Collaborative Research: Mechano-Lipidomics and Mechano-Cytosis of Drug Delivery Liposomes

合作研究：药物递送脂质体的机械脂质组学和机械胞质作用

• 批准号: 1232339
• 负责人: Robert Campbell
• 金额: $ 7.52万
• 依托单位: Massachusetts College of Pharmacy
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-10-01 至 2016-09-30
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1232339&HistoricalAwards=false
• 关键词: Collaborative; Research; Mechano; Lipidomics; Cytosis

The research goal of this proposal is to build a comprehensive model of mechano-lipidomics and mechanocytosis by designing careful experiments and constructing solid-mechanics based models that are consistent with the classical understanding of membrane fusion mechanics. Nano-/micro-scale liposomes and freestanding membranes will be fabricated using common drug delivery lipids and lipid extracts from cell membrane of ovarian cancer cells. Empirical investigations will include: (i) membrane-elasticity characterization, where a nano-indenter or AFM tip indents and taps the sample vesicles and freestanding membranes, and an optical microscope monitors and records the deformed profiles in-situ; and (ii) mechano-cytosis test, where a mechanical probe forces endocytosis of a liposome into a freestanding membrane or to another liposome. A comprehensive model of deformation-adhesion-endocytosis mechanics will be constructed based on (i) linear elastic approximation, (ii) visco-hyperelastic behavior of lipid membranes, (iii) nonspecific intersurface forces at liposome-membrane and liposome-liposome interfaces, (iv) thermodynamic energy balance for adhesion-fusion. Analytical solutions will first be derived by assuming axisymmetric geometries, linear elastic material responses, and square-well adhesion potential (i.e. cohesive zone approximation), in order to identify the system parameters. The more realistic but sophisticated materials laws and surface potential will then be implemented using numerical routines. Despite progress in empirical design of drug delivery liposomes, mechanical deformation is missing from the fundamental understanding of lipid membrane fusion and endocytotic energetics. This research will address this shortcoming by designing feasible experiments to investigate the mechanical aspects of lipid membranes and liposomes with a focus in mechano-cytosis and constructing biomechanics models, aiming to build mechano-lipidomics. The research will addres a small but critical part of mechano-lipidomics, rather than building a comprehensive model for lipidomics and drug delivery. Outcomes from these measurements, models and analysis will be used by pharmacist to design and fabricate the next generation of drug delivery liposomes to be tested in-vivo in the future.

该提案的研究目标是通过设计仔细的实验​​并构建基于固体力学的模型来构建机械 - 脂质细胞和机械核细胞增多症的综合模型，这些模型与对膜融合力学的经典理解一致。纳米/微尺度脂质体和独立膜将使用卵巢癌细胞细胞膜的常见药物递送脂质和脂质提取物制成。实证研究将包括：（i）膜弹性表征，其中纳米式或AFM尖端凹痕并敲击样品囊泡和独立膜，以及光学显微镜监测器，并记录了Situ中的变形曲线； （ii）机械性 - 胞菌病测试，其中机械探针会将脂质体的内吞作用加入独立膜或另一个脂质体。将基于（i）线性弹性近似，（ii）脂质膜的粘性 - 混音行为，（iii）非特异性互感的粘性 - 透明度行为，（III）非特异性的互感性在Liposome-membrane和Liposome-mosome-liposome-liposome-liposome interface intody-fromplose（III）基础上构建变形 - 粘附性 - 粘着性化学力学的综合模型。为了识别系统参数，将首先通过假设轴对称几何形状，线性弹性材料响应和方形粘附电位（即凝聚区近似）来得出分析溶液。然后，将使用数值例程实施更现实但复杂的材料法律和表面电位。尽管在药物输送脂质体的经验设计方面取得了进展，但对脂质膜融合和内吞能量学的基本了解仍缺少机械变形。这项研究将通过设计可行的实验来解决这一缺点，以研究脂质膜和脂质体的机械方面，并重点是机械性 - 胞植物和构建生物力学模型，旨在构建机械脂肪态学。这项研究将增加机械脂质态学的一个小但关键的部分，而不是为脂肪态学和药物递送的综合模型。这些测量结果，模型和分析的结果将被药剂师使用，以设计和制造下一代的药物递送脂质体，以将来在体内进行测试。