Transferrin ornamented thymoquinone loaded PEG-PLGA nanoparticle furnishes anticarcinogenic effect in non-small cell lung carcinoma through modulation of miR-34a and miR-16

Non-small cell lung carcinoma (NSCLC) is a highly lethal type of cancer with limited therapeutic avenues available till date. In the present study we have formulated a PEGylated PLGA Thymoquinone nanoparticle (TQ-Np) for improved TQ delivery to the NSCLC cells. Transferrin (TF), a biodegradable, non-immunogenic and non-toxic protein, is well known to bind to TFR (transferrin receptor) over-expressed on non small cell lung carcinoma A549 cells. Thus, further decoration of PEGylated PLGA Thymoquinone nanoparticle with Transferrin (TF-TQ-Np) enhanced nanoparticle internalization within the A549 cells as well as the activity of TQ. We have established TF-TQ-Np as a potent anti-tumorigenic agent through the involvement of p53 and ROS feedback loop in regulating the microRNA (miRNA) circuitry to control apoptosis and migration of NSCLC cells. TF-TQ-Np mediated p53 up-regulation favored a potential simultaneous activation of miR-34a and miR-16 targeting Bcl2 to induce apoptosis in the A549 cells. Additionally, TF-TQ-Np also restricted the migration through actin de-polymerization via activation of the p53/miR-34a axis. Studies extended in chick CAM xenograft models reconfirmed the anti-cancer activity of TF-TQ-Np via controlling the p53/miR-34a/miR-16 axis. Furthermore, in vivo experiments done in xenograft model in immunosuppressed Balb/c mice also proved the efficacy of the nanoparticle as an antitumor agent against NSCLC. Our findings thus cumulatively suggests that Transferrin adorned TQ-Np successfully couples two distinct miRNA pathway to potentiate the apoptotic death cascade in the very lethal NSCLC cells and also restricts migration of these cells without imparting any significant toxicity like the widely used chemotherapeutic combinations. These findings thereby rekindle new hopes for development of improved targeted therapeutic options with specified molecular objectives for combating the deadly NSCLC.