LAQV, REQUIMTE, Departamento de Ciências Químicas, Faculdade de Farmácia, Universidade do Porto, Portugal.
LAQV, REQUIMTE, Departamento de Ciências Químicas, Faculdade de Farmácia, Universidade do Porto, Portugal.
Colloids Surf B Biointerfaces. 2017 Dec 1;160:610-618. doi: 10.1016/j.colsurfb.2017.09.058. Epub 2017 Oct 3.
The anthracyclines daunorubicin and doxorubicin are widely used antineoplastic agents due to their therapeutic activity against a broad variety of human cancers. Although, the classical model to explain anthracyclines' cytotoxicity has been based in the direct interference with nucleic acid function, evidence suggests that the plasma membrane is also involved in the drug's mechanism of action. In this work, the interaction of these drugs with two-dimensional membrane models were studied in order to gain further insights at the molecular level regarding anthracyclines membrane interactions. For that purpose, Langmuir monolayers composed of 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), sphingomyelin (SM) and cholesterol (Chol) were used, since these are the most common lipids found in biological membranes. Several biophysical techniques were employed: surface pressure (π) - area (A) isotherms measurements were used to investigate the adsorption and penetration of drugs, polarization-modulation infrared reflection-absorption spectroscopy (PM-IRRAS) to acquire structural information and Brewster angle microscopy (BAM) to record images of the monolayers on the micrometer scale. The interactions of anthracyclines were assessed by alterations in the monolayers' shape, characteristic parameters (C values and area per lipid molecule at 30mN·m and under maximum packing conditions) and morphology of each 2D model studied. The presence of the drugs in the interface led to the production of less ordered monolayers, as evidenced by the decrease in the compressibility modulus. In addition, the drugs' effect on the membrane organization is related with their chemical structure and depends on the membraneś phase. For lower surface pressures, both electrostatic and hydrophobic interactions led to significant modifications in the monolayer order. With further compression, the impact of such interactions is reduced, resulting in the squeezing-out of some drug molecules from the interface. Furthermore, BAM images showed a clear anticancer drug interplay with the lipid monolayer by changes in the domains shape and appearance of bright dots, which are located in the frontier between the condensed and expanded lipid phases.
蒽环类药物柔红霉素和多柔比星由于其对多种人类癌症的治疗活性而被广泛用作抗肿瘤药物。尽管解释蒽环类药物细胞毒性的经典模型基于直接干扰核酸功能，但有证据表明质膜也参与了药物的作用机制。在这项工作中，研究了这些药物与二维膜模型的相互作用，以便在分子水平上进一步了解蒽环类药物与膜的相互作用。为此，使用了由 1,2-二棕榈酰-sn-甘油-3-磷酸胆碱 (DPPC)、神经鞘磷脂 (SM) 和胆固醇 (Chol) 组成的 Langmuir 单层，因为这些是生物膜中最常见的脂质。采用了几种生物物理技术：表面压力（π）-面积（A）等温线测量用于研究药物的吸附和渗透，偏振调制红外反射吸收光谱（PM-IRRAS）用于获取结构信息，以及布鲁斯特角显微镜（BAM）用于记录单层在微米尺度上的图像。通过改变单层的形状、特征参数（C 值和在 30mN·m 下最大堆积条件下每个脂质分子的面积）以及研究的每个 2D 模型的形态，评估了蒽环类药物的相互作用。药物在界面中的存在导致形成了较无序的单层，这可以通过压缩模量的降低来证明。此外，药物对膜组织的影响与其化学结构有关，并取决于膜的相。在较低的表面压力下，静电和疏水相互作用都会导致单层有序性的显著改变。随着进一步压缩，这种相互作用的影响会降低，导致一些药物分子从界面中挤出。此外，BAM 图像显示，抗癌药物与脂质单层之间存在明显的相互作用，表现为畴形状的变化和亮点的出现，亮点位于凝聚和扩展脂质相的边界处。
