Key Laboratory of Protein and Peptide Pharmaceuticals, CAS-University of Tokyo Joint Laboratory of Structural Virology and Immunology , Institute of Biophysics, Chinese Academy of Sciences , Beijing 100101 , China.
Key Laboratory of Molecular Imaging of Chinese Academy of Sciences , Institute of Automation, Chinese Academy of Sciences , Beijing 100190 , China.
ACS Nano. 2018 May 22;12(5):4105-4115. doi: 10.1021/acsnano.7b06969. Epub 2018 Apr 4.
Over the last decades, considerable efforts have been put into developing active nanocarrier systems that cross the blood brain barrier (BBB) to treat brain-related diseases such as glioma tumors. However, to date none have been approved for clinical usage. Here, we show that a human H-ferritin (HFn) nanocarrier both successfully crosses the BBB and kills glioma tumor cells. Its principle point of entry is the HFn receptor (transferrin receptor 1), which is overexpressed in both BBB endothelial cells (ECs) and glioma cells. Importantly, we found that HFn enters and exits the BBB via the endosome compartment. In contrast, upon specifically targeting and entering glioma cells, nearly all of the HFn accumulated in the lysosomal compartment, resulting in the killing of glioma tumor cells, with no HFn accumulation in the surrounding healthy brain tissue. Thus, HFn is an ideal nanocarrier for glioma therapy and possesses the potential to serve as a therapeutic approach against a broad range of central nervous system diseases.
在过去的几十年中，人们投入了大量的精力来开发能够穿透血脑屏障（BBB）的主动纳米载体系统，以治疗脑相关疾病，如神经胶质瘤肿瘤。然而，迄今为止，还没有一种被批准用于临床应用。在这里，我们展示了一种人类铁蛋白（HFn）纳米载体，它既能成功穿透血脑屏障，又能杀死神经胶质瘤肿瘤细胞。它的主要进入点是 HFn 受体（转铁蛋白受体 1），该受体在 BBB 内皮细胞（ECs）和神经胶质瘤细胞中均过度表达。重要的是，我们发现 HFn 通过内体隔室进入和离开 BBB。相比之下，当专门针对神经胶质瘤细胞并进入这些细胞时，几乎所有的 HFn 都积累在溶酶体隔室中，导致神经胶质瘤肿瘤细胞死亡，而周围健康的脑组织中没有 HFn 积累。因此，HFn 是神经胶质瘤治疗的理想纳米载体，并有可能成为治疗广泛的中枢神经系统疾病的一种治疗方法。
