Selective dendrimer delivery to brain tumors

Abstract

A composition comprising poly(amidoamine) (PAMAM) hydroxyl-terminated dendrimers covalently linked to at least one therapeutic, prophylactic or diagnostic agent for the treatment or alleviation of one or more symptoms of a brain tumor have been developed. The dendrimers comprise one or more ethylene diamine-core poly(amidoamine) (PAMAM) hydroxyl-terminated generation-4, 5, 6, 7, 8, 9, or 10, most preferably generation 6 (G4-10-OH) dendrimers. The G6 dendrimers have demonstrated unexpectedly high uptake into the brain. The dendrimers provide a means for selective delivery through the blood brain barrier (“BBB”) of chemotherapeutic, immunotherapeutic and palliative agents. The dendrimers also have the advantage that two different classes of compounds, having one or more mechanisms of action can be bound to the dendrimers, providing simultaneous delivery. The dendrimers may be administered alone by intravenous injection, or as part of a multi-prong therapy with radiation.

1 - 32 . (canceled) 
     
     
         33 . A composition comprising hydroxyl-terminated poly(amidoamine) (PAMAM) dendrimers covalently linked to or complexed with one or more chemotherapeutic agents consisting of alkylating agents, angiogenesis inhibitors, modulators of tumor immune response, aromatase inhibitors, antimetabolites, anthracyclines, antitumor antibiotics, platinum compounds, topoisomerase inhibitors, radioactive isotopes, radiosensitizing agents, checkpoint inhibitors, APRKinase inhibitors, plant alkaloids, glycolytic inhibitors and prodrugs thereof. 
     
     
         34 . The composition of  claim 33 , wherein the one or more modulators of tumor immune response are selected from the group consisting of colony stimulating factor-1 (CSF-1) receptor inhibitors, MAPKinase inhibitors, inhibitors of STAT, and combinations thereof. 
     
     
         35 . The composition of  claim 34 , wherein the CSF-1 receptor inhibitor is selected from the group consisting of BLZ-945 and PLX3397. 
     
     
         36 . The composition of  claim 33 , wherein the chemotherapeutic agents are selected from the group consisting of paclitaxel, BCNU, camptothecin, doxycycline, cisplatin, and derivatives, analogues, and prodrugs thereof. 
     
     
         37 . The composition of  claim 33 , wherein the chemotherapeutic agents are selected from the group consisting of MDX-1106 and pembrolizumab. 
     
     
         38 . The composition of  claim 33 , wherein the chemotherapeutic agents are selected from the group consisting of inhibitors of glutamate formation/release and NMDA receptor antagonists. 
     
     
         39 . The composition of  claim 33 , wherein the hydroxyl-terminated PAMAM dendrimers are selected from the group consisting of generation 4, generation 5, generation 6, generation 7, generation 8, generation 9, and generation 10 PAMAM dendrimers. 
     
     
         40 . The composition of  claim 33 , wherein the hydroxyl-terminated PAMAM dendrimers are generation 4 or generation 6 PAMAM dendrimers. 
     
     
         41 . A composition comprising hydroxyl-terminated poly(amidoamine) (PAMAM) dendrimers covalently linked to or complexed with one or more diagnostic agents selected from the group consisting of paramagnetic molecules, fluorescent compounds, magnetic molecules, radionuclides, x-ray imaging agents, contrast media, fluorescent dyes, Near infra-red dyes, SPECT imaging agents, PET imaging agents, and radioisotopes. 
     
     
         42 . The composition of  claim 41 , wherein the SPECT or PET imaging agent is a chelator selected from the group consisting of di-ethylene tri-amine penta-acetic acid (DTPA), 1,4,7,10-tetra-azacyclododecane-1,4,7,10-tetraacetic acid (DOTA), di-amine dithiols, activated mercaptoacetyl-glycyl-glycyl-gylcine (MAG3), and hydrazidonicotinamide (HYNIC). 
     
     
         43 . The composition of  claim 41 , wherein the radioisotopes are selected from the group consisting of Tc-94m, Tc-99m, In-111, Ga-67, Ga-68, Gd 3+ , Y-86, Y-90, Lu-177, Re-186, Re-188, Cu-64, Cu-67, Co-55, Co-57, F-18, Sc-47, Ac-225, Bi-213, Bi-212, Pb-212, Sm-153, Ho-166, and Dy-166. 
     
     
         44 . A pharmaceutical formulation comprising the composition of  claim 33  and one or more pharmaceutically acceptable excipients. 
     
     
         45 . The pharmaceutical formulation of  claim 44  formulated for enteral or parenteral administration. 
     
     
         46 . The pharmaceutical formulation of  claim 44  formulated for intravenous, intraperitoneal, or subcutaneous administration.