A tumor spheroid array chip for high-fidelity evaluation of liposomal drug delivery through the EPR effect

Abstract

Conventional two-dimensional (2D) culture systems fail to recapitulate the structural and functional complexity of the tumor microenvironment (TME), limiting their utility for preclinical drug evaluation. Here, we present a perfusable, high-throughput microfluidic Tumor Spheroid Array (TSA)-Chip that supports dynamic co-culture of tumor spheroids and vascular networks under perfusable conditions. The platform enables real-time visualization and quantitative analysis of nanoparticle transport, therapeutic response, and vascular remodeling. Fluorescent liposome tracking revealed EPR-like, tumor-selective accumulation, which was absent in 2D or tumor-free models. Liposomal 5-fluorouracil (5-FU) induced localized cytotoxicity and peritumoral vessel pruning while preserving overall vascular integrity. Furthermore, combination treatment with Cyramza™ (ramucirumab) enhanced tumor suppression and barrier normalization. Compared to conventional models, the TSA-chip offers robust analytical capabilities for assessing nanocarrier delivery and combination therapy effects in a scalable and physiologically relevant format, advancing its utility in precision oncology research.