Composite embolization beads

Abstract

The present invention relates to compositions and methods for imaging and treating various diseases and disorders, including cancers. The composition of the invention can include a plurality of biodegradable micro-beads, each embedding a plurality of nano-beads, further including a polymer, a radionuclide, a radionuclide chelator, a radioligand, a chemotherapeutic agent, and a cell-penetrating peptide. Upon injection into a blood vessel supplying a cancer tumor, the micro-beads lodge into the tumor and degrade, releasing the nano-beads with a therapeutic or diagnostic agent. The compositions and methods of the invention provide a more homogeneous and deeper distribution of radiation or chemotherapeutic agents throughout the target tumor. The micro-beads provide a local, sustained, and controlled delivery nano-beads including therapeutic or diagnostic agents.

1 . A micro-bead comprising:
 a matrix; and   a plurality of nano-beads;   wherein the nano-beads comprise at least one selected from the group consisting of a polymer, a radionuclide, a radionuclide chelator, a ligand, a chemotherapeutic agent, a metal, color pigments, and a cell-penetrating peptide.   
     
     
         2 . The micro-bead of  claim 1 , wherein the matrix comprises a polymer selected from the group consisting of polyglycolic acid (PGA), polylactic acid (PLA), poly(lactic-co-glycolic acid) (PLGA), polycaprolactone (PCL), collagen, gelatin, glass, polymethylmethacrylate (PMMA), and polystyrene. 
     
     
         3 . The micro-bead of  claim 1 , wherein the polymer is selected from the group consisting of poly(methyl methacrylate) (PMMA), polystyrene, carboxymethyl chitosan (CCN), PLGA, and carboxymethyl cellulose (CMC). 
     
     
         4 . The micro-bead of  claim 1 , wherein the nano-beads comprise a biodegradable polymer. 
     
     
         5 . The micro-bead of  claim 1 , wherein the nano-beads comprise a non-biodegradable polymer. 
     
     
         6 . The micro-bead of  claim 1 , wherein the nano-beads comprise a radionuclide that is a radioactive isotope of an element selected from the group consisting of actinium, astatine, bismuth, cesium, chromium, cobalt, dysprosium, erbium, holmium, iodine, iridium, iron, lead, lutetium, lutetium, molybdenum, palladium, phosphorus, potassium, radium, rhenium, samarium, selenium, sodium, strontium, sulfur, technetium, tritium, xenon, ytterbium, yttrium, carbon, nitrogen, oxygen, fluorine, copper, gallium, germanium, indium, krypton, rubidium, strontium, and thallium. 
     
     
         7 . The micro-bead of  claim 1 , wherein the radionuclide chelator is selected from the group consisting of triethylenetetramine (TETA), 1,4,7-triazacyclononane-1,4,7-trisacetic acid (NOTA), and 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA). 
     
     
         8 . The micro-bead of  claim 1 , wherein the ligand is selected from the group consisting of [ 18 F]altanserin, [ 18 F]setoperone, [ 18 F]ketanserin, [ 18 F]flumazenil, [ 11 C]3-amino-4-(2-dimethylaminomethylphenylsulfanyl)-benzonitrile ([ 11 C]DASB), [ 11 C]raclopride, [ 123 I]Ioflupane, and [ 123 I]Altropane. 
     
     
         9 . The micro-bead of  claim 1 , wherein the nano-beads comprise an MRI contrast agent, a PET contrast agent, gold nanoparticles, color pigments, or a radiopaque contrast agent. 
     
     
         10 . The micro-beads of  claim 1 , wherein the nano-beads further comprise boron-10 or gadolinium-157. 
     
     
         11 . The micro-bead of  claim 1 , wherein the chemotherapeutic agent is selected from the group consisting of doxorubicin, cisplatin, taxol, vinblastine, vincristine, bleomycin, fluorouracil, methotrexate, bortezomib, and etoposide. 
     
     
         12 . The micro-bead of  claim 1 , wherein the cell-penetrating peptide is selected from the group consisting of R9, TAT, HSV, gH625, penetratin, VP22, Xentry and transportan. 
     
     
         13 . A micro-bead comprising:
 a biodegradable matrix;   and a sub-microbead embedded in the biodegradable matrix;   wherein the biodegradable matrix comprises at least one of a biodegradable polymer, radionuclide, a radionuclide chelator, a ligand, a cell penetrating peptide, boron-10, gadolinium-157, an MRI contrast agent, a PET contrast agent, a radiopaque contrast agent, and a chemotherapeutic agent.   
     
     
         14 . The micro-bead of  claim 13 , wherein the biodegradable matrix further comprises a plurality of nano-beads. 
     
     
         15 . The micro-bead of  claim 13 , further comprising a separation layer between the sub-microbead and the biodegradable matrix, wherein the separation layer comprises at least one lipid. 
     
     
         16 . A method of treating a disease or disorder in a subject, comprising:
 administering to the subject a composition comprising a plurality of micro-beads of  claim 1 .   
     
     
         17 . The method of  claim 16 , wherein the micro-beads degrade over a period of time between 1 and 90 days. 
     
     
         18 . The method of  claim 16 , wherein the disease or disorder is cancer. 
     
     
         19 . The method of  claim 18 , wherein the cancer is selected from the group consisting of primary renal cell carcinoma (RCC), primary hepatocellular carcinoma (HCC), and liver metastatic lesions from other primary cancers. 
     
     
         20 . The method of  claim 19 , wherein the primary cancers are selected from the group consisting of gastric cancer, colorectal cancer, breast cancer, pancreatic cancer, lung cancer, and prostate cancer. 
     
     
         21 . A method of treating cancer in a subject in need thereof, the method comprising the steps of:
 administering to the subject the micro-beads of  claim 10 ; and   exposing the subject to a neutron source.