Anticancer and Chemosensitizing Effects of Menadione-Containing Peptide-Targeted Solid Lipid Nanoparticles

• Published in: Journal of pharmaceutical sciences 2024-08, Vol.113 (8), p.2258-2267
• Main Authors: Zoughaib, Mohamed, Pashirova, Tatiana N., Nikolaeva, Viktoriia, Kamalov, Marat, Nakhmetova, Fidan, Salakhieva, Diana V., Abdullin, Timur I.
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents - administration & dosage; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Cancer cells; Cell Line, Tumor; Chemosensitizing agents; Cisplatin; Cisplatin - administration & dosage; Cisplatin - pharmacology; Doxorubicin; Doxorubicin - administration & dosage; Doxorubicin - chemistry; Doxorubicin - pharmacokinetics; Doxorubicin - pharmacology; Drug Carriers - chemistry; Female; Glutathione - metabolism; Glutathione depletion; Humans; Lipids - chemistry; Liposomes; Male; Menadione; Nanoparticles - chemistry; Oligopeptides - chemistry; Oligopeptides - pharmacology; PC-3 Cells; Solid lipid nanoparticles; Targeting peptides; Vitamin K 3 - pharmacology
• ISSN: 0022-3549; 1520-6017; 1520-6017
• DOI: 10.1016/j.xphs.2024.03.009

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 nanoparticles (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 system maintained adequate 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 PC-3 prostate cancer cells attributed to improved cellular pharmacokinetics of the targeted formulation. Furthermore, this formulation effectively sensitized PC-3 cells and OVCAR-4 ovarian cancer cells to free doxorubicin and cisplatin so that cell growth was inhibited by MD–drug composition at nontoxic 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. [Display omitted] •ECM peptide-targeted menadione-loaded solid lipid nanoparticles were developed.•Characteristics of RGD peptide-targeted SLN were optimized for delivery into cancer cells.•Cellular effects of SLN formulation of menadione were studied for the first time.•The formulation showed enhanced peptide-mediated prooxidant and GSH-depleting activities.•The formulation promoted cytotoxicity of doxorubicin and cisplatin at nontoxic concentrations.