Delivery of disulfiram by Copper-doped mesoporous silica nanoparticles in combination with doxycycline for treating colorectal cancer liver metastasis

Colorectal cancer liver metastasis (CCLM) remains a major therapeutic challenge due to chemoresistance and dose-limiting toxicities of conventional therapies. This study developed a copper-doped mesoporous silica nanoparticle (DSF@Cu-MSNs-BSA) for co-delivering disulfiram (DSF) and doxycycline (DOX) to synergistically target CCLM. The nanocomposite was synthesized via Sol-gel co-condensation, surface amination, and albumin adsorption, achieving a high DSF loading capacity (12.69 ± 2.47% w/w) with sustained release. Physicochemical characterization confirmed uniform spherical morphology (160.8 ± 20.7 nm), Cu2+ incorporation (4.74% atomic ratio), and exceptional colloidal stability (>24 h). In vitro studies demonstrated synergistic cytotoxicity in CT26.WT cells, with combination therapy reducing IC50 by 2.5-fold versus monotherapes (P < 0.01), mediated by ROS overproduction (6.7-fold vs control) and mitochondrial depolarization. Pharmacological ROS quenching attenuated cytotoxicity by 46.5%, validating redox-driven mechanisms. In an orthotopic CCLM model, DSF@Cu-MSNs-BSA/DOX combination suppressed hepatic metastasis by 72-75%, extending median survival by 51% versus control (P < 0.01), comparable to capecitabine (P > 0.05). Histopathology revealed minimal metastatic burden and reduced hepatotoxicity in combinatorial groups. The Goldie-Coldman synergy index (q = 1.18) confirmed supra-additive efficacy. This nanoplatform addresses DSF’s pharmacokinetic limitations while leveraging DOX’s mitochondrial targeting, offering a promising strategy for metastatic CRC management with favorable safety profiles.