CROSSLINKED POLYMER NANO-ASSEMBLIES AND USES THEREOF

• US 20140112881A1
• Filed: 05/22/2012
• Published: 04/24/2014
• Est. Priority Date: 05/23/2011
• Status: Active Grant

• Current Assignee: University Of Massachusetts
• Original Assignee: University Of Massachusetts
• Inventors: Thayumanavan, Sankaran
• Granted Patent: US 9,592,302 B2
• Time in Patent Office: Days
• US Class Current: 424/78.29
• 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 nano-assembly for controlled delivery of a therapeutic or diagnostic agent to a biological site, comprising:

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

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

4. The nano-assembly of claim 1, wherein the nano-assembly further comprises a targeting moiety covalently linked to or non-covalently associated with the polymer host and wherein the targeting moiety is selected from an antibody, an aptamer, a peptide, and a small molecule ligand.

5. The nano-assembly of claim 1, wherein the guest molecule comprises a therapeutic agent, a diagnostic agent or an imaging agent non-covalently associated with the polymer host.

8. The nano-assembly of claim 1, wherein at least a portion of the guest molecule is hydrophobic.

10. The nano-assembly of claim 1, wherein the polymer host comprises a crosslinked network of co-polymer molecules and wherein the co-polymer molecules comprise one or more pendant hydrophilic side chains.

16. The nano-assembly of claim 1, wherein the polymer host comprises a crosslinked network of a block or random co-polymer having the structural formula:

19. The nano-assembly of claim 16, wherein W is

22. The nano-assembly of claim 16, wherein W is a charged group selected from —

CO₂⁻

, —

HPO₃⁻

, —

SO₃⁻

, —

NR₂, —

NR₃⁺, wherein R is hydrogen or a C₁-C₁₅ alkyl group.

24. The nano-assembly of claim 16, wherein W is a zwitterionic group selected from:

26. The nano-assembly of claim 16, wherein W is a charge-neutral group.

28. The nano-assembly of claim 16, wherein the polymer host comprises a network of a block or random co-polymer having the structural formula:

30. The nano-assembly of claim 16, wherein X comprises a disulfide group.

31. The nano-assembly of claim 30, wherein X comprises a

35. The nano-assembly of claim 31, wherein X_L is a peptide having from about 1 to about 20 amino acid units that are cleavable by an enzyme.

36. The nano-assembly of claim 16, wherein Y is selected from a linear or branched C₁-C₂₀ alkyl substituted with an aromatic moiety.

40. The nano-assembly of claim 1, wherein the crosslinked network of polymer molecules is crosslinked both inter-molecularly and intra-molecularly.

41. The nano-assembly of claim 1, wherein the crosslinked network of polymer molecules is crosslinked via disulfide bonds.

47. The nano-assembly of claim 1, wherein the de-crosslinking of the crosslinked polymer molecules is due to a biological or chemical stimulus at the biological site.

48. The nano-assembly of claim 47, wherein the stimulus is a pH value at the biological site.

49. The nano-assembly of claim 1, wherein the stimulus is induced by an external light signal.

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11-15. -15. (canceled)

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50-56. -56. (canceled)

57. A nano-assembly for controlled concurrent delivery of small molecule and non-small molecule therapeutic, diagnostic or imaging agents to a biological site, comprising:

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

a guest small molecule therapeutic, diagnostic or imaging agent non-covalently associated within the crosslinked network of polymer molecules, wherein the guest small molecule 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 guest non-small molecule therapeutic, diagnostic or imaging agent covalently linked to or non-covalently associated with the polymer host, wherein the guest non-small molecule therapeutic, diagnostic or imaging agent is releasable at or near the biological site.

58-89. -89. (canceled)

90. 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; and

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;

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.

91-141. -141. (canceled)