Multiscale Modeling of the Nanocarrier-Cell Ahesion Interface in Targeted Drug Delivery

靶向给药是纳米技术的一种新兴应用。它包括通过将药物包装到纳米载体中来设计药物，并针对这些药物直接静脉注射到患病组织中。这种方法的好处包括药物到达病变组织的最佳药物剂量（增强治疗效果）和同时到达正常组织的药物减少（降低毒性）。成功直接取决于载体颗粒的设计和合成，这些载体颗粒具有特定的特征，例如颗粒大小/形状和表面覆盖特定于正在治疗的疾病的生物标志物（靶受体）的结合分子。优化设计导致所需的和必要的初始事件，即载体颗粒选择性地与病变组织内血管中的内皮细胞结合和阻滞，随后在阻滞后载体内化到细胞中。利用计算建模和工程原理，该项目将研究实验和设计参数，如纳米载体上的受体密度，纳米载体的大小和形状，以及对血流的结合反应，以优化纳米载体对特定（病变）细胞的靶向性。该模型将整合多个长度和时间尺度，包括血流、纳米载体阻滞、细胞膜迁移和生物分子受体-配体相互作用，所有这些都有助于纳米载体结合的物理环境，并共同定义纳米载体阻滞在靶细胞上的功效。该模型将描述由血流、内皮细胞表面特异性（靶）受体的表达水平、它们在膜上的横向扩散、糖萼的存在或缺失以及细胞膜的流动性所产生的流体动力影响下纳米载体的结合和阻滞。该模型将通过定量细胞和动物实验进行验证，并将用于预测纳米载体的最佳设计。靶向药物递送方案的成功部分依赖于合理技术的发展，设计纳米载体药物和将这种功能化的靶向药物载体注射到靠近疾病组织的血流中的临床方法。该项目的结果将直接导致针对内皮细胞的靶向纳米载体的设计平台，内皮细胞排列血管。模型的通用性与实验方法相结合，将使其在特定的药理学应用中具有实用性，例如，为特定/不同的疾病状态设计载体，预防（预防性）靶向与治疗靶向，动脉靶向与静脉靶向，以及对毒性进行控制。项目结果将直接为优化工程设计提供便利，并影响此类药物输送系统用于靶向疾病治疗的临床转化。

1236514PI: RadhakrishnanTargeted drug delivery is an emerging application of nanotechnology. It involves designing pharmaceuticals by packaging them into nanocarriers and targeting them for intravenous delivery directly to the diseased tissue. Benefits of this approach include optimal drug dosage in-terms of the drug reaching diseased tissue (enhanced therapeutic efficacy) and a concomitant decrease in drug reaching normal tissue (reduced toxicity). Success is directly dependent on the design and synthesis of carrier particles that have specific features such as particle size/shape and surface coverage with binding molecules specific to the biomarkers (target receptors) of diseases being treated. Optimal design leads to the desired, and necessary, initial event, namely, selective binding and arrest of the carrier particle to endothelial cells in blood vessels within the diseased tissue, followed by carrier internalization into the cells post arrest. Using computational modeling and engineering principles, the project will investigate experimental and design parameters such as receptor density on nanocarriers, nanocarrier size & shape, and binding response to blood flow in order to optimize the targeting the nanocarriers to specific (diseased) cells. The model will integrate multiple length and time scales involving blood flow, nanocarrier arrest, cell membrane mobility, and biomolecular receptor-ligand interactions, all of which contribute to the physical environment for nanocarrier binding, and collectively define the efficacy of nanocarrier arrest on the target cell. The model will delineate nanocarrier binding and arrest influenced by hydrodynamic forces resulting from blood flow, expression-levels of specific (target) receptors on the endothelial cell surface, their lateral diffusion on the membrane, the presence or absence of a glycocalyx, and cell membrane mobility. The model will be validated against quantitative cellular and animal experiments and will be employed to make predictions for optimal design of nanocarriers.Success of targeted drug delivery protocols relies in part on the development of rational technologies designing nanocarrier pharmaceuticals and clinical methods for injecting such functionalized, targeted drug carriers into the blood stream close to the disease tissue. The results of the project will lead directly to a design platform for targeted nanocarriers to endothelial cells, which line blood vessels. The versatility of the modeling combined with experimental approaches will then enable their utility in context specific pharmacological applications, e.g., designing carriers for specific/different disease states, preventive (prophylactic) versus therapeutic targeting, targeting in arteries versus veins, and exercising control on toxicity. Project results will directly facilitate the optimal engineering design, as well as impact the clinical translation of such drug delivery systems for targeted disease treatment.