Bio-reductive Co(III)-doxorubicin complex for cancer cell-selective delivery of doxorubicin and potent anticancer activity

Abstract

The utility of bio-reductive prodrugs in cancer research has emerged as an attractive strategy. We synthesized and characterized couple of cobalt(III)-Schiff base complexes of general molecular formula, Co(L1)(L2) [Co(III)-dione] and Co(L1)(dox) [Co(III)-dox]), where L1 and L2 are N,N-(ethane-1,2-diyl)bis(1-(pyridine-2-yl)methanimine) and 1-Phenyl-1,3-butanedione, and dox= doxorubicin as the bio-reductive prodrugs. UV-vis and fluorescence spectroscopic assays confirmed the reductive release of doxorubicin from the complex, [Co(III)-dox] in a GSH-dependent manner under physiological conditions, showing its potential for in vitro 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, [Co(III)-dox] primarily targets mitochondria and displayed remarkable anticancer effects against A549, hypoxic A549, HT29, and MDA-MB-231 cells with the IC50 values in the range 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, [Co(III)-dox] to inhibit tumor growth, migration, and invasion. Furthermore, RT-PCR analysis showed a notable downregulation of key hypoxia-adaptive genes (HIF-1α, VEGF, and GLUT-1), disrupting tumor survival mechanisms. Overall, the complex, [Co(III)-dox] emerged as an excellent bioreductive prodrug for safer and potent anticancer activity.