Targeted microcarrier design and optimization

靶向微载体设计和优化

• 批准号: 7793603
• 负责人: DAVID M ECKMANN
• 金额: $ 35.08万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-01 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7793603
• 关键词: Accounting; Address; Antibodies; Arteries; Binding; Blood; Blood Circulation; Blood Vessels; Blood flow; Cell Culture Techniques; Cell membrane; Cell model; Cell surface; Cells; Cellular Morphology; Cellular Stress; Characteristics; Clinical; Complex; Computer Simulation; Coupling; Diffusion; Disease; Disorder by Site; Dose; Drug Carriers; Drug Delivery Systems; Endothelial Cells; Event; Exercise; Experimental Designs; Experimental Models; Glycocalyx; In Vitro; Institutes; Intercellular adhesion molecule 1; Kinetics; Lateral; Lead; Length; Life; Ligand Binding; Ligands; Mechanics; Membrane; Methods; Modeling; Motion; Normal tissue morphology; Particle Size; Pathology; Pennsylvania; Pharmaceutical Preparations; Physical environment; Physiological; Polystyrenes; Process; Property; Protocols documentation; Regulation; Research Personnel; Rheology; Site; Stream; Structure; Surface; System; Technology; Testing; Therapeutic; Time; Tissues; Toxic effect; Translations; Treatment Efficacy; Tube; Universities; Veins; Work; base; blood rheology; cell fixing; cell motility; density; design; engineering design; improved; in vivo; multi-scale modeling; nanocarrier; nanoscale; particle; prophylactic; prototype; receptor; receptor density; receptor expression; research study; response; shear stress; success; targeted delivery; technology development; therapeutic target; translational medicine

DESCRIPTION (provided by applicant): A strategic approach to improve the treatment of many diseases is to package a drug into carrier particles and then target that drug carrier for bloodstream delivery directly to the diseased tissue. Benefits of this approach include the possibility of an increase in the dose of the drug reaching diseased tissue (enhanced therapeutic efficacy) and a concomitant decrease in the dose of drug reaching normal tissue (reduced toxicity). Success of this approach relies in part on the development of technologies and clinical methods for injecting functionalized, targeted drug carriers into the blood stream close to the disease tissue. Success is directly dependent on the design and manufacture of carrier particles that have specific features such as particle size and surface coverage with binding molecules specific to the diseases being treated that lead to the desired, and necessary, initial event: binding of the carrier particle to endothelial cells in blood vessels within the diseased tissue. The complex interplay between targeted nanocarrier motion in flow, biomolecular receptor- ligand interactions governing specific binding, and thermal/transport dynamics of receptors on the cell membrane, is inherently a multiscale problem. The physical environment for binding ultimately defines the efficacy of nanocarrier arrest on the target cell. The nanocarrier binding and arrest are influenced by hydrodynamic forces resulting from blood flow, expression-levels of specific target determinants on the cell surface, their lateral diffusion on the membrane, the presence or absence of a glycocalyx, and membrane mobility. We hypothesize that experimental and design parameters such as receptor density on nanocarriers, carrier size, and binding response to flow characteristics such as shear stress levels can be optimized for enhancing the targeting the nanocarriers to specific (stressed) cells. To test this hypothesis, we propose four specific aims: 1) develop a spatially resolved stochastic multiscale model for predicting the energetic and kinetics of targeted spherical nanocarriers binding to endothelial cells; 2) experimentally quantify the kinetics of binding for ligand functionalized nanocarriers of varying size to fixed cells under static and shear conditions; 3) experimentally quantify the kinetics of binding for ligand functionalized nanocarriers of varying size to live cells under static and shear conditions and 4) extend the model in Aim 1 to a) include additional effects on binding due to membrane mobility, lateral diffusion of receptors and the mechano/hydrodynamic barrier posed by the glycocalyx in live cells; b) include effects of RBC-nanocarrier interactions and non-Newtonian rheology. We will develop a synergistic modeling and experimental platform for accessing and bridging the multiple length and time scales relevant for vascular delivery of targeted nanocarriers. Our objectives of quantitatively characterizing and predicting the transient nanoscale binding mechanics and dynamics for spherical nanocarrier binding to fixed and live endothelial cells under shear flow as a function of the various experimentally tunable parameters will lead to improvements in therapeutics for many diseases. A strategic approach to improve the treatment of many diseases is to package a drug into carrier particles and then target that drug carrier for bloodstream delivery directly to the diseased tissue. We will develop a synergistic experimental and computational platform addressing bloodstream delivery of targeted nanocarriers. This work to characterize quantitatively and predict computationally the binding mechanics and dynamics for nanocarrier binding to endothelial cells will lead to improvements in therapeutics for many diseases.

描述（由申请人提供）：改善许多疾病治疗的战略方法是将药物包装到载体颗粒中，然后将药物载体靶向直接传递到患病组织的血液中。这种方法的益处包括可能增加患病组织的药物剂量增加（治疗功效增强），并伴随着达到正常组织的药物剂量的降低（毒性降低）。这种方法的成功部分依赖于技术和临床方法的发展，用于将功能化的，有针对性的药物载体注入接近疾病组织的血液中。成功直接取决于具有特定特征的载体颗粒的设计和制造，例如粒径和表面覆盖范围，其结合分子具有特定于处理的疾病的结合分子，这些疾病会导致所需的，必要的初始事件：载体粒子与患病组织内血管内皮细胞的结合。靶向纳米载体运动，流量中的靶向纳米载体运动之间的复杂相互作用，控制特定结合的生物分子受体相互作用和细胞膜上受体的热/传输动力学之间的复杂相互作用是一个固有的多尺度问题。结合的物理环境最终定义了纳米载体在靶细胞上停滞的功效。纳米载体的结合和停滞受血流引起的流体动力，细胞表面上特定靶标决定因素的表达水平，它们在膜上的横向扩散，糖蛋白的存在或不存在，以及膜的迁移率。我们假设可以优化实验和设计参数，例如纳米载体上的受体密度，载体大小以及对流动特性（例如剪切应力水平）的结合反应，以增强靶向纳米载体对特定（应激）细胞的靶向。为了检验这一假设，我们提出了四个具体目的：1）开发一个空间分辨的随机多尺度模型，以预测靶向球形纳米载体与内皮细胞结合的靶向球形纳米载体的能量和动力学； 2）实验量化在静态和剪切条件下与固定细胞不同大小的配体功能化纳米载体的结合动力学； 3）实验量化在静态和剪切条件下与活细胞的配体功能化纳米载体结合的动力学，4）4）4）将模型扩展到AIM 1至a）包括膜迁移率，由于受体的横向扩散以及机械/流体性障碍物在实时细胞中对结合产生的其他影响。 b）包括RBC - 纳米载体相互作用和非牛顿流变学的影响。我们将开发一个协同的建模和实验平台，用于访问和桥接与靶向纳米载体的血管递送相关的多长度和时间尺度。我们的定量表征和预测球形纳米载体与剪切流下固定和活内皮细胞结合的瞬时纳米级结合力学和动力学的目标，这是各种实验可调的参数的函数的函数，可改善许多疾病的治疗方法。改善许多疾病治疗的一种战略方法是将药物包装到载体颗粒中，然后将药物载体靶向直接输送到患病组织的血液中。我们将开发一个协同的实验和计算平台，以解决目标纳米载体的血液传递。这项工作以定量表征并在计算上预测纳米载体结合到内皮细胞的结合力学和动力学将导致许多疾病的治疗方法改善。