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（由应用提供）：鉴于在肿瘤细胞中调节个体基因表达的能力，RNA剂（例如小干扰RNA（siRNA）和Messenger RNA（mRNA）（mRNA）具有巨大的潜力，可以揭示特定基因改变的功能以及实现癌症治疗的新型治疗方法。然而，对于RNA技术在癌症研究和治疗中的宽度应用中，有效的全身性RNA传递向肿瘤仍然是一个巨大的挑战。在该项目中，我们建议（i）开发可靠的纳米颗粒（NP）平台，以有效地在体内递送siRNA和mRNA向肿瘤组织，并且（ii）将此技术应用于相关的癌症治疗靶标本以治疗 非小细胞肺癌（NSCLC）。在最近的努力中，我们构思并开发了新一代的脂质聚合物混合动力NP，具有有希望的全身性siRNA递送特征，包括长血液循环，高肿瘤积累和令人印象深刻的基因沉默效果。我们还成功地利用了这些混合NP来探索NSCLC中推定的治疗靶标，PRIBINITIN1（PHB1），并将抑制肿瘤抑制的mRNA传递给癌细胞，这是通过体外抑制肿瘤细胞生长的抑制，在体外抑制了肿瘤细胞的生长，并在体内递送后全身递送。鉴于这些广泛而令人鼓舞的初步结果，我们假设新型的脂质 - 聚合物混合介导的NP介导的全身RNA递送将成为体内评估癌症靶标和开发新型RNA疗法的有用平台。在AIM 1中，我们将系统地优化，理解和评估具有的特定参数，这些参数被证明可以控制混合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）。在AIM 2中，我们建议探索PHB1沉默诱导的抗肿瘤效应的机制和途径，使用来自AIM 1的优化siRNA NP。用于全身性抗PHB1 siRNA的杂交NP将在多个NSCLC Xenographic和Orthopopic模型中进行广泛研究。在AIM 3中，我们将扩展和完善新的混合动力NP，以提供与NSCLC相关的肿瘤补充剂编码的mRNA编码，包括PTEN和LKB1。这种用于癌症治疗的mRNA递送方法将在体外和NSCLC特征和基因工程小鼠模型中进行系统地研究。在该项目的结论中，我们期望创新的RNA递送策略和肿瘤生物学的重大发现的融合将进一步加强我们针对NSCLC和其他侵略性癌症的治疗方法。