PDF(Pubmed)
Abstract：
Doxorubicin (DOX) is a commonly used chemotherapeutic drug, from the anthracycline class, which is genotoxic to neoplastic cells via a DNA intercalation mechanism. It is effective and universal; however, it also causes numerous side effects. The most serious of them are cardiotoxicity and a decrease in the number of myeloid cells. For this reason, targeted DOX delivery systems are desirable, since they would allow lowering the drug dose and therefore limiting systemic side effects. Recently, synthetic dyes, in particular Congo red (CR), have been proposed as possible DOX carriers. CR is a planar molecule, built of a central biphenyl moiety and two substituted naphthalene rings, connected with diazo bonds. In water, it forms elongated ribbon-shaped supramolecular structures, which are able to selectively interact with immune complexes. In our previous studies, we have shown that CR aggregates can intercalate DOX molecules. In this way, they preclude DOX precipitation in water solutions and increase its uptake by MCF7 breast cancer cells. In the present work, we further explore the interactions between DOX, CR, and their aggregates (CR/DOX) with phospholipid membranes. In addition to neutral molecules, the protonated doxorubicin form, DXP, is also studied. Molecular dynamics simulations are employed to study the transfer of CR, DOX, DXP, and their aggregates through POPC bilayers. Interactions of CR, DOX, and CR/DOX with model monolayers are studied with Langmuir trough measurements. This study shows that CR may support the transfer of doxorubicin molecules into the bilayer. Both electrostatic and van der Waals interactions with lipids are important in this respect. The former promote the initial stages of the insertion process, the latter keep guest molecules inside the bilayer.
摘要：
多柔比星（DOX）是一种常用的化疗药物，从蒽环类，通过DNA嵌入机制对肿瘤细胞具有遗传毒性。它是有效和普遍的；然而，它也引起许多副作用。其中最严重的是心脏毒性和骨髓细胞数量的减少。出于这个原因,有针对性的DOX递送系统是可取的，因为它们可以降低药物剂量，从而限制全身副作用。最近,合成染料，特别是刚果红（CR），已被提议作为可能的DOX载体。CR是一个平面分子,由一个中央联苯部分和两个取代的萘环组成，与重氮键相连。在水中,它形成细长的带状超分子结构，能够选择性地与免疫复合物相互作用。在我们之前的研究中,我们已经证明CR聚集体可以嵌入DOX分子。这样,它们阻止了DOX在水溶液中的沉淀，并增加了MCF7乳腺癌细胞对DOX的吸收。在目前的工作中,我们进一步探索了DOX之间的相互作用，CR,和它们与磷脂膜的聚集体(CR/DOX)。除了中性分子,质子化的阿霉素形式，DXP,也被研究过。分子动力学模拟用于研究CR的转移，DOX,DXP,以及它们通过POPC双层的聚集体。CR的相互作用，DOX,用Langmuir槽测量研究了具有模型单层的CR/DOX。这项研究表明，CR可能支持阿霉素分子转移到双层中。在这方面,与脂质的静电和范德华相互作用都是重要的。前者促进了插入过程的初始阶段，后者将客体分子保留在双层内。
