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):在靶向血管药物递送中,需要广泛的长度和时间尺度来描述流体动力学和

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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