Nanoparticles for drug delivery

Abstract

The invention provides nanoparticles, methods for making nanoparticles, and methods for using nanoparticles.

1 . A therapeutic magnetic nanoparticle, or a salt thereof, comprising a magnetic nanoparticle covalently bonded to one or more -L-D groups wherein D is a residue of a therapeutic agent and L is a linker capable of undergoing an intramolecular cyclization. 
     
     
         2 . The therapeutic magnetic nanoparticle of  claim 1 , wherein the linker capable of undergoing an intramolecular cyclization is suitable to release the therapeutic agent from the linker upon intramolecular cyclization. 
     
     
         3 . The therapeutic magnetic nanoparticle of  claim 1 , wherein the linker capable of undergoing an intramolecular cyclization can form a 3-8 membered heterocyclic ring upon cyclization. 
     
     
         4 . The therapeutic magnetic nanoparticle of  claim 3 , wherein the 3-8 membered ring comprises a group selected from an amide, carbamate, urea, carbamothioate, thioamide, thiocarbamate, thiourea and carbamodithioate. 
     
     
         5 . The therapeutic magnetic nanoparticle of  claim 1 , wherein the magnetic nanoparticle further comprises a coating. 
     
     
         6 . The magnetic nanoparticle of  claim 5 , wherein the coating is silica. 
     
     
         7 . The therapeutic magnetic nanoparticle of  claim 1 , wherein the magnetic nanoparticle comprises iron. 
     
     
         8 . The therapeutic magnetic nanoparticle of  claim 1 , wherein the linker comprises about 4-50 atoms. 
     
     
         9 . The therapeutic magnetic nanoparticle of  claim 1 , wherein -L-D has the following formula I: 
       
         
           
           
               
               
           
         
       
       wherein
 V is —OSi(G) 2 -, and the dashed line represents a covalent bond between the oxygen atom of —OSi(G) 2 - and the magnetic nanoparticle; 
 L 1  is (C 1 -C 6 )alkylene, (C 1 -C 6 )heteroalkylene, (C 2 -C 6 )alkenylene, (C 2 -C 6 )alkynylene, phenylene or (C 3 -C 7 )carbocyclene, wherein (C 1 -C 6 )alkylene, (C 1 -C 6 )heteroalkylene, (C 2 -C 6 )alkenylene, (C 2 -C 6 )alkynylene, phenylene or (C 3 -C 7 )carbocyclene are optionally substituted with one or more halogen; 
 each J is C(R b ) 2  wherein one C(R b ) 2  of J may be replaced by —O—, —S— or —N(R e )—; 
 (a) W is NH, X is CR c R d , and n is an integer from 0-5; or 
 (b) W is NH, X is O, NR e  or S, and n is an integer from 1-5; or 
 (c) W is 
 
       
         
           
           
               
               
           
         
          X is CR c R d , O, NR e , S or absent, m is an integer from 0-5 and n is an integer from 0-5, wherein the sum of m and n is 0-5; 
         Y is O or S; 
         Z-D 1  is a residue of a therapeutic agent wherein Z is O, NR h  or S; 
         each G is independently —OR a1 , —OR a2  or (C 1 -C 6 )alkyl; 
         R a1  is a covalent bond between the oxygen atom of —OR a1  and the magnetic nanoparticle; 
         each R a2  is independently H or (C 1 -C 6 )alkyl; or two —OR a2  groups of two adjacent L-D groups together form —O—; 
         each R b  is independently selected from H and (C 1 -C 3 )alkyl; or two R b  groups together with the carbon to which they are attached form a (C 3 -C 7 )carbocycle; 
         each R c  is independently selected from H and (C 1 -C 6 )alkyl, and each R d  is independently selected from H and (C 1 -C 6 )alkyl; or an R c  group and an R d  group together with the carbon to which they are attached form a (C 3 -C 7 )carbocycle; 
         each R e  is independently selected from H and (C 1 -C 6 )alkyl; 
         each R f  is independently selected from H and (C 1 -C 6 )alkyl; or two R f  groups together with the carbon to which they are attached form a (C 3 -C 7 )carbocycle; 
         R g  is selected from H and (C 1 -C 6 )alkyl; and 
         R h  is selected from H and (C 1 -C 6 )alkyl. 
       
     
     
         10 . The therapeutic magnetic nanoparticle of  claim 9 , wherein each G is —OR a1  or —OR a2 , wherein each —OR a2  together with another —OR a2  group on an adjacent L-D group form an —O—. 
     
     
         11 . The therapeutic magnetic nanoparticle of  claim 9 , wherein L 1  is (C 1 -C 6 )alkylene optionally substituted with one or more halogen. 
     
     
         12 . The therapeutic magnetic nanoparticle of  claim 9 , wherein:
 (a) W is NH, X is CR c R d , and n is an integer from 0-5; or   (b) W is NH, X is O, NR e  or S, and n is an integer from 1-5.   
     
     
         13 . The therapeutic magnetic nanoparticle of  claim 9 , wherein each J is C(R b ) 2  and wherein each R b  is independently H or methyl. 
     
     
         14 . The therapeutic magnetic nanoparticle of  claim 9 , wherein Y is O. 
     
     
         15 . The therapeutic magnetic nanoparticle of  claim 9 , wherein the portion of formula I as shown in the formula below: 
       
         
           
           
               
               
           
         
         is selected from; 
       
       
         
           
           
               
               
           
         
       
     
     
         16 . The therapeutic magnetic nanoparticle of  claim 1 , wherein the residue of a therapeutic agent is a residue of a chemotherapeutic agent, an antibiotic agent, an antifungal agent, an antiparasitic agent or an antiviral agent or a prodrug thereof. 
     
     
         17 . The therapeutic magnetic nanoparticle of  claim 1 , wherein the residue of a therapeutic agent is a residue of Cladribine, Azacitidine, Abraxane, Adcetris, Doxorubicin, Afinitor, Vinblastine, Amifostine, Amifostine, Arabinosylcytosine, Cytarabine, Pamidronic Acid, Nelarabine, Bicalutamide, Blemycin, Bortezomib, Cabazitaxel, Irinotecan, Camptothecin, Capecitabine, Temsirolimus, Daunorubicin, Cortisone, Decitabine, Dasatinib, Dexamethasone, Prednisolone, Dexamethasone Acetate, Mitoxantrone, Docetaxel, Hydroxycarbamide, Methylprednisolone, Epirubicin, Curcumin, Estramustine, Eribulin, Etoposide, Everolimus, Raloxifene, Fulvestrant, Floxuridine, Fludarabine, Fluoxymesterone, Gemcitabine, Goserelin, Topotecan, Hydrocortisone, Hydrocortone Phosphate, Idarubicin, Ixabepilone, Vincristine, Leuprolide (Leuprorelin), Megestrol, Vinorelbine, Nelarabine, Pentostatin, Octreotide, Paclitaxel, Streptozotocin, Teniposide, Valrubicin, Vorinostat, Zoledronic Acid Cladribine, Azacitidine, Mecaptopurine, Tioguanine, Actinomycin D, Doxorubicin, Anagrelide, Pemetrexed, Vinblastine, Melphalan, Methotrexate, Amifostine, Aminoglutethimide, Arabinosylcytosine, Cytarabine, Pamidronic Acid, Nelarabine, Axitinib, Bleomycin, Bosutinib, Folinic Acid (Na or Ca), Leucovorin, Vandetanib, Lenalidomide, Daunorubicin, Crizotinib, Dacarbazine, Decitabine, Dasatinib, Mitoxantrone, Eribulin, Erlotinib, Fludarabine, Pralatrexate, Gefitinib, Gemcitabine, Imatinib, Goserelin, Idarubicin, Lapatinib, Vincristine, Leuprolide, Procarbazine, Methotrexate, Mitomycin, Vinorebine, Nelarabine, Nilotinib, Pentostatin, Octreotide, Pazopanib, Sunitinib, Abraxane, Actinomycin D, Doxorubicin, Afinitor, Exemestane, Carfilzomib, Daunorubicin, Cortisone, Prednisolone, Prednisone, Dexamethasone Acetate, Docetaxel, Methylprednisolone, Epirubicin, Curcumin, Everolimus, Fluoxymesterone, Hydrocortisone, Hydrocortone Phosphate, Idarubicin, Ixabepilone, Vincristine, Megestrol, Valrubicin, Mesna, 13-cis-Retinoic Acid, Isotretinoin, Alitretinoin, Melphalan, Tretinoin, Methotrexate, Anastrozole, Bendamustine, Bexarotene, Carmustine, Lomustine, Chlorambucil and Ibritumomab Tiuxetan. 
     
     
         18 . A pharmaceutical composition comprising a therapeutic magnetic nanoparticle as described in  claim 1 , or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. 
     
     
         19 . A method for administering a therapeutic agent to an animal comprising administering the therapeutic magnetic nanoparticle as described in  claim 1  or a pharmaceutically acceptable salt thereof, to the animal. 
     
     
         20 . A method for treating cancer, a bacterial infection, a fungal infection, a parasitic infection or an antiviral infection in an animal in need thereof that has been administered an effective amount of a therapeutic magnetic nanoparticle as described in  claim 1  or a pharmaceutically acceptable salt thereof, comprising providing conditions to release the therapeutic agent from the therapeutic magnetic nanoparticle.