CHOLESTEROL METABOLISM IN THE PHARMACOLOGY OF LIPOSOMAL THERAPEUTICS

摘要 使用脂质体的药物输送增加了肿瘤药物的积聚，同时保留了正常组织。几种脂质体 化疗被批准用于治疗癌症。不幸的是，脂质纳米粒，如脂质体，与 免疫系统及其对肿瘤免疫环境的影响在很大程度上是未知的。我们已经报道了 由磷脂和胆固醇组成的脂质体，与患者使用的相似，使肿瘤体积增加了一倍 通过抑制对肿瘤的免疫反应来抑制小鼠。我们最近发现巨噬细胞是一种 对这些有害影响负有责任。在这项提议中，我们试图确定准确的分子 机械装置。我们的初步数据显示，脂质体中的胆固醇被代谢成已知的氧化甾醇。 改变巨噬细胞的功能。在此基础上，我们推测脂质体氧化甾醇导致巨噬细胞。 抑制抗肿瘤免疫，促进肿瘤生长。值得注意的是，β-谷甾醇(A)的氧化代谢产物 植物甾醇)缺乏氧化甾醇的促癌炎症活性，这表明更有效的脂质体 药物配方可以用胆固醇的类似物来开发。这项建议的目标是 了解脂质体胆固醇的代谢并开发无致癌作用的胆固醇类似物 对脂质体药物制剂的影响。我们将通过进行时间依赖的方式来剖析代谢途径 在免疫细胞和小鼠模型中的研究。以确定代谢和细胞信号通路是 我们将在野生型和基因敲除小鼠以及捐赠者人类免疫细胞中进行机制研究。 最后，我们将设计和测试免疫细胞中胆固醇类似物的免疫和抗癌效果。 在癌症的小鼠模型中也是如此。我们的团队拥有成功完成任务所需的独特专业知识 这个项目的。这项提议预计将产生积极影响，解决当前 了解免疫系统在脂质体药物药理学中的作用以及氧化甾醇的作用 在癌症中。这很可能导致新的治疗靶点和药物配方策略，具有潜在的 极大地促进了癌症药物的投放和免疫治疗。

ABSTRACT Drug delivery using liposomes increases tumor drug accumulation while sparing normal tissue. Several liposomal chemotherapies are approved to treat cancer. Unfortunately, lipid nanoparticles such as liposomes interact with the immune system and their impact on the tumor immunologic milieu is largely unknown. We have reported that liposomes composed of phospholipids and cholesterol, similar to those used in patients, doubled tumor size in mice by suppressing the immune response against tumors. We recently identified macrophages as the cells that are responsible for these detrimental effects. In this proposal, we seek to identify the precise molecular mechanisms. Our preliminary data show that liposomal cholesterol is metabolized into oxysterols that are known to alter the function of macrophages. Based on this, we theorize that liposomal oxysterols cause macrophages to suppress antitumor immunity and enhance tumor growth. Notably, oxidized metabolites of beta-sitosterol (a plant sterol) lack the protumoral inflammatory activity of oxysterols, suggesting that more efficacious liposomal drug formulations can be developed using analogs of cholesterol. The objectives of this proposal are to understand the metabolism of liposomal cholesterol and to develop cholesterol analogs without tumorigenic effects for liposomal drug formulation. We will dissect the metabolism pathways by conducting time-dependent studies in immune cells and in mouse models. To identify the metabolic and cell signaling pathways that are involved, we will conduct mechanistic studies in wildtype and knockout mice, and donor human immune cells. Finally, we will design and test the immunological and anticancer effects of cholesterol analogs in immune cells and in mouse models of cancer. Our team has unique combined expertise necessary for successful completion of this project. This proposal is expected to have a positive impact by addressing critical gaps in current understanding of the role of the immune system in liposomal drug pharmacology and the role of oxidized sterols in cancer. This is likely to lead to new therapeutic targets and drug formulation strategies with potential to significantly advance both cancer drug delivery and immunotherapy.