Functional, cross-linked nanostructures for tandem optical imaging and therapy
View Patent ↗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.
1. A composition comprising:
an optical agent comprising cross linked block copolymers, wherein each of the block copolymers comprises a hydrophilic block and a hydrophobic block;
wherein the hydrophilic block is a poly(acrylic acid) polymer block which has a number of monomers selected from the range of 10 to 250, and wherein the hydrophobic block is a polystyrene polymer block which has a number of monomers selected from the range of 40 to 100; 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;
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 composition of claim 1 wherein said optical agent has a cross linking density of 5% to 35% and the mole ratio of the linking groups to monomers of the hydrophilic blocks is selected over a range of 1:100 to 99:100.
3. The composition of claim 1 further comprising one or more targeting moieties.
4. The composition of claim 3 , wherein a targeting moiety is bonded to the hydrophilic blocks of at least a portion of the block copolymers.
5. The composition of claim 4 , wherein the targeting moiety is a peptide, a protein, an oligonucleotide, an antibody, a carbohydrate, a hormone, a lipid or a drug.
6. The composition of claim 5 , wherein the targeting moiety comprises a ST receptor binding agent, a bombesin receptor binding agent, a leukemia peptide, and a folate receptor binding agent.
7. A method comprising administering a composition of claim 1 to a mammal, the method comprising:
administering to a mammal an effective amount of the composition of claim 1 , wherein the one or more photoactive moieties comprise one or more chromophores and/or fluorophores, wherein the therapeutic agent is paclitaxel, doxorubicin, an isolated polypeptide, comprising the amino acid sequence of SEQ ID NO: 1, that is released from the supramolecular structure;
exposing the optical agent administered to the mammal to electromagnetic radiation; and
detecting electromagnetic radiation transmitted, scattered or emitted by the optical agent.
8. The composition of claim 7 wherein the optical agent is exposed to electromagnetic radiation having wavelengths selected over a range of 400 nanometers to 1300 nanometers.
9. The composition of claim 1 wherein the procedure further comprises exciting luminescence from the optical agent.
10. The composition of claim 1 wherein the procedure comprises a method of imaging a tumor of the mammal, wherein the administering provides the optical agent to the tumor.
11. A shell-cross linked nanostructure comprising:
cross linked block copolymers, wherein each of the block copolymers comprises a hydrophilic block and a hydrophobic block; wherein the hydrophilic block is a poly(acrylic acid) polymer block which has a number of monomers selected from the range of 10 to 250, wherein the hydrophobic block is a polystyrene polymer block which has a number of monomers selected from the range of 40 to 100; and wherein the hydrophilic block is directly or indirectly bonded to the hydrophobic block;
pyrazine-containing linking groups covalently cross linking at least a portion of the poly(acrylic acid) polymer blocks of the block copolymers, wherein the copolymers form a supramolecular structure; and
a therapeutic agent that is at least partially encapsulated by the supramolecular structure;
wherein the nanostructure has a cross linking density of 5% to 35%, and wherein the nanostructure is rod-shaped.
12. The shell-cross linked nanostructure of claim 11 wherein the mole ratio of the pyrazine-containing linking groups to monomers of the poly(acrylic acid) polymer block is selected over a range of 1:100 to 99:100.
13. The composition of claim 1 and at least one carrier or excipient resulting in a pharmaceutically acceptable composition.
14. A pharmaceutically acceptable composition comprising at least one carrier or excipient and a composition of claim 1 .
15. A composition according to claim 1 , wherein the therapeutic agent 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 Type I photodynamic compound, a Type II photodynamic compound, a leukemia cell binding peptide, doxorubicin or paclitaxel.
16. A composition according to claim 1 , wherein the therapeutic agent is an isolated polypeptide, comprising the amino acid sequence of SEQ ID NO: 1, paclitaxel or doxorubicin.
17. A composition according to claim 1 , wherein the therapeutic agent is paclitaxel or doxorubicin.