Copper-olsalazine metal-organic frameworks as a nanocatalyst and epigenetic modulator for efficient inhibition of colorectal cancer growth and metastasis

Despite the extensive explorations of nanoscale metal-organic frameworks (nanoMOFs) in drug delivery, the intrinsic bioactivity of nanoMOFs, such as anticancer activity, is severely underestimated owing to the overlooked integration of the hierarchical components including nanosized MOFs and molecular-level organic ligands and metal-organic complexes. Herein, we propose a de novo design of multifunctional bioactive nanoMOFs ranging from molecular to nanoscale level, and demonstrate this proof-of-concept by a copper-olsalazine (Olsa, a clinically approved drug for inflammatory bowel disease, here as a bioactive linker and DNA hypomethylating agent) nanoMOF displaying a multifaceted anticancer mechanism: (1) Cu-Olsa nanoMOF-mediated redox dyshomeostasis for enhanced catalytic tumor therapy, (2) targeting downregulation of cyclooxygenase-2 by the organic complex of Cu²⁺ and Olsa, and (3) Olsa-mediated epigenetic regulation. Cu-Olsa nanoMOF displayed an enzyme-like catalytic activity to generate cancericidal species ·OH and ¹O₂ from rich H₂O₂ in tumors, improved the expression of tumor suppressors TIMP3 and AXIN2 by epigenetic modulation, and fulfilled selective inhibition of colorectal cancer cells over normal cells. The hyaluronic acid-modified nanoMOF further verified the efficient suppression of CT26 colorectal tumor growth and metastasis in murine models. Overall, these results suggest that Olsa-based MOF presents a platform of epigenetic therapy-synergized nanomedicine for efficient cancer treatment and provides a powerful strategy for the design of intrinsically bioactive nanoMOFs. STATEMENT OF SIGNIFICANCE: Metal-organic frameworks (MOFs) with intrinsic bioactivities such as anticancer and antibacterial activity are of great interest. Herein, we reported a bioactive copper-olsalazine (Cu-Olsa) nanoMOF as a nanodrug for colorectal cancer treatment. This nanoMOF per se displayed enzyme-like catalytic activity to generate cancericidal species ·OH and ¹O₂ from rich H₂O₂ in tumors for nanocatalytic tumor therapy. Upon dissociation into small molecular copper-organic complex and olsalazine in cancer cells, COX-2 inhibition and epigenetic modulation were fulfilled for selective inhibition of colorectal cancer growth and metastasis.