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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

基本信息

批准号：
7906658
负责人：
Liang Xu
金额：
$ 0.52万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-09-27 至 2010-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7906658
关键词：
Animal Model Antibodies Antisense Oligonucleotides Apoptosis Apoptotic BCL-Xs protein Bioluminescence Cancer cell line Cell Death Charge Clinical Research Development Doctor of Medicine Doctor of Philosophy Double-Stranded RNA Drug resistance FDA approved Failure Folate Gene Expression Gene Silencing Genes Goals Human Image In Vitro Legal patent Ligands Malignant Neoplasms Membrane Modeling Molecular Molecular Mechanisms of Action Molecular Target Mus Nanostructures Neoplasm Metastasis Normal Cell Normal tissue morphology Nude Mice Oncogenes Pharmaceutical Preparations Prostatic Neoplasms Proteins RNA Interference Radiation Radiation therapy Research Personnel Resistance Signal Transduction Pathway Small Interfering RNA Specificity Structure Surface System TP53 gene Testing Therapeutic Toxic effect Transfection Transferrin Transferrin Receptor Treatment Efficacy Validation Virion Xenograft Model anticancer research base cancer cell cancer therapy chemotherapeutic agent chemotherapy conventional therapy design folate-binding protein gene therapy human disease improved in vivo knock-down mouse model nanoparticle nanovector novel novel therapeutics overexpression prevent programs receptor success targeted delivery therapy resistant tool tumor tumor initiation tumor progression tumor specificity

项目摘要

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 在许多癌症中过度表达，并有助于肿瘤的发生、进展和对治疗的抵抗。 Bcl-2/Bcl-xL 的分子调节代表了克服当前癌症治疗诱导的细胞凋亡抵抗的一种有前途的策略。通过小干扰 RNA (siRNA) 实现的有效序列特异性基因沉默已成为癌症研究的有力工具，并具有作为癌症新型分子疗法的巨大潜力。然而，高效、特异地针对肿瘤及其转移瘤提供基于 siRNA 的治疗方法仍然是一个巨大的挑战。我们开发了一种肿瘤特异性、配体靶向、自组装 DNA 纳米载体系统，该系统在将各种基因和反义寡核苷酸靶向递送至人类癌症方面显示出良好的效率和特异性，而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，可以有效敲低 Bcl-2/Bcl-xL，从而导致广泛的癌细胞死亡（美国专利正在申请中）。我们建议使用我们的专利纳米载体系统来开发基于 siRNA 的疗法，用于肿瘤靶向沉默 Bcl-2/Bcl-xL。我们将测试两个相互关联的假设：(1) siRNA 的肿瘤靶向递送将有效沉默 Bcl-2/Bcl-xL，并诱导依赖 Bcl-2/Bcl-xL 生存的人类癌细胞凋亡； (2) 抗凋亡Bcl-2/Bcl-xL的敲低依次将克服耐药性并恢复癌细胞对化疗/放疗的敏感性。我们的长期目标是开发肿瘤靶向 siRNA 纳米载体，作为针对 Bcl-2/Bcl-xL 过度表达的人类癌症的新型分子疗法。为了检验我们的假设，我们建议实现三个具体目标：目标 1：制备和优化 siRNA 纳米载体，以便在体外和体内有效地将 siRNA 递送至人类肿瘤；目的2：研究siRNA纳米载体联合放化疗的体外抗肿瘤活性及作用机制；目标 3：研究 Bcl-2/Bcl-xL siRNA 纳米载体在高水平 Bcl-2/Bcl-xL 人类癌症裸鼠异种移植模型中的体内治疗潜力将基于 siRNA 的 Bcl-2/Bcl-xL 分子治疗与常规治疗相结合将提高疗效并克服对当前癌症治疗的耐药性，特别是对于肿瘤转移，其中 Bcl-2/Bcl-xL 蛋白过度表达，常规疗法对此不太有效。如果成功进行，我们的研究将提供概念证明，证明 siRNA 可以通过自组装纳米载体传递，用于肿瘤靶向沉默对癌症进展和抵抗至关重要的基因。