Omega-functionalized polymers, junction-functionalized block copolymers, polymer bioconjugates, and radical chain extension polymerization

Patent metadata

Field	Value
Publication number	US-9593169-B2
Application number	US-200913133355-A
Country	US
Kind code	B2
Filing date	Dec 8, 2009
Priority date	Dec 8, 2008
Publication date	Mar 14, 2017
Grant date	Mar 14, 2017

Abstract

Polymeric compounds having spatially controlled bioconjugation sites are described. Functionalization is achieved by selective ω-terminal chain extension of polymer chains by radical polymerization, such as reversible addition-fragmentation chain transfer (RAFT) polymerization.

First claim

What is claimed is:

1. A compound of formula IA:

wherein
P n is a polymer chain,
E is a chain extension residue corresponding to formula E3

j, k and l are each independently selected integers, where j ranges from 0 to 9, k is >1, l ranges from 0 to 9, and the sum (j+k+l) is <10,
L is a linking moiety,
Q is a biomolecular agent covalently bonded through L to R 5 of chain extension residue E, the biomolecular agent being a therapeutic agent, a targeting agent, a diagnostic agent, or an analytical agent,
R 1 and R 4 are each hydrogen,
R 2 , N—R 5 , and R 3 together form an N-substituted imidyl moiety represented by the formula —C(O)NR 5 C(O)—,
R 5 is a C 1 -C 20 moiety comprising a functional group or comprising a functional group covalently coupled to the biomolecular agent, Q, through a linking moiety, L, wherein the C 1 -C 20 moiety is selected from the group consisting of hydrocarbyl, substituted hydrocarbyl, hetero-hydrocarbyl, substituted hetero-hydrocarbyl, carbocyclic, substituted carbocyclic, heterocyclic, substituted heterocyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, and fused-multiring structures comprising one or more of the foregoing, and wherein the functional group is selected from the group consisting of amino, ammonio, imino, amido, imidyl, nitrile, azo, azido, cyano, cyanato, isocyanato, isothiocyanto, hydrazide, nitro, nitroso, nitrosooxy, pyridyl, hydroxyl, alkoxy, carboxyl, ester, acyl, halo, haloformyl, phosphino, phosphoric, phospho, sulfide, di-sulfide, thio, thiol, sulfonyl, sulfo, sulfinyl, alkenyl, alkynl, allenyl, and silyl, and
Y is a thiocarbonylthio moiety having a formula —SC(═S)Z, where Z is an activating group.

2. The compound of claim 1 wherein the targeting agent is a ligand having affinity for one or more receptors effective for mediating endocytosis.

3. The compound of claim 1 wherein the therapeutic agent is a polynucleotide.

4. The compound of claim 3 wherein the polynucleotide is selected from the group consisting of a dicer substrate, siRNA, RNAi, miRNA, and shRNA.

5. The compound of claim 3 wherein the polynucleotide is a siRNA.

6. A compound comprising a polymer having a formula IIA
P n -(E) k -Y  (IIA),

wherein
P n is a polymer chain,
E is a chain extension residue having a formula E3:

wherein
R 1 and R 4 are each hydrogen,
R 2 , N—R 5 , and R 3 together form an N-substituted imidyl moiety represented by the formula —C(O)NR 5 C(O)—, and
R 5 is a C 1 -C 20 moiety comprising a primary or secondary amine, wherein the C 1 -C 20 moiety is selected from the group consisting of hydrocarbyl, substituted hydrocarbyl, hetero-hydrocarbyl, substituted hetero-hydrocarbyl, carbocyclic, substituted carbocyclic, heterocyclic, substituted heterocyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, and fused-multiring structures comprising one or more of the foregoing,
k is an integer ranging from 1 to 10, and
Y is a thiocarbonylthio moiety having a formula —SC(═S)Z, where Z is an activating group.

7. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable excipient.

8. A method for modulating the expression of a gene that mediates angiogenesis comprising administering to a patient in need thereof a compound of claim 1 wherein the biomolecular agent is selected from a dicer substrate, siRNA, RNAi, miRNA, and shRNA.

Assignees

• Stayton Patrick S
• Hoffman Allan S
• Convertine Anthony J
• Henry Scott M
• Overell Robert W
• Johnson Paul H
• Univ Washington
• Phaserx Inc

Inventors

• Stayton Patrick S
• Hoffman Allan S
• Convertine Anthony J
• Henry Scott M
• Overell Robert W
• Johnson Paul H

Classifications

• C08F2438/03

  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 title

• C08F293/005 Primary

  using free radical "living" or "controlled" polymerisation, e.g. using a complexing agent · CPC title

• C12N15/111

  General methods applicable to biologically active non-coding nucleic acids · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• C08F220/54

  Amides {, e.g. N,N-dimethylacrylamide or N-isopropylacrylamide} · CPC title