The long-term goal of the proposed research is to develop a non-viral nanovector that can serve as an imaging marker, targeting agent, and drug delivery carrier for non-invasive diagnosis, staging, treatment, and therapy-response assessment of brain cancers among others. In this proposed research, the effectivity of the engineered nanovector will be demonstrated with the brain cancer, medulloblastoma. Brain tumor therapy is currently severely limited by the inability to non-invasively diagnose and stage disease, and monitor the response to treatment in affected individuals. Like all cancers of the brain, medulloblastoma is difficult to treat because of possible neurotoxicity complications, tumor treatment-resistance, and limited mobility of potential therapeutics across the blood-brain barrier. The proposed nanovector will be composed of a superparamagnetic iron oxide core and a biodegradable polymeric shell, encapsulating or conjugated to tumor targeting ligands and siRNA therapeutic agents. The nanovector is designed to maintain high dispersity and biostability, prolonged blood circulation time, and the ability to safely load and effectively deliver biologies. The nanovector will specifically and efficiently target medulloblastoma, induce endocytosis in the targeted cells, selectively block gene expression, and engage in prolonged residence inside the tissue.
Specific aims of the proposed research are to: (1) synthesize the tumor-targeted core-shell nanoconjugate and validate its MR contrast enhancement capabilities;(2) synthesize the nanovector by encapsulating siRNA in the nanoconjugate developed in aim 1 and demonstrate siRNA delivery and subsequent suppression of the reporter gene in 9L/LacZ cells;and (3) deliver siRNA against Nmyc, a gene necessary for medulloblastoma proliferation, and evaluate the efficacy of nanovector-delivered Nmyc siRNA in medulloblastoma cells in vitro and in vivo using mouse intracranial models of medulloblastoma. The nanovector is designed to be able to target primary cancers of neuroectodermal origin, and thus the research findings can be generalized to treat other cancers such as such as prostate and breast cancers in addition to medulloblastoma. We anticipate that the technology based on this biodegradable, nontoxic nanovector will have significant implications for the diagnosis, prognosis, and effective treatment of medulloblastoma, and consequently offer a new avenue for eliminating the suffering and death of children afflicted with brain cancer.
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