Immolative cell-penetrating complexes for nucleic acid delivery
AssigneeThe Board of Trustees of the Leland Stanford Junior University
InventorsRobert M Waymouth, Paul Wender, Jessica R. Vargas, Tim R. Blake, Colin J. McKinlay, Ronald Levy, Ole Audun Werner Haabeth, Nancy Benner, Katherine Near
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Abstract
There are provided herein, inter alia, complexes, compositions and methods for the delivery of therapeutic, diagnostic and imaging agents, including nucleic acid, into a cell. The complexes, compositions and methods may facilitate complexation, protection, delivery and release of oligonucleotides and polyanionic cargos into target cells, tissues, and organs both in vitro and in vivo.
Claims23
A method of transfecting a nucleic acid into a cell in vivo, the method comprising contacting the cell in vivo with a cationic amphipathic polymer non-covalently bound to a nucleic acid, the cationic amphipathic polymer having the formula:
- wherein
- Ring A is a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
- z5 is 1-10
- CART has the formula:
- -L1-[(LP1)z1-(IM)z2-(LP2)z3]z4-L2-R2A
- wherein
- L1 and L2 are independently a bond, —C(O)O—, —O—, —S—, —NH—, -C(O)NH—, —NHC(O)—, —S(O)2—, —S(O)NH—, —NHC(O)NH—, substituted or unsubstituted C1-C20 alkylene or heteroalkylene, substituted or unsubstituted C3-C8 cycloalkylene or heterocycloalkylene, substituted or unsubstituted C6-C10 arylene or heteroarylene;
- LP1 and LP2 are independently a bond or a lipophilic polymer domain, wherein at least one of LP1 and LP2 is the lipophilic polymer domain, wherein the lipophilic polymer domain has the formula:
- and wherein R is independently hydrogen, unbranched C1-C30 alkyl, which may be fully saturated, mono- or polyunsaturated, or cholesterol;
- IM is a pH-sensitive immolation domain of formula (1), (2), or (3):
- z1 and z3 are independently 0 to 30 and at least one of z1 and z3 is not 0;
- z4 is 1 to 100;
- and
- z2 is 2 to 50.
A cationic amphipathic polymer of the formula:
- wherein
- Ring A is a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
- z5 is 1-10
- CART has the formula:
- -L1-[(LP1)z1-(LP3)z1a-(IM)z2-(LP2)z3-(LP4)z3b]z4-L2-H
- wherein,
- L1 and L2 are independently a bond, —C(O)O—, —O—, —S—, —NH—, —C(O) NH—, —NHC(O)—, —S(O)2—, —S(O)NH—, —NHC(O)NH—, substituted or unsubstituted C1-C20 alkylene or heteroalkylene, substituted or unsubstituted C3-C8 cycloalkylene or heterocycloalkylene, substituted or unsubstituted C6-C10 arylene or heteroarylene;
- LP1, LP2, LP3 and LP4 are independently a bond or a lipophilic polymer domain, wherein at least two of LP1, LP2, LP3 and LP4 are a lipophilic polymer domain;
- z1, z1a, z3, and z3b are independently 0 to 100, wherein at least two of z1, z1a,
- z3, and z3b are not 0;
- z4 is 2 to 100;
- and
- z2 is 2 to 100;
- wherein the lipophilic polymer domain has the formula:
- wherein R is unbranched C1-C30 alkyl, which may be fully saturated, monounsaturated, polyunsaturated, or cholesterol;
- and
- wherein IM is a pH-sensitive immolation domain of formula (1), (2), or (3):
Dependencies are inferred from the claim text.