Systemic RNA Delivery to Tumors

全身性 RNA 递送至肿瘤

• 批准号: 9197972
• 负责人: Jinjun Shi
• 金额: $ 54.74万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-12-21 至 2020-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9197972
• 关键词: Address; Adverse effects; Animals; Biodistribution; Biological Sciences; Blood Circulation; Cancer Etiology; Cations; Cell Survival; Cessation of life; Charge; Clinical Research; Code; Collaborations; DNA; DNA Sequence Alteration; Development; Dissociation; Drug Kinetics; Evaluation; Excretory function; Exhibits; Face; Formulation; Gene Expression; Gene Mutation; Gene Silencing; Generations; Genes; Genetically Engineered Mouse; Genomics; Goals; Human; Hybrids; In Vitro; Individual; Kidney; Kinetics; Label; Lead; Light; Lipids; Malignant Neoplasms; Malignant neoplasm of lung; Mediating; Messenger RNA; Methods; MicroRNAs; Modeling; Mononuclear; Nanotechnology; Non-Small-Cell Lung Carcinoma; Nucleic Acids; Oncogenes; PTEN gene; Particle Size; Pathway interactions; Patients; Phagocytes; Physiological; Polymers; Predisposition; Property; Proteins; RNA; STK11 gene; Small Interfering RNA; Solid; Surface; Survival Rate; Synthetic Vaccines; System; Technology; Therapeutic; Time; Toxic effect; Translating; Tumor Biology; Tumor Burden; Tumor Suppressor Proteins; Tumor Tissue; United States; Validation; Woman; Xenograft procedure; antibody inhibitor; anticancer research; antitumor effect; base; biomacromolecule; cancer cell; cancer genome; cancer therapy; cell growth; cost; humanized antibody; in vivo; innovation; macromolecule; men; mouse model; nanoparticle; neoplastic cell; novel; nuclease; phase I trial; public health relevance; research and development; restoration; self assembly; small molecule; smoking cessation; targeted treatment; therapeutic target; tumor; tumor growth; uptake

 DESCRIPTION (provided by applicant): Given the capability of modulating individual gene expression in tumor cells, RNA agents such as small interfering RNA (siRNA) and messenger RNA (mRNA) have demonstrated tremendous potential in revealing the functionality of specific gene alterations and enabling novel classes of therapies for cancer treatment. The effective systemic RNA delivery to tumors, however, remains a formidable challenge for the widespread application of RNA technologies in cancer research and therapy. In this project, we propose to (i) develop robust nanoparticle (NP) platforms for effective in vivo delivery of siRNA and mRNA to tumor tissue, and (ii) apply this technology to relevant cancer therapeutic targets for treating non-small cell lung cancer (NSCLC). In recent efforts, we have conceived and developed a new generation of lipid-polymer hybrid NPs with promising features for systemic siRNA delivery, including long blood circulation, high tumor accumulation, and impressive gene silencing efficacy. We have also successfully employed these hybrid NPs to explore a putative therapeutic target, Prohibitin1 (PHB1), in NSCLC and to deliver tumor suppressor-encoded mRNA to cancer cells, as evidenced by inhibition of tumor cell growth in vitro and following systemic delivery in vivo. In light of these extensive and encouraging preliminary results, we hypothesize that the new lipid-polymer hybrid NP-mediated systemic RNA delivery will become a useful platform for in vivo evaluation of cancer targets and for the development of novel RNA therapies for cancer treatment. In Aim 1, we will systematically optimize, understand and evaluate specific parameters that have been shown to control gene silencing efficiency and in vivo properties (e.g., pharmacokinetics, biodistribution, and side effects) of the hybrid NPs. In Aim 2, we propose to explore the mechanisms and pathways underlying the PHB1 silencing-induced anti-tumor effect, using the optimized siRNA NPs from Aim 1. The hybrid NPs for systemic delivery of anti-PHB1 siRNA will be extensively examined in multiple NSCLC xenograft and orthotopic models. In Aim 3, we will expand and refine the new hybrid NPs to deliver mRNA coding for tumor suppressors relevant to NSCLC, including PTEN and LKB1. This mRNA delivery approach for cancer therapy will be systematically investigated in vitro and in NSCLC xenograft and genetically engineered mouse models. At the conclusion of this project, we expect that the convergence of innovative RNA delivery strategy and significant discoveries in tumor biology will further strengthen our arsenal of therapies against NSCLC and other aggressive cancers.

 描述（由申请人提供）：考虑到调节肿瘤细胞中个体基因表达的能力，小干扰RNA（siRNA）和信使RNA（mRNA）等RNA制剂在揭示特定基因改变的功能和实现新颖的治疗方面已表现出巨大的潜力。然而，对肿瘤进行有效的全身性 RNA 递送对于 RNA 技术在癌症研究和治疗中的广泛应用仍然是一个巨大的挑战，我们将 (i) 开发强大的纳米颗粒 (NP)。平台有效地将 siRNA 和 mRNA 体内递送至肿瘤组织，以及（ii）将该技术应用于相关癌症治疗靶点以进行治疗 在最近的努力中，我们构思并开发了新一代脂质聚合物混合纳米粒子，其具有用于全身 siRNA 递送的良好特性，包括长血液循环、高肿瘤积累和令人印象深刻的基因沉默功效。我们还成功地利用这些混合 NP 来探索 NSCLC 中的假定治疗靶标 Prohibitin1 (PHB1)，并将肿瘤抑制因子编码的 mRNA 传递至癌细胞，这通过抑制肿瘤细胞生长来证明。鉴于这些广泛且令人鼓舞的初步结果，我们发现新的脂质聚合物杂化 NP 介导的系统性 RNA 递送将成为体内评估癌症靶点和开发癌症药物的有用平台。在目标 1 中，我们将系统地优化、理解和评估已被证明可以控制杂合 NP 的基因沉默效率和体内特性（例如药代动力学、生物分布和副作用）的特定参数。在目标 2，我们建议使用目标 1 中优化的 siRNA NP 来探索 PHB1 沉默诱导的抗肿瘤作用的机制和基础。用于全身递送抗 PHB1 siRNA 的混合 NP 将在多个 NSCLC 异种移植物和在目标 3 中，我们将扩展和完善新的混合 NP，以提供与 NSCLC 相关的肿瘤抑制因子的 mRNA 编码，包括 PTEN 和LKB1。这种用于癌症治疗的 mRNA 递送方法将在体外以及 NSCLC 异种移植和基因工程小鼠模型中进行系统研究。在该项目结束时，我们预计创新的 RNA 递送策略与肿瘤生物学的重大发现将进一步融合。加强我们针对非小细胞肺癌和其他侵袭性癌症的治疗方法。