Nanoscale biomimetic nano system for the co-delivery of SNS032 and tumor necrosis factor related apoptosis inducing ligand to enhance therapeutic efficacy in oral squamous cell carcinoma cell line SCC25

Abstract

Tumor necrosis factor related apoptosis inducing ligand (TRAIL) has been used extensively as an anticancer agent in vitro and clinical trials. However, due to poor pharmacokinetics and drug resistance, TRAIL only exert limited therapeutic effects on malignant tumor. SNS032 is a new and effective selective CDK inhibitor. SNS032 and TRAIL transfected MSC (MSCT) derived extracellular vesicles (MSCT-EXO) can both inhibit RNA synthesis and induce apoptosis of cancer cells. Previous studies have shown that SNS032 and TRAIL have a synergistic effect in the treatment of cancer. Objective: Construct a biomimetic nano system for synergistically deliver SNS032 and TRAIL to induce apoptosis of SCC25 cells. Methods: SNS032 loaded gelatin nanoparticles (G-SNS032) were prepared by single coacervation method, SNS032/TRAIL gelatin biomimetic exosomes cocarrier (MSCT-EXO/G-SNS032) were isolated and purified by ultracentrifugation and filtration. The expression of specific proteins was detected by BCA method to confirm the source of EXO. The in vitro release curve was drawn by a validated liquid chromatography tandem mass spectrometry assay. This study examines the antitumor effects at molecular and cellular levels in response to MSCT-EXO/G-SNS032 treatment in vitro. Results: MSCT-EXO/G-SNS032 granules were round and well dispersed with a diameter of 187±23 nm. At the same time, it has high drug loading and good release profile. SNS032, G-SNS032 and MSCT-EXO inhibited growth of SCC25 tumor cells with dose dependence manner. MSCT-EXO + SNS032 and MSCT-EXO + GSNS032 showed a satisfactory synergistic action in the ratio range of 200:1-20:1 (Combination index, CI < 1). At the ratio of 2000:1 to 20:1, the synergistic effect of MSCT-EXO/G-SNS032 was preferable to MSCT-EXO+GSNS032 group (P <0.05). MSCT-EXO/G-SNS032 could inhibit the expression of JAKs/STAT signaling pathway as well as the expression of related anti-apoptotic proteins, regulate p53 signaling pathway and its downstream pathway simultaneously. Conclusion: SNS032/TRAIL delivered by gelatin biomimetic exosomes, show a high inhibitory effect on oral squamous cell carcinoma cells though multiple signaling pathways, over which provides a new idea for the treatment of multidrug-resistant tumors.