Targeted delivery of doxorubicin to tumour tissues by a novel legumain sensitive polygonal nanogel
Targeted delivery of doxorubicin to tumour tissues by a novel legumain sensitive polygonal nanogel
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通过新型legumain敏感的多边形纳米凝胶将阿霉素靶向递送至肿瘤组织
DOI：
10.1039/c6nr05870a
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发表时间：
2016-01-01
期刊：
影响因子：
6.7
通讯作者：
Nan, Kaihui
中科院分区：
文献类型：
--
作者：
Lin, Sen;Li, Tong;Nan, Kaihui
靶向向肿瘤组织输送细胞毒药物对化疗的成功具有重要意义。Legumain是一种天冬酰胺内肽酶，在许多实体肿瘤中高度上调。本工作的目的是制备一种新型的透明质酸(HA)豆类敏感纳米凝胶，用于阿霉素的体外和体内高效靶向传递。豆类的敏感特性是通过豆类底物多肽桥将阿霉素与透明质酸偶联而实现的。这种羟基磷灰石衍生物在水/油溶剂体系中进一步交联，形成多边形纳米凝胶。由于豆蛋白和透明质酸酶的共同作用，肿瘤组织中释放的阿霉素得以持续，这两种酶在肿瘤组织中都过度表达。透明质酸可作为CD44(HA受体)的靶向剂，进一步提高体内靶向效应，增强体外细胞摄取。所开发的纳米凝胶在肺癌小鼠模型中显示出高治疗指数，提高了肿瘤抑制效果，并降低了系统毒性。这些结果突出了使用这种多功能材料成功地输送阿霉素抗癌的优势。
Targeted delivery of cytotoxic drugs to tumour tissue has great importance for successful chemotherapy. Legumain is an asparaginyl endopeptidase that is highly up-regulated in a number of solid tumours. The aim of this work was to prepare a novel hyaluronic acid (HA) based legumain sensitive nanogel for the delivery of doxorubicin with a high targeting efficiency both in vitro and in vivo. The legumain sensitive property is achieved by the conjugation of doxorubicin with HA via a legumain substrate peptide bridge. This HA derivative is further crosslinked in a water/oil solvent system to form a polygonal nanogel. Doxorubicin released in the tumour tissue is sustained thanks to the combined action of legumain and hyaluronidase, which are both overexpressed in tumour tissues. Hyaluronic acid could act as a targeting agent to CD44 (HA receptor), which further improved the in vivo target effect and enhanced in vitro cellular uptake. The developed nanogel exhibited a high therapeutic index that improved tumour inhibition effects and reduced system toxicity in a lung cancer mice model. These results highlighted the advantages of using this multi-functional material for a successful delivery of doxorubicin against cancer.