Synthetic Lipid Switches for Controlling Liposome Assembly and Release

用于控制脂质体组装和释放的合成脂质开关

• 批准号: 1807689
• 负责人: Michael Best
• 金额: $ 45万
• 依托单位: University of Tennessee Knoxville
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1807689&HistoricalAwards=false
• 关键词: Synthetic; Lipid; Switches; Controlling; Liposome

Non-Technical SummaryLiposomes represent promising molecular carriers for enhancing the delivery of therapeutic agents due to their ability to encapsulate a wide range of cargo and deliver these contents to cells in a manner that limits side effects. While great advancements have been made to improve delivery properties using liposomes, several challenges remain. In particular, the ability to control the location and time of the release of encapsulated contents has been a longstanding obstacle. In this project, a novel paradigm for controlled release from liposomes is being pursued by which the discharge of cargo is caused by specific biological molecules that are overexpressed in and around diseased cells. Toward this end, designer liposomes composed of synthetic lipids will be developed that undergo changes in assembly properties in the presence of biological species to cause the release of contents. This project will result in fundamental scientific progress by advancing the ability to manipulate the assembly properties of liposomes and to program changes in these properties that occur in response to different chemical and biological conditions. This work will also advance national health as it will culminate in new technology aimed at improving the therapeutic properties of liposomes.Technical SummaryLiposomes exhibit many favorable attributes as they are biocompatible nanocarriers that can encapsulate both hydrophobic and hydrophilic molecular cargo. As such, there has been significant interest in developing designer liposomes by which their self-assembly properties can be controlled. Of particular interest is the ability to trigger the release of encapsulated contents when in the presence of different stimuli. In this project, novel strategies are proposed for triggering release from liposomes driven by binding interactions with chemical species. Toward this end, switchable lipids will be developed that are designed to undergo conformational changes that destabilize membrane properties and trigger content release upon the formation of binding interactions with target molecules. This research will investigate how the design of synthetic lipid analogs can be used to modulate the supramolecular properties of liposomes. In particular, switchable lipid analogs will be developed that contain molecular recognition groups embedded within their structures for the binding of target molecules. These lipids are designed such that they will initially form stable membrane bilayers. However, upon the formation of host-guest binding interactions with target molecules, these lipids are envisaged to undergo conformational changes that destabilize the liposome membrane, thereby altering lipid packing and self-assembly properties, and triggering the release of contents. The research performed during this project will entail comprehensive efforts for the design, synthesis and assessment of these switchable lipids to evaluate and optimize controlled release properties. Initial studies will be focused on understanding the fundamental release properties of liposomes containing these lipids. Subsequently, the ability of these designer liposomes to infiltrate cells and deliver encapsulated cargo with different properties will be evaluated. In this way, the proposed studies provide innovative approaches for modulating the self-assembly properties of lipid-based nanomaterials.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

非技术摘要脂质体代表了有前途的分子载体，可增强治疗剂的递送，因为它们能够封装多种货物并以限制副作用的方式将这些内容物递送至细胞。尽管在使用脂质体改善递送特性方面已经取得了巨大进步，但仍然存在一些挑战。特别是，控制封装内容物释放位置和时间的能力一直是一个长期存在的障碍。在该项目中，正在寻求一种脂质体受控释放的新范例，通过该范例，货物的释放是由在患病细胞内和周围过度表达的特定生物分子引起的。为此，将开发由合成脂质组成的设计脂质体，该脂质体在生物物种存在的情况下会发生组装特性的变化，从而导致内容物的释放。该项目将通过提高操纵脂质体组装特性的能力以及对这些特性因不同化学和生物条件而发生的变化进行编程的能力，从而取得基础性的科学进步。这项工作还将促进国民健康，因为它将最终产生旨在改善脂质体治疗特性的新技术。技术摘要脂质体表现出许多有利的属性，因为它们是生物相容性纳米载体，可以封装疏水性和亲水性分子货物。因此，人们对开发可控制其自组装特性的设计脂质体产生了浓厚的兴趣。特别令人感兴趣的是在存在不同刺激时触发封装内容物释放的能力。在该项目中，提出了通过与化学物质的结合相互作用来触发脂质体释放的新策略。为此，将开发可转换的脂质，其设计用于经历构象变化，从而破坏膜特性的稳定并在与目标分子形成结合相互作用时触发内容物释放。这项研究将研究如何设计合成脂质类似物来调节脂质体的超分子特性。特别是，将开发可转换的脂质类似物，其结构中嵌入有分子识别基团，用于结合目标分子。这些脂质被设计成它们最初会形成稳定的膜双层。然而，在与靶分子形成主客体结合相互作用后，这些脂质预计会发生构象变化，使脂质体膜不稳定，从而改变脂质堆积和自组装特性，并引发内容物的释放。该项目期间进行的研究将需要对这些可转换脂质的设计、合成和评估进行全面的努力，以评估和优化控释特性。初步研究将集中于了解含有这些脂质的脂质体的基本释放特性。随后，将评估这些设计的脂质体渗透细胞并递送具有不同特性的封装货物的能力。通过这种方式，拟议的研究为调节脂质纳米材料的自组装特性提供了创新方法。该奖项反映了 NSF 的法定使命，并通过使用基金会的智力优点和更广泛的影响审查标准进行评估，被认为值得支持。

项目成果

ATP-Responsive Liposomes via Screening of Lipid Switches Designed to Undergo Conformational Changes upon Binding Phosphorylated Metabolites

• DOI: 10.1021/jacs.2c00191
• 发表时间: 2022-03-02
• 期刊: JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
• 影响因子: 15
• 作者: Lou, Jinchao;Schuster, Jennifer A.;Best, Michael D.
• 通讯作者: Best, Michael D.

Liposome triggered content release through molecular recognition of inositol trisphosphate

脂质体通过肌醇三磷酸的分子识别触发内容物释放

• DOI: 10.1039/d2cc00951j
• 发表时间: 2022
• 期刊: Chemical Communications
• 影响因子: 4.9
• 作者: Bottcher, Sydney E.;Lou, Jinchao;Best, Michael D.
• 通讯作者: Best, Michael D.

Sticking the Landing: Enhancing Liposomal Cell Delivery using Reversible Covalent Chemistry and Caged Targeting Groups

坚持着陆：利用可逆共价化学和笼状靶向基团增强脂质体细胞递送

• DOI: 10.1002/cbic.202200436
• 发表时间: 2022
• 期刊: ChemBioChem
• 影响因子: 3.2
• 作者: Lou, Jinchao;Qualls, Megan L.;Best, Michael D.
• 通讯作者: Best, Michael D.

Bis‐Boronic Acid Liposomes for Carbohydrate Recognition and Cellular Delivery

用于碳水化合物识别和细胞递送的双硼酸脂质体

• DOI: 10.1002/cbic.202200402
• 发表时间: 2022
• 期刊: ChemBioChem
• 影响因子: 3.2
• 作者: Qualls, Megan L.;Hagewood, Hannah;Lou, Jinchao;Mattern‐Schain, Samuel I.;Zhang, Xiaoyu;Mountain, Deidra J.;Best, Michael D.
• 通讯作者: Best, Michael D.

Cell mimetic liposomal nanocarriers for tailored delivery of vascular therapeutics

• DOI: 10.1016/j.chemphyslip.2018.12.009
• 发表时间: 2019-01-01
• 期刊: CHEMISTRY AND PHYSICS OF LIPIDS
• 影响因子: 3.4
• 作者: Mattern-Schain, Samuel I.;Fisher, Richard K.;Mountain, Deidra J. H.
• 通讯作者: Mountain, Deidra J. H.