School of Dental Medicine, University of Pennsylvania, Philadelphia, PA 19019, USA.
Oral and Maxillofacial Surgery, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Int J Mol Sci. 2024 Aug 27;25(17):9292. doi: 10.3390/ijms25179292.
5-fluorouracil (5-FU), a chemotherapeutic agent against oral squamous cell carcinoma (OSCC), is limited by poor pharmacokinetics and toxicity. The pH-sensitive zeolite imidazolate framework-8 (ZIF-8) may increase the selectivity and length of 5-FU released into the acidic tumor microenvironment. This study examined the in vitro 5-FU absorption and release profiles of ZIF-8, and then progressed to cytotoxicity assays using the OSCC primary cell line SCC7. The 5-FU loading capacity of ZIF-8 was calculated with UV-vis spectroscopy (λ = 260 nm). 5-FU release was quantified by submerging 5-FU@ZIF-8 in pH 7.4 and 5.5 acetate buffer over 48 h. For the cytotoxicity assays, 5-FU, ZIF-8, and 5-FU@ZIF-8 were added to SCC7 cultures at 25, 50, and 100 μg/mL. Cell viability was assessed through toluidine blue staining and further quantified through transcriptomic RNA sequencing. ZIF-8 stabilized at a maximum absorption of 2.71 ± 0.22 mg 5-FU, and released 0.66 mg more 5-FU at pH 5.5 than 7.4 for at least 72 h. The cytotoxicity assays showed that 5-FU@ZIF-8 had a synergistic inhibitory effect at 50 μg/mL. The RNA sequencing analysis further revealed the molecular targets of 5-FU@ZIF-8 in SCC7. 5-FU@ZIF-8 may release 5-FU based on the pH of the surrounding microenvironments and synergistically inhibit OSCC.
5-氟尿嘧啶（5-FU）是一种用于治疗口腔鳞状细胞癌（OSCC）的化疗药物，但由于其药代动力学和毒性较差而受到限制。pH 敏感的沸石咪唑酯骨架-8（ZIF-8）可以增加酸性肿瘤微环境中释放的 5-FU 的选择性和释放长度。本研究考察了 ZIF-8 的体外 5-FU 吸收和释放特性，然后使用 OSCC 原代细胞系 SCC7 进行细胞毒性测定。通过紫外可见光谱（λ = 260nm）计算 ZIF-8 的 5-FU 载药量。将 5-FU@ZIF-8 浸泡在 pH 7.4 和 5.5 的醋酸盐缓冲液中 48 小时，定量释放 5-FU。对于细胞毒性测定，将 5-FU、ZIF-8 和 5-FU@ZIF-8 分别以 25、50 和 100μg/mL 的浓度加入 SCC7 培养物中。通过甲苯胺蓝染色评估细胞活力，并通过转录组 RNA 测序进一步定量。ZIF-8 的最大吸收稳定在 2.71±0.22mg 5-FU，在 pH 5.5 下至少 72 小时内比 pH 7.4 多释放 0.66mg 5-FU。细胞毒性测定表明，5-FU@ZIF-8 在 50μg/mL 时具有协同抑制作用。RNA 测序分析进一步揭示了 5-FU@ZIF-8 在 SCC7 中的分子靶标。5-FU@ZIF-8 可能会根据周围微环境的 pH 释放 5-FU，并协同抑制 OSCC。
