Targeted Microcarrier Design and Optimization

描述（由申请人提供）：通过血管内注射靶向纳米载体（NCs）给药是纳米技术治疗疾病的有力应用。靶向药物纳米载体设计和医疗应用的许多方面，如载体尺寸、浓度、靶向分子表面覆盖和药物货物包装的优化，都适用于多尺度计算模型。模拟用于为制造和临床应用提供适当特性的预测值，可以减少时间，费用和其他大规模实验所需的资源。例如，在血流、内皮细胞结合和细胞内化过程中，介导NC运动和货物卸载的流体动力学和微观相互作用是发生在多个长度和时间尺度上的可定义的机械和分子事件的复杂相互作用。我们假设，这些关键的流体动力学和分子事件的计算建模和模拟可以用于优化设计参数，使纳米载体装载可追踪的货物，并以内皮决定因子（例如，ICAM-1表面分子）的靶向分子装饰，将：i)有效地竞标内皮细胞，ii)进入内皮内体，iii)有效地将货物卸载到这个隔间。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，包括输送货物在靶细胞内的分散。我们的模型包括敏感性分析，将通过协同动物和细胞培养实验验证NC结合力学和细胞内货物卸载效率。这将通过三个具体目标来实现：目标1：在血管靶向药物递送中介导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：宏观制度，润滑

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.