Targeted Microcarrier Design and Optimization

描述(申请人提供)：使用血管内注射靶向纳米载体(NCS)的药物输送是纳米技术在治疗疾病方面的有效应用。靶向药物纳米载体的设计和医疗应用的许多方面，如载体尺寸、浓度、靶向分子的表面覆盖和药物货物包装的优化，都适用于多尺度计算建模。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其他大规模实验所需的时间、费用和其他资源。例如，流体力学和微观相互作用调节NC运动和血液中的货物卸载，内皮细胞结合和细胞内化是在多个长度和时间尺度上发生的可定义的机械和分子事件的复杂相互作用。我们假设，这些关键的流体力学和分子事件的计算建模和模拟可以被用来优化设计参数，以便装载可追踪货物并装饰有针对内皮决定因素(例如ICAM-1表面分子)的靶向分子的纳米载体将：i)有效地与内皮细胞竞争，ii)进入内皮内体，iii)有效地将它们的货物卸载到这个隔室中。我们建议开发和验证一个多尺度计算模拟平台来优化血管内皮细胞药物输送，包括在靶细胞内分散输送的货物。我们的模型包括敏感性分析，将通过动物和细胞协同培养实验来验证NC结合机制和细胞内卸货效率。这将通过三个具体目标来实现：目标1：涉及三个不同尺度的血管靶向给药中调节NC运动的流体动力学和微观相互作用的多尺度模拟：宏观区域、润滑 制度和附合制度。目的2：多尺度模型的传输和受控药物释放从一个目标的NC血流。目标1和目标2中的计算模型方法将通过对重要控制参数的灵敏度分析进行调整。目的3：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给药 装载原型模型荧光标记货物的水凝胶纳米载体。我们将利用与生理相关的体外和体内系统进行这些实验。数值模拟结果(目标1和目标2)的验证将通过将预测与实验观察到的传输和释放特性(目标3)进行比较来进行。我们的工程师、材料科学家、药理学家和血管生物学家团队将建模和实验方法的专业知识结合在一起，这些方法是多才多艺的。这将使我们能够使协议适应于特定应用，以优化NC药物输送的工程设计和临床翻译，以用于靶向疾病治疗。

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.