Mahdi Wael A, Imam Syed Sarim, Alotaibi Abdulkarim, Alhallaf Saad, Alzhrani Riyad F, Alshehri Sultan
Department of Pharmaceutics, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia.
ACS Omega. 2025 Jan 13;10(3):3006-3017. doi: 10.1021/acsomega.4c09614. eCollection 2025 Jan 28.
Silymarin (SLM) is a bioactive, water-insoluble flavonoid reported against different types of cancer. In the present research, the SLM inclusion complex was prepared by the freeze-drying method using different cyclodextrins. The phase solubility study was performed to assess the stability constant and complexation efficiency. The prepared SLM inclusion complexes (F1, F2, and F3) were characterized for different physicochemical and in vitro parameters. Based on the results, the selected inclusion complex (F2) was converted to a topical gel. Finally, it was evaluated for antioxidant, protein denaturation, and cell viability assay (B16F10; skin cancer cell line). The in vitro results were further confirmed by performing a molecular docking study. The phase solubilization results showed the formation of a stable complex with a stability constant value of 548 mol L (βCD-PLX), 911 mol L (HP βCD-PLX), and 736 mol L (M βCD-PLX). A marked increase in release pattern was found from the prepared inclusion complex (80.9 ± 2.2-97.8 ± 3.1%) compared to free SLM (24.1 ± 2.8%). DSC as well as the IR studies confirm the formation of a stable complex. SEM and X-ray diffraction results confirmed the conversion to the amorphous form. The molecular docking studies exhibited the high docking score of SLM with both colchicine-binding sites of the tubulin protein (-6.28 kcal/mol) and complexing agents, viz., βCD (-4.61 kcal/mol), HP βCD (-5.77 kcal/mol), and M βCD (-5.61 kcal/mol). The antioxidant assay results showed that the activity was significantly improved (1.2-1.6 fold) compared to free SLM. The in vitro cell viability assay outcome displayed concentration-dependent activity with a significantly lower IC50 value from F2G2 (145.3 ± 4.2 μg/mL) than free SLM (304.7 ± 5.7 μg/mL). The above conclusions demonstrated that the developed SLM inclusion complex-based gel system could be an ideal delivery system for skin cancer.
水飞蓟素（SLM）是一种具有生物活性、水不溶性的类黄酮，据报道可对抗不同类型的癌症。在本研究中，采用冷冻干燥法使用不同的环糊精制备了水飞蓟素包合物。进行了相溶解度研究以评估稳定常数和络合效率。对制备的水飞蓟素包合物（F1、F2和F3）的不同物理化学和体外参数进行了表征。根据结果，将选定的包合物（F2）转化为局部凝胶。最后，对其进行了抗氧化、蛋白质变性和细胞活力测定（B16F10；皮肤癌细胞系）。通过进行分子对接研究进一步证实了体外结果。相溶解结果表明形成了稳定的络合物，其稳定常数分别为548 mol/L（β环糊精-水飞蓟素）、911 mol/L（羟丙基-β环糊精-水飞蓟素）和736 mol/L（甲基-β环糊精-水飞蓟素）。与游离水飞蓟素（24.1±2.8%）相比，制备的包合物的释放模式有显著增加（80.9±2.2 - 97.8±3.1%）。差示扫描量热法以及红外研究证实了稳定络合物的形成。扫描电子显微镜和X射线衍射结果证实其转化为无定形形式。分子对接研究显示水飞蓟素与微管蛋白的两个秋水仙碱结合位点（-6.28 kcal/mol）以及络合剂，即β环糊精（-4.61 kcal/mol）、羟丙基-β环糊精（-5.77 kcal/mol）和甲基-β环糊精（-5.61 kcal/mol）具有较高的对接分数。抗氧化测定结果表明，与游离水飞蓟素相比，其活性显著提高（1.2 - 1.6倍）。体外细胞活力测定结果显示出浓度依赖性活性，F2G2的IC50值（145.3±4.2 μg/mL）明显低于游离水飞蓟素（304.7±5.7 μg/mL）。上述结论表明，所开发的基于水飞蓟素包合物的凝胶系统可能是皮肤癌的理想给药系统。
