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: 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
• 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

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和 微观分子相互作用介导纳米载体（NC）运动中的运动和内皮细胞结合中的运动。我们可以将NC设计的特征和优化的特征纳入临床应用，包括NC维度，浓度，靶向分子的密度以及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特征。 模拟可以限制大规模N体内和体外实验的需求。 我们假设开发桥接相关的分子动力学所需的计算技术，中尺度的结合相互作用和控制NC运输和细胞粘附的流体动力学对于建立多尺度计算作为优化内皮靶向的基于NC的，基于NC的药物输送的手段至关重要。 虽然我们主要相关的治疗目标是优化抗氧化剂和抗炎剂的内皮输送，以减轻急性肺部炎症和氧化应激，并在急性肺损伤（ALI/ARDS）（ALI/ARDS）和缺血性渗透性（I/R）等条件下，在哪种肺部呈肺内皮含量上的拟态性，并增加了模型的型号，该型模型均具有模型的含量。任何器官系统。 我们的桥接建模将通过有选择性开发的NC的结合的协同细胞培养和动物实验来验证。 这将研究VA的三个特定目的：目标1：实施血流中NC运动的流体动力和微观相互作用的多尺度建模。我们将开发桥接技术，以严格考虑多长度和时间尺度，以治疗糖脂流动和电阻的多价粘附相互作用以及流体动力和近壁影响。 AIM 2：开发NC结合与多价抗原抗体相互作用介导的内皮细胞的随机多尺度粘附模型。该模型将在不同的长度尺度上桥接多个自由度以结合：（i）NC翻译和旋转以及抗原/抗体的翻译，方向和屈曲〜（ii）TETHERS对构象可及性的影响（II）介导型和结合〜（iii）与GlyCocococococalex captoration在Aimec中的流动效果的影响（III）的效果（IIV）的构建（IV和IIV）的构建效果（IV），IV和IV技术的构建效果（IV）。中尺度NC模型。 计算建模方法将通过灵敏度分析调整。 AIM 3：使用NC在体外和体内量化NC靶向动力学，使用NCS融合了一系列链状单链变量片段（SCFV）和替代表面分子，用于抗ICAMAM活性，使用不同的长度PEG Tethers在不同尺寸的NC上使用不同的长度PEG TETHER。数值模拟的验证将基于直接比较预测与细胞结合的实验测量。我们的建模和实验方法将使我们能够开发和桥接多尺度技术以进行临床翻译。