Tumor-targeted silencing of Bcl-2/Bcl-xL by the self-assembled siRNA-nanovectors

通过自组装 siRNA 纳米载体对 Bcl-2/Bcl-xL 进行肿瘤靶向沉默

• 批准号: 7115416
• 负责人: Liang Xu
• 金额: $ 26.63万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-27 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7115416
• 关键词: human; neoplasm /cancer

DESCRIPTION (provided by applicant): Anti-apoptotic proteins Bcl-2 and Bcl-xL are overexpressed in many cancers and contribute to tumor initiation, progression and resistance to therapy. Molecular modulation of Bcl-2/Bcl-xL represents a promising strategy for overcoming the resistance to apoptosis induced by current cancer therapy. The potent, sequence-specific gene silencing by small interfering RNA (siRNA) has become a powerful tool in cancer research and holds significant potential as novel molecular therapy for cancer. However, delivering the siRNA-based therapeutics efficiently and specifically to tumor and its metastases remains a great challenge. We have developed a tumor-specific, ligand-targeting, self-assembled DNA-nanovector system which shows promising efficiency and specificity in targeted delivery of various genes and anti-sense oligonucleotides to human cancer, with limited effect on normal tissues (US Patent No. 6,749,863). We have also designed siRNAs for human Bcl-2 and Bcl-xL that can potently knock-down Bcl-2/Bcl-xL leading to extensive cancer cell death (US Patent pending). We propose to use our patented nanovector system to develop siRNA-based therapeutics for tumor- targeted silencing of Bcl-2/Bcl-xL. We will test two inter-related hypotheses: (1) Tumor-targeted delivery of siRNA will efficiently silence Bcl-2/Bcl-xL, and induce apoptosis in human cancer cells that depend on Bcl- 2/Bcl-xL for survival; (2) Knock-down of the anti-apoptotic Bcl-2/Bcl-xL in turn will overcome resistance and restore sensitivity of cancer cells to chemo/radiotherapy. Our long-term goal is to develop the tumor- targeting siRNA-nanovectors as novel molecular therapy targeting Bcl-2/Bcl-xL for human cancers with Bcl- 2/Bcl-xL over-expression. To test our hypothesis, we propose to carry out three SPECIFIC AIMS: AIM 1: To prepare and optimize the siRNA-nanovectors for efficient siRNA delivery to human tumors in vitro and in vivo; AIM 2: To investigate in vitro anti-tumor activities and the mechanism of action of siRNA-nanovectors in combination with chemo/radiotherapy; AIM 3: To investigate the in vivo therapeutic potential of Bcl-2/Bcl-xL siRNA-nanovectors in nude mouse xenograft models of human cancers with high levels of Bcl-2/Bcl-xL Combining siRNA-based Bcl-2/Bcl-xL molecular therapy with conventional therapy would improve the efficacy and overcome the resistance to current cancer treatment, especially for tumor metastasis, in which Bcl-2/Bcl-xL protein is overexpressed and for which conventional therapy is not very effective. Successfully carried out, our studies will provide proof-of-concept that siRNA can be delivered by the self-assembled nanovectors for tumor-targeted silencing of the genes critical for cancer progression and resistance.

描述（由申请人提供）：抗凋亡蛋白Bcl-2和Bcl-XL在许多癌症中过表达，并有助于肿瘤的启动，进展和对治疗的耐药性。 Bcl-2/bcl-XL的分子调节是克服当前癌症治疗引起的对凋亡的抵抗力的有前途的策略。小型干扰RNA（siRNA）的有效的，序列特异性的基因沉默已成为癌症研究的强大工具，并具有作为癌症的新分子治疗的巨大潜力。但是，将基于siRNA的治疗剂有效地，专门针对肿瘤及其转移仍然是一个巨大的挑战。我们已经开发了一种肿瘤特异性的，靶向配体的，自组装的DNA-NANANOVECTOR系统，该系统在针对性递送各种基因和抗敏感性寡核苷酸对人类癌症的靶向输送方面显示出有希望的效率和特异性，对正常组织的影响有限（美国专利号6,749,863）。我们还为人类BCL-2和BCL-XL设计了siRNA，这些siRNA可以有效地击倒Bcl-2/bcl-XL导致广泛的癌细胞死亡（美国专利待处理）。我们建议使用我们的专利纳米动物系统开发基于siRNA的治疗剂，以靶向BCL-2/BCL-XL的肿瘤沉默。我们将检验两个相互关联的假设：（1）siRNA的肿瘤递送将有效地沉默Bcl-2/bcl-XL，并诱导依赖Bcl-2/bcl-XL的人类癌细胞中的凋亡，以生存； （2）抗凋亡的Bcl-2/bcl-XL反过来敲击将克服癌细胞对化学/放射疗法的敏感性。我们的长期目标是开发靶向siRNA-nanovectors作为靶向Bcl-2/bcl-XL的新型分子疗法，用于BCl-2/bcl-XL过表达的人类癌症。为了检验我们的假设，我们建议执行三个具体目标：目标1：准备和优化siRNA-NANANOVECTOR，以在体外和体内有效地递送到人类肿瘤；目标2：研究体外抗肿瘤活性和siRNA-NANANONOVECTOR与化学/放射疗法结合使用的作用机理；目的3：研究在裸小鼠异种移植物模型中，Bcl-2/bcl-XL siRNA-nanovector的体内治疗潜力，具有高水平的Bcl-2/bcl-XL结合基于siRNA的Bcl-2/bcl-XL分子治疗的人类癌模型，将其用于效率和癌症治疗，特别是在癌症治疗中，尤其是在癌症治疗中，尤其是在癌症治疗方Bcl-2/bcl-XL蛋白过表达，并且常规疗法不是很有效。成功进行的研究将提供概念证明，即siRNA可以由自组装的纳米分离器传递，以实现对癌症进展至关重要的肿瘤靶向沉默的沉默。