Endosomolytic poly(vinyl ether) polymers

• US 8,008,355 B2
• Filed: 06/17/2008
• Issued: 08/30/2011
• Est. Priority Date: 03/11/2002
• Status: Expired due to Fees

• Current Assignee: Arrowhead Madison Inc (Arrowhead Pharmaceuticals, Inc.)
• Original Assignee: Roche Madison Inc. (Arrowhead Pharmaceuticals, Inc.)
• Inventors: Monahan, Sean D., Hagstrom, James E., Higgs, Lori, Wolff, Jon A., Rozema, David B., Wakefield, Darren H.
• Primary Examiner(s): KETTER, JAMES S
• Application Number:
  US12/140,681
• Publication Number:
  US 20080287628A1
• Time in Patent Office: 1,169 Days
• Field of Search: None
• US Class Current: 514/772.2
• CPC Class Codes: A01K 2217/058 due to expression of inhibitory nucleic acid, e.g. siRNA, antisense
• CPC Class Codes: A01K 2267/0362 Animal model for lipid/glucose metabolism, e.g. obesity, type-2 diabetes
• 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: C12N 15/87 Introduction of foreign genetic material using processes not otherwise provided for, e.g. co-transformation

Abstract

The present invention is directed to membrane active polymers useful for cellular delivery of compounds. Described are polyconjugates systems that incorporate targeting, anti-opsonization, anti-aggregation, and transfection activities into small biocompatible in vivo delivery conjugates. The use of reversible modification provides for physiologically responsive activity modulation.

Claims

1. A membrane active random poly(vinyl ether) comprising:

a plurality of amine-containing monomers, a plurality of lower hydrophobic monomers, and a plurality of higher hydrophobic monomers wherein said first and second hydrophobic monomers are different, wherein the ratio of amine-containing monomers to lower hydrophobic monomers to higher hydrophobic monomer is 4-8;

3-5;

1.

2. The membrane active poly(vinyl ether) of claim 1 wherein said lower and higher hydrophobic monomers contain hydrophobic groups selected from the list consisting of:

alkyl group, alkenyl group, alkynyl group, aryl group, aralkyl group, aralkenyl group, and aralkynyl group, each of which may be linear, branched, or cyclic and may can contain one or more substitutions or heteroatoms, sterol, steroid, and steroid derivative.

3. The membrane active poly(vinyl ether) of claim 1 wherein said first hydrophobic monomers contain butyl groups and said second hydrophobic monomers contain octadecyl groups.

4. The membrane active poly(vinyl ether) of claim 1 wherein the poly(vinyl ether) further comprises one or more third hydrophobic monomers wherein said third hydrophobic monomers are different from said lower and higher hydrophobic monomers.

5. The membrane active poly(vinyl ether) of claim 4 wherein said third hydrophobic monomers contain hydrophobic groups selected from the group consisting of:

alkyl group, aryl group, aralkyl group, aralkenyl group, aralkynyl group, sterol, steroid, and steroid derivative.

6. The membrane active poly(vinyl ether) of claim 1 wherein the poly(vinyl ether) further comprises one or more monomers containing targeting groups.

7. The membrane active poly(vinyl ether) of claim 6 wherein the targeting groups are selected from the group consisting of:

cell receptor ligand, saccharide, galactose, galactose derivative, mannose, mannose derivative, aptamer, folate, biotin, vitamin, vitamin A, vitamin D, peptide, and Arg-Gly-Asp (RGD)-containing peptide.

8. A reversibly masked membrane active random poly(vinyl ether) comprising:

membrane active poly(vinyl ether) having a plurality of amine-containing monomers, a plurality of lower hydrophobic monomers, and a plurality of higher hydrophobic monomers in a ratio of 4-8;

3-5;

1 wherein one or more amines of the amine-containing monomers are linked to targeting groups via physiologically labile bonds thereby inhibiting membrane activity of the membrane active random poly(vinyl ether).

9. The reversibly masked membrane random poly(vinyl ether) of claim 8 wherein said lower and higher hydrophobic monomers contain hydrophobic groups selected from the list consisting of:

alkyl group, alkenyl group, alkynyl group, aryl group, aralkyl group, aralkenyl group, and aralkynyl group, each of which may be linear, branched, or cyclic and may can contain one or more substitutions or heteroatoms, sterol, steroid, and steroid derivative.

10. The reversibly masked membrane active random poly(vinyl ether) of claim 9 wherein said lower hydrophobic monomers contain butyl groups and said higher hydrophobic monomers contain octadecyl groups.

11. The reversibly masked membrane active random poly(vinyl ether) of claim 8 wherein the poly(vinyl ether) further comprises one or more third hydrophobic monomers wherein said third hydrophobic monomers are different from said lower and higher hydrophobic monomers.

12. The reversibly masked membrane active random poly(vinyl ether) of claim 11 wherein said third hydrophobic monomers contain hydrophobic groups selected from the group consisting of:

aryl group, aralkyl group, aralkenyl group, aralkynyl group, sterol, steroid, and steroid derivative.

13. The reversibly masked membrane active random poly(vinyl ether) of claim 8 wherein the poly(vinyl ether) further comprises one or more monomers containing targeting groups.

14. The reversibly masked membrane active random poly(vinyl ether) of claim 13 wherein the targeting groups are selected from the group consisting of:

cell receptor ligand, saccharide, galactose, galactose derivative, mannose, mannose derivative, aptamers, folate, biotin, vitamin A, vitamin D, peptide, and Arg-Gly-Asp (RGD)-containing peptide.