Gou Yi, Zhang Yao, Zhang Zhenlei, Wang Jun, Zhou Zuping, Liang Hong, Yang Feng
State Key Laboratory for the Chemistry and Molecular Engineering of Medicinal Resources, Ministry of Science and Technology of China, Guangxi Normal University , Guilin, Guangxi, China.
School of Pharmacy, Nantong University , Nantong, Jiangsu, China.
Mol Pharm. 2017 Jun 5;14(6):1861-1873. doi: 10.1021/acs.molpharmaceut.6b01074. Epub 2017 May 9.
We not only modified the types and numbers of coordinated ligands in a metal agent to enhance its anticancer activity, but we also designed a metal prodrug based on the N-donor residues of the human serum albumin (HSA) IIA subdomain to improve its delivery efficiency and selectivity in vivo. However, there may be a conflict in simultaneously achieving the two goals because Lys199 and His242 in the IIA subdomain of HSA can replace its two coordinated ligands, which will decrease its anticancer activity relative to the original metal agent. Thus, to improve the delivery efficiency of the metal agent and simultaneously avoid decreasing its anticancer activity in vivo, we decided to develop an anticancer metal prodrug by regulating its pharmacophore ligand so that it would not be displaced by the Lys199 residue of the folic acid (FA)-functionalized HSA nanoparticle (NP) carrier. To this end, we first synthesized two (E)-N'-(5-chloro-2-hydroxybenzylidene)benzohydrazide Schiff base (HL) Cu(II) compounds by designing a second ligand with a different coordinating atom with Cu/Cu(L)(QL)(Br) [C1, QL = quinolone] and Cu(L)(DMF)(Br) [C2, DMF = N,N-dimethylformamide]. As revealed by the structures of the two HSA complexes, the Cu compounds bind to the hydrophobic cavity in the HSA IIA subdomain. The QL ligand of C1 is replaced by Lys199, which coordinates with Cu, whereas the DMF ligand of C2 is kept intact and His242 is replaced with Br of C2 and coordinates with Cu. The cytotoxicity of the Cu compounds was enhanced by the FA-HSA NPs in the Bel-7402 cells approximately 2-4-fold; however, they raise the cytotoxicity levels in the normal cells in vitro, and the FA-HSA NPs did not. Importantly, the in vivo data showed that FA-HSA-C2 NPs increased selectivity and the capacity to inhibit tumor growth and were less toxic than HSA-C2 NPs and C2. Moreover, C2/HSA-C2 NPs/FA-HSA-C2 NPs induced Bel-7402 cell death by potentially multiple mechanisms.
我们不仅通过改变金属制剂中配位配体的类型和数量来增强其抗癌活性，还基于人血清白蛋白（HSA）IIA亚结构域的氮供体残基设计了一种金属前药，以提高其在体内的递送效率和选择性。然而，同时实现这两个目标可能存在冲突，因为HSA的IIA亚结构域中的Lys199和His242可以取代其两个配位配体，这相对于原始金属制剂会降低其抗癌活性。因此，为了提高金属制剂的递送效率并同时避免在体内降低其抗癌活性，我们决定通过调节其药效基团配体来开发一种抗癌金属前药，使其不会被叶酸（FA）功能化的HSA纳米颗粒（NP）载体的Lys199残基取代。为此，我们首先通过设计与Cu/Cu(L)(QL)(Br) [C1，QL =喹诺酮]和Cu(L)(DMF)(Br) [C2，DMF = N，N-二甲基甲酰胺]具有不同配位原子的第二配体，合成了两种（E）-N'-（5-氯-2-羟基苄叉基）苯甲酰肼席夫碱（HL）Cu（II）化合物。正如两种HSA配合物的结构所示，Cu化合物与HSA IIA亚结构域中的疏水腔结合。C1的QL配体被与Cu配位的Lys199取代，而C2的DMF配体保持完整，C2的Br取代了His242并与Cu配位。在Bel-7402细胞中，FA-HSA NPs使Cu化合物的细胞毒性提高了约2-4倍；然而，它们在体外提高了正常细胞中的细胞毒性水平，而FA-HSA NPs则没有。重要的是，体内数据表明，FA-HSA-C2 NPs提高了选择性和抑制肿瘤生长的能力，并且比HSA-C2 NPs和C2毒性更小。此外，C2/HSA-C2 NPs/FA-HSA-C2 NPs可能通过多种机制诱导Bel-7402细胞死亡。
