Chemistry Department, Federal University of São Carlos, CP 676, São Carlos, 13565-905, SP, Brazil; São Carlos Institute of Physics, University of São Paulo, P.O Box 369, 13560-970, São Carlos, SP, Brazil.
São Carlos Institute of Physics, University of São Paulo, P.O Box 369, 13560-970, São Carlos, SP, Brazil.
Colloids Surf B Biointerfaces. 2020 Dec;196:111357. doi: 10.1016/j.colsurfb.2020.111357. Epub 2020 Sep 21.
The fight against drug resistance in chemotherapy requires a molecular-level understanding of the drug interaction with cell membranes, which today is feasible with membrane models. In this study, we report on the interaction of gemcitabine (GEM), a pyrimidine nucleoside antimetabolite used to treat pancreatic cancer, with Langmuir films that mimic healthy and cancerous cell membranes. The cell membrane models were made with eight compositions of a quaternary mixture containing 1,2-dipalmitoyl-sn-glycerol-3-phosphocholine (DPPC), 1,2-dipalmitoyl-sn-glycero-3-phosphoserine (DPPS), sphingomyelin (SM), and cholesterol (CHOL). The relative concentration of SM was increased so that four of these compositions represented cancerous cells. GEM was found to increase the mean molecular area, also increasing their surface elasticity, with stronger interactions being observed for membranes corresponding to cancerous cells. More specifically, GEM penetrated deepest in the membrane with the highest SM concentration (40 mol%), as inferred from polarization-modulated infrared reflection absorption spectroscopy (PM-IRRAS). This finding was confirmed with molecular dynamics simulations that also indicated how GEM approaches the membrane, which could be useful for guiding the design of drug delivery systems. The experimental and simulation results are consistent with the preferential attachment of GEM onto cancerous cells and highlight the role of SM on drug-cell interactions.
化疗中抗药性的斗争需要从分子水平上了解药物与细胞膜的相互作用，而这在今天可以通过膜模型来实现。在这项研究中，我们报告了用于治疗胰腺癌的嘧啶核苷抗代谢物吉西他滨（GEM）与模拟健康和癌细胞膜的 Langmuir 膜的相互作用。细胞膜模型由包含 1,2-二棕榈酰-sn-甘油-3-磷酸胆碱（DPPC）、1,2-二棕榈酰-sn-甘油-3-磷酸丝氨酸（DPPS）、鞘磷脂（SM）和胆固醇（CHOL）的四元混合物的八种成分制成。SM 的相对浓度增加，使得其中四种成分代表癌细胞。发现 GEM 增加了平均分子面积，也增加了它们的表面弹性，与对应于癌细胞的膜的相互作用更强。更具体地说，从偏振调制红外反射吸收光谱（PM-IRRAS）推断，GEM 渗透到具有最高 SM 浓度（40mol%）的膜中最深。分子动力学模拟也证实了这一发现，该模拟还表明了 GEM 接近膜的方式，这对于指导药物输送系统的设计可能是有用的。实验和模拟结果与 GEM 优先附着在癌细胞上的结果一致，并强调了 SM 在药物与细胞相互作用中的作用。
