Delivery of disulphiram 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 disulphiram (DSF) and doxycycline (DOX) to synergistically target CCLM. The nanocomposite was synthesised <i>via</i> 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 characterisation confirmed uniform spherical morphology (160.8 ± 20.7 nm), Cu²⁺ incorporation (4.74% atomic ratio), and exceptional colloidal stability (>24 h). <i>In vitro</i> studies demonstrated synergistic cytotoxicity in CT26.WT cells, with combination therapy reducing IC₅₀ by 2.5-fold versus monotherapes (<i>p</i> < 0.01), mediated by ROS overproduction (6.7-fold vs control) and mitochondrial depolarisation. 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 (<i>p</i> < 0.01), comparable to capecitabine (<i>p</i> > 0.05). Histopathology revealed minimal metastatic burden and reduced hepatotoxicity in combinatorial groups. The Goldie-Coldman synergy index (<i>q</i> = 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 favourable safety profiles.