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聚乙二醇表面密度和链长对甲氨蝶呤载壳聚糖纳米粒的药代动力学和生物分布的影响。

Effects of PEG surface density and chain length on the pharmacokinetics and biodistribution of methotrexate-loaded chitosan nanoparticles.

机构信息

Shanghai Key Laboratory of Functional Materials Chemistry, East China University of Science and Technology, Shanghai, People's Republic of China,

Department of Chemical Engineering, Imperial College London, South Kensington Campus, London, UK,

出版信息

Int J Nanomedicine. 2018 Sep 24;13:5657-5671. doi: 10.2147/IJN.S167443. eCollection 2018.

DOI:10.2147/IJN.S167443
PMID:30288039
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6161721/
Abstract

BACKGROUND: One of the most important aspects of drug delivery is extended nanoparticle (NP) residence time in vivo. Herein, we report a series of methotrexate (MTX)-loaded chito-san (CS) NPs coated with differently sized methoxy polyethylene glycol (mPEG) at different mPEG surface densities. MATERIALS AND METHODS: MTX was incorporated into NPs (112.8-171.2 nm in diameter) prepared from the resulting mPEG-g-CS. The NPs had a zeta potential of +7.4-35.0 mV and MTX loading efficiency of 17.1%-18.4%. MTX/mPEG-g-CS NPs showed an initial burst release of MTX followed by a sustained-release profile in PBS at pH 7.4. RESULTS: The in vitro cellular uptake study showed that MTX accumulation in J774A.1 macrophage cells decreased with increasing the mPEG surface density or the mPEG molecular weight. The pharmacokinetic study on Sprague Dawley rats revealed an increase in AUC0-72 h (area under the plasma drug concentration-time curve over a period of 72 hours) with increasing the mPEG surface density or the mPEG molecular weight and a linear correlation between the mPEG surface density and AUC. CONCLUSION: The biodistribution study on Institute of Cancer Research (ICR) mice revealed that MTX/mPEG-g-CS NPs significantly enhanced blood circulation time in the body and decreased accumulation in liver, spleen, and lung. These results suggest the potential of the mPEG-g-CS NPs as a promising candidate for drug delivery.

摘要

背景：药物输送最重要的方面之一是延长纳米粒子（NP）在体内的驻留时间。在此，我们报告了一系列甲氨蝶呤（MTX）负载的壳聚糖（CS）NP，这些 NP 用不同大小的甲氧基聚乙二醇（mPEG）在不同的 mPEG 表面密度下进行了涂层处理。

材料和方法：将 MTX 掺入由所得的 mPEG-g-CS 制备的 NP（直径为 112.8-171.2nm）中。NP 的 ζ 电位为+7.4-35.0mV，MTX 载药效率为 17.1%-18.4%。MTX/mPEG-g-CS NP 在 PBS（pH7.4）中表现出 MTX 的初始突释释放，随后是持续释放特征。

结果：体外细胞摄取研究表明，随着 mPEG 表面密度或 mPEG 分子量的增加，J774A.1 巨噬细胞中 MTX 的积累减少。Sprague Dawley 大鼠的药代动力学研究表明，随着 mPEG 表面密度或 mPEG 分子量的增加，AUC0-72h（72 小时内血浆药物浓度-时间曲线下面积）增加，并且 mPEG 表面密度与 AUC 呈线性相关。

结论：在 ICR 小鼠中的体内分布研究表明，MTX/mPEG-g-CS NP 显著延长了体内血液循环时间，并减少了肝脏、脾脏和肺部的积累。这些结果表明，mPEG-g-CS NP 作为药物输送的有前途的候选物具有潜力。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6623/6161721/edd7f54fa38e/ijn-13-5657Fig8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6623/6161721/6dce76b3ae31/ijn-13-5657Fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6623/6161721/b1268aa20f4b/ijn-13-5657Fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6623/6161721/e064ab30ba7b/ijn-13-5657Fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6623/6161721/5512a4b54d41/ijn-13-5657Fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6623/6161721/3d5da6137e6d/ijn-13-5657Fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6623/6161721/5ad1d5e1d331/ijn-13-5657Fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6623/6161721/a7f6699313a9/ijn-13-5657Fig7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6623/6161721/edd7f54fa38e/ijn-13-5657Fig8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6623/6161721/6dce76b3ae31/ijn-13-5657Fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6623/6161721/b1268aa20f4b/ijn-13-5657Fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6623/6161721/e064ab30ba7b/ijn-13-5657Fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6623/6161721/5512a4b54d41/ijn-13-5657Fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6623/6161721/3d5da6137e6d/ijn-13-5657Fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6623/6161721/5ad1d5e1d331/ijn-13-5657Fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6623/6161721/a7f6699313a9/ijn-13-5657Fig7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6623/6161721/edd7f54fa38e/ijn-13-5657Fig8.jpg

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本文引用的文献

[1]
Impact of PEG Chain Length on the Physical Properties and Bioactivity of PEGylated Chitosan/siRNA Nanoparticles in Vitro and in Vivo.

ACS Appl Mater Interfaces. 2017-4-3

[2]
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J Colloid Interface Sci. 2016-11-15

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Int J Biol Macromol. 2016-10

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Acta Biomater. 2015-9

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Biomed Pharmacother. 2015-2

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Mol Pharm. 2014-7-7

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Int J Pharm. 2013-5-17

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Int J Pharm. 2013-2-16

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Int J Pharm. 2012-4-10

[10]
Study on formulation variables of methotrexate loaded mesoporous MCM-41 nanoparticles for dissolution enhancement.

Eur J Pharm Sci. 2011-10-31

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