Immolative cell-penetrating complexes for nucleic acid delivery
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.
1 . A 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;
CART comprises a poly(alpha aminoester) immolation domain (IM) which has the formula:
-L 1 -[(LP 1 ) z1 -(IM) z2 -(LP 2 ) z3 ] z4 -L 2 -R 2A
wherein,
R 2A is hydrogen, halogen, —CCl 3 , —CBr 3 , —CF 3 , —CI 3 , CHCl 2 , —CHBr 2 , —CHF 2 , —CHI 2 , —CH 2 Cl, —CH 2 Br, —CH 2 F, —CH 2 I, —CN, —OH, —NH 2 , —COOH, —CONH 2 , —NO 2 , —SH, —SO 3 H, —SO 4 H, —SO 2 NH 2 , —NHNH 2 , —ONH 2 , —NHC(O)NHNH 2 , —NHC(O)NH 2 , —NHSO 2 H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl 3 , —OCF 3 , —OCBr 3 , —OCI 3 , —OCHCl 2 , —OCHBr 2 , —OCHI 2 , —OCHF 2 , —OCH 2 Cl, —OCH 2 Br, —OCH 2 I, —OCH 2 F, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
L 1 and L 2 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 alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene;
LP 1 and LP 2 are independently a bond or a lipophilic polymer domain, wherein at least one of LP 1 or LP 2 is a lipophilic polymer domain;
z5 is an integer from 1 to 10;
z1 and z3 are independently integers from 0 to 30 and at least one of z1 and z3 is not 0;
z4 is an integer from 1 to 100; and
z2 is from 2 to 50;
wherein the lipophilic polymer domain independently has the formula:
and
R 20 is independently hydrogen, unbranched C 1 -C 30 alkyl, which may be fully saturated, mono- or polyunsaturated, or
and
wherein the poly(alpha aminoester) immolation domain independently has the formula:
2 . The cationic amphipathic polymer of claim 1 , wherein the cationic amphipathic polymer has the formula:
3 . The cationic amphipathic polymer of claim 1 , wherein L 1 is —CH 2 —O—, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene.
4 . The cationic amphipathic polymer of claim 3 , wherein L 1 is
—CH 2 —O—,
5 . The cationic amphipathic polymer of claim 1 , wherein R20 is independently hydrogen, a stearyl moiety, an oleyl moiety, a linoleyl moiety, a dodecyl moiety, or a nonenyl moiety.
6 . A cationic amphipathic polymer having the formula
wherein:
R 1A is a phenyl,
R 20 is independently hydrogen, stearyl, oleyl, linoleyl, dodecyl, nonenyl, or
z1 is from 2 to 25, and z2 is from 2 to 40.
7 . A cationic amphipathic polymer having the formula:
wherein R 1A is a phenyl substituted with a methoxy linker.
8 . The cationic amphipathic polymer of claim 1 , wherein the polymer is complexed with a nucleic acid.
9 . The cationic amphipathic polymer of claim 8 , wherein the nucleic acid is RNA or DNA.
10 . The cationic amphipathic polymer of claim 9 , wherein the nucleic acid is messenger RNA, small interference RNA, short hairpin RNA, micro RNA, guide RNA, CRISPR RNA, transactivating RNA, plasmid DNA, minicircle DNA, or genomic DNA.
11 . A nanoparticle composition comprising a plurality of the cationic amphipathic polymer of claim 8 .
12 . A pharmaceutical composition comprising the nanoparticle composition of claim 11 or the cationic amphipathic polymer of claim 8 .
13 . A vaccine composition comprising the nanoparticle composition of claim 11 or the cationic amphipathic polymer of claim 8 , and optionally an immunological adjuvant.
14 . The cationic amphipathic polymer of claim 1 , wherein the cationic amphipathic polymer has the formula:
15 . The cationic amphipathic polymer of claim 1 , wherein the polymer is complexed with mRNA.
16 . The cationic amphipathic polymer of claim 6 , wherein the polymer is complexed with mRNA.
17 . The cationic amphipathic polymer of claim 7 , wherein the polymer is complexed with mRNA.
18 . A pharmaceutical composition comprising the cationic amphipathic polymer of claim 16 .
19 . A pharmaceutical composition comprising the cationic amphipathic polymer of claim 17 .