Evaluation of a targeted drug delivery system on breast tumor spheroids on a chip

Targeted combination nanomedicine can be employed as a potent approach for cancer treatment. However, the inadequacy of most preclinical tumor models for drug/nanotherapeutic screening has limited their clinical translation. As promising in vitro models, three-dimensional (3D)-printed microfluidic devices can be fabricated in a high-throughput cost-effective manner for various biomedical applications. In this study, using a 3D printed mold, a microwell-based breast tumor-on-a-chip was developed. A modified protocol was devised for the surface treatment of the resin-based 3D-printed template making it suitable for repeated long-term polydimethylsiloxane (PDMS) casting. The versatility of the chip was demonstrated through both biorelevant scaffold-free 3D tumor spheroid culture and nanomedicine screening. Representative of avascular tumor tissues, tumor spheroids were generated in this platform and exhibited tight structure with a size range of 300–500 μm, internal cellular layers, and in vivo pathophysiology conditions. A targeted drug delivery system of 5-fluorouracil, curcumin, and piperine co-loaded folate-conjugated human serum albumin nanoparticles (FA-5FU-CUR-PIP-HSA-NPs) was synthesized by the self-assembly method and both hydrophobic and hydrophilic drugs were encapsulated in the NPs. The transport mechanism and efficacy of the NPs were investigated on the tumor model tissue. Possessing proper physical, biological, and pharmaceutical drug combination, the targeted NPs formulation with the potential of cancer theranostics demonstrated enhanced internalization and accumulation into triple-negative MDA-MB-231 breast cancer microtissues upon both passive and active targeting. The increased penetration and uptake of the targeted NPs in tumor spheroids were translated into boosted anticancer activity. Compatible with the uptake and cytotoxicity test, higher cell apoptosis was observed for the targeted nanomedicine than for the non-targeted NPs. Together, the combination of microfluidics and nanomedicine approaches can benefit basic research related to human disease.