Abstract
Thymoquinone (TQ), a natural polyphenol, has been associated with various pharmacological responses; however, low bioavailability of TQ limits its clinical application. Thus, a novel phytosomal delivery system of TQ-Phospholipon® 90H complex (TQ-phytosome) was developed by refluxing combined with anti-solvent precipitation. This TQ delivery system was optimized by a three-factor, three-level Box-Behnken design. The optimized TQ-phytosome size was (45.59 ± 1.82 nm) and the vesicle size was confirmed by transmission electron microscopy. The in vitro release pattern of the formulation indicated a biphasic release pattern, where an initial burst release was observed within 2 h, followed by a prolonged release. A remarkable increase in dose-dependent cytotoxicity was evident from the significant decrease in IC50 value of TQ-phytosomes (4.31 ± 2.21 µM) against the A549 cell line. The differential effect of TQ-phytosomes in cell cycle analysis was observed, where cancer cells were accumulated on G2-M and pre-G1 phases. Furthermore, increased apoptotic induction and cell necrosis of TQ-phytosomes were revealed with the annexin V staining technique via activation of caspase-3. In reactive oxygen species (ROS) analysis, TQ-phytosomes acted to significantly increase ROS generation in A549 cells. In conclusion, the sustained release profile with significantly-improved anticancer potential could be obtained with TQ by this phytosomal nanocarrier platform.
Highlights
Lung cancer is among the most frequent and severe cancer types
TQ potentiates the generation of cellular reactive oxygen species (ROS) during a mitochondrial malfunction, which contributes towards cellular apoptosis [10]
Apoptosis, programmed cell death, is a physiological mechanism that is precisely regulated at the genetic level, resulting in programmed removal of damaged cells.The differential effect of TQ-phytosomes on pre-G1 and G2-M phases of the A549 cell line clearly demonstrated that the phytosomal formulation of TQ possesses augmentation property of TQ by the novel nanocarrier platform
Summary
Lung cancer is among the most frequent and severe cancer types. The early stages of lung cancer typically do not exhibit signs or symptoms. Five-year survival rate for lung cancer (18.6%) is worse than for many other tumor types, such as colorectal (64.5%), breast (89.6%), and prostate (98.2%) [2,3,4]. Several limitations of this promising natural compound prevent translation from laboratory to the clinic Amongst these limitations, the main one is poor bioavailability, which is due to the low aqueous solubility of the component. Focus on phytosome-based drug delivery is a novel concept, where poorly soluble polyphenolic phytoconstituents are formulated into vesicular dosage form by interacting with phospholipids in an aqueous environment. This novel delivery has shown the potential to improve the oral bioavailability of the active phytoconstituents [17,18]. Extensive analysis of the optimized formulation was performed against A549 cell lines to establish the efficacy and mechanism of action of the TQ-phytosomes in the treatment of lung cancer
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