Anticancer and Chemosensitizing Effects of Menadione-containing Peptide-targeted Solid Lipid Nanoparticles

Vitamin K derivatives such as menadione (MD) have been recognized as promising redox-modulating and chemosensitizing agents for anticancer therapy, however, their cellular activities in peptide-targeted nanocarriers have not been elucidated to date. This study provides the guidelines for developing MD-loaded solid lipid nanoparticle (SLN) modified with extracellular matrix (ECM)-derived peptides. Relationships between RGD peptide concentration and changes in DLS characteristics as well as accumulation of SLN in cancer cells were revealed to adjust the peptide-lipid ratio. SLN maintained their nanoparticle concentration and low dispersity after introduction of MD and MD/RGD, whereas formulated MD was protected from immediate conjugation with reduced glutathione (GSH). RGD-modified MD-containing SLN showed enhanced prooxidant, GSH-depleting and cytotoxic activities toward prostate cancer cells PC-3 attributed to improved cellular pharmacokinetics of the targeted formulation. Furthermore, this formulation effectively sensitized PC-3 and ovarian cancer cells OVCAR-4 to free doxorubicin and cisplatin so that cell growth was inhibited by MD–drug composition at non-toxic concentrations of the ingredients. These results provide an important background for further improving chemotherapeutic methods based on combination of conventional cytostatics with peptide-targeted SLN formulations of MD.