MICELLES OF HYDROPHILICALLY SHIELDED MEMBRANE-DESTABILIZING COPOLYMERS
Provided herein are micelles comprising a plurality of copolymers. In certain instances, micelles provided herein are pH sensitive particles.
1 . A composition comprising a micelle and a polynucleotide associated with the micelle, the micelle comprising a plurality of block copolymers, each including a hydrophilic block and a hydrophobic block;
the micelle being stable in an aqueous medium of about neutral pH;
the hydrophobic block comprising a pH dependent membrane destabilizing block;
the hydrophilic block of the copolymer comprising a plurality of constitutional units from a polymerizable monomer having a pendant group comprising a moiety of formula I
where
R 1 and R 2 are each independently selected from the group consisting of hydrogen, halogen, C 1 -C 3 fluoroalkyl, and optionally substituted C 1 -C 3 alkyl, and
n is an integer ranging from 2 to 20.
2 . (canceled)
3 . The composition of claim 1 , wherein the pH dependent membrane destabilizing block comprises a plurality of pendant groups that are anionic at about neutral pH, and uncharged at about an endosomal pH.
4 . The composition of claim 1 , wherein the pH dependent membrane destabilizing block comprises a plurality of pendant groups that are cationic at about neutral pH, and cationic at about an endosomal pH.
5 . (canceled)
6 . The composition of claim 1 , wherein the pH dependent membrane destabilizing block comprises a pendant group that is hydrophobic at about neutral pH and at about an endosomal pH.
7 . The composition of claim 1 , wherein the polynucleotide is not in the core of the micelle.
8 - 9 . (canceled)
10 . The composition of claim 1 wherein the micelle is covalently coupled to the polynucleotide.
11 . A polymeric micelle, the micelle comprising
a block copolymer comprising a hydrophilic block and a hydrophobic block;
the micelle being stable in an aqueous medium of about neutral pH;
the hydrophobic block comprising a pH dependent membrane destabilizing block;
the hydrophilic block of the copolymer comprising a plurality of constitutional units from a polymerizable monomer having a pendant group comprising a moiety of formula I
where R 1 and R 2 are each independently selected from the group consisting of hydrogen, halogen, C 1 -C 3 fluoroalkyl, and optionally substituted C 1 -C 3 alkyl, and
n is an integer ranging from 2 to 20.
12 - 14 . (canceled)
15 . The polymeric micelle of claim 1 , wherein the pH dependent membrane destabilizing block comprises a plurality of pendant groups that are anionic at about neutral pH, and uncharged at about an endosomal pH.
16 . The polymeric micelle of claim 15 , wherein the pH dependent membrane destabilizing block comprises a plurality of pendant groups that are cationic at about neutral pH and cationic at about an endosomal pH.
17 . The polymeric micelle of claim 15 , wherein the pH dependent membrane destabilizing block comprises a plurality of pendant groups that are hydrophobic at about neutral pH and at about an endosomal pH.
18 - 19 . (canceled)
20 . A block copolymer comprising one or more hydrophilic blocks and one or more hydrophobic blocks,
the one or more hydrophilic blocks comprising
a plurality of constitutional units having a species charged or chargeable to a cation, and
a plurality of constitutional units from a polymerizable monomer having a pendant group comprising a moiety of formula I
where R 1 and R 2 are each independently selected from the group consisting of hydrogen, halogen, C 1 -C 3 fluoroalkyl, and optionally substituted C 1 -C 3 alkyl, and
n is an integer ranging from 2 to 20, and
the one or more hydrophobic blocks comprises
a plurality of constitutional units having a species charged or chargeable to an anion, and
a plurality of constitutional units having a hydrophobic species.
21 - 24 . (canceled)
25 . The block copolymer of claim 20 wherein the hydrophobic block of the block copolymer further comprises a plurality of constitutional units having a species charged or chargeable to an anion, and a plurality of constitutional units having a hydrophobic species.
26 . The block copolymer of claim 20 wherein the hydrophobic block of the block copolymer further comprises a plurality of constitutional units having a species charged or chargeable to an anion, a plurality of constitutional units having a species charged or chargeable to a cation, and a plurality of constitutional units having a hydrophobic species.
27 - 32 . (canceled)
33 . The block copolymer of claim 20 wherein the constitutional units are derived from a polymerizable monomer having a formula II
wherein
R 3 is hydrogen, halogen, hydroxyl, or optionally substituted C 1 -C 3 alkyl;
R 4 is —SR 5 , —OR 5 , —NR 6 R 7 , or
R 4 is a polyoxylated alkyl, optionally substituted by hydroxyl, thiol, —NR 9 R 10 , a cleavable moiety or a functionalizable moiety;
R 5 is a polyoxylated alkyl, optionally substituted by hydroxyl, thiol, —NR 9 R 10 , a cleavable group or a functionalizable group;
R 6 and R 7 are each independently H or polyoxylated alkyl, optionally substituted by hydroxyl, thiol, —NR 9 R 10 , a cleavable group or a functionalizable group, provided that R 6 and R 7 are not both H; or
R 6 and R 7 together with the nitrogen to which they are attached form an optionally substituted heterocycle;
R 9 and R 10 are each independently H or C 1 -C 6 alkyl; or
R 9 and R 10 together with the nitrogen to which they are attached form a heterocycle.
34 . The block copolymer of claim 33 , wherein R 4 is an optionally substituted polyoxylated alkyl.
35 . (canceled)
36 . The block copolymer of claim 33 wherein the block copolymer comprises a plurality of constitutional units derived from a polymerizable monomer having a formula III
where
X is absent or optionally substituted C 1 -C 3 alkyl;
R 1 , R 2 and R 3 are each independently hydrogen, halogen, C 1 -C 3 fluoroalkyl or optionally substituted C 1 -C 3 alkyl;
n is an integer ranging from 2 to 20,
R 8 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkenyl, C 1 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl optionally substituted by hydroxyl, thiol, —NR 9 R 10 , a cleavable group or a functionalizable group;
R 9 and R 10 are each independently H or C 1 -C 6 alkyl; or
R 9 and R 10 together with the nitrogen to which they are attached form a heterocycle.
37 . The block copolymer of claim 36 , wherein R 1 and R 2 are each H.
38 . The block copolymer of claim 37 wherein the block copolymer comprises a plurality of constitutional units derived from a polymerizable monomer having a formula IV
where
R 1 , R 2 and R 3 are each independently hydrogen, halogen, C 1 -C 3 fluoroalkyl or optionally substituted C 1 -C 3 alkyl;
n is an integer ranging from 2 to 20,
R 8 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkenyl, C 1 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl optionally substituted by hydroxyl, thiol, —NR 9 R 10 , a cleavable group or a functionalizable group;
R 9 and R 10 are each independently H or C 1 -C 6 alkyl; or
R 9 and R 10 together with the nitrogen to which they are attached form a heterocycle.
39 . The block copolymer of claim 38 , wherein R 1 and R 2 are each H.
40 - 43 . (canceled)
44 . A method for intracellular delivery of a polynucleotide, comprising contacting a cell with the composition of claim 1 .