Key Laboratory of Drug Targeting and Drug Delivery Systems, Ministry of Education, West China School of Pharmacy, Sichuan University, Chengdu, Sichuan, PR China.
J Drug Target. 2011 Aug;19(7):540-51. doi: 10.3109/1061186X.2010.521158.
To investigate the influence of N-acetylation of chitosan on the renal targeting.
Hydroxyethyl chitosans (HECs) with different N-acetylation degrees of 10.0%, 52.7%, and 81.8% (HECs-10, HECs-53, and HECs-82) were synthesized. Then, in vitro evaluations including cellular uptake and cytotoxicity were performed. Finally, tissue distribution of HECs in normal mice and megalin-shedding mice models were evaluated.
HECs-10 exhibited the highest binding affinity and uptake capacity to MDCK cells, expressing the megalin receptor. Additionally, cytotoxicity assay showed that there were no obvious effects of HECs on the viability of L929 and MDCK cells. Consistent with the cellular uptake study, it was shown in vivo study that all HECs exhibited renal-targeting profile. Especially, HECs-10 with low N-acetylation overwhelmingly accumulated in the kidneys, while urinary excretion of HECs-10 was low, in comparison with that of HECs-53 and HECs-82. Finally, the renal accumulation of HECs in megalin-shedding mice was dramatically reduced by over ~50% as compared with that in normal animals and the specific renal uptake of HECs was increasingly inhibited with the N-acetylation increased.
Inspired by these observations, we can conclude that decreasing the N-acetylation could enhance accumulation of low-molecular-weight chitosan in kidneys and amino groups in the structure could be essential for renal-targeting profile of chitosan.
研究壳聚糖的 N-乙酰化对其肾靶向性的影响。
合成了不同 N-乙酰化度（10.0%、52.7%和 81.8%）的羟乙基壳聚糖（HECs），即 HECs-10、HECs-53 和 HECs-82。然后，进行了包括细胞摄取和细胞毒性在内的体外评价。最后，在正常小鼠和 megalin 脱落小鼠模型中评价了 HECs 在组织中的分布。
HECs-10 对表达 megalin 受体的 MDCK 细胞表现出最高的结合亲和力和摄取能力。此外，细胞毒性试验表明 HECs 对 L929 和 MDCK 细胞的活力没有明显影响。与细胞摄取研究一致，体内研究表明所有 HECs 均表现出肾靶向特征。特别是，低 N-乙酰化的 HECs-10 大量积聚在肾脏中，而 HECs-10 的尿排泄量较低，与 HECs-53 和 HECs-82 相比。最后，与正常动物相比，megalin 脱落小鼠中 HECs 的肾积累减少了约 50%以上，并且随着 N-乙酰化的增加，HECs 的特异性肾摄取受到越来越大的抑制。
受这些观察结果的启发，我们可以得出结论，降低 N-乙酰化度可以增强低分子量壳聚糖在肾脏中的积累，并且结构中的氨基对于壳聚糖的肾靶向特征是必不可少的。
