Immolative cell-penetrating complexes for nucleic acid delivery to the lung

Patent metadata

Field	Value
Publication number	US-11931416-B2
Application number	US-202017427362-A
Country	US
Kind code	B2
Filing date	Jan 31, 2020
Priority date	Feb 1, 2019
Publication date	Mar 19, 2024
Grant date	Mar 19, 2024

Abstract

There are provided herein, inter alia, cationic amphipathic polymers, complexes, and compositions comprising same, and methods for their use including for the delivery of therapeutic, diagnostic and imaging agents, including nucleic acids, into a cell. The complexes, compositions and methods may facilitate delivery and targeted release of the therapeutic, diagnostic and imaging agents to particular cell types and tissues.

First claim

What is claimed is:

1. A cationic amphipathic polymer of formula:

wherein n21 is an integer from 10 to 20 and
z2 is independently an integer from 3-10;
or

wherein n22 is an integer from 10 to 35 and
z2 is independently an integer from 5-20;
wherein
R 1A is independently hydrogen, —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, 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;
and each of R 201 and R 202 is independently hydrogen, 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.

2. The cationic amphipathic polymer of claim 1 , wherein n21 is 14, R 201 is dodecyl and z2 is 8.

3. The cationic amphipathic polymer of claim 1 , wherein n22 is 14, R 202 is dodecyl and z2 is 7.

4. A mixture comprising the cationic amphipathic polymer of claim 1 and a second cationic amphipathic polymer, wherein said second cationic amphipathic polymer has the formula:

n23 is an integer from 1 to 100;
z6 is an integer from 5-15;
R 3A is independently hydrogen, —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, 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; and
R 203 is independently hydrogen, 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.

5. The mixture of claim 4 , wherein n23 is 13; z6 is 11; and R 203 is dodecyl.

6. The mixture of claim 4 , wherein said first cationic amphipathic polymer has the formula:

wherein n21 is 14, R 201 is dodecyl and z2 is 8; or

wherein n22 is an integer from 10-35, R 202 is dodecyl and z2 is 3-15; and
wherein said second cationic amphipathic polymer has the formula:

wherein n23 is 13, R 203 is dodecyl and z6 is 11.

7. The cationic amphipathic polymer of claim 1 , 2 , or 3 , wherein the polymer is non-covalently bound to a nucleic acid to form a cell-penetrating complex.

8. The mixture of claim 4 , 5 or 6 , wherein the polymer is non-covalently bound to a nucleic acid to form a cell-penetrating complex.

9. A pharmaceutical composition comprising a plurality of cell-penetrating complexes according to claim 7 , and a pharmaceutical excipient.

10. A pharmaceutical composition comprising a plurality of cell-penetrating complexes according to claim 8 , and a pharmaceutical excipient.

11. A method of transfecting a nucleic acid into a cell, the method comprising contacting the cell with a plurality of cell-penetrating complexes according to claim 7 .

12. A method of transfecting a nucleic acid into lung tissue of a subject, the method comprising administering to the subject the pharmaceutical composition of claim 7 .

13. A method of transfecting a nucleic acid into a reticulocyte cell or hematopoietic stem cell, the method comprising contacting the cell with a plurality of cell-penetrating complexes according to claim 8 .

Assignees

• Univ Leland Stanford Junior

Inventors

• Blake Tim R
• Wender Paul
• Waymouth Robert M
• Levy Ronald
• Haabeth Ole Audun Werner
• Mcclellan Rebecca
• Sallets Adrienne

Classifications

• A61P11/00

  Drugs for disorders of the respiratory system · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61K48/0041

  the non-active part being polymeric · CPC title

• A61K31/7088

  Compounds having three or more nucleosides or nucleotides · CPC title

• A61K47/34

  Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers (A61K47/10 takes precedence) · CPC title