Photolabile lipids bilayers and liposomes

光不稳定脂质双层和脂质体

基本信息

批准号：
7173011
负责人：
ANDREI G KUTATELADZE
金额：
$ 20.77万
依托单位：
UNIVERSITY OF DENVER (COLORADO SEMINARY)
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-02-01 至 2009-01-31
项目状态：
已结题

项目摘要

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）：该提案的目的是开发一种通用的模块化方法，以制定适合（i）可以诱使生物学效应剂（例如药物）的脂质体制备，例如药物和（ii）可以在照射下释放其含量。此外，我们旨在设计这样的输送系统，为此，光线发光是有条件的，即在系统变得光敏之前，必须发生“臂”系统的触发事件。 PI基于羟基（或氨基）烷基二烷和Trithiane衍生物中的光诱导的碳碳键碎片开发了方法，该衍生物可随时可以访问能够具有光化学“拆卸”的各种分子和大分子系统。这种基本的光化学方法将进一步优化，以适应这项研究的目标。我们的一般方法基于外部灵敏的系统，它本质地适合这些应用。这是因为潜在的基于二硫化二硫代的两亲本可能不是轻灵敏感，但是当应用外部刺激时，可以使光敏度敏感，例如，分子识别事件使敏化器/引发剂会使更接近Dithiane-Carbonyl Photolabile“ latch”。该项目不可或缺的一部分是合成将光纤维脂质绑在聚乙烯甘油聚合物链上以进行隐形脂质体制造。这样的脂质体将能够在辐照后脱掉它们的聚合物外套，从而极大地改变其稳定性。这些类型递送囊泡的基本面将在模型系统上证明，从而使用RGD-整合素识别作为模型靶向机制将荧光分子探针传递到活细胞。我们将在照射后将囊泡对接到细胞壁和探针分子的内在化。这些研究将为靶向隐形脂质体设计和开发奠定基础，这些脂质体可用于各种分子生物学应用，以在辐射后传递生物学效应剂并在辐射后内化（一种光诱导的内吞作用）。最终，这些研究将为开发具有靶向脂质体的靶向脂质体铺平道路。