Tumor-Microenvironment-on-a-Chip for Evaluating Nanoparticle-Loaded Macrophages for Drug Delivery.

Targeted drug delivery remains attractive but challenging for cancer therapy. Cell-mediated drug delivery has emerged as a promising strategy to improve targeted drug delivery to tumors due to the intrinsic ability of certain types of cells (., macrophage) to pass through physiological barriers and specifically home to tumors. To fundamentally understand how macrophage-based drug carriers transport and interact with the tumor microenvironment, we developed a tumor-microenvironment-on-a-chip (TMOC) model that enables the coculture of tumor spheroids and macrophages in a three-dimensional (3D) gel matrix. By introducing drug-loaded macrophages, the TMOC model allows real-time observation of macrophage migration toward the tumor, infiltration into tumor spheroids, and subsequent response of tumor to drugs. Our results demonstrated the superior capability of macrophages migrating toward the tumor and infiltrate tumor spheroids. Drug loading in macrophages had minimum effect on their cell viability, and drug-carrying macrophages exhibited greater tumor cell cytotoxicity compared to their nanoparticle counterparts. Our work highlighted the great potential of macrophages as novel drug carriers for targeted drug delivery, and the TMOC model serves as a versatile platform to enable quick evaluation of such cell-mediated drug delivery systems.