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。鉴于高比例的 同时存在动脉粥样硬化的癌症患者中， 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相一致。 结果。透明质酸（HA）具有独特的性质，其对于生物相容性药物的开发是期望的。 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递送系统。我们已经开发 一种与PD 1蛋白肽缀合的透明质酸纳米颗粒（HANP），其靶向并阻断免疫 检查点蛋白PD-L1并携带降胆固醇药物Avasimibe（PD 1 Y-HANP/Ava）。Avasimibe是一种 一种减少胆固醇积累、抑制肿瘤细胞生长和增强免疫功能的多功能药剂， 通过激活细胞毒性T细胞的反应。我们发现，PD 1 Y-HANP/Ava的全身给药导致 靶向递送到肿瘤和动脉粥样硬化斑块中，抑制肿瘤生长和动脉粥样硬化 进展，以及在双重小鼠癌症和动脉粥样硬化模型中小鼠存活率的显著改善。 在这项研究中，我们假设全身递送尿激酶纤溶酶原激活物受体（uPAR），PD- 携带Avasimibe的L1和CD 44共靶向HANP（ATF/PD 1 Y-HANP/Ava）导致有效递送 HANP/Ava可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， 肿瘤细胞增殖的抑制、细胞毒性CD 8 + T细胞的活化和 肿瘤微环境中的ATF/PD 1 Y-HANP/Ava。我们进一步假设，靶向PD 1 Y的递送- HANP/Ava进入动脉粥样硬化斑块减少了富含胆固醇的巨噬细胞和浸润的免疫细胞， 从而防止动脉粥样硬化进展。为了开发和验证所提出的免疫疗法，我们 将首先开发ATF/PD 1 Y-HANP/Ava，并检查转移性小鼠结肠中靶向递送的效率 癌症模型（Aim 1）。靶向PD 1 Y-HANP/Ava后的疗效和免疫应答 将在小鼠癌症中评价单独或与化疗药物伊立替康组合的治疗 模型（目标1）。然后，我们将确定靶向PD 1 Y-HANP/Ava对靶向递送、免疫应答和免疫应答的影响。 在双重小鼠结肠癌中的肿瘤和动脉粥样硬化斑块中的反应和治疗功效， 动脉粥样硬化模型（目的2）。肿瘤和动脉粥样硬化斑块的免疫学分析将使我们能够 确定免疫细胞类型和功能的治疗相关变化，特别是CD 8 + 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在癌症患者中翻译的可行性， 靶向PD 1 Y-HANP/Ava在结肠癌患者来源的异种移植物模型中的作用（目的3）。最后， 将在小鼠中测定药代动力学、毒性、生物分布和全身免疫应答（目的4）。 这项研究的结果应该为我们提供临床前数据的翻译发展的1期临床 试验使用这种新的靶向免疫治疗转移性结肠癌患者合并动脉粥样硬化。

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.