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（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，可原位测定肿瘤对多种抗癌药物的局部反应。该测定与其他临床标准相结合，有可能用于预测癌症患者的最佳治疗。该技术由直接放置在肿瘤中的微型植入装置组成，该装置包含大量储库，每个储库装有微剂量的单一药物或联合疗法。该装置以精确控制的方式从多个储库以生理相关浓度原位释放药物微剂量到局部不同的肿瘤区域。确定每个储库的局部药物反应，提供关于哪些药物在给定肿瘤中最有效的信息。光学分析方法集成到设备中，以实现每个储库的药物作用的实时连续读数。该技术相对于现有体外测定的优势在于它研究药物在天然肿瘤组织中的作用， 因此考虑到表观遗传学、肿瘤微环境、基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研究和治疗产生变革性影响。它将能够在单个生物体中并行研究数十种化合物或组合，而现在每个实验只能研究一种疗法。这将使联合疗法或合成致死率的更强有力的研究成为可能，并可能在未来用作识别适应性临床试验中早期反应的工具。我们实施这项技术的策略分为三个阶段。在第一阶段，我们将为八种广泛使用的抗癌药物设计从设备储库到组织的精确释放和运输动力学。药代动力学参数将与这些药物的全身治疗过程中获得的参数相匹配。然后，我们将开发通过组织学方法提取和分析肿瘤组织相关区域的方法，以评估每个储库的药物反应。最后，我们将微型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该设备技术的影响，该研究测量两种充分描述的肿瘤模型中多种疗法的差异药物反应。这项技术的植入建立在我们实验室通过植入设备输送精确控制数量的药物方面的丰富经验的基础上。我们与贡献者罗伯特·兰格 (Robert Langer)、泰勒·杰克斯 (Tyler Jacks) 和布雷特·鲍马 (Brett Bouma) 一起汇集了专业知识，能够实现每个项目的具体目标，这将把强大而有力的实践付诸实践。 癌症领域的革命性新技术。

项目成果

An implantable microdevice to perform high-throughput in vivo drug sensitivity testing in tumors.

一种可植入的微装置，用于在肿瘤中进行高通量体内药物敏感性测试。

• 发表时间: 2015-04-22
• 影响因子: 17.1
• 作者: Jonas, Oliver;Landry, Heather M;Fuller, Jason E;Santini Jr, John T;Baselga, Jose;Tepper, Robert I;Cima, Michael J;Langer, Robert
• 通讯作者: Langer, Robert