CROSSLINKED POLYMER NANO-ASSEMBLIES AND USES THEREOF

• US 20170216450A1
• Filed: 02/07/2017
• Published: 08/03/2017
• 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 10,358,531 B2
• Time in Patent Office: Days
• 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

1-89. -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. The method of claim 90, wherein the nano-assembly further comprises a targeting moiety covalently linked to or non-covalently associated with the polymer host.

93. The method of claim 91, wherein the targeting moiety is selected from an antibody, an aptamer, a peptide, and a small molecule ligand.

94. The method of claim 90, wherein at least a portion of the guest molecule is hydrophobic and the polymer molecules comprise pendant hydrophilic side chains.

99. The method of claim 90, wherein the polymer host is covalently attached to a

100. The method of claim 90, wherein the polymer host comprises a network of a block or random co-polymer having the structural formula:

101. The method of claim 100, wherein each of R₂, R′

₂, R″

₂, R₃, R′

₃ and R″

₃ is a hydrogen, and each of R₁, R′

₁ and R″

₁ is a methyl group.

102. The method of claim 101, wherein each of L₁, L₂ and L₃ is independently a group selected from

103. The method of claim 100, wherein W is

104. The method of claim 100, wherein W is a charged group, a zwitterionic group or a charge-neutral group.

110. The method of claim 100, wherein the polymer host comprises a crosslinked network of a block or random co-polymer having the structural formula:

111. The method of claim 100, wherein X comprises a disulfide group.

112. The method of claim 100, wherein X comprises a

116. The method of claim 112, wherein X_L is a peptide having from about 1 to about 20 amino acid units that are cleavable by an enzyme.

117. The method of claim 100, wherein Y is selected from a linear or branched C₁-C₁₆ alkyl group substituted with an aromatic moiety.

118. The method of claim 100, 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.

121. The method of claim 90, wherein the crosslinked network of polymer molecules are crosslinked both inter-molecularly and intra-molecularly.

124. The method of claim 90, wherein the therapeutic agent is an anti-tumor agent.

126. The method of claim 90, wherein the loading weight percentage of the guest molecule is from about 0.5% to about 70%.

130. The method of claim 90, wherein the biological site is within an organ or tissue or a cell.

92. (canceled)

95-98. -98. (canceled)

105-109. -109. (canceled)

113-115. -115. (canceled)

119. (canceled)

120. (canceled)

122. (canceled)

123. (canceled)

125. (canceled)

127-129. -129. (canceled)

131-141. -141. (canceled)