Abstract:
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.
摘要:
维生素K衍生物,如甲萘醌(MD)已被认为是有前途的氧化还原调节和化学增敏剂,用于抗癌治疗。然而,迄今为止,它们在肽靶向纳米载体中的细胞活性尚未阐明。这项研究提供了开发用细胞外基质(ECM)衍生肽修饰的MD负载固体脂质纳米颗粒(SLN)的指南。揭示了RGD肽浓度与DLS特性的变化以及SLN在癌细胞中的积累之间的关系,以调节肽-脂质比。引入MD和MD/RGD后,SLN保持了其纳米颗粒浓度和低分散性,而配制的MD可防止与还原型谷胱甘肽(GSH)立即缀合。RGD修饰的含MD的SLN显示出增强的促氧化剂,对前列腺癌细胞PC-3的GSH消耗和细胞毒性活性归因于靶向制剂的改善的细胞药代动力学。此外,该制剂有效地使PC-3和卵巢癌细胞OVCAR-4对游离阿霉素和顺铂敏感,因此在无毒浓度的成分下,MD-药物组合物抑制细胞生长。这些结果为基于常规细胞抑制剂与肽靶向的MDSLN制剂的组合进一步改进化疗方法提供了重要背景。