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Targeted Microcarrier Design and Optimization

靶向微载体设计和优化

基本信息

批准号：
8664376
负责人：
DAVID M ECKMANN
金额：
$ 47.26万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-07-01 至 2017-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8664376
关键词：
Adhesions Agreement Animals Antibodies Behavior Binding Blood Blood Circulation Blood Vessels Blood flow Cell Culture Techniques Cell Surface Receptors Cells Characteristics Clinical Complex Computer Simulation Dextrans Diffusion Disease Drug Controls Drug Delivery Systems Drug Targeting Elements Encapsulated Endosomes Endothelial Cells Engineering Equation Event Experimental Models Fluorescence Free Energy Glycocalyx Hybrids Hydrogels Immunoglobulin G In Vitro Injection of therapeutic agent Intercellular adhesion molecule 1 Kinetics Label Length Life Ligands Liquid substance Lubrication Mechanics Mediating Medical Memory Methods Microscopic Modeling Molecular Motion Nanosphere Nanotechnology Particulate Pharmaceutical Preparations Pharmacotherapy Polymers Predictive Value Property Protocols documentation Research Personnel Resistance Resources Rodent Scientist Shapes Solutions Surface Swelling System Testing Time Tissues Translations Validation Work base clinical application controlled release density design dextran engineering design fluid flow in vivo intercellular cell adhesion molecule models and simulation multi-scale modeling nanocarrier particle programs prototype public health relevance receptor receptor density research study simulation

项目摘要

DESCRIPTION (provided by applicant): Drug delivery using intravascular injection of targeted nanocarriers (NCs) is a potent application of nanotechnology to treat disease. Many aspects of targeted drug nanocarrier design and medical use such as optimization of carrier size, concentration, surface coverage with targeting molecule and drug cargo packaging are amenable to multiscale computational modeling. Simulation used to provide predictive values of appropriate characteristics for manufacture and clinical application can reduce the time, expense and other resources necessary for otherwise large scale experimentation. For instance, hydrodynamic and microscopic interactions mediating NC motion and cargo offloading occurring in bloodflow, endothelial cell binding and cell internalization are complex interplay of defineable mechanical and molecular events occuring at multiple length and time scales. We hypothesize that computational modeling and simulation of these critical hydrodynamic and molecular events can be accessed to optimize design parameters such that nanocarriers loaded with trackable cargoes and decorated with targeting molecules to endothelial determinants (e.g., ICAM-1 surface molecules) will: i) efficiently bid to endothelial cells, ii) enter endothelial endosomes and, iii) effectively unload their cargo in this compartment. We propose to develop and validate a multiscale computational modeling platform to optimize endothelial drug delivery, including dispersal of the delivered cargo within target cells. Our model includes sensitivity analysis~ it will be validated through synergistic animal and cell culture experiments of NC binding mechanics and intracellular cargo offloading efficiency. This will be accomplished via three specific aims: Aim 1: Multiscal modeling of hydrodynamic and microscopic interactions mediating NC motion in vascular targeted drug delivery involving three distinct scales: a macroscopic regime, a lubrication regime and an adhesion regime. Aim 2: Multiscale modeling of transport and controlled drug release from a targeted NC in blood flow. The computational model approaches in Aims 1 and 2 will be tuned using sensitivity analysis on important governing parameters. Aim 3: Experimentally quantify NC targeting kinetics (using prototype anti-ICAM and alternative surface molecules), carrier internalization and intracellular drug delivery using dextran hydrogel nanocarriers loaded with prototype model fluorescence-labeled cargoes. We will utilize physiologically relevant in vitro and in vivo systems forthese experiments. Validation of numerical simulation results (Aims 1 and 2) will be made by comparison of predictions with experimentally observed transport and release properties (Aim 3). Our team of Engineers, Materials Scientists, Pharmacologists and Vascular Biologists brings combined expertise in modeling and experimental approaches that are versatile. This will enable us to adapt protocols to specific applications for optimal engineering design and clinical translation of NC drug delivery for targeted disease treatment.

描述（由申请人提供）：使用血管内注射靶向纳米载体（NC）进行药物输送是纳米技术治疗疾病的有效应用。靶向药物纳米载体设计和医疗用途的许多方面，例如载体尺寸、浓度、靶向分子的表面覆盖和药物包装的优化，都适合多尺度计算建模。用于为制造和临床应用提供适当特性的预测值的模拟可以减少大规模实验所需的时间、费用和其他资源。例如，介导血流中发生的 NC 运动和货物卸载、内皮细胞结合和细胞内化的流体动力学和微观相互作用是在多个长度和时间尺度上发生的可定义机械和分子事件的复杂相互作用。我们假设可以对这些关键的流体动力学和分子事件进行计算建模和模拟来优化设计参数，使得装载有可追踪货物并装饰有内皮决定簇靶向分子（例如 ICAM-1 表面分子）的纳米载体将：i）有效地作用于内皮细胞，ii）进入内皮核内体，以及 iii）有效在这个车厢里卸下货物。我们建议开发和验证一个多尺度计算建模平台，以优化内皮药物输送，包括目标细胞内所输送货物的分散。我们的模型包括敏感性分析〜它将通过NC结合力学和细胞内货物卸载效率的协同动物和细胞培养实验进行验证。这将通过三个具体目标来实现：目标 1：介导血管靶向药物输送中 NC 运动的流体动力学和微观相互作用的多尺度建模，涉及三个不同的尺度：宏观状态、润滑制度和粘附制度。目标 2：对血流中目标 NC 的转运和受控药物释放进行多尺度建模。目标 1 和 2 中的计算模型方法将通过对重要控制参数的敏感性分析进行调整。目标 3：通过实验量化 NC 靶向动力学（使用原型抗 ICAM 和替代表面分子）、载体内化和使用葡聚糖的细胞内药物递送装载有原型模型荧光标记货物的水凝胶纳米载体。我们将利用生理相关的体外和体内系统进行这些实验。将通过将预测与实验观察到的传输和释放特性（目标 3）进行比较来验证数值模拟结果（目标 1 和 2）。我们的工程师、材料科学家、药理学家和血管生物学家团队带来了多用途建模和实验方法方面的综合专业知识。这将使我们能够根据具体应用调整方案，以实现最佳工程设计和 NC 药物输送的临床转化，以进行靶向疾病治疗。