Liposome Targeting and Triggered Release Driven by Reactive Oxygen Species

项目摘要 脂质体是一种超分子脂质组合物，具有高效的包埋、递送、 增强多种性能较差的药物载体的药代动力学特性 在没有纳米载体的情况下。然而，同时实现脂质体靶向性和时空靶向性 控制具有高度病态细胞特异性的释放仍然是一项重大挑战，必须 被克服，以优化药物效力，并最大限度地减少偏离目标的影响。我们超越的方法 这些问题需要开发“智能”脂质体，以应对过多的脂肪 活性氧物种(ROS)，以定位药物输送到疾病细胞。为此，我们有 率先开发了ROS反应脂质体，旨在选择性地引发 在ROS上调的情况下，治疗性货物的释放。这些脂质体可以利用 笼状基团氧化裂解导致脂类分解的合成脂类开关 这会破坏脂质体膜的稳定性，从而引发内容物释放。在此，我们建议 开发下一代ROS定向脂质体，这将标志着一项重要的技术 向临床可行性迈进。 拟议的工作将通过开发包括两种可激活的脂质体实现这一目标 表现出ROS反应特性的细胞靶向基团和脂质开关。首先，我们将 通过开发先进的牺牲脂质结构来最大限度地释放有效载荷 促进脂质体在被ROS氧化时完全分解(目标1)。这些结构将 利用程序化分子内反应将ROS响应性脂质开关降解为 非脂质体形成的小分子。第二，我们将开发一系列笼式细胞穿透 仅在ROS之后才能激活细胞靶向和进入的多肽-(CPP-)脂质结合物 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反应的脂质开关 和可激活的目标群体，无论是单独的还是组合的，都将经历全面的 确定最佳结构和制剂的脂质体释放和细胞递送评价 最大限度地提高治疗效果和疾病细胞特异性(目标3)。这些研究是 有望在临床上有效的新脂质体技术中达到顶峰，成为“智能”载体 表现出病态的细胞专一性和最佳的释放特性。

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.