Engineering HepG2 spheroids with injectable fiber fragments as predictable models for drug metabolism and tumor infiltration

AbstractIn vitro cell and tissue models are playing essential roles in the identification of active pharmaceutical ingredients. Though HepG2 cells have attractive profiles over primary hepatocytes in the availability and viability retention, the expression of metabolizing enzymes is quite low. In the current study, three ‐dimensional (3D) HepG2 spheroids with smaller sizes of 150 μm (3Ds) and bigger sizes of 300 μm (3Db) are engineered using injectable fiber fragments as the substrate. In contrast to two‐dimensional (2D) culture, the enzyme activities for drug metabolisms are restored in 3Ds and the pathop hysiological profiles of tumor tissues are rebuilt in 3Db spheroids. Compared with spheroid culture without fiber fragments, 3Ds spheroids show higher activities of metabolizing enzymes (CYP3A4, CYP2A9, and phase II) and higher sensitivities to enzyme inducers (rifampicin and glutathione) and inhibi tors (ketoconazole and probenecid). The drug clearance and toxicity to 3Ds spheroids predict better the clinical observations and drug–drug interactions. In addition, compared to scaffold‐free spheroid culture, stronger expressions of E‐cadherin and hypoxia‐inducible factor‐1α (HIF‐1α) and higher fibronectin secretions are determined in 3Db spheroids, displaying apparent hypoxic and apoptotic regions similar to those found in solid tumors. In contrast to the overestimated drug toxicity in other systems, the infiltrations of free drug and drug‐loaded mic...
Source: Journal of Biomedical Materials Research Part B: Applied Biomaterials - Category: Materials Science Authors: Tags: ORIGINAL RESEARCH REPORT Source Type: research