Bio-reductive Co(iii)-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(L)(L) and Co(L)(dox) , where L and L are ,-(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 in a GSH-dependent manner under physiological conditions, showing its potential for drug release. The rate of doxorubicin release was found to be 8.20 min at pH 5.5 in the presence of 10 mM GSH. The complex primarily targets mitochondria and displayed remarkable anticancer effects against A549, hypoxic A549, HT29, and MDA-MB-231 cells with IC 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 IC value determined against HaCaT cells was >30 μM. The colony formation, wound healing, and invasion assays revealed the capacity of the complex 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 emerged as an excellent bio-reductive prodrug for safer and potent anticancer activity.