Random copolymer therapeutic agent carriers and assemblies thereof

Patent metadata

Field	Value
Publication number	US-2016279251-A1
Application number	US-201415035721-A
Country	US
Kind code	A1
Filing date	Nov 12, 2014
Priority date	Nov 12, 2013
Publication date	Sep 29, 2016
Grant date	—

Abstract

Provided herein are particles assemblies including a shell surrounding a core. The shell includes a particle-stabilizing random copolymer. The core includes a core random copolymer. The particle assemblies have a biomimetic design in which the polymeric components containing discrete chemical and biological functionalities are designed to spontaneously self-assemble into particles. Also provided herein are random copolymers having conjugated therapeutic agents that can be cleaved from the copolymers by an enzyme or water.

First claim

1 - 20 . (canceled)

21 . A random copolymer, comprising
(i) at least one constitutional unit selected from cationic constitutional units, anionic constitutional units, any combination thereof, and hydrophobic uncharged constitutional units, and (ii) constitutional units comprising a covalently-bound antibiotic agent or kinase inhibitor, wherein the antibiotic agent or kinase inhibitor is cleavable from the random copolymer by an enzyme or water.

22 . The random copolymer of claim 21 , wherein the random copolymer comprises cationic constitutional units, hydrophobic uncharged constitutional units, and constitutional units comprising a covalently-bound antibiotic agent or kinase inhibitor.

23 . The random copolymer of claim 21 , comprising greater than 0 to 90 mole percent of cationic constitutional units, greater than 0 to 70 mole percent of hydrophobic uncharged constitutional units, and greater than 0 to 50 mole percent of constitutional units comprising a covalently-bound antibiotic agent or kinase inhibitor, wherein a total mole percentage of the cationic constitutional units, hydrophobic uncharged constitutional units, and constitutional units comprising a covalently-bound antibiotic agent or kinase inhibitor is 100 mole percent.

24 . The random copolymer of claim 21 , wherein the random copolymer has a positive or negative net charge.

25 . The random copolymer of claim 21 , wherein the random copolymer has a neutral net charge.

26 . A random copolymer, comprising:
(i) hydrophobic uncharged constitutional units, cationic constitutional units, or anionic constitutional units, or any combination thereof, (ii) hydrophilic constitutional units, and (iii) constitutional units comprising a covalently-bound antibiotic agent or kinase inhibitor; wherein the antibiotic agent or kinase inhibitor is cleavable from the random copolymer by an enzyme or water.

27 . The random copolymer of claim 26 , comprising greater than 0 to 90 mole percent of hydrophobic uncharged constitutional units, greater than 0 to 90 mole percent of hydrophilic constitutional units, and greater than 0 to 50 mole percent of constitutional units comprising a covalently-bound antibiotic agent or kinase inhibitor, wherein a total mole percentage of hydrophobic uncharged constitutional units, hydrophilic constitutional units, and constitutional units comprising a covalently-bound antibiotic agent or kinase inhibitor is 100 mole percent.

28 . The random copolymer of claim 26 , comprising greater than 0 to 45 mole percent of anionic constitutional units, greater than 0 to 45 mole percent of cationic constitutional units, greater than 0 to 50 mole percent of hydrophilic constitutional units, and greater than 0 to 50 mole percent of constitutional units comprising a covalently bound antibiotic agent or kinase inhibitor, wherein a total mole percentage of anionic constitutional units, cationic constitutional units, hydrophilic constitutional units, and constitutional units comprising a covalently-bound antibiotic agent or kinase inhibitor is 100 mole percent.

29 . The random copolymer of claim 26 , comprising greater than 0 to 70 mole percent of anionic constitutional units, greater than 0 to 70 mole percent of hydrophilic constitutional units, and greater than 0 to 50 mole percent of constitutional units comprising a covalently bound antibiotic agent or kinase inhibitor, wherein a total mole percentage of anionic constitutional units, hydrophilic constitutional units, and constitutional units comprising a covalently-bound antibiotic agent or kinase inhibitor is 100 mole percent.

30 . The random copolymer of claim 26 , comprising greater than 0 to 70 mole percent of cationic constitutional units, and greater than 0 to 70 mole percent of hydrophilic constitutional units, and 0 to 50 mole percent of constitutional units comprising a covalently bound antibiotic agent or kinase inhibitor, wherein a total mole percentage of cationic constitutional units, hydrophilic constitutional units, and constitutional units comprising a covalently-bound antibiotic agent or kinase inhibitor is 100 mole percent.

31 . The random copolymer of claim 26 , wherein the anionic constitutional unit is selected from

wherein L 4b is selected from absent, C 1-6 alkylene, C 2-6 alkenylene, and arylene, and wherein said C 2-6 alkenylene or arylene is optionally substituted with 1, 2, 3, or 4 substituents independently selected from halo and COOH.

32 . The random copolymer of claim 26 , wherein the cationic constitutional unit is selected from the group consisting of

wherein R 6 and R 7 are each independently selected from H and C 1-6 alkyl.

33 . The random copolymer of claim 26 , wherein the hydrophobic uncharged constitutional units each comprises a C 8 -C 26 fatty acid side chain.

34 . The random copolymer of claim 26 , wherein the hydrophilic constitutional units comprise poly(alkylene glycol) having at least 5 alkylene glycol constitutional units.

35 . (canceled)

36 . The random copolymer of claim 26 , wherein the hydrophilic constitutional units comprise a polysaccharide.

37 . The random copolymer of claim 26 , wherein the antibiotic agent is selected from the group consisting of ciproflaxin, meropenem, doxycycline, and ceftazidime.

38 . The random copolymer of claim 26 , wherein the kinase inhibitor is dasatinib.

39 . The random copolymer of claim 26 , wherein the antibiotic agent or kinase inhibitor is conjugated to the copolymer via an ester linkage, hydrazone linkage, or an amide linkage.

40 . The random copolymer of claim 26 , optionally comprising a targeting agent selected from the group consisting of transferrin, glycan, biotin, folic acid, and vitamin B.

41 . The random copolymer of claim 26 , wherein when the random copolymer releases the antibiotic agent or the kinase inhibitor in a linear manner over a period of 1 to 900 hours, when subjected to physiological conditions.

42 - 46 . (canceled)

Assignees

• Univ Washington Through Its Center For Commercialization

Inventors

• Stayton Patrick S
• Convertine Anthony
• Ratner Daniel M
• Srinivasan Selvi
• Das Debobrato
• Su Fang-Yi
• Chen Jasmin
• Chiu David Yee-Shawn
• Lane Daniel Douglas

Classifications

• A61K47/6907

  the form being a microemulsion, nanoemulsion or micelle · CPC title

• A61K9/1271 Primary

  Non-conventional liposomes, e.g. PEGylated liposomes or liposomes coated or grafted with polymers (liposomes as conjugates {A61K47/6911}) · CPC title

• A61K47/60

  the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol · CPC title

• A61K9/1075

  Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers (A61K9/0026 takes precedence) · CPC title

• A61K47/6915

  the form being a liposome with polymerisable or polymerized bilayer-forming substances, e.g. polymersomes · CPC title