Department of Medicinal Chemistry, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran; Student Research Committee, Mashhad University of Medical Sciences, Mashhad, Iran.
Department of Pharmacodynamics and Toxicology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran.
Int J Pharm. 2020 Sep 25;587:119650. doi: 10.1016/j.ijpharm.2020.119650. Epub 2020 Jul 15.
Targeting inhibitors of apoptosis proteins (IAPs) family comprising high level expression in many cancer cells, could sensitize tumor cells to conventional chemotherapies. In the present study, we designed both doxorubicin and SmacN6 (an antagonist of the IAPs) encapsulated polymeric nanoparticles (NPs) and investigated their synergistic effect of combination therapy in vitro and in vivo. According to the results, NPs-SmacN6 significantly enhanced the cytotoxicity effect of NPs-DOX and reduced its IC in MCF-7, 4T1 and C26 cancer cells. Western blot analysis confirmed mechanism of cell apoptosis via caspase activation through intrinsic and also extrinsic pathways. Moreover, 5TR1 aptamer-modified NPs could effectively deliver DOXor SmacN6 to C26 cancer cells (MUC1 positive) in comparison with the non-targeted one (p < 0.001). However, they could not be efficiently internalized into CHO cells (MUC1 negative), showing less cytotoxicity in this cell line. In vivo experiments in BALB/c mice bearing C26 tumor indicated that Apt-NPs-DOX in combination with Apt-NPs-SmacN6 had significant tumor growth inhibition in comparison with mice receiving either free DOX or Apt-NPs-DOX with p < 0.0001 and p < 0.05, respectively. Our results revealed that combination therapy of DOX and SmacN6 via Apt-modified nanoparticles can lead to improvement of therapeutic index of DOX in MUC1 positive cancer cells.
靶向凋亡抑制蛋白（IAPs）家族的抑制剂，这些抑制剂在许多癌细胞中高表达，可使肿瘤细胞对常规化疗更敏感。在本研究中，我们设计了同时包载阿霉素和 SmacN6（IAPs 的拮抗剂）的聚合物纳米粒（NPs），并研究了其在体外和体内联合治疗的协同作用。结果表明，NPs-SmacN6 显著增强了 NPs-DOX 的细胞毒性作用，并降低了 MCF-7、4T1 和 C26 癌细胞中的 IC50。Western blot 分析证实了通过内在和外在途径激活半胱天冬酶导致细胞凋亡的机制。此外，与非靶向 NPs 相比，5TR1 适配体修饰的 NPs 能更有效地将 DOX 或 SmacN6 递送到 C26 癌细胞（MUC1 阳性）（p<0.001）。然而，它们不能有效地被内吞到 CHO 细胞（MUC1 阴性）中，在该细胞系中表现出较低的细胞毒性。在携带 C26 肿瘤的 BALB/c 小鼠体内实验中，与单独接受游离 DOX 或 Apt-NPs-DOX 的小鼠相比，Apt-NPs-DOX 联合 Apt-NPs-SmacN6 具有显著的肿瘤生长抑制作用（p<0.0001 和 p<0.05）。我们的结果表明，通过 Apt 修饰的纳米粒联合 DOX 和 SmacN6 的治疗可以提高 DOX 在 MUC1 阳性癌细胞中的治疗指数。
