Polyethylene glycol lipid and use thereof
A new typepolyethylene glycol lipid and the use thereof. The lipid is free of in-vivo cleavable bonds, and can deliver a bioactive substance to a target cell or organ more stably. In addition, the new typepolyethylene glycol lipid can be positively charged in a specific pH environment, and can more easily form stable particles with the bioactive substance, so that the bioactive substance plays a role in the target cell or organ.
1 . A polyethylene glycol lipid having a structure of formula I below:
wherein R 1 and R 2 are identical or different long chain hydrocarbyl, and the long chain hydrocarbyl contains 11 to 17 carbon atoms;
PEG is a polyethylene glycol chain; and
L 1 , L 2 and L 3 are absent or are in-vivo non-cleavable linkers.
2 . The polyethylene glycol lipid according to claim 1 , wherein the long chain hydrocarbyl contains 14 carbon atoms.
3 . The polyethylene glycol lipid according to claim 1 , wherein the polyethylene glycol chain comprises a repeating unit of —(OCH 2 CH 2 ) n —, wherein the n is selected from integers of 20 to 300.
4 . The polyethylene glycol lipid according to claim 3 , wherein the polyethylene glycol chain is —(OCH 2 CH 2 ) n —X, wherein X is a terminal group of the polyethylene glycol chain, and is selected from methyl, methoxy, hydroxyl, amino, thiol, and maleimide.
5 . The polyethylene glycol lipid according to claim 1 , wherein the in-vivo non-cleavable linker is C1 to C10 alkylene.
6 . The polyethylene glycol lipid according to claim 1 , wherein the polyethylene glycol lipid has a structure of formula II below:
wherein R 1 and R 2 are as defined in claim 1 ;
X is a terminal group of the polyethylene glycol chain, and is selected from methyl, methoxy, hydroxyl, amino, thiol, and maleimide;
n is selected from integers of 20 to 300;
i is selected from integers of 2 to 7.
7 . The polyethylene glycol lipid according to claim 1 , wherein the polyethylene glycol lipid has a structure below:
wherein, X is a terminal group of the polyethylene glycol chain, and is selected from methyl, methoxy, hydroxyl, amino, thiol, and maleimide;
n is selected from integers of 20 to 300;
i is selected from integers of 2 to 7.
8 . A delivery system, wherein the delivery system comprises a bioactive substance and the polyethylene glycol lipid according to claim 1 .
9 . The delivery system according to claim 8 , wherein the bioactive substance is a nucleic acid.
10 . The delivery system according to claim 8 , wherein the bioactive substance delivery system is a lipid or lipid nanoparticle delivery system.
11 . The delivery system according to claim 8 , wherein the bioactive substance delivery system is an mRNA vaccine.
12 . A lipid nanoparticle, wherein the lipid nanoparticle comprises a bioactive substance and the polyethylene glycol lipid compound according to claim 1 .
13 . The lipid nanoparticle according to claim 12 , wherein the lipid nanoparticle further comprises a cationic lipid, a steroid lipid, and a neutral lipid.
14 . The lipid nanoparticle according to claim 13 , wherein the cationic lipid is selected from ((4-hydroxybutyl)azadialkyl)bis(hexane-6,1-diyl)bis(2-hexyldecanoate) (ALC-0315), octadecan-9-yl 8-((2-hydroxyethyl) (6-oxo-6-(undecyloxy)hexyl) amino)octanoate (SM-102), 1,2-dioleoyloxy-3-(trimethylammonium)propane (DOTAP), 313-[N—(N′,N′-dimethylaminoethane)-carbamoyl]cholesterol (DC cholesterol), dimethyldioctadecylammonium (DDA), 1,2-dimyristoyl-3-trimethylammonium propane (DMTAP), dipalmitoyl(C16: 0)trimethylammonium propane (DPTAP), distearoyltrimethylammonium propane (DSTAP), N-[1-(2,3-diallyloxy) propyl]-N,N,N-trimethylammonium chloride (DOTMA), N,N-dioleoyl-N,N-dimethylammonium chloride (DODAC), 1,2-dioleoyl-sn-trioxy-3-ethylphosphocholine (DOEPC), 1,2-dioleoyl-3-dimethylammonium propane (DODAP), 1,2-dioleyloxy-3-dimethylaminopropane (DLinDMA);
the neutral lipid is selected from 1,2-distearoyl-sn-glycerol-3-phosphocholine (DSPC), 1,2-dipalmitoyl-sn-glycerol-3-phosphocholine (DPPC), 1,2-dioleoyl-sn-glycerol-3-phosphoethanolamine (DOPE), 1,2-dipalmitoyl-sn-glycerol-3-phosphoethanolamine (DPPE), 1,2-dimyristoyl-sn-glycero-3-phosphoethanolamine (DMPE), 2-dioleoyl-sn-glycero-3-phospho-(1′-rac-glycerol) (DOPG), oleoyl phosphatidylcholine (POPC), 1-palmitoyl-2-oleoyl phosphatidylethanolamine (POPE);
the steroid lipid is selected from avenasterol, B-sitosterol, brassicasterol, ergocalciferol, campesterol, cholestanol, cholesterol, coprosterol, dehydrocholesterol, desmosterol, dihydroergocalciferol, dihydrocholesterol, dihydroergosterol, campesterol, epicholesterol, ergosterol, fucosterol, hexahydrosterol, hydroxycholesterol, lanosterol, photosterol, fucosterol, sitostanol, sitosterol, stigmastanol, stigmasterol, cholic acid, glycocholic acid, taurocholic acid, deoxycholic acid, and lithocholic acid.