Fe‐containing metal–organic framework with D‐penicillamine for cancer‐specific hydrogen peroxide generation and enhanced chemodynamic therapy

Chemodynamic therapy (CDT) is based on the production of cytotoxic reactive oxygen species, such as hydroxyl radicals ((•)OH). Thus, CDT can be advantageous when it is cancer‐specific, in terms of efficacy and safety. Therefore, we propose NH(2)‐MIL‐101(Fe), a Fe‐containing metal–organic framework (MOF), as a carrier of Cu (copper)‐chelating agent, d‐penicillamine (d‐pen; i.e., the NH(2)‐MIL‐101(Fe)/d‐pen), as well as a catalyst with Fe‐metal clusters for Fenton reaction. NH(2)‐MIL‐101(Fe)/d‐pen in the form of nanoparticles was efficiently taken into cancer cells and released d‐pen in a sustained manner. The released d‐pen chelated Cu that is highly expressed in cancer environments and this produces extra H(2)O(2), which is then decomposed by Fe in NH(2)‐MIL‐101(Fe) to generate (•)OH. Therefore, the cytotoxicity of NH(2)‐MIL‐101(Fe)/d‐pen was observed in cancer cells, not in normal cells. We also suggest a formulation of NH(2)‐MIL‐101(Fe)/d‐pen combined with NH(2)‐MIL‐101(Fe) loaded with the chemotherapeutic drug, irinotecan (CPT‐11; NH(2)‐MIL‐101(Fe)/CPT‐11). When intratumorally injected into tumor‐bearing mice in vivo, this combined formulation exhibited the most prominent anticancer effects among all tested formulations, owing to the synergistic effect of CDT and chemotherapy.