-assembled particles comprising the same as defined in claim 10, for use as a carrier.

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