Lipids, lipid compositions, and methods of using them

摘要

Disclosed are formulation and optimization protocols for delivery of therapeutically effective amounts of biologically active agents to liver, tumors, and/or other cells or tissues. Also provided are compositions and uses for cationic lipid compounds of formula (I).;
The invention also relates to compositions and uses for stealth lipids of formula (XI).
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Also provided are processes for making such compounds, compositions, and formulations, plus methods and uses of such compounds, compositions, and formulations to deliver biologically active agents to cells and/or tissues.

主权项

1. A stealth lipid of formula (XI)or a salt or pharmaceutically acceptable derivative thereof,wherein:
Z is a hydrophilic head group component selected from PEG and polymers based on poly(oxazoline), poly(ethyleneoxide), poly(vinyl alcohol), poly(glycerol), poly(N-vinylpyrrolidone), poly[N-(2-hydroxypropyl)methacrylamide] and poly(amino acid)s, wherein the polymer may be linear or branched, and wherein the polymer may be optionally substituted;
wherein Z is polymerized by n subunits; n is a number-averaged degree of polymerization between 10 and 200 units of Z, wherein n is optimized for different polymer types; L1 is an optionally substituted C1-10 heteroalkylene linker including one, two or more of an ester (e.g., —C(O)O—), succinate (e.g., —O(O)C—CH2—CH2—C(O)O—)), carbamate (e.g., —OC(O)—NR′—), carbonate (e.g., —OC(O)O—), ketone (e.g., —C—C(O)—C—), carbonyl (e.g., —C(O)—), urea (e.g., —NRC(O)NR′—), amine (e.g., —NR′—), amide (e.g., —C(O)NR′—), imine (e.g., —C(NR′)—), thioether (e.g., —S—), xanthate (e.g., —OC(S)S—), and phosphodiester (e.g., —OP(O)2O—); any of which may be substituted by zero, one or more Z groups; wherein R′ is independently selected from —H, —NH—, —NH2, —O—, —S—, a phosphate or an optionally substituted C1-10 alkylene; X1 and X2 are independently selected from a carbon or a heteroatom selected from —NH—, —O—, —S— or a phosphate; and A1 and A2 are independently selected from a C6-30 alkyl, C6-30 alkenyl, and C6-30 alkynyl, wherein A1 and A2 may be the same or different.