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Systemic RNA Delivery to Tumors

全身性 RNA 递送至肿瘤

基本信息

批准号：
10297216
负责人：
Jinjun Shi
金额：
$ 58.56万
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/10297216
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 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 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.

摘要