Capturing dynamic and inter-dependent biointerfaces in nanotechnology designs

在纳米技术设计中捕获动态且相互依赖的生物界面

• 批准号: 8536806
• 负责人: Jessie L.-S. Au
• 金额: $ 29.43万
• 依托单位: OPTIMUM THERAPEUTICS, LLC
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8536806
• 关键词: Accounting; Address; Affect; Antibodies; Apoptosis; Binding; Biocompatible Materials; Biodiversity; Biological; Biosensor; Blood Circulation; Caliber; Cell Density; Cell Surface Receptors; Cell membrane; Cells; Characteristics; Charge; Computer Simulation; Convection; Data; Deposition; Development; Diagnostic; Diffusion; Dilatation - action; Dose; Drug Kinetics; Endocytosis; Equation; Equilibrium; Evaluation; Extravasation; Frequencies; Generations; Genes; Goals; Heart Neoplasms; Heterogeneity; Human; In Vitro; Individual; Injection of therapeutic agent; Kidney; Latex Bead; Laws; Ligand Binding; Ligands; Literature; Liver; Malignant Neoplasms; Measurement; Measures; Modeling; Modification; Nanotechnology; Nature; Outcome; Paclitaxel; Penetration; Performance; Perfusion; Pharmaceutical Preparations; Property; Proteins; RNA Interference; Research; Route; Simulate; Site; Solid Neoplasm; Spatial Distribution; Spleen; Surface; System; Therapeutic; Time; Treatment Protocols; Uncertainty; chemotherapy; density; design; in vivo; interstitial; intravenous injection; models and simulation; monolayer; nanoparticle; neoplastic cell; predictive modeling; research study; small molecule; tumor; vector

DESCRIPTION (provided by applicant): Nanoparticle systems (NP) can be used to deliver diagnostics and therapeutics including small and large molecules, gene vectors, and biosensor. As NP is versatile and can be made of different types of materials, and can have different sizes, surface charges, and surface modifications, there is the potential to tailor the design of NP for its intended function. Such goals can be greatly facilitated by quantitative models that predict the NP delivery to target sites and the biointerfaces (e.g., NP disposition and interactions with targets). In general, tumor properties, biological in nature, are dynamic and altered by a variety of variables and can produce diverse and at times unexpected effects on NP disposition. These situations in turn create uncertainties on the fate of NP at target sites and hence questions on the NP design. For example, how should one design NP in anticipation of intratumoral heterogeneity in the transport mechanisms (diffusion vs convection) in different parts of a tumor, or treatment-induced changes in tumor vasculature or properties? What are the margins of error if the NP design/selection does not take into account the diverse/dynamic tumor properties? Similarly, some NP properties by design will produce uncertain or opposite outcomes. For example, NP is frequently surface-modified with targeting ligands, but binding of ligands to cell surface receptors limits NP transport. What are the binding characteristics that would yield an optimal balance between tumor selectivity and tumor penetration? Pegylation increases circulation times but also decreases the endocytosis of NP. What is the range of % pegylation to enable optimal tumor targeting? We propose that the above and similar questions can be addressed by developing computation models that use relatively few in vitro and in vivo experimental data to describe the extravasation, interstitial deposition and transport, and internalization of NP in solid tumors as functions of NP/tumor properties and biointerfaces, and treatment schedules (dose intensity and frequency). We will take a balanced empirical-theoretical approach that uses our combined expertise in pharmacokinetics, drug/NP delivery, modeling, simulations, tumor heterogeneity, and in vitro and in vivo experimentations. The model parameters are either lab-generated, obtained from the literature, calculated using well-known equations, or, in the case of parameters that cannot be measured, by fitting the data to equations. Model performance is evaluated by conducting experiments and comparing the lab-generated data to the model-predicted data. We have developed first-generation models that successfully used in vitro data of drug/NP-cell-protein interactions in 2-D monolayers to predict the in vivo transport/delivery of a small molecule drug and NP to tumors. We further used these models, together with in vivo measurements of vessel density and diameter, to simulate the effect of chemotherapy, as well as the effects of intra-tumoral heterogeneity. This project is expected to contribute to NP design principles and accelerate the development of cancer nanotechnology.

描述（由申请人提供）：纳米颗粒系统（NP）可用于提供诊断和治疗剂，包括小分子和大分子，基因载体和生物传感器。由于NP是多功能的，可以由不同类型的材料制成，并且可以具有不同的尺寸，表面电荷和表面修饰，因此有可能根据其预期功能来量身定制NP的设计。通过定量模型可以极大地促进此类目标，这些模型可以预测NP向目标站点和生物区域的传递（例如，NP处置和与目标的相互作用）。 通常，本质上生物学的肿瘤特性是动态的，并且会因多种变量而改变，并且可能对NP处置产生各种各样的意外影响。这些情况反过来又对目标站点的NP命运造成了不确定性，因此对NP设计产生了问题。例如，在肿瘤的不同部位的传输机制（扩散与对流）中，如何设计NP，或者如何在肿瘤脉管系统或肿瘤脉管系统或特性变化的转运机制（扩散与对流）中设计NP？如果不考虑多种/动态肿瘤的特性，则NP设计/选择不考虑NP设计/选择的差距是多少？同样，某些划分设计的NP属性会产生不确定或相反的结果。例如，NP经常通过靶向配体进行表面修饰，但是配体与细胞表面受体的结合限制了NP的转运。哪些结合特性在肿瘤选择性和肿瘤渗透之间产生最佳平衡？卵高增加循环时间，但也减少了NP的内吞作用。达到最佳肿瘤靶向的百分比范围是多少？ 我们提出，可以通过开发使用相对较少的体外和体内实验数据来描述固体瘤中NP的渗出，间质沉积和运输以及NP作为NP/肿瘤特性的功能以及生物区接口的功能以及治疗方案（剂量强度和频率）（剂量强度和频率）来描述上述问题和类似问题。我们将采用平衡的经验理论方法，该方法使用我们在药代动力学，药物/NP递送，建模，模拟，肿瘤异质性以及体外和体内实验方面的综合专业知识。模型参数要么是实验室生成的，是从文献中获得的，使用众所周知的方程计算得出，要么在无法测量的参数中通过将数据拟合到方程式中。通过进行实验并将实验室生成的数据与模型预测的数据进行比较来评估模型性能。我们开发了第一代模型，这些模型成功地使用了2-D单层中药物/NP细胞 - 蛋白质相互作用的体外数据，以预测小分子药物的体内运输/递送到肿瘤中。我们进一步使用了这些模型，以及容器密度和直径的体内测量，以模拟化学疗法的作用以及肿瘤内异质性的影响。预计该项目将有助于NP设计原理，并加速癌症纳米技术的发展。