Photolabile lipids bilayers and liposomes

描述（由申请人提供）：本提案的目标是开发一种通用的模块化方法，用于制备脂质体(i)可以捕获生物效应剂，例如药物，并且（ii）可以在照射后释放其内容物。此外，我们的目标是设计这样一个传输系统，其光释放是有条件的，即在系统变得光敏之前，必须发生触发事件来“武装”系统。PI开发了一种基于羟基（或氨基）烷基二硫烷和三硫烷衍生物的光诱导碳-碳键断裂的方法，这种方法为能够光化学“分解”的各种分子和大分子系统提供了一种现成的途径。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。我们基于外部敏化系统的一般方法天生就适合这些应用。这是因为潜在的光可切割的二硫乙烯基两亲体本身不是光敏的，但当外部刺激被应用时，可以使光敏，例如，分子识别事件使敏剂/引发剂更接近二硫乙烯-羰基光敏“锁存器”。

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.