Background: Microtubule-targeted drugs are the most effective drugs for adult patients with certain solid tumors. Taccalonolide AJ (AJ) can stabilize tubulin polymerization by covalently binding to β-tubulin, which enables it to play a role in the treatment of tumors. However, its clinical applications are largely limited by low water solubility, chemical instability in water, and a narrow therapeutic window. Clear-cell renal-cell carcinoma (cc RCC) accounts for approximately 70% of RCC cases and is prone to resistance to particularly targeted therapy drugs. Methods: we prepared a water-soluble cyclodextrin-based carrier to serve as an effective treatment for cc RCC. Results: Compared with AJ, taccalonolide AJ-hydroxypropyl-β-cyclodextrin (AJ-HP-β-CD) exhibited superior selectivity and activity toward the cc RCC cell line 786-O vs. normal kidney cells by inducing apoptosis and cell cycle arrest and inhibiting migration and invasion of tumor cells in vitro. According to acute toxicity testing, the maximum tolerated dose (MTD) of AJ-HP-β-CD was 10.71 mg/kg, which was 20 times greater than that of AJ. Assessment of weight changes showed that mouse body weight recovered over 7–8 days, and the toxicity could be greatly reduced by adjusting the injections from once every three days to once per week. In addition, we inoculated 786-O cells to generate xenografted mice to evaluate the anti-tumor activity of AJ-HP-β-CD in vivo and found that AJ-HP-β-CD had a better tumor inhibitory effect than that of docetaxel and sunitinib in terms of tumor growth and endpoint tumor weight. These results indicated that cyclodextrin inclusion greatly increased the anti-tumor therapeutic window of AJ. Conclusions: the AJ-HP-β-CD complex developed in this study may prove to be a novel tubulin stabilizer for the treatment of cc RCC. In addition, this drug delivery system may broaden the horizon in the translational study of other chemotherapeutic drugs.

中文翻译：

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他卡洛内酯 AJ-羟丙基-β-环糊精包合物治疗肾透明细胞癌的研制

背景：微管靶向药物是治疗某些实体瘤成年患者最有效的药物。他卡洛内酯 AJ (AJ) 可以通过与 β-微管蛋白共价结合来稳定微管蛋白聚合，使其在肿瘤治疗中发挥作用。然而，其临床应用在很大程度上受到水溶性低、化学性质不稳定和治疗窗窄的限制。透明细胞肾细胞癌 (cc RCC) 约占 RCC 病例的 70%，并且容易对特定靶向治疗药物产生耐药性。方法：我们制备了一种基于水溶性环糊精的载体，作为 cc RCC 的有效治疗方法。结果：与 AJ 相比，他卡洛内酯 AJ-羟丙基-β-环糊精 (AJ-HP-β-CD) 对 cc RCC 细胞系 786-O 与 786-O 表现出优异的选择性和活性。通过在体外诱导细胞凋亡和细胞周期阻滞以及抑制肿瘤细胞的迁移和侵袭，正常肾细胞。根据急性毒性试验，AJ-HP-β-CD的最大耐受剂量（MTD）为10.71 mg/kg，是AJ的20倍。体重变化评估表明，小鼠体重在 7-8 天内恢复，通过将注射量从每三天一次调整为每周一次，可以大大降低毒性。此外，我们接种786-O细胞产生异种移植小鼠以评价AJ-HP-β-CD在体内的抗肿瘤活性，发现AJ-HP-β-CD比多西紫杉醇具有更好的抑瘤作用。和舒尼替尼在肿瘤生长和终点肿瘤重量方面。这些结果表明环糊精的加入大大增加了 AJ 的抗肿瘤治疗窗口。结论：本研究中开发的 AJ-HP-β-CD 复合物可能被证明是一种用于治疗 cc RCC 的新型微管蛋白稳定剂。此外，这种给药系统可能会拓宽其他化疗药物转化研究的视野。