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

使用植物病毒样颗粒进行双管齐下的纳米药物输送。

基本信息

批准号：
10224677
负责人：
Nicole Franziska Steinmetz
金额：
$ 42.62万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-01 至 2022-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10224677
关键词：
4T1 Address Anatomy Animals Antibodies Antitumor Response 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 Immune Immune response Immunofluorescence Immunologic Immunologic Memory Immunomodulators Immunotherapeutic agent Immunotherapy Knockout Mice Lead Libraries Life Ligands Location Malignant Neoplasms Malignant neoplasm of ovary Mediating Memory Molecular Mouse Strains Mus Nanotechnology Nature Neoplasm Metastasis Nucleic Acids Oncolytic Immunotherapy Particulate Pathway interactions Patients Plant Viruses Plants Play Primary Neoplasm Progesterone Receptors Prognosis 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 anti-tumor immune response antitumor effect arm base chemotherapy engineering design immune activation immunogenic improved in vivo imaging insight melanoma mortality mouse model nanocarrier nanodrug nanoparticle nanotherapy particle response serial imaging success targeted treatment therapy outcome triple-negative invasive breast carcinoma tumor tumor microenvironment

4T1 Address Anatomy Animals Antibodies Antitumor Response 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 Immune Immune response Immunofluorescence Immunologic Immunologic Memory Immunomodulators Immunotherapeutic agent Immunotherapy Knockout Mice Lead Libraries Life Ligands Location Malignant Neoplasms Malignant neoplasm of ovary Mediating Memory Molecular Mouse Strains Mus Nanotechnology Nature Neoplasm Metastasis Nucleic Acids Oncolytic Immunotherapy Particulate Pathway interactions Patients Plant Viruses Plants Play Primary Neoplasm Progesterone Receptors Prognosis 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 anti-tumor immune response antitumor effect arm base chemotherapy engineering design immune activation immunogenic improved in vivo imaging insight melanoma mortality mouse model nanocarrier nanodrug nanoparticle nanotherapy particle response serial imaging success targeted treatment therapy outcome triple-negative invasive breast carcinoma tumor tumor microenvironment

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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.

概括三重阴性乳腺癌（TNBC）是一种侵略性威胁生命的疾病，预后不良和有限的治疗选择。为了满足这一临床需求，我们提出了一种双管制药物输送方法将化学和免疫药物与高效的药物输送平台相结合，该平台本身具有抗肿瘤功效。该赠款的应用是基于我们最近的证明，即病毒样颗粒（VLP）引入肿瘤微环境时，植物病毒牛pea马赛克病毒（CPMV）引起了局部有效的局部和全身性抗肿瘤免疫，并保护动物免受转移性疾病的生长或复发该疾病[自然纳米技术2016]。我们已经在多种鼠标模型中证明了功效多个解剖位置和多种小鼠菌株的原发性和转移性肿瘤，包括小鼠 TNBC的模型。纳米颗粒工程设计空间和免疫激活的途径尚未 Derstood，此R01赠款申请的一个部门将破译基础机制。第二，我们会的通过将纳米颗粒平台与化学疗法和免疫药物以增强治疗并能够治疗后期疾病。我们将满足以下特定目标：1）我们将解决抗肿瘤效应是否为CPMV特异性，WHETH- er颗粒性质是一种要求，纳米颗粒形状和大小是否起作用。一个将研究不同分子组成，大小和形状的植物来源的VLP库，功效将使用TNBC的4T1小鼠模型进行评估。 2）我们将确定细胞和信号通路在VLP诱导的抗肿瘤免疫反应中进行了体积。纵向成像与组织化学结合尝试和流式细胞仪将为生物学反应提供全面的见解。确定潜力涉及的信号通路，将在缺乏ASC，MYD88或TRIF的敲除鼠标模型中进行研究适配器分子。 3）免疫疗法作为单一疗法通常仅对小肿瘤有效，并且大多数患者对单一方法免疫疗法没有反应。治疗方案的结合，即但是，多种免疫疗法或与化学疗法结合的结合可能形成BA- SIS成功。首先，我们将通过共同辅助将VLP与阿霉素（免疫原性化疗）相结合给药（未缀合）或共递送（与VLP共轭）。第二，我们将与VLP与已知的“免疫原性危险信号”和联合信号SSRNA或CPG通过Toll样重新激活信号传导 CEPTORS。我们假设免疫刺激VLP和化学或免疫药的组合安装全身性抗肿瘤免疫反应和记忆时，将增强功效，这将是通过治疗携带4T1原发性肿瘤和转移性肿瘤的小鼠测试。最近获得了Onco-的批准裂解免疫疗法T-VEC突出了基于病毒的治疗剂的潜力。我们的应用是不同的，因为我们使用植物VLP进行双管肿瘤治疗和抗肿瘤免疫记忆的启动。