Systemic RNA Delivery to Tumors

全身性 RNA 递送至肿瘤

• 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
• 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

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.

摘要 使用RNA技术特异性靶向肿瘤细胞中的遗传改变已经显示出巨大的潜力， 成为癌症治疗的一种新的治疗方式。然而，RNA试剂的全身递送， 作为信使RNA（mRNA）在体内进入肿瘤细胞通常面临着多重障碍，包括稳定性低、快速 通过肾排泄消除、细胞摄取不足、内体逃逸差和瞬时活性。我们 长期目标是开发强大的纳米颗粒（NP）平台，用于有效和安全的RNA递送到固体 肿瘤，并沿着体内癌症靶点验证，最终将RNA纳米药物转化为 临床发展。在上一个资助周期中，脂质-聚合物杂交RNA NP系统已经被工程化， 有利的特征，如小尺寸、高RNA包封、有效的胞质易位，以及相对 长时间的血液循环。我们还开创了将这些混合纳米颗粒用于mRNA递送以恢复 肿瘤抑制剂（例如，在不同的癌症类型中，包括前列腺癌（PCa）和非小细胞肺癌（NSCLC）， 它代表了一种新的癌症治疗方法，不依赖于癌基因拮抗作用。在 我们的最新工作，我们进一步揭示了PTEN缺失/突变的小鼠肿瘤细胞系中的PTEN恢复可以诱导 免疫原性细胞死亡（ICD）。初步的体内研究表明，PTEN mRNA NP处理触发细胞毒性， T细胞应答，调节免疫抑制性肿瘤微环境，并改善免疫应答。 免疫检查点阻断疗法。在此更新申请中，我们建议i）解决独特的挑战 通过开发新一代杂交mRNA NP来实现mRNA递送中的瞬时生物活性，以及ii）应用 新的杂交mRNA NPs用于探索PTEN诱导的ICD并评估PTEN的抗肿瘤功效 恢复沿着免疫检查点阻断。具体而言，该建议的三个基本目标是： 为了优化新一代的杂合纳米粒，并研究纳米粒介导的长持续mRNA生物活性， 使用尽可能少的注射实现PCa肿瘤中延长的PTEN表达的目标; 2） 应用优化的mRNA纳米颗粒研究PTEN介导的ICD和抗- 肿瘤免疫应答，并评估皮下移植，原位， 以及PCa的转基因模型;以及3）将新的杂交mRNA NP扩展到系统性共递送PTEN mRNA和CpG寡脱氧核苷酸（一种toll样受体-9激动剂）用于更强的ICD，并测试共同递送 用于PCa治疗的NP与免疫检查点抑制剂一起。我们期待这一工作的顺利完成， 该项目将导致开发一种新的合成mRNA纳米疗法，可以使癌症患者受益， PTEN缺失/突变。此外，这种NP递送策略可以容易地扩展到其他肿瘤抑制剂- 编码各种恶性肿瘤的mRNA。