Tumor targeted RNAi by novel nanovectors for molecular therapy of prostate cancer

新型纳米载体肿瘤靶向RNAi用于前列腺癌的分子治疗

• 批准号: 7475129
• 负责人: Liang Xu
• 金额: $ 12.77万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-01 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7475129
• 关键词: Animal Model; Antibodies; Antisense Oligonucleotides; Apoptosis; Apoptotic; BCL-Xs protein; Biological; Cell Death; Charge; Clinical Research; Development; Double-Stranded RNA; Drug Formulations; Drug resistance; Gene Delivery; Gene Expression; Gene Silencing; Gene Targeting; Genes; Goals; Human; In Vitro; Legal patent; Ligands; Malignant Neoplasms; Malignant neoplasm of prostate; Mediating; Membrane; Molecular; Molecular Target; Nanostructures; Neoplasm Metastasis; Normal Cell; Normal tissue morphology; Nude Mice; Oncogenes; Phase I Clinical Trials; Pilot Projects; Plasmids; Prostate; Prostate Cancer therapy; Prostatic Neoplasms; Protein Overexpression; Proteins; RNA; RNA Interference; Radiation therapy; Resistance; Small Interfering RNA; Specificity; Structure; Surface; System; Testing; Therapeutic; Transferrin; Transferrin Receptor; Treatment Efficacy; United States Food and Drug Administration; Validation; Viral; Virion; Xenograft Model; anticancer research; base; cancer cell; cancer therapy; concept; design; gene therapy; human disease; improved; in vivo; knock-down; nanoparticle; nanovector; novel; novel therapeutics; receptor; size; small hairpin RNA; success; targeted delivery; therapy resistant; tool; tumor; tumor initiation; tumor progression

DESCRIPTION (provided by applicant): 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 prostate cancer and its metastases remains a great challenge. We have developed a tumor-specific, ligand-targeting, self-assembled DNA-nanovector system for prostate cancer gene delivery. The nanovectors show promising efficiency and specificity in targeted delivery of various genes and anti-sense oligonucleotides to human prostate cancer, with limited effect on normal tissues (US Patent No. 6,749,863). This nanovector system is now in Phase I clinical trial for non-viral p53 gene therapy. The objective of this pilot project proposal is to explore the feasibility of using our patented nanovector system for tumor-targeted delivery of siRNA-based therapeutics for human prostate cancer. In our preliminary studies, we have designed siRNAs for human Bcl-2 and Bcl-xL that can potently knock-down Bcl-2/Bcl-xL up to 95%, leading to extensive cancer cell death (US Patent pending). We propose to use Bcl-2/Bcl-xL siRNA to test two inter-related hypotheses: (1) the self-assembled nanovectors can selectively deliver siRNA to prostate cancer and efficiently silence the target Bcl-2/Bcl-xL; (2); Knock-down of the anti-apoptotic Bcl-2/Bcl-xL will induce apoptosis in human prostate cancer cells that depend on Bcl-2/Bcl-xL for survival, thus overcome resistance and restore sensitivity of prostate cancer cells to chemo/radiotherapy. Our long-term goal is to develop the tumor-targeting siRNA-nanovectors as novel molecular therapy for prostate cancer. To test our hypothesis, we propose to carry out two SPECIFIC AIMS: AIM 1: To prepare and optimize the nanovectors for efficient RNA interference for human prostate cancer in vitro and in vivo; AIM 2: To investigate anti-tumor activities and target validation of Bcl-2/Bcl-xL siRNA-nanovectors in nude mouse xenograft models of human prostate cancer with high levels of Bcl-2/Bcl-xL. Anti-apoptotic proteins Bcl-2 and Bcl-xL are overexpressed in most of prostate cancer and contribute to prostate 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. Combining siRNA-based 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 study will provide proof-of-concept that siRNA can be delivered by the self-assembled nanovectors for tumor-targeted RNA interference of the genes critical for prostate cancer progression and resistance. Combining tumor-targeted RNA interference of Bcl-2/Bcl-xL with conventional therapy would improve the efficacy and overcome the drug resistance to current cancer treatment, especially for 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 prostate tumor progression and resistance. The success of tumor-targeted RNA interference by nanovectors in vivo will have a major impact on the development of siRNA-based novel therapeutics for various molecular targets of human prostate cancer.

描述（由申请人提供）：小干扰RNA （siRNA）有效的序列特异性基因沉默已成为癌症研究的有力工具，并具有作为新型癌症分子治疗的巨大潜力。然而，将基于sirna的治疗方法有效和特异性地用于前列腺癌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、配体靶向、自组装的dna纳米载体系统，用于前列腺癌基因的传递。纳米载体在靶向递送各种基因和反义寡核苷酸到人类前列腺癌方面显示出良好的效率和特异性，对正常组织的影响有限（美国专利号：6,749,863）。这种纳米载体系统目前正处于非病毒p53基因治疗的I期临床试验中。该试点项目提案的目的是探索使用我们的专利纳米载体系统用于肿瘤靶向递送基于sirna的人类前列腺癌治疗方法的可行性。在我们的初步研究中，我们设计了针对人类Bcl-2和Bcl-xL的sirna，可以有效地敲除Bcl-2/Bcl-xL高达95%，导致广泛的癌细胞死亡（美国专利正在申请中）。我们提出使用Bcl-2/Bcl-xL siRNA来验证两个相互关联的假设：(1)自组装纳米载体可以选择性地将siRNA传递到前列腺癌，并有效地沉默靶点Bcl-2/Bcl-xL；(2);抑制抗凋亡的Bcl-2/Bcl-xL可诱导依赖Bcl-2/Bcl-xL生存的人前列腺癌细胞发生凋亡，从而克服耐药，恢复前列腺癌细胞对化疗/放疗的敏感性。我们的长期目标是开发肿瘤靶向sirna纳米载体作为前列腺癌的新型分子疗法。为了验证我们的假设，我们提出了两个特定的目标：目标1：制备和优化纳米载体，在体外和体内有效地干扰人类前列腺癌的RNA；目的2：研究Bcl-2/Bcl-xL sirna纳米载体在高水平Bcl-2/Bcl-xL人前列腺癌裸鼠异种移植模型中的抗肿瘤活性和靶标验证。抗凋亡蛋白Bcl-2和Bcl-xL在大多数前列腺癌中过表达，参与前列腺肿瘤的发生、发展和对治疗的抵抗。Bcl-2/Bcl-xL的分子调控是克服当前癌症治疗诱导的细胞凋亡抗性的一种有希望的策略。基于sirna的分子治疗与常规治疗相结合，可以提高疗效，克服当前癌症治疗的耐药性，特别是对于Bcl-2/Bcl-xL蛋白过表达、常规治疗效果不佳的肿瘤转移。如果成功进行，我们的研究将提供概念证明，siRNA可以通过自组装的纳米载体传递，用于肿瘤靶向RNA干扰前列腺癌进展和耐药性关键基因。将肿瘤靶向RNA干扰Bcl-2/Bcl- xl与常规治疗相结合，可以提高疗效，克服目前癌症治疗的耐药，特别是对于Bcl-2/Bcl- xl蛋白过表达、常规治疗效果不佳的转移性肿瘤。如果成功进行，我们的研究将提供概念证明，siRNA可以通过自组装的纳米载体传递，用于肿瘤靶向沉默对前列腺肿瘤进展和耐药性至关重要的基因。纳米载体在体内肿瘤靶向RNA干扰的成功将对基于sirna的人类前列腺癌各种分子靶点的新疗法的发展产生重大影响。

项目成果

MicroRNA miR-34 inhibits human pancreatic cancer tumor-initiating cells.

microRNA miR-34抑制人类胰腺癌肿瘤发射细胞。

• DOI: 10.1371/journal.pone.0006816
• 发表时间: 2009-08-28
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Ji Q;Hao X;Zhang M;Tang W;Yang M;Li L;Xiang D;Desano JT;Bommer GT;Fan D;Fearon ER;Lawrence TS;Xu L
• 通讯作者: Xu L

Design and synthesis of novel Gefitinib analogues with improved anti-tumor activity.

• DOI: 10.1016/j.bmc.2010.04.046
• 发表时间: 2010-06-01
• 期刊: BIOORGANIC & MEDICINAL CHEMISTRY
• 影响因子: 3.5
• 作者: Wu, Xiaoqing;Li, Mingdong;Qu, Yang;Tang, Wenhua;Zheng, Youguang;Lian, Jiqin;Ji, Min;Xu, Liang
• 通讯作者: Xu, Liang

Restoration of tumor suppressor miR-34 inhibits human p53-mutant gastric cancer tumorspheres.

• DOI: 10.1186/1471-2407-8-266
• 发表时间: 2008-09-21
• 期刊: BMC cancer
• 影响因子: 3.8
• 作者: Ji Q;Hao X;Meng Y;Zhang M;Desano J;Fan D;Xu L
• 通讯作者: Xu L

Design, synthesis, and in vitro antitumor activity evaluation of novel 4-pyrrylamino quinazoline derivatives.

• DOI: 10.1111/j.1747-0285.2011.01234.x
• 发表时间: 2011-12
• 期刊: Chemical biology & drug design
• 影响因子: 3
• 作者: Wu X;Li M;Tang W;Zheng Y;Lian J;Xu L;Ji M
• 通讯作者: Ji M

Tumor-targeted RNA-interference: functional non-viral nanovectors.

• 发表时间: 2011-09
• 期刊: American journal of cancer research
• 影响因子: 5.3
• 作者: Xinghua Pan;R. Thompson;Xiaojie Meng;Daocheng Wu;Liang Xu