Systemic RNA Delivery to Tumors

全身性 RNA 递送至肿瘤

基本信息

批准号：
10447166
负责人：
Jinjun Shi
金额：
$ 53.52万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-12-21 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10447166
关键词：
Address Adjuvant Aftercare Agonist American Cancer Society Animal Model Apoptosis Autophagocytosis Biodistribution Biological Markers Blood Circulation Cancer Patient Cells Cessation of life Charge Combined Modality Therapy Cytotoxic T-Lymphocytes Development Disease Drug Kinetics Economic Burden Engineering Excretory function Face Formulation Foundations Funding Gene Expression Generations Genetically Engineered Mouse Goals Growth HMGB1 Protein Hybrids Immune Immune checkpoint inhibitor Immune response Immunocompetent Immunologic Memory In Vitro Individual Injections Kidney Light Lipids Malignant Neoplasms Malignant neoplasm of prostate Mediating Messenger RNA Modality Modeling Molecular Molecular Weight Mus Mutate Mutation Nature Neoplasm Metastasis Non-Small-Cell Lung Carcinoma Oncogenes PTEN gene Pathway interactions Pattern Pharmaceutical Preparations Phenotype Polymers Predisposition Prostate Cancer therapy RNA RNA delivery Regulatory T-Lymphocyte Research Project Grants Role Safety Series Small Interfering RNA Solid Neoplasm Surface System T cell response TLR9 gene TP53 gene Technology Testing Therapeutic Therapeutic Effect Transfection Transgenic Model Translations Tumor Cell Line Tumor Immunity Tumor Suppressor Proteins United States Validation Work antagonist anti-PD1 antibodies anti-PD1 therapy anti-tumor immune response base cancer cell cancer therapy cancer type clinical development cytokine cytotoxic cytotoxicity immune checkpoint immune checkpoint blockade immunogenic cell death improved in vivo metastasis prevention nanomedicine nanoparticle nanoparticle delivery nanotherapy neoplastic cell novel novel strategies novel therapeutics nuclease programmed cell death protein 1 prostate cancer cell prostate cancer model protein expression restoration social subcutaneous tumor tumor growth tumor microenvironment tumor-immune system interactions uptake

项目摘要

ABSTRACT The use of RNA technologies to specifically target genetic alterations in tumor cells has shown great potential of becoming a novel therapy modality for cancer treatment. Nevertheless, systemic delivery of RNA agents such as messenger RNA (mRNA) to tumor cells in vivo commonly faces multiple barriers, including low stability, rapid elimination by renal excretion, insufficient cellular uptake, poor endosomal escape, and transient activities. Our long-term objective is to develop robust nanoparticle (NP) platforms for effective and safe RNA delivery to solid tumors, and along with cancer target validation in vivo, to eventually transition the RNA nanomedicines into clinical development. In the last funding cycle, a lipid-polymer hybrid RNA NP system has been engineered with favorable features, such as small size, high RNA encapsulation, efficient cytosolic translocation, and relatively long blood circulation. We have also pioneered the application of these hybrid NPs for mRNA delivery to restore tumor suppressors (e.g., PTEN) in different cancer types including prostate cancer (PCa) and non-small cell lung cancer, which represents a novel approach to cancer treatment that is independent of oncogene antagonism. In our latest work, we further reveal that PTEN restoration in PTEN-null/mutated murine tumor cell lines can induce immunogenic cell death (ICD). Preliminary in vivo studies show that PTEN mRNA NP treatment triggers cytotoxic T cell responses, modulates the immunosuppressive tumor microenvironment, and improves the responses of immune checkpoint blockade therapy. In this renewal application, we propose to i) address the unique challenge of transient bioactivity in mRNA delivery by developing a new generation of hybrid mRNA NPs, and ii) apply the new hybrid mRNA NPs to explore PTEN restoration-induced ICD and evaluate the anti-tumor efficacy of PTEN restoration along with immune checkpoint blockade. Specifically, the three Aims underlying the proposal are: 1) To optimize the new generation of hybrid NPs and study the NP-mediated long duration of mRNA bioactivity with the goal of achieving prolonged PTEN expression in PCa tumors using as infrequent injections as possible; 2) To apply the optimized mRNA NPs to investigate the mechanisms underlying PTEN-mediated ICD and anti- tumor immune responses and to evaluate the therapeutic effect and safety in subcutaneously grafted, orthotopic, and transgenic models of PCa; and 3) To expand the new hybrid mRNA NPs to systemic co-delivery of PTEN mRNA and CpG oligodeoxynucleotide (a toll-like receptor-9 agonist) for stronger ICD and to test the co-delivery NPs for PCa treatment together with immune checkpoint inhibitors. We expect that successful completion of this project will lead to development of a novel synthetic mRNA nanotherapy that could benefit cancer patients with loss/mutation of PTEN. Moreover, this NP delivery strategy could be readily expanded to other tumor suppressor- encoding mRNAs for various malignancies.

抽象的使用RNA技术专门针对肿瘤细胞中的遗传改变已显示出很大的潜力成为癌症治疗的新型疗法。然而，RNA剂的全身输送作为信使RNA（mRNA）到体内肿瘤细胞通常面对多个障碍，包括低稳定性，快速通过肾脏排泄，细胞摄取不足，内体逃生和瞬态活性消除。我们的长期目标是开发强大的纳米颗粒（NP）平台，以有效且安全的RNA递送至实体肿瘤以及体内癌症靶标验证，最终将RNA纳米药物转变为临床发展。在上一个融资周期中，脂质聚合物混合RNA NP系统已通过有利的特征，例如小尺寸，高RNA封装，有效的胞质易位和相对长血液循环。我们还开创了这些混合NP在mRNA递送中的应用不同癌症类型的肿瘤抑制（例如PTEN），包括前列腺癌（PCA）和非小细胞肺癌症代表了一种与癌基因拮抗作用无关的新型癌症治疗方法。在我们的最新工作，我们进一步揭示了PTEN恢复PTEN-NULL/突变的鼠肿瘤细胞系可能会诱导免疫原性细胞死亡（ICD）。初步体内研究表明，PTEN mRNA NP治疗触发细胞毒性 T细胞反应，调节免疫抑制性肿瘤微环境，并改善免疫检查点阻滞疗法。在此续签应用中，我们建议i）解决独特的挑战通过开发新一代的杂交mRNA NP，在mRNA传递中的瞬时生物活性，ii）应用新的混合mRNA NP，以探索PTEN恢复引起的ICD并评估PTEN的抗肿瘤功效恢复以及免疫检查点封锁。具体而言，该提案的三个目标是：1）优化新一代杂种NP并研究NP介导的mRNA生物活性的长时间使用尽可能不经常注射的PCA肿瘤中长时间PTEN表达的目的； 2）应用优化的mRNA NP来研究PTEN介导的ICD和抗 - 肿瘤免疫反应并评估皮下移植，原位的治疗效果和安全性和PCA的转基因模型； 3）将新的混合mRNA NP扩展到PTEN的系统性共同交付 mRNA和CpG寡脱氧核苷酸（一种类似于Toll的受体-9激动剂），用于更强的ICD并测试共递送 NP与免疫检查点抑制剂一起进行PCA处理。我们希望成功完成项目将导致开发新的合成mRNA纳米疗法，该疗法可能使癌症患者受益 PTEN的损失/突变。此外，这种NP输送策略可以很容易地扩展到其他抑制肿瘤 - 编码mRNA各种恶性肿瘤。