Asymmetric bifunctional silyl monomers and particles thereof as prodrugs and delivery vehicles for pharmaceutical, chemical and biological agents

Patent metadata

Field	Value
Publication number	US-9913916-B2
Application number	US-201615283574-A
Country	US
Kind code	B2
Filing date	Oct 3, 2016
Priority date	Sep 16, 2010
Publication date	Mar 13, 2018
Grant date	Mar 13, 2018

Abstract

Asymmetric bifunctional silyl (ABS) monomers comprising covalently linked pharmaceutical, chemical and biological agents are described. These agents can also be covalently bound via the silyl group to delivery vehicles for delivering the agents to desired targets or areas. Also described are delivery vehicles which contain ABS monomers comprising covalently linked agents and to vehicles that are covalently linked to the ABS monomers. The silyl modifications described herein can modify properties of the agents and vehicles, thereby providing desired solubility, stability, hydrophobicity and targeting.

First claim

The which is claimed:

1. A method for making a particle comprising:
a. first, covalently linking a monomer and a silyl via an O, N, S, or carboxyl of said monomer to form a silyl functionalized monomer;
b. second, covalently linking a nucleic acid to said silyl functionalized monomer to form a first nucleic acid-silyl functionalized monomer; and
c. third, forming a particle from the first nucleic acid-silyl functionalized monomer of step b,
wherein the nucleic acid-silyl functionalized monomer has the structure:

wherein R 1′ and R 2′ are independently alkyl;
wherein M is a monomer selected from the group consisting of 2-hydroxyethyl acrylate, 2-hydroxyethyl methacrylate , vinyl pyrrolidone, acrylic acid, ethylene oxide, poly(ethylene oxide), vinyl alcohol, a protein, an amino acid, and a polysaccharide;
wherein X a and X b are independently selected from the group consisting of O, NH, S, and a carboxyl; and
wherein R 3′ is a nucleic acid.

2. The method of claim 1 , wherein forming the particle comprises molding the first nucleic acid-silyl functionalized monomer in a mold cavity.

3. The method of claim 1 , wherein forming the particle further comprises associating a biocompatible polymer with the first nucleic acid-silyl functionalized monomer through a covalent link, physical entanglement, electrostatic association or hydrostatic association.

4. The method of claim 1 , further comprising a second nucleic acid-silyl functionalized monomer.

5. The method of claim 4 , wherein the second nucleic acid-silyl functionalized monomer comprises the same or different monomer or nucleic acid as the first nucleic acid-silyl functionalized monomer.

6. The method of claim 1 , wherein the nucleic acid comprises a ratio of 0.1 mg of nucleic acid to 1 mg of particle.

7. The method of claim 1 , wherein the nucleic acid-silyl functionalized monomer comprises between 1 wt % and 50 wt % of the particle.

8. The method of claim 1 , wherein the nucleic acid-silyl functionalized monomer comprises between 1 wt % and 40 wt % of of the particle.

9. The method of claim 1 , wherein the nucleic acid-silyl functionalized monomer comprises between 2 wt % and 20 wt % of the particle.

10. The method of claim 4 , wherein forming the particle comprises molding the nucleic acid-silyl functionalized monomers in a mold cavity.

11. The method of claim 1 , wherein the nucleic acid is selected from the group consisting of RNA, siRNA, DNA, and combinations thereof.

12. The method of claim 1 , wherein X a and X b are both O.

13. The method of claim 1 , wherein R 1′ and R 2′ are independently selected from the group consisting of methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, and tert-butyl.

14. The method of claim 1 , wherein the particle has a release rate of approximately 4 times slower at pH 7.4 relative to a release rate at pH 5.0.

15. The method of claim 1 , wherein the particle has a release rate of approximately 50.4 times slower at pH 5.0 and 201 times slower at pH 7.4 relative to a release rate at pH 5.0 wherein R 1′ and R 2′ are ethyl.

Assignees

• Univ North Carolina Chapel Hill

Inventors

• Desimone Joseph M
• Finniss Mathew
• Napier Mary
• Pandya Ashish
• Parrott Matthew

Classifications

• C07K19/00

  Hybrid peptides {, i.e. peptides covalently bound to nucleic acids, or non-covalently bound protein-protein complexes} · CPC title

• C07H23/00

  Compounds containing boron, silicon or a metal, e.g. chelates or vitamin B12 (esters with inorganic acids C07H11/00) · CPC title

• C12N2310/14

  interfering nucleic acids [NA] · CPC title

• C07F7/083

  Syntheses without formation of a Si-C bond · CPC title

• C12N2310/3515

  Lipophilic moiety, e.g. cholesterol · CPC title