CHOLESTEROL METABOLISM IN THE PHARMACOLOGY OF LIPOSOMAL THERAPEUTICS

摘要 使用脂质体的药物递送增加肿瘤药物积聚，同时保留正常组织。几种脂质体 化疗被批准用于治疗癌症。不幸的是，脂质纳米颗粒如脂质体与脂质体相互作用。 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 脂质体由磷脂和胆固醇组成，与患者使用的脂质体相似， 通过抑制小鼠对肿瘤的免疫反应。我们最近发现巨噬细胞是 对这些有害影响负责。在这个建议中，我们试图确定精确的分子 机制等我们的初步数据表明，脂质体胆固醇代谢成氧化固醇， 来改变巨噬细胞的功能基于此，我们推测脂质体氧固醇导致巨噬细胞 抑制抗肿瘤免疫并增强肿瘤生长。值得注意的是，β-谷甾醇的氧化代谢物（a 植物甾醇）缺乏氧甾醇的促肿瘤炎症活性，这表明更有效的脂质体 可以使用胆固醇的类似物开发药物制剂。本提案的目标是 了解脂质体胆固醇的代谢，并开发不致癌的胆固醇类似物 对脂质体药物制剂的影响。我们将通过进行时间依赖性的 免疫细胞和小鼠模型的研究。为了确定代谢和细胞信号传导途径， 我们将在野生型和基因敲除小鼠以及供体人免疫细胞中进行机制研究。 最后，我们将设计并测试胆固醇类似物在免疫细胞中的免疫和抗癌作用 和小鼠癌症模型中的研究。我们的团队拥有成功完成所需的独特综合专业知识 这个项目的。预计这一提议将产生积极影响，解决目前存在的重大差距， 了解免疫系统在脂质体药物药理学中的作用和氧化甾醇的作用 在癌症中。这可能导致新的治疗靶点和药物制剂策略， 显著地促进了癌症药物递送和免疫治疗。

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.