Encapsulated diagnostics and therapeutics in nanoparticles - conjugated to tropic cells and methods for their use

Abstract

A therapeutic or diagnostic delivery vehicle is provided. The delivery vehicle may include one or more particles, such as microparticles, nanoparticles and stimuli-responsive particles, conjugated to a tropic cell that targets at least one pathological entity or site. In addition. a pharmaceutical composition is provided. The pharmaceutical composition may include, among other things, a particle conjugated to a tropic cell such as those discussed above and at least one diagnostic or therapeutic agent, such as those described herein. In some aspects, the tropic cell may target at least one pathological entity or site. Further, methods for diagnosing, monitoring or treating a pathological condition in a subject are provided. Such methods may include administering a therapeutically effective amount of the pharmaceutical composition to a subject.

What is claimed is: 
     
         1 . A therapeutic or diagnostic delivery vehicle comprising a particle conjugated to a tropic cell that targets at least one pathological entity or site. 
     
     
         2 . The delivery vehicle of  claim 1 , wherein the tropic cell is a neural stem cell, a mesenchymal stem cell, a mesenchymal stromal cell, a hematopoietic stem cell, an adoptively transferred T-lymphocyte, a macrophage, a liver stem cell, or an embryoid body. 
     
     
         3 . The delivery vehicle of  claim 1 , wherein the tropic cell is a genetically modified neural stem cell. 
     
     
         4 . The delivery vehicle of  claim 3 , wherein the neural stem cell expresses cytosine deaminase, v-myc, or both cytosine deaminase and v-myc. 
     
     
         5 . The delivery vehicle of  claim 1 , wherein the tropic cell targets at least one pathological entity or site selected from the group consisting of solid tumors, benign tumors, malignant tumors, primary tumors, metastatic tumors, microsatellite tumors, glioma, medulloblastoma, inaccessible hypoxic tumor regions, brain tumors, stroke, head injury, dopaminergic dysfunction, brain tumors and amyloid plaques, amyotrophic lateral sclerosis, spinal chord dysfunction, hepatic tumors, lung tumors, breast tumors, glioma, ovarian carcinoma, hypoxia and ischemia, subcutaneous wounds, radiation damage lung, thymus, bone, skin, cerebellum, and gastrointestinal tract, liver, bone marrow, bone, skin, brain, spleen, myocardial infarction, subarachnoidal space for autoimmune diseases, gastric glands, gastric cancer, Kaposi's sarcoma, brain cancer, multiple sclerosis, chronic inflammation, chronic wounds, tissue damage, inflamed central nervous system, muscular dystrophy, osteogenesis imperfect, Glioma, brain tumors, lung tumors, prostate tumors, breast tumors, brain tumors, breast tumors, prostate tumor, infections, bacterial infections, melanoma, ovarian cancer, breast carcinoma, Hodgkin's lymphoma, and lung cancer, graft-versus-host disease, and hepatocellular carcinoma. 
     
     
         6 . The delivery vehicle of  claim 1 , wherein the particle is a microparticle or a nanoparticle. 
     
     
         7 . The delivery vehicle of  claim 1 , wherein the particle comprises gold, poly(lactic-co-glycolic) acid, poly(ethylene)glycol-poly(lactic-co-glycolic) acid, polystyrene, or silica. 
     
     
         8 . The delivery vehicle of  claim 1 , wherein the particle is a stimuli-responsive particle. 
     
     
         9 . The delivery vehicle of  claim 1 , wherein the particle comprises: (i) methyl ether polyethylene glycol conjugated to a poly(β-amino ester); (ii) poly(histidine)-β-polyethylene glycol; (iii) polyethylene glycol conjugated to a pH-labile crosslinker comprising a moiety selected from the group consisting of ester, hydrazone, carboxy dimethylaleic anhydride, orthoester, imine, beta-thiopropianoate, vinylether, and phophoramididate; (iv) a thiolated heparin nanogel; (v) polyethylene oxide-beta-aspartic acid; or (vi) a polyKetal. 
     
     
         10 . The delivery vehicle of  claim 1 , further comprising a chemotherapeutic agent encapsulated by the particle. 
     
     
         11 . The delivery vehicle of  claim 10 , wherein the chemotherapeutic agent is temozolomide, carboplatin, cyclophosphamide, docetaxel, doxorubicin, gemcitabine, methotrexate, paclitaxel, sunitinib, cisplatin, 5-fluorouracil, 7-ethyl-10-hydroxycamptothecin, or a combination thereof. 
     
     
         12 . The delivery vehicle of  claim 1 , further comprising a diagnostic agent; wherein the diagnostic agent is a superparamagnetic iron-oxide nanoparticle, fluorine-19, a long organic chain labeled with fluorine-19, a CdT luminescent compound, gold, quantum dots, a radioisotope, or a material that is activated by thermal neutrons. 
     
     
         13 . The delivery vehicle of  claim 1 , wherein the particle is covalently conjugated to the surface of a genetically modified neural stem cell; and wherein the covalent conjugation is a result of a reaction between the functional groups on the surface of the particle and the genetically modified neural stem cell, wherein the functional groups are azide and phosphine; carbonyl and hydrazide; thiol and maleimide; or amine and N-hydroxysuccinimide ester, and wherein the particle comprises poly(lactic-co-glycolic) acid, poly(ethylene)glycol-poly(lactic-co-glycolic) acid, polystyrene, or silica 
     
     
         14 . A pharmaceutical composition comprising a particle conjugated to a tropic cell and at least one diagnostic or therapeutic agent. 
     
     
         15 . The pharmaceutical composition of  claim 14 , wherein the tropic cell is a neural stem cell, a mesenchymal stem cell, a mesenchymal stromal cell, a hematopoietic stem cell, an adoptively transferred T-lymphocyte, a macrophage, a liver stem cell or an embryoid body. 
     
     
         16 . The pharmaceutical composition of  claim 14 , wherein the particle is a stimuli-responsive particle. 
     
     
         17 . The pharmaceutical composition of  claim 14 , wherein the particle is conjugated to at least one therapeutic agent selected from the group consisting of temozolomide, carboplatin, cyclophosphamide, docetaxel, doxorubicin, gemcitabine, methotrexate, paclitaxel, sunitinib, Cisplatin, 5-fluorouracil, 7-ethyl-10-hydroxycamptothecin (SN-38), or a combination thereof. 
     
     
         18 . The pharmaceutical composition of  claim 14 , wherein the particle is conjugated to at least one diagnostic agent selected from the group consisting of a superparamagnetic iron-oxide nanoparticle, fluorine-19, a long organic chain labeled with fluorine-19, a CdT luminescent compound, gold, quantum dots, a radioisotope, or a material that is activated by thermal neutrons. 
     
     
         19 . A method for diagnosing, monitoring, or treating a pathological condition in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition of  claim 14 . 
     
     
         20 . The method of  claim 19 , wherein the pathological condition is a cancer, amyotrophic lateral sclerosis, hypoxia, ischemia, muscular dystrophy, osteogenesis imperfect, graft-versus-host disease, subcutaneous wounds, radiation sickness, a viral infection, a bacterial infection, a chronic inflammatory or proliferative disease, a chronic wound, Kaposi's sarcoma, an autoimmune disease, inflammation related to tissue damage, wound or injury, dopaminergic dysfunction, Alzheimer's disease, or spinal chord dysfunction.