Multiblock copolymers

• US 9,464,300 B2
• Filed: 11/06/2009
• Issued: 10/11/2016
• Est. Priority Date: 11/06/2008
• Status: Expired due to Fees

• Current Assignee: Roivant Hepatology GmbH, Washington University In St Louis
• Original Assignee: PhaseRx, Inc., University of Washington
• Inventors: Prieve, Mary G., Johnson, Paul H., Stayton, Patrick S., Hoffman, Allan S., Overell, Robert W., Gall, Anna S., Paschal, Amber E. E., Diab, Charbel, De, Priyadarsi, DeClue, Michael S., Monahan, Sean D.
• Primary Examiner(s): Ault, Addison D
• Application Number:
  US13/127,959
• Publication Number:
  US 20110286957A1
• Time in Patent Office: 2,531 Days
• US Class Current: 1/1
• CPC Class Codes: A61K 31/713 Double-stranded nucleic acids or oligonucleotides
• CPC Class Codes: A61K 47/545 Heterocyclic compounds A61K47/558 takes precedence
• CPC Class Codes: A61K 47/58 obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. poly[meth]acrylate, polyacrylamide, polystyrene, polyvinylpyrrolidone, polyvinylalcohol or polystyrene sulfonic acid resin
• CPC Class Codes: A61K 47/6907 the form being a microemulsion, nanoemulsion or micelle
• CPC Class Codes: A61K 48/00 Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
• CPC Class Codes: C08F 220/286 and containing polyethylene oxide in the alcohol moiety, e.g. methoxy polyethylene glycol (meth)acrylate
• CPC Class Codes: C08F 2438/03 Use of a di- or tri-thiocarbonylthio compound, e.g. di- or tri-thioester, di- or tri-thiocarbamate, or a xanthate as chain transfer agent, e.g . Reversible Addition Fragmentation chain Transfer [RAFT] or Macromolecular Design via Interchange of Xanthates [MADIX]
• CPC Class Codes: C08F 293/005 using free radical "living" or "controlled" polymerisation, e.g. using a complexing agent
• CPC Class Codes: C12N 15/113 Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing when used in plants C12N15/8218
• CPC Class Codes: C12N 15/87 Introduction of foreign genetic material using processes not otherwise provided for, e.g. co-transformation
• CPC Class Codes: C12N 2310/14 interfering N.A.
• CPC Class Codes: Y02A 50/30 Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

Provided herein are multiblock copolymers, as well as micelles and therapeutic compositions thereof.

Claims

1. A composition comprising a block copolymer associated with a polynucleotide, the block copolymer consisting of a first, a second and a third compositionally distinct blocks,

wherein the first block is a hydrophilic polymer block consisting of repeat units derived from polymerization of a monomer of Formula IV

2. The composition of claim 1 wherein the ratio of the number of repeat units having Formula 1A to the number of repeat units corresponding to Formula 1E in the third block is between about 20:

1 and 1;

4, respectively.

3. The composition of claim 1 wherein the number of repeat units having Formula 1A in the third block is at least equal to the number of repeat units having Formula 1C in third block.

4. The composition of claim 1 wherein the polynucleotide is a deoxyribonucleotide, an siRNA, an antisense oligonucleotide, a dicer substrate, an miRNA, an aiRNA or an shRNA.

5. The composition of claim 4 wherein the polynucleotide is an siRNA.

6. A pharmaceutical composition comprising the composition of claim 1 and a pharmaceutically acceptable excipient.

7. The composition of claim 1 wherein X⁴⁵ comprises the polynucleotide, and the polynucleotide is covalently bound to the composition through the disulfide moiety of X⁴⁵.

8. The composition of claim 1 wherein X⁴⁵ is pyridyl disulfide substituted ethyl.

9. The composition of claim 1 wherein the targeting moiety group is galactose, N-acetyl galactosamine, or folate.

12. A method for intracellular delivery of a polynucleotide, comprising transfecting a cell with a composition of claim 1.

10. A composition comprising a polymeric micelle and a polynucleotide associated with the micelle, the micelle comprising a plurality of block copolymers consisting of

(i) a first block, wherein the first block is a hydrophilic polymer block consisting of repeat units derived from polymerization of a monomer of Formula IV

11. The composition of claim 10 wherein the polynucleotide is a deoxyribonucleotide, an siRNA, an antisense oligonucleotide, a dicer substrate, an miRNA, an aiRNA or an shRNA.