CHOLESTEROL METABOLISM IN THE PHARMACOLOGY OF LIPOSOMAL THERAPEUTICS

脂质体治疗药理学中的胆固醇代谢

基本信息

批准号：
10715758
负责人：
Ninh La-Beck
金额：
$ 49.71万
依托单位：
TEXAS TECH UNIVERSITY HEALTH SCIS CENTER
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-19 至 2028-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10715758
关键词：
27-hydroxycholesterol Address Antineoplastic Agents Attenuated Blood Cells Cancer Model Cancer Patient Cell physiology Cells Cholesterol Cholesterol Homeostasis Clinical Clinical Trials Cytotoxic Chemotherapy Data Development Disease Doxorubicin Drug Carriers Drug Delivery Systems Drug Formulations Drug Kinetics Drug toxicity Encapsulated Enzymes FDA approved Failure Functional disorder Health Human Hydroxycholesterols Immune Immune System Diseases Immune response Immune system Immunologic Tests Immunologics Immunosuppression Immunotherapy In Vitro Inflammatory Interferon Type II Knockout Mice Knowledge Liposomal Doxorubicin Liposomes Macrophage Malignant Neoplasms Mediator Membrane Meta-Analysis Metabolic Metabolic Pathway Metabolism Mixed Function Oxygenases Modeling Molecular Mus Normal tissue morphology Pathogenesis Pathway interactions Patients Pharmaceutical Preparations Pharmacology Phospholipids Phytosterols Production Progression-Free Survivals Property Reporting Role STAT3 gene STAT6 gene Safety Signal Pathway Signal Transduction Sitosterols Solid Neoplasm Sterols Testing Therapeutic Therapeutic Effect Time Translating Tumor Antigens Tumor Immunity Wild Type Mouse Work analog anti-cancer anti-cancer therapeutic antigen-specific T cells biophysical properties cancer infiltrating T cells cancer therapy chemotherapy cholesterol analog design immune function immunoregulation improved in vivo inhibitor lipid metabolism lipid nanoparticle liposomal delivery liposomal formulation mouse model nanoparticle drug new therapeutic target novel novel anticancer drug objective response rate pharmacologic randomized, clinical trials response screening smoothened signaling pathway theories tumor tumor growth tumorigenic

项目摘要

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.

抽象的使用脂质体的药物输送会增加肿瘤药物的积累，同时不影响正常组织。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（例如脂质体）与免疫系统及其对肿瘤免疫环境的影响在很大程度上尚不清楚。我们曾报道过由磷脂和胆固醇组成的脂质体，与患者使用的相似，使肿瘤大小增加了一倍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有责任。在本提案中，我们寻求确定精确的分子机制。我们的初步数据表明，脂质体胆固醇代谢成已知的氧甾醇改变巨噬细胞的功能。基于此，我们推测脂质体氧甾醇会导致巨噬细胞抑制抗肿瘤免疫并促进肿瘤生长。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类似物来开发药物制剂。该提案的目标是了解脂质体胆固醇的代谢并开发无致瘤性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分析来剖析代谢途径免疫细胞和小鼠模型的研究。确定代谢和细胞信号传导途径我们将参与其中，对野生型和基因敲除小鼠以及捐赠的人类免疫细胞进行机制研究。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学和抗癌作用以及小鼠癌症模型中。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。该提案预计将通过解决当前的关键差距而产生积极影响。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。这可能会带来新的治疗靶点和药物配方策略，并有可能显着促进癌症药物输送和免疫治疗。