Development of multifunctional drug and immune modulator delivery nanoparticles for the treatment of cancer patients with comorbid atherosclerosis

开发多功能药物和免疫调节剂递送纳米粒子，用于治疗患有动脉粥样硬化的癌症患者

• 批准号: 10334547
• 负责人: Lily Yang
• 金额: $ 53.22万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-02-01 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10334547
• 关键词: Acyl Coenzyme A; Address; Adverse effects; Affect; Aorta; Apolipoprotein E; Area; Arterial Fatty Streak; Atherosclerosis; Binding; Binding Proteins; Biocompatible Materials; Biodistribution; Biological Process; CD44 gene; CD8-Positive T-Lymphocytes; CT26; Cancer Model; Cancer Patient; Cardiology; Cardiovascular Diseases; Cardiovascular system; Cause of Death; Cell Proliferation; Cell physiology; Cells; Cholesterol; Clinical; Colon; Colon Carcinoma; Colonic Neoplasms; Cytotoxic T-Lymphocytes; Data; Dendritic Cells; Dendritic cell activation; Development; Disease; Dose; Drug Delivery Systems; Drug Kinetics; Drug Targeting; Encapsulated; Engineering; Future; Goals; High Fat Diet; Human; Hyaluronic Acid; Immune; Immune response; Immunologics; Immunomodulators; Immunotherapeutic agent; Immunotherapy; Incidence; Infiltration; Inflammatory; Inflammatory Response; Investigation; Lesion; MC38; Malignant Neoplasms; Microsatellite Instability; Modeling; Mus; Nanoimmunotherapy; Neoplasm Metastasis; Organ; Outcome; Patients; Peptides; Pharmaceutical Preparations; Phase I Clinical Trials; Play; Property; Proteins; Research; Research Project Grants; Resistance; Role; Signal Transduction; Solid Neoplasm; Sterol O-Acyltransferase; Symptoms; System; T-Lymphocyte; Therapeutic; Thrombosis; Tissues; Toxic effect; Translations; Treatment Efficacy; Tumor Tissue; Tumor-infiltrating immune cells; United States; Urokinase Plasminogen Activator Receptor; activating transcription factor; anti-PD-1; anti-PD-L1 antibodies; anti-tumor immune response; biomaterial compatibility; biophysical properties; cancer immunotherapy; cancer therapy; cell growth; cell type; checkpoint therapy; chemotherapy; clinical development; clinical translation; colon cancer patients; comorbidity; cytotoxic; cytotoxic CD8 T cells; design; effector T cell; high risk; immune activation; immune checkpoint; immunoregulation; improved; improved outcome; inhibitor; irinotecan; macrophage; metastatic colorectal; mouse model; nanoparticle; nanoparticle delivery; nanoparticle drug; nanotherapeutic; neoantigens; neoplastic cell; novel; novel therapeutics; patient derived xenograft model; phase I trial; pre-clinical; preclinical study; prevent; programmed cell death ligand 1; programmed cell death protein 1; response; side effect; systemic toxicity; targeted delivery; targeted treatment; translational goal; treatment response; tumor; tumor growth; tumor microenvironment; tumor-immune system interactions; viscoelasticity; wound healing

Project Summary Cancer and cardiovascular disease are leading causes of death in the United States. Given the high percentage of cancer patients with co-existing atherosclerosis, the development of cancer therapeutics that prevent progression of atherosclerosis have the potential to align cancer therapy goals with favorable cardiovascular outcomes. Hyaluronic acid (HA) has unique properties that are desirable for the development of biocompatible and biodegradable nanoparticle drug delivery systems for both cancer and atherosclerosis. We have developed a hyaluronic acid nanoparticle (HANP) conjugated with PD1 memetic peptides that target and block immune checkpoint protein PD-L1 and carry the cholesterol-lowering drug Avasimibe (PD1Y-HANP/Ava). Avasimibe is a multifunctional agent that decreases cholesterol accumulation, inhibits tumor cell growth, and enhances immune response by activating cytotoxic T cells. We found that systemic administrations of PD1Y-HANP/Ava led to targeted delivery into tumors and atherosclerotic plaques, inhibition of tumor growth and atherosclerosis progression, and significant improvement in mouse survival in a dual mouse cancer and atherosclerosis model. In this study, we hypothesize that systemic delivery of urokinase plasminogen activator receptor (uPAR), PD- L1 and CD44 co-targeted HANP carrying Avasimibe (ATF/PD1Y-HANP/Ava) leads to the efficient delivery of the HANP/Ava into tumors and atherosclerotic plaques, resulting in a significant anti-tumor growth effect by direct inhibition of tumor cell proliferation, activation of cytotoxic CD8+ T cells, and pro-immune modulatory effect of ATF/PD1Y-HANP/Ava in tumor microenvironment. We further hypothesize that delivery of targeted PD1Y- HANP/Ava into atherosclerotic plaques decreases cholesterol-rich macrophages and infiltrating immune cells, and thereby prevents atherosclerosis progression. To develop and validate the proposed immunotherapy, we will first develop ATF/PD1Y-HANP/Ava and examine the efficiency of targeted delivery in metastatic mouse colon cancer models (Aim 1). Therapeutic efficacy and immune responses following targeted PD1Y-HANP/Ava treatment, alone or in combination with a chemotherapy drug, irinotecan, will be evaluated in the mouse cancer models (Aim 1). We will then determine the effect of the targeted PD1Y-HANP/Ava on targeted delivery, immune responses and therapeutic efficacy in tumor and atherosclerotic plaques in a dual mouse colon cancer and atherosclerosis model (Aim 2). Immunological analysis of tumors and atherosclerotic plaques will allow us to determine therapy-related changes in immune cell types and functions, especially CD8+ T cell activity. We will then investigate the feasibility of translation in cancer patients by examining targeted delivery and direct cytotoxic effect of the targeted PD1Y-HANP/Ava in colon cancer patient derived xenograft models (Aim 3). Finally, pharmacokinetics, toxicity, biodistribution and systemic immune responses will be determined in mice (Aim 4). Results of this research should provide us with preclinical data for translational development of a phase 1 clinical trial using this novel targeted immunotherapy for metastatic colon cancer patients with comorbid atherosclerosis.

项目摘要 癌症和心血管疾病是美国的主要死亡原因。考虑到很高的百分比 共存动脉粥样硬化的癌症患者，癌症治疗剂的发展 动脉粥样硬化的进展有可能使癌症治疗目标与有利的心血管相结合 结果。透明质酸（HA）具有独特的特性，可用于生物相容性的发展 以及用于癌症和动脉粥样硬化的可生物降解纳米粒子药物输送系统。我们已经发展了 透明质酸纳米颗粒（HANP）与PD1模因肽结合，靶向和阻塞免疫 检查点蛋白PD-L1并携带降低胆固醇的药物avasimibe（PD1Y-HANP/AVA）。 Avasimibe是一个 多功能剂可降低胆固醇的积累，抑制肿瘤细胞的生长并增强免疫 通过激活细胞毒性T细胞的反应。我们发现PD1Y-HANP/AVA的系统管理导致 针对性地递送到肿瘤和动脉粥样硬化斑块，抑制肿瘤生长和动脉粥样硬化 在双重小鼠癌和动脉粥样硬化模型中，小鼠存活的进展，并显着提高。 在这项研究中，我们假设全身递送尿激酶纤溶酶原激活剂受体（UPAR），PD- L1和CD44携带avasimibe（ATF/PD1Y-HANP/AVA）共同靶向HANP可有效地递送 HANP/AVA进入肿瘤和动脉粥样硬化斑块，导致直接的抗肿瘤生长效应显着 抑制肿瘤细胞增殖，细胞毒性CD8+ T细胞的激活以及促免疫调节作用 肿瘤微环境中的ATF/PD1Y-HANP/AVA。我们进一步假设有针对性的PD1Y-的传递 HANP/AVA进入动脉粥样硬化斑块可降低富含胆固醇的巨噬细胞和浸润的免疫细胞，即 从而防止动脉粥样硬化进展。为了开发和验证提出的免疫疗法，我们 将首先开发ATF/PD1Y-HANP/AVA，并检查转移性小鼠结肠中靶向递送的效率 癌症模型（目标1）。靶向PD1Y-HANP/AVA后的治疗功效和免疫反应 将在小鼠癌中评估单独或与化学疗法药物Irinotecan的治疗 模型（目标1）。然后，我们将确定目标PD1Y-HANP/AVA对靶向递送的影响 双小鼠结肠癌的肿瘤和动脉粥样硬化斑块的反应和治疗功效 动脉粥样硬化模型（AIM 2）。肿瘤和动脉粥样硬化斑块的免疫学分析将使我们能够 确定与治疗相关的免疫细胞类型和功能的变化，尤其是CD8+ T细胞活性。我们将 然后通过检查靶向分娩和直接细胞毒性来研究癌症患者翻译的可行性 靶向PD1Y-HANP/AVA在结肠癌患者衍生的异种移植模型中的影响（AIM 3）。最后， 将在小鼠中确定药代动力学，毒性，生物分布和全身免疫反应（AIM 4）。 这项研究的结果应为我们提供临床前数据，以用于1阶段临床的翻译发展 使用这种新型的针对性化结肠癌患者的靶向免疫疗法的试验。