Study On Bio-responsive Drug Delivery System For Treatment Of Oral Squamous Cell Carcinoma

Objective:Oral squamous cell carcinoma(OSCC),which accounts for about 90%of oral malignancies,is one of the most widespread oral cancers in the world.Currently,there is no effective method for the treatment of progressive,recurrent,or metastatic OSCC.Gambogic acid(GA)has widely anti-cancer activity and shows good anti-cancer effects on both metastatic and non-metastatic breast cancer,melanoma,and so on.However,there is barely any study on gambogic acid for treat OSCC.Based on this,we have developed a bio-responsive drug delivery system laded with GA micelles,which could achieve tumor local injection and controlled drug release.We further explored its anti-tumor effect on the OSCC-bearring mouse model and its influence on the tumor immune microenvironment.Methods:Firstly,GA micelles(GA-MIC)were prepared to improve the dispersibility of GA in water.Secondly,the triblock copolymer PLEL was synthesized by ring-opening polymerization.Thirdly,GA-MIC was mixed with PLEL to form an injectable thermosensitive gel(GA-MIC-GEL).Fourthly,GA-MIC-GEL was subcutaneously injected into C57BL/6 mice,and the safety evaluation was performed through blood cell analysis,blood biochemical analysis,and H&E staining.Finally,the anti-tumor effects of different formulations of GA were studied on OSCC-bearing mice.Results:This work successfully prepared the GA-MIC(average particle diameter of 26.8±0.5 nm)and the GA-MIC loaded temperature-sensitive hydrogel GA-MIC-GEL.At 37°C,GA-MIC-GEL sol could quickly turn into a gel within 25seconds.GA-MIC could be loaded into the 3D network structure of PLEL.Biological safety evaluation showed that mice treated with GA-MIC-GEL were not significantly different from normal mice.The results of the anti-tumor studies on the single-side OSCC model showed that the tumor inhibition rate of GA-MIC-GEL was 48.74%.The GA-MIC-GEL also showed a good inhibition effect on the bilateral tumor model.The results of flow cytometry showed that the number of CD8~+PD-1~+cells in the blood of the mice treated with GA-MIC-GEL decreased,and the number of F4/80~+CD11b~+CD206~+cells in the tumor of mice was also decreased.Conclusion:A bio-responsive drug delivery system(GA-MIC-GEL)with a 3D mesh structure was developed,which had a sensitive"sol-gel"phase change characteristic under body temperature.Animal experiments show that GA-MIC-GEL has good biological safety and anti-tumor effect.Besides,GA-MIC-GEL could not only reduce the expression of PD-1 on T cells in the blood but also regulate the number of M2 tumor-associated macrophages in tumor tissues,which might improve the tumor immunological surveillance and activate the anti-tumor immune response.