Whole-process 3D ECM-encapsulated organoid-based automated high-throughput screening platform accelerates drug discovery for rare diseases.

IF 6
Life medicine Pub Date : 2025-06-14 eCollection Date: 2025-10-01 DOI:10.1093/lifemedi/lnaf021
Zhaoting Xu, Hui Yang, Yuru Zhou, Emmanuel Enoch Dzakah, Bing Zhao
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Abstract

Organoid-based high-throughput screening (HTS) is revolutionizing pharmaceutical development. However, the complexity of handling extracellular matrix (ECM) components with traditional HTS devices leads to the use of suspension cultures for organoids during HTS, which alters their transcriptomic landscape and drug responses. Although automated generation techniques for 3D ECM-encapsulated organoids have been established, limitations in operational simplicity and time efficiency remain barriers to achieving high throughput. Here, we develop a whole-process 3D ECM-encapsulated organoid-based automated HTS (wp3D-OAHTS) platform, which achieves superior throughput compared to existing reported systems for 3D organoid drug screening. Utilizing this automated platform, we generated more than 10,000 homogeneous 3D organoid domes of neuroendocrine cervical cancer (NECC) and evaluated their drug responses to 2802 compounds in 13 days. This highly efficient and reproducible approach finally enabled the identification of 5 top hits that significantly inhibited NECC organoids in vitro with half-maximal inhibitory concentration (IC50) of lower than 10 nM. The representative candidate, Quisinostat 2HCl, demonstrated significantly stronger anti-tumor efficacy than clinically used agents in vivo. This platform significantly improves the rapidity and efficiency of 3D ECM-encapsulated organoid drug screening and facilitates new drug discovery for rare diseases.

全流程3D ecm封装类器官自动化高通量筛选平台加速罕见疾病药物的发现。
基于类器官的高通量筛选(HTS)正在彻底改变药物开发。然而,使用传统HTS设备处理细胞外基质(ECM)成分的复杂性导致在HTS过程中使用悬浮培养的类器官,这改变了它们的转录组景观和药物反应。虽然3D ecm封装类器官的自动化生成技术已经建立,但操作简单性和时间效率的限制仍然是实现高通量的障碍。在这里,我们开发了一个全流程3D ecm封装的基于类器官的自动化HTS (wp3D-OAHTS)平台,与现有的3D类器官药物筛选系统相比,该平台具有更高的吞吐量。利用这个自动化平台,我们生成了超过10,000个神经内分泌宫颈癌(NECC)的均匀3D类器官穹顶,并在13天内评估了它们对2802种化合物的药物反应。该方法高效、可重复性好,最终鉴定出5个对NECC类器官有显著抑制作用的top hits,半数最大抑制浓度(IC50)均小于10 nM。具有代表性的候选药物喹司他2HCl在体内的抗肿瘤效果明显强于临床使用的药物。该平台显著提高了三维ecm包封类器官药物筛选的速度和效率,促进了罕见疾病新药的发现。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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