(PQD5) Development of in Vitro Vascularized Microtumors for Drug Screening

(PQD5) 用于药物筛选的体外血管化微肿瘤的开发

基本信息

批准号：
8591210
负责人：
CHRISTOPHER C. W. HUGHES
金额：
$ 31.24万
依托单位：
UNIVERSITY OF CALIFORNIA-IRVINE
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-08-01 至 2017-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8591210
关键词：
3-Dimensional Address Adverse effects Antineoplastic Agents Area Biomedical Engineering Blood Vessels Blood capillaries Cell Line Cells Clinical Trials Complex Critical Pathways Death Rate Dependence Development Devices Drug Combinations Drug Delivery Systems Drug Targeting Drug toxicity Endothelial Cells Environment Extracellular Matrix Failure Genomics Goals Green Fluorescent Proteins Growth Hand Housing Human In Vitro Lead Left Libraries Life Marketing Measurable Metabolism Methods Microfluidic Microchips Mus Nutrient Oxygen PECAM1 gene Partner in relationship Patients Pericytes Pharmaceutical Preparations Pharmacodynamics Phase III Clinical Trials Plastics Preclinical Drug Evaluation Proteins Role Route SW620 Staging Staining method Stains Stromal Cells System Technology Testing Therapeutic Agents Time Tissues Toxic effect Vascular blood supply Venous system Work anticancer research arteriole cancer cell cancer therapy capillary cell type cost cost effective drug candidate drug discovery drug efficacy high throughput screening improved lentiviral-mediated monolayer mouse model neoplastic cell novel public health relevance research clinical testing response screening success three dimensional structure tissue culture tumor venule

项目摘要

DESCRIPTION (provided by applicant): Since current methods to predict the efficacy or toxicity of new drug candidates in humans are often inaccurate, can we develop new methods to test potential therapeutic agents that yield better predictions of response? Provocative questions demand bold answers. Here we propose a radically new bioengineering approach to drug screening that employs arrayed human 3D microtumors, supported by perfused capillaries. Tumor cells grow within a small chamber filled with complex ECM and stromal cells, and are nourished by a network of newly-formed capillaries that are connected to an artificial arteriovenous system. Hundreds of chambers can be arranged on a single chip, each with its own vascular supply, thereby allowing for development of a high- throughput screening (HTS) platform. Tumor lines can be used for drug-discovery, or patient-specific tumor cells for personalized screening. This system combines the advantages of tissue culture - defined, rapid, cost- effective and reproducible - with the advantages of mouse models - 3-dimensional, multiple cell types interacting, complex pharmacodynamics, and dependence on vasculature for survival and drug-delivery. In addition, lentiviral-mediated expression of red, yellow and green fluorescent proteins in the tumor cells, endothelial cells and stromal cells will allow for repeate, rapid and quantitative assessment of drug toxicity/efficacy against each cell type over time. Importantly, the key technologies underlying this proposal have already passed the proof-of-concept stage - we now seek to optimize and harmonize the components into a working HTS platform that will more accurately predict how drugs will act in humans.

描述（由申请人提供）：由于当前预测新药候选者在人类中的疗效或毒性的方法通常不准确，我们是否可以开发新方法来测试潜在的治疗剂以产生更好的反应预测？挑衅性的问题需要大胆的答案。在这里，我们提出了一种用于药物筛查的根本新的生物工程方法，该方法采用了由灌注毛细血管支持的人类3D微型量。肿瘤细胞在一个充满复杂的ECM和基质细胞的小室内生长，并通过与人工动静脉系统相连的新形成毛细血管网络进行滋养。数百个腔室可以安排在一个芯片上，每个芯片都有自己的血管供应，从而可以开发高通量筛选（HTS）平台。肿瘤系可用于药物发现或患者特异性肿瘤细胞进行个性化筛查。该系统结合了组织培养的优势 - 定义，快速，成本效益和可再现的 - 与小鼠模型的优势 - 三维，多种细胞类型相互作用，复杂的药效学以及对脉管系统的依赖性，用于生存和药物交付。此外，慢病毒介导的肿瘤细胞中红色，黄色和绿色荧光蛋白的表达，内皮细胞和基质细胞将允许对每种细胞类型的药物毒性/效率进行重复，快速和定量评估。重要的是，该提案基于的关键技术已经通过了概念验证阶段 - 我们现在试图将组件优化和协调到工作的HTS平台中，以更准确地预测药物如何在人类中起作用。