Photolabile lipids bilayers and liposomes

光不稳定脂质双层和脂质体

• 批准号: 6846580
• 负责人: ANDREI G KUTATELADZE
• 金额: $ 21.15万
• 依托单位: UNIVERSITY OF DENVER (COLORADO SEMINARY)
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-02-01 至 2008-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6846580
• 关键词: amphiphilicity; drug delivery systems; fluorescent dye /probe; green fluorescent proteins; lipid bilayer membrane; liposomes; method development; molecular shape; photochemistry; radiation sensitivity; transmission electron microscopy

DESCRIPTION (provided by applicant): The goal of this proposal is to develop a general modular approach to photolabile amphiphiles, suitable for preparation of liposomes that (i) can entrap a biological effecter, such as a pharmaceutical, and (ii) can release their content upon irradiation. Furthermore, we aim to design such a delivery system, for which the photorelease is conditional, i.e. before the system becomes light-sensitive, a triggering event has to occur to "arm" the system. The PI has developed methodology, based on photoinduced carbon-carbon bond fragmentation in hydroxy- (or amino) alkyl dithiane and trithiane derivatives, which offers a ready access to various molecular and macromolecular systems capable of photochemical "disassembly". This basic photochemical methodology will be further optimized to suit the goals of this research. Our general approach, which is based on externally sensitized systems, is inherently suitable for these applications. This is because the potentially photocleavable dithiane-based amphiphiles are not light sensitive per se, but can be made light sensitive when an external stimulus is applied, for example, a molecular recognition event brings a sensitizer/initiator closer to the dithiane-carbonyl photolabile "latch". An integral part of this project will be to synthesize photolabile lipids tethered to polyethylene glycol polymeric chains for stealth liposome fabrication. Such liposomes will be able to shed their polymeric coat upon irradiation, thus dramatically changing their stability. The fundamentals of these type delivery vesicles will be demonstrated on a model system, whereby a fluorescent molecular probe will be delivered to a living cell using RGD-integrin recognition as a model targeting mechanism. We will demonstrate docking of the vesicles to the cell wall and internalization of the probe molecules upon irradiation. These studies will lay the groundwork for design and development of targeted stealth liposomes that can be used in various molecular biology applications to deliver biological effecters to living cells and internalize them upon irradiation (a kind of photoinduced endocytosis). Ultimately, these studies will pave way for development of photolabile targeted liposomes for drug delivery.

描述（由申请人提供）：本提案的目的是开发一种适用于制备脂质体的光不稳定两亲物的通用模块化方法，该脂质体（i）可以捕获生物效应物，如药物，（ii）可以在辐照时释放其内容物。此外，我们的目标是设计这样的递送系统，其中光释放是有条件的，即在系统变得光敏之前，必须发生触发事件以“装备”系统。PI开发了基于羟基-（或氨基）烷基二噻烷和三噻烷衍生物中光诱导碳-碳键断裂的方法，该方法提供了能够进行光化学“分解”的各种分子和大分子系统的便捷途径。这种基本的光化学方法将进一步优化，以适应本研究的目标。我们的一般方法，这是基于外部敏化系统，本质上是适合这些应用。这是因为潜在的可光裂解的基于二噻烷的两亲物本身不是光敏的，但是当施加外部刺激时可以变得光敏，例如，分子识别事件使敏化剂/引发剂更接近二噻烷-羰基光不稳定的“闩锁”。 该项目的一个组成部分将是合成与聚乙二醇聚合物链相连的光不稳定脂质，用于隐形脂质体制造。这样的脂质体将能够在照射时脱落它们的聚合物涂层，从而显著改变它们的稳定性。 这些类型的递送囊泡的基本原理将在模型系统上得到证明，由此荧光分子探针将使用RGD-整联蛋白识别作为模型靶向机制递送到活细胞。我们将展示囊泡与细胞壁的对接和照射后探针分子的内化。这些研究将为靶向隐形脂质体的设计和开发奠定基础，该脂质体可用于各种分子生物学应用，以将生物效应物递送至活细胞并在照射后使其内化（一种光诱导的内吞作用）。最终，这些研究将为开发用于药物递送的光不稳定靶向脂质体铺平道路。