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

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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.