Development of multifunctional drug and immune modulator delivery nanoparticles for the treatment of 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。鉴于很高的百分比 与动脉粥样硬化并存的癌症患者，预防癌症治疗的发展 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疾病保持一致 结果。透明质酸(HA)具有开发生物相容性所需的独特性质 以及可生物降解的纳米药物输送系统，用于癌症和动脉粥样硬化。我们已经开发出 一种与PD1表位多肽偶联的透明质酸纳米粒(HANP)，用于靶向和阻断免疫 检查点蛋白PD-L1和携带降胆固醇药物阿瓦西米(PD1Y-HANP/AVA)。阿瓦西米是一种 多功能制剂，减少胆固醇积聚，抑制肿瘤细胞生长，增强免疫力 通过激活细胞毒性T细胞进行反应。我们发现，全身注射PD1Y-HANP/AVA会导致 靶向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，进展和显著改善小鼠的存活率。 在本研究中，我们假设尿激酶型纤溶酶原激活剂受体(UPAR)的全身性递送。 L1和CD44共同靶向携带avasimibe的HANP(ATF/PD1Y-HANP/AVA)可有效地传递 HANP/AVA通过直接进入肿瘤和动脉粥样硬化斑块，产生显著的抗肿瘤生长作用。 抑制肿瘤细胞增殖，激活细胞毒性CD8 T细胞，促进免疫调节作用 ATF/PD1Y-HANP/AVA在肿瘤微环境中的表达我们进一步假设，靶向PD1Y- HANP/AVA进入动脉粥样硬化斑块会减少富含胆固醇的巨噬细胞和渗入的免疫细胞， 从而防止动脉粥样硬化的进展。为了开发和验证建议的免疫疗法，我们 将首先开发ATF/PD1Y-HANP/AVA，并检测靶向递送在转移的小鼠结肠中的效率 肿瘤模型(目标1)。靶向PD1Y-HANP/AVA的治疗效果和免疫应答 单独或联合化疗药物伊立替康的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-HANP/AVA对靶向传递、免疫的影响 小鼠结肠癌和结肠癌双重模型对肿瘤和动脉粥样硬化斑块的反应及疗效 动脉粥样硬化模型(目标2)。对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，特别是CD8 T细胞的活性。我们会 然后通过检测靶向传递和直接细胞毒作用来研究翻译在癌症患者中的可行性。 靶向PD1Y-HANP/AVA在结肠癌患者来源的异种移植模型中的作用(目标3)。最后， 将测定小鼠体内的药代动力学、毒性、生物分布和系统免疫反应(目标4)。 这项研究的结果应该为一期临床的翻译开发提供临床前数据 使用这种新的靶向免疫疗法治疗合并动脉粥样硬化的转移性结肠癌患者的试验。

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.