Mitigation of Tacrolimus-Associated Nephrotoxicity by PLGA Nanoparticulate Delivery Following Multiple Dosing to Mice while Maintaining its Immunosuppressive Activity
Mitigation of Tacrolimus-Associated Nephrotoxicity by PLGA Nanoparticulate Delivery Following Multiple Dosing to Mice while Maintaining its Immunosuppressive Activity
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DOI：
10.1038/s41598-020-63767-1
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发表时间：
2020-04-21
影响因子：
4.6
通讯作者：
Lavasanifar, Afsaneh
中科院分区：
文献类型：
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作者：
Alshamsan, Aws;Binkhathlan, Ziyad;Lavasanifar, Afsaneh
本研究的目的是评估PLGA纳米粒(NPs)在多剂量给药后减轻他克莫司(TAC)相关肾毒性的能力。制备的纳米粒平均粒径为227~263 nm，载药量为8.32%。此外，TAC纳米粒的体外释放曲线显示，药物在12天内仅释放不到30%。流式细胞术和荧光显微镜结果证实树突状细胞摄取了FITC标记的PLGA纳米粒。体外研究表明，TAC纳米粒显著抑制了CD4(+)和CD8(+)细胞的增殖，与对照制剂(Prograf)相当。给药后对小鼠的体内免疫抑制活性和肾功能进行了评估。动物皮下注射TAC，每日1 mg/kg，连续30天，作为对照制剂(Prograf)或TAC载药纳米粒。结果显示，对于TAC负载的PLGA纳米粒，药物相关毒性显著降低，其活性与Prograf相当。这些发现表明，PLGA纳米粒在降低TAC的肾毒性的同时保持其免疫抑制活性具有潜力。
The aim of this study was to assess the ability of PLGA nanoparticles (NPs) to reduce the tacrolimus (TAC)-associated nephrotoxicity following multiple dose administration. The mean diameter of prepared NPs was in the range of 227 to 263nm with an 8.32% drug loading (w/w). Moreover, in vitro release profile of TAC-loaded NPs showed a sustained release of the drug with only less than 30% release within 12 days. Flow cytometry as well as fluorescence microscopy results confirmed the uptake of FITC-labelled PLGA NPs by dendritic cells. The ex vivo study showed that TAC-loaded NPs caused a significant suppression of the proliferation of CD4(+) and CD8(+) cells, which was comparable to the control formulation (Prograf). In vivo immunosuppressive activity as well as the kidney function were assessed following drug administration to mice. The animals received TAC subcutaneously at a daily dose of 1mg/kg for 30 days delivered as the control formulation (Prograf) or TAC-loaded NPs. The results revealed significantly lower drug-associated toxicity with an activity comparable to Prograf for TAC-loaded PLGA NPs. These findings show a potential for PLGA NPs in reducing the nephrotoxicity of TAC while preserving the immunosuppressive activity.