Novel "Carrier-Free" Nanofiber Codelivery Systems with the Synergistic Antitumor Effect of Paclitaxel and Tetrandrine through the Enhancement of Mitochondrial Apoptosis
Novel "Carrier-Free" Nanofiber Codelivery Systems with the Synergistic Antitumor Effect of Paclitaxel and Tetrandrine through the Enhancement of Mitochondrial Apoptosis
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新型“无载体”纳米纤维递送系统通过增强线粒体凋亡发挥紫杉醇和粉防己碱的协同抗肿瘤作用
DOI：
10.1021/acsami.9b17363
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发表时间：
2020-03-04
影响因子：
9.5
通讯作者：
Xu, Huae
中科院分区：
文献类型：
--
作者：
Li, Xiaolin;Yu, Na;Xu, Huae
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。粉防己碱（tetrandrine，泰特）是一种双苄基异喹啉类生物碱，具有潜在的抗肿瘤作用。除了直接的抗癌作用外，泰特被证明在胃癌中协同增强Ptx的抗肿瘤作用。然而，组合策略的应用受到两种药物溶解度差的限制。纳米药物递送系统，包括聚合物纳米颗粒、自组装纳米纤维、水凝胶等，保持潜力以满足需要。在这里，一种新的超分子纳米材料，基于“无载体纳米药物”的概念，被报道为一个可行的协同药物输送平台。Ptx-SA-RGD通过Ptx和肿瘤特异性肽RGD（甘氨酸-天冬氨酸）与作为接头的琥珀酸（SA）缀合而获得。Ptx-SA-RGD可自组装成载药效率高的Ptx纳米纤维。然后将泰特包封到P-NFs中，得到新型Ptx和泰特共掺杂的自组装纳米纤维（P/T-NFs）。摄取研究显示P/T-NFs被胃癌细胞系MGC-803动态内化。P/T-NFs能显著诱导胃癌细胞MGC 803内活性氧（ROS）的积累，并进一步降低线粒体膜电位，诱导线粒体凋亡，对游离药物具有较强的上级细胞毒性。此外，P/T-NFs抑制p-STAT 3和p-JAK的表达，启动细胞色素C的释放，促进caspase蛋白的表达。此外，P/T-NF表现出最强的肿瘤延迟作用和最低的毒性。因此，自组装的P/T-NFs纳米纤维在体内外均表现出较强的抗肿瘤作用，并能促进线粒体凋亡水平的提高，有望成为提高Ptx治疗胃癌的临床疗效和降低其毒副作用的潜在途径。
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 drugloading 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-C 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.