Photolabile lipids bilayers and liposomes

光不稳定脂质双层和脂质体

• 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
• 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
• 来源: https://reporter.nih.gov/project-details/7173011
• 关键词: Aldehydes; Area; Benzophenones; Biological; Biological Models; Burn injury; Carbon; Cell Wall; Cells; Cholesterol; Choline; Classification; Development; Docking; Drug Delivery Systems; Drug Formulations; Endocytosis; Ensure; Event; Fibroblasts; Goals; Green Fluorescent Proteins; Head; Incubated; Integrin Binding; Integrins; Life; Light; Link; Lipid Bilayers; Lipids; Liposomes; Membrane; Methodology; Modeling; Molecular; Molecular Biology; Molecular Probes; Object Attachment; Pharmacologic Substance; Polyethylene Glycols; Preparation; Process; RGD (sequence); Reaction; Research; Rhodamine; Rhodamines; Stimulus; Structure; System; Tail; Testing; Time; Upper arm; Vesicle; adduct; base; benzophenone; design; dithiane; improved; irradiation; molecular recognition

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）：本提案的目标是开发一种通用的模块化方法来处理对光不稳定的两亲物，适用于制备脂质体，该脂质体（i）可以捕获生物效应物，例如药物，并且（ii）可以释放其辐照后的含量。此外，我们的目标是设计这样一种传输系统，其光释放是有条件的，即在系统变得对光敏感之前，必须发生触发事件来“武装”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，该方法为各种能够进行光化学“分解”的分子和大分子系统提供了方便的途径。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。我们基于外部敏感系统的通用方法本质上适合这些应用。这是因为潜在的可光裂解的二噻烷基两亲物本身对光不敏感，但当施加外部刺激时可以变得对光敏感，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”闩锁”。 该项目的一个组成部分是合成与聚乙二醇聚合物链相连的光不稳定脂质，用于隐形脂质体的制造。这种脂质体在辐射后能够脱落其聚合物涂层，从而显着改变其稳定性。 这些类型的递送囊泡的基本原理将在模型系统上得到演示，其中荧光分子探针将使用 RGD-整合素识别作为模型靶向机制被递送到活细胞。我们将演示囊泡与细胞壁的对接以及照射后探针分子的内化。这些研究将为设计和开发靶向隐形脂质体奠定基础，该脂质体可用于各种分子生物学应用，将生物效应物传递到活细胞并在照射时将其内在化（一种光诱导内吞作用）。最终，这些研究将为开发用于药物输送的光不稳定靶向脂质体铺平道路。

项目成果

When ethyl is infinitely different from methyl: double addition of lithiated dithianes to aromatic carboxylates revisited.

当乙基与甲基无限不同时：重新审视锂化二噻烷与芳香族羧酸盐的双重加成。

• 发表时间: 2006-06-23
• 作者: Valiulin, Roman A;Kottani, Rudresha;Kutateladze, Andrei G
• 通讯作者: Kutateladze, Andrei G

Direct screening of solution phase combinatorial libraries encoded with externally sensitized photolabile tags.

直接筛选用外部敏化的不稳定性标签编码的溶液相组合文库。

• 发表时间: 2006-09-19
• 影响因子: 11.1
• 作者: Kottani, Rudresha;Valiulin, Roman A;Kutateladze, Andrei G
• 通讯作者: Kutateladze, Andrei G

Photolabile Amphiphiles with Fluorogenic Thioxanthone-Dithiane Functionality: Synthesis and Photoinduced Fragmentation in Micelles.

具有荧光噻吨酮-二噻烷功能的光不稳定两亲物：胶束中的合成和光诱导断裂。

• 发表时间: 2008
• 作者: Ezhov, Roman N;Rozhkov, Vladimir V;Majjigapu, Janaki R R;Kutateladze, Andrei G
• 通讯作者: Kutateladze, Andrei G

Photoactive barbiturate receptors: an ultimate lock-and-key system in which the key unlocks the lock.

光活性巴比妥酸盐受体：一种终极的锁钥匙系统，钥匙可以打开锁。

• 发表时间: 2007-03-15
• 影响因子: 5.2
• 作者: Lakkakula, Suman;Mitkin, Oleg D;Valiulin, Roman A;Kutateladze, Andrei G
• 通讯作者: Kutateladze, Andrei G

Release and report: a new photolabile caging system with a two-photon fluorescence reporting function.

发布和报告：一种具有双光子荧光报告功能的新型不稳定性囚禁系统。

• DOI: 10.1021/ja053654m
• 发表时间: 2005-09-14
• 期刊: Journal of the American Chemical Society
• 影响因子: 15
• 作者: Janaki R R Majjigapu;A. Kurchan;R. Kottani;Tiffany P. Gustafson;A. Kutateladze
• 通讯作者: A. Kutateladze