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Dual-pronged nano-drug delivery using plant virus-like particles

使用植物病毒样颗粒的双管齐下纳米药物输送

基本信息

批准号：
9372245
负责人：
Nicole Franziska Steinmetz
金额：
$ 47.01万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-01 至 2018-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9372245
关键词：
4T1 Address Anatomy Animals Antibodies Applications Grants Artificial nanoparticles Biological Breast Cancer Patient Capsid Proteins Cells Clinical Colon Carcinoma Cowpea Mosaic Viruses Data Development Disease Distant Metastasis Doxorubicin Drug Delivery Systems ERBB2 gene Estrogen Receptors Flow Cytometry Histocytochemistry Image Immune Immune response Immunofluorescence Immunologic Immunologic Memory Immunotherapy Knockout Mice Lead Libraries Life Ligands Location Malignant Neoplasms Malignant neoplasm of ovary Mediating Memory Molecular Mosaic Viruses Mouse Strains Mus Nanotechnology Nature Neoplasm Metastasis Nucleic Acids Oncolytic Particulate Pathway interactions Patients Pharmaceutical Preparations Plant Viruses Plants Play Primary Neoplasm Progesterone Receptors Recurrence Research Role Shapes Signal Pathway Signal Transduction TLR7 gene Testing Therapeutic Time Toll-like receptors Translating Treatment Efficacy Tumor Debulking Tumor Immunity Virus Virus-like particle Woman antitumor effect arm base chemotherapy engineering design immune activation immunogenic improved in vivo imaging insight melanoma mortality mouse model nanocarrier nanodrug nanoparticle nanotherapy outcome forecast particle response success targeted treatment therapy outcome triple-negative invasive breast carcinoma tumor tumor microenvironment

项目摘要

Summary Triple negative breast cancer (TNBC) is an aggressive life-threatening disease with poor prognosis and limited treatment options. To address this clinical need, we propose a dual-pronged drug delivery approach that combines chemo- and immune-drugs with a highly potent drug delivery platform, that itself has anti-tumor efficacy. This grant application is based on our recent demonstration that virus-like particles (VLP) from the plant virus cowpea mosaic virus (CPMV), when introduced into the tumor microenvironment, elicit potent local and systemic anti-tumor immunity and protects animals from outgrowth of metastatic disease or recurrence of the disease [Nature Nanotechnology 2016]. We have demonstrated efficacy in multiple mouse models treating primary and metastatic tumors in multiple anatomic locations and multiple mouse strains, including mouse models of TNBC. The nanoparticle engineering design space and pathway of immune-activation is not yet un- derstood, and one arm of this R01 grant application will decipher the underlying mechanism. Second, we will develop and test dual-pronged therapeutic approaches through combination of the nanoparticle platform with chemotherapies and immune-drugs to potentiate the therapy and enable treatment of late-stage disease. We will fulfill the following specific aims: 1) We will address whether the anti-tumor effect is CPMV-specific, wheth- er the particulate, multivalent nature is a requirement, and whether nanoparticle shape and size plays a role. A library of plant-derived VLPs of distinct molecular composition, size, and shape will be studied and efficacy will be assessed using the 4T1 mouse model of TNBC. 2) We will determine the cells and signaling pathways in- volved in the VLP-induced anti-tumor immune response. Longitudinal imaging in combination with histochemis- try and flow cytometry will provide comprehensive insight into the biological response. To identify the potential signaling pathways involved, studies will be performed in knockout mouse models that lack ASC, Myd88 or Trif adaptor molecules. 3) Immunotherapy as monotherapy is generally effective only against small tumors, and most patients do not respond to single approach immunotherapy. The combination of therapeutic regimes, i.e. the combination of multiple immunotherapies or combination with chemotherapy, however, could form the ba- sis for success. First, we will combine VLPs with doxorubicin (an immunogenic chemotherapy) through co- administration (unconjugated) or co-delivery (conjugated to the VLP). Second, we will combine VLPs with known `immunogenic danger signals' and co-deliver ssRNA or CpGs to activate signaling through Toll-like re- ceptors. We hypothesize that the combination of the immune-stimulatory VLP and chemo- or immune-drugs will potentiate efficacy while mounting a systemic anti-tumor immune response and memory, and this will be tested through treatment of mice bearing 4T1 primary and metastatic tumors. The recent approval of the onco- lytic immunotherapy T-VEC highlights the potential of virus-based therapeutics. Our application is distinct, be- cause we use a plant VLP for dual-pronged tumor treatment and priming of anti-tumor immune memory.

总结