Stealth stabilized lipopolyamino acid

Abstract

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

Description

[Technical field]

[0001] This application claims the benefit of European Patent Application No. 22382135.6, filed February 18, 2022.

[0002] Technical Field The present disclosure relates to lipo-polyamino acid conjugates comprising a polyamino acid (PAA) moiety conjugated to a lipid-like moiety, which can form self-assembled nanoparticles, such as lipid nanoparticles (LNPs), and can be used as non-viral vectors for the delivery of active ingredients, including nucleic acids, to cells. [Background technology]

[0003] Nucleic acids have emerged in recent years to provide promising drug candidates for a wide range of diseases, including cancer, infectious diseases, and cardiovascular, inflammatory, and neurodegenerative diseases in particular. Nucleic acids exert their action through gene inhibition, addition, replacement, or editing. However, their clinical effectiveness is very limited due to their inability to cross physiological barriers. The negative charge and hydrophilicity of nucleic acids prevent their passive diffusion through cell membranes. In addition, the association of nucleic acids with serum proteins and their susceptibility to enzymatic degradation by endogenous nucleases also prevent their efficient translation into functional responses.

[0004] Non-viral vectors such as LNPs are known to penetrate cell membranes and thus can deliver nucleic acids to cells. LNPs are vesicles composed of a mixture of lipids that physically associate with each other through intermolecular forces to form a micellar structure. LNPs have a small diameter, usually less than 200 nm. LNPs are used as drug delivery systems due to their ability to encapsulate biologically active agents and deliver them to specific locations in the body at desired times. The lipid components of LNPs may include ionizable or cationic lipids, helper lipids such as phospholipids, and structural lipids such as sterols or cholesterol, ionizable / cationic lipids, which have a persistent or ionizable positively charged head group followed by a hydrophobic tail and can form complexes with negatively charged nucleic acids through electrostatic binding.

[0005] One of the potential problems of LNPs is that after they are injected, they may be recognized by the immune system as foreign particles and then cleared from the bloodstream by phagocytes.To address this issue, different strategies may be used, including reducing the particle size of the vesicles or modifying their surface.For example, the surface of LNPs may be modified by conjugating the hydrophilic polymer polyethylene glycol (PEG) to lipids such as phospholipids or long-chain fatty acids to form PEG-lipids.

[0006] PEG is a hydrophilic polymer that is widely used in drug delivery and nanotechnology due to its stealth properties and biocompatibility, which allow particulate delivery systems containing PEG to evade the immune system and consequently circulate in the body for long periods of time.

[0007] Notwithstanding the above, it has recently been reported that the presence of covalently attached PEG also significantly reduces the efficiency of transfection, as the neutral surface of the nanoparticles may reduce the efficiency of cellular uptake. PEG is also known to generate anti-PEG antibodies, which may cause immunogenic and allergic reactions.

[0008] Other hydrophilic polymers such as poly(vinylpyrrolidone), poly(acryloyl-morpholine), or polyoxazolines have been reported as alternatives to PEG-lipids, but LNPs containing such polymers are not yet commercially available.

[0009] Polysarcosine (pSar) is a polypeptoid based on the endogenous amino acid sarcosine (N-methylated glycine) that previously showed strong stealth properties. Lipid nanoparticles (LNPs) assembled using pSarcosinylated lipids for therapeutic applications of messenger RNA have been reported as a promising tool for particle engineering (ACS Appl. Nano Mater., 2020, 3, 10634–10645), but this is still under development and no clinical data have yet been presented including this polymer within LNPs.

[0010] Thus, from what is known in the art, there remains a need to develop alternative LNPs that overcome the shortcomings of the prior art. Summary of the Invention

[0011] The present inventors have developed novel lipo-polyamino acid conjugates comprising a polyamino acid (PAA) moiety conjugated to at least one lipid-like moiety, which can form self-assembled nanoparticles, such as lipid nanoparticles (LNPs), and due to their stealth properties and resulting improved plasma half-life, can be effectively used as non-viral vectors for the delivery of active ingredients, including nucleic acids.

[0012] Furthermore, lipo-polyamino acid conjugates exhibit low cytotoxicity, high biodegradability, and may confer enhanced efficiency, high stability to the final nanosystems, with limited or even complete inhibition of aggregation issues in the bloodstream and potential targeting to different cells and tissues.

[0013] Thus, a first aspect of the present invention relates to a lipo-polyamino acid conjugate of formula (I), a salt thereof, or any stereoisomer or mixture of stereoisomers of a compound of formula (I) or a salt thereof: [ka] (In the formula, n is an integer from 5 to 250, m is 0 or 1; X is selected from the group consisting of N, S, and O; R1 is 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 the group consisting of (II), (III), (IV), and (V); [ka] (wherein a, b, c, and d are independently integers from 1 to 4); R3 is H or -(C1-C6)alkyl; A is 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, a protecting group, a radical R4, a lipid-like moiety R5, and an active moiety; A is optionally substituted with 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, -SON2NH2, -SO2-N((C1-C6)alkyl)2, -COOH, -CONH2, and -CON((C1-C6)alkyl)2; A' is 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 )Aralkoxy, -(C5-C 10 )heteroaralkoxy, -(C1-C 10 )Alkyl-O-(C6-C 10 ) aryloxy, amino protecting groups, radicals R4', lipid-like moieties R5', amino acid-like moieties R6, and active moieties; A' is optionally substituted with 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, -SON2NH2, -SO2-N((C1-C6)alkyl)2, -COOH, -CONH2, and -CON((C1-C6)alkyl)2; however, i) When m is 0, A' is 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 ) heterocycloalkyl, amino protecting groups, amino acid-like moieties R6, and active moieties, A' is optionally substituted with 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, -SON2NH2, -SO2-N((C1-C6)alkyl)2, -COOH, -CONH2, and -CON((C1-C6)alkyl)2; When m is 1, A' is 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 )Aralkoxy, -(C5-C 10 )heteroaralkoxy, -(C1-C 10 )Alkyl-O-(C6-C 10 ) aryloxy, a radical R4', a lipid-like moiety R5', and an active moiety; A' is optionally substituted with 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, -SON2NH2, -SO2-N((C1-C6)alkyl)2, -COOH, -CONH2, and -CON((C1-C6)alkyl)2; ii) at least one of A and A' is a lipid-like moiety R5 or R5'; R4 is a radical of formula (VIa), [ka] R4' is a radical of formula (VIb), [ka] During the ceremony, n' is an integer from 0 to 250, m' is 0 or 1; X″ is selected from the group consisting of N, S, and O; R1″ is a radical having any of the meanings of R1, with the proviso that if X″ is O or S then 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 of 1 to 18; A'' is 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 )Aralkoxy, -(C5-C 10 )heteroaralkoxy, -(C1-C 10 )Alkyl-O-(C6-C 10) aryloxy, amino protecting groups, lipid-like moieties R5', amino acid-like moieties R6, and active moieties; A'' is optionally substituted with 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, -SON2NH2, -SO2-N((C1-C6)alkyl)2, -COOH, -CONH2, and -CON((C1-C6)alkyl)2; however, When m' is 0, A'' is 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 moiety R6, and an active moiety; A″ is optionally substituted with 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, —SON2NH2, —SO2-N((C1-C6)alkyl)2, —COOH, —CONH2, and —CON((C1-C6)alkyl)2; When m' is 1, A'' is 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)Aralkoxy, -(C5-C 10 )heteroaralkoxy, -(C1-C 10 )Alkyl-O-(C6-C 10 ) aryloxy, lipid-like moieties R5', and active moieties; A'' is optionally substituted with 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, -SON2NH2, -SO2-N((C1-C6)alkyl)2, -COOH, -CONH2, and -CON((C1-C6)alkyl)2; A''' is 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, a protecting group, a lipid-like moiety R5, and an active moiety; A''' is optionally substituted with 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, -SON2NH2, -SO2-N((C1-C6)alkyl)2, -COOH, -CONH2, and -CON((C1-C6)alkyl)2; Each R5 is independently -(C1-C 18 ) alkyl, -(C2-C 18 ) alkenyl, and radicals of formula (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XXI), (XXII), or (XXIII); [ka] JPEG2025508733000007.jpg100135 Each R5' is independently -X'(R1')-(C1-C 18 ) alkyl, -X'(R1')(C2-C 18 ) alkenyl, and radicals of formula (VII'), (VIII'), (IX'), (X'), (XI'), (XII'), (XIII'), (XIV'), (XXI'), (XXII'), or (XXIII'); [ka] JPEG2025508733000009.jpg131156In formula, 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 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 the group consisting of N, S, and O. R1' is a radical having one of the meanings of R1, with the proviso that if X' is O or S, then R1' is absent; t is 0 or 1, except that if X=O, then t is 0, and if X is other than O, then t is 1; t' is 0 or 1, except that when m is 0, t' is 1; R 22 , R 33 , and R44 is independently selected from the group consisting of hydrogen, fluorine, methyl, -CH2F, -CHF2, and -CF3; Dashed bond [ka] each is independently a single bond or alternatively a double bond; L is a biradical chain comprising one or more moieties selected from the group consisting of -CH=CH-, -C≡C-, -CH2-, -N=CH-, -CH=NH-, -NH-, -NH-NH-, -NH-N=CH-, -O-, -O(CH2)O-, -CO-, -O-(CO)-, -(CO)O-, -C(=CH2)-, -C(=NH)-, -CONH-, -NHCO-, NH(CO)NH-, -S-, -SS-, -SO-, -SO2-, -SON2NH2-, and -phenylene-; L is optionally selected from halogen, -OH, -NR a R b , -SH, -NHNH2, -COOR c , -CF3, -OCF3, [ka] and is substituted with one or more substituents selected from the group consisting of When L contains a CH2 moiety, the two hydrogen atoms attached to the carbon atom can optionally be joined to the ring: [ka] is replaced by Each R6 is independently (XV), (XVI), and (XVII). [ka] (In the formula, a', b', and c' are independently integers of 1 to 4.) is a radical selected from the group consisting of Each active moiety is independently selected from the group consisting of pharma- ceutical active agents, penetration enhancers, cell targeting agents, cosmetic active agents, and diagnostic active agents.

[0014] Using appropriate surface functionality, the lipo-polyamino acid conjugates of the present disclosure may be modified with cell targeting groups, either A, A', A'', or A''', which can actively target cells and aid in cell entry, resulting in conjugates with improved cell-specific delivery. The lipo-polyamino acid conjugates may also be modified with penetration enhancers where increased penetration into cells or skin is desired. Furthermore, the lipo-polyamino acid conjugates may also be used to deliver pharma- ceutical, cosmetically, or diagnostically active agents attached to the backbone of the A, A', A'', or A''' conjugates.

[0015] Furthermore, due to their amphiphilic nature, the lipo-polyamino acid conjugates of the present invention can form self-assembled particles in solution, such as liposomes or lipid nanoparticles that can be used to encapsulate and deliver molecules of different nature. Thus, the lipo-polyamino acid conjugates of the present invention are not only bound to the structure of the conjugate, but are also included in the self-assembled particles formed from the conjugates. It allows for the carrying and / or delivery of different active agents at the same time.Accordingly, another aspect of the present invention relates to self-assembled particles comprising a lipo-polyamino acid conjugate of formula (I) as defined herein and, optionally, one or more active agents selected from the group consisting of a pharma- ceutical active agent, a cell targeting agent, a penetration enhancer, a cosmetic active agent, a diagnostic active agent, a nucleic acid, a peptide, a protein, and mixtures thereof.

[0016] The lipo-polyamino acid conjugates of the present invention can be formulated together with excipients and carriers into various compositions, including pharmaceutical compositions, cosmetic compositions, and diagnostic compositions. Thus, another aspect of the present invention relates to compositions comprising the lipo-polyamino acid conjugates defined herein, together with one or more suitable excipients or carriers; or alternatively, self-assembled particles comprising them.

[0017] The lipo-polyamino acid conjugates of the present invention, their self-assembled particles, and compositions thereof can be used in medical, cosmetic, and diagnostic applications.

[0018] Thus, another aspect of the present invention relates to a therapeutic product comprising: a) a lipo-polyamino acid conjugate of formula (I) as defined herein (wherein at least one of A, A', A'', or A''' is a pharma- ceutical active agent); or alternatively b) a self-assembled particle comprising lipo-polyamino acid conjugate a); or alternatively c) a composition comprising lipo-polyamino acid conjugate a) or self-assembled particle b); or alternatively d) a self-assembled particle comprising a lipo-polyamino acid conjugate as defined herein and one or more active agents selected from the group consisting of a pharma- ceutical active agent, a nucleic acid, a peptide, a protein, and mixtures thereof; or alternatively e) a composition comprising self-assembled particle d), for use in medicine.

[0019] According to another aspect, the present invention relates to a diagnostic product comprising: a') a lipo-polyamino acid conjugate as defined herein (wherein at least one of A, A', A'', or A''' is a diagnostically active agent); or b') a self-assembled particle comprising lipo-polyamino acid conjugate a'); or alternatively c') a composition comprising lipo-polyamino acid conjugate a') or self-assembled particle b'); or alternatively d') a self-assembled particle comprising a lipo-polyamino acid conjugate as defined herein and a diagnostically active agent; or alternatively e') a composition comprising self-assembled particle d').

[0020] According to another aspect, the present invention relates to a cosmetic composition comprising: a'') a lipo-polyamino acid conjugate as defined herein (wherein at least one of A, A', A'', or A''' is a cosmetically active agent); or alternatively b'') a self-assembled particle comprising lipo-polyamino acid conjugate a''); or alternatively c'') a composition comprising a') or self-assembled particle b''); or alternatively d'') a self-assembled particle comprising a lipo-polyamino acid conjugate as defined herein and one or more cosmetically active agents; or alternatively e') a composition comprising self-assembled particle d'').

[0021] Another aspect of the present invention relates to the use of a lipo-polyamino acid conjugate of formula (I) as defined herein as a carrier, wherein A, A', A'', or A''' is other than an active moiety. [Brief description of the drawings]

[0022] [Figure 1] Figure 1 shows an agarose gel (2%) for the detection of free mRNA from different LNP formulations: M) free mRNA; 1) reference LNP formulation; 2) reference LNP formulation + 10% Triton X100 and 2 mg / mL heparin; 3) LNP4 formulation; 4) LNP formulation + 10% Triton X100 and 2 mg / mL heparin; 5) LNP9 formulation; 6) LNP9 formulation + 10% Triton X100 and 2 mg / mL heparin; 7) LNP12 formulation; 8) LNP12 formulation + 10% Triton X100 and 2 mg / mL heparin; 9) LNP11 formulation; 10) LNP11 formulation + 10% Triton X100 and 2 mg / mL heparin. [Diagram 2] FIG. 2 shows the in vivo mRNA transfection ability in mice of LNPs containing the lipo-polyamino acid conjugate of the present invention (LNP15) and comparative LNPs using DMG-PEG as a lipo-shield compound (total counts per gram of tissue in liver (A), ALN (B), spleen (C), and lung (D)). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0023] All terms used herein in this application are to be understood in their ordinary sense as known in the art, unless otherwise specified. Other, more specific definitions for certain terms used in this application are set forth below and are intended to apply throughout the specification and claims.

[0024] The term "about" or "around" as used herein refers to a range of values ​​of +10% of the stated value. For example, the expression "about 10" includes ±10% of 10, i.e., 9 to 11.

[0025] As used herein, the indefinite articles "a" and "an" are equivalent to "at least one" or "one or more." Unless otherwise stated, definite articles used herein, such as "the," also include the plural form of a noun.

[0026] The term "moiety" refers to a specific segment or functional group of a molecule or compound.

[0027] As used herein, the term "subject" refers to any mammal, including both humans and other mammals.

[0028] The term -(C1-Cx)alkyl refers to a saturated straight or branched hydrocarbon chain containing from 1 to x carbon atoms and only single bonds. Examples of alkyl groups can 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-Cx)alkyl refers to a saturated straight or branched hydrocarbon chain containing from 1 to x carbon atoms and only single bonds. Examples of alkyl groups can 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. x ) Alkenyl refers to an unsaturated branched or straight hydrocarbon chain containing 2 to x carbon atoms and at least one double bond. Examples of alkenyl groups can include, but are not limited to, ethenyl (i.e., vinyl), allyl, propenyl, butenyl, pentenyl and hexenyl, dodecenyl, tetradecenyl, and hexadecenyl.

[0029] The term “-(C1-C 10 "Alkoxy" refers to an alkyl group, as defined herein, containing from 1 to 10 carbon atoms, attached to the remainder of the molecule via an oxygen atom. Examples of alkoxy groups can include, but are not limited to, methoxy, ethoxy, 1-propoxy, and 2-propoxy.

[0030] The term “-(C5-C 10 "Aryl" refers to an aromatic carbocyclic monocyclic or bicyclic ring system containing from 5 to 10 carbon ring atoms. Examples of aryl groups can include, but are not limited to, phenyl, biphenyl, and naphthyl.

[0031] The term “-(C6-C 10 "Aryloxy" refers to an aryl group, as defined herein, containing 6 to 10 carbon ring atoms, attached to the remainder of the molecule via an oxygen atom. Examples of aryloxy can include, but are not limited to, phenoxy and biphenyloxy.

[0032] The term “-(C5-C 10 "Heteroaryl" refers to an aromatic carbocyclic monocyclic or bicyclic ring system containing 5 to 10 ring atoms in which at least one aromatic ring contains 1, 2, or 3 ring heteroatoms selected from N, O, and S, and the remaining ring atoms are carbon atoms. Examples of heteroaryl groups can include pyridyl, azetidinyl, furyl, pyrrolyl, thienyl, thiazolyl, oxazolyl, imidazolyl, tetrazolyl, benzofuryl, isoquinolinyl, benzothiazolyl, benzimidazolyl, benzothiazolyl, quinolyl, and quinazolyl.

[0033] The term “-(C6-C 10 "Aralkyl" refers to an aryl group, as defined herein (e.g., -(C5-C 10(aryl) refers to a lower alkyl group, as defined herein (e.g., -(C1-C6)alkyl), substituted with aryl. Examples of aralkyl groups can include, but are not limited to, benzyl, phenethyl, and methylbenzyl.

[0034] The term “-(C6-C 10 "Aralkoxy" refers to an aryl group, as defined herein (e.g., -(C5-C 10 (aryl) refers to a lower alkoxy group, as defined herein (e.g., -(C1-C6)alkoxy), substituted with (C1-C6)aryl). Examples of aralkoxy groups can include, but are not limited to, benzyloxy, phenethoxy, and methylbenzyloxy.

[0035] The term “-(C5-C 10 "Heteroaralkoxy" refers to a heteroaryl group, as defined herein (e.g., -(C5-C 10 (C1-C6)alkoxy) refers to a lower alkoxy group, as defined herein, substituted with (heteroaryl). Examples of heteroaralkoxy groups can include, but are not limited to, furyloxy, pyridyloxy, and azetidinyloxy.

[0036] The term “-(C5-C 10 )Heterocycloalkyl" refers to a 5-10 membered mono- or bicyclic (fused or bridged), saturated or unsaturated ring structure in which one or more of the ring atoms is a heteroatom selected from N, O, and S. Examples of heterocycloalkyl groups can include, but are not limited to, piperidyl, piperazyl, tetrahydropyranyl, tetrahydrofuryl, 1,4-dioxolanyl, oxazolidyl, isoxazolyl, morpholinyl, thiomorpholyl.

[0037] As used herein, the term "protecting group" refers to a group of atoms that, when attached to a reactive group of a molecule mask, reduces or prevents its reactivity. Protecting groups for carboxyl and amino groups are described, for example, in TW Green and PGM Wuts, Protective Groups in Organic Chemistry (Wiley, 3rd ed. 1999), Chapter 5 (pp. 369-451) and Chapter 7 (pp. 495-653), respectively.

[0038] The term "substituted" means that one or more hydrogen atoms of the specified atom or group are replaced with a selection from the indicated group, provided that the replacement does not exceed the normal valence of the specified atom in its current state. Combinations of substituents and / or variables are permissible.

[0039] The term "optionally substituted" means that the number of substituents can be equal to or different from 0. Unless otherwise stated, an optionally substituted group can be substituted with as many optional substituents as can be accommodated by replacing hydrogen atoms on any available carbon or nitrogen atom with non-hydrogen substituents. The group of the conjugate of the present invention can be substituted with 1, 2, 3, 4, or 5 identical or different substituents, in particular 1, 2, or 3 substituents.

[0040] In those embodiments of the invention where the substitution or unsubstitution of a particular group is not specified, i.e., no particular substitution for that group is specified, nor is the group specified to be unsubstituted, it should be understood that the possible substitution of that group is the broadest as defined herein.

[0041] Lipo-polyamino acid conjugates A first aspect of the present invention relates to a lipo-polyamino acid conjugate of formula (I), a salt thereof, or any stereoisomer or mixture of stereoisomers of a compound of formula (I) or a salt thereof: [ka] (wherein A, X, R1, R2, R3, n, m, and A' are as defined herein).

[0042] For the purposes of the present invention, the term "lipo-polyamino acid conjugate" refers to a molecule comprising a) a polyamino acid-based moiety and b) at least one lipid-like moiety. The term "lipid-like moiety" refers to a moiety that cannot itself be considered a lipid, but that structurally and / or functionally resembles a lipid. The term lipid-like moiety is intended to include moieties that can form an amphiphilic layer. The term "lipid" refers to a group of organic compounds that are insoluble in water, such as, for example, fatty acids, glycerolipids, glycerophospholipids, sphingolipids, glycolipids, sterols, etc.

[0043] There is no limitation on the type of salt of the lipo-polyamino acid conjugate that can be used, as long as it is pharma-ceutically, cosmetically, or diagnostically acceptable when used for pharmaceutical, cosmetic, or diagnostic purposes, respectively. The term "pharma-ceutically, cosmetically, or diagnostically acceptable salt" includes commonly used non-toxic salts. The preparation of the pharma-ceutically, cosmetically, or diagnostically acceptable salt of the lipo-polyamino acid conjugate of the present invention can be carried out by a method well known in the art. In general, such salts can be prepared by reacting the free acid or free base form of the lipo-polyamino acid conjugate of the present invention with a stoichiometric amount of a suitable base or acid in a suitable solvent such as water, an organic solvent, or a mixture thereof.

[0044] Examples of pharma- ceutically , cosmetically , or diagnostically acceptable salts include those from inorganic acids, such as hydrochloric, hydrobromic, sulfuric, nitric, hydroiodic, metaphosphoric, or phosphoric acid; and organic acids, such as succinic, maleic, acetic, fumaric, citric, tartaric, benzoic, trifluoroacetic, malic, lactic, formic, propionic, glycolic, gluconic, camphorsulfonic, isothionic, mucic, gentisic, isonicotinic, saccharic, glucuronic, furoic, glutamic, ascorbic, anthranilic, salicylic, phenylacetic, mandelic, embonic (pamoic), ethanesulfonic, Pantothenic acid, stearic acid, sulfanilic acid, alginic acid, and galacturonic acid; and acid addition salts formed with arylsulfonic acids, such as benzenesulfonic acid, p-toluenesulfonic acid, oxalic acid, methanesulfonic acid, or naphthalenesulfonic acid; and base addition salts formed with alkali and alkaline earth metals and organic bases, such as N,N-dibenzylethylene-diamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine), lysine, and procaine; and internally formed salts. The lipo-polyamino acid conjugates and their salts of the present invention may differ in some physical properties, but are equivalent for the purposes of the present invention.

[0045] Some of the lipo-polyamino acid conjugates of the present invention may have chiral centers that can give rise to various stereoisomers. As used herein, the term "stereoisomer" refers to all isomers of individual lipo-polyamino acid conjugates that differ only in the orientation of their atoms in space. The term stereoisomer includes mirror images (enantiomers), mixtures of mirror images (racemates, racemic mixtures), geometric isomers (cis / trans or syn / anti or E / Z), and isomers of lipo-polyamino acid conjugates that have more than one chiral center that are not mirror images of each other (diastereoisomers). The present invention relates to each of these stereoisomers and mixtures thereof as well. Thus, the lipo-polyamino acid conjugates of formula (I) are also intended to include the chemical structure of all R- and S-isomers in any ratio, for example, with enrichment of one of the possible isomers (i.e., enantiomeric excess or diastereomeric excess) and a correspondingly small ratio of the other isomers. In the case of certain amino acids, these may be available in the L- or D-configuration.

[0046] Diastereoisomers 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 give optically pure isomers. This resolution can be carried out on any chiral synthetic intermediate or polymer of the invention.

[0047] In all embodiments of the present invention referring to lipo-polyamino acid conjugates, their pharma- ceutically , cosmetically , or diagnostically acceptable salts, and any stereoisomers or mixtures of stereoisomers of the lipo-polyamino acid conjugates or their pharma-ceutically , cosmetically , or diagnostically acceptable salts, are always contemplated, even if they are not specifically mentioned.

[0048] The lipo-polyamino acid conjugate of the present invention may be in crystalline form as a free solvated lipo-polyamino acid conjugate or as a solvate (e.g., hydrate). All these forms are intended to be within the scope of the present invention. Methods of solvation are generally known in the art. For the purposes of the present invention, solvated forms with pharma- ceutically, cosmetically, or diagnostically acceptable solvents such as water, ethanol, etc. are equivalent to unsolvated forms.

[0049] Unless otherwise specified, the lipo-polyamino acid conjugates of the present disclosure also include lipo-polyamino acid conjugates that differ only in the presence of one or more isotopically enriched atoms. Examples of isotopically enriched atoms include, but are not limited to, deuterium, tritium, 13 C or 14 C, or 15 Nitrogen atoms with high N content, or 18 It is a fluorine atom that contains a lot of F.

[0050] The lipo-polyamino acid conjugates of the present invention are polymeric structures that include as repeating units polyamino acid (PAA)-based moieties of formula (XVIII): [ka] (In the ceremony, `` * " indicates the point of attachment of the PAA-based moiety to the remainder of the molecule). The orientation of the PAA-based moieties does not affect the amphiphilic behavior of the polymers described herein, and as a result, the demonstrated activity is maintained.

[0051] According to one embodiment, optionally in combination with any of the embodiments provided above or below, the lipo-polyamino acid conjugate of formula (I) has the formula (I′): [ka] (wherein A, A', X, R1, R2, R3, n, and m are as defined herein).

[0052] As described above, the lipo-polyamino acid conjugate of the present invention further comprises at least one lipid-like moiety. The lipid-like moiety can be located at either end of the PAA-based moiety. The lipo-polyamino acid conjugate of the present invention can also comprise lipid-like moieties at both ends of the molecule. For example, the lipid-like moiety can be located on the left side of the molecule of the depicted formula (I) when A is R5, or on the right side when A' is R5', or on both ends when A is R5 and A is R5', but at least one of A and A' must be a lipid-like moiety (R5 for A or R5' for A').

[0053] The lipo-polyamino acid conjugates of the present invention are characterized by their molecular weight, which may be the average molecular weight (MW) or number average molecular weight (Mn), the degree of polymerization, and the polydispersity index. The molecular weight may be measured by methods well known in the art, such as size exclusion chromatography (SEC) (also called gel permeation chromatography (GPC)), matrix-assisted laser desorption / ionization time-of-flight mass spectrometry (MALDI-TOF MS), among others. The composition and ratios may be measured by, for example, the molecular weight (MW) or molecular weight (Mn) of the polyamino acid conjugates of the present invention. 1 The compounds are characterized by H-NMR spectroscopy, some of which are illustrated in more detail in the examples below.

[0054] As used herein, the term "repeating unit" refers to a monomeric amino acid-based unit and is defined by the square brackets ([]) shown around it. The number at the bottom right of the brackets (represented by the letter "n") refers to the degree of polymerization (DP) of each monomeric unit as a statistical value. DP is calculated by dividing the corrected molecular weight of the polymer determined by the SEC-MALS technique by the molecular weight of the monomeric unit (minus the MW of the initiator). DP values ​​are reported as the median of a normal distribution that includes polymers of variable DP (depending on the inherent polydispersity). DP values ​​have a certain degree of uncertainty due to the ring-opening polymerization mechanism and may be contemplated in the context of the present invention to be within the range of ±20%, preferably ±15%, more preferably ±10%, even more preferably ±5%, and particularly preferably ±2%.

[0055] The term "polydispersity index" (PDI) is used as a measure of the broadness of the molecular weight distribution. The higher the PDI, the broader the molecular weights. The PDI of a polymer is calculated as the ratio of the weight average molecular weight (Mw) to the number average molecular weight (Mn). Polydispersity index=Mw / Mn

[0056] In the lipo-polyamino acid conjugate of formula I, n is an integer from 5 to 250. In one embodiment, optionally in combination with any of the embodiments provided above or below, n is an integer from 5 to 150, more specifically from 5 to 100, even more specifically from 5 to 50, and even more specifically from 5 to 30 or 5 to 25.

[0057] In the lipo-polyamino 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 specifically -(C 12 In another embodiment, optionally in combination with any of the above or below provided embodiments, X is N and R is -(C2-C 18 ) alkenyl, more specifically -(C 12 ) alkenyl.

[0058] In another embodiment, optionally in combination with any of the embodiments provided above or below, in the lipo-polyamino acid conjugate of formula (I), X is O and R is absent. In another embodiment, optionally in combination with any of the embodiments provided above or below, X is S and R is absent.

[0059] In the lipo-polyamino 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 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 groups, amino acid-like moieties R6, and active moieties, and A' is optionally substituted with 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, -SON2NH2, -SO2-N((C1-C6)alkyl)2, COOH, CONH2, and CON((C1-C6)alkyl). In another embodiment, optionally in combination with any of the embodiments provided above or below, m is 1 and A' is H, -OH, -(C1-C6)alkyl, -(C5 ... 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 )Aralkoxy, -(C5-C 10 )heteroaralkoxy, -(C1-C 10 )Alkyl-O-(C6-C 10) aryloxy, a radical R4', a lipid-like moiety R5', and an active moiety, where A' is optionally substituted with 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, -SON2NH2, -SO2-N((C1-C6)alkyl)2, -COOH, -CONH2, and -CON((C1-C6)alkyl)2.

[0060] In the lipo-polyamino acid conjugate of formula (I), R2 is a radical selected from the group consisting of (II), (III), (IV), and (V), and a, b, c, and d are independently integers from 1 to 4.

[0061] In one embodiment, optionally in combination with any of the embodiments provided above or below, in the lipo-polyamino acid conjugate of formula (I), R2 is a radical of formula (II), more specifically, in the radical of formula (II), a is 1 or 2.

[0062] According to another embodiment, optionally in combination with any of the embodiments provided above or below, in the lipo-polyamino acid conjugate of formula (I), R2 is a radical of formula (III), more particularly, in the radical of formula (III), b is 1 or 2.

[0063] In another embodiment, optionally in combination with any of the embodiments provided above or below, in the lipo-polyamino acid conjugate of formula (I), R2 is a radical of formula (IV), more specifically in the radical of formula (IV), c is 1 or 2.

[0064] In another embodiment, optionally in combination with any of the embodiments provided above or below, in the lipo-polyamino acid conjugate of formula (I), R2 is a radical of formula (V), more specifically in the radical of formula (V), d is 1 or 2.

[0065] In the lipo-polyamino acid conjugate of formula (I), R3 is H or -(C1-C6) alkyl. In one embodiment, optionally in combination with any of the embodiments provided above or below, in the lipo-polyamino acid conjugate of formula (I), R3 is H. According to another embodiment, optionally in combination with any of the embodiments provided above or below, in the lipo-polyamino acid conjugate of formula (I), R3 is -(C1-C6) alkyl, more specifically, R3 is -CH3.

[0066] In the lipo-polyamino acid conjugate of formula (I), A is 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 A' is selected from the group consisting of H, -OH, -(C1-C6)alkyl, -(C5 ... 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 )Aralkoxy, -(C5-C 10 )heteroaralkoxy, -(C1-C 10 )Alkyl-O-(C6-C10 ) selected from the group consisting of aryloxy, amino protecting groups, radicals R4', lipid-like moieties R5', amino acid-like moieties R6, and active moieties; A and A' are independently optionally substituted with 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, -SON2NH2, -SO2-N((C1-C6)alkyl)2, -COOH, -CONH2, and -CON((C1-C6)alkyl)2; however, i) When m is 0, A' is 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 groups, amino acid-like moieties R6, and active moieties, A' is optionally substituted with 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, -SON2NH2, -SO2-N((C1-C6)alkyl)2, -COOH, -CONH2, and -CON((C1-C6)alkyl)2; When m is 1, A' is 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 )Aralkoxy, -(C5-C 10 )heteroaralkoxy, -(C1-C 10 )Alkyl-O-(C6-C 10 ) aryloxy, a radical R4', a lipid-like moiety R5', and an active moiety; A' is optionally substituted with 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, -SON2NH2, -SO2-N((C1-C6)alkyl)2, -COOH, -CONH2, and -CON((C1-C6)alkyl)2; ii) At least one of A and A' is a lipid-like moiety R5 or R5'.

[0067] In one embodiment, optionally in combination with any of the embodiments provided above or below, in the lipo-polyamino acid conjugate of formula (I), one of A and A' is a lipid-like moiety R5 or R5' as defined herein, and the other of A and A' is other than a lipid-like moiety R5 or R5', respectively.

[0068] In another embodiment, optionally in combination with any of the embodiments provided above or below, in the lipo-polyamino acid conjugate of formula (I), A is a lipid-like moiety R5 and A' is other than a lipid-like moiety R5', more particularly, A' is 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)Aralkoxy, -(C5-C 10 )heteroaralkoxy, -(C1-C 10 )Alkyl-O-(C6-C 10 ) aryloxy, an amino protecting group, a radical R4', an amino acid-like moiety R6, and an active moiety; A' is optionally substituted with 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, -SON2NH2, -SO2-N((C1-C6)alkyl)2, -COOH, -CONH2, and -CON((C1-C6)alkyl)2.

[0069] In another embodiment, optionally in combination with any of the embodiments provided above or below, in the lipo-polyamino acid conjugate of formula (I), A' is a lipid-like moiety R5' and A is other than the lipid-like moiety R5, more specifically, A is 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 groups, the radical R4, and active moieties; A is optionally substituted with 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, -SON2NH2, -SO2-N((C1-C6)alkyl)2, -COOH, -CONH2, and -CON((C1-C6)alkyl)2.

[0070] The lipid-like moiety R5 of A in the lipo-polyamino acid conjugate of formula (I) and / or A''' of the radical R4' of formula (VIb) is independently -(C1-C 18 ) alkyl, -(C2-C 18 ) alkenyl, and radicals of formula (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XXI), (XXII), or (XXIII): [ka] (In the formula, Y, Y', Q, Q', Z, g, h, i, j, t, R 22 , R 33 , R 44 , dashed bond [ka] , and L is as defined herein.

[0071] In one embodiment, optionally in combination with any of the embodiments provided above or below, A in the lipo-polyamino acid conjugate of formula (I) and / or the lipid-like moiety R5 of A''' of radical R4' of formula (VIb) are independently -(C1-C 18 ) alkyl, -(C2-C 18 ) alkenyl, and radicals of formula (VII), (VIII), (IX), (X), (XI), (XII), (XIII), or (XIV).

[0072] 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 specifically -(C6-C 18 ) alkyl. More specifically, the lipid-like moiety R5 has the formula (XIX): [ka] (wherein k is an integer from 1 to 16, more specifically, k is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16).

[0073] 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 specifically -(C6-C 18 ) alkenyl. Even more specifically, the lipid-like moiety R5 has the formula (XX): [ka] (wherein k is an integer from 1 to 16, more specifically, 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 specifically, q is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18).

[0074] In another embodiment, optionally in combination with any of the embodiments provided above or below, the lipid-like moiety R5 has the formula (VII): [ka] (wherein g is an integer from 0 to 16, more specifically g is 0 to 12, and even more specifically g is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12).

[0075] In another embodiment, optionally in combination with any of the embodiments provided above or below, the lipid-like moiety R5 has the formula (VIII): [ka] (wherein each g is independently an integer from 0 to 16; more specifically, each g is independently an integer from 0 to 12; even more specifically, each g is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12).

[0076] In another embodiment, optionally in combination with any of the embodiments provided above or below, the lipid-like moiety R5 has the formula (IX): [ka] 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 ) alkenyl). More specifically, in the lipid-like moiety R5 of formula (IX), each Rx is independently a radical selected from formulas (ixa) and (ixb): [ka] in which 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 specifically, k is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16, p and q are independently integers from 0 to 18, more specifically, 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 specifically, r is 0, 1, 2, 3, 4, 5, or 6.

[0077] In one particular embodiment, optionally in combination with any of the embodiments provided above or below, in the lipid-like moiety 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 moiety R5 of formula (IX), Y and Y' are different.

[0078] In another particular embodiment, optionally in combination with any of the embodiments provided above or below, the lipid-like moiety R5 of formula (IX) is selected from formulas (ix1), (ix2), (ix3), (ix4), (ix5), (ix6), (ix7), and (ix8): [ka] (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; each p and each q is independently an integer from 0 to 18, more specifically each p and each q is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18; each r is independently an integer from 0 to 6, more specifically each r is independently 0, 1, 2, 3, 4, 5, or 6).

[0079] According to certain embodiments, 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 other certain embodiments, optionally in combination with any of the embodiments provided above or below, in the lipid-like moiety R5 of formula (ix6) and (ix7), each r has the same meaning and each q has the same meaning.

[0080] In another embodiment, optionally in combination with any of the embodiments provided above or below, the lipid-like moiety R5 has the formula (X): [ka] 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 specifically, in the lipid-like moiety R5 of formula (X), each Ry is independently a radical selected from formulas (xa), (xb), and (xc): [ka] in which 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 specifically, k is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16, p and q are independently integers from 0 to 18, more specifically, 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 specifically, r is 0, 1, 2, 3, 4, 5, or 6.

[0081] In one particular 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 particular 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.

[0082] In another particular embodiment, optionally in combination with any of the embodiments provided above or below, the lipid-like moiety R5 of formula (X) is selected from formulas (x1), (x2), (x3), and (x4): [ka] wherein k is an integer from 1 to 16, more specifically k is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16; each p and each q is independently an integer from 0 to 18, more specifically each p and each q is 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 specifically i is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12.

[0083] In another embodiment, optionally in combination with any of the embodiments provided above or below, the lipid-like moiety R5 has the formula (XI): [ka] 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 specifically, each h is independently 1 to 12, even more specifically, each h is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12; i is an integer from 0 to 18; more specifically, i is 0 to 12, even more specifically, i is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12. More specifically, in the lipid-like moiety R5 of formula (XI), each Ry is independently a radical selected from formulas (xia), (xib), and (xic): [ka] in which 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 specifically, k is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16, p and q are independently integers from 0 to 18, more specifically, 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 specifically, r is 0, 1, 2, 3, 4, 5, or 6.

[0084] In one particular 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 particular 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.

[0085] In another particular embodiment, optionally in combination with any of the embodiments provided above or below, the lipid-like moiety R5 of formula (XI) has the formula (xi1): [ka] (wherein each p and each q is independently an integer from 0 to 18, more specifically each p and each q is 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 specifically 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 specifically i is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12).

[0086] In another embodiment, optionally in combination with any of the embodiments provided above or below, the lipid-like moiety R5 has the formula (XII): [ka] (wherein i is an integer from 0 to 18; more specifically, i is 0 to 12; even more specifically, 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 specifically, each j is independently selected from 0 to 12; even more specifically, each j is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12).

[0087] In another embodiment, optionally in combination with any of the embodiments provided above or below, the lipid-like moiety R5 has the formula (XIII): [ka] wherein i is an integer from 0 to 18; more specifically, i is 0 to 12; even more specifically, i is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12; and each j is independently from 0 to 18; more specifically, each j is independently selected from 0 to 12; even more specifically, j is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12.

[0088] In another embodiment, optionally in combination with any of the embodiments provided above or below, the lipid-like moiety R5 has the formula (XIV): [ka] 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, and each Ry and Rz is independently -(C1-C 18) alkyl or -(C2-C 18 ) alkenyl, where i is an integer from 0 to 18, more particularly, i is 0 to 12, and 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 a radical selected from formula (xiva) and (xivb): [ka] in which 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 specifically, k is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16, p and q are independently integers from 0 to 18, more specifically, 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 specifically, r is 0, 1, 2, 3, 4, 5, or 6.

[0089] In one particular 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 particular 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 particular 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 particular 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'.

[0090] In another particular embodiment, optionally in combination with any of the embodiments provided above or below, the lipid-like moiety R5 of formula (XIV) is selected from formulas (xiv1) and (xiv2): [ka] (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 0 to 12, more specifically i is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12).

[0091] In another embodiment, optionally in combination with any of the embodiments provided above or below, the lipid-like moiety R5 has the formula (XXI): [ka] (wherein i is an integer from 0 to 18, more specifically i is 0 to 12, even more specifically i is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, and each j is an integer from 0 to 18, more specifically each j is independently selected from 0 to 12, even more specifically each j is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12). In one particular embodiment, optionally in combination with any of the embodiments provided above or below, the lipid-like moiety R5 of formula (XXI) has formula (xxi1): [ka] (wherein 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).

[0092] In another embodiment, optionally in combination with any of the embodiments provided above or below, the lipid-like moiety R5 has the formula (XXII): [ka] wherein Q and Q' are independently selected from -OCORy and -COORy, and each Ry is independently -(C1-C 18 ) alkyl or -(C2-C 18 ) alkenyl; i is an integer from 0 to 18, more particularly, i is 0 to 12, and even more particularly, i is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12). More specifically, in the lipid-like moiety R5 of formula (XXII), each Ry is independently a radical selected from formulas (xxiia) and (xxiib): [ka] in which 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 specifically, k is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16, p and q are independently integers from 0 to 18, more specifically, 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 specifically, r is 0, 1, 2, 3, 4, 5, or 6.

[0093] In one particular embodiment, optionally in combination with any of the embodiments provided above or below, in the lipid-like moiety R5 of formula (XXII), Q and Q' are both -OCORy. In another particular embodiment, optionally in combination with any of the embodiments provided above or below, in the lipid-like moiety R5 of formula (XXII), Q and Q' are both -COORy.

[0094] In another particular embodiment, optionally in combination with any of the embodiments provided above or below, the lipid-like moiety R5 of formula (XXII) is selected from formulas (xxii1) and (xxii2): [ka] (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).

[0095] In another embodiment, optionally in combination with any of the embodiments provided above or below, the lipid-like moiety R5 has the formula (XXIII): [ka] (In the formula, t, R 22 , R 33 , R 44 , dashed bond [ka] , and L is as defined herein.

[0096] In more specific embodiments, in the radical of formula (XXIII), each dashed bond in the alkyl chain attached to the chroman ring is a single bond, and R 22 , R 33 , and R 44 is selected from the following meanings: 22 , R 33 , and R 44 is methyl, and (ii) R 22 , R 44 is methyl, R 33 is hydrogen, and (iii) R 33 and R 44 is methyl, R 22 is hydrogen, and (iv) R 44 is methyl, R 22 and R 33 is hydrogen. Even more specifically, each of the dashed bonds in the alkyl chain attached to the chroman ring is a single bond, and R 22 , R 33, and R 44 is methyl. Even more specifically, formula (XXIII) has the formula (xxiii1): [ka]

[0097] In another more specific embodiment, in the radical of formula (XXIII), each of the dashed bonds in the alkyl chain attached to the chroman ring is a double bond, and R 22 , R 33 , and R 44 is selected from the following meanings: 22 , R 33 , and R 44 is methyl, and (ii) R 22 , R 44 is methyl, R 33 is hydrogen, and (iii) R 33 and R 44 is methyl, R 22 is hydrogen, and (iv) R 44 is methyl, R 22 and R 33 is hydrogen. In more specific embodiments, each of the dashed bonds in the alkyl chain attached to the chroman ring is a double bond, and R 22 , R 33 , and R 44 is methyl.

[0098] In another embodiment, optionally in combination with any of the embodiments provided above or below, A is a lipid-like moiety R5 having formula (XXIII), X is O and R1 is absent, i.e. the lipo-polyamino acid conjugate of formula (I) has formula (Ih): [ka] (In the formula, A', R2, R3, m, n, R 22 , R 33 , R 44 , and dashed bonds [ka] is as defined herein).

[0099] In another embodiment, optionally in combination with any of the embodiments provided above or below, A is a lipid-like moiety R5 having formula (XXIII) and t is 1, i.e. the lipo-polyamino acid conjugate of formula (I) has formula (Ij). [ka] (In the formula, A', R2, R3, m, n, R 22 , R 33 , R 44 , L, and dashed bonds [ka] is as defined herein).

[0100] In certain embodiments, optionally in combination with any of the embodiments provided above or below, in the radical of formula (XXIII), the linker L is selected from halogen, —OH, —NR aa R bb , -SH, -NHNH2, -COOR cc , -CF3, and OCF3 (C1-C 12 ) Alkylene (R aa , R bb , and R cc is selected from the group consisting of H, -phenyl, -(C-C)alkyl, -(C-C)alkenyl, (C-C)alkylphenyl, and -phenyl(C-C)alkyl; -(C-C)alkyl-CO-: -CO-(C-C)-; and a biradical independently selected from the group consisting of a biradical of formula (IIID), (IVD), (VD), (VID), (VIID), (VIIID), (IXD), (XD), (XID), (XIID), (XIIID), (XIVD), (XVD), (XVID), (XVIID), (XVIIID), or (XIXD): [ka] JPEG2025508733000050.jpg172130 (in the formula, * " represents the point of attachment of the biradical L to the oxygen atom of X or the vitamin E-based moiety, and " *3 " represents the point of attachment of the biradical L to X, and " *4 " represents the point of attachment of the biradical to an oxygen atom of the vitamin E based moiety; 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, with the proviso that if b1 is 0 then at least one of a1 or c2 is other than 0, and if g1 is 0 then at least one of f1 or h1 is other than 0; X1' is -O or -NH-; p1 is 0 or 1, Dashed Bond [ka] are each independently a single bond or alternatively a double bond).

[0101] When a bond point is depicted, the bond point is referred to herein as " * ". Unless a particular point of attachment is specified, this means that the linker can be attached to the rest of the molecule interchangeably in any orientation.

[0102] In one embodiment, optionally in combination with one or more of the features of the various embodiments described above or below, in the radical of formula (XXIII), L is -(C 12 ) alkylene-, more specifically -(C1-C6) alkyl-, optionally substituted as defined herein.

[0103] In another embodiment, optionally in combination with one or more of the 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-, optionally substituted as defined herein.

[0104] In another embodiment, optionally in combination with one or more of the features of the various embodiments described above or below, in the radical of formula (XXIII), L is a biradical of formula (IIID), more particularly a biradical of formula (IIID), b1 is 0 and a1+c1 is selected from 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12, and even more particularly, L is [ka] is a biradical of formula (IIID) selected from the group consisting of:

[0105] In another embodiment, optionally in combination with one or more of the features of the various embodiments described above or below, in the radical of formula (XXIII), L is a biradical selected from formulae (IVD), (VD) and (VID), more particularly in the biradical of formula (IVD), a1 is 1 and the dashed bond is a double bond, i.e. the biradical of formula (IVD) has formula (IVDa), and in the biradical of formula (VD), the dashed bond is more particularly a double bond, i.e. the biradical of formula (VD) has formula (VDa). [ka]

[0106] In another embodiment, optionally in combination with one or more of the features of the various embodiments described above or below, in the radical of formula (XXIII), L is a biradical selected from formulae (VID), (VIID) and (VIIID), more particularly in the biradical of formula (VIIID), a1 is 1.

[0107] In another embodiment, optionally in combination with one or more of the features of the various embodiments described above or below, in the radical of formula (XXIII), L is a radical of formula (IXD), more specifically a biradical of formula (IXD) in which b1 and g1 are 0 and a1, c1, d1, e1, f1 and h1 are 1, i.e. a biradical of formula (IXDa). [ka]

[0108] In another embodiment, optionally in combination with one or more of the features of the various embodiments described above or below, in the radical of formula (XXIII), L is a biradical selected from formulae (XD) and (XID), more specifically, in the biradicals of formulae (XD) and (XID), b1 and g1 are 0 and a1, c1, d1, e1, f1, and h1 are 1, i.e., the biradicals of formulae (XD) and (XID) have the formulae (XDa) and (XIDa), respectively. [ka]

[0109] In another embodiment, optionally in combination with one or more of the features of the various embodiments described above or below, in the radical of formula (XXIII), L is a biradical selected from formulas (XIID) and (XIIID), more particularly in the biradicals of formulas (XIID) and (XIIID), b1 is 0 and a1, c1, and d1 are 1.

[0110] In another embodiment, optionally in combination with one or more of the features of the various embodiments described above or below, in the radical of formula (XXIII), L is a biradical selected from formulae (XIVD), (XVD), (XVID), (XVIID) and (XVIIID), more particularly in the biradicals of formulae (XIVD), (XVD), (XVID), (XVIID) and (XVIIID), b1 is 0 and a1 and c1 are 1.

[0111] In another embodiment, optionally in combination with one or more of the characteristics of the various embodiments described above or below, in the radical of formula (XXIII), L is a biradical of formula (XIXD), p1 is 0, j1 and k1 are 1. In another embodiment, optionally in combination with one or more of the characteristics of the various embodiments described above or below, in the radical of formula (XXIII), L is a biradical of formula (XIXD), p1 is 1, X1' is -NH-, j1 and k1 are 1. In another embodiment, optionally in combination with one or more of the characteristics of the various embodiments described above or below, in the radical of formula (XXIII), L is a biradical selected from formula (XIXD), p1 is 1, X1' is -O-, j1 and k1 are 1.

[0112] According to one embodiment, optionally in combination with any of the embodiments provided above or below, in the lipo-polyamino acid conjugate of formula (I), A is a)-(C1-C 18 ) alkyl, more specifically -(C6-C 18 ) alkyl, and more particularly a radical of formula (XIX) as defined above; b)-(C2-C 18 ) alkenyl, more specifically -(C6-C 18 ) alkenyl, and more particularly a radical of formula (XX) as defined above; c) a radical of formula (VII) as defined herein; d) a radical of formula (VIII) as defined herein; e) radicals of formula (IX) as defined herein, more particularly radicals selected from formulae (ix1), (ix2), (ix3), (ix4), (ix5), (ix6), (ix7), and (ix8) as defined above; f) radicals of formula (X) as defined herein, more particularly radicals selected from formulae (x1), (x2), (x3) and (x4) as defined above; g) a radical of formula (XI) as defined herein, more particularly a radical of formula (xi1) as defined above; h) a radical of formula (XII) as defined herein; i) a radical of formula (XIII) as defined herein; j) a radical of formula (XIV) as defined herein, more particularly a radical selected from formulae (xiv1) and (xiv2); k) a radical of formula (XXI) as defined herein, more particularly a radical of formula (xxi1) as defined above; l) radicals of formula (XXII) as defined herein, more particularly radicals selected from formulae (xxii1) and (xxii2); and m) a radical of formula (XXIII) as defined herein a lipid-like moiety R selected from the group consisting of 5 It is.

[0113] In another embodiment, optionally in combination with any of the embodiments provided above or below, in the lipo-polyamino acid conjugate of formula (I), A and R1 are the same and -(C1-C 18 ) alkyl and X is N. More specifically, in this embodiment, the lipo-polyamino acid conjugate of formula (I) has formula (Ia): [ka] (wherein A', R2, R3, m, n, are as defined herein, and 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). Even more specifically, in the lipo-polyamino acid conjugate of formula (Ia), each k has the same meaning.

[0114] According to one embodiment, optionally in combination with any of the embodiments provided above or below, in the lipo-polyamino acid conjugate of formula (I), the lipid-like moiety R5 as defined herein, m is 0 and A' is H.

[0115] In another embodiment, optionally in combination with any of the embodiments provided above or below, in the lipo-polyamino acid conjugate of formula (I), A is a lipid-like moiety R5 as defined herein, m is 0, and A' is an amino protecting group. Any suitable amino protecting group known in the art may be used, including but not limited to. Non-limiting examples of amino protecting groups include acyl-based groups, carbamate-based groups, imide-based groups, sulfonamide-based groups, and the like. In certain embodiments, the amino protecting group is selected from the group consisting of acetyl, methyloxycarbonyl, benzyloxycarbonyl (Cbz), p-methoxybenzyloxycarbonyl, t-butyloxycarbonyl (Boc), 9-fluorenylmethyloxy-carbonyl (Fmoc), allyloxycarbonyl (Alloc), 2,2,2-trichloroethoxycarbonyl group (Troc), benzoyl (Bz), benzyl (Bn), p-methoxybenzyl (PMB), 3,4-dimethoxybenzyl (DMPM), p-methoxyphenyl (PMP), tosyl (Ts), trimethylsilylethoxycarbonyl (Teoc), benzhydryl, triphenylmethyl (trityl), (4-methoxyphenyl)diphenylmethyl (MMT), dimethoxytrityl (DMT), and diphenylphosphino, and even more particularly, the amino protecting group is acetyl.

[0116] Introduction and removal of amino 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 7 (pp. 495-653).

[0117] According to another embodiment, optionally in combination with any of the embodiments provided above or below, in the lipo-polyamino acid conjugate of formula (I), A is a lipid-like moiety R5 as defined herein, m is 1, A' is a radical R4', R4' is a radical of formula (VIb): [ka] (In the formula, n' is an integer from 5 to 250, X″ is selected from the group consisting of N, S, and O; R1″ is a radical having any of the meanings of R1, with the proviso that if X′ is O or S then 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 of 1 to 18; A''' is 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) selected from the group consisting of heterocycloalkyl, protecting groups, lipid-like moieties R5, and active moieties, where A''' is optionally substituted with 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, -SON2NH2, -SO2-N((C1-C6)alkyl)2, -COOH, -CONH2, and -CON((C1-C6)alkyl)2; That is, the lipo-polyamino acid conjugate of formula (I) has the formula (Ib): [ka] (wherein R5, A''', X, X'', R1, R1'', R2, R2', R3, R3', n, n', e, f, B, and B' are as defined herein).

[0118] All embodiments described herein relating to the meanings of A, X, R1, R2, and R3 in the lipo-polyamino acid conjugate of formula (I) also apply to the meanings of A''', X'', R1'', R2', and R3', respectively, in the lipo-polyamino acid conjugate of formula (Ib).

[0119] In one particular embodiment, the lipo-polyamino acid conjugate of formula (Ib) is a dimer in which 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, respectively.

[0120] According to another embodiment, optionally in combination with any of the embodiments provided above or below, in the lipo-polyamino acid conjugate of formula (I), A is a lipid-like moiety R5 as defined herein, m is 0, A' is an amino acid-like moiety R6, R6 being selected from the group consisting of (XV), (XVI) and (XVII): [ka] (wherein a', b', and c' are independently integers from 1 to 4).

[0121] In one particular embodiment, in the lipo-polyamino acid conjugate of formula (I), R2 is a radical of formula (II), A is a lipid-like moiety R5 as defined herein, m is 0, A' is an amino acid-like moiety R6, and R6 is a radical of formula (XV), i.e., the lipo-polyamino acid conjugate of formula (I) has the formula (IC): [ka] (wherein X, R1, R3, R5, n, a, and a' are as defined herein). More specifically, in the lipo-polyamino acid conjugate of formula (IC), a and a' have the same meaning, and even more specifically, a and a' are both 1 or 2.

[0122] In another more specific embodiment, in the lipo-polyamino acid conjugate of formula (I), R2 is a radical of formula (III), A is a lipid-like moiety R5 as defined herein, m is 0, A' is an amino acid-like moiety R6, and R6 is a radical of formula (XVI), i.e. the lipo-polyamino acid conjugate of formula (I) has the formula (Id): [ka] (wherein X, R1, R3, R5, n, b, and b' are as defined herein). More specifically, in the lipo-polyamino acid conjugate of formula (Id), b and b' have the same meaning, and even more specifically, b and b' are both 1 or 2.

[0123] In another more specific embodiment, in the lipo-polyamino acid conjugate of formula (I), R2 is a radical of formula (IV), A is a lipid-like moiety R5 as defined herein, m is 0, A' is an amino acid-like moiety R6, and R6 is a radical of formula (XVII), i.e. the lipo-polyamino acid conjugate of formula (I) has the formula (Ie): [ka] (wherein X, R1, R3, R5, n, c, and c' are as defined herein). More specifically, in the lipo-polyamino acid conjugate of formula (Ie), c and c' have the same meaning, and even more specifically, c and c' are both 1 or 2.

[0124] In another more specific embodiment, in the lipo-polyamino acid conjugate of formula (I), R2 is a radical of formula (IV), A is a lipid-like moiety R5 as defined herein, and m is 0, i.e., the lipo-polyamino acid conjugate of formula (I) has the formula (Ig): [ka] (wherein X, R1, R3, R5, n, and c are as defined herein; A' is 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 with 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, -SON2NH2, -SO2-N((C1-C6)alkyl)2, -COOH, -CONH2, and -CON((C1-C6)alkyl)2, more specifically A' is methyl).

[0125] In another more specific embodiment, in the lipo-polyamino acid conjugate of formula (I), R2 is a radical of formula (IV), A is a lipid-like moiety R5 as defined herein, and m is 1, i.e., the lipo-polyamino acid conjugate of formula (I) has the formula (Ig'): [ka] is a lipid-like moiety R5 and A' is a lipid-like moiety R5' as defined herein.

[0126] In another embodiment, optionally in combination with any of the embodiments provided above or below, in the lipo-polyamino acid conjugate of formula (I), A is a lipid-like moiety R5 as defined herein, m is 1, and A' is an active moiety selected from the group consisting of a pharma- ceutical active agent, a cell targeting agent, a penetration enhancer, a cosmetically active agent, and a diagnostically active agent.

[0127] The active moiety in A' may be directly bonded to the nitrogen atom of the lipo-polyamino acid conjugate, or alternatively, it may be bonded via a linker. The nature of the linker is not limited, so long as it can be bonded to the remainder of the molecule by a chemically feasible bond. For example, the linker may be a biradical chain comprising one or more moieties selected from the group consisting of -CH=CH-, -C≡C-, -CH2-, -N=CH-, -CH=NH-, -NH-, -NH-NH-, -NH-N=CH-, -O-, -O(CH2)O-, -CO-, -O(CO)-, -COO-, -C(=CH2)-, -C(=NH)-, -CONH-, -NHCO-, -NH(CO)NH-, -S-, -SS-, -SO-, -SO2-, -SONH2-, -phenylene-, and the like. The linker may comprise 1 to 50 moieties, more specifically 2 to 30 or 2 to 20 or 2 to 15 moieties, as defined above, and may be bonded to the nitrogen atom of the PAA by a chemically feasible bond selected from the group consisting of an amine bond, an amide bond, a carbamate bond or a urea bond.

[0128] The lipid-like moiety R5' of the lipo-polyamino acid conjugate A' of formula (I) and A'' of the radical R4 of formula (VIa) are independently -X'(R1')-(C1-C 18 ) alkyl, -X'(R1')-(C2-C 18 ) alkenyl, and radicals of formula (VII'), (VIII'), (IX'), (X'), (XI'), (XII'), (XIII'), (XIV'), (XXI'), (XXII'), or (XXIII'): [ka] (In the formula, Y, Y', Q, Q', Z', X', R1', g, h, i, j, t', R 22 , R 33 , R 44 , dashed bond [ka] , and L is as defined herein.

[0129] In one embodiment, optionally in combination with any of the embodiments provided above or below, the lipid-like moiety R5' in A' of the lipo-polyamino acid conjugate of formula (I) and / or A'' of the radical R4 of formula (VIa) is independently -X'(R1')-(C1-C 18 ) alkyl, X'(R1')-(C2-C 18 ) alkenyl, and radicals of formula (VII'), (VIII'), (IX'), (X'), (XI'), (XII'), (XIII'), or (XIV').

[0130] 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 specifically -X'(R1')-(C6-C 18 ) alkyl. More specifically, the lipid-like moiety R5' has the formula (XIX'): [ka] (wherein X' and R1' are as defined herein, and k is an integer from 1 to 16, more specifically, k is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16).

[0131] 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, X' is N, and R' is (C1-C 18 ) alkyl, more specifically the lipid-like moiety R5′ has the formula (XIX″): [ka] (wherein X' and R1' are as defined herein, and 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 even more specifically each k has the same meaning).

[0132] 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 specifically -X'(R1')-(C6-C 18 ) alkenyl. Even more specifically, the lipid-like moiety R5' has the formula (XX'): [ka] (wherein X' and R1' are as defined herein; k is an integer from 1 to 16, more specifically 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 specifically q is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18).

[0133] In another embodiment, optionally in combination with any of the embodiments provided above or below, the lipid-like moiety R5' has the formula (VII'): [ka] (wherein g is an integer from 0 to 18, more specifically q is 0 to 12, and even more specifically g is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12).

[0134] In another embodiment, optionally in combination with any of the embodiments provided above or below, the lipid-like moiety R5' has the formula (VIII'): [ka] (wherein each g is independently an integer from 0 to 18; more specifically, each g is independently an integer from 0 to 12; even more specifically, each g is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12).

[0135] In another embodiment, optionally in combination with any of the embodiments provided above or below, the lipid-like moiety R5' has the formula (IX'): [ka] wherein X′ and R′ are as defined herein; Y and Y′ are independently selected from —OH, —COOR, and —OCOR; and each R is independently —(C 18 ) alkyl or -(C2-C 18 ) alkenyl). More specifically, in the lipid-like moiety R5' of formula (IX'), each Rx is independently a radical selected from formulas (ixa') and (ixb'): [ka] (wherein X' and R1' are as defined herein, 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 specifically, k is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16, p and q are independently integers from 0 to 18, more specifically, 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; r is an integer from 0 to 6, more specifically, r is 0, 1, 2, 3, 4, 5, or 6).

[0136] In one particular embodiment, optionally in combination with any of the embodiments provided above or below, in the lipid-like moiety R5' of formula (IX'), Y and Y' are the same. In another particular embodiment, optionally in combination with any of the embodiments provided above or below, in the lipid-like moiety of formula (IX'), Y and Y' are different.

[0137] In another particular embodiment, optionally in combination with any of the embodiments provided above or below, the lipid-like moiety R5' of formula (IX') is selected from formulas (ix1'), (ix2'), (ix3'), (ix4'), (ix5'), (ix6'), (ix7'), and (ix8'): [ka] (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; each p and each q is independently an integer from 0 to 18, more specifically each p and each q is 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 specifically each r is independently 0, 1, 2, 3, 4, 5, or 6).

[0138] In certain embodiments, 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 particular 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.

[0139] In one embodiment, optionally in combination with any of the embodiments provided above or below, the lipid-like moiety R5' has the formula (X'): [ka] wherein X′ and R′ are as defined herein; Q and Q′ are independently selected from —OCORy and —COORy; and each Ry is independently —(C1-C 18 ) alkyl or -(C2-C 18 ) alkenyl, where each h is independently an integer from 1 to 18, more specifically, each h is independently 1 to 12, even more specifically, 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 specifically, i is 0 to 12, even more specifically, i is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12. More specifically, in the lipid-like moiety R5 of formula (X), each Ry is independently a radical selected from formula (xa'), (xb'), and (xc'): [ka] (wherein X' and R1' are as defined herein, 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 specifically, k is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16, p and q are independently integers from 0 to 18, more specifically, 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; r is an integer from 0 to 6, more specifically, r is 0, 1, 2, 3, 4, 5, or 6).

[0140] In one particular 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 particular 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.

[0141] In another particular embodiment, optionally in combination with any of the embodiments provided above or below, the lipid-like moiety R5' of formula (X') is selected from formulas (x1'), (x2'), (x3'), and (x4'): [ka] wherein X' and R1' are as defined herein; k is an integer from 1 to 16, more specifically k is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16; each p and each 1 is independently an integer from 0 to 18, more specifically each p and each q is 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 specifically i is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12.

[0142] In one embodiment, optionally in combination with any of the embodiments provided above or below, the lipid-like moiety R5' has the formula (XI'): [ka] (X′ and R′ are as defined herein; Q and Q′ are independently selected from —OCORy and —COORy; and each Ry is independently —(C1-C 18 ) alkyl or -(C2-C 18) alkenyl, where 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 independently a radical selected from formula (xia'), (xib'), and (xic'): [ka] (wherein X' and R1' are as defined herein, 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 specifically, k is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16, p and q are independently integers from 0 to 18, more specifically, 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; r is an integer from 0 to 6, more specifically, r is 0, 1, 2, 3, 4, 5, or 6).

[0143] In one particular 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 particular 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.

[0144] In another particular embodiment, optionally in combination with any of the embodiments provided above or below, the lipid-like moiety R5' of formula (XI') has the formula (xi1'): [ka] (wherein X' and R' are as defined herein; each p and each q is independently an integer from 0 to 18, more specifically each p and each 1 is 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 specifically 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 specifically i is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12.

[0145] In one embodiment, optionally in combination with any of the embodiments provided above or below, the lipid-like moiety R5' has the formula (XII'): [ka] (wherein X' and R1' are as defined herein; i is an integer from 0 to 18, more specifically, i is 0 to 12, and even more specifically, 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 specifically, each j is independently selected from 0 to 12, and even more specifically, each j is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12).

[0146] In one embodiment, optionally in combination with any of the embodiments provided above or below, the lipid-like moiety R5' has the formula (XIII'): [ka] (wherein X' and R1' are as defined herein; i is an integer from 0 to 18; more specifically, i is 0 to 12; even more specifically, 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 specifically, each j is independently selected from 0 to 12; even more specifically, each j is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12).

[0147] In another embodiment, optionally in combination with any of the embodiments provided above or below, the lipid-like moiety R5' has the formula (XIV'): [ka] wherein X′ and R′ 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, and each Ry and Rz is independently —(C1-C 18 ) alkyl or -(C2-C 18 ) alkenyl, where i is an integer from 0 to 18, more specifically, i is 0 to 12, and even more specifically, i is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12). More specifically, in the lipid-like moiety R5' of formula (XIV'), R y is independently a radical selected from formulae (xiva) and (xivb): [ka] in which 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 specifically, k is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16, p and q are independently integers from 0 to 18, more specifically, 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 specifically, r is 0, 1, 2, 3, 4, 5, or 6.

[0148] In one particular 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 particular 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 particular 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 particular 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'.

[0149] In another particular embodiment, optionally in combination with any of the embodiments provided above or below, the lipid-like moiety R5' of formula (XIV') is selected from formulas (xiv1') and (xiv2'): [ka] wherein X' and R' 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.

[0150] In another embodiment, optionally in combination with any of the embodiments provided above or below, the lipid-like moiety R5' has the formula (XXI'): [ka] (wherein X' and R1' are as defined herein; i is an integer from 0 to 18, more specifically, i is from 0 to 12, even more specifically, 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 specifically, each j is independently selected from 0 to 12, even more specifically, each j is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12). In one particular embodiment, optionally in combination with any of the embodiments provided above or below, the lipid-like moiety R5' of formula (XXI') has formula (xxi1'): [ka] In another embodiment, optionally in combination with any of the embodiments provided above or below, the lipid-like moiety R5' has the formula (XXII'): [ka] wherein X′ and R′ are as defined herein; Q and Q′ are independently selected from —OCORy and —COORy; and each Ry is independently —(C1-C 18 ) alkyl or -(C2-C 18) alkenyl, where i is an integer from 0 to 18, more particularly, i is 0 to 12, and 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 a radical selected from formulas (xxiia) and (xxiib): [ka] in which 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 specifically, k is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16, p and q are independently integers from 0 to 18, more specifically, 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 specifically, r is 0, 1, 2, 3, 4, 5, or 6.

[0151] In one particular embodiment, optionally in combination with any of the embodiments provided above or below, in the lipid-like moiety R5' of formula (XXII'), Q and Q' are both -OCORy. In another particular embodiment, optionally in combination with any of the embodiments provided above or below, in the lipid-like moiety R5' of formula (XXII'), Q and Q' are both -COORy.

[0152] In another particular embodiment, optionally in combination with any of the embodiments provided above or below, the lipid-like moiety R5' of formula (XXII') is selected from formulas (xxii1'), and (xxii2'): [ka] (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).

[0153] In another embodiment, optionally in combination with any of the embodiments provided above or below, the lipid-like moiety R5 has the formula (XXIII'): [ka] (In the formula, t', R 22 , R 33 , R 44 , dashed bond [ka] , and L is as defined herein.

[0154] In more specific embodiments, in the radical of formula (XXIII′), each of the dashed bonds in the alkyl chain attached to the chroman ring is a single bond, and R 22 , R 33 , and R 44 is selected from the following meanings: 22 , R 33 , and R 44 is methyl, and (ii) R 22 , R 44 is methyl, R 33 is hydrogen, and (iii) R 33 and R 44 is methyl, R 22 is hydrogen, and (iv) R 44 is methyl, R 22 and R 33 is hydrogen. Even more specifically, each of the dashed bonds in the alkyl chain attached to the chroman ring is a single bond, and R 22 , R 33 , and R44 is methyl. Even more specifically, formula (XXIII') has the formula (xxiii1'): [ka]

[0155] In another more specific embodiment, in the radical of formula (XXIII′), each of the dashed bonds in the alkyl chain attached to the chroman ring is a double bond, and R 22 , R 33 , and R 44 is selected from the following meanings: 22 , R 33 , and R 44 is methyl, and (ii) R 22 , R 44 is methyl, R 33 is hydrogen, and (iii) R 33 and R 44 is methyl, R 22 is hydrogen, and (iv) R 44 is methyl, R 22 and R 33 is hydrogen. In more specific embodiments, each of the dashed bonds in the alkyl chain attached to the chroman ring is a double bond, and R 22 , R 33 , and R 44 is methyl.

[0156] In another embodiment, optionally in combination with any of the embodiments provided above or below, A is a lipid-like moiety R5 having the formula (XXIII′), m is 0 and t′ is 1, i.e. the lipo-polyamino acid conjugate of formula (I) has the formula (Ih′): [ka] (In the formula, A, X, R1, R2, R3, n, R 22 , R 33 , R 44 , L, and dashed bonds [ka] is as defined herein).

[0157] In another embodiment, optionally in combination with any of the embodiments provided above or below, A is a lipid-like moiety R5 having the formula (XXIII′) and m is 1, i.e. the lipo-polyamino acid conjugate of formula (I) has the formula (Ij′): [ka] (In the formula, A', R2, R3, m, n, R 22 , R 33 , R 44 , L, and dashed bonds [ka] is as defined herein).

[0158] According to certain embodiments, optionally in combination with any of the embodiments provided above or below, in the radical of formula (XXIII′), the linker L is selected from the group consisting of halogen, —OH, —NR aa R bb , -SH, -NHNH2, -COOR cc , -CF3, and -OCF3, optionally substituted with one or more substituents selected from the group consisting of -X1'-(C1-C 12 ) alkylene; R aa , R bb , and R cc is selected from the group consisting of H, -phenyl, -(C1-C6)alkyl, -(C2-C6)alkenyl, -(C1-C6)alkylphenyl, and phenyl(C1-C6)alkyl; X'-(C1-C6)alkyl-CO-; and a biradical of formula (IIID'), (IVD'), (VD'), (VID'), (VIID), (VIIID), (IXD'), (XD'), (XID'), (XIID'), (XIIID'), (XIVD'), (XVD'), (XVID'), (XVIID'), (XVIIID'), or (XIXD'): [ka] JPEG2025508733000099.jpg99117 (In the ceremony, `` * " represents the point of attachment of the biradical L to the oxygen atom of the PAA or vitamin E-based moiety, and " *3 " represents the point of attachment of the biradical L to PAA, and " *4 " represents the point of attachment of the biradical to an oxygen atom of the vitamin E based moiety; 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, with the proviso that if b1 is 0 then at least one of a1 or c1 is other than 0, and if g1 is 0 then at least one of f1 or h1 is other than 0; X1' is -O or -NH-; Dashed bond [ka] are each independently a single bond or alternatively a double bond).

[0159] When a bond point is depicted, the bond point is referred to herein as " * ". Unless a particular point of attachment is specified, it is meant that the linker may be attached interchangeably to the remainder of the molecule.

[0160] In one embodiment, optionally in combination with one or more of the features of the various embodiments described above or below, in the radical of formula (XXIII′), L is —X1′-(C1-C 12 ) alkylene, more specifically -X1'-(C1-C6) alkyl-, optionally substituted as defined herein.

[0161] In another embodiment, optionally in combination with one or more of the 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-, optionally substituted as defined herein.

[0162] In another embodiment, optionally in combination with one or more of the features of the various embodiments described above or below, in the radical of formula (XXIII'), L is a biradical of formula (IIID'), more particularly a biradical of formula (IIID') where b is 0 and a1+c1 is selected from 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12, and even more particularly, L is [ka] is a biradical of formula (IIID') selected from the group consisting of:

[0163] In another embodiment, optionally in combination with one or more of the features of the various embodiments described above or below, in the radical of formula (XXIII'), L is a biradical selected from formulae (IVD'), (VD') and (VID'), more particularly X1' is -NH-, and even more particularly, in the biradical of formula (IVD'), a1 is 1 and the dashed bond is a double bond, i.e. the biradical of formula (IVD') has the formula (IVDa'), and in the biradical of formula (VD'), the dashed bond is more particularly a double bond and X1' is -NH-, i.e. the biradical of formula (VD') has the formula (VDa'). [ka]

[0164] In another embodiment, optionally in combination with one or more of the features of the various embodiments described above or below, in the radical of formula (XXIII'), L is a biradical selected from formulas (VID'), (VIID') and (VIIID'), more particularly in the biradical of formula (VIIID'), a1 is 1.

[0165] In another embodiment, optionally in combination with one or more of the features of the various embodiments described above or below, in the radical of formula (XXIII'), L is a biradical of formula (IXD'), more specifically a biradical 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 biradical of formula (IXDa'): [ka]

[0166] In another embodiment, optionally in combination with one or more of the features of the various embodiments described above or below, in the radical of formula (XXIII'), L is a biradical selected from formulae (XD') and (XID'), more specifically in the biradical of formulae (XD') and (XID'), b1 and g1 are 0, a1, c1, d1, e1, f1, and h1 are 1, and X1' is -NH-, i.e. the biradicals of formulae (XD') and (XID') have the formulae (XDa') and (XIDa'), respectively. [ka]

[0167] In another embodiment, optionally in combination with one or more of the features of the various embodiments described above or below, in the radical of formula (XXIII'), L is selected from formulas (XIID') and (XIIID'), more specifically, in the biradical of formulas (XIID') and (XIIID'), b1 is 0, a1, c1, and d1 are 1, and X1' is -NH-.

[0168] In another embodiment, optionally in combination with one or more of the features of the various embodiments described above or below, in the radical of formula (XXIII'), L is a biradical selected from formulae (XIVD'), (XVD'), (XVID'), (XVIID'), and (XVIIID'), more specifically, in the biradical of formulae (XIVD'), (XVD'), (XVID'), (XVIID'), and (XVIIID'), b1 is 0, a1 and c1 are 1, and X1' is -NH-.

[0169] In another embodiment, optionally in combination with one or more of the features of the various embodiments described above or below, in the radical of formula (XXIII'), L is a biradical selected from formula (XIXD'), X' is -NH-, and j1 and k1 are 1. In another embodiment, optionally in combination with one or more of the features of the various embodiments described above or below, in the radical of formula (XXIII'), L is a biradical selected from formula (XIXD'), X' is -O-, and j1 and k1 are 1.

[0170] According to one embodiment, optionally in combination with any of the embodiments provided above or below, in the lipo-polyamino acid conjugate of formula (I), A' is a)-X'(R1')-(C1-C 18 ) alkyl, more specifically -X'(R1')-(C6-C 18 ) alkyl, and more particularly a radical of formula (XIX') or formula (XIX'') as defined above; b)-X'(R1')-(C2-C18 ) alkenyl, more specifically -X'(R1')-(C6-C 18 ) alkenyl, and more particularly radicals of formula (XX') as defined above; c) a radical of formula (VII') as defined herein; d) a radical of formula (VIII') as defined herein; e) radicals of formula (IX') as defined herein, more particularly radicals selected from formulae (ix1'), (ix2'), (ix3'), (ix4'), (ix5'), (ix6'), (ix7') and (ix8') as defined above; f) a radical of formula (X') as defined herein, more particularly a radical selected from formulae (x1'), (x2'), (x3') and (x4') as defined above; g) a radical of formula (XI') as defined herein, more particularly a radical of formula (xi1') as defined above; h) a radical of formula (XII') as defined herein; i) a radical of formula (XIII') as defined herein; j) a radical of formula (XIV') as defined herein; more particularly a radical selected from formulae (xiv1'), and (xiv2') as defined above; k) a radical of formula (XXI') as defined herein, more particularly a radical selected from formula (xxi1'); l) radicals of formula (XXII') as defined herein, more particularly radicals selected from formulae (xxii1'), and (xxii2') as defined above; and m) a radical of formula (XXIII') as defined herein a lipid-like moiety R selected from the group consisting of 5 ' is.

[0171] In another embodiment, optionally in combination with any of the embodiments provided above or below, in the lipo-polyamino acid conjugate of formula (I), A' is a lipid-like moiety R5' as defined herein, m is 1 and A is H.

[0172] In another embodiment, optionally in combination with any of the embodiments provided above or below, in the lipo-polyamino acid conjugate of formula (I), A' is a lipid-like moiety R5' as defined herein, m is 1, and A is a protecting group. In a more specific embodiment, in the lipo-polyamino 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 specifically, the amino protecting group is acetyl, methyloxycarbonyl, benzyloxycarbonyl, p-methoxybenzyloxycarbonyl, t-butyloxycarbonyl (Boc), 9-fluorenylmethyloxycarbonyl (Fmoc), allyloxycarbonyl (Alloc), 2,2,2-trichloro-ethoxycarbonyl, acetyloxycarbonyl (Ala), ... The amino protecting group is selected from the group consisting of methoxycarbonyl (Troc), benzoyl (Bz), benzyl (Bn), p-methoxybenzyl (PMB), 3,4-dimethoxybenzyl (DMPM), p-methoxyphenyl (PMP), tosyl (Ts), trimethylsilylethoxycarbonyl (Teoc), benzhydryl, triphenylmethyl (trityl), (4-methoxyphenyl)-diphenylmethyl (MMT), dimethoxytrityl (DMT), and diphenylphosphino, and even more particularly the amino protecting group is acetyl.

[0173] In another more specific embodiment, in the lipo-polyamino acid conjugate of formula (I), A' is a lipid-like moiety R5' as defined herein, m is 1, X is O, and A is a carboxy protecting group. Any suitable carboxy protecting group known in the art can be used without limitation. Representative carboxy protecting groups include alkyl, aryl, or benzyl esters, silyl esters, amides, or hydrazides. In certain embodiments, the carboxy protecting group is selected from the group consisting of -(C1-C6) alkyl, benzyl, p-methoxyphenyl, trimethylsilyl, and [2-(trimethylsilyl)ethoxy]methyl (SEM).

[0174] The introduction and removal of these protecting groups can be carried out by standard methods, for example those described in TW Green and PGM Wuts, Protective Groups in Organic Chemistry, Wiley, 3rd ed. 1999, Chapter 5 (pp. 369-451).

[0175] In another more specific embodiment, in the lipo-polyamino 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 the group consisting of -(C1-C6)alkyl, benzyl, p-methoxyphenyl, trimethylsilyl, and [2-(trimethylsilyl)ethoxy]methyl (SEM).

[0176] In another embodiment, optionally in combination with any of the embodiments provided above or below, in the lipo-polyamino acid conjugate of formula (I), m is 1 and A is a radical R4, where R4 is a radical of formula (VIa): [ka] (In the formula, n' is an integer from 5 to 250, m' is 0 or 1; X″ is selected from the group consisting of N, S, and O; R1″ is a radical having any of the meanings of R1, with the proviso that if X′ is O or S then 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 of 1 to 18; A'' is 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 )Aralkoxy, -(C5-C 10 )heteroaralkoxy, -(C1-C 10 )Alkyl-O-(C6-C 10 ) aryloxy, amino protecting groups, lipid-like moieties R5', amino acid-like moieties R6, and active moieties, A'' is optionally substituted with 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, -SON2NH2, -SO2-N((C1-C6)alkyl)2, -COOH, -CONH2, and -CON((C1-C6)alkyl)2; however, When m' is 0, A'' is 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 groups, amino acid-like moieties R6, and active moieties, A″ is optionally substituted with 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, —SON2NH2, —SO2-N((C1-C6)alkyl)2, —COOH, —CONH2, and —CON((C1-C6)alkyl)2; When m' is 1, A'' is 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 )Aralkoxy, -(C5-C 10 )heteroaralkoxy, -(C1-C 10 )Alkyl-O-(C6-C 10 ) aryloxy, lipid-like moieties R5', and active moieties, where A'' is optionally substituted with 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, -SON2NH2, -SO2-N((C1-C6)alkyl)2, -COOH, -CONH2, and -CON((C1-C6)alkyl)2; That is, the lipo-polyamino acid conjugate of formula (I) has the formula (Ib'): [ka] (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).

[0177] All embodiments described herein relating to the meanings of A', X, R1, R2, and R3 in the lipo-polyamino acid conjugate of formula (I) also apply to the meanings of A'', X'', R1'', R2', and R3', respectively, in the lipo-polyamino acid conjugate of formula (Ib').

[0178] In a more specific embodiment, the lipo-polyamino acid conjugate of formula (Ib') is a dimer in which 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.

[0179] In another embodiment, optionally in combination with any of the embodiments provided above or below, in the lipo-polyamino acid conjugate of formula (I), A' is a lipid-like moiety R5' as defined herein, m is 1, A is 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, a protecting group, a radical R4, a lipid-like moiety R5, an active moiety; A is optionally 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, -SON2NH2, -SO2-N((C1-C6)alkyl)2, -COOH, -CONH2, and -CON((C1-C6)alkyl)2, more particularly, A is methyl.

[0180] In another embodiment, optionally in combination with any of the embodiments provided above or below, in the lipo-polyamino acid conjugate of formula (I), A' is a lipid-like moiety R5' as defined herein, m is 1, and A is an active moiety selected from the group consisting of a pharma- ceutical active agent, a cell targeting agent, a penetration enhancer, a cosmetically active agent, and a diagnostically active agent.

[0181] The active moiety of A may be directly bonded to Z, or alternatively it may be bonded via a linker. The nature of the linker is not limited, provided that it can be bonded to the remainder of the molecule by any chemically feasible bond. For example, the linker can be a biradical chain comprising one or more moieties selected from the group consisting of -CH=CH-, -C≡C-, -CH2-, -N=CH-, -CH=NH-, NH-, -NH-NH-, -NH-N=CH-, -O-, -O(CH2)O-, -CO-, -O(CO)-, -COO-, -C(=CH2)-, -C(=NH)-, -CONH-, -NHCO-, -NH(CO)NH-, -S-, -SS-, -SO-, -SO2-, -SONH2-, -phenylene, and the like. The linker may comprise 1 to 50 moieties, more particularly 2 to 30 or 2 to 20 or 2 to 15 moieties, as defined above, and may be bonded to X by any chemically feasible linkage, such as an ether linkage, a thioether linkage, or an amide linkage.

[0182] Preparation process Processes for the preparation of the lipo-polyamino acid conjugates of formula (I) are also part of the present invention. The conjugates may be prepared by synthetic processes well known in the art.

[0183] As described above, the lipo-polyamino acid conjugate of formula (I) must contain at least one lipid-like moiety, which may be a lipid-like moiety R5 of A or a lipid-like moiety R5' of A', or both.

[0184] The lipo-polyamino acid conjugates of formula (I), where A is a lipid-like moiety R5, can be prepared by ring-opening polymerization (ROP) of N-carboxyanhydrides (NCAs). In particular, the oxazolidine-2,5-dione derivatives of amino acids containing R2 as side chains (compounds of formula (A)) can be reacted with amines, alcohols, or thiols of formula (B), which already contain a lipid-like moiety R5 and are used as initiators. As a result, polyamino acid polymers of formula (I) are obtained. [ka] (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 including 4° C. to room temperature, preferably at a temperature of about 10° C. The ratio of monomer (NCA) to initiator (alcohol / amine) can control the degree of polymerization (DP).

[0185] Alternatively, the above reaction may also be carried out using an NCA containing a precursor of R2 instead of the R2 moiety, which is then converted to the R2 moiety after the polymer is formed. For example, an NCA compound derived from a natural amino acid such as glutamic acid or lysine, which may be optionally protected with a suitable protecting group, may be polymerized in the presence of compound (B) to obtain a lipo-polyamino acid conjugate of formula (If), where R2 is the side chain of the natural amino acid used. This precursor may be deprotected as necessary and further reacted with other reagents to obtain the desired R2 moiety, as illustrated in the following examples.

[0186] The resulting polyamino acids may optionally be purified by any known method, such as fractionation, precipitation, ultracentrifugation, dialysis, size-exclusion chromatography, affinity chromatography, or tangential flow filtration.

[0187] If desired, the polymer conjugate of formula (If) can be converted into a further polymer conjugate of formula (I) by reacting the terminal amine with a further group.For example, the terminal amine can be directly reacted with an active agent or can be linked via a linker.Depending on the chemical group present on the active agent, those skilled in the art can easily determine the appropriate method for linking the selected active agent to the backbone of the lipo-polyamino acid conjugate.

[0188] Alternatively, the polymer conjugate of formula (I) where A' is R5' and m' is 1 may be prepared from a compound of formula (If) as defined above, where A can have any of the meanings defined herein, by reacting it with a compound of formula R5'(CO)Z, where Z can be OH or halogen.

[0189] When Z is a hydroxy group, the reaction can be carried out in a suitable solvent, preferably in the presence of a base, in the presence of an activating agent such as 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium tetrafluoroborate (DMTMMBF4), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDC.HCl) or hydroxybenzotriazole (HOBt). When Z is a halogen atom, the reaction can be carried out in a suitable solvent, in the presence of a base such as triethylamine. When Z is a halogen atom, the compound R5'-(CO)Z can be prepared from the corresponding carboxylic acid by methods well known in the art.

[0190] Alternatively, a compound of formula (I) where A' is R5' and m' is 1 can also be prepared from a compound of formula (If) as defined above by reacting it with a compound of formula R5'H. In this case, the reaction can be carried out in a suitable organic solvent in the presence of a carbonyl source such as 1,1'-carbonyldiimidazole (CDI), N,N'-disuccinimidyl carbonate (DSC), or bis(trichloromethyl)carbonate (BTC).

[0191] Self-assembled particles As mentioned above, the lipo-polyamino acid conjugates of the present invention have amphiphilic properties since they contain a polyamino acid-based portion (hydrophilic portion) and at least one lipid-like portion (hydrophobic portion). Due to their amphiphilic properties, the lipo-polyamino acid conjugates of the present invention can form self-assembled particles in solution.

[0192] Thus, the present invention also relates to self-assembled particles comprising a lipo-polyamino acid conjugate of formula (I) as defined herein and, optionally, one or more active agents selected from the group consisting of pharma- ceutical active agents, penetration enhancers, cell targeting agents, cosmetically active agents, diagnostically active agents, nucleic acids, peptides, proteins, and mixtures thereof.

[0193] As used herein, the term "self-assembled particle" refers to the arrangement of lipo-polyamino acid conjugate molecules in a solvent, and the self-assembled particles, especially the small ones, can be included in any shape, usually spherical and / or tubular structures. The term "self-assembled particle" is intended to encompass any of the many structures known in the art formed from amphiphilic polymers. Non-limiting examples of self-assembled particles include micelles (also referred to herein 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 virally.

[0194] The self-assembled particles may exhibit various sizes, in particular they may be nanoparticles or microparticles. A "nanoparticle", as defined herein, is any particle of nanometer size, with a minimum end-to-end diameter of 1-900, more particularly 1-700 nm, more particularly 1-500 nm, 1-300 nm, 1-200 nm, and 1-100 nm. A "microparticle", as defined herein, is any particle of micrometer size, typically with a minimum end-to-end diameter of 1-100 μm. Typically, in compositions containing multiple particles, the appropriate diameter is the number-average diameter.

[0195] As used herein, the term "size" refers to a characteristic physical dimension. For example, for a particle that is substantially spherical, the particle size corresponds to the diameter of the particle. For a particle that is substantially rod-shaped with a substantially circular cross section, such as a wire or tube, the particle size is determined by the diameter of the two relevant cross-sectional dimensions of the particle. For a particle that is substantially box-shaped, such as a cube, box, or cage, the size of a nanoparticle corresponds to the maximum width. When referring to a set of specific particle sizes, it is contemplated that the set of particles may have a distribution size around the stated size. Thus, as used herein, the size of a set of particles may represent a form of a distribution size, such as the peak size of a size distribution.

[0196] As used herein, the term "diameter" refers to the average diameter, which may also be designated Z-average or Z-ave. The average diameter corresponds to the average hydrodynamic diameter (Dh) and may be measured by dynamic light scattering (DLS) as shown in the examples below. In one embodiment, optionally in combination with one or more of the 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 specifically 10 to 1100 nm, 10 to 1000 nm, 10 to 700, 20 to 500 nm, 20 to 400 nm, 20 to 300 nm, 30 to 200 nm, or 50 to 150 nm.

[0197] All embodiments described for the lipo-polyamino acid conjugates of formula (I) also apply to the self-assembled particles.

[0198] In one embodiment, optionally in combination with one or more of the features of the various embodiments described above or below, in a self-assembled particle comprising a lipo-polyamino acid conjugate of formula (I), the lipid-like portion (hydrophobic portion) faces inward and the polar head group (PAA) faces outward.

[0199] In another embodiment, optionally in combination with one or more of the features of the various embodiments described above or below, the self-assembled particle is a core-shell structure comprising an inner core and an outer shell. More specifically, the lipo-polyamino acid conjugate of formula (I) forms the outer shell of the self-assembled particle, and the active agent is optionally encapsulated or loaded in the inner core.

[0200] In one embodiment, optionally in combination with one or more of the features of the various embodiments described above or below, the self-assembled particle is a nanoparticle, more specifically selected from the group consisting of a micelle, a reverse micelle, a planar bilayer, a crystalline nanoparticle, a liposome, a microbubble, and a lipid nanoparticle, and even more specifically, the self-assembled particle is a lipid nanoparticle or a liposome.

[0201] For purposes of the present invention, the term "liposome" refers to an artificially prepared self-assembled particle composed of concentric lipid bilayers containing one or more aqueous compartments. Non-limiting examples of liposomes include monolamellar liposomes, multilamellar liposomes, multivesicular liposomes, and polymer-coated liposomes.

[0202] The term "lipid nanoparticle" refers to particles that are generally spherical, on the order of nanometers (eg, 1-1000 nm), that comprise lipids and are stable and dispersible in aqueous media.

[0203] For the purposes of the present invention, the term "crystalline nanoparticles" refers to artificially prepared crystals composed of solid lipids containing one or more hydrophobic compartments. The term "crystalline nanoparticles" refers to particles of different shapes on the order of nanometers (e.g., 1-1000 nm) that contain lipids and are stable and dispersible in aqueous media.

[0204] In another embodiment, optionally in combination with one or more of the features of the various embodiments described above or below, the present invention relates to a lipid nanoparticle (LNP) or liposome comprising a lipo-polyamino acid conjugate of formula (I) as defined herein and optionally one or more active agents selected from the group consisting of a pharma- ceutical active agent, a cell targeting agent, a penetration enhancer, a cosmetically active agent, a diagnostically active agent, a nucleic acid, a peptide, a protein, and mixtures thereof.

[0205] The liposomes and lipid nanoparticles disclosed herein can comprise any suitable lipid, including ionizable lipids, cationic lipids, zwitterionic lipids, neutral lipids, or anionic lipids.

[0206] Suitable ionizable lipids include, but are not limited to, (2S)-2,5-bis(3-aminopropylamino)-N-[2-(dioctadecyl-amino)acetyl]pentanamide (DOGS), N1-[2-((1S)-1-[(3-aminopropyl)amino]-4-[di(3-aminopropyl)amino]-butylcarboxamido)ethyl]-3,4-di[oleyloxy]-benzamide (MVL5), 3β-[N-(N′,N′-dimethyl aminoethane)-carbamoyl]cholesterol (DC-cholesterol), (1,2-distearyloxy-N,N-dimethyl-3-aminopropane (DSDMA), 1,2-dilinoleyloxy-N,N-dimethyl-3-aminopropane (DLin-DMA), 1,2-dilinolenyloxy-N,N-dimethyl-3-aminopropane (DLenDMA), 1,2-di-y-linolenyloxy-N,N-dimethylaminopropane (γ-DLenDMA) , 2-Dilinoleyl-4-dimethyl-aminomethyl[1,3]-dioxolane (DLin-K-DMA), 2,2-Dilinoleyl-4-dimethylaminoethyl-[1,3]-dioxolane (also known as DLin-KC2-DMA, DLin-C2K-DMA, XTC2, and C2K), 2,2-Dilinoleyl 4-(3-dimethylaminopropyl)-[1,3]-dioxolane (DLin-KC3-DMA), 2,2-Dilinoleyl 4-(4- dimethylaminopropyl)-[1,3]-dioxolane (DLin-KC4-DMA), 1,2-dilinolenyloxy-4-(2-dimethylaminoethyl)-1,3-dioxolane (DLen-C2K-DMA), 1,2-di-y-linolenyloxy-4-(2-dimethylaminoethyl)-1,3-dioxolane (y-DLen-C2K-DMA), (6Z,9Z,28Z,31Z)-heptatriaconta-6,9,28,31-tetraen-19-yl 3-(dimethylamino)propanoate (also known as DLin-M-C2-DMA, MC2), (6Z,9Z,28Z,31Z)-heptatriaconta-6,9,28,31-tetraen-19-yl 4-(dimethylamino)-butanoate (also known as DLin-M-C3-DMA, MC3), and 3-((6Z,9Z,28Z,31Z)-heptatriaconta-6,9,28,31-tetraen-19-yloxy)-N,N-dimethylpropan-1-amine (DLin-MP-DMA, also known as 1-B11).

[0207] Suitable cationic lipids include, but are not limited to, N,N-dioleyl-N,N-dimethyl ammonium chloride (DODAC), N,N-distearyl-N,N-dimethyl ammonium bromide (DDA13), N-(1-(2,3-dioleoyloxy)propyl)-N,N,N-trimethyl trimethyl ammonium chloride (DOTAP), N-(1-(2,3-dioleyloxy)propyl)-N,N,N-trimethyl ammonium chloride (DOTMA), N-[1-(2,3-ditetradecyloxy)propyl-N,N-dimethyl-N-hydroxyethyl ammonium bromide (DMRIE), N-[1-(2,3-dioleyloxy)propyl]-N,N-dimethyl These include di-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-propanaminium trifluoroacetate (DOSPA), ethylphosphatidylcholine, (ePC), N,N-dimethyl-2,3-dioleyloxy)propylamine (DODMA), and ([(4-hydroxybutyl)azanediyl]di(hexane-6,1-diyl)bis(2-hexyldecanoate)) (ALC-0315).

[0208] Examples of anionic lipids include, but are not limited to, phosphatidylglycerol, diacylphosphatidylserine, diacylphosphatidic acid, N-succinylphosphatidylethanolamine, N-glutarylphosphatidylethanolamine cholesterol hemisuccinate (CHEMS), lysylphosphatidylglycerol, N-dodecanoylphosphatidylethanolamine, cardiolipin, and combinations thereof.

[0209] Suitable neutral lipids can be uncharged or zwitterionic lipids, and include, but are not limited to, steroids, phospholipids, and combinations thereof.

[0210] Examples of steroids include, but are not limited to, cholesterol, progesterone, cortisone, aldosterone, estradiol, testosterone, and combinations thereof.

[0211] 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 (DPPC), and phospholipids such as phospholipids (MPG), phospholipids (MPI ... DSPG), dioleoylphosphatidylglycerol (DOPG), dipalmitoylphosphatidylglycerol (DPPG), dimyristoylphosphatidylserine (DMPS), distearoylphosphatidylserine (DSPS), dioleoylphosphatidylserine (DOPS), dipalmitoylphosphatidylserine (DPPS), dioleoylphosphatidylethanolamine (DOPE), palmitoyloleoylphosphatidylcholine (POPC), palmitoyloleoyl-phosphatidylethanolamine (POPE) and dioleoyl-phosphatidylethanolamine 4-(N-maleimidomethyl-cyclohexane-1-carboxylate (DOPE-mal), dipalmitoylphosphatidylethanolamine (DPPE), dimyristoylphosphoethanolamine (DMPE), distearoylphosphatidyl-ethanolamine (DSPE);Lysophosphatidylcholine, lysophosphatidylethanolamine, 1,2-distearoyl-sn-glycero-3-phosphocholine (DAPC), dilauryloyl phosphatidylcholine (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-dieicosenoyl-sn-glycero-3-phosphocholine (DEPC), and combinations thereof.

[0212] In the liposomes and lipid nanoparticles disclosed herein, the lipo-polyamino acid conjugates preferably provide stealth properties. As used herein, the term "stealth" refers to the ability of a liposome or lipid nanoparticle to be detected by the immune system of a host to which it is administered. This refers to the fact that liposomes or lipid nanoparticles are not detectable, sequestered, and / or degraded, thereby increasing the length of time that they may persist in vivo.

[0213] In one embodiment, optionally in combination with one or more of the features of the various embodiments described above or below, the liposomes and lipid nanoparticles disclosed herein do not comprise (i.e., lack) polyethylene glycol (PEG)-lipid conjugates, i.e., lipids that contain polyethylene glycol.

[0214] In another embodiment, optionally in combination with one or more of the features of the various embodiments described above or below, the self-assembled particles of the invention, in particular liposomes and lipid nanoparticles, are devoid of polyethylene glycol (PEG).

[0215] The liposomes and lipid nanoparticles disclosed herein may also contain one or more cationic polymers, such as cationic amine-containing polymers. Typically, 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(beta-amino ester), etc.

[0216] In another embodiment, optionally in combination with one or more of the features of the various embodiments described above or below, the present invention relates to a lipid nanoparticle (LNP) or liposome comprising a lipo-polyamino acid conjugate of formula (I) as defined herein and one or more lipids selected from the group consisting of ionizable lipids, cationic lipids, neutral lipids, and anionic lipids. More specifically, the lipid nanoparticle (LNP) or liposome comprises a lipo-polyamino acid conjugate of formula (I) as defined herein, an ionizable lipid or cationic lipid, a phospholipid, and a sterol. Even more specifically, it comprises: i) a lipo-polyamino acid conjugate of formula (I) as defined herein in an amount of 0.1-10 mol%, more specifically 1-5 mol% or 1-6 mol%, even more specifically 2-5% mol%; ii) an ionizable lipid or a cationic lipid in an amount of 30-70 mol%, more specifically 40-60 mol%; iii) a phospholipid in an amount of 1-20 mol%, more specifically 5-15 mol%; and iv) a sterol in an amount of 20-60 mol%, more specifically 30-50 mol%, where the percentages are expressed relative to the sum of the mol% of lipid and lipo-polyamino acid conjugate of formula (I).

[0217] In another embodiment, optionally in combination with one or more of the features of the various embodiments described above or below, the present invention relates to a lipid nanoparticle (LNP) or liposome comprising a lipo-polyamino acid conjugate of formula (I) as defined herein, one or more lipids selected from the group consisting of ionizable lipids, cationic lipids, neutral lipids, and anionic lipids, and one or more nucleic acids.

[0218] Lipid nanoparticles and liposomes containing one or more nucleic acids can be prepared by standard methods.Usually, the process for preparing LNPs includes: i) preparing a first alcoholic mixture containing one or more lipids and the lipo-polyamino acid conjugate of the present invention in a suitable alcohol, such as ethanol; ii) preparing a second aqueous composition containing one or more nucleic acids and an aqueous solvent (acidic buffer); and iii) mixing i) with ii) in a microfluidic mixing device.This microfluidic mixing allows the lipid phase and the nucleic acid phase to be mixed completely and quickly in a microscale device.Depending on the parameters of the process, especially the total flow rate, the skilled person can adjust the size of LNPs.

[0219] Activator As noted above, the lipo-polyamino acid conjugates of the invention may include one or more active moieties in the structure of either A, A', A'', or A''', which are independently selected from the group consisting of pharma- ceutical active agents, cell targeting agents, penetration enhancers, cosmetically active agents, and diagnostically active agents.

[0220] Additionally, the lipo-polyamino acid conjugates of the present invention may form self-assembled particles that may contain one or more active agents selected from the group consisting of pharma- ceutical active agents, cell targeting agents, penetration enhancers, cosmetically active agents, diagnostically active agents, nucleic acids, peptides, proteins, and mixtures thereof.

[0221] As used herein, the term "pharmacologically active agent" refers to an agent that has pharmacological activity and is used to cure, alleviate, treat, or prevent disease in mammals, particularly humans. 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, condition, cleanse, color, or protect the skin, nails, or hair.

[0222] 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 that can direct a conjugate or its self-assembled particle, for example by selectively binding to a receptor expressed or overexpressed on a specific cell type, thereby directing them to a target site for therapeutic treatment. Cell targeting groups are well known in the art. Thus, the term includes ligands for a specific receptor or antigen, for example, an antibody for a specific antigen, a sugar such as folate for its receptor, or galactose for its hepatic receptor. The targeting agent may be attached to the backbone of any of the lipo-polyamino acid conjugates A, A', A'', or A''', and / or may be included in the self-assembled particle formed from the conjugate.

[0223] 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, 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 moieties, arabino-galactan, chitosan, azo-based polyphosphazenes, azo groups, and 4-amino-benzyl-carbamate, succinate, 4,4'-Dihydroxyazobenzene-3-carboxylic acid, cyclic RGD penta-peptide, aspartic acid octapeptide, alendronate, transferrin, bisphosphonate 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, gut homing peptide, integrin homing peptide, angiogenic tumor endothelium homing peptide, ovary homing peptide, uterus homing peptide, sperm homing peptide homing peptides, microglia homing peptides, synovial membrane homing peptides, urothelium homing peptides, prostate homing peptides, lung homing peptides (e.g., RCPLSHSLICY), laminin receptor binding peptides (e.g., YIGSR), skin homing peptides, retina homing peptides, pancreas homing peptides, liver homing peptides, lymph node homing peptides, adrenal gland homing peptides, thyroid homing peptides, bladder homing peptides, breast homing peptides, neuroblastoma homing peptides, lymphoma homing peptides, muscle homing peptides, wound vasculature homing peptides, adipose tissue homing peptides, virus binding peptides, or membrane fusogenic peptides.

[0224] The term "penetration enhancer," as used herein, refers to a moiety or compound that increases the permeability of an active agent, particularly an active agent selected from pharma- ceutical active agents, cell targeting agents, cosmetic active agents, and diagnostic active agents. Penetration enhancers are also known as penetration enhancers.

[0225] 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; e.g., lauryl sarcosine, octoxynol, phenylsulfonates, pluronics, sodium laurate, sodium oleate, sorbitan dilaurate, sorbitan dioleate, sorbitan trilaurate, sorbitan trioleate, sodium octyl sulfate, alkyl ammonium halides, decanol, dodecanol, linolenyl alcohol, oleyl alcohol, butyl acetate, cetyl lactate, lauryl lactate, myristyl lactate, diethyl sebacate, diethyl succinate, sebace ... diisopropyl stearate, glycerol monolaurate, glycerol monooleate, glycerol monolinoleate, isopropyl isostearate, isopropyl linoleate, isopropyl myristate, isopropyl palmitate, methyl caprate, methyl laurate, methyl valerate, octyl acetate, oleyl oleate, sorbitan dilaurate, dodecyl acetate, sorbitan dioleate, sorbitan monolaurate, sorbitan trilaurate, sorbitan trioleate, capric acid, hexanoic acid, lactic acid, lauric acid, linoleic acid, linolenic acid, neodecanoic acid, oleic acid, palmitic acid, lecithin, phospholipids, sodium deoxycholate, and sodium taurocholate.

[0226] For purposes of the present invention, pharma- ceutical active agents include low molecular weight drugs, peptides, antibodies, hormones, enzymes, nucleic acids, proteins, and combinations thereof.

[0227] As used herein, the term "nucleic acid" refers to DNA or RNA. In certain embodiments, optionally in combination with any of the embodiments provided above or below, the nucleic acid is, for example, a DNA / RNA hybrid, small interfering RNA (siRNA), microRNA (miRNA), single guide RNA (sgRNA), donor DNA, self-amplifying / replicating RNA, circular RNA (oRNA), plasmid DNA (pDNA), closed linear DNA (clDNA), small hairpin RNA (shRNA), messenger RNA (mRNA), and antisense RNA (aRNA), messenger RNA (mRNA), CRISPR guide RNA, antisense nucleic acid, decoy nucleic acid, aptamer, and ribozyme, including nucleotide sequence and any structural embodiment thereof, such as double-stranded, single-stranded, helical, hairpin, etc., and may include modified or unmodified bases. Where distinct nucleic acids are provided, these may be all DNA molecules or all RNA molecules, or may be a mixture of DNA and RNA molecules, or molecules that contain an association of DNA and RNA strands.

[0228] The nucleic acid may be a polynucleotide or an oligonucleotide, such as an oligo or poly double-stranded RNA, an oligo or poly double-stranded DNA, an oligo or poly single-stranded RNA, or an oligo or poly single-stranded DNA. Each of the nucleotides contained in the nucleic acid may be a naturally occurring nucleotide, or a chemically modified, non-naturally occurring nucleotide. The length of the nucleic acid is not particularly limited, and the nucleic acid may have a short chain in the range of 1 to 200 bases, preferably 20 to 180 bases, preferably 25 to 100 bases, preferably 30 to 50 bases; or the nucleic acid may have a relatively long chain of 200 to 20,000 bases, more preferably 250 to 15,000 bases.

[0229] In certain embodiments, optionally in combination with any of the embodiments provided above or below, the nucleic acid is a closed linear DNA (clDNA), i.e., a molecule with a double-stranded region flanked and protected by two single-stranded loops, thereby generating a dumbbell-shaped molecule.

[0230] 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 covalently closed at both ends by hairpin loops, and the clDNA comprises at least two modified nucleotides.

[0231] As used herein, the term "closed linear DNA" or "clDNA" refers to a single-stranded covalently closed DNA molecule that forms a "dumbbell" or "dogbone" shaped structure under conditions that allow hybridization of nucleotides. Thus, clDNA is formed by a single-stranded DNA molecule, but the formation of the "dumbbell" structure by hybridization of two complementary sequences within the same molecule creates a structure consisting of a double-stranded central segment flanked by two single-stranded loops. Those skilled in the art are aware of how to generate clDNA from open or closed double-stranded DNA using routine molecular biology techniques. For example, those skilled in the art are aware that clDNA can be generated by attaching a hairpin DNA adapter to both ends of an open double-stranded DNA, for example by the action of a ligase. A "hairpin DNA adapter" refers to a single-stranded DNA that forms a stem-loop structure by hybridization of two complementary sequences, where the formed stem region is closed at one end by a single-stranded loop and open at the other end.

[0232] A "modified nucleotide" is any nucleotide (e.g., adenosine, guanosine, cytidine, uracil, and thymidine) that has been chemically modified by modification of the base, sugar, or phosphate group, or that incorporates a non-natural moiety into its structure. Thus, modified nucleotides can be naturally or non-naturally occurring, depending on the modification.

[0233] As used herein, the term "peptide" refers to a molecule that includes two or more consecutive amino acids linked together via peptide bonds. The term peptide includes oligopeptides and polypeptides. The term "protein" refers to large peptides, particularly peptides having at least about 50 amino acids. For purposes of the present invention, the terms peptide and protein are used interchangeably.

[0234] Examples of proteins of interest include, but are not limited to, cytokines, interleukins, tumor necrosis factors (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 factors (CSF), and the like.

[0235] In the context of the present disclosure, the expression "diagnostically active agent" is also called "labeling agent or imaging agent" and refers to any substance that is used as a label or enhances a particular structure in any imaging technique. Thus, imaging agents include optical imaging agents, magnetic resonance imaging agents, radioisotopes, and contrast agents. Imaging agents or labeling agents are well known in the art. Specific examples of imaging agents or labeling agents are gases, such as sterile air, oxygen, argon, nitrogen, fluorite, perfluorocarbons, carbon dioxide, nitrogen dioxide, sulfur hexafluoride, xenon, and helium; commercially available agents used in positron emission tomography (PET), computer-assisted tomography (CAT), single photon emission tomography, x-ray, fluoroscopy, and magnetic resonance imaging (MRI). Examples of materials suitable for use as contrast agents in MRI include currently available gadolinium chelates, such as diethylenetriaminepentaacetic acid (DTPA), and gadopentetate dimeglumine, as well as iron, magnesium, manganese, copper, and chromium. Examples of materials useful for CAT and x-ray include iodine-based materials for intravenous administration, ionic monomers such as diatrizoate and iothalamate, non-ionic monomers such as iopamidol, iohexol, and ioversol, non-ionic dimers such as iotrol and iodixanol, and ionic dimers such as ioxagalte. Other useful materials include barium for oral use, and insoluble salts such as zinc acetate. In some molecules, the contrast agent is a dye. In some molecules, the contrast agent is a fluorescent moiety. In some molecules, the fluorescent moiety is selected from a fluorescent protein, a fluorescent peptide, a fluorescent dye, a fluorescent substance, or a combination thereof.Examples of fluorescent dyes include, but are not limited to, xanthenes (e.g., rhodamine, rhodol, and fluorescein, and their derivatives); bimanes; coumarins and their derivatives (e.g., umbelliferone and aminomethylcoumarin); aromatic amines (e.g., dansyl; squarate dyes); benzofurans; fluorescent cyanines; indocarbocyanines; carbazoles; dicyanomethylenepyrans; polymethines; oxabenzanthranes; xanthenes; pyryliums; carbostyls; perylenes; acridones; quinacridones; rubrenes; anthracenes; coronenes; phenanthrenes; pyrenes; butadienes; stilbenes; porphyrins; pthalocyanines; lanthanide metal chelate complexes; rare earth metal chelate complexes; and derivatives of such dyes. Examples of fluorescein dyes include, but are not limited to, 5-carboxyfluorescein, fluorescein-5-isothiocyanate, fluorescein-6-isothiocyanate, and 6-carboxyfluorescein. Examples of rhodamine dyes include, but are not limited to, tetramethylrhodamine-6-isothiocyanate, 5-carboxytetramethylrhodamine, 5-carboxyrhodol derivatives, tetramethyl and tetraethylrhodamine, diphenyldimethyl and diphenyldiethylrhodamine, dinaphthylrhodamine, rhodamine 101 sulfonyl chloride (sold under the trade name TEXAS RED®). Examples of cyanine dyes include, but are not limited to, Cy3, Cy3B, Cy3.5, Cy5, Cy5.5, Cy7, IRDYE680, Alexa Fluor 750, IRDye800CW, ICG. Examples of fluorescent peptides include GFP (Green Fluorescent Protein) or derivatives of GFP (e.g., EBFP, EBFP2, Azurite, mKalama1, ECFP, Cerulean, CyPet, YFP, Citrine, Venus, YPet). The fluorescent label is detected by any suitable method.For example, fluorescent labels can be detected by exciting the fluorochrome with light of an appropriate wavelength and detecting the resulting fluorescence, for example, by a microscope, visual inspection, through photographic film, or by using electronic detectors such as charge-coupled devices (CCDs), photomultipliers, etc. In some molecules, the imaging agents are labeled with positron-emitting isotopes (e.g., 18F) for positron emission tomography (PET), gamma-emitting isotopes (e.g., 99mTc) for single-photon emission computed tomography (SPECT), or paramagnetic molecules or nanoparticles (e.g., Gd3+ chelates or coated magnetic nanoparticles) for magnetic resonance imaging (MRI). In some molecules, the imaging agents are labeled with gadolinium chelates, iron oxide particles, superparamagnetic iron oxide particles, small molecule superparamagnetic particles, manganese chelates, or gallium-containing agents. Examples of gadolinium chelates include, but are not limited to, diethylenetriaminepentaacetic acid (DTPA), 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), and 1,4,7-triazacyclononane-N,N',N'-triacetic acid (NOTA). In some molecules, the imaging agent is a near-infrared fluorophore for near-IR imaging, luciferase (firefly, bacteria, or coelenterate) or other fluorescent molecules for bioluminescence imaging, or self-assembled particles loaded in perfluorocarbon for ultrasound. In some molecules, the imaging agent is a nuclear probe. In some molecules, the imaging agent is a radionuclide probe for SPECT or PET. In some molecules, the radionuclide probe is selected from technetium chelates, copper chelates, radioactive fluorides, radioactive iodines, and indiuim chelates. Examples of Tc chelates include, but are not limited to, HYNIC, DTPA, and DOTA. In some molecules, the imaging agent is a radioisotope, e.g. 211 At, 131 I, 125 I, 90 Y, 186 Re, 188 Re, 153 Sm, 212 Bi, 32 P, 64Radioisotopes of Cu, Lu, and others. Diagnostically active agents may be attached to the backbone of the A, A', A'', or A''' lipo-polyamino acid conjugates and / or may be included in the self-assembled particles formed from the conjugates.

[0236] composition The present invention also relates to compositions comprising a lipo-polyamino acid conjugate or alternatively a self-assembled particle as defined herein, together with one or more suitable excipients or carriers.

[0237] In one embodiment, optionally in combination with one or more of the features of the various embodiments described above or below, the composition is a pharmaceutical composition comprising a therapeutically effective amount of (a) a lipo-polyamino acid conjugate as defined herein (wherein at least one of A, A', A'', or A''' is a pharma- ceutical active agent), or alternatively (b) a self-assembled particle comprising lipo-polyamino acid conjugate (a), or alternatively (c) a self-assembled particle comprising a lipo-polyamino acid conjugate as defined herein and one or more active agents selected from the group consisting of a pharma- ceutical active agent, a nucleic acid, a peptide, a protein, and mixtures thereof, together with one or more pharma- ceutical acceptable excipients or carriers.

[0238] The expression "therapeutically effective amount" as used herein refers to an amount of polymer that, when administered, is sufficient to prevent or reduce to some extent the onset of one or more of the symptoms of the disease presented. The specific dose of the polymer of the present invention to obtain a therapeutic benefit may vary depending on the specific circumstances of the individual patient, including, inter alia, 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.

[0239] For the purposes of the present invention, the term "pharmaceutical acceptable excipient or carrier" refers to a composition suitable for use in pharmaceutical techniques to prepare a composition for medical use. Each component must be "acceptable" in the sense of being compatible with the other components of the composition. When used in contact with human and animal tissues or organs, it must not have excessive toxicity, irritation, allergic response, immunogenicity, or other problems or complications and must be commensurate with a reasonable benefit-risk ratio.

[0240] The lipo-polyamino acid conjugates described in the present disclosure, as well as the self-assembled particles and pharmaceutical compositions comprising them, can be used with other additional drugs to provide combination therapy, which may be part of the same pharmaceutical composition or, alternatively, may be provided in the form of separate compositions for simultaneous or non-simultaneous administration.

[0241] In another embodiment, optionally in combination with one or more of the features of the various embodiments described above or below, the composition is a diagnostic composition comprising (a') a lipo-polyamino 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 lipo-polyamino acid conjugate (a'), or alternatively (c') a diagnostically effective amount of a lipo-polyamino acid conjugate as defined herein and one or more diagnostically active agents, together with one or more diagnostically acceptable excipients or carriers.

[0242] The term "diagnostic composition" refers to a composition suitable for use in diagnostic techniques, particularly imaging diagnostic techniques. The term "diagnostically effective amount" as used herein refers to an effective amount of the detection polymer that, when administered, is sufficient for the diagnosis of a disease or disorder, particularly for use in imaging diagnostics as a contrast agent. The dose of the detection polymer administered will of course be determined by the particular circumstances surrounding the case, including the polymer administered, the route of administration, the particular pathology being diagnosed, and similar considerations. The diagnostic composition of the present invention includes one or more diagnostically acceptable excipients or carriers. The term "diagnostically acceptable" refers to an excipient or carrier suitable for use in diagnostic techniques for the preparation of a composition for diagnostic use, particularly by use in imaging diagnostics. Detection of these diagnostic agents in the patient's body can be performed by well-known techniques such as those used in magnetic resonance imaging (MRI) and X-ray imaging diagnostics.

[0243] In another embodiment, optionally in combination with one or more of the features of the various embodiments described above or below, the composition is a cosmetic composition comprising (a'') a lipo-polyamino acid conjugate as defined herein (wherein at least one of A, A', A'', or A''' is a cosmetically active agent), or alternatively (b'') a self-assembled particle comprising lipo-polyamino acid conjugate (a''), or alternatively (c'') a cosmetically effective amount of a lipo-polyamino acid conjugate as defined herein and one or more cosmetically active agents, together with one or more cosmetically acceptable excipients or carriers.

[0244] The term "cosmetically effective amount" as used herein refers to an amount of a cosmetically active agent that, when administered, is intended to improve the appearance or beautify, preserve, condition, cleanse, color, or protect the skin, nails, or hair without medical application. The terms "cosmetically acceptable" or "dermatologically acceptable" excipient or carrier are used interchangeably herein and refer to ingredients that are suitable for use in contact with human skin, particularly without toxicity, incompatibility, instability, or undue allergic response.

[0245] The composition of the present invention can be in solid or liquid form. Non-limiting examples of solid form include frozen form, lyophilized form, and spray-dried form. Depending on the desired purpose, those skilled in the art will know the most suitable formulation and excipient to use. Examples of excipients or carriers include, but are not limited to, diluents, binders, glidants, disintegrants, lubricants, colorants, mixtures thereof, and other components known in the art. Any route of administration can be used, such as oral, topical, rectal, or parenteral (including subcutaneous, intraperitoneal, intradermal, intramuscular, intravenous, etc.).

[0246] use The lipo-polyamino acid conjugates, self-assembled particles and compositions thereof of the present invention can be used in therapeutic applications.In particular, they can be used as the non-viral vectors commonly used for biomedical applications, such as vaccines or gene therapy, which are effective for transfection of host eukaryotic cells, unicellular parasites and bacteria in in vivo or ex vivo culture, including gene editing using CRISP / Cas9 methodology.Furthermore, they can be used in protein-based therapy; in particular in protein-based vaccines against viral infections, or as therapeutic protein-based vaccines against cancer or infectious diseases.

[0247] Thus, the present invention relates to a therapeutic product which is or comprises a) a lipo-polyamino acid conjugate of formula (I) as defined herein (wherein at least one of A, A', A'', or A''' is a pharma- ceutical active agent), or alternatively b) a self-assembled particle comprising lipo-polyamino acid conjugate a), or alternatively c) a composition comprising lipo-polyamino acid conjugate a) or self-assembled particle b), or alternatively d) a self-assembled particle comprising a lipo-polyamino acid conjugate as defined herein and one or more active agents selected from the group consisting of a pharma- ceutical active agent, a nucleic acid, a peptide, a protein, and mixtures thereof, or alternatively e) a composition comprising the self-assembled particle d), for use in medicine.

[0248] This aspect may also be described as a method for treating or preventing a disease or disorder in a subject, more particularly a mammal, and even more particularly a human, comprising the step of administering a therapeutic product as defined herein and one or more pharma- ceutically acceptable excipients or carriers.

[0249] Non-limiting examples of diseases that may be treated and / or prevented by the derivatives of the present invention include, but are not limited to, neurodegenerative disorders, neurological diseases, cancer, infectious diseases, age-related disorders, neuroinflammation, demyelinating disorders, multiple sclerosis, ischemic disorders, ischemia-reperfusion injury, amyloid diseases, cardiomyopathies, spinal cord injuries, immune disorders, inflammatory disorders, rare diseases, wound healing, skin-related diseases, and lysosomal storage diseases.

[0250] Non-limiting examples of neurodegenerative diseases include Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, cerebral ischemia, postencephalitic parkinsonism, dystonia, Tourette's syndrome, periodic limb movement disorder, restless legs syndrome, attention deficit hyperactivity disorder, Huntington's disease, progressive supranuclear palsy, Pick's disease, frontotemporal dementia, and neuromuscular diseases.

[0251] In one embodiment, optionally in combination with any of the embodiments provided above or below, the present invention relates to a therapeutic product which is or comprises: a) a lipo-polyamino acid conjugate of formula (I), where any of A, A', A'', or A''' is an anti-cancer or anti-infective agent as defined herein; or alternatively b) a self-assembled particle comprising lipo-polyamino acid conjugate a), or alternatively c) a composition comprising lipo-polyamino acid conjugate a) or self-assembled particle b), or alternatively d) a self-assembled particle comprising a lipo-polyamino acid conjugate as defined herein and one or more anti-cancer or anti-infective agents, or alternatively e) a composition comprising self-assembled particle d), for use in the treatment and / or prevention of cancer or an infectious disease, respectively.

[0252] The term "disorder", as used herein, is generally synonymous with, and used interchangeably with, the terms "disease", "syndrome", and "pathology" (medical condition), in that all reflect an abnormal condition of one of the human or animal bodies or parts thereof that impairs normal functioning and is usually manifested by distinguishing signs and symptoms.

[0253] In the context of the present invention, the terms "treat", "treating" and "treatment" as used herein refer to ameliorating the symptoms associated with a disease or disorder, including preventing or delaying the onset of a disease or disorder symptom and / or reducing the severity or frequency of a disease or disorder symptom.

[0254] In one embodiment, optionally in combination with any of the embodiments provided above or below, the invention relates to a therapeutic product as defined herein: (i) for use as a transfection reagent for transfecting at least one active agent into a cell; (ii) for use in vivo or ex vivo production of a biologic encoding a recombinant protein, peptide, or antibody or for production of a recombinant virus; (iii) for use as a therapeutic or preventive vaccine against viral infection or as a therapeutic vaccine against cancer or infectious disease; or (iv) for use in genome engineering, cell reprogramming, cell differentiation, or gene editing.

[0255] According to certain embodiments, optionally in combination with any of the embodiments provided above or below, the present invention relates to a therapeutic product, defined herein as a transfection reagent 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 specifically, the active agent is selected from the group consisting of low molecular weight drugs, peptides, proteins, antibodies, nucleic acids, aptamers, and combinations thereof.

[0256] The present invention also relates to methods for the in vitro, ex vivo and in vivo delivery of active agents, including the therapeutic products defined herein.

[0257] In certain embodiments, optionally in combination with any of the embodiments provided above or below, the therapeutic product is a self-assembled particle comprising a lipo-polyamino acid conjugate as defined herein and one or more nucleic acid molecules, or alternatively a composition comprising a self-assembled particle comprising a lipo-polyamino acid conjugate as defined herein and one or more nucleic acid molecules.

[0258] The transfection reagents of the invention are also useful for co-transfecting two or more active agents simultaneously, for example, two or more nucleic acids simultaneously. Transfection compositions (e.g., kits) and methods of using the transfection reagents to deliver nucleic acids to target cells are also within the scope of the invention.

[0259] The present invention also relates to therapeutic products as defined herein for inducing a regulatory effect on the expression of one or more target proteins that are responsible for or involved in a genetic or complex genetic disease, an immune disease, a cancer, a viral infection, or a tumor in various tissues / organs.

[0260] The present invention also relates to the in vitro or ex vivo use of therapeutic products defined herein in the production of biological products, particularly biological products that code recombinant proteins, peptides or antibodies; or in the production of recombinant viruses, such as adeno-associated viruses (AAV), lentiviruses (LV), adenoviruses, oncolytic viruses, or baculoviruses, or viral or virus-like particles.In particular, said products comprise the lipo-polyamino acid conjugate of the present invention for transfection and at least one nucleic acid molecule.As used herein, the term "biological products" refers to proteins or nucleic acids or combinations thereof, biological entities, such as cells or viruses, cell compartments, organoids, and tissues.

[0261] 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 a lipo-polyamino acid conjugate of the present invention and at least one nucleic acid molecule for transfection, genome editing, cell reprogramming, cell differentiation or gene editing.

[0262] Compositions for transfecting cells include therapeutic products as defined herein, in particular lipo-polyamino acid conjugates of the invention for transfection and at least one nucleic acid molecule, as well as acceptable excipients, buffers, cell culture media, or transfection media.

[0263] The present invention also targets the therapeutic product defined herein for use as a therapeutic or preventive vaccine against viral infections, or as a therapeutic vaccine against cancer.Generally, in this embodiment, the vaccine is delivered via direct administration, such as systemic administration, intramuscular administration, intradermal administration, intraperitoneal administration, intratumoral administration, oral administration, topical administration, or subcutaneous administration, in which the composition is associated with a pharmaceutically acceptable vehicle.In other words, the vaccine can be directly injected into the body, particularly a human individual, to induce cellular and / or humoral responses.

[0264] Cellular targeting is achieved through different mechanisms and will vary depending on the nature and characteristics of the transfection reagent, the composition or formulation of the method or protocol, and the route of administration.

[0265] The lipo-polyamino acid conjugates of the present invention, their self-assembled particles and compositions may also be used in cosmetic and diagnostic applications.

[0266] Thus, another aspect of the present invention relates to a diagnostic product which is or comprises a') a lipo-polyamino acid conjugate as defined herein (wherein at least one of A, A', A'', or A''' is a diagnostically active agent), or alternatively b') a self-assembled particle comprising lipo-polyamino acid conjugate i'), or alternatively c') a composition comprising lipo-polyamino acid conjugate i') or self-assembled particle ii'), d') a self-assembled particle comprising a lipo-polyamino acid conjugate as defined herein and one or more diagnostically active agents, or alternatively e) a composition comprising self-assembled particle iv'), for use in diagnosis.

[0267] This aspect of the invention may also be described as the use in diagnosis of a') a lipo-polyamino 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 lipo-polyamino acid conjugate a'), or alternatively c') a composition comprising lipo-polyamino acid conjugate a') or self-assembled particle b'), or alternatively d') a self-assembled particle comprising a lipo-polyamino acid conjugate as defined herein and one or more diagnostically active agents, or alternatively e') a composition comprising self-assembled particle d'). Furthermore, it may also be described as a method for diagnosing a disease or condition, comprising the step of administering a') a lipo-polyamino acid conjugate as defined herein (at least one of A, A', A'', or A''' is a diagnostically active agent), or alternatively b') a self-assembled particle comprising lipo-polyamino acid conjugate a'), or alternatively c') a composition comprising lipo-polyamino acid conjugate a') or self-assembled particle b'), or alternatively d') a self-assembled particle comprising a lipo-polyamino acid conjugate as defined herein and one or more diagnostically active agents, or alternatively e') a composition comprising self-assembled particle d'), to a subject in need thereof, more particularly a mammal, and even more particularly a human.

[0268] In a particular embodiment, the present invention relates to microbubbles comprising a lipo-polyamino acid conjugate as defined herein and one or more diagnostically active agents, in particular contrast agents, for use in diagnosis.

[0269] Detection of these contrast agents may be performed by 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-ray, positron emission tomography (PET), single photon emission computed tomography (SPECT), fluorescence microscopy, and in vivo fluorescence.

[0270] According to another aspect, the present invention relates to the cosmetic use of a cosmetic product which is or comprises a'') a lipo-polyamino acid conjugate as defined herein (at least one of A, A', A'', or A''' is a cosmetically active agent), or alternatively b'') a self-assembled particle comprising lipo-polyamino acid conjugate a'), or alternatively c'') a composition comprising a'') or the self-assembled particle b''), or alternatively d'') a self-assembled particle comprising a lipo-polyamino acid conjugate as defined herein and one or more cosmetically active agents, or alternatively e'') a composition comprising the self-assembled particle d'').

[0271] Throughout the specification and claims, the word "comprises" and variations of this word are not intended to exclude other technical features, additives, ingredients, or steps. Furthermore, the word "comprises" encompasses the case of "consisting of." Additional objects, advantages, and properties of the present invention will become apparent to those skilled in the art upon examination of the description or may be learned by practice of the invention. The following examples and figures are provided by way of illustration and are not intended to limit the invention. Moreover, the present invention includes within its scope all possible combinations of specific and preferred embodiments described herein.

[0272] Working Example Analysis method NMR spectroscopy NMRE spectra were recorded at 27°C (300K) on a 300 Ultrashield™ from Bruker (Billerica MA, USA). Data were processed with the software Topspin (Bruker GmbH, Karlsruhe, Germany). Samples were prepared at concentrations of approximately 20-10 mg / mL in the required solvent.

[0273] Size Exclusion Chromatography (SEC) For SEC measurements in dimethylformamide (DMF) containing 0.1 (w / w)% lithium bromide as additive, a GPC max (Malvern Instruments) autosampler was used at a flow rate of 0.7 mL / min at 60 °C with a SKgel Alpha-4000 column from Tosoh Bioscience. A Viscotek TDA-302 was used as the integrated detection system. The system was calibrated with polymethylmethacrylate (PMMA) from PSS (Mw = 65 kDa; PDI = 1.05). For this Mw determination, an integrated triple detection system was used [refractive index, light scattering (two angles: 7 and 90º) and UV-Vis detector].

[0274] For SEC measurements in water with 0.1 M sodium nitrate and 0.005% sodium azide as additives, a GPC max (Malvern Instruments) pump and autosampler was used at a flow rate of 0.7 mL / min at 25°C with a TSKGel PWXL G5000 column from Tosoh Bioscience. A Viscotek TDA-305 was used as the integrated detection system. The system was calibrated with polyethylene oxide (PEO) (Mw=24 kDa; PDI=1.01) from Malvern Panalytical. For this Mw determination, an integrated triple detection system was used [refractive index, light scattering (two angles: 7 and 90º) and UV-Vis detector].

[0275] Size Distribution Dynamic light scattering (DLS) measurements were performed using a Malvern Zetasizer NanoZS instrument equipped with a 532 nm laser at a fixed scattering angle of 173°. Polymer solutions were prepared under different conditions (MilliQ water or PBS at different concentrations and temperatures), the solutions were sonicated for 10 min, left for the required time, filtered through a 1.20 μm cellulose membrane filter and measured. Size distributions were measured (diameter, nanometers) in triplicate for each polymer with n>3 measurements, and automatic optimization of beam focusing and attenuation was applied for each sample.

[0276] Example 1. LipoShield C 14 Synthesis of -PGA(DIOL) 1.1.C 14 General procedure for polymerization of -PGlu(OBzl) [ka] Glutamic acid benzyl ester NCA (10 g, 40.12 mmol) was added to a Schlenk tube equipped with a stir bar and stopper. After three cycles of vacuum / N2, the mixture was dissolved in anhydrous DMF (150 mg of reagent per ml of DMF). Then, the initiator (tetradecylamine 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 and stirred at 10 °C for 16 h. After the consumption of NCA was confirmed by IR, 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 homopolymer (C 14 -PGluOBzl) was isolated as a white solid. Yield: 70–90%. 1H NMR (300 MHz, DMSO) δ 8.38 – 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).

[0277] Following the above general procedure, the polymers shown in Table 1 were obtained.

[0278] [Table 1]

[0279] 1.2. General Procedure for N-Terminal Capping [ka]

[0280] 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 equiv.) and DIPEA (3 equiv.) were added to the reaction mixture. The mixture was then stirred at RT for 1 h. The reaction mixture was poured into diethyl ether to precipitate the product. The precipitate (C 14 -PGlu(OBzl)-COCH3) was isolated by centrifugation (3750 rpm, 4 min) and dried under vacuum. Yield: 60-70%. 1H NMR (300 MHz, TFA) δ 8.05 – 7.73 (brs, CH aryl), 5.69 (m, CH2 benzyl), 5.25 (m, CH), 3.88 (s, CH3), 3.26 – 2.36 (m, CH2), 1.83 (brs, CH2), 1.40 (t, J = 6.6 Hz, CH3).

[0281] Following the above general procedure, the polymers shown in Table 2 were obtained.

[0282] [Table 2]

[0283] 1.3. General Procedure for the Deprotection Step [ka]

[0284] Lipo-polymer C obtained in Example 1.2 14-PGlu(OBzl)-COCH3 (Lipo-PGA1-4: 6.4 mmol) was dissolved in thiofluoroacetic acid (100 mg / mL) and HBr 48% (2 equivalents per glutamic acid unit) was added. The mixture was stirred at RT for 16 h. 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 the pH was 4-5. The product was then washed again with diethyl ether, isolated by centrifugation (3750 rpm, 4 min) and dried under vacuum. The polymer (C 14 -PGA) was isolated as a white solid. Yield: 95%. 1 H NMR (300MHz, D2O) δ 4.35 (m, CH), 3.22 (m, CH3), 2.69 – 1.76 (m, CH2), 1.53 (brs, CH2), 1.30 (s, CH2), 0.89 (t, J = 6.4 Hz, CH3)

[0285] Following the above general procedure, the polymers shown in Table 3 were obtained.

[0286] [Table 3]

[0287] 1.4.C 14 General procedure for peptide coupling with CDI for the synthesis of -PGA(DIOL) [ka] C obtained in Example 1.3 14-PGA (PGADIOL 0.4 g, 3.1 mmol) was dissolved in DMF (50 mg / mL). CDI (1.6 equivalents per glutamic acid unit) was then added to the reaction mixture and stirred at room temperature for 30 min. After this time, 3-aminopropane-1,2-diol (1.3 equivalents per glutamic acid unit) dissolved in 2 mL of DMF was added. The mixture was stirred at room temperature for 16 h. The reaction mixture was poured into acetone to precipitate the product. The precipitate was isolated by centrifugation (3750 rpm, 4 min) and dried under vacuum. The final product was isolated as a white solid. Yield: 50-60%. 1 H NMR(300 MHz, D2O) δ 4.38 (brs, CH), 3.83 (brs, CH), 3.59 (ddd, J = 18.1, 11.8, 5.2 Hz, CH2), 3.32 (ddd, J = 21.1, 14.0, 5.8 Hz, CH2), 2.66 – 1.82 (m, CH2),1.53 (brs. CH2), 1.29 (s, CH2), 0.88 (t, J = 6.5 Hz, CH3).

[0288] Following the above general procedure, the polymers shown in Table 4 were obtained. [Table 4]

[0289] Example 2. LipoShield C 14 -PLys (thioglycerol) x Synthesis of 2.1 C 14 General procedure for polymerization of -PLys(OBzl) [ka]

[0290] L-Lysine benzyl ester NCA (10 g, 32.64 mmol) was added to a Schlenk tube equipped with a stir bar and stopper. After three cycles of vacuum / N2, the mixture was dissolved in anhydrous DMF (150 mg of reagent per ml of DMF). The initiator (tetradecylamine 96%, TCI EUROPE NV: DP23: 0.319 g, 1.42 mmol, DP8: 0.917 g, 1.08 mmol) was then diluted in DMF (5 mL) and added to the reaction mixture and stirred at 10° C. for 16 h. After the consumption of NCA was confirmed by IR, 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 homopolymer (C 14 -PLys(OBzl)) was isolated as a white solid. 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, CH2 benzyl), 2.92 (m, CH2), 2.07 – 1.09 (m, CH2), 0.83 (t, J= 5.5 Hz, CH3).

[0291] Following the above general procedure, the polymers shown in Table 5 were obtained. [Table 5]

[0292] 2.2 General procedure for N-terminal capping [ka]

[0293] C obtained in Example 2.1 14 -PLys(OBzl) (PLysTG1: 1.5 g, 0.24 mmol, PLysTG2: 1.5 g, 0.65 mmol) was captured by the procedure described above in Example 1.2. Yield: 60-70%. 1H NMR (300MHz, 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).

[0294] After this procedure, the polymers shown in Table 6 were obtained. [Table 6]

[0295] 2.3 General procedure for the deprotection step [ka] Lipo-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 HBr 33% (4 equivalents per lysine unit) was added. The mixture was stirred at RT for 16 h. An orange solid appeared. It was collected by filtration and washed with diethyl ether. The precipitate was washed with a mixture of acetonitrile:H2O (8:2) until the pH reached 4-5. The product was washed again with diethyl ether, isolated by centrifugation (3750 rpm, 4 min) and dried under vacuum. The polymer was isolated as a yellowish solid. Final purification by dialysis (Mw cutoff 2000 Da) gave a white solid (C 14 -PLys) was obtained. Yield: 70%. 1 H NMR(300MHz, D2O) δ 4.29 (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)

[0296] After this procedure the polymers shown in Table 7 were obtained. [Table 7]

[0297] 2.4.C 14 General Procedure for Peptide Coupling with Chloroacetic Anhydride for the Synthesis of -PLys(ClAc) [ka]

[0298] C obtained in Example 2.3 14 -PLys (PLys 0.5 g, 0.1 mmol) was dissolved in cold DMF (50 mg / mL). 2,6-lutidine (0.25 mL / mL DMF) was then added to the reaction mixture and stirred at 4° C. for 75 min. After this time, cold chloroacetic anhydride (4 equivalents per lysine unit) dissolved in DMF (514 mg / mL) was added dropwise. The mixture was stirred at 4° C. for 16 h. The reaction mixture was poured into hot ethanol. The mixture was left at 4° C. for 45 min to precipitate the product. The precipitate was isolated by filtration, washed with ethanol, and dried under vacuum. The final product (C 14 -PLys(ClAc)) was isolated as a white solid. Yield: 80-90%. 1 H NMR (300 MHz, TFA) δ 5.19 (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).

[0299] After this procedure the polymers shown in Table 8 were obtained. [Table 8]

[0300] 2.5.C 14General Procedure for Thioglycerol Coupling for the Synthesis of -PLys(Thioglycerol) [ka]

[0301] 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 equivalents per lysine unit) and DIPEA (8 equivalents per lysine unit) were added to the reaction mixture. The reaction mixture was stirred at room temperature for 16 hours. After this time, the reaction mixture was poured into diethyl ether and the precipitate was isolated by filtration, washed with diethyl ether and dried under vacuum. The product was dissolved in HO, purified by a sephadex column (PD-10 desalting column) and lyophilized. The final product was isolated as a white solid. Yield: 60-70%. 1 H NMR (300 MHz, D2O) δ 4.10 (brs, CH), 3.88 (brs, CH), 3.64 (ddd, J= 22.9, 12.1, 4.6 Hz, CH2), 3.34 (brs, CH2), 3.25 (brs, CH2), 2.75 (ddd, J = 21.4, 13.8, 6.1 Hz, CH2), 2.20 – 1.14 (m, CH2), 0.88 (m, CH3).

[0302] After this procedure the polymers shown in Table 9 were obtained. [Table 9]

[0303] Example 3. Liposhield C 14 Synthesis of -PLys(betaine) 3.1.C 14 General procedure for polymerization of -PLys(TFA) [ka] L-Lysine TFA NCA (10 g, 37.29 mmol, DP 5) was added to a Schlenk tube equipped with a stir bar and stopper. After three cycles of vacuum / N2, the mixture was dissolved in anhydrous DMF (150 mg of reagent per ml of DMF). The initiator (1.67 g, 7.45 mmol, tetradecylamine 96%, TCI EUROPE NV) was then diluted in DMF (5 mL) and added to the reaction mixture and stirred at 10° C. for 16 h. After the consumption of the NCA was confirmed by IR, 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 homopolymer (C 14 -PLys(TFA)) was isolated as a white solid. 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)

[0304] After the general procedure, the polymers shown in Table 10 were obtained. [Table 10]

[0305] 3.2. General Procedure for the Deprotection Step [ka] Lipo-polymer C obtained in Example 3.1 14 -PLys(TFA) was dissolved in cold methanol (300 mg / mL) and cold aqueous NaOH (1.5 equivalents per lysine unit) was added. The mixture was stirred at RT for 16 h. The reaction mixture was quenched with HBr 48% until pH 2. The precipitate was washed with a mixture of acetone, isolated by centrifugation (3750 rpm, 4 min) and dried under vacuum. The product was dissolved in HO, the pH was adjusted to 4 with NaOH (1 M) and lyophilized. The polymer (C 14-PLys) was isolated as a white solid. Yield: 70-80%. 1 H NMR (300 MHz, TFA) δ 5.31 (m, CH), 3.94 (m, CH2), 2.92 – 2.12 (m, CH2), 1.95 (brs, CH2), 1.49 (t, J = 6.7 Hz, CH3).

[0306] Following the above general procedure, the polymers shown in Table 11 were obtained. [Table 11]

[0307] 3.3.C 14 -PLys n General procedure for the dimethylation of the amine group of [ka]

[0308] Lipo-polymer C obtained in Example 3.2 14 -Plys was dissolved in formaldehyde (1 equivalent per lysine unit) and formic acid (2.3 equivalents per lysine unit). The mixture was heated to 85°C and stirred for 16 hours. The reaction mixture was concentrated by Rotavapor and redissolved in methanol. The mixture was precipitated with diethyl ether, isolated by centrifugation (3750 rpm, 4 min) and dried under vacuum. The product was dissolved in HO, purified by a sephadex column (PD-10 desalting column) and lyophilized. The polymer (C 14 -PLys(Dimet)) was isolated as a white solid. Yield: 50%. 1 H NMR (300 MHz, D2O) δ 4.49 – 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 = 6.7 Hz, CH3).

[0309] Following the above general procedure, the polymers shown in Table 12 were obtained. [Table 12]

[0310] 3.4.C 14 General procedure for incorporating tert-butyl bromoacetate onto -PLys(Dimet) [ka]

[0311] C obtained in Example 3.3 14 -PLys(Dimet) was dissolved in DMF (50 mg / mL). Then tert-butyl bromoacetate (6 eq. per lysine unit) was added to the reaction mixture and stirred at RT for 5 min. After this time, TBAI (0.5 eq. per lysine unit) and DIPEA (3 eq. per lysine unit) were added. The mixture was stirred at RT for 16 h. The reaction mixture was concentrated by rotavapor and redissolved in DCM. The mixture was precipitated with diethyl ether, isolated by centrifugation (3750 rpm, 4 min) and dried under vacuum. The product was used without further purification or characterization. Yield: 75%.

[0312] 3.5. General Procedure for tert-Butyl Deprotection Step [ka] Protected lipo-polymer C obtained in Example 3.4 14 -Pbet was dissolved in cold fluoroacetic acid (50 mg / mL) and stirred at RT for 24 h. 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 HO, dialyzed against miliQ water (3750 rpm, 4 min) for 24 h, and lyophilized. The polymer was isolated as a white solid. 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)

[0313] Following the above general procedure, the polymers shown in Table 13 were obtained. [Table 13]

[0314] Example 4. Synthesis of LipoShield DMPE(14:0)-PGA(DIOL) 4.1. General Procedure for Polymerization of DMPE(14:0)-PgluOBzl [ka] N-Carboxy-glutamic acid-benzyl-anhydride (NCA) was added to a Schlenk tube equipped with a stir bar and stopper. After three cycles of vacuum / N2, the mixture 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, which was stirred at room temperature for 16 h. After the consumption of NCA was confirmed by IR, the reaction mixture was poured into diethyl ether to precipitate the product. The precipitate (DMPE(14:0)-PGlu(OBzl)) was isolated by centrifugation (3750 rpm, 4 min) and dried under vacuum. Yield: 70-90%. 1H NMR (300 MHz, TFA) δ 8.08 (m, CH aryl), 5.93 (m, CH2 benzyl), 5.49 (brs, CH), 3.56 – 2.71 (m, CH2), 2.49 (m, CH2), 2.08 (m, CH2), 1.64 (t, J = 6.6 Hz, CH3)

[0315] Following the above general procedure, the polymers shown in Table 14 were obtained. [Table 14]

[0316] General Procedure for the Deprotection Step [ka]

[0317] The lipo-polymer DMPE(14:0)-PGlu(OBzl) obtained in Example 4.1 was dissolved in trifluoroacetic acid (100 mg / mL) and HBr 48% (2 equivalents per glutamic acid unit) was added. The mixture was stirred at RT for 16 h. The reaction mixture was poured into diethyl ether to precipitate the product. The precipitate was washed with acetonitrile:H2O (8:2) until the pH was 4-5. The product was then washed again with diethyl ether, isolated by centrifugation (3750 rpm, 4 min) and dried under vacuum.

[0318] The polymer (DMPE(14:0)-PGA) was isolated as a white solid. Yield: 80%. 1 H NMR (300 MHz, D2O) δ 4.47 – 3.80 (m, CH), 2.45 – 1.76 (m, CH2), 1.57 (brs, CH2), 1.24 (m, CH2), 0.83 (t, J = 6.55 Hz, CH3)

[0319] Following the above general procedure, the polymers shown in Table 15 were obtained. [Table 15]

[0320] 4.3 General procedure for peptide coupling with CDI for the synthesis of DMPE(14:0)-PGA(DIOL) [ka] 3-Aminopropane-1,2-diol was introduced into the side chain of DMPE(14:0)-PGA obtained in Example 4.2 according to the procedure described above in Example 1.4 to prepare the corresponding DMPE(14:0)-PGA(DIOL). Yield: 60-70. 1 H NMR (300 MHz, D2O) δ 4.38 (brs, CH), 3.87 (brs, CH), 3.63 (ddd, J = 18.2, 12.0, 5.5 Hz, CH2), 3.35 (ddd, J = 21.1, 14.1, 5.7 Hz, CH2), 2.68– 1.92 (m, CH2), 1.34 (brs, CH2), 0.94 (s, CH3)

[0321] Following the above general procedure, the polymers shown in Table 16 were obtained.

[0322] [Table 16]

[0323] Example 5. LipoShield Dimyrist-GABA-PGA (DIOL) n Synthesis of [ka]

[0324] 5.1. General procedure for the synthesis of initiator (y) [ka]

[0325] 5.1. General Procedure for the Synthesis of tert-Butyl (4-(ditetradecylamino)-4-oxobutyl)carbamate [ka] 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 at rt for 30 min. Dimyrist (ditetradecylamine: 1.1 eq., 2.16 mmol, 885 mg) was then added and the reaction mixture was stirred at room temperature for 16 h. Completion of the reaction was monitored by TLC. The reaction was filtered and the filtrate was concentrated to dryness using rotary evaporation. The crude reaction was then purified by flash column chromatography using hexane:ethyl acetate (8:2) as the eluent. The resulting product was concentrated to dryness and isolated as a yellowish oil (obtained m: 1.12 g). Yield: 95% 1 H NMR (300 MHz, CHCl3) δ 4.84 (brs, CH), 3.27 (m, CH2), 3.17 (dd, J = 13.6, 6.4 Hz, CH2), 2.32 (t, J= 7 Hz, CH2), 1.82 (p, J = 6.6 Hz, CH), 1.57-1.46 (m, CH2), 1.42 (s, CH3), 1.26 (brs, CH2), 0.87 (t, J = 6.7 Hz, CH3

[0326] 5.1b. General Procedure for the Deprotection Step [ka] 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 at room temperature for 16 h. The reaction crude was then dried using rotary evaporation and used in the next reaction without prior purification. Yield: 100%. 1H NMR (300 MHz, CHCl3) δ 7.80 (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 = 6.7 Hz, CH3).

[0327] 5.2 General procedure for polymerization of dimyrist-GABA-PGlu(OBzl) [ka] Glutamic acid benzyl ester NCA (1.33 g, 10.29 mmol) was added to a Schlenk tube equipped with a stir bar and stopper. After three cycles of vacuum / N2, the mixture was dissolved in anhydrous DMF (150 mg of reagent per ml of DMF). The initiator (Dimyrist-GABA-NH3TFA.:DP20: 254 mg, 0.51 mmol) was then diluted with DMF (5 mL) and DIPEA (1 eq., 0.51 mmol, 896 μL) was added to the initiator solution. The initiator solution was then added to the reaction mixture and stirred at 10° C. for 16 h. After the consumption of NCA was confirmed by IR, 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 homopolymer (Dimyrist-GABA-PGluOBzl) was isolated as a white solid. Yield: 70-90%. 1 H NMR (300 MHz, TFA) δ 7.36 (m, CH aryl), 5.35 (m, CH benzyl), 4.78 (m, CH), 3.66 (m, CH2), 2.92 – 1.98 (m, CH2), 1.84 (d, J = 7.7 Hz, CH2), 1.53-1.30 (m, CH2), 0.82 (t, J = 5.9 Hz, CH3).

[0328] [Table 17]

[0329] 5.3 General Procedure for the Deprotection Step [ka]

[0330] The lipo-polymer Dimyrist-GABA-PGlu(OBzl)-COCH3 (1. g, 4.8 mmol) obtained in Example x.2 was dissolved in trifluoroacetic acid (100 mg / mL) and HBr 48% (2 equivalents per glutamic acid unit) was added. The mixture was stirred at RT for 16 h. 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 the pH was 4-5. The product was then washed again with diethyl ether, isolated by centrifugation (3750 rpm, 4 min) and dried under vacuum. The polymer (Dimyrist-GABA-PGA) was isolated as a white solid. Yield: 95%. 1 H NMR (300 MHz, D2O) δ 4.92 (m, CH), 3.70 (m, CH3), 3.13-2.08 (m, CH2), 1.87 (brs, CH2), 1.44 (m, CH2), 0.94 (brs, CH3). [Table 18]

[0331] 5.4.C 14 -PGA(DIOL) n General procedure for peptide coupling with CDI for the synthesis of [ka] Dimyrist-GABA-PGA (PGADIOL 0.4 g, 3.3 mmol) obtained in Example 5.3 was dissolved in DMF (50 mg / mL). CDI (1.6 equivalents per glutamic acid unit) was then added to the reaction mixture and stirred at room temperature for 30 min. After this time, 3-aminopropane-1,2-diol (1.3 equivalents per glutamic acid unit) dissolved in 2 mL of DMF was added. The mixture was stirred at room temperature for 16 h. The reaction mixture was poured into acetone to precipitate the product. The precipitate was isolated by centrifugation (3750 rpm, 4 min) and dried under vacuum. The final product was isolated as a white solid. Yield: 50-60%. 1 H NMR (300 MHz, D2O) δ 4.33 (brs, CH), 3.88 (brs, CH), 3.71-3.49 (m, CH2), 3.43-3.20 (m, CH2), 2.98 (dd, J = 13.2, 3.5 Hz, CH2), 2.83 (dd, J = 13.2, 8.5 Hz, CH2), 2.56 – 1.91 (m, CH2),1.30 (brs. CH2), 0.90 (brs, CH3)

[0332] [Table 19]

[0333] Example 6. Lipid nanoparticle formulations In the following examples, the oligonucleotides used were pDNA with reference number PF461 (pCMV-luc) containing 6233 bp expressing luciferase, purchased from PlasmidFactory, and mRNA with reference number L-1201-1000 CleanCap Fluc mRNA (5 moU), expressing luciferase as a reporter gene, purchased from Trilink. Any other oligonucleotides with the above mentioned characteristics could be used to carry out the following experiments.

[0334] The ionizable lipid DLin-MC3-DMA, or (6Z,9Z,28Z,31Z)-heptatriaconta-6,9,28,31-tetraen-19-yl 4-(dimethylamino)butanoate, was purchased from Nanosoft Polymers, and the shield lipid 1,2-dimyristoyl-rac-glycero-3-methoxypolyethylene glycol-2000 (DMG-PEG2000) was purchased from Avanti Polar Lipids. Both polymers were used to form the reference LNPs. The structural lipids used to form the LNPs were 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC, Avanti Polar Lipids, 850365P) and cholesterol (Sigma-Aldrich, C8667).

[0335] A microfluidic Herringbone Mixer from Darwing Microfluidics was used for the formulation of LNP1-12. The reactor presents two inlet channels (one for DNA in the aqueous phase and the other for the lipid mixture in ethanol) and one outlet channel. The mixer specifications are as follows: Slide format: 25×75m Channel depth: 0.08mm Channel width: 0.1~0.5mm Volume: 3.3μL Mixer volume: 0.47 μL Mixer length: 28.7mm Material: Glass Connectors: 1 / 4″-28 Fittings

[0336] Additionally, two programmable pumps control the flow rate of the syringes (NE-1000 Programmable Single Syringe Pump, Syringe Pump, USA). The system allows injection rates of 0.73 μL / h (1 mL syringe) to 2100 mL / h (60 mL syringe). This method offers reproducibility for the formation of LNPs and the possibility to scale up the process. The reference LNPs were formulated as follows: The lipids were dissolved in a molar ratio of 50 / 10 / 38.5 / 1.5 (MC3 / DSPC / cholesterol / DMG-PEG). The pDNA was diluted in 25 mM acetate buffer, pH 4. The amine:phosphate ratio (N / P) was four. The flow ratio was 3:1 (ethanol:H2O). The total flow rate was 2 mL / min. The inner diameter of the tube was 0.5 mm. After formulation, the LNPs were diluted in 10 mM phosphate buffered saline (PBS) (pH 7.4) and concentrated in a centrifugal concentrator (Vivaspin™ 500, Sigma) to remove ethanol.

[0337] Formulations containing lipo-polyamino acid conjugates of formula (I) were similarly prepared, except that lipo-polyamino acid conjugates of formula (I) were used in place of DNG-PEG and the lipid ratios were different (as shown below).

[0338] The reference LNP13-17 was formulated using a NanoScaler (KNAUER) as follows: Lipids were dissolved in ethanol in a molar ratio of 46.3 / 9.4 / 42.7 / 1.6 (ALC-0315 / DSPC / cholesterol / DMG-PEG). The mRNA was diluted in 25 mM acetate buffer, pH 4. The amine:phosphate ratio (N / P) was 6.2. The flow ratio was 1.3 (ethanol:H2O). The total flow rate of LNP was 4.5 mL / min (3 mL / min neat LNP + 1.5 mL / min in-line dilution with PBS).

[0339] After formulation, the LNPs were further diluted in 10 nM phosphate buffered saline (PBS) pH 7.4 to reduce the ethanol concentration and purified with a centrifugal concentrator (Vivaspin™ 500, Sigma) to remove the ethanol. Formulations containing the polymers of the invention were similarly prepared, except that different LipoPAA was used in place of the shield lipid DMG-PEG and the lipid ratios were different (as shown in Tables 27 and 28).

[0340] Example 7. Characterization of LNPs 7.1 Size and polydispersity Size and polydispersity (PDI) of formulated LNPs containing mRNA or pDNA with different N / P ratios (positively chargeable polymeric amine (N = nitrogen) groups: negatively charged nucleic acid phosphate (P)), different molar ratios and shielding polymers were performed using a Malvern Zetasizer NanoZS instrument equipped with a 532 nm laser at a fixed scattering angle of 173°. 50 μl of sample was measured using a quartz glass high performance cuvette (Hellma Analytics). Size distribution was measured (diameter, nm) with n > 3 measurements.

[0341] A reference LNP containing MC3 as the ionizable lipid, DMG-PEG as the shield lipid, and mRNA as the cargo was formulated with MC3 / DSPC / cholesterol / DMG-PEG in a molar ratio of 50 / 10 / 38.5 / 1.5 with the following results:

[0342] [Table 20]

[0343] The presence of DMG-PEG at 1.5% is sufficient to stabilize the LNPs and obtain good size (expressed as Z-average) and PDI and reproducible formulations.

[0344] Table 21 shows the results obtained for Lipo-PAA1 formulated at 2% and 5% molar ratios containing pDNA as cargo. [Table 21]

[0345] The results suggest that the best results were achieved with 2% Lipo-PAA1, which consistently showed low PDI values ​​and suitable size across all replicates. This composition was also used to formulate LNPs with mRNA, which also obtained low PDI values ​​and suitable size (Table 22).

[0346] [Table 22]

[0347] Table 23 shows the results obtained for Lipo-PAA2 formulated at a molar ratio of 0.5% containing pDNA as cargo.

[0348] [Table 23]

[0349] In this case, the results suggest that the best results were achieved with 5% Lipo-PAA2. Moreover, when using 5% polymer, the results were consistent across all replicates, showing low PDI values ​​and appropriate size. This composition was also used to formulate LNPs with mRNA, resulting in low PDI values ​​and appropriate size (Table 24).

[0350] [Table 24]

[0351] Table 25 shows the results obtained for Lipo-PAA7 formulated at a molar ratio of 5% directly containing mRNA as cargo.

[0352] [Table 25]

[0353] Since Lipo-PAA9 is similar to Lipo-PAA1, table 26 shows the results obtained at a molar ratio of 2% directly containing mRNA as cargo.

[0354] [Table 26]

[0355] Reference LNPs containing ALC-0315 as the ionizable lipid, DMG-PEG as the shielding lipid, and mRNA as cargo were prepared as ALC-0315 / DSPC / cholesterol / DMG-PEG or C 14 -Psar was formulated at a molar ratio of 46.3 / 9.4 / 44.3-x / x, with the following results:

[0356] [Table 27]

[0357] LNPs with good size (expressed as Z-average) and PDI and reproducible formulation were obtained.

[0358] Table 28 shows the results obtained for Lipo-PAA1, Lipo-PAA8 and Lipo-PAA10 formulated at a molar ratio of 2% with mRNA as cargo.

[0359] [Table 28]

[0360] The results suggest that 2% Lipo-PAA1, Lipo-PAA8, and Lipo-PAA10 were consistent across all replicate experiments, showing low PDI values ​​and appropriate size.

[0361] 7.2 Detection of free oligonucleotides by gel electrophoresis The possible presence of free pDNA or mRNA after formulation of LNPs was evaluated using electrophoretic gels as a first screening method. An E-gel Power Snap electrophoresis device and an E-Gel Power Snap Camera (Invitrogen) were used. A 2% agarose gel was prepared with SYBR Gold DNA marker (E-Gel™ EX agarose gel, 2%, Invitrogen) according to the manufacturer's instructions. LNPs (20 μl) composed of different lipo-polypeptide shields as shown in FIG. 1 were evaluated, as well as the degradation of LNPs in the presence of 10% Triton X100 (Scharlab, SL) and 2 mg / mL heparin (PanReacAppliChem, Spain). After loading the gel (20 μl / well), the instrument protocol was selected according to the type of gel used (in our case, a protocol of about 10 minutes, but the time can be modified depending on the sample).

[0362] In all cases, no free mRNA was observed when different lipo-polypeptide shields were tested, however, when 10% Triton X100 was used, a free mRNA signal was observed, since Triton X100 as a detergent is able to degrade different components of the LNPs and thus release the LNP cargo (a representative gel image can be seen in Figure 1).

[0363] 7.3 pKa of formulated LNPs The positively charged amino groups in the nanoparticles are dependent on the pH of the medium, and the apparent pKa can predict these charges. The effect of lipo-polypeptides on the LNP surface can change this apparent pKa and thus affect transfection efficiency. The apparent pKa values ​​of LNPs were determined by measuring the fluorescence of 2-(p-toluidino)-6 naphthalenesulfonic acid (TNS) during titration with different buffer solutions: 20 mM acetate buffer at pH 4-5.5 (0.5 pH increments); 20 mM phosphate buffer at pH 6-7.5 (0.5 pH increments); 20 mM borate buffer at pH 8-9 (0.5 pH increments). The formulations were diluted in different buffer solutions to a lipid concentration of 20 μM and added to a black 96-well plate. TNS solution (0.3 mM in DMSO) was added to a final concentration of 6 μM. The fluorescence was measured at λ em = 445 nm, λ ex = 321 nm, and the pH at half-maximum fluorescence intensity was defined as pKa.

[0364] [Table 29]

[0365] The pKa of LNPs formulated with Lipo-PAA1 and Lipo-PAA2 is similar to that of the reference LNP, which is included between 6.2 and 6.7. This range of pKa has been reported to be ideal for obtaining the best performance of LNPs.

[0366] Example 8. In vitro biological testing in HeLa cells 8.1 Cell culture HeLa cells were cultured in DMEM (high glucose) with Glutamax (Gibco- Thermo Fisher # 61965-059) supplemented with 10% fetal bovine serum (Hyclone # SV30160.03HI, provided by GE Healthcare Europe GmbH) and 1% penicillin / streptomycin. Transfections were performed on 96-well plates with 10000 cells / well in a final volume of 100 μl and cells were incubated for 24 hours at 37° C. and 5% CO2. 24 hours after cell seeding, the medium was removed and replenished with 90 μL of complete medium. 10 μl of each LNP formulation was added to the cells. In the case of the positive control (Lipofectamine™ 2000 Transfection Reagent, Invitrogen™), the manufacturer's guidelines were followed. After 24 hours, cells were harvested and processed.

[0367] 8.2 ATP Evaluation for Evaluation of Cytotoxicity After 24 hours post-incubation with LNP formulations, the medium was aspirated and 50 μl / well of ATPLite reagent (ATPLite PerkinElmer #6016731) was added. Plates were incubated for 10 minutes in the dark at room temperature. Luminiscence was read spectrophotometrically using VictorNivo (PerkinElmer) according to the manufacturer's instructions and data was expressed as a percentage of cell viability, with untreated control cells taken as 100%.

[0368] 8.3. Luciferase assay for evaluation of transfection efficiency After 24 hours post-incubation with LNP formulations, 100 μl of BrightGlo Reagent (Promega # E2620) was added to each well according to the manufacturer's instructions. After 5 minutes of incubation at room temperature, luciferase activity was measured using VictorNivo (PerkinElmer). Data was expressed as luminescence versus percentage of transfection compared to a positive transfection control.

[0369] 8.4 Biological activity of LNPs in HeLa cells The transfection efficiency and cell viability of LNP formulations in HeLa cells are reported in the table below. Transfection data are expressed as % of the positive control Lipofectamine™ 2000, which is 100% after 24 hours of treatment, and cell viability is compared to untreated (NT) cells, with the readout of the ATP content of NT equal to 100%.

[0370] [Table 30]

[0371] According to these results, the transfection obtained from both LNPs containing PGADIOL derivatives was higher than that of LNPs containing DMG-PEG. Moreover, compound Lipo-PAA1 transfected cells 2.5 times more efficiently than Lipofectamine in absolute standard. Therefore, it can be concluded that the addition of Lipo-PAA to LNPs results in: i) stable nanoparticles with acceptable size and polydispersity; ii) non-cytotoxic formulations; and iii) high transfection efficiency. These results demonstrate that Lipo-PAA presented in this application can be an alternative to real DMG-PEG compounds.

[0372] Example 9. In vitro biological testing in HEK293 cells 9.1 Cell culture HEK293 cells were cultured in high glucose DMEM with Glutamax (Gibco- Thermo Fisher # 61965-059) supplemented with 10% fetal bovine serum (Hyclone # SV30160.03HI, provided by GE Healthcare Europe GmbH) and 1% penicillin / streptomycin. Transfections were performed on 96-well plates containing 30000 cells / well in a final volume of 100 μl and cells were incubated for 24 hours at 37°C and 5% CO2. 24 hours after cell seeding, the medium was removed and replenished with 90 μL of complete medium. 10 μl of each LNP formulation was added to the cells. After 24 hours, cells were harvested and processed.

[0373] 9.2 Evaluation of ATP for assessment of cytotoxicity After 24 hours post-incubation with LNP formulations, the medium was aspirated and 50 μl / well of ATPLite reagent (ATPLite PerkinElmer #6016731) was added. Plates were incubated for 10 minutes at room temperature in the dark. Luminiscence was read spectrophotometrically using VictorNivo (PerkinElmer) according to the manufacturer's instructions and data was expressed as a percentage of cell viability, with untreated control cells taken as 100%.

[0374] 9.3 Luciferase assay for evaluation of transfection efficiency After 24 hours post-incubation with LNP formulations, 100 μl of BrightGlo Reagent (Promega # E2620) was added to each well according to the manufacturer's instructions. After 5 minutes of incubation at room temperature, luciferase activity was measured using VictorNivo (PerkinElmer). Data was expressed as luminescence versus percentage of transfection compared to a positive transfection control.

[0375] 9.4. Biological activity of LNPO in HEK293 cells The transfection efficiency and cell viability of LNP formulations in HEK293 cells are reported in the table below. Transfection data are expressed as % of ALC-0315 / DSPC / cholesterol / DMG-PEG or positive control DMG-PEG with formulations reported in molar ratios of 46.3 / 9.4 / 44.3-x / x for LipoPAA, where x is the different molar ratio for each LipoPAA used, the positive control is 100% after 24 hours of treatment, cell viability is compared to non-treated (NT) cells, and ATP content is the readout of NT (non-treated) cells corresponding to 100%.

[0376] [Table 31]

[0377] These results indicate that transfection from LNPs containing Lipo-PAA1, Lipo-PAA8, and Lipo-PAA10 was higher than that from LNPs containing DMG-PEG and the PEG substitute C14-PSar. Moreover, it is noteworthy that the structurally different conjugates transfected cells 1.9-3.3 times (Lipo-PAA1), 3.1-3.3 times (Lipo-PAA8), and 3.3-5.1 times (Lipo-PAA10) more efficiently than the commercial standard DMG-PEG at different concentrations, whereas C14PSar showed transfection just as efficiently as DMG-PEG.

[0378] Therefore, it can be concluded that the addition of Lipo-PAA to LNPs results in: i) stable nanoparticles with acceptable size and polydispersity; ii) non-cytotoxic formulations; and iii) high transfection efficiency. These results demonstrate that Lipo-PAA presented in this application can be a practical alternative to DMG-PEG and C13PASar.

[0379] Example 10. In vivo transfection ability of LNPs 10.1 Experimental details All animal experiments were performed according to approved animal protocols. For in vivo mRNA transfection, 6-week-old male Balb / c mice were intravenously (iv) administered Comp.LNP13 and LNP15 (n=3-5). Four and 24 hours after injection of Comp.LNP13 (n=4) and LNP15 (n=5), mice were subcutaneously injected with luciferin (15mg / kg), and 10 minutes later mice were euthanized via CO2 inhalation and organs were dissected (blood, liver, spleen, lungs, kidneys, and ALN (axillary lymph node)). Image acquisition was completed with IVIS Spectrum (settings: Binning factor 8 F / Stop 1 Exp AUTO FOV 22,5 (D)). Weights of different organs were obtained and then frozen in N2 and -80°C. Image analysis was performed using Living Image 4.5.4 (Settings: ROI (Draw auto, threshold 2%)) and data were expressed as total counts / g of tissue.

[0380] 10.2 In vivo transfection results The body weight of the mice after administration of the different formulations was measured with the following results in Table 32. [Table 32]

[0381] The body weight of the mice remained in the range of 20-22 g and showed no significant differences. Image analysis by Living Image 4.5.4 of the different dissected organs showed the total counts per gram of tissue represented in Figure 2. Statistical analysis by Kruskal-Wallis test determined no significant differences between Comp.LNP13 24h and LNP15 4h in the liver (A) and Comp.LNP13 (with DMG-PEG) at 4 h. Organs B-D (ALN, spleen, and lung, respectively) show no significant differences between Comp.LNP13 and LNP15. Thus, the transfection capacity between the positive control (Comp.LNP13) and LNP15 at 4 h has comparable results.

[0382] Citation List - Nogueira S. et al., “Polysarcosine-Functionalized Lipid Nanoparticles for Therapeutic mRNA Delivery”, ACS Appl. Nano Mater., 2020, 3, 10634–10645 - TW Green and PGM Wuts, Protective Groups in Organic Chemistry, Wiley, 3rd ed. 1999, Chapter 5 (pp. 369-451) - TW Green and PGM Wuts, Protective Groups in Organic Chemistry, Wiley, 3rd ed. 1999, Chapter 7 (pp. 495-653)

[0383] For reasons of completeness, various aspects of the invention are described in the following subsections.

[0384] Additional notes 1. A lipo-polyamino acid conjugate of formula (I), a salt thereof, or any stereoisomer or mixture of stereoisomers of a compound of formula (I) or a salt thereof, [ka] (In the formula, n is an integer from 5 to 250, m is 0 or 1; X is selected from the group consisting of N, S, and O; R1 is 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 the group consisting of (II), (III), (IV), and (V), wherein a, b, c, and d are independently integers from 1 to 4; R3 is H or -(C1-C6)alkyl; A is 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, a protecting group, a radical R4, a lipid-like moiety R5, and an active moiety; A is optionally substituted with 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, -SON2NH2, -SO2-N((C1-C6)alkyl)2, -COOH, -CONH2, and -CON((C1-C6)alkyl)2; A' is 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 )Aralkoxy, -(C5-C 10 )heteroaralkoxy, -(C1-C 10 )Alkyl-O-(C6-C 10) aryloxy, amino protecting groups, radicals R4', lipid-like moieties R5', amino acid-like moieties R6, and active moieties; A' is optionally substituted with 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, -SON2NH2, -SO2-N((C1-C6)alkyl)2, -COOH, -CONH2, and -CON((C1-C6)alkyl)2; however, i) When m is 0, A' is 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 ) is selected from the group consisting of heterocycloalkyl, amino protecting groups, amino acid-like moieties R6, and active moieties; When m is 1, A' is 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 )Aralkoxy, -(C5-C 10 )heteroaralkoxy, -(C1-C 10 )Alkyl-O-(C6-C 10 ) selected from the group consisting of aryloxy, a radical R4', a lipid-like moiety R5', and an active moiety; ii) at least one of A and A' is a lipid-like moiety R5 or R5'; R4 is a radical of formula (VIa), R4' is a radical of formula (VIb), (In the formula, n' is an integer from 5 to 250, m' is 0 or 1; X″ is selected from the group consisting of N, S, and O; R1″ is a radical having any of the meanings of R1, with the proviso that if X″ is O or S then 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 integers from 1 to 18. A'' is 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 )Aralkoxy, -(C5-C 10 )heteroaralkoxy, -(C1-C 10 )Alkyl-O-(C6-C 10 ) aryloxy, amino protecting groups, lipid-like moieties R5', amino acid-like moieties R6, and active moieties; A'' is optionally substituted with 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, -SON2NH2, -SO2-N((C1-C6)alkyl)2, -COOH, -CONH2, and -CON((C1-C6)alkyl)2; however, When m' is 0, A'' is 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 ) selected from the group consisting of heterocycloalkyl, amino protecting groups, amino acid-like moieties R6, and active moieties; When m' is 1, A'' is 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 )Aralkoxy, -(C5-C 10 )heteroaralkoxy, -(C1-C 10 )Alkyl-O-(C6-C 10 ) selected from the group consisting of aryloxy, a lipid-like moiety R5', and an active moiety; A''' is 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, a protecting group, a lipid-like moiety R5, and an active moiety; A''' is optionally substituted with 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, -SON2NH2, -SO2-N((C1-C6)alkyl)2, -COOH, -CONH2, and -CON((C1-C6)alkyl)2; Each R5 is independently -(C1-C 18 ) alkyl, -(C2-C 18 ) alkenyl, and radicals of formula (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XXI), (XXII), or (XXIII); Each R' is independently -X'(R')-(C 18 ) alkyl, -X'(R1')(C2-C 18 ) alkenyl, and radicals of formula (VII'), (VIII'), (IX'), (X'), (XI'), (XII'), (XIII'), (XIV'), (XXI'), (XXII'), or (XXIII'); (In the formula, 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 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 1 to 18; each j is independently an integer from 0 to 18; X' is selected from the group consisting of N, S, and O. R1' is a radical having any one of the meanings of R1, with the proviso that if X' is O or S, then R1' is absent; t is 0 or 1, except that if X=O, then t is 0, and if X is other than O, then t is 1; t' is 0 or 1, except that when m is 0, t' is 1; R 22 , R 33 , and R 44 is independently selected from the group consisting of hydrogen, fluorine, methyl, -CH2F, -CHF2, and -CF3; Dashed Bond [ka] each is independently a single bond or alternatively a double bond; L is a biradical chain comprising one or more moieties selected from the group consisting of -CH=CH-, -C≡C-, -CH2-, -N=CH-, -CH=NH-, -NH-, -NH-NH-, -NH-N=CH-, -O-, -O(CH2)O-, -CO-, -O-(CO)-, -(CO)O-, -C(=CH2)-, -C(=NH)-, -CONH-, -NHCO-, NH(CO)NH-, -S-, -SS-, -SO-, -SO2-, -SON2NH2-, and -phenylene-; L is optionally selected from halogen, -OH, -NR a R b , -SH, -NHNH2, -COOR c , -CF3, -OCF3, [ka] and is substituted with one or more substituents selected from the group consisting of When L contains a CH2 moiety, the two hydrogen atoms attached to the carbon atom can optionally be joined to the ring: [ka] is replaced by Each R6 is independently (XV), (XVI), and (XVII). (In the formula, a', b', and c' are independently integers of 1 to 4.) is selected from the group consisting of Each active moiety is independently selected from the group consisting of pharma- ceutical active agents, penetration enhancers, cell targeting agents, cosmetically active agents, and diagnostically active agents.

[0385] Additional note 2. When m is 0, A' is 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 ) is selected from the group consisting of heterocycloalkyl, amino protecting groups, amino acid-like moieties R6, and active moieties; When m is 1, A' is 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 )Aralkoxy, -(C5-C 10 )heteroaralkoxy, -(C1-C 10 )Alkyl-O-(C6-C 10 ) selected from the group consisting of aryloxy, a radical R4', a lipid-like moiety R5', and an active moiety; When m' is 0, A'' is H, -(C1-C6)alkyl, -(C5-C 10 )Aryl, -(C5-C 10 )heteroaryl, -(C6-C 10 ) aralkyl, -(C1-C6) alkyl-O-(C5-C10 )Aryl, -(C5-C 10 ) is selected from the group consisting of heterocycloalkyl, amino protecting groups, amino acid-like moieties R6, and active moieties; When m' is 1, A'' is 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 )Aralkoxy, -(C5-C 10 )heteroaralkoxy, -(C1-C 10 )Alkyl-O-(C6-C 10 aryloxy, a lipid-like moiety R5', and an active moiety; Each R5 is independently -(C1-C 18 ) alkyl, -(C2-C 18 ) alkenyl, and radicals of formula (VII), (VIII), (IX), (X), (XI), (XII), (XIII), or (XIV), Each R' is independently -X'(R')-(C 18 ) alkyl, X'(R1')-(C2-C 18 ) alkenyl, and radicals of formula (VII'), (VIII'), (IX'), (X'), (XI'), (XII'), (XIII'), or (XIV'), A lipo-polyamino acid conjugate according to claim 1.

[0386] Additional note 3 3. The lipo-polyamino acid conjugate according to any one of appendix 1 to 2, wherein the lipo-polyamino acid conjugate of formula (I) has formula (I′). [ka]

[0387] Additional note 4 The lipo-polyamino acid conjugate according to any one of appendix 1 to 3, wherein n is an integer from 5 to 150, more specifically from 5 to 100, even more specifically from 5 to 50, and even more specifically from 5 to 30 or 5 to 25.

[0388] Additional note 5 5. The lipo-polyamino acid conjugate according to any one of appendix 1 to 4, wherein X is N and R1 is H.

[0389] Additional note 6 X is N and R1 is -(C1-C 18 ) alkyl, more specifically -(C1-C 12 5. The lipo-polyamino acid conjugate according to any one of claims 1 to 4, wherein the aryl group is aryl, aryl, or aryl.

[0390] Additional note 7 X is N and R1 is -(C2-C 18 ) alkenyl, more specifically -(C 12 5. The lipo-polyamino acid conjugate according to any one of appended items 1 to 4, wherein R is 1 or 2;

[0391] Additional note 8 The lipo-polyamino acid conjugate according to any one of appendix 1 to 4, wherein X is O and R1 is absent.

[0392] Additional note 9 The lipo-polyamino acid conjugate according to any one of appendix 1 to 4, wherein X is S and R1 is absent.

[0393] Additional note 10 m is 0 and A' is 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 groups, amino acid-like moieties R6, and active moieties, and A' is optionally substituted with 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, -SON2NH2, -SO2-N((C1-C6)alkyl)2, -COOH, -CONH2, and -CON((C1-C6)alkyl)2; 10. The lipo-polyamino acid conjugate according to any one of appended items 1 to 9.

[0394] Additional note 11 m is 1 and A' is 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 )Aralkoxy, -(C5-C 10 )heteroaralkoxy, -(C1-C 10 )Alkyl-O-(C6-C 10 ) aryloxy, a radical R4', a lipid-like moiety R5', and an active moiety, where A' is optionally substituted with 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, -SON2NH2, -SO2-N((C1-C6)alkyl)2, -COOH, -CONH2, and -CON((C1-C6)alkyl)2; 10. The lipo-polyamino acid conjugate according to any one of appended items 1 to 9.

[0395] Addendum 12. 12. The lipo-polyamino acid conjugate according to any one of claims 1 to 11, wherein R2 is a radical of formula (II), more specifically, in the radical of formula (II), a is 1 or 2.

[0396] Additional note 13 12. The lipo-polyamino acid conjugate according to any one of claims 1 to 11, wherein R2 is a radical of formula (III), more specifically, in the radical of formula (III), b is 1 or 2.

[0397] Addendum 14. 12. The lipo-polyamino acid conjugate according to any one of claims 1 to 11, wherein R2 is a radical of formula (IV), more specifically, in the radical of formula (IV), c is 1 or 2.

[0398] Additional note 15 12. The lipo-polyamino acid conjugate according to any one of appended items 1 to 11, wherein R2 is a radical of formula (V), more specifically, in the radical of formula (V), d is 1 or 2.

[0399] Additional note 16 16. The lipo-polyamino acid conjugate according to any one of appendix 1 to 15, wherein R3 is H.

[0400] Additional note 17 16. The lipo-polyamino acid conjugate according to any one of claims 1 to 15, wherein R3 is -(C1-C6)alkyl, more specifically, R3 is -CH3.

[0401] Additional note 18 A is a lipid-like moiety R5 and A' is other than a lipid-like moiety R5', more specifically A' is H, -OH, -(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 )heterocycloalkyl, -(C1-C 10 )Alkoxy, -(C6-C 10 )aryloxy, -(C6-C 10 )Aralkoxy, -(C5-C 10 )heteroaralkoxy, -(C1-C 10 )Alkyl-O-(C6-C 10 ) aryloxy, amino protecting groups, radicals R4', amino acid-like moieties R6, and active moieties, where A' is optionally substituted with 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, -SO3H, -SON2NH2, -SO2-N((C1-C6)alkyl)2, -COOH, -CONH2, and -CON((C1-C6)alkyl)2; 18. The lipo-polyamino acid conjugate according to any one of appended items 1 to 17.

[0402] Additional note 19 A is -(C1-C 18 ) alkyl, more specifically -(C6-C 18 19. The lipo-polyamino acid conjugate according to any one of appendix 1 to 18, wherein the lipid-like moiety R5 is an alkyl, and more specifically a radical of formula (XIX).

[0403] Additional note 20 A is -(C2-C 18 ) alkenyl, more specifically -(C6-C 18 19. The lipo-polyamino acid conjugate according to any one of appendix 1 to 18, wherein the lipid-like moiety R5 is an alkenyl, and more specifically a radical of formula (XX).

[0404] Addendum 21. 19. The lipo-polyamino acid conjugate according to any one of claims 1 to 18, wherein A is a lipid-like moiety R5 which is a radical of formula (VII).

[0405] Additional note 22 19. The lipo-polyamino acid conjugate according to any one of claims 1 to 18, wherein A is a lipid-like moiety R5 which is a radical of formula (VIII).

[0406] Additional note 23 19. The lipo-polyamino acid conjugate according to any one of appendixes 1 to 18, wherein A is a lipid-like moiety R5 which is a radical of formula (IX), more specifically a radical selected from formulas (ix1), (ix2), (ix3), (ix4), (ix5), (ix6), (ix7), and (ix8).

[0407] Additional note 24 19. The lipo-polyamino acid conjugate according to any one of appendix 1 to 18, wherein A is a lipid-like moiety R5 which is a radical of formula (X), more specifically a radical selected from formulas (x1), (x2), (x3), and (x4).

[0408] Additional note 25 19. The lipo-polyamino acid conjugate according to any one of appendix 1 to 18, wherein A is a lipid-like moiety R5 which is a radical of formula (XI), more specifically a radical of formula (xi1).

[0409] Additional note 26 19. The lipo-polyamino acid conjugate according to any one of claims 1 to 18, wherein A is a lipid-like moiety R5 which is a radical of formula (XII).

[0410] Additional note 27 19. The lipo-polyamino acid conjugate according to any one of claims 1 to 18, wherein A is a lipid-like moiety R5 which is a radical of formula (XIII).

[0411] Additional note 28 19. The lipo-polyamino acid conjugate according to any one of appendix 1 to 18, wherein A is a lipid-like moiety R5 which is a radical of formula (XIV), more specifically a radical selected from formulae (xiv1) and (xiv2).

[0412] Additional note 29 19. The lipo-polyamino acid conjugate according to any one of appended items 1 to 18, wherein A is a lipid-like moiety R5 which is a radical of formula (XXI), more specifically a radical of formula (xxi1).

[0413] Additional note 30 19. The lipo-polyamino acid conjugate according to any one of appendix 1 to 18, wherein A is a lipid-like moiety R5 which is a radical of formula (XXII), more specifically a radical selected from formulae (xxii1) and (xxii2).

[0414] Additional note 31 19. The lipo-polyamino acid conjugate according to any one of claims 1 to 18, wherein A is a lipid-like moiety R5 which is a radical of formula (XXIII).

[0415] Additional note 32 32. The lipo-polyamino acid conjugate according to any one of claims 1 to 31, wherein A is a lipid-like moiety R5, m is 0, and A' is H.

[0416] Additional note 33 32. The lipo-polyamino acid conjugate according to any one of claims 1 to 31, wherein A is a lipid-like moiety R5, m is 0, and A' is an amino protecting group.

[0417] Additional note 34 18. The lipo-polyamino acid conjugate according to any one of claims 1 to 4 or 10 to 17, having the formula (Ia):

[0418] Additional note 35 A lipo-polyamino acid conjugate according to any one of appendixes 1 to 9 or 12 to 17, having formula (Ib), more specifically, the lipo-polyamino acid conjugate of formula (Ib) is a dimer in which 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, respectively.

[0419] Additional note 36 18. The lipo-polyamino acid conjugate according to any one of claims 1 to 9 or 16 to 17, having the formula (Ic):

[0420] Additional note 37 18. The lipo-polyamino acid conjugate according to any one of claims 1 to 9 or 16 to 17, having the formula (Id):

[0421] Additional note 38 The lipo-polyamino acid conjugate according to any one of appendixes 1 to 9 or 16 to 17, having appendix (Ie).

[0422] Additional note 39 The compound has the formula (Ig), and A' is 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 1018. The lipo-polyamino acid conjugate of any one of claims 1 to 9 or 16 to 17, wherein A' is optionally substituted with one or more substituents 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, -SON2NH2, -SO2-N((C1-C6)alkyl)2, -COOH, -CONH2, and -CON((C1-C6)alkyl)2, more specifically A' is methyl.

[0423] Additional notes 40 It has the formula (Ig'), and A' is 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 )Aralkoxy, -(C5-C 10 )heteroaralkoxy, -(C1-C 10 )Alkyl-O-(C6-C 10 18. The lipo-polyamino acid conjugate of any one of claims 1 to 9 or 16 to 17, wherein A' is optionally substituted with 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, -SON2NH2, -SO2-N((C1-C6)alkyl)2, -COOH, -CONH2, and -CON((C1-C6)alkyl)2, and more specifically, A' is methyl.

[0424] Additional note 41 18. The lipo-polyamino acid conjugate according to any one of claims 1 to 4 or 10 to 17, having the formula (Ih):

[0425] Additional note 42 18. The lipo-polyamino acid conjugate according to any one of claims 1 to 17, having the formula (Ij):

[0426] Additional note 43 32. The lipo-polyamino acid conjugate according to any one of claims 1 to 9, 12 to 17, or 19 to 31, having the formula (Ih').

[0427] Additional note 44 The lipo-polyamino acid conjugate according to any one of appended items 1 to 9, 12 to 17, or 19 to 31, having the formula (Ij'):

[0428] Additional note 45 The lipo-polyamino acid conjugate according to any one of appendixes 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 the group consisting of a pharma- ceutical active agent, a cell targeting agent, a penetration enhancer, a cosmetically active agent, and a diagnostically active agent.

[0429] Additional note 46 A' is -X'(R1')-(C1-C 18 ) alkyl, more specifically -X'(R1')-(C6-C 18 18. The lipo-polyamino acid conjugate according to any one of appendixes 1 to 17, wherein the lipid-like moiety R5' is an alkyl, and more specifically a radical of formula (XIX'), or formula (XIX'').

[0430] Additional note 47 A' is -X'(R1')-(C2-C 18 ) alkenyl, more specifically -X'(R1')-(C6-C 1818. The lipo-polyamino acid conjugate according to any one of appendix 1 to 17, wherein the lipid-like moiety R5' is an alkenyl, and more specifically a radical of formula (XX').

[0431] Additional note 48 18. The lipo-polyamino acid conjugate according to any one of claims 1 to 17, wherein A' is a lipid-like moiety R5' which is a radical of formula (VII').

[0432] Additional note 49 18. The lipo-polyamino acid conjugate according to any one of claims 1 to 17, wherein A' is a lipid-like moiety R5' which is a radical of formula (VIII').

[0433] Additional notes 50 18. The lipo-polyamino acid conjugate according to any one of appended items 1 to 17, wherein A' is a lipid-like moiety R5' which is a radical of formula (IX'), more specifically a radical selected from formulas (ix1'), (ix2'), (ix3'), (ix4'), (ix5'), (ix6'), (ix7'), and (ix8').

[0434] Additional note 51 18. The lipo-polyamino acid conjugate according to any one of appended claims 1 to 17, wherein A' is a lipid-like moiety R5' which is a radical of formula (X'), more specifically a radical selected from formulas (x1'), (x2'), (x3'), and (x4').

[0435] Additional note 52 18. The lipo-polyamino acid conjugate according to any one of claims 1 to 17, wherein A' is a lipid-like moiety R5' which is a radical of formula (XI'), more specifically a radical of formula (xi1').

[0436] Additional note 53 18. The lipo-polyamino acid conjugate according to any one of claims 1 to 17, wherein A' is a lipid-like moiety R5' which is a radical of formula (XII').

[0437] Additional note 54 18. The lipo-polyamino acid conjugate according to any one of claims 1 to 17, wherein A' is a lipid-like moiety R5' which is a radical of formula (XIII').

[0438] Additional note 55 18. The lipo-polyamino acid conjugate according to any one of appendix 1 to 17, wherein A' is a lipid-like moiety R5' which is a radical of formula (XIV'), more specifically a radical selected from formulae (xiv1') and (xiv2').

[0439] Additional note 56 18. The lipo-polyamino acid conjugate according to any one of claims 1 to 17, wherein A' is a lipid-like moiety R5' which is a radical of formula (XXI'), more specifically a radical of formula (xxi1').

[0440] Additional note 57 The lipo-polyamino acid conjugate according to any one of appendix 1 to 17, wherein A' is a lipid-like moiety R5' which is a radical of formula (XXII'), more specifically a radical selected from formulae (xxii1') and (xxii2').

[0441] Additional note 58 18. The lipo-polyamino acid conjugate according to any one of claims 1 to 17, wherein A' is a lipid-like moiety R5' which is a radical of formula (XXIII').

[0442] Additional note 59 59. The lipo-polyamino acid conjugate according to any one of claims 1 to 9, or 12 to 17, 19 to 31, or 46 to 58, wherein A is a lipid-like moiety R5 and A' is a lipid-like moiety R5'.

[0443] Additional notes 60 59. The lipo-polyamino acid conjugate according to any one of claims 1 to 9, 12 to 17, or 46 to 58, wherein A' is a lipid-like moiety R5', m is 1, and A is H.

[0444] Additional note 61 59. The lipo-polyamino acid conjugate according to any one of claims 1 to 9, 12 to 17, or 46 to 58, wherein A' is a lipid-like moiety R5', m is 1, and A is a protecting group.

[0445] Additional note 62 A lipo-polyamino acid conjugate according to any one of appendixes 1 to 9 or 12 to 17, having formula (Ib'), more specifically, the lipo-polyamino acid conjugate of formula (Ib') is a dimer in which 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, respectively.

[0446] Additional note 63 A' is a lipid-like moiety R5', m is 1, and A is 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 59. The lipo-polyamino acid conjugate of any one of claims 1 to 9 or 12 to 17 or 46 to 58, wherein A is selected from the group consisting of: heterocycloalkyl, protecting group, radical R4, lipid-like moiety R5, active moiety, and A is optionally substituted with 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, -SON2NH2, -SO2-N((C1-C6)alkyl)2, -COOH, -CONH2, and -CON((C1-C6)alkyl)2, more specifically A is methyl.

[0447] Additional note 64 59. The lipo-polyamino acid conjugate according to any one of claims 1 to 9, 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 the group consisting of a pharma- ceutical active agent, a cell targeting agent, a penetration enhancer, a cosmetically active agent, and a diagnostically active agent.

[0448] Additional note 65 A self-assembled particle comprising a lipo-polyamino acid conjugate of formula (I) as defined in any one of claims 1 to 64, and optionally one or more active agents selected from the group consisting of a pharma- ceutical active agent, a cell targeting agent, a penetration enhancer, a cosmetically active agent, a diagnostically active agent, a nucleic acid, a peptide, a protein, and mixtures thereof.

[0449] Additional note 66 66. The self-assembled particle of claim 65, which is a nanoparticle, more specifically a nanoparticle selected from the group consisting of micelles, reverse micelles, planar bilayers, crystalline nanoparticles, liposomes, microbubbles, and lipid nanoparticles, and even more specifically, the self-assembled particle is a lipid nanoparticle (LNP) or a liposome.

[0450] Additional note 67 67. The self-assembled particle of any one of claims 65 to 66, which is a lipid nanoparticle (LNP) and further comprises one or more lipids selected from the group consisting of ionizable lipids, cationic lipids, neutral lipids, and anionic lipids.

[0451] Additional note 68 68. The self-assembled particle of any of claims 65 to 67, which is a lipid nanoparticle (LNP) and further comprises an ionizable or cationic lipid, a phospholipid, and a sterol.

[0452] Additional note 69 i) a lipo-polyamino acid conjugate of formula (I) as defined in any one of appendixes 1 to 64 in an amount of 0.1 to 10 mol %, more specifically 1 to 6 mol %, and even more specifically 2 to 5 mol %; ii) an ionizable or cationic lipid in an amount of 30 to 70 mol%, more specifically 40 to 60 mol%, iii) phospholipids in an amount of 1 to 20 mol%, more specifically 5 to 15 mol%, iv) sterols in an amount of 20-60 mol %, more specifically 30-50 mol %; Including, The percentages are expressed relative to the sum of the lipid and the lipo-polyamino acid conjugate of formula (I), 69. The self-assembled particle according to any one of claims 65 to 68.

[0453] Additional notes 70 70. The self-assembled particle of claim 69, which is a lipid nanoparticle further comprising a nucleic acid.

[0454] Additional note 71 71. The self-assembled particle of any of claims 65 to 70, which is devoid of polyethylene glycol (PEG).

[0455] Additional note 72 A composition comprising a lipo-polyamino acid conjugate of formula (I) as defined in any of claims 1 to 64, or alternatively a self-assembled particle as defined in any of claims 65 to 71, together with one or more suitable excipients or carriers.

[0456] Additional note 73 For use in medicine, a) a lipo-polyamino acid conjugate of formula (I) as defined in any of clauses 1 to 64, wherein at least one of A, A', A'', or A''' is a pharma- ceutical active agent; or b) a self-assembled particle as defined in any one of claims 65 to 71, comprising a lipo-polyamino acid conjugate a); or alternatively, c) a composition as defined in claim 72 comprising a lipo-polyamino acid conjugate a) or a self-assembled particle b), or alternatively d) self-assembled particles as defined in any one of claims 65 to 71, comprising one or more active agents selected from the group consisting of pharma- ceutical active agents, nucleic acids, peptides, proteins, and mixtures thereof; or, alternatively, e) a composition as defined in claim 72 comprising self-assembled particles d) The therapeutic product.

[0457] Additional note 74 (i) for use as a transfection reagent for transfecting at least one active agent into a cell; (ii) for use in vivo or ex vivo production of a biological product encoding a recombinant protein, peptide, or antibody or for production of a recombinant virus; (iii) for use as a therapeutic or preventive vaccine against a viral infection or as a therapeutic vaccine against cancer or an infectious disease; or (iv) for use in genome editing, cell reprogramming, cell differentiation, or gene editing, as described in appended claim 73.

[0458] Additional note 75 For diagnostic use, a') a lipo-polyamino acid conjugate of formula (I) as defined in any of subparagraphs 1 to 64, wherein at least one of A, A', A'', or A''' is a diagnostically active agent; or b') a self-assembled particle as defined in any one of claims 65 to 71, comprising a lipo-polyamino acid conjugate a'); or c') a composition as defined in claim 72 comprising a lipo-polyamino acid conjugate a') or a self-assembled particle b'), or alternatively d') a self-assembled particle as defined in any of claims 65 to 71, comprising one or more diagnostically active agents; or e') a composition as defined in claim 72, comprising self-assembled particles d'). A diagnostic product comprising:

[0459] Additional note 76 a″) a lipo-polyamino acid conjugate of formula (I) as defined in any of subparagraphs 1 to 64, wherein at least one of A, A′, A″, or A′″ is a cosmetically active agent; or b'') a self-assembled particle as defined in any of claims 65 to 71, comprising a lipo-polyamino acid conjugate a''); or c'') a composition as defined in claim 72 comprising a lipo-polyamino acid conjugate a'') or a self-assembled particle b''); or d'') self-assembled particles as defined in any of claims 65 to 71, comprising one or more cosmetically active agents; or e'') a composition as defined in claim 72, comprising self-assembled particles d''). 2. The cosmetic use of a cosmetic product comprising:

[0460] Additional note 77 Use of a lipo-polyamino acid conjugate of formula (I) as defined in any of claims 1 to 64, or alternatively a self-assembled particle comprising same, as defined in any of claims 59 to 65, as a carrier, wherein A, A', A'', and A''' are other than the active moiety.

Claims

1. A lipo-polyamino acid conjugate of formula (I), a salt thereof, or any stereoisomer or mixture of stereoisomers of a compound of formula (I) or a salt thereof: 【Chemistry 1】 (In the formula, n is an integer from 5 to 250, m is 0 or 1; X is selected from the group consisting of N, S, and O; R １ is H, -(C １ -C １８ ) alkyl, and -(C ２ -C １８ ) alkenyl, provided that when X is O or S, R １ does not exist, R ２ is a radical selected from the group consisting of (II), (III), (IV), and (V); 【Chemistry 2】 wherein a, b, c, and d are independently integers from 1 to 4; R ３ is H or -(C １ -C ６ ) alkyl; A is H, -(C １ -C ６ ) alkyl, —CO(C １ -C ６ ) alkyl, -(C ５ -C １０ ) aryl, -(C ５ -C １０ ) heteroaryl, -(C ６ -C １０ ) aralkyl, -(C １ -C ６ ) alkyl-O-(C ５ -C １０ ) aryl, -(C ５ -C １０ ) Heterocycloalkyl, protecting group, radical R ４ , lipid-like moiety R ５ and an active moiety; A is optionally selected from the group consisting of -OH, halogen, -CF ３ , -NH ２ , -NH-(C １ -C ４ ) alkyl, —NH—CO—(C １ -C ６ ) alkyl, -(C １ -C ６ ) alkyl, -NO ２ , -N ３ , -CO-(C １ -C ６ ) alkyl, —CO—O—(C １ -C ６ ) alkyl, -SO ３ H, -SO ２ N.H. ２ , -SO ２ -N((C １ -C ６ ) alkyl) ２ , -COOH, -CONH ２ , and -CON((C １ -C ６ ) alkyl) ２ and is substituted with one or more groups selected from the group consisting of A' is H, -OH, -(C １ -C ６ ) alkyl, -(C ５ -C １０ ) aryl, -(C ５ -C １０ ) heteroaryl, -(C ６ -C １０ ) aralkyl, -(C １ -C ６ ) alkyl-O-(C ５ -C １０ ) aryl, -(C ５ -C １０ ) heterocycloalkyl, -(C １ -C １０ ) alkoxy, -(C ６ -C １０ ) aryloxy, -(C ６ -C １０ ) aralkoxy, -(C ５ -C １０ ) heteroaralkoxy, -(C １ -C １０ ) alkyl-O-(C ６ -C １０ ) aryloxy, amino protecting group, radical R ４ ', lipid-like moiety R ５ ', amino acid-like portion R ６ and an active moiety; A' is optionally selected from the group consisting of -OH, halogen, -CF ３ , -NH ２ , -NH-(C １ -C ４ ) alkyl, —NH—CO—(C １ -C ６ ) alkyl, -(C １ -C ６ ) alkyl, -NO ２ , -N ３ , -CO-(C １ -C ６ ) alkyl, —CO—O—(C １ -C ６ ) alkyl, -SO ３ H, -SO ２ N.H. ２ , -SO ２ -N((C １ -C ６ ) alkyl) ２ , -COOH, -CONH ２ , and -CON((C １ -C ６ ) alkyl) ２ and is substituted with one or more groups selected from the group consisting of however, i) When m is 0, A′ is H, —(C １ -C ６ ) alkyl, -(C ５ -C １０ ) aryl, -(C ５ -C １０ ) heteroaryl, -(C ６ -C １０ ) aralkyl, -(C １ -C ６ ) alkyl-O-(C ５ -C １０ ) aryl, -(C ５ -C １０ ) Heterocycloalkyl, amino protecting group, amino acid-like moiety R ６ and an active moiety, A' is optionally selected from the group consisting of -OH, halogen, -CF ３ , -NH ２ , -NH-(C １ -C ４ ) alkyl, —NH—CO—(C １ -C ６ ) alkyl, -(C １ -C ６ ) alkyl, -NO ２ , -N ３ , -CO-(C １ -C ６ ) alkyl, —CO—O—(C １ -C ６ ) alkyl, -SO ３ H, -SO ２ N.H. ２ , -SO ２ -N((C １ -C ６ ) alkyl) ２ , -COOH, -CONH ２ , and -CON((C １ -C ６ ) alkyl) ２ and is substituted with one or more groups selected from the group consisting of When m is 1, A′ is H, —OH, —(C １ -C ６ ) alkyl, -(C ５ -C １０ ) aryl, -(C ５ -C １０ ) heteroaryl, -(C ６ -C １０ ) aralkyl, -(C １ -C ６ ) alkyl-O-(C ５ -C １０ ) aryl, -(C ５ -C １０ ) heterocycloalkyl, -(C １ -C １０ ) alkoxy, -(C ６ -C １０ ) aryloxy, -(C ６ -C １０ ) aralkoxy, -(C ５ -C １０ ) heteroaralkoxy, -(C １ -C １０ ) alkyl-O-(C ６ -C １０ ) aryloxy, radical R ４ ', lipid-like moiety R ５ A' is optionally selected from the group consisting of -OH, halogen, -CF ３ , -NH ２ , -NH-(C １ -C ４ ) alkyl, —NH—CO—(C １ -C ６ ) alkyl, -(C １ -C ６ ) alkyl, -NO ２ , -N ３ , -CO-(C １ -C ６ ) alkyl, —CO—O—(C １ -C ６ ) alkyl, -SO ３ H, -SO ２ N.H. ２ , -SO ２ -N((C １ -C ６ ) alkyl) ２ , -COOH, -CONH ２ , and -CON((C １ -C ６ ) alkyl) ２ and is substituted with one or more groups selected from the group consisting of ii) at least one of A and A′ is a lipid-like moiety R ５ Or R ５ ' and R ４ is a radical of formula (VIa) 【Chemistry 3】 R ４ ' is a radical of formula (VIb), 【Chemistry 4】 During the ceremony, n′ is an integer from 0 to 250, m′ is 0 or 1; X″ is selected from the group consisting of N, S, and O; R １ '' is R １ with the proviso that if X″ is O or S, then R １ '' does not exist, R ２ ' is R ２ is a radical having one of the meanings R ３ ' is R ３ is a radical having one of the meanings B and B' are independently S or CH ２ and e and f are independently integers from 1 to 18; A″ is H, —OH, (C １ -C ６ ) alkyl, -(C ５ -C １０ ) aryl, -(C ５ -C １０ ) heteroaryl, -(C ６ -C １０ ) aralkyl, -(C １ -C ６ ) alkyl-O-(C ５ -C １０ ) aryl, -(C ５ -C １０ ) heterocycloalkyl, -(C １ -C １０ ) alkoxy, -(C ６ -C １０ ) aryloxy, -(C ６ -C １０ ) aralkoxy, -(C ５ -C １０ ) heteroaralkoxy, -(C １ -C １０ ) alkyl-O-(C ６ -C １０ ) aryloxy, amino protecting group, lipid-like moiety R ５ ', amino acid-like portion R ６ and an active moiety; A″ is optionally selected from the group consisting of —OH, halogen, —CF ３ , -NH ２ , -NH-(C １ -C ４ ) alkyl, —NH—CO—(C １ -C ６ ) alkyl, -(C １ -C ６ ) alkyl, -NO ２ , -N ３ , -CO-(C １ -C ６ ) alkyl, —CO—O—(C １ -C ６ ) alkyl, -SO ３ H, -SO ２ N.H. ２ , -SO ２ -N((C １ -C ６ ) alkyl) ２ , -COOH, -CONH ２ , and -CON((C １ -C ６ ) alkyl) ２ and is substituted with one or more groups selected from the group consisting of however, When m′ is 0, A″ is H, —(C １ -C ６ ) alkyl, -(C ５ -C １０ ) aryl, -(C ５ -C １０ ) heteroaryl, -(C ６ -C １０ ) aralkyl, -(C １ -C ６ ) alkyl-O-(C ５ -C １０ ) aryl, -(C ５ -C １０ ) Heterocycloalkyl, amino protecting group, amino acid-like moiety R ６ and an active moiety; A″ is optionally selected from the group consisting of —OH, halogen, —CF ３ , -NH ２ , -NH-(C １ -C ４ ) alkyl, —NH—CO—(C １ -C ６ ) alkyl, -(C １ -C ６ ) alkyl, -NO ２ , -N ３ , -CO-(C １ -C ６ ) alkyl, —CO—O—(C １ -C ６ ) alkyl, -SO ３ H, -SO ２ N.H. ２ , -SO ２ -N((C １ -C ６ ) alkyl) ２ , -COOH, -CONH ２ , and -CON((C １ -C ６ ) alkyl) ２ and is substituted with one or more groups selected from the group consisting of When m′ is 1, A″ is H, —OH, —(C １ -C ６ ) alkyl, -(C ５ -C １０ ) aryl, -(C ５ -C １０ ) heteroaryl, -(C ６ -C １０ ) aralkyl, -(C １ -C ６ ) alkyl-O-(C ５ -C １０ ) aryl, -(C ５ -C １０ ) heterocycloalkyl, -(C １ -C １０ ) alkoxy, -(C ６ -C １０ ) aryloxy, -(C ６ -C １０ ) aralkoxy, -(C ５ -C １０ ) heteroaralkoxy, -(C １ -C １０ ) alkyl-O-(C ６ -C １０ ) aryloxy, lipid-like moiety R ５ A″ is optionally selected from the group consisting of —OH, halogen, —CF ３ , -NH ２ , -NH-(C １ -C ４ ) alkyl, —NH—CO—(C １ -C ６ ) alkyl, -(C １ -C ６ ) alkyl, -NO ２ , -N ３ , -CO-(C １ -C ６ ) alkyl, —CO—O—(C １ -C ６ ) alkyl, -SO ３ H, -SO ２ N.H. ２ , -SO ２ -N((C １ -C ６ ) alkyl) ２ , -COOH, -CONH ２ , and -CON((C １ -C ６ ) alkyl) ２ and is substituted with one or more groups selected from the group consisting of A''' is H, -(C １ -C ６ ) alkyl, —CO(C １ -C ６ ) alkyl, -(C ５ -C １０ ) aryl, -(C ５ -C １０ ) heteroaryl, -(C ６ -C １０ ) aralkyl, -(C １ -C ６ ) alkyl-O-(C ５ -C １０ ) aryl, -(C ５ -C １０ ) Heterocycloalkyl, protecting group, lipid-like moiety R ５ and an active moiety; A''' is optionally selected from the group consisting of -OH, halogen, -CF ３ , -NH ２ , -NH-(C １ -C ４ ) alkyl, —NH—CO—(C １ -C ６ ) alkyl, -(C １ -C ６ ) alkyl, -NO ２ , -N ３ , -CO-(C １ -C ６ ) alkyl, —CO—O—(C １ -C ６ ) alkyl, -SO ３ H, -SO ２ N.H. ２ , -SO ２ -N((C １ -C ６ ) alkyl) ２ , -COOH, -CONH ２ , and -CON((C １ -C ６ ) alkyl) ２ and is substituted with one or more groups selected from the group consisting of Each R ５ are independently -(C １ -C １８ ) alkyl, -(C ２ -C １８ ) alkenyl, and radicals of formula (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XXI), (XXII), or (XXIII); 【Chemistry 5】 【change】 Each R ５ ' is independently -X'(R １ ')-(C １ -C １８ ) alkyl, —X′(R １ ') (C ２ -C １８ ) alkenyl, and radicals of formula (VII'), (VIII'), (IX'), (X'), (XI'), (XII'), (XIII'), (XIV'), (XXI'), (XXII'), or (XXIII'); 【Chemistry 6】 【change】 During the ceremony, 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 Rx, Ry, and Rz is independently -(C １ -C １８ ) alkyl, or -(C ２ -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 the group consisting of N, S, and O; R １ ' is R １ with the proviso that if X′ is O or S, then R １ ' does not exist, t is 0 or 1, except that when X=O, t is 0, and when X is other than O, t is 1; t' is 0 or 1, except that when m is 0, t' is 1; R ２２ , R ３３ , and R ４４ are independently hydrogen, fluorine, methyl, -CH ２ F, -CHF ２ , and -CF ３ is selected from the group consisting of Dashed Bond 【Chemistry 7】 each is independently a single bond or alternatively a double bond; L is -CH=CH-, -C≡C-, -CH ２ -, -N=CH-, -CH=NH-, -NH-, -NH-NH-, -NH-N=CH-, -O-, -O(CH ２ )O-, -CO-, -O-(CO)-, -(CO)O-, -C(=CH ２ )-, -C(=NH)-, -CONH-, -NHCO-, NH(CO)NH-, -S-, -S-S-, -SO-, -SO ２ -, -SO ２ N.H. ２ -phenylene-, -phenylene-, and L is optionally a halogen, -OH, -NR ａ R ｂ , -SH, -NHNH ２ , -COOR ｃ , -CF ３ , -OCF ３ , 【Chemistry 8】 and is substituted with one or more substituents selected from the group consisting of L is -CH ２ When the - moiety is included, the two hydrogen atoms attached to the carbon atom can optionally be joined to the ring: 【Chemistry 9】 is replaced by Each R ６ are independently (XV), (XVI), and (XVII), 【Chemistry 10】 (wherein a', b', and c' are independently integers from 1 to 4). is selected from the group consisting of Each active moiety is independently selected from the group consisting of pharma- ceutical active agents, penetration enhancers, cell targeting agents, cosmetically active agents, and diagnostically active agents.

2. The lipo-polyamino acid conjugate according to claim 1 , wherein n is an integer from 5 to 100.

3. R ３ The lipo-polyamino acid conjugate according to any one of claims 1 to 2, wherein is H.

4. X is N and R １ H, and -(C １ -C １８ 4. The lipo-polyamino acid conjugate according to claim 1, wherein the aryl group is selected from the group consisting of aryl, ...

5. A is a lipid-like moiety R ５ and A′ is a lipid-like moiety R ５ The lipo-polyamino acid conjugate according to any one of claims 1 to 4, wherein said lipo-polyamino acid conjugate is other than '.

6. R ５ But -(C １ -C １８ ) alkyl, -(C ２ -C １８ 6. The lipo-polyamino acid conjugate of claim 5, wherein the radical is selected from the group consisting of alkenyl, and a radical of formula (IX), (X), (XII), (XIII), (XIV), or (XXI).

7. A' is H, -(C １ -C ６ ) alkyl, -(C ５ -C １０ ) aryl, -(C ５ -C １０ ) heteroaryl, -(C ６ -C １０ ) aralkyl, -(C １ -C ６ ) alkyl-O-(C ５ -C １０ ) aryl, -(C ５ -C １０ ) heterocycloalkyl, -(C １ -C １０ ) alkoxy, -(C ６ -C １０ ) aryloxy, -(C ６ -C １０ ) aralkoxy, -(C ５ -C １０ )heteroaralkoxy, and -(C １ -C １０ ) alkyl-O-(C ６ -C １０ 7. The lipo-polyamino acid conjugate according to claim 5, wherein the lipo-polyamino acid conjugate is selected from the group consisting of aryloxy.

8. A' is a lipid-like moiety R ５ ', where A is a lipid-like moiety R ５ The lipo-polyamino acid conjugate according to any one of claims 1 to 4, which is other than

9. R ５ ', -(C １ -C １８ ) alkyl, -(C ２ -C １８ 9. The lipo-polyamino acid conjugate of claim 8, wherein the radical is selected from the group consisting of alkenyl, and a radical of formula (IX'), (X'), (XII'), (XIII'), (XIV'), or (XXI').

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

11. A composition comprising a lipo-polyamino acid conjugate of formula (I) as defined in any one of claims 1 to 9, or alternatively a self-assembled particle as defined in claim 10, together with one or more suitable excipients or carriers.

12. For use in medicine, a) a lipo-polyamino 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 pharma- ceutical active agent; or, alternatively, b) a self-assembled particle as defined in claim 10 comprising a lipo-polyamino acid conjugate a); or alternatively, c) a composition as defined in claim 11 comprising a lipo-polyamino acid conjugate a) or a 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 pharma- ceutical active agents, nucleic acids, peptides, proteins, and mixtures thereof; or, alternatively, e) a composition as defined in claim 11 comprising self-assembled particles d). A therapeutic product comprising

13. 13. The therapeutic product for use according to claim 12: (i) for use as a transfection reagent for transfecting at least one active agent into a cell; (ii) for use in the in vivo or ex vivo production of a biological agent encoding a recombinant protein, peptide or antibody, or for use in the production of a recombinant virus; (iii) for use as a therapeutic or preventive vaccine against a viral infection or as a therapeutic vaccine against cancer or an infectious disease; or (v) for use in genome editing, cell reprogramming, cell differentiation, or gene editing.

14. For use in diagnosis, a) a lipo-polyamino 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 a lipo-polyamino acid conjugate a'); or alternatively, c') a composition as defined in claim 11 comprising a lipo-polyamino acid conjugate a') or a 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 self-assembled particles d'). A diagnostic product comprising:

15. a″) a lipo-polyamino 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 cosmetically active agent; or alternatively, b″) a self-assembled particle as defined in claim 10 comprising a lipo-polyamino acid conjugate a″); or alternatively, c'') a composition as defined in claim 11 comprising a lipo-polyamino acid conjugate a'') or a self-assembled particle b''); or alternatively, d″) a self-assembled particle as defined in claim 10, comprising one or more cosmetically active agents; or, alternatively, e″) a composition as defined in claim 11 comprising self-assembled particles d′).

2. The cosmetic use of a cosmetic product comprising:

16. 10. Use of a lipo-polyamino acid conjugate of formula (I) as defined in any one of claims 1 to 9, wherein A, A', A'', or A''' is other than an active moiety, or alternatively a self-assembled particle as defined in claim 10 comprising same as a carrier.

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