CATION-PI INTERACTIONS OF ANTHRACYCLINE DRUGS

描述：拟议的调查旨在确定以下因素 控制蒽环类抗生素与细胞的非共价相互作用 膜。这些药物-膜缔合作用在 药物的治疗活性，调节细胞毒作用的选择性 正常组织和肿瘤组织，决定细胞访问，并影响 肿瘤细胞多药耐药的发生。膜性能 将被确定为解释(A)表面结合的存在 蒽环类药物与细胞的脂插层相互作用 膜和(B)蒽环类药物结合力的显著降低 抗生素对耐药细胞膜的影响 药物敏感细胞。以表面活性剂为基础的反胶束系统将发挥作用 以及两种生物膜的特征模型， 这些药物相互作用，脂质体系统用作递送载体 为了这些毒品。蒽环类药物的分配和结合 这些反胶束系统的类似物将通过以下方法进行评估 荧光光谱技术。两个具体的假设是 经检验：(1)阳离子-pi相互作用为显著的非共价结合 调节芳香族药物在体内的分配和释放的力 以表面活性剂为基础的药物输送系统和生物膜内。(2) 脂头基团的大小和电荷以及脂尾的结构和线形 维度影响绑定和分区的程度和方式 细胞和脂质体中的蒽环类药物。的差异交互作用 蒽环类药物和反胶束系统的各种组合将 揭示药物结构和分配之间的对应关系，以及 表面活性剂参数在决定药物-膜相互作用中的作用。 这些结果将为更好地理解并环素膜提供依据。 未来优化蒽环类药物活性的相互作用。

DESCRIPTION: The proposed investigations seek to identify the factors that govern the non-covalent interactions of anthracycline antibiotics with cell membranes. These drug-membrane associations play a critical role in the therapeutic activity of the drugs, governing cytotoxic selectivity between normal and tumor tissue, dictating cell access, and affecting the development of multiple drug resistance by tumor cells. Membrane properties will be identified to account for (a) the existence of both surface-bound and lipid-intercalated interactions of anthracycline drugs with cell membranes and (b) the substantial decrease in the binding of anthracycline antibiotics to the membranes of drug-resistant cells as compared to those of drug-sensitive cells. Surfactant -based reverse micellar systems will serve as well characterized models of both the biological membranes with which these drugs interact and the liposomal systems employed as delivery vehicles for these drugs. The partitioning and binding of anthracycline drugs and analogs with these reverse micelle systems will be assessed with fluorescence spectroscopic techniques. Two specific hypotheses will be tested: (1) The cation-pi interaction is significant non-covalent binding force that mediates the partioning and release of aromatic drugs within surfactant-based drug delivery systems and within biological membranes. (2) The lipid head group size and charge and the lipid tail structure and linear dimensions influence the extent and mode of binding and partitioning of anthracycline drugs in cells and liposomes. Differential interactions of various combinations of anthracyclines and reverse micelle systems will reveal the correspondence between drug structure and partitioning and the role of surfactant parameters in dictating drug-membrane interactions. These results will provide a greater understanding of anthracycline-membrane interactions for future optimization of anthracycline activity.