Local delivery of gambogic acid to improve anti-tumor immunity against oral squamous cell carcinoma

Oral squamous cell carcinoma (OSCC) accounts for nearly 90% of oral cavity malignancies. However, despite significant advances in the last four decades, little improvement has been achieved in the overall survival rates for OSCC patients. While gambogic acid (GA) is a potential candidate compound for treating a variety of ma-lignancies, its anti-cancer impact on OSCC has not to be completely investigated. The tumor immune micro -environment (TIME) has been proven to play a crucial role in the prognosis of cancer patients. Although there are few reports on the T cell activation effect of GA, the regulation of GA on the TIME of OSCC has barely been studied yet. In this study, GA was applied to treat OSCC-bearing mice through in situ controlled release. First, GA -loaded mPEG2000-PCL micelles (GA-MIC) were prepared by the thin-film hydration method to improve the aqueous dispersibility of GA. Second, poly(D, L-lactide)-poly(ethylene glycol)-poly(D, L-lactide) (PLEL) was synthesized for thermosensitive hydrogel preparation. Third, GA-MIC was mixed with PLEL to form an injectable therapeutic hydrogel (GA-MIC-GEL). The anti-tumor and TIME regulation effects of GA-MIC-GEL on tumor -bearing mice were further examined. The results showed that the thermosensitive GA-MIC-GEL with sensitive sol-gel transition characteristics could form hydrogel at 37 ? within 24 s, facilitating the local delivery and sustained GA release. Biochemical, hematological, and pathological analysis proved that GA-MIC-GEL has good biological safety. Moreover, GA-MIC-GEL promoted an obvious regression of both primary and distant tumors on the OSCC mouse models. Mechanically, GA-MIC-GEL down-regulated the expression of PD-1, increased the frequency of cytotoxic T cells and reduced the immunosuppressive cellular components, which boosted the anti-tumor immunity of OSCC-bearing mice. The constructed thermosensitive hydrogel for local delivery of GA has provided a safe and effective strategy with great potential for OSCC therapy.

Automated summary

Oral squamous cell carcinoma (OSCC) is the main type of oral malignancy, but little improvement has been achieved in the overall survival rates for OSCC patients. Gambogic acid (GA) is a potential candidate compound for treating various malignancies, but its anti-cancer impact on OSCC has not been fully investigated. In this study, a thermosensitive hydrogel for local delivery of GA was developed and shown to have a significant anti-tumor effect on OSCC-bearing mice.