Nanovectors For Brain Tumor Diagnosis And Treatment

描述（由申请人提供）：拟议研究的长期目标是开发一种非病毒纳米载体，可作为成像标记物、靶向剂和药物递送载体，用于脑癌等的非侵入性诊断、分期、治疗和治疗反应评估。在这项拟议的研究中，工程纳米载体的有效性将被证明与脑癌，髓母细胞瘤。脑肿瘤治疗目前受到严重限制，因为无法进行非侵入性诊断和疾病分期，以及监测受影响个体对治疗的反应。像所有脑癌一样，髓母细胞瘤很难治疗，因为可能存在神经毒性并发症、肿瘤治疗耐药性以及潜在治疗方法通过血脑屏障的移动性有限。所提出的纳米载体将由超顺磁性氧化铁核和可生物降解的聚合物外壳组成，包封或偶联肿瘤靶向配体和siRNA治疗剂。纳米载体旨在保持高分散性和生物稳定性，延长血液循环时间，以及安全加载和有效递送生物的能力。该纳米载体将特异有效地靶向成神经管细胞瘤，诱导靶细胞内吞作用，选择性阻断基因表达，并在组织内长期停留。本研究的具体目的是：(1)合成肿瘤靶向核-壳纳米缀合物并验证其MR增强能力；(2)通过将siRNA包封在aim 1中开发的纳米偶联物中合成纳米载体，并在9L/LacZ细胞中证明siRNA的传递和随后的报告基因抑制；(3)传递siRNA对抗髓母细胞瘤增殖所必需的Nmyc基因，并利用小鼠颅内髓母细胞瘤模型，在体外和体内评估纳米载体传递的Nmyc siRNA对髓母细胞瘤细胞的作用。纳米载体被设计为能够靶向神经外胚层起源的原发性癌症，因此研究结果可以推广到除髓母细胞瘤外的其他癌症，如前列腺癌和乳腺癌。我们预计，基于这种可生物降解、无毒的纳米载体的技术将对髓母细胞瘤的诊断、预后和有效治疗产生重大影响，从而为消除脑癌患儿的痛苦和死亡提供新的途径。

DESCRIPTION (provided by applicant): 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.