Core-Shell Metal-Organic Frameworks as Fe2+ Suppliers for Fe2+-Mediated Cancer Therapy under Multimodality Imaging

Integrated theranostic agents can provide comprehensive and efficient tools for simultaneous cancer diagnosis and therapy; however, limitations on efficiency and safety offer great room for improvement. Artesunate (AS), as an iron-dependent drug, has been investigated in cancer therapy, depending on free-radical generation for its action, which may reduce side effects commonly associated with conventional chemotherapy agents with low selectivity to target tumors. However, rapid clearance of its free form and limited availability of Fe ion in tumor sites become the main bottlenecks in cancer therapy. Herein, core-hell Mn-3[Co(CN)(6)](2)@MLL-100(Fe) metal-organic frameworks (CS-MOFs) nanocube was designed using a layer-by-layer method, which holds great potential for synchronous co-delivery of AS and ferric ions for cancer therapy. Moreover, the heterogeneous hybrid CS-MOFs show single- and two-photon fluorescence, together with T-2 and enhanced T-1 magnetic resonance imaging ability. pH-responsive degradation of CS-MOFs enables on-demand Fe(III) and AS release in the tumor microenvironment. The intracellular ferric ions will further be reduced to ferrous ion that catalyze AS to generate carbon-centered free radicals and reactive oxygen species (ROS). The potential of this alternative antitumor modality under multimodality imaging is demonstrated both in vitro and in vivo. In addition, compared with free AS alone, the nanodrug system CS-MOFs@AS shows significantly enhanced tumor delivery specificity and negligible long-term toxicity. In vivo therapy results indicate that the antitumor efficacy of CS-MOFs@AS was 5.79 times greater than that of free AS, making it a promising Fe2+-mediated drugs delivery system.