Folate-conjugated chitosan/Zn-MOF for targeted 5-fluorouracil delivery in hepatocellular carcinoma

Cancer treatment struggles with toxicity, driving the development of targeted drug delivery systems like MOFs for better efficacy and reduced side effects in hepatocellular carcinoma HCC. This study was to evaluate the anticancer efficacy and biocompatibility of formulations, Zn-MOF, Zn-MOF/5FU, and FA-Cs/Zn-MOF/5FU against HepG2 cancer cells and LO2 normal cells at a 40 μM concentration. 5FU, a commonly used chemotherapeutic agent, demonstrated high cytotoxicity against HepG2 cells (70.39% inhibition, IC₅₀: 22.4 ± 0.5 μM) but exhibited significant toxicity (22.86%) in normal cells, indicating its non-selective activity. Incorporating 5FU into Zn-based metal-organic frameworks (MOFs) (Zn-MOF/5FU) enhanced its efficacy (77.12% inhibition, IC₅₀: 21.3 ± 0.2 μM), although it still caused 19.04% toxicity in normal cells. The functionalized nanoplatform FA-Cs/Zn-MOF/5FU exhibited the highest anticancer activity, 81.67% inhibition (IC₅₀: 16.2 ± 0.6 μM), with least toxicity to normal cells, 11.02%, due to folate receptor targeting along with chitosan functionalization, which enhanced stability, drug loading, controlled release, and selectivity through increased cellular uptake. Zn-MOF without modification presented the lowest anticancer activity, 61.49% inhibition (IC₅₀: 34.4 ± 0.6 μM), but it was biocompatible, having 16.76% toxicity. Thus, the structure-activity relationship supports the progressive enhancements of anticancer activity and selectivity in these functional modifications. These results confirm that FA-Cs/Zn-MOF/5FU presents the most promising anticancer effect among the series with controlled release, reduced toxicity, and improved cellular uptake. This study novel insights into targeted cancer therapy designs by using metal-organic frameworks (MOF) and functionalized drug delivery systems.