González-Ruiz Víctor, Cores Ángel, Martín-Cámara Olmo, Orellana Karen, Cervera-Carrascón Víctor, Michalska Patrycja, Olives Ana I, León Rafael, Martín M Antonia, Menéndez J Carlos
Swiss Centre for Applied Human Toxicology, School of Pharmaceutical Sciences and Institute of Pharmaceutical Sciences of Western Switzerland, University of Geneva, 1205 Geneva, Switzerland.
Unidad de Química Orgánica y Farmacéutica, Departamento de Química en Ciencias Farmacéuticas, Facultad de Farmacia, Universidad Complutense de Madrid, 28040 Madrid, Spain.
Pharmaceutics. 2021 Oct 3;13(10):1609. doi: 10.3390/pharmaceutics13101609.
The use of cyclodextrins as drug nano-carrier systems for drug delivery is gaining importance in the pharmaceutical industry due to the interesting pharmacokinetic properties of the resulting inclusion complexes. In the present work, complexes of the anti-cancer alkaloids camptothecin and luotonin A have been prepared with β-cyclodextrin and hydroxypropyl-β-cyclodextrin. These cyclodextrin complexes were characterized by nuclear magnetic resonance spectroscopy (NMR). The variations in the H-NMR and C-NMR chemical shifts allowed to establish the inclusion modes of the compounds into the cyclodextrin cavities, which were supported by docking and molecular dynamics studies. The efficiency of the complexation was quantified by UV-Vis spectrophotometry and spectrofluorimetry, which showed that the protonation equilibria of camptothecin and luotonin A were drastically hampered upon formation of the inclusion complexes. The stabilization of camptothecin towards hydrolysis inside the cyclodextrin cavity was verified by the quantitation of the active lactone form by reverse phase liquid chromatography fluorimetric detection, both in basic conditions and in the presence of serum albumin. The antitumor activity of luotonin A and camptothecin complexes were studied in several cancer cell lines (breast, lung, hepatic carcinoma, ovarian carcinoma and human neuroblastoma) and an enhanced activity was found compared to the free alkaloids, particularly in the case of hydroxypropyl-β-cyclodextrin derivatives. This result shows that the cyclodextrin inclusion strategy has much potential towards reaching the goal of employing luotonin A or its analogues as stable analogues of camptothecin.
由于所得包合物具有有趣的药代动力学性质，环糊精作为药物纳米载体系统用于药物递送在制药行业中变得越来越重要。在本研究中，已制备了抗癌生物碱喜树碱和路脱宁A与β-环糊精和羟丙基-β-环糊精的复合物。这些环糊精复合物通过核磁共振光谱（NMR）进行了表征。H-NMR和C-NMR化学位移的变化有助于确定化合物进入环糊精空腔的包合模式，对接和分子动力学研究也支持了这一点。通过紫外可见分光光度法和荧光分光光度法定量了络合效率，结果表明，包合物形成后，喜树碱和路脱宁A的质子化平衡受到极大阻碍。通过反相液相色谱荧光检测法定量活性内酯形式，在碱性条件下和存在血清白蛋白的情况下，均验证了喜树碱在环糊精空腔内对水解的稳定性。在几种癌细胞系（乳腺癌、肺癌肝癌、卵巢癌和人神经母细胞瘤）中研究了路脱宁A和喜树碱复合物的抗肿瘤活性，发现与游离生物碱相比活性增强，特别是在羟丙基-β-环糊精衍生物的情况下。这一结果表明，环糊精包合策略在实现将路脱宁A或其类似物用作喜树碱稳定类似物的目标方面具有很大潜力。
