PURPOSE: To investigate the influence of N-acetylation of chitosan on the renal targeting. METHODS: 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. RESULTS: 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. CONCLUSION: 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.
PURPOSE: To investigate the influence of N-acetylation of chitosan on the renal targeting. METHODS: 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. RESULTS: 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. CONCLUSION: 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.
Authors: Shan Gao; San Hein; Frederik Dagnæs-Hansen; Kathrin Weyer; Chuanxu Yang; Rikke Nielsen; Erik I Christensen; Robert A Fenton; Jørgen Kjems Journal: Theranostics Date: 2014-08-13 Impact factor: 11.556