Shanxi 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.
Department of Pediatric and Preventive Dentistry, Shanxi Medical University School and Hospital of Stomatology, Taiyuan, 030001, People's Republic of China.
Int J Nanomedicine. 2024 Nov 4;19:11235-11255. doi: 10.2147/IJN.S478308. eCollection 2024.
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.
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.
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.
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.
化疗是治疗口腔鳞状细胞癌（OSCC）最常用的方法之一，但由于耐药性和严重的全身毒性，其应用受到限制。为了消除这些副作用并提高抗肿瘤疗效，已经开发了几种治疗方法与化疗联合使用。在本研究中，我们开发了一种基于石墨烯的脂质调节纳米平台（NSD），该平台携带 SB-204990，一种针对三磷酸腺苷柠檬酸裂解酶（ACLY）的小分子抑制剂，以及阿霉素（DOX），一种化疗药物，三者协同作用，通过脂质饥饿、化疗和光热疗法治疗 OSCC。
我们首先确定 ACLY 在 OSCC 中的表达是否上调，然后评估 SB-204990 对 SCC-15 细胞的生长抑制作用以及脂质（乙酰辅酶 A、游离脂肪酸和胆固醇）水平的变化。我们对 NSD 进行了表征，然后评估了 NSD 的稳定性、光热特性、药物载药量和释放能力。最后，通过体外和体内实验研究了 NSD 对 OSCC 的治疗效果，并进一步评估了 ACLY 抑制后 OSCC 组织中脂质水平的变化。
结果表明，ACLY 在 OSCC 中高表达，ACLY 抑制导致 SCC-15 细胞的繁殖受到抑制，脂质水平降低。NSD 纳米平台具有良好的稳定性、光热性能、高载药量和可控释放能力。此外，三重治疗在体内和体外实验中均取得了令人满意的抗肿瘤效果，NSD+激光治疗组的肿瘤抑制率高达 99.4%。
ACLY 抑制诱导的肿瘤细胞脂质水平变化和细胞增殖抑制表明，ACLY 可能是脂质饥饿治疗和化疗耐药的有前途的靶点，其抑制剂有望成为新型抗癌药物。NSD 纳米载体系统能够与脂质饥饿、化疗和光热疗法协同治疗，为抗肿瘤提供了一种创新的方法。
