Developing an anticancer copper(II) pro-drug based on the nature of cancer cell and human serum albumin carrier IIA subdomain: mouse model of breast cancer.
Developing an anticancer copper(II) pro-drug based on the nature of cancer cell and human serum albumin carrier IIA subdomain: mouse model of breast cancer.
复制标题
基于癌细胞性质和人血清白蛋白载体IIA子域开发抗癌铜(II)前药：乳腺癌小鼠模型
DOI：
10.18632/oncotarget.11465
复制
发表时间：
2016-10-11
期刊：
影响因子：
--
通讯作者：
Yang F
中科院分区：
文献类型：
--
作者：
Gou Y;Zhang Y;Qi J;Chen S;Zhou Z;Wu X;Liang H;Yang F
人血清白蛋白（HSA）为载体的药物传递系统有望提高抗癌药物的传递效率、抗癌活性和选择性。为合理指导抗癌金属药物HSA载体的设计，根据HSA载体IIA亚结构域与癌细胞的特性，建立了抗癌铜（Cu）前药的乳鼠模型。因此，我们首先合成了一种新的Cu（II）化合物，其衍生自三齿（E）-N '-（5-溴-2-羟基苯亚甲基）苯甲酰肼席夫碱配体（HL），含有2个潜在的离去基团[吲唑（Ind）和NO3−]，即[Cu（L）（Ind）NO3]。HSA复合物的结构分析表明，Cu（L）（Ind）（NO3）可以结合到HSA IIA亚结构域的疏水口袋。Lys 199和His 242通过取代[Cu（L）（Ind）NO3]的吲唑和NO3配体与Cu 2+配位。在不同的pH水平下，铜化合物从HSA络合物中的释放行为是不同的。[Cu（L）（Ind）NO_3]与HSA合用，对癌细胞的细胞毒作用增强2倍，但对正常细胞无明显作用。重要的是，我们的体内结果表明，HSA复合物显示出增加的选择性和抑制肿瘤生长的能力，并且比单独的[Cu（L）（Ind）NO3]毒性更小。
Human serum albumin (HSA)-based drug delivery systems are promising for improving delivery efficiency, anticancer activity and selectivity of anticancer agents. To rationally guide to design HSA carrier for anticancer metal agent, we built a breast mouse model on developing anti-cancer copper (Cu) pro-drug based on the nature of IIA subdomain of HSA carrier and cancer cells. Thus, we first synthesized a new Cu(II) compound derived from tridentate (E)-N'-(5-bromo-2-hydroxybenzylidene)benzohydrazide Schiff base ligand (HL) containing 2 potential leaving groups [indazole (Ind) and NO3−], namely, [Cu(L)(Ind)NO3]. Structural analysis of the HSA complex showed that Cu(L)(Ind)(NO3) could bind to the hydrophobic pocket of the HSA IIA subdomain. Lys199 and His242 coordinate with Cu2+ by replacing the indazole and NO3 ligands of [Cu(L)(Ind)NO3]. The release behavior of the Cu compound from the HSA complex is different at different pH levels. [Cu(L)(Ind)NO3] can enhance cytotoxicity by 2 times together with HSA specifically in cancer cells but has no such effect on normal cells in vitro. Importantly, our in vivo results showed that the HSA complex displayed increased selectivity and capacity to inhibit tumor growth and was less toxic than [Cu(L)(Ind)NO3] alone.