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Cross-linked (R)-(+)-lipoic acid nanoparticles loaded with silibinin induce apoptosis and autophagy in glioblastoma
1Department of Basic Teaching, Zunyi Medical and Pharmaceutical College Zunyi 563006, Guizhou, China.
Objective:
To overcome the limitations of poor water solubility and suboptimal tumour-targeting efficiency of silibinin (SF), this study aimed to develop a novel (R)-(+)-lipoic acid (LA)-derived nanocarrier platform to enhance its delivery efficiency and to investigate its antitumor effects and underlying mechanisms in glioblastoma.
Methods:
Silibinin-loaded (R)-(+)-lipoic acid nanoparticles (SF@LA-NPs) were prepared by a self-assembly approach combined with ultraviolet light-induced crosslinking. Their physicochemical properties, drug encapsulation efficiency, and glutathione (GSH)-responsive release were systematically characterized. Human glioblastoma U87-MG cells were used to evaluate the anti-glioblastoma effects and underlying mechanisms through cytotoxicity assays, intracellular uptake analysis, apoptosis/autophagy analysis, and exploration of the interplay between autophagy and apoptosis.
Results:
SF@LA-NPs exhibited uniform particle sizes, high drug encapsulation, and rapid GSH-responsive cargo release. Compared to free SF, SF@LA-NPs markedly enhanced intracellular uptake and cytotoxicity. SF@LA-NPs induced overproduction of reactive oxygen species (ROS), leading to mitochondrial damage and activation of the Caspase-3-dependent apoptosis pathway. Notably, SF@LA-NPs concurrently triggered a protective autophagic response, as indicated by increased LC3-II conversion and reduced p62. In addition, a functional antagonistic relationship was uncovered: pharmacologic inhibition of autophagy enhanced apoptosis and cytotoxicity, while inhibition of apoptosis attenuated cell death and altered autophagic activity.
Conclusion:
SF@LA-NPs developed in this study significantly enhanced the delivery efficiency and antitumor activity of silibinin in glioblastoma cells. Moreover, a dual-mechanism mode of action was elucidated, involving ROS-induced mitochondrial apoptosis and compensatory protective autophagy. These findings provide a promising nano-platform and a theoretical basis for combination therapies targeting apoptosis-autophagy crosstalk in glioblastoma.
