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: 10548149
• 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/10548149
• 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; CD8B1 gene; 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; 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; Macrophage; 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; United States; Urokinase Plasminogen Activator Receptor; activating transcription factor; anti-PD-L1 antibodies; anti-PD1 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 cell infiltrate; immune checkpoint; immunoregulation; improved; improved outcome; inhibitor; irinotecan; 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.

项目概要 癌症和心血管疾病是美国的主要原因。鉴于比例很高 针对同时存在动脉粥样硬化的癌症患者，开发预防癌症的治疗方法 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疾病保持一致 结果。透明质酸 (HA) 具有独特的特性，有利于开发生物相容性材料 以及用于癌症和动脉粥样硬化的可生物降解的纳米颗粒药物输送系统。我们开发了 与 PD1 模因肽结合的透明质酸纳米颗粒 (HANP)，可靶向并阻断免疫 检查点蛋白 PD-L1 并携带降胆固醇药物 Avasimibe (PD1Y-HNP/Ava)。阿瓦西贝是一种 减少胆固醇积累、抑制肿瘤细胞生长、增强免疫力的多功能剂 通过激活细胞毒性 T 细胞做出反应。我们发现全身给予 PD1Y-HNP/Ava 会导致 靶向递送至肿瘤和动脉粥样硬化斑块，抑制肿瘤生长和动脉粥样硬化 在小鼠癌症和动脉粥样硬化双重模型中，小鼠存活率显着提高。 在这项研究中，我们假设尿激酶纤溶酶原激活剂受体（uPAR）的全身递送，PD- L1 和 CD44 共同靶向携带 Avasimibe (ATF/PD1Y-HANP/Ava) 的 HANP 导致有效递送 HANP/Ava进入肿瘤和动脉粥样硬化斑块，直接产生显着的抗肿瘤生长作用 抑制肿瘤细胞增殖、激活细胞毒性 CD8+ T 细胞以及促免疫调节作用 肿瘤微环境中的 ATF/PD1Y-HNP/Ava。我们进一步假设靶向 PD1Y- 的递送 HANP/Ava 进入动脉粥样硬化斑块，减少富含胆固醇的巨噬细胞和浸润免疫细胞， 从而防止动脉粥样硬化的进展。为了开发和验证所提出的免疫疗法，我们 将首先开发 ATF/PD1Y-HNP/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-HNP/Ava 后的治疗效果和免疫反应 单独或与化疗药物伊立替康联合治疗将在小鼠癌症中进行评估 模型（目标 1）。然后我们将确定靶向 PD1Y-HNP/Ava 对靶向递送、免疫的影响 双小鼠结肠癌和动脉粥样硬化斑块的反应和治疗效果 动脉粥样硬化模型（目标 2）。肿瘤和动脉粥样硬化斑块的免疫学分析将使我们能够 确定治疗相关的免疫细胞类型和功能变化，尤其是 CD8+ T 细胞活性。我们将 然后通过检查靶向递送和直接细胞毒性来研究癌症患者中翻译的可行性 靶向 PD1Y-HNP/Ava 在结肠癌患者衍生的异种移植模型中的效果（目标 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（目标 4）。 这项研究的结果应该为我们提供一期临床转化开发的临床前数据 使用这种新型靶向免疫疗法治疗患有动脉粥样硬化的转移性结肠癌患者的试验。