Nanoscale carriers for the delivery or co-delivery of chemotherapeutics, nucleic acids and photosensitizers

Abstract

Nanoscale coordination polymer nanoparticles for the co-delivery of multiple therapeutic agents are described. The multiple therapeutic agents can include a combination of different chemotherapeutic agents, a combination of one or more chemotherapeutic agents and one or more nucleic acids, such as small interfering RNA (siRNA) or microRNA, a combination of one or more chemotherapeutic agents and a photosensitizer (i.e., for use in photodynamic therapy), or a plurality of different siRNAs. Pharmaceutical formulations including the nanoparticles, methods of using the nanoparticles to treat cancer, and methods of making the nanoparticles are also described.

1 - 43 . (canceled) 
     
     
         44 . A nanoscale particle for co-delivery of a plurality of therapeutic agents, said nanoscale particle comprising:
 a core comprising a metal-organic matrix material, optionally wherein the metal-organic matrix material comprises a coordination polymer; and   a plurality of therapeutic agents, wherein said plurality of therapeutic agents comprises at least one chemotherapeutic agent and at least one photosensitizer.   
     
     
         45 . The nanoscale particle of  claim 44 , wherein the at least one chemotherapeutic agent is a non-nucleic acid chemotherapeutic agent incorporated in the metal-organic matrix material core, optionally wherein the non-nucleic acid chemotherapeutic agent is incorporated in the metal-organic matrix material core via a covalent or coordination bond. 
     
     
         46 . The nanoscale particle of  claim 44 , wherein the chemotherapeutic agent is selected from the group consisting of cisplatin or oxaliplatin prodrugs, gemcitabine, methotrexate, leucovorin, pemetrexed disodium, doxorubicin, vinblastine, vincristine, vindesine, cytarabine, azathioprine, melphalan, imatinib, anastrozole, letrozole, carboplatin, paclitaxel, docetaxel, etoposide, and vinorelbine. 
     
     
         47 . The nanoscale particle of  claim 44 , wherein the chemotherapeutic agent is a bisphosphonate cisplatin or oxaliplatin prodrug and the metal-organic matrix material core comprises a metal bisphosphonate coordination polymer comprising a multivalent metal ion and said bisphosphonate cisplatin or oxaliplatin prodrug. 
     
     
         48 . The nanoscale particle of  claim 47 , wherein the multivalent metal ion is selected from the group consisting of Ca 2+ , Mg 2+ , Mn 2+ , Zn 2+ , and combinations thereof. 
     
     
         49 . The nanoscale particle of  claim 47 , wherein the bisphosphonate cisplatin or oxaliplatin prodrug is a bisphosphonate ester of cis, cis-trans-[Pt(NH 3 ) 2 Cl 2 (OH) 2 ] and/or wherein the multivalent metal ion is Zn 2+ . 
     
     
         50 . The nanoscale particle of  claim 44 , wherein the nanoscale particle comprises one or more coating layers covering at least a portion of the outer surface of the metal-organic matrix material core, wherein the one or more coating agents or layers are selected from a metal oxide, a polymer, a single lipid layer, a lipid bilayer, and combinations thereof. 
     
     
         51 . The nanoscale particle of  claim 50 , wherein the photosensitizer is covalently attached to a coating layer or layers. 
     
     
         52 . The nanoscale particle of  claim 51 , wherein the metal-organic matrix material core is coated with a lipid bilayer or lipid single layer comprising a pyrolipid, wherein said pyrolipid is a lipid covalently attached to a porphyrin or a derivative or analog thereof. 
     
     
         53 . The nanoscale particle of  claim 52 , wherein the lipid bilayer or lipid single layer further comprises one or more of cholesterol, 1,2-distearoyl-sn-glycero-3-phosphoethanolamine (DSPE), 1,2-Distearoyl-sn-glycero-3-phosphocholine (DSPC) 1,2-dioleoyl-3-trimethylammonium propane (DOTAP), 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), 1,2-dioleoyl-sn-glycero-3-phosphate sodium salt (DOPA), and pegylated-DSPE. 
     
     
         54 . The nanoscale particle of  claim 44 , wherein the nanoscale particle has a diameter between about 90 nm and about 180 nm. 
     
     
         55 . A pharmaceutical formulation comprising a nanoscale particle of  claim 44  and a pharmaceutically acceptable carrier. 
     
     
         56 . A method of treating cancer in a subject in need thereof, the method comprising administering to the subject a composition comprising a nanoscale particle of  claim 44 , and irradiating the subject or a treatment area of the subject with radiation having a wavelength suitable to activate the photosensitizer. 
     
     
         57 . The method of  claim 56 , wherein the at least one chemotherapeutic agent is a cisplatin or oxaliplatin prodrug. 
     
     
         58 . The method of  claim 56 , wherein the cancer is a head and neck cancer, optionally wherein the head and neck cancer is a cisplatin resistant head and neck cancer. 
     
     
         59 . A method of preparing a nanoscale particle of  claim 44 , wherein the method comprises:
 (a) contacting a microemulsion comprising a metal ion with a microemulsion comprising a bisphosphonate, optionally wherein the bisphosphonate is a cisplatin or oxaliplatin prodrug, thereby forming a metal bisphosphonate coordination polymer nanoparticle; and   (b) dispersing the nanoparticle from (a) in a solution comprising a pyrolipid to form a pyrolipid-coated nanoparticle.   
     
     
         60 . The method of  claim 59 , wherein the solution comprising the pyrolipid further comprises one or more additional lipid coating components, optionally, wherein the solution comprising the pyrolipid further comprises cholesterol, 1,2-Distearoyl-sn-glycero-3-phosphocholine (DSPC), and pegylated 1,2-distearoyl-sn-glycero-3-phosphoethanolamine (DSPE).