A microfluidic platform for personalized throughput drug screening using cancer spheroids

癌症仍然是世界范围内的主要死亡原因。对于许多患者，标准治疗包括手术切除原发性肿瘤，但手术后通常会在远处生长继发性微肿瘤。需要对微转移有毒性或将其锁定在休眠状态的治疗，但评估药物对在不同环境中生长的具有不同保护特性的微肿瘤的有效性是一个挑战。 ** 目前，缺乏重建微转移用于评价治疗剂的工具。动物模型是昂贵的，劳动和耗时的;一般来说，只提供终点分析，可以说，是不相关的人类。二维细胞培养产生微肿瘤模型，其性质和表型与在生理3D环境中生长的微肿瘤模型有很大不同，因此可能不能作为药物筛选的有效模型。多细胞癌球体（MCS）是二维细胞培养和动物模型的桥梁，在药物筛选中具有广阔的应用前景，但目前用于药物筛选的MCS模型存在许多局限性。 ** 该提案旨在开发一个微流体（MF）平台，用于筛选新药和优化现有药物制剂，用于治疗癌症。该技术利用源自在MF装置中的仿生水凝胶中生长的患者来源的细胞的大小均匀的MCS的大阵列，在接近生理流动条件下将药物递送至这些MCS，以及MCS治疗的药物功效的通量筛选。MF-MCS平台包括多行平行微孔，每行最多100个MCS。该平台能够使特定因子在不同行之间系统地变化，从而能够筛选在特定环境中从特定细胞类型生长的MCS的药物功效，以及药物剂量和组合的影响，仅举几例，所有这些都在单个MF装置中进行的一系列实验中。**************

Cancer remains the leading cause of death worldwide. For many patients, standard-of-care therapy involves surgical removal of the primary tumour, however the surgery is often followed by the growth of secondary microtumours at distant locations. Therapies are required that are either toxic toward micrometastases or that lock them in the dormant state, yet there is a challenge to assess the effectiveness of drugs for microtumors grown in different environments with varying protective properties. ** Currently, there is lack of tools that recreate micrometastasis for the evaluation of therapeutic agents. Animal models are expensive, labor- and time-consuming; generally, provide only endpoint analyses and arguably, are not relevant for humans. Two-dimensional cell culture yields microtumor models that differ considerably in their properties and phenotype from those grown in physiological 3D environments, and thus may not serve as an efficient model for drug screening. Multicellular cancer spheroids (MCS) bridge 2D cell culture and animal models, and have very promising applications in drug screening however presently used MCS models for drug screening suffer from a number of limitations. ** This proposal aims at the development of a microfluidic (MF) platform for screening of new drugs and optimization of existing drug formulations for therapeutic cancer treatment. The technology utilizes large arrays of uniformly-sized MCSs derived from patient-derived cells that are grown in a biomimetic hydrogel in a MF device, the delivery of drugs to these MCSs under close-to-physiological flow conditions, and throughput screening of drug efficacy for MCS treatment. The MF-MCS platform includes multiple parallel rows of microwells, with up to 100 MCSs in each row. The platform enables systematic variation of a particular factor between different rows, thus enabling screening of drug efficacy for MCSs grown from a particular cell type in a specific environment, and the effect of drug dosages and combinations, to name just a few, all in one series of experiments conducted in a single MF device. **************