Functional, cross-linked nanostructures for tandem optical imaging and therapy

Patent metadata

Field	Value
Publication number	US-9295650-B2
Application number	US-201113697149-A
Country	US
Kind code	B2
Filing date	Nov 17, 2011
Priority date	May 14, 2010
Publication date	Mar 29, 2016
Grant date	Mar 29, 2016

Abstract

The present invention provides optical agents comprising optically functional cross linked supramolecular structures and assemblies useful for tandem optical imaging and therapy. Supramolecular structures and assemblies of the present invention include optically functional shell-cross linked micelles wherein optical functionality is achieved via incorporation of one or more linking groups that include one or more photoactive moieties. The present invention further includes imaging and therapeutic methods using one or more optical agents of the present invention including optically functional shell cross-linked micelles having an associated therapeutic agent.

First claim

What is claimed is:

1. An optical agent comprising:
an optical agent comprising cross linked block copolymers, wherein each of the block copolymers comprises a hydrophilic block and a hydrophobic block; and
linking groups covalently cross linking at least a portion of the hydrophilic blocks of the block copolymers, wherein at least a portion of the linking groups comprise one or more photoactive moieties; and
a therapeutic agent that is a cytotoxic moiety, a DNA intercalating anthracycline, a chemotherapy agent, an alkylating agent, a DNA intercalator, a microtubule-targeting molecule, a folate antagonist, a nucleoside antimetabolite, an antineoplastic agent, a platinum complex, a Taxol, a Type I photodvnamic compound or a Type II photodvnamic compound;
wherein the optical agent forms a supramolecular structure in aqueous solution, the supramolecular structure having an interior hydrophobic core and a covalently cross linked hydrophilic shell, wherein the interior hydrophobic core comprises the hydrophobic blocks of the block copolymers, and the covalently cross linked hydrophilic shell comprises the hydrophilic blocks of the block copolymers, wherein the therapeutic agent is at least partially encapsulated by the supramolecular structure and the therapeutic agent is non-covalently associated with the hydrophobic core, and wherein the optical agent is a shell-cross linked rod-shaped nanostructure.

2. The optical agent of claim 1 wherein the one or more photoactive moieties comprise one or more fluorophores capable of excitation upon absorption of electromagnetic radiation having wavelengths selected over a range of 400 nanometers to 1300 nanometers, and capable of emission of electromagnetic radiation having wavelengths selected over a range of 400 nanometers to 1300 nanometers.

3. The optical agent of claim 1 wherein the one or more photoactive moieties comprises a Type I or Type II phototherapeutic agent.

4. The optical agent of claim 1 wherein the one or more photoactive moieties comprises a pyrazine.

5. The optical agent of claim 1 wherein the mole ratio of the linking groups to monomers of the hydrophilic blocks is selected over a range of 1:100 to 99:100.

6. The optical agent of claim 1 wherein the block copolymers are diblock copolymers, triblock copolymers, polyblock copolymers or graft colymers.

7. The optical agent of claim 1 wherein the hydrophobic block is a poly(p-hydroxystyrene) polymer block; a polystyrene polymer block; a poly(p-hydroxystyrene) polymer block; a polyacrylate polymer block; a poly(propylene glycol) polymer block; a poly(ester) polymer block; a polylactic acid polymer block; a poly(tert-butylacrylate) polymer block; a poly(N-acryloxysuccinimide) polymer block; a poly(methyl acrylate) polymer block; a poly(ε-caprolactone) polymer block; a poly(glycolic acid) polymer block; a polylactide polymer block; or a polyglycolide polymer block; or a copolymer thereof.

8. The optical agent of claim 1 wherein the hydrophilic block is a poly(acrylic acid) polymer block; a poly(ethylene glycol) polymer block; a poly(acetoxystyrene) polymer block; or a copolymer thereof.

9. The optical agent of claim 1 wherein a hydrophilic block is a poly(acrylic acid) polymer block, a hydrophobic block is a poly(p-hydroxystyrene) block and the linking groups are bound to monomers of the poly(acrylic acid) polymer block by amide bonds.

10. The optical agent of claim 1 wherein at least a portion of the hydrophilic blocks of the block copolymers and linking groups have the formula:

wherein each of R 1 -R 6 is independently selected from the group consisting of —R, —COOR,—COR, —CON(R) 2 , —OCON(R) 2 , —N(R) 2 , —SR, —SO 2 R, —SOR, —OCOOR, —SO 2 N(R) 2 , and —OR; each R is independently selected from the group consisting of a hydrogen, C 1 -C 20 alkyl, C 5 -C 20 aryl, C 1 -C 20 carbonyl, C 2 -C 20 alkenyl, C 2 -C 20 alkynyl, C 5 -C 20 alkylaryl, C 1 -C 20 alkoxy, halo, amine, amide, hydroxyl, carboxyl, cyano, a nitrile group, an azide group, a nitro group, an acyl group, a thiol group or a natural or non-natural amino acid or fragment thereof; each of Z 1 and Z 2 is independently

wherein one or more CH 2 groups may be replaced by NH, O, S, a carbonyl (C═O), or a sulfonyl (S═O or O═S═O); two adjacent CH 2 groups may be replaced by —CH═CH— or —C═C—; and wherein each e is independently is selected from the range of 0 to 10; and each of a and b is independently 0 or 1; or wherein at least a portion of the hydrophilic blocks of the block copolymers and linking groups have the formula:

wherein each of R 1 -R 14 is independently selected from the group consisting of —R, —COOR, —COR, —CON(R) 2 , —OCON(R) 2 , —N(R) 2 , —SR, —SO 2 R, —SOR, —OCOOR, —SO 2 N(R) 2 , and —OR; each R is independently selected from the group consisting of a hydrogen, C 1 -C 20 alykl, C 5 -C 20 aryl, C 1 -C 20 carbonyl, C 2 -C 20 alkenyl, C 5 -C 20 alkynyl, C 5 -C 20 alkylaryl, C 1 -C 20 alkoxy, halo, amine, amide, hydroxyl, carboxyl, cyano, a nitrile group, an azide group, a nitro group, an acyl group, a thiol group or a natural or non-natural amino acid or fragment thereof; each of u and v is independently selected from the range of 0 to 10; each of Z 3 -Z 6 is independently

wherein one or more CH 2 groups may be replaced by NH, O, S, a carbonyl (C═O), or a sulfonyl (S═O or O═S═O); two adjacent CH 2 groups may be replaced by —CH═CH— or —C═C—; and wherein each e is independently is selected from the range of 0 to 10.

11. The optical agent of claim 10 wherein at least one of R 8 , R 11 , R 13 , and R 14 is:

12. The optical agent of claim 1 wherein at least a portion of the hydrophilic blocks of the block copolymers and linking groups have the formula:

wherein each p is selected from the range of 20 to 250, wherein independently for each value of p, n is independently a number from 1 to 0 and m is independently a number from 1 to 0; wherein each of R 1 -R 6 is independently selected from the group consisting of —R, —COOR, —COR, —CON(R) 2 , —OCON(R) 2 , —N(R) 2 , —SR, —SO 2 R, —SOR, —OCOOR, —SO 2 N(R) 2 , and —OR; each R is independently selected from the group consisting of a hydrogen, C 1 -C 20 alkyl, C 5 -C 20 aryl, C 1 -C 20 carbonyl, C 2 -C 20 alkenyl, C 2 -C 20 alkynyl, C 5 -C 20 alkylaryl, C 1 -C 20 alkoxy, halo, amine, amide, hydroxyl, carboxyl, cyano, a nitrile group, an azide group, a nitro group, an acyl group, a thiol group or a natural or non-natural amino acid or fragment thereof; each of R 17 and R 18 is independently selected from the group consisting of —R, —COOR, —COR, —CON(R) 2 , —OCON(R) 2 , —N(R) 2 , —SR, —SO 2 R, —SOR, —OCOOR, —SO 2 N(R) 2 , and —OR; each R is independently selected from the group consisting of a hydrogen, C 1 -C 20 alkyl, C 5 -C 20 aryl, C 1 -C 20 carbonyl, C 2 -C 20 alkenyl, C 2 -C 20 alkynyl, C 5 -C 20 alkylaryl, C 1 -C 20 alkoxy, halo, amine, amide, hydroxyl, carboxyl, cyano, a nitrile group, an azide group, a nitro group, an acyl group, a thiol group, a natural or non-natural amino acid or fragme

Assignees

• Neumann William L
• Dorshow Richard B
• Freskos John N
• Wooley Karen L
• Lee Nam S
• Lin Yun
• Sun Guorong
• Mallinckrodt Llc
• Texas A & M Univ Sys
• Univ Washington

Inventors

• Neumann William L
• Dorshow Richard B
• Freskos John N
• Wooley Karen L
• Lee Nam S
• Lin Yun
• Sun Guorong

Classifications

• A61K49/0093

  Nanoparticle, nanocapsule, nanobubble, nanosphere, nanobead, i.e. having a size or diameter smaller than 1 micrometer, e.g. polymeric nanoparticle · CPC title

• A61K9/1075

  Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers (A61K9/0026 takes precedence) · CPC title

• A61K9/0092

  Hollow drug-filled fibres, tubes of the core-shell type, coated fibres, coated rods, microtubules or nanotubes · CPC title

• A61K31/337

  having four-membered rings, e.g. taxol · CPC title

• A61K9/5192

  Processes · CPC title