Bio-reductive Co( <scp>iii</scp> )–doxorubicin complex for cancer cell-selective delivery of doxorubicin and potent anticancer activity

The utility of bio-reductive prodrugs in cancer research has emerged as an attractive strategy. We synthesized and characterized a couple of cobalt(iii)-Schiff base complexes of general molecular formula Co(L¹)(L²) <b>[Co(iii)-dione]</b> and Co(L¹)(dox) <b>[Co(iii)-dox]</b>, where L¹ and L² are <i>N</i>,<i>N</i>-(ethane-1,2-diyl)bis(1-(pyridine-2-yl)methanimine) and 1-phenyl-1,3-butanedione, and dox = doxorubicin, as bio-reductive prodrugs. UV-vis and fluorescence spectroscopic assays confirmed the reductive release of doxorubicin from the complex <b>[Co(iii)-dox]</b> in a GSH-dependent manner under physiological conditions, showing its potential for <i>in vitro</i> drug release. The rate of doxorubicin release was found to be 8.20 min^-1 at pH 5.5 in the presence of 10 mM GSH. The complex <b>[Co(iii)-dox]</b> primarily targets mitochondria and displayed remarkable anticancer effects against A549, hypoxic A549, HT29, and MDA-MB-231 cells with IC₅₀ values in the range of 9.88-17.89 μM (24 h incubation), suggesting its ability to overcome multidrug resistance (MDR) and reduce side effects associated with traditional doxorubicin therapy. The IC₅₀ value determined against HaCaT cells was >30 μM. The colony formation, wound healing, and invasion assays revealed the capacity of the complex <b>[Co(iii)-dox]</b> to inhibit tumor growth, migration, and invasion. Furthermore, RT-PCR analysis showed notable downregulation of key hypoxia-adaptive genes (HIF-1α, VEGF, and GLUT-1), disrupting tumor survival mechanisms. Overall, the complex <b>[Co(iii)-dox]</b> emerged as an excellent bio-reductive prodrug for safer and potent anticancer activity.