Implantable device for high-throughput in vivo drug sensitivity testing

用于高通量体内药物敏感性测试的植入装置

• 批准号: 9094541
• 负责人: Michael J Cima
• 金额: $ 19.42万
• 依托单位: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-08 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9094541
• 关键词: Accounting; Affect; Animals; Antineoplastic Agents; Apoptosis; Apoptotic; Area; Biocompatible Materials; Biological; Biological Assay; Biopsy; Breast Cancer Model; Cancer Patient; Cell Death; Cells; Clinical; Clinical Trials; Combined Modality Therapy; Confined Spaces; Detection; Development; Device Designs; Devices; Diagnostic; Dissection; Dose; Doxorubicin; Drug Exposure; Drug Kinetics; Drug effect disorder; Engineering; Environment; Epigenetic Process; Erlotinib; Fluorescence Microscopy; Formulation; Future; Gel; Genetic Predisposition to Disease; Health; Histological Techniques; Histopathology; Image; Immune system; Immunofluorescence Immunologic; Implant; In Situ; Induction of Apoptosis; Kinetics; Laboratories; Life; Liquid substance; Malignant Neoplasms; Mass Spectrum Analysis; Measurement; Measures; Membrane; Methods; Microscopic; Modeling; Molecular; Monitor; Necrosis; Optics; Organism; Patients; Pharmaceutical Preparations; Pharmacotherapy; Phase; Physicians; Procedures; Property; Research Personnel; Shapes; Solid; Staining method; Stains; Techniques; Technology; Testing; Therapeutic Agents; Time; Tissues; Translations; Tumor Tissue; anticancer research; antitumor effect; cancer therapy; clinically relevant; cohort; compound 30; drug efficacy; drug sensitivity; experience; implantable device; implantation; in vitro Assay; in vivo; light scattering; miniaturize; minimally invasive; neoplastic; neoplastic cell; new technology; novel; optical fiber; pre-clinical; research study; response; screening; seal; therapy design; tool; treatment response; triple-negative invasive breast carcinoma; tumor; tumor microenvironment

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.

描述(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，以原位检测肿瘤对各种抗癌药物的局部反应。这一检测结合其他临床标准，可能有助于预测癌症患者的最佳治疗方案。这项技术由一个微型可植入设备组成，该设备直接放置在肿瘤内，并包含大量的储存库，每个储存库都装载了微剂量的单一药物或联合治疗。该设备以精确控制的方式从多个储存库以生理上相关的浓度将药物微剂量原位释放到肿瘤的局部不同区域。确定每个储存库的局部药物反应，提供关于哪些药物对给定肿瘤最有效的信息。光学分析方法被集成到设备中，以实现对每个储藏者的药物作用的实时连续读数。与现有的体外检测相比，这项技术的优势在于它研究了天然肿瘤组织中的药物作用， 从而考虑了表观遗传学、肿瘤微环境、间质和免疫系统的影响。这项技术可能会对临床前和临床癌症的研究和治疗产生革命性的影响。它将使在单个有机体中并行研究数十种化合物或组合成为可能，现在每个实验只能研究一种治疗方法。这将使对联合疗法或合成致死性的更强大的研究成为可能，并在未来可能被用作在适应性临床试验中识别早期反应的工具。我们实施这项技术的战略分为三个阶段。在第一阶段，我们将设计八种广泛使用的抗癌药物的精确释放和从设备储存库到组织的传输动力学。药代动力学参数将与这些药物全身治疗期间获得的参数相匹配。然后，我们将开发方法，通过组织学方法提取和分析肿瘤组织的相关区域，以评估每个储存库的药物反应。最后，我们将把微型化的光学技术集成到植入式设备中，以便实时测量局部药物暴露对肿瘤细胞的影响。我们将在一项研究中展示设备技术的影响，该研究在两个描述良好的肿瘤模型中衡量多种治疗方法的不同药物反应。这项技术的植入建立在我们实验室通过植入式设备输送精确控制量的药物方面的丰富经验基础上。与我们的贡献者罗伯特·兰格、泰勒·杰克和布雷特·布玛一起，我们汇集了专业知识，使每个项目的特定目标得以实现，这将使一个强大的和 癌症领域的变革性新技术。