Ran Li,1,2,* Yanwei Li,1,2,* Zijian Song,1,2 Yixuan Gu,1,2 Xiaofeng Jiao,1,2 Chaoqiong Wan,1,2 Tiantian Liu,1,2 Rongrong Zhang,1,2 Ruifang Gao,1,2 Xiangyu Wang1,2 

1Shanxi Province Key Laboratory of Oral Diseases Prevention and New Materials, Shanxi Medical University School and Hospital of Stomatology, Taiyuan, 030001, People’s Republic of China; 2Department of Pediatric and Preventive Dentistry, Shanxi Medical University School and Hospital of Stomatology, Taiyuan, 030001, People’s Republic of China

*These authors contributed equally to this work

Correspondence: Ran Li; Xiangyu Wang, Email lraner@163.com; wangxiangyu76@163.com

Purpose: Chemotherapy is one of the most commonly used treatments for oral squamous cell carcinoma (OSCC), but its use is limited by drug resistance and severe systemic toxicity. To eliminate these side effects and improve anti-tumor efficacy, several therapeutic approaches have been developed for use with chemotherapy. In this study, we developed a graphene-based lipid modulation nanoplatform (NSD) that carries SB-204990, a small molecule inhibitor specific for ATP citrate lyase (ACLY), and doxorubicin (DOX), a chemotherapeutic agent, and the trio enables synergistic treatment of OSCC with lipid starvation, chemotherapy, and photothermal therapy.
Methods: We first determined whether ACLY expression was upregulated in OSCC, and then assessed the growth inhibitory effects of SB-204990 on SCC-15 cells and changes in lipid (acetyl coenzyme A, free fatty acids, and cholesterol) levels. We characterized NSD and then evaluated the stability, photothermal properties, drug loading, and release ability of NSD. Finally, the therapeutic effects of NSD on OSCC were investigated by in vitro and in vivo experiments, and the changes in lipid levels in OSCC tissues after ACLY inhibition were further evaluated.
Results: The results showed that ACLY was highly expressed in OSCC, and ACLY inhibition produced reproductive suppression and decreased lipid levels in SCC-15 cells. The NSD nanoplatform possessed good stability, photothermal properties, high drug loading capacity and controlled release. In addition, the triple therapy achieved satisfactory anticancer effects in both in vivo and in vitro assays, and the inhibition rate of tumors was as high as 99.4% in the NSD+Laser treatment group.
Conclusion: The changes in tumor cell lipid levels and cell proliferation arrest induced by ACLY inhibition suggest that ACLY may be a promising target for lipid starvation therapy and resistance to chemoresistance, and its inhibitors are expected to become new anticancer drugs. The NSD nanocarrier system enables synergistic treatment with lipid starvation, chemotherapy, and photothermal therapy, which represents an innovative approach to combating tumors.

Keywords: starvation therapy, ACLY, nanotechnology, chemotherapy resistance, OSCC