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:
    8554530
  • 负责人:
  • 金额:
    $ 54.04万
  • 依托单位:
  • 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

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):在靶向血管给药中,需要广泛的长度和时间尺度来描述流体力学和 微观分子相互作用调节血流中纳米载体(NC)的运动和内皮细胞的结合。我们可以将NC设计和优化用于临床应用的特征,包括NC尺寸、靶向分子的浓度、密度和用于连接靶向分子的连接子的特性,整合到连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,连接相关分子动力学、中尺度结合相互作用和控制NC运输和细胞黏附的流体动力学所需的计算技术的发展,对于建立多尺度计算作为优化内皮靶向、NC为基础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在肺内皮细胞ICAM-1表面密度增加的急性肺损伤(ALI/ARDS)和缺血/再灌注(I/R)等条件下优化抗氧化剂和抗炎药的内皮递送,以减轻急性肺炎症和氧化应激,但该模型适用于任何器官系统的血管内皮细胞靶向。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。这将通过三个具体目标进行研究:目标1:实现NC运动在血液流动中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,以严格考虑多个长度和时间尺度,以处理多价黏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。目的: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黏附模型。该模型将在不同的长度尺度上桥接多个自由度,以纳入:(I)NC平移和旋转以及抗原/抗体的平移、定向和弯曲~(Ii)介导构象可及性的系链的效应和结合~(Iii)由于目标1中捕获的糖萼而产生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模型相结合。将使用敏感性分析来调整计算建模方法。目的:在不同大小、不同表面密度的纳米粒上使用不同长度的聚乙二醇链系留在不同大小的纳米粒上,以不同的表面密度,在体内和体外实验量化NC靶向动力学。数值模拟的验证将基于对细胞结合的预测与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沟通临床翻译的多尺度技术。

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(1)

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DAVID M ECKMANN其他文献

DAVID M ECKMANN的其他文献

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{{ truncateString('DAVID M ECKMANN', 18)}}的其他基金

Physician Postdoctoral Research Training in Perioperative Medicine (PPRTPM)
围手术期医学医师博士后研究培训 (PPRTPM)
  • 批准号:
    9067407
  • 财政年份:
    2015
  • 资助金额:
    $ 54.04万
  • 项目类别:
Physician Postdoctoral Research Training in Perioperative Medicine (PPRTPM)
围手术期医学医师博士后研究培训 (PPRTPM)
  • 批准号:
    9476336
  • 财政年份:
    2015
  • 资助金额:
    $ 54.04万
  • 项目类别:
Physician Postdoctoral Research Training in Perioperative Medicine (PPRTPM)
围手术期医学医师博士后研究培训 (PPRTPM)
  • 批准号:
    8795021
  • 财政年份:
    2015
  • 资助金额:
    $ 54.04万
  • 项目类别:
Physician Postdoctoral Research Training in Perioperative Medicine (PPRTPM)
围手术期医学医师博士后研究培训 (PPRTPM)
  • 批准号:
    9282740
  • 财政年份:
    2015
  • 资助金额:
    $ 54.04万
  • 项目类别:
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
  • 财政年份:
    2013
  • 资助金额:
    $ 54.04万
  • 项目类别:
Activation of clotting & cell adhesion: gas embolism
激活凝血
  • 批准号:
    7851187
  • 财政年份:
    2009
  • 资助金额:
    $ 54.04万
  • 项目类别:
Activation of clotting & cell adhesion: gas embolism
激活凝血
  • 批准号:
    7384351
  • 财政年份:
    2009
  • 资助金额:
    $ 54.04万
  • 项目类别:
Targeted microcarrier design and optimization
靶向微载体设计和优化
  • 批准号:
    7793603
  • 财政年份:
    2008
  • 资助金额:
    $ 54.04万
  • 项目类别:
Targeted Microcarrier Design and Optimization
靶向微载体设计和优化
  • 批准号:
    8664376
  • 财政年份:
    2008
  • 资助金额:
    $ 54.04万
  • 项目类别:
Targeted Microcarrier Design and Optimization
靶向微载体设计和优化
  • 批准号:
    8500720
  • 财政年份:
    2008
  • 资助金额:
    $ 54.04万
  • 项目类别:

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