Combination of micheliolide derivatives or nanoparticles with ionizing radiation and checkpoint inhibitors for cancer therapy

Abstract

Nanoparticles comprising micheliolide (MCL) or derivatives thereof, and optionally additional therapeutic agents, such as chemotherapeutic agents, are described. Also described are methods of treating diseases, such as cancer, comprising the use of combinations of MCL or a derivative thereof with X-ray irradiation and/or other therapeutic agents, such as immune checkpoint inhibitors. The use of the combinations can provide synergistic anticancer therapeutic efficacy, for example, as the MCL or derivative thereof can both sensitize cancer cells to therapy and target resistant cancer stem cells (CSCs) for selective cell death.

What is claimed is: 
     
         1 . A composition comprising a nanoparticle and micheliolide (MCL) or a derivative thereof. 
     
     
         2 . The composition of  claim 1 , comprising a derivative of MCL, wherein said derivative is dimethylamino micheliolide (DMAMCL) or a lipid conjugate of MCL. 
     
     
         3 . The composition of  claim 1 , wherein the MCL or the derivative thereof is attached to or sequestered within the nanoparticle. 
     
     
         4 . The composition of  claim 1 , wherein the nanoparticle is selected from the group consisting of a polymeric micelle, a liposome, a dendrimer, an organic polymer-based nanoparticle, a silica-based nanoparticle, a nanoscale coordination polymer, a nanoscale metal-organic framework, and an inorganic nanoparticle. 
     
     
         5 . The composition of  claim 1 , wherein the nanoparticle comprises a core and one or more coating layers or agents covering at least a portion of an outer surface of the core. 
     
     
         6 . The composition of  claim 5 , wherein the core comprises an organic polymer, a silica-based material, a nanoscale coordination polymer, a metal-organic framework, or an inorganic material. 
     
     
         7 . The composition of  claim 5 , 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. 
     
     
         8 . The composition of  claim 5 , wherein the one or more coating agents or layers further comprise a passivating agent, a targeting agent, and/or an imaging agent. 
     
     
         9 . The composition of  claim 5 , wherein the MCL or derivative thereof is attached to or sequestered in the nanoparticle core. 
     
     
         10 . The composition of  claim 5 , wherein the MCL or the derivative thereof is attached to or sequestered in a nanoparticle coating layer. 
     
     
         11 . The composition of  claim 1 , further comprising a chemotherapeutic agent and/or an immunotherapy agent. 
     
     
         12 . The composition of  claim 11 , wherein the chemotherapeutic agent is attached or sequestered in a nanoparticle core or a nanoparticle coating layer. 
     
     
         13 . The composition of  claim 11 , wherein the chemotherapeutic agent is selected from the group consisting of cisplatin, oxaliplatin, or prodrugs thereof; doxorubicin, daunorubicin, docetaxel, mitoxanthrone, paclitaxel, digitoxin, gemcitabine, methotrexate, leucovorin, pemetresed disodium, vinblastine, vincristine, vindesine, cytarabine, azathioprine, melphalan, imitinib, anastrozole, letrozole, carboplatin, etoposide, vinorelbine, and septacidin. 
     
     
         14 . The composition of  claim 11 , wherein the immunotherapy agent is selected from the group consisting of an anti-CD52 antibody, an anti-CD20 antibody, anti-CD47 antibody, an anti-GD2 antibody, polysaccharide K, a cytokine, Alemtuzumab, Ofatumumab, Rituximab, Zevalin, Adcetris, Kadcyla, Ontak, a PD-1 inhibitor, a PD-L1 inhibitor, a CTLA-4 inhibitor, an IDO inhibitor, a CCR7 inhibitor, an OX40 inhibitor, a TIM3 inhibitor, and a LAG3 inhibitor. 
     
     
         15 . The composition of  claim 11 , wherein the immunotherapy agent is attached to or sequestered in a nanoparticle coating layer. 
     
     
         16 . A pharmaceutical composition comprising a composition of  claim 1  and a pharmaceutically acceptable carrier. 
     
     
         17 . A method for treating a disease in a subject in need thereof, the method comprising:
 administering to the subject micheliolide (MCL) or a derivative thereof; and   exposing at least a portion of the subject to ionizing irradiation energy.   
     
     
         18 . The method of  claim 17 , wherein administering the MCL or derivative thereof comprises administering a nanoparticle and/or a nanoscale coordination polymer (NCP) comprising the MCL or derivative thereof. 
     
     
         19 . The method of  claim 17 , wherein the ionizing irradiation energy is X-rays or protons. 
     
     
         20 . The method of  claim 17 , wherein the disease is cancer. 
     
     
         21 . The method of  claim 17 , wherein the disease is selected from the group consisting of a skin cancer, a connective tissue cancer, an adipose cancer, a breast cancer, a head and neck cancer, a lung cancer, a stomach cancer, a pancreatic cancer, an ovarian cancer, a cervical cancer, a uterine cancer, an anogenital cancer, a kidney cancer, a bladder cancer, a colon cancer, a prostate cancer, a central nervous system (CNS) cancer, a retinal cancer, a blood cancer, a neuroblastoma, multiple myeloma, and a lymphoid cancer. 
     
     
         22 . The method of  claim 17 , wherein the method further comprises administering to the subject an additional therapeutic agent or treatment selected from an immunotherapy agent and/or a cancer treatment, wherein the cancer treatment is selected from the group consisting of surgery, chemotherapy, toxin therapy, cryotherapy and gene therapy. 
     
     
         23 . The method of  claim 22 , wherein the additional therapeutic agent or treatment comprises an immunotherapy agent. 
     
     
         24 . The method of  claim 23 , wherein the immunotherapy agent is an immune checkpoint inhibitor. 
     
     
         25 . The method of  claim 24 , wherein the immune checkpoint inhibitor is selected from the group consisting of a PD-1 inhibitor, a PD-L1 inhibitor, a CTLA-4 inhibitor, an IDO inhibitor, a CCR7 inhibitor, an OX40 inhibitor, a TIM3 inhibitor, and a LAG3 inhibitor. 
     
     
         26 . A method for treating a disease in a subject in need thereof, the method comprising:
 administering to the subject micheliolide (MCL) or a derivative thereof; and   administering to the subject one or more additional therapeutic agent or treatment.   
     
     
         27 . The method of  claim 26 , wherein administering to the subject MCL or a derivative thereof comprises administering to the subject a nanoparticle comprising MCL or a derivative thereof. 
     
     
         28 . The method of  claim 26 , wherein the one or more additional therapeutic agent or treatment agent is selected from a chemotherapeutic agent, an immune therapy agent, radiotherapy, surgery, chemotherapy, toxin therapy, cryotherapy and gene therapy. 
     
     
         29 . The method of  claim 26 , wherein the disease is cancer. 
     
     
         30 . The method of  claim 26 , wherein the disease is selected from the group consisting of a skin cancer, a connective tissue cancer, an adipose cancer, a breast cancer, a head and neck cancer, a lung cancer, a stomach cancer, a pancreatic cancer, an ovarian cancer, a cervical cancer, a uterine cancer, an anogenital cancer, a kidney cancer, a bladder cancer, a colon cancer, a prostate cancer, a central nervous system (CNS) cancer, a retinal cancer, a blood cancer, a neuroblastoma, multiple myeloma, and a lymphoid cancer. 
     
     
         31 . The method of  claim 26 , wherein the one or more additional therapeutic agent or treatment comprises an immunotherapeutic agent. 
     
     
         32 . The method of  claim 31 , wherein the immunotherapeutic agent is an immune checkpoint inhibitor. 
     
     
         33 . The method of  claim 31 , wherein the one or more additional therapeutic agent or treatment further comprises radiotherapy. 
     
     
         34 . The method of  claim 33 , wherein the one or more additional therapeutic agent or treatment agent further comprises one or more of surgery, toxin therapy, cryotherapy and gene therapy. 
     
     
         35 . The method of  claim 26 , wherein the one or more additional treatment agent comprises chemotherapy.