Synthetic Lipid Switches for Controlling Liposome Assembly and Release

非技术概述脂质体能包裹多种物质，并以限制副作用的方式将这些内容物输送到细胞，因此在增强治疗剂输送方面是很有前途的分子载体。虽然利用脂质体改善给药性能已经取得了很大的进展，但仍然存在一些挑战。特别是，控制封装内容发布的位置和时间的能力一直是一个长期的障碍。在这个项目中，人们正在寻求一种新的脂质体控制释放的范例，通过这种范例，货物的排放是由特定的生物分子在疾病细胞及其周围过度表达引起的。为此，将开发由合成脂类组成的设计脂质体，在生物物种存在的情况下，其组装性质会发生变化，从而导致内容物释放。该项目将通过提高操纵脂质体组装属性的能力，并对这些属性因不同的化学和生物条件而发生的变化进行编程，从而导致基础性的科学进步。这项工作还将促进国民健康，因为它将产生旨在改善脂质体治疗性能的新技术。技术概述脂质体具有许多有利的属性，因为它们是生物相容性的纳米载体，可以同时包裹疏水和亲水分子货物。因此，人们对开发可以控制其自组装特性的设计脂质体产生了极大的兴趣。特别令人感兴趣的是当存在不同刺激时触发封装内容的释放的能力。在这个项目中，提出了一种新的策略，通过与化学物种的结合作用来触发脂质体的释放。为此，将开发可切换的脂类，其设计用于经历构象变化，这些构象变化破坏膜性质并在与目标分子形成结合作用时触发内容物释放。这项研究将探索如何利用合成类脂类似物的设计来调节脂质体的超分子性质。具体地说，将开发包含嵌入在其结构中用于结合靶分子的分子识别基团的可切换脂质类似物。这些脂类的设计使得它们最初会形成稳定的膜双层。然而，一旦与靶分子形成主客体结合作用，这些脂类就会发生构象变化，破坏脂膜的稳定性，从而改变脂类的堆积和自组装特性，并触发内容物的释放。在该项目期间进行的研究将需要对这些可切换脂质的设计、合成和评估进行全面的努力，以评估和优化控制释放性能。最初的研究将集中在了解含有这些脂类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和运送具有不同性质的包裹货物的能力。通过这种方式，拟议的研究为调节脂基纳米材料的自组装特性提供了创新的方法。这一奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

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.