Bridging multiple scales in modeling targeted drug nanocarrier delivery

在靶向药物纳米载体输送建模中桥接多个尺度

• 批准号: 8554530
• 负责人: DAVID M ECKMANN
• 金额: $ 54.04万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-20 至 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8554530
• 关键词: Accounting; Acute; Acute Lung Injury; Adhesions; Adhesives; Adopted; Adult Respiratory Distress Syndrome; Affinity; Animal Experiments; Anti-Inflammatory Agents; Antibodies; Antigens; Antioxidants; Avidity; Behavior; Binding; Blood; Blood Platelets; Blood Vessels; Blood flow; Cell Adhesion; Cell Culture Techniques; Cells; Cereals; Characteristics; Clinical; Computational Technique; Computer Simulation; Computing Methodologies; Dependence; Development; Dimensions; Disease; Drug Delivery Systems; Drug Formulations; Drug Targeting; Elements; Endothelial Cells; Endothelium; Entropy; Epitopes; Equilibrium; Experimental Models; Freedom; Glycocalyx; Goals; Hematocrit procedure; Human; Hyperoxia; In Vitro; Intercellular adhesion molecule 1; Ischemia; Kinetics; Length; Life; Ligands; Lubrication; Lung; Lung diseases; Measures; Mechanics; Mediating; Methodology; Methods; Microscopic; Modeling; Molecular; Molecular Models; Motion; Organ; Oxidative Stress; Particulate; Physics; Pneumonia; Polymers; Reperfusion Therapy; Research; Resistance; Rodent; Rotation; Sampling; Scheme; Specificity; Surface; System; Techniques; Therapeutic; Time; Translations; Validation; Work; antigen antibody binding; base; body system; clinical application; density; design; in vivo; intercellular cell adhesion molecule; molecular dynamics; molecular modeling; multi-scale modeling; nanocarrier; particle; public health relevance; receptor; receptor density; research study; shear stress; simulation; synergism; therapy design

DESCRIPTION (provided by applicant): In targeted vascular drug delivery a wide range of length and time scales are required for describing the physics of hydrodynamic and microscopic molecular interactions mediating nanocarrier (NC) motion in blood flow and endothelial cell binding. We can incorporate features of NC design and optimization for clinical applications, including NC dimension, concentration, density of targeting molecules and characteristics of linkers used to attach targeting molecules into computational models bridging the relevant multiple scales. Simulations can limit the need for large scale n vivo and in vitro experimentation. We hypothesize that development of computational techniques required to bridge relevant molecular dynamics, mesoscale binding interactions and hydrodynamics governing NC transport and cellular adhesion is essential to establishing multiscale computation as a means of optimizing endothelial-targeted, NC-based drug delivery. While our main associated therapeutic goal is to optimize endothelial delivery of antioxidant and anti-inflammatory agents for alleviation of acute pulmonary inflammation and oxidative stress in conditions such as acute lung injury (ALI/ARDS) and ischemia-reperfusion (I/R) in which pulmonary endothelial ICAM-1 surface density increases, the modeling is adaptable for vascular endothelial targeting n any organ system. Our bridged modeling will be validated through synergistic cell cultue and animal experiments of binding of selectively developed NCs. This will be studied va three specific aims: Aim 1: Implement multiscale modeling of hydrodynamic and microscopic interactions of NC motion in blood flow. We will develop bridging techniques to account rigorously for multiple length and time scales to treat multivalent adhesion interactions and hydrodynamic and near-wall effects of glycocalyx flow and resistance. Aim 2: Develop a stochastic multiscale adhesion model of NC binding to endothelial cells mediated by multivalent antigen-antibody interactions. The model will bridge multiple degrees of freedom at different length scales to incorporate: (i) NC translation and rotation as well as antigen/antibody translation, orientation and flexure~ (ii) effect of tethers mediating conformational accessibility and binding~ (iii) effects of flow and resistance due to glycocalyx captured in Aim 1~ and (iv) a bridging technique developed to integrate molecular models of binding interactions with the mesoscale NC model. Computational modeling approaches will be tuned using sensitivity analysis. Aim 3: Experimentally quantify NC targeting kinetics in vitro and in vivo using NCs incorporating a range of tethered single-chain variable fragments (scFv) and alternative surface molecules for anti-ICAM activity, using different length PEG tethers on different size NCs at varying surface density. Validation of numerical simulations will be based on direct comparison of predictions with experimental measures of cell binding. Our modeling and experimental approaches will enable us to develop and bridge multiscale techniques for clinical translation.

描述（由申请人提供）：在靶向血管药物递送中，需要宽范围的长度和时间尺度来描述流体动力学的物理特性， 微观分子相互作用介导血流中的纳米载体（NC）运动和内皮细胞结合。我们可以将NC设计和优化的特征用于临床应用，包括NC尺寸、浓度、靶向分子的密度和用于将靶向分子连接到桥接相关多个尺度的计算模型中的接头的特征。 模拟可以限制对大规模体内和体外实验的需要。 我们假设，所需的桥梁相关的分子动力学，中尺度结合的相互作用和流体力学控制NC运输和细胞粘附的计算技术的发展是必不可少的建立多尺度计算作为一种手段，优化内皮靶向，NC为基础的药物输送。 虽然我们的主要相关治疗目标是优化抗氧化剂和抗炎剂的内皮递送，以减轻急性肺炎症和急性肺损伤等疾病中的氧化应激，（ALI/ARDS）和其中肺内皮细胞ICAM-1表面密度增加的缺血-再灌注（I/R），该建模适用于任何器官系统中的血管内皮靶向。 我们的桥接模型将通过协同细胞培养和选择性开发的NCs结合的动物实验来验证。 这将是研究va三个具体目标：目标1：实现多尺度建模的流体动力学和微观相互作用的NC运动在血液流动。我们将开发桥接技术，以严格考虑多个长度和时间尺度，以治疗多价粘附相互作用和水动力学和近壁效应的糖萼流动和阻力。目的2：建立多价抗原抗体相互作用介导的NC与内皮细胞结合的随机多尺度粘附模型。该模型将以不同的长度尺度桥接多个自由度，以纳入：（i）NC平移和旋转以及抗原/抗体平移，取向和弯曲~（ii）介导构象可及性和结合的系链效应~（iii）Aim 1中捕获的糖萼对流动和阻力的影响~（iv）一种桥接技术，用于将结合相互作用的分子模型与中尺度NC模型相结合。 计算建模方法将使用敏感性分析进行调整。 目标3：实验定量NC靶向动力学在体外和体内使用NC纳入了一系列拴系的单链可变片段（scFv）和抗ICAM活性的替代表面分子，使用不同长度的PEG拴在不同大小的NC在不同的表面密度。数值模拟的验证将基于预测与细胞结合的实验测量的直接比较。我们的建模和实验方法将使我们能够开发和桥接临床翻译的多尺度技术。