Synergistic effects of lactoferrin in enhancing cisplatin activity: From molecular interactions to improved drug...

This study presents the development of lactoferrin-cisplatin complexes as a targeted drug delivery system designed to enhance the therapeutic efficacy of cisplatin while mitigating its adverse side effects. Complexes were synthesized in both sodium chloride and sodium bicarbonate buffers and subjected to comprehensive physicochemical characterization using spectroscopic techniques (FTIR, Raman, UV-Vis, and fluorescence spectroscopy), dynamic light scattering, and microscopic analysis (SEM). The NaCl-derived formulation remained predominantly within a small-size protein population, whereas the NaHCO₃-derived formulation displayed pronounced aggregation. A non-covalent molecular-dynamics model of intact cisplatin associated with bovine lactoferrin under NaCl-relevant conditions identified Asp392, Tyr432, Thr458, Gly465, Trp466, Tyr525 and His594 as residues contributing to stabilization of the initial protein-drug association; this model was not intended to represent the covalent Pt-protein adduct expected after cisplatin aquation. In vitro assays using Caco-2 and L929 cell lines demonstrated that the lactoferrin-cisplatin complexes exhibit significantly enhanced cytotoxic effects compared to cisplatin alone, likely due to improved receptor-mediated endocytosis and cellular uptake. Consistently, platinum uptake measurements in Caco-2 cells after 3 h exposure showed significantly higher intracellular Pt accumulation for the developed LTF_Pt_NaCl complex than for free cisplatin, supporting uptake-driven enhancement of activity. These findings underscore the potential of lactoferrin not only as a passive carrier but also as an active component that may synergistically boost anticancer efficacy. This innovative approach opens new avenues for the design of nanocarrier systems aimed at achieving higher selectivity and reduced systemic toxicity in cancer chemotherapy.