Department of Geriatric Gastroenterology, the First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China.
State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Bioactive Materials, Ministry of Education, and College of Life Sciences, Nankai University, Tianjin 300071, China.
ACS Appl Mater Interfaces. 2020 Mar 4;12(9):10096-10106. doi: 10.1021/acsami.9b17363. Epub 2020 Feb 20.
Paclitaxel (Ptx), a type of microtubule depolymerization inhibitor, is one of the main components in gastric cancer chemotherapy. Some studies have demonstrated that tetrandrine (Tet), a bisbenzylisoquinoline alkaloid, has potential antitumor effects in several cancers. Aside from the direct anticancer effect, Tet is proved to synergistically enhance the antitumor effect of Ptx in gastric cancer. However, the application of the combinational strategy is limited by the poor solubility of both drugs. Nanodrug delivery systems including polymeric nanoparticles, self-assembled nanofibers, hydrogels, etc., hold the potential to meet the need. Here, a novel supramolecular nanomaterial, based on the concept of "carrier-free nanodrugs", is reported as a feasible platform for synergistic drug delivery. Ptx-SA-RGD is obtained through the conjugation of Ptx and the tumor-specific peptide RGD (arginine-glycine-aspartic acid) with succinic acid (SA) as a linker. Ptx-SA-RGD could self-assemble into Ptx nanofibers (P-NFs) with high drug-loading efficiency. Tet was then encapsulated into P-NFs to acquire novel Ptx and Tet coloaded self-assembled nanofibers (P/T-NFs). The uptake study shows the dynamic internalization of P/T-NFs by the gastric cancer cell line MGC-803. P/T-NFs significantly triggered the accumulation of reactive oxygen species (ROS) in gastric cancer cells MGC803 and further decreased the mitochondrial membrane potential, which led to the induction of mitochondrial apoptosis with superior cytotoxicity against free drugs. Moreover, P/T-NFs suppressed the expressions of p-STAT3 and p-JAK, initiated cytochrome- release, and promoted caspase protein expression. Furthermore, P/T-NFs demonstrated the strongest tumor-delaying effect as well as the lowest toxicity. Therefore, self-assembled nanofibers of P/T-NFs demonstrated an increase of the mitochondrial apoptosis level and a stronger antitumor effect both in vitro and in vivo, which could be a potential way to enhance the clinical efficacy and reduce the side-effects of Ptx in gastric cancer.
紫杉醇（Ptx）是一种微管解聚抑制剂，是胃癌化疗的主要成分之一。一些研究表明，汉防己甲素（Tet），一种双苄基异喹啉生物碱，在几种癌症中有潜在的抗肿瘤作用。除了直接的抗癌作用外，Tet 被证明可协同增强胃癌中 Ptx 的抗肿瘤作用。然而，联合策略的应用受到两种药物溶解度差的限制。包括聚合物纳米粒子、自组装纳米纤维、水凝胶等在内的纳米药物递送系统具有满足这一需求的潜力。在这里，报道了一种基于“无载体纳米药物”概念的新型超分子纳米材料，作为协同药物递送的可行平台。Ptx-SA-RGD 通过将 Ptx 与肿瘤特异性肽 RGD（精氨酸-甘氨酸-天冬氨酸）与琥珀酸（SA）连接，获得 Ptx-SA-RGD。Ptx-SA-RGD 可以自组装成具有高载药效率的 Ptx 纳米纤维（P-NFs）。然后将 Tet 封装到 P-NFs 中，获得新型 Ptx 和 Tet 共载自组装纳米纤维（P/T-NFs）。摄取研究表明，胃癌细胞系 MGC-803 动态内化 P/T-NFs。P/T-NFs 显著增加了胃癌细胞 MGC803 中活性氧（ROS）的积累，并进一步降低了线粒体膜电位，从而诱导了线粒体凋亡，并具有优于游离药物的细胞毒性。此外，P/T-NFs 抑制了 p-STAT3 和 p-JAK 的表达，引发细胞色素 c 释放，并促进了 caspase 蛋白的表达。此外，P/T-NFs 表现出最强的肿瘤抑制作用和最低的毒性。因此，P/T-NFs 的自组装纳米纤维在体外和体内均显示出增加线粒体凋亡水平和更强的抗肿瘤作用，这可能是提高胃癌中 Ptx 临床疗效和降低副作用的一种潜在方法。
