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: 8738826
• 负责人: Michael J Cima
• 金额: $ 25.9万
• 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/8738826
• 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 Formulations; Drug Kinetics; Drug effect disorder; Engineering; Environment; Epigenetic Process; Erlotinib; Fluorescence Microscopy; Future; Gel; Genetic Predisposition to Disease; 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; Relative (related person); Research Personnel; Shapes; Solid; Staining method; Stains; Techniques; Technology; Testing; Therapeutic Agents; Time; Tissues; Translations; Tumor Tissue; anticancer research; 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; public health relevance; 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）：我们的目的是开发一种快速，高通量的诊断设备技术，该技术对肿瘤进行了肿瘤，以便其对广泛的抗癌药物的局部反应。该测定法结合其他临床标准，有可能有助于预测癌症患者的最佳治疗。这项技术由一个小型植入式装置组成，该设备直接放入肿瘤中，并包含大量储层，每种储层都装有单一药物或联合疗法的微剂量。该设备从生理相关浓度的多个储层中以精确控制的方式将药物微剂量释放到肿瘤的局部不同区域。确定每个储层的局部药物反应，提供有关哪些药物在给定肿瘤中最有效的信息。将光学分析方法集成到设备中，以实现每个储层的实时连续读数药物作用。该技术比现有的体外测定法的优点是，它研究了在天然肿瘤组织中的药物作用， 因此考虑了表观遗传学，肿瘤微环境，基质和免疫系统的影响。该技术可能会对临床前和临床癌症研究和治疗产生变革性的影响。它将能够研究单个生物体中的数十种化合物或组合，现在每个实验只能研究一种单一的疗法。这将实现对组合疗法或合成致死性的更强大的研究，并且将来可以用作自适应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，我们将设计精确的释放和将动力学从设备储层转移到八种广泛使用的抗癌药物的组织中。药代动力学参数将与使用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，以评估每个储层的药物反应。最后，我们将将微型光学技术整合到可植入的装置中，以实时测量肿瘤细胞如何受到局部药物暴露的影响。我们将在一项研究中证明设备技术的影响，该研究测量了两个描述的肿瘤模型中MUKLTIPE疗法的差异药物反应。这项技术的植入基于我们实验室在通过可植入的设备提供精确控制的药物方面的丰富经验。与我们的贡献者罗伯特·兰格（Robert Langer），泰勒·杰克斯（Tyler Jacks）和布雷特·布玛 癌症的变革性新技术。