Liu Xiangyou, Wei Wei, Huang Shijiao, Lin Shrong-Shi, Zhang Xin, Zhang Chuanmao, Du Yuguang, Ma Guanghui, Li Mei, Mann Stephen, Ma Ding
Beijing National Laboratory for Molecular Sciences, College of Chemistry and Molecular Engineering, Peking University, Beijing 100871, China.
J Mater Chem B. 2013 Jul 7;1(25):3136-3143. doi: 10.1039/c3tb20081g. Epub 2013 May 13.
Chemotherapy has been widely used in clinical practice for cancer treatment. A major challenge for a successful chemotherapy is to potentiate the anticancer activity, whilst reducing the severe side effects. In this context, we design a bio-inspired protein-gold nanoconstruct (denoted as AFt-Au hereafter) with a core-void-shell structure which exhibits a high selectivity towards carcinoma cells. Anticancer drug 5-fluorouracil (5-FU) can be sequestered into the void space of the construct to produce an integrated nanoscale hybrid AFt-AuFU that exhibits an increased cellular uptake of 5-FU. More importantly, AFt-Au, serving as a bio-nano-chemosensitizer, renders carcinoma cells more susceptible to 5-FU by cell-cycle regulation, and thus, leads to a dramatic decrease of the IC value (i.e. the drug concentration required to kill 50% of the cell population) of 5-FU in HepG2 cells from 138.3 μM to 9.2 μM. Besides HepG2 cells, a remarkably enhanced anticancer efficacy and potentially reduced side effects are also achieved in other cell lines. Our further work reveals that the drug 5-FU is internalized into cells with AFt-Au primarily via receptor-mediated endocytosis (RME). After internalization, AFt-AuFU colocalizes with lysosomes which trigger the release of 5-FU under acidic conditions. Overall, our approach provides a novel procedure in nanoscience that promises an optimal chemotherapeutic outcome.
化疗已在癌症治疗的临床实践中广泛应用。成功进行化疗的一个主要挑战是增强抗癌活性，同时减少严重的副作用。在此背景下，我们设计了一种具有核-空-壳结构的仿生蛋白质-金纳米结构（以下简称AFt-Au），它对癌细胞具有高选择性。抗癌药物5-氟尿嘧啶（5-FU）可以被隔离到该结构的空隙空间中，以产生一种集成的纳米级杂化物AFt-AuFU，其表现出5-FU细胞摄取量增加。更重要的是，AFt-Au作为一种生物纳米化学增敏剂，通过细胞周期调控使癌细胞对5-FU更敏感，因此，导致5-FU在HepG2细胞中的IC值（即杀死50%细胞群体所需的药物浓度）从138.3 μM大幅降至9.2 μM。除了HepG2细胞外，在其他细胞系中也实现了显著增强的抗癌疗效和潜在降低的副作用。我们的进一步研究表明，药物5-FU与AFt-Au一起主要通过受体介导的内吞作用（RME）进入细胞。内化后，AFt-AuFU与溶酶体共定位，溶酶体在酸性条件下触发5-FU的释放。总体而言，我们的方法在纳米科学中提供了一种新的程序，有望实现最佳的化疗效果。
