Functionalized nanoparticles and methods of use thereof

Abstract

Certain embodiments of the present invention provide functionalized nanoparticles and methods of use thereof. Certain embodiments provide nanoparticles functionalized with streptokinase. Certain embodiments of the present invention provide methods for treating a pathological fibrin associated disorder (e.g., cancer) in an animal.

What is claimed is: 
     
         1 . A nanoparticle covalently attached directly or indirectly through a linker to one or more moieties independently selected from streptokinase (kabinkinase, streptase), urokinase (abbokinase), arvin, brinase, tissue plasminogen activator (tPA), recombinant tissue plasminogen activator (r-tPA), nattokinase, lumbrokinase, serrapeptase, prourokinase, reptilase, anisoylated purified streptokinase activator complex (APSAC), thrombinase, anistreplase (eminase) and staphylokinase. 
     
     
         2 . The nanoparticle of  claim 1 , wherein the one or more moieties are streptokinase. 
     
     
         3 . The nanoparticle of  claim 1 , wherein the nanoparticle comprises poly-(lactic-co-glycolic acid). 
     
     
         4 . The nanoparticle of  claim 1 , wherein the linker comprises a block co-polymer selected from poly-lactic acid and poly-(ethylene glycol); poly-lactic acid and poly-(ethylene oxide); poly-(lactic-co-glycolic acid) and poly-(ethylene glycol); and poly-(lactic-co-glycolic acid) and poly-(ethylene oxide). 
     
     
         5 . The nanoparticle of  claim 4 , wherein the poly-(ethylene glycol) or the poly-(ethylene oxide) comprises a functionalized terminal moiety. 
     
     
         6 . The nanoparticle of  claim 5 , wherein the moiety is carboxy, maleimide, sulfhydryl, aldehyde, azide, or amino. 
     
     
         7 . The nanoparticle of  claim 1 , further comprising one or more therapeutic agents. 
     
     
         8 . The nanoparticle of  claim 7 , wherein the one or more therapeutic agents is an anti-cancer agent independently selected from All-trans retinoic acid, Azacitidine, Azathioprine, Bleomycin, Bortezomib, Carboplatin, Capecitabine, Cisplatin, Chlorambucil, Cyclophosphamide, Cytarabine, Daunorubicin, Docetaxel, Doxifluridine, Doxorubicin, Epirubicin, Epothilone, Etoposide, Fluorouracil, Gemcitabine, Hydroxyurea, Idarubicin, Imatinib, Mechlorethamine, Mercaptopurine, Methotrexate, Mitoxantrone, Oxaliplatin, Paclitaxel, silicate prodrug of Paclitaxel, Pemetrexed, Teniposide, Tioguanine, Valrubicin, Vinblastine, Vincristine, Vindesine, Vinorelbine, a tyrosine kinase inhibitor, an antibody (e.g., Herceptin and bevacizumab), and pharmaceutically acceptable salts thereof, or combinations thereof. 
     
     
         9 . The nanoparticle of  claim 1 , further comprising one or more imaging agents independently selected from coumarin-6, SDB5491, rhodamine derivatives, cy5.5, radiolabels for PET imaging and diagnostic agents suitable for MRI imaging. 
     
     
         10 . A compound of formula (I):
   A-B-C-D   (I)
   wherein A is poly-lactic acid or and poly-(lactic-co-glycolic acid); B is poly-(ethylene glycol) or poly-(ethylene oxide); C is methyl and D is absent; or C is a linking group and D is one or more moieties independently selected from streptokinase (kabinkinase, streptase), urokinase (abbokinase), arvin, brinase, tissue plasminogen activator (tPA), recombinant tissue plasminogen activator (r-tPA), nattokinase, lumbrokinase, serrapeptase, prourokinase, reptilase, anisoylated purified streptokinase activator complex (APSAC), thrombinase, anistreplase (eminase) and staphylokinase.   
     
     
         11 . The compound of  claim 10 , wherein the linking group is a direct bond, carboxy, —OC(═O)(CH 2 ) n C(═O)O—, maleimide, sulfhydryl, aldehyde, azide, or amino, wherein n is 1-10. 
     
     
         12 . The compound of  claim 10 , wherein D is streptokinase. 
     
     
         13 . A nanoparticle comprising poly-(lactic-co-glycolic acid) and one or more units of formula (I) as described in  claim 10 . 
     
     
         14 . The nanoparticle of  claim 13 , wherein A is embedded or partially embedded in the poly-(lactic-co-glycolic acid). 
     
     
         15 . The nanoparticle of  claim 13 , further comprising one or more therapeutic agents. 
     
     
         16 . The nanoparticle of  claim 15 , wherein the one or more therapeutic agents is an anti-cancer agent independently selected from All-trans retinoic acid, Azacitidine, Azathioprine, Bleomycin, Bortezomib, Carboplatin, Capecitabine, Cisplatin, Chlorambucil, Cyclophosphamide, Cytarabine, Daunorubicin, Docetaxel, Doxifluridine, Doxorubicin, Epirubicin, Epothilone, Etoposide, Fluorouracil, Gemcitabine, Hydroxyurea, Idarubicin, Imatinib, Mechlorethamine, Mercaptopurine, Methotrexate, Mitoxantrone, Oxaliplatin, Paclitaxel, silicate prodrug of Paclitaxel, Pemetrexed, Teniposide, Tioguanine, Valrubicin, Vinblastine, Vincristine, Vindesine, Vinorelbine, a tyrosine kinase inhibitor, an antibody (e.g., Herceptin and bevacizumab), and pharmaceutically acceptable salts thereof, or combinations thereof. 
     
     
         17 . The nanoparticle of  claim 13 , further comprising one or more imaging agents independently selected from coumarin-6, SDB5491, rhodamine derivatives, cy5.5, radiolabels for PET imaging and diagnostic agents suitable for MRI imaging. 
     
     
         18 . A pharmaceutical composition comprising a nanoparticle as described in  claim 1  and a pharmaceutically acceptable carrier. 
     
     
         19 . A method for treating a pathological fibrin associated disorder in an animal, comprising administering to the animal a nanoparticle as described in  claims 1 . 
     
     
         20 . The method of  claim 19 , wherein the pathological fibrin associated disorder is cancer.