Crosslinked polymer nano-assemblies and uses thereof

• US 10,358,531 B2
• Filed: 02/07/2017
• Issued: 07/23/2019
• Est. Priority Date: 05/23/2011
• Status: Active Grant

• Current Assignee: University Of Massachusetts
• Original Assignee: University Of Massachusetts
• Inventors: Thayumanavan, Sankaran
• Primary Examiner(s): Shomer, Isaac
• Application Number:
  US15/427,017
• Publication Number:
  US 20170216450A1
• Time in Patent Office: 896 Days
• Field of Search: None
• CPC Class Codes: A61K 31/436 the heterocyclic ring system containing a six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin
• CPC Class Codes: A61K 31/4745 condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines yohimbine derivatives, vinblastine A61K31/475; ergoline derivatives A61K31/48
• CPC Class Codes: A61K 31/704 attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin digitoxin A61K31/7048
• CPC Class Codes: A61K 9/06 Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels composition of ointments, creams or gels A61K47/00
• CPC Class Codes: A61K 9/5138 obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C08F 220/20 of polyhydric alcohols or phenols , e.g. 2-hydroxyethyl (meth)acrylate or glycerol mono-(meth)acrylate
• CPC Class Codes: C08F 220/26 Esters containing oxygen in addition to the carboxy oxygen
• CPC Class Codes: C08F 220/385 and containing nitrogen
• CPC Class Codes: C08F 220/387 and containing nitrogen and oxygen
• CPC Class Codes: C08F 226/02 by a single or double bond to nitrogen
• CPC Class Codes: C08F 2810/20 leading to a crosslinking, either explicitly or inherently
• CPC Class Codes: C08F 8/00 Chemical modification by after-treatment graft polymers, block polymers, crosslinking with unsaturated monomers or with polymers C08F251/00 - C08F299/00; of conjugated diene rubbers C08C
• CPC Class Codes: C08J 2333/14 of esters containing halogen, nitrogen, sulfur, or oxygen atoms in addition to the carboxy oxygen
• CPC Class Codes: C08J 3/075 Macromolecular gels
• CPC Class Codes: C08J 3/24 Crosslinking, e.g. vulcanising, of macromolecules mechanical aspects B29C35/00; crosslinking agents C08K
• CPC Class Codes: Y10S 977/773 Nanoparticle, i.e. structure having three dimensions of 100 nm or less
• CPC Class Codes: Y10S 977/906 Drug delivery

Abstract

The invention provides a novel system of nano-assemblies and related method for delivery of therapeutic, diagnostic or imaging agent to biological sites. The compositions and methods of the invention enable the syntheses of novel polymeric nano-assemblies (nanoparticles) under non-emulsion conditions with the incorporation of hydrophobic guest molecules. The versatilities and advantages of the polymer nanoparticles of the invention include: (i) the guest molecules (e.g., drug molecules) can be readily incorporated non-covalently within the nanoparticles; (ii) the surface of the nanoparticles are functionalizable; (iii) the non-covalently encapsulated guest molecule (payload) can be released in response to a biologically relevant stimulus at the target site; (iv) the payload is held by the polymeric nanoparticle before being internalized in cells and can be released within the cellular interiors; (v) encapsulating lipophilic small molecules within its crosslinked interiors and binding proteins on its surface through electrostatic interactions; (vi) facile synthetic methods for ligand functionalization that can be utilized to decorate nanogels with cell targeting ligands that facilitate receptor-dependent cellular uptake, and (vii) the payload release kinetics is tunable and controllable.

Claims

1. A method for delivering a therapeutic, diagnostic or imaging agent to a biological site, comprising:

providing a nano-assembly, comprising;

a water-soluble polymer host comprising a crosslinked network of polymer molecules;

a guest molecule comprising a therapeutic, diagnostic or imaging agent non-covalently associated with the polymer host, wherein the therapeutic, diagnostic or imaging agent is releasable upon partial or complete de-crosslinking of the crosslinked network of polymer molecules at or near the biological site; and

a targeting moiety, covalently linked to or non-covalently associated with the polymer host, selected from an antibody, an aptamer, a peptide, and a small molecule ligand;

transporting the nano-assembly to the biological site; and

causing at least partial de-crosslinking of the crosslinked network of polymer molecules, thereby releasing the therapeutic, diagnostic or imaging agent at or near the biological site,

wherein the polymer host comprises a crosslinked network of a block or random co-polymer having the structural formula;

2. The method of claim 1, wherein the targeting moiety is a peptide.

3. The method of claim 1, wherein the co-polymer has a molecular weight from about 1,000 to about 100,000 and the ratio of i:

j is in the range from about 2;

8 to about 8;

2.

4. The method of claim 1, wherein the crosslinked network of polymer molecules is crosslinked both inter-molecularly and intra-molecularly.

5. The method of claim 1, wherein the therapeutic agent is an anti-tumor agent.

6. The method of claim 1, wherein the loading weight percentage of the guest molecule is from about 0.5% to about 70%.

7. The method of claim 1, wherein the biological site is within an organ or tissue or a cell.

8. A method for delivering a therapeutic, diagnostic or imaging agent to a biological site, comprising:

providing a nano-assembly, comprising;

a water-soluble polymer host comprising a crosslinked network of polymer molecules;

a guest molecule comprising a therapeutic, diagnostic or imaging agent non-covalently associated with the polymer host, wherein the therapeutic, diagnostic or imaging agent is releasable upon partial or complete de-crosslinking of the crosslinked network of polymer molecules at or near the biological site; and

a targeting moiety, covalently linked to or non-covalently associated with the polymer host, selected from an antibody, an aptamer, a peptide, and a small molecule ligand;

transporting the nano-assembly to the biological site; and

causing at least partial de-crosslinking of the crosslinked network of polymer molecules, thereby releasing the therapeutic, diagnostic or imaging agent at or near the biological site,

wherein the polymer host comprises a crosslinked network of a block or random co-polymer having the structural formula;