Evaluation of drug combination for glioblastoma based on an intestine-liver metabolic model on microchip.

ABSTRACT

An intestine-liver-glioblastoma biomimetic system was developed to evaluate the drug combination therapy for glioblastoma. A hollow fiber (HF) was embedded into the upper layer of the microfluidic chip for culturing Caco-2 cells to mimic drug delivery as an artificial intestine. HepG2 cells cultured in the bottom chamber of the chip acted as an artificial liver for metabolizing the drugs. The dual-drug combination to glioblastoma U251 cells was evaluated based on the intestine-liver metabolic model. The drugs, irinotecan (CPT-11), temozolomide (TMZ) and cyclophosphamide (CP), were used to dynamically stimulate the cells by continuous infusion into the intestine unit. After intestine absorption and liver metabolism, the prodrugs were transformed to active metabolites, which induced glioblastoma cells apoptosis. The anticancer activity of the CPT-11 and TMZ combination is significantly enhanced compared to that of the single drug treatments. Combination index (CI) values of the combination groups, CPT-11 and TMZ, CPT-11 and CP, and TMZ and CP, at half maximal inhibitory concentration were 0.137, 0.288, and 0.482, respectively. The results indicated that the CPT-11 and TMZ combination was superior to the CPT-11 and CP group as well as the TMZ and CP group towards the U251 cells. The metabolism mechanism of CPT-11 and TMZ was further studied by coupling with mass spectrometric analysis. The biomimetic model enables the performance of long-term cell co-culture, drug delivery, metabolism and real-time analysis of drug effects, promising systematic in vitro mimicking of physiological and pharmacological processes.