Tuning quercetin delivery through in-situ and ex-situ loading of UiO-66-NH2 for pH-responsive liver cancer therapy

This study investigates the incorporation of quercetin, a natural anticancer agent, into UiO-66-NH2 metal-organic frameworks (MOFs) using two strategies: in-situ encapsulation during MOF synthesis and ex-situ loading into preformed frameworks. Both methods successfully produced quercetin-loaded MOFs with distinct structural and functional features. In-situ loading caused significant structural changes, reducing surface area and porosity, 67.13 % for ex-situ formulations. Both systems displayed pH-responsive release, but with different mechanisms: the in-situ formulation followed a super Case II transport, showing rapid quercetin release under acidic conditions (up to 90.98 % at pH 1.2), while the ex-situ formulation exhibited anomalous (non-Fickian) diffusion, providing gradual and sustained release, especially at physiological pH. Biological evaluation in liver cancer cell lines (Huh7 and JHH6) showed that the ex-situ formulation retained higher anticancer activity compared to the in-situ formulation. These findings highlight that the method of drug incorporation strongly influences MOF structure, release behavior, and therapeutic performance, offering valuable guidance for designing responsive nanocarriers for targeted cancer therapy.