Liposome Targeting and Triggered Release Driven by Reactive Oxygen Species

活性氧驱动的脂质体靶向和触发释放

• 批准号: 10439073
• 负责人: Michael D. Best
• 金额: $ 45.9万
• 依托单位: UNIVERSITY OF TENNESSEE KNOXVILLE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10439073
• 关键词: Address; Advanced Development; Automobile Driving; Biological Assay; Blood Circulation; Cell Separation; Cells; Charge; Clinic; Clinical; Development; Disease; Drug Delivery Systems; Drug Kinetics; Drug Targeting; Engineering; Evaluation; Excision; Exhibits; Fluorescence Microscopy; Formulation; Goals; Infiltration; Length; Lipids; Liposomes; Masks; Mediating; Membrane; Membrane Fusion; Modeling; Peptides; Performance; Pharmaceutical Preparations; Population; Property; Reaction; Reactive Oxygen Species; Research; Scheme; Series; Specificity; Structure; Techniques; Technology; Therapeutic; Therapeutic Agents; Tissues; Translating; Work; cell type; clinical efficacy; controlled release; design; guanidinium; improved; innovation; liposomal delivery; liposome vector; nanocarrier; next generation; novel strategies; overexpression; oxidation; small molecule; spatiotemporal; success

Project Summary Liposomes are supramolecular lipid assemblies that are highly effective at entrapping, delivering, and enhancing the pharmacokinetic properties of a variety of drug cargo with poor performance in the absence of a nanocarrier. However, achieving both liposome targeting and spatiotemporal control over release with high diseased-cell specificity remains a significant challenge that must be overcome to optimize drug potency and minimize off-target effects. Our approach to surmount these issues entails the development of “smart” liposomes that respond to overly abundant reactive oxygen species (ROS) to localize drug delivery to diseased cells. To this end, we have pioneered the development of ROS-responsive liposomes designed to selectively trigger therapeutic cargo release in the presence of upregulated ROS. These liposomes harness synthetic lipid switches in which oxidative cleavage of caging groups leads to lipid decomposition that destabilizes the liposome membrane to trigger content release. Herein, we propose to develop next-generation ROS-directed liposomes that will mark a significant technological advance toward clinical viability. The proposed work will achieve this goal by developing liposomes that include both activatable cell-targeting groups and lipid switches that exhibit ROS-responsive properties. First, we will maximize payload release through the development of advanced immolating lipid structures that facilitate complete liposome breakdown upon oxidation by ROS (Aim 1). These structures will exploit programmed intramolecular reactions that degrade ROS-responsive lipid switches into non-liposome-forming small molecules. Second, we will develop a series of caged cell-penetrating peptide- (CPP-)lipid conjugates that will activate cell targeting and entry only following ROS oxidation (Aim 2). These compounds will exploit the exceptional cell delivery properties of CPPs while solving their primary drawback of poor selectivity. Finally, ROS-responsive lipid switches and activatable targeting groups, both separately and in combination, will undergo comprehensive liposome release and cellular delivery evaluations to identify optimal structures and formulations that maximize therapeutic delivery and diseased-cell specificity (Aim 3). These studies are expected to culminate in new clinically effective liposomal technology as “smart” carriers exhibiting diseased cell specificity and optimized release properties.

项目摘要 脂质体是超分子脂质组装体，其在包封、递送 以及增强各种性能差的药物货物的药代动力学性质 在不存在纳米载体的情况下。然而，实现脂质体靶向和时空靶向两者， 控制具有高疾病细胞特异性的释放仍然是一个重大的挑战， 以优化药物效力并最小化脱靶效应。我们的方法是超越 这些问题需要开发“智能”脂质体， 活性氧（ROS）来定位药物递送至患病细胞。为此我们 开创了ROS响应脂质体的发展，旨在选择性地触发 在存在上调的ROS的情况下的治疗性货物释放。这些脂质体利用 合成脂质开关，其中笼状基团的氧化裂解导致脂质分解 其使脂质体膜不稳定以触发内容物释放。在此，我们建议 开发下一代ROS导向脂质体，这将标志着一个重要的技术 向临床可行性迈进。 拟议的工作将通过开发脂质体来实现这一目标， 细胞靶向基团和表现出ROS响应特性的脂质开关。一是 通过开发先进的牺牲脂质结构， 促进脂质体在被ROS氧化时完全分解（目的1）。这些结构将 利用程序化的分子内反应，将ROS响应性脂质开关降解为 非脂质体形成小分子。其次，我们将开发一系列的笼状细胞穿透 肽-（CPP-）脂质缀合物将激活细胞靶向和仅在ROS后进入 氧化（目标2）。这些化合物将利用CPP的特殊细胞递送特性 同时解决了它们选择性差的主要缺点。最后，ROS响应脂质开关 和可激活的靶向组，无论是单独还是组合，将进行全面的 脂质体释放和细胞递送评价以鉴定最佳结构和制剂 最大化治疗传递和疾病细胞特异性（目标3）。这些研究 有望在新的临床有效的脂质体技术作为“智能”载体达到高潮 表现出患病细胞特异性和优化的释放性质。