Implantable device for high-throughput in vivo drug sensitivity testing

描述（由申请人提供）：我们的目标是开发一种快速，高通量的诊断设备技术，用于原位检测肿瘤对各种抗癌药物的局部反应。该分析与其他临床标准相结合，可以潜在地预测癌症患者的最佳治疗方法。该技术由一个微型可植入装置组成，该装置直接放置在肿瘤中，并包含大量储存器，每个储存器装载微剂量的单一药物或联合治疗。该装置以一种精确控制的方式从多个生理相关浓度的储存库中原位释放药物微剂量到肿瘤的局部不同区域。每个储存库的局部药物反应是确定的，提供了哪些药物对给定肿瘤最有效的信息。光学分析方法集成到设备中，实现每个储存库药物作用的实时连续读数。与现有的体外实验相比，这项技术的优势在于，它可以研究药物在原生肿瘤组织中的作用，

DESCRIPTION (provided by applicant): Our aim is to develop a rapid, high-throughput diagnostic device technology that assays a tumor in situ for its local response to a wide range of anti-cancer agents. This assay, combined with other clinical criteria, can potentially serve to predict the optimal therapy for a cancer patient. This technology is comprised of a miniaturized implantable device that is placed directly into the tumor and contains a large number of reservoirs, each loaded with a microdose of a single agent or combination therapy. The device releases drug microdoses in situ in a precisely controlled manner from multiple reservoirs in physiologically relevant concentrations into locally distinct regions of tumor. The local drug response is determined for each reservoir, providing information on which drugs are most effective in a given tumor. Optical analysis methods are integrated into the device to achieve real time continuous readouts of drug action for each reservoir. The advantage of this technology over existing in vitro assays is that it studies drug action in the native tumor tissue, thus taking into account the effects of epigenetics, tumor microenvironment, stroma and immune system. This technology will potentially have a transformative effect on preclinical and clinical cancer research and treatment. It will enable the study of dozens of compounds or combinations in parallel in a single organism, where now only a single therapy can be studied per experiment. This will enable more powerful studies of combination therapies or synthetic lethality, and may in the future be used as a tool to identify early response in adaptive clinical trials. Our strategy for implementing this technology is divided into three phases. In the first phase, we will engineer precise release and transport kinetics from device reservoirs into tissue for eight widely used anticancer drugs. The pharmacokinetic parameters will be matched to those achieved during systemic treatments with these drugs. We will then develop methods to extract and analyze relevant regions of tumor tissue by histological methods to assess drug response for each reservoir. Lastly, we will integrate miniaturized optical technologies into the implantable device in order to measure in real time how tumor cells are affected by local drug exposure. We will demonstrate the impact of the device technology in a study that measures differential drug response of mukltiple therapies in two well-described tumor models. The implantation of this technology builds on the extensive experience in our laboratory in the delivery of precisely controlled amounts of drugs via implantable devices. With our contributors Robert Langer, Tyler Jacks and Brett Bouma, we have assembled the expertise that enables the fulfillment of each of the project's specific aims, which will put into practice a powerful and transformative new technology in cancer.