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

基本信息

批准号：
8723200
负责人：
DAVID M ECKMANN
金额：
$ 52.42万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
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/8723200
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

项目摘要

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）：在靶向血管药物输送中，需要广泛的长度和时间尺度来描述流体动力学和介导血流和内皮细胞结合中纳米载体（NC）运动的微观分子相互作用。我们可以将 NC 设计和优化的特征纳入临床应用，包括 NC 尺寸、浓度、靶向分子的密度以及用于连接靶向分子的连接体的特征到桥接相关多个尺度的计算模型中。模拟可以限制大规模体内和体外实验的需要。我们假设，发展连接相关分子动力学、介观结合相互作用和控制 NC 运输和细胞粘附的流体动力学所需的计算技术，对于建立多尺度计算作为优化内皮靶向、基于 NC 的药物输送的手段至关重要。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传递，以减轻急性肺损伤（ALI/ARDS）和缺血再灌注（I/R）等情况下的急性肺部炎症和氧化应激，其中随着肺内皮 ICAM-1 表面密度的增加，该模型适用于任何器官系统的血管内皮靶向。我们的桥接模型将通过协同细胞培养和选择性开发的 NC 结合的动物实验进行验证。这将通过三个具体目标进行研究：目标 1：实现血流中 NC 运动的流体动力学和微观相互作用的多尺度建模。我们将开发桥接技术来严格考虑多个长度和时间尺度，以处理多价粘附相互作用以及糖萼流动和阻力的流体动力学和近壁效应。目标 2：开发由多价抗原-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。该模型将桥接不同长度尺度的多个自由度，以纳入：(i) NC 平移和旋转以及抗原/抗体平移、方向和弯曲~(ii) 介导构象可及性和结合的系绳效应~(iii) 效应目标 1~ 中捕获的糖萼引起的流动和阻力的影响，以及 (iv) 开发的桥接技术，用于将结合相互作用的分子模型与中尺度 NC 模型相集成。将使用敏感性分析来调整计算建模方法。目标 3：使用包含一系列系留单链可变片段 (scFv) 和替代表面分子的 NC 进行体外和体内靶向动力学实验量化，以实现抗 ICAM 活性，并在不同表面的不同尺寸 NC 上使用不同长度的 PEG 系链密度。数值模拟的验证将基于预测与细胞结合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转化的多尺度技术。