Nanoparticle Transport as a function of Physiologic and Hyperthermic Conditions in a 3D Vascularized Microfluidic Tumor Platform

产品说明：纳米颗粒在与激光激发相结合时可以充当优异的光吸收剂，从而增强光热和光化学治疗的功效。靶向配体与纳米颗粒结合使用可以潜在地提供与传统治疗如化疗和手术切除不同的治疗选择性。然而，将纳米颗粒运输到预期目标并在所需治疗范围内实现适当的纳米颗粒分布一直是用光基疗法实现有利结果的主要障碍。关于纳米颗粒特征（例如，表面性质、形状、尺寸）、生理条件（例如，血液动力学、内皮渗透性、基质组成）和治疗相关的热剂量对纳米颗粒通过脉管系统、穿过内皮和在肿瘤组织内的运输的影响的有限知识已经抑制了纳米治疗剂的优化。通过开发和利用三维体外细胞培养模型，可以显着推进纳米医学，该模型复制了肿瘤微环境的内在复杂性，并为研究特定生理刺激和治疗参数对纳米颗粒转运和肿瘤反应的影响提供了框架。通过将组织工程策略与癌症生物学、微流体学和光流诊断相结合，将开发一种肿瘤平台，该平台模拟肿瘤微环境，并允许动态测量流场和纳米颗粒运输。具体而言，该平台将复制生理基质力学、血液动力学、光学和热特性以及肿瘤微环境的细胞组成，从而能够对涉及脉管系统、内皮和肿瘤组织的广泛纳米颗粒相互作用响应于生理和高热条件进行定量和组合研究。该平台将与高分辨率、微创粒子图像测速技术集成，用于通道中的流动表征以及纳米颗粒运输和肿瘤反应的时空测量。这一创新的研究计划是由以下具体目标驱动：1）为纳米颗粒增强的光热疗法创建光学、热学和生理学上代表性的肿瘤平台，2）确定不同生理学相关的血液动力学条件的影响（流动特性，内皮渗透性）对纳米颗粒转运的影响，以及3）确定光热疗法的高热特性对纳米颗粒运输和肿瘤响应的影响。该应用的结果将是用于纳米颗粒研究的新方法和平台技术，其将能够基于对系统的生理学和治疗参数如何影响纳米颗粒迁移和肿瘤反应的透彻理解来优化纳米颗粒特征以增强运输和功效。

DESCRIPTION: Nanoparticles can serve as excellent photo-absorbers when coupled with laser excitation, thereby enhancing the efficacy of photothermal and photochemical treatments. The use of targeting ligands in conjunction with nanoparticles can potentially provide therapy selectivity unlike traditional treatments such as chemotherapy and surgical resection. However, transport of nanoparticles to the intended target and attainment of appropriate nanoparticle distributions within desired treatment margins has been a dominant barrier to achieving favorable outcomes with photo-based therapies. Limited knowledge regarding the influence of nanoparticle features (e.g. surface properties, shape, size), physiologic conditions (e.g. hemodynamics, endothelial permeability, matrix composition), and therapeutically relevant thermal dose on transport of nanoparticles through the vasculature, across the endothelium, and within tumor tissue has inhibited optimization of nanotherapeutics. Nanomedicine could be significantly advanced by development and utilization of three-dimensional in vitro cell culture models which replicate the intrinsic complexity of the tumor microenvironment and provide a framework for investigating the influence of specific physiologic stimuli and therapeutic parameters on nanoparticle transport and tumor response. By integrating tissue engineering strategies with cancer biology, microfluidics, and optical flow diagnostics, a tumor platform will be developed which mimics the tumor microenvironment and permits dynamic measurement of flow fields and nanoparticle transport. Specifically the platform will replicate physiological matrx mechanics, hemodynamics, optical and thermal properties, and cellular composition of the tumor microenvironment enabling quantitative and combinational study of a broad range of nanoparticle interactions involving the vasculature, endothelium, and tumor tissue in response to physiologic and hyperthermic conditions. This platform will be integrated with high resolution, minimally invasive particle image velocimetry for flow characterization in the channel and spatiotemporal measurement of nanoparticle transport and tumor response. This innovative research program is driven by the following specific aims: 1) Create an optically, thermally, and physiologically representative tumor platform for nanoparticle enhanced photothermal therapies, 2) Determine the influence of varying physiologically relevant hemodynamic conditions (flow properties, endothelial permeability) on nanoparticle transport, and 3) Determine the influence of hyperthermia characteristic of a photothermal therapy on nanoparticle transport and tumor response. The outcome of this application will be a new approach and platform technology for nanoparticle investigation which will enable optimization of nanoparticle features for enhanced transport and efficacy based on a thorough understanding of how the physiology of the system and parameters of the treatment influence nanoparticle migration and tumor response.