Affiliation of Author(s):[1]Univ Elect Sci & Technol China, Sichuan Prov Peoples Hosp, Sch Med, Dept Pharm,Personalized Drug Therapy Key Lab Sichu, Chengdu 610072, Peoples R China;[2]Wuhan Univ, Sch & Hosp Stomatol, Dept Oral & Maxillofacial Head Neck Oncol, State Key Lab Breeding Base Basic Sci Stomatol Hub, Wuhan 430079, Peoples R China;[3]Wuhan Univ, Sch & Hosp Stomatol, Dept Oral & Maxillofacial Head Neck Oncol, Key Lab Oral Biomed,Minist Educ, Wuhan 430079, Peoples R China;[4]First Peoples Hosp Zigong, Dept Pathol, Zigong 643000, Peoples R China
Journal:JOURNAL OF CONTROLLED RELEASE
Key Words:Oral squamous cell carcinoma; Gambogic acid; Hydrogel; Local drug delivery; Tumor immune microenvironment
Abstract: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.
Document Type:Article
Volume:351
Page Number:381-393
ISSN No.:0168-3659
Translation or Not:no