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，用于非侵入性诊断、分期、治疗和治疗-脑癌的反应评估等。在这项拟议的研究中，工程纳米载体的有效性将在脑癌髓母细胞瘤中得到证明。脑肿瘤治疗目前受到严重限制，无法非侵入性地诊断和分期疾病，并监测受影响个体对治疗的反应。像所有的脑部癌症一样，髓母细胞瘤很难治疗，因为可能的神经毒性并发症，肿瘤治疗抗性，以及潜在治疗剂穿过血脑屏障的有限流动性。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壳组成，封装或缀合到肿瘤靶向配体和siRNA治疗剂。纳米载体的设计目的是保持高分散性和生物稳定性，延长血液循环时间，以及安全装载和有效输送生物制剂的能力。纳米载体将特异性且有效地靶向髓母细胞瘤，诱导靶细胞中的内吞作用，选择性地阻断基因表达，并参与组织内的长期驻留。所提出的研究的具体目标是：（1）合成肿瘤靶向核-壳纳米缀合物并验证其MR对比度增强能力;（2）通过将siRNA包封在目标1中开发的纳米缀合物中来合成纳米载体，并证明siRNA递送和随后在9 L/LacZ细胞中对报告基因的抑制;和（3）递送针对Nmyc（成神经管细胞瘤增殖所必需的基因）的siRNA，并使用成神经管细胞瘤的小鼠颅内模型在体外和体内评价纳米载体递送的Nmyc siRNA在成神经管细胞瘤细胞中的功效。纳米载体被设计成能够靶向神经外胚层起源的原发性癌症，因此研究发现可以推广到治疗其他癌症，例如除了髓母细胞瘤之外的前列腺癌和乳腺癌。我们预计，基于这种可生物降解，无毒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，从而为消除患有脑癌的儿童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.