Nanovectors For Brain Tumor Diagnosis And Treatment

描述(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，它可以作为成像标记物、靶向剂和药物输送载体，用于脑癌的非侵入性诊断、分期、治疗和治疗反应评估等。在这项拟议的研究中，工程化纳米载体的有效性将在脑癌、髓母细胞瘤中得到验证。脑肿瘤治疗目前受到严重限制，因为无法非侵入性地诊断和分期疾病，并监测受影响个体的治疗反应。像所有的脑癌一样，髓母细胞瘤很难治疗，因为可能有神经毒性并发症，肿瘤治疗抵抗，以及潜在治疗药物在血脑屏障上的流动性有限。提出的纳米载体将由一个超顺磁性氧化铁核心和一个可生物降解的聚合物外壳组成，包裹或连接到肿瘤靶向配体和siRNA治疗剂上。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，以及安全加载和有效输送生物的能力。该纳米载体将特异而有效地靶向髓母细胞瘤，诱导靶细胞的内吞作用，选择性地阻断基因表达，并在组织内长期停留。拟议研究的具体目的是：(1)合成肿瘤靶向的核壳纳米结合物并验证其增强磁共振对比度的能力；(2)通过将siRNA包裹在Aim 1中开发的纳米结合物中来合成纳米载体，并展示siRNA在9L/LacZ细胞中的传递以及随后对报告基因的抑制；(3)针对髓母细胞瘤增殖所必需的基因Nmyc的siRNA载体，以及使用小鼠髓母细胞瘤模型评估纳米载体载体Nmyc siRNA在髓母细胞瘤细胞中的疗效。这种纳米载体被设计成能够针对起源于神经外胚层的原发癌症，因此研究结果可以推广到治疗其他癌症，如前列腺癌和乳腺癌以及髓母细胞瘤。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、预后和有效治疗具有重要意义，从而为消除儿童脑癌患者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.