In vivo biodistribution and small animal PET of (64)Cu-labeled antimicrobial peptoids.
In vivo biodistribution and small animal PET of (64)Cu-labeled antimicrobial peptoids.
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DOI：
10.1021/bc300091d
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发表时间：
2012-05-16
影响因子：
4.7
通讯作者：
Cheng, Zhen
中科院分区：
文献类型：
--
作者：
Seo, Jiwon;Ren, Gang;Liu, Hongguang;Miao, Zheng;Park, Minyoung;Wang, Yihong;Miller, Tyler M.;Barron, Annelise E.;Cheng, Zhen
类肽是一类快速发展的仿生聚合物，基于寡聚 N 取代的甘氨酸主链，旨在模拟肽和蛋白质。受天然抗菌肽的启发，成功发现了一组具有强效广谱抗病原菌活性的阳离子两亲性肽；然而，解决类肽体内药代动力学的研究有限。在此，合成了三种不同类肽和两种对照肽的 64Cu 标记的 DOTA 缀合物，并通过生物分布研究和小动物正电子发射断层扫描 (PET) 进行了体内分析。该研究旨在评估肽模拟物的结构差异如何影响体内药代动力学。作为两亲性分子，类肽的主要摄取发生在肝脏。通过删除类肽中的一个疏水残基观察到肾脏摄取增加，并且 64Cu-3 在本研究中测试的所有缀合物中实现了最高的肾脏摄取。与肽相比，我们的数据表明类肽具有较高的组织积累、较慢的消除和较高的体内稳定性的一般体内特性。使用拟肽研究了不同的给药途径（静脉内、腹膜内和口服）。口服给药时，类肽的生物利用度较差，与肽的生物利用度相似。但是，观察到类肽在没有快速消化的情况下通过胃肠道的时间明显更长。类肽的这些独特的体内特性通过有效的细胞膜渗透性和类肽的蛋白酶抗性而合理化。生物分布研究中观察到的结果可以通过 PET 成像得到证实，这为非侵入性实时评估类肽的体内药代动力学特性提供了可靠的方法。这里提供的药代动力学数据可以为抗菌肽作为药物的进一步开发提供见解。
Peptoids are a rapidly developing class of biomimetic polymers based on oligo-N-substituted glycine backbones, designed to mimic peptides and proteins. Inspired by natural antimicrobial peptides, a group of cationic amphipathic peptoids has been successfully discovered with a potent and broad-spectrum activity against pathogenic bacteria; however, there are limited studies to address the in vivo pharmacokinetics of the peptoids. Herein, 64Cu labeled DOTA conjugates of three different peptoids and two control peptides were synthesized and assayed in vivo by both biodistribution studies and small animal positron emission tomography (PET). The study was designed in a way to assess how structural differences of the peptidomimetics affect in vivo pharmacokinetics. As amphipathic molecules, major uptake of the peptoids occurred at the liver. Increased kidney uptake was observed by deleting one hydrophobic residue in the peptoid, and 64Cu-3 achieved the highest kidney uptake of all the conjugates tested in this study. In comparison to peptides, our data indicated that peptoids had general in vivo properties of higher tissue accumulation, slower elimination, and higher in vivo stability. Different administration routes (intravenous, intraperitoneal, and oral) were investigated with peptoids. When administered orally, the peptoids showed poor bioavailability, reminiscent to that of peptide. But, remarkably longer passage through the gastrointestinal (GI) tract without rapid digestion was observed for peptoids. These unique in vivo properties of peptoids were rationalized by efficient cellular membrane permeability and protease resistance of peptoids. The results observed in the biodistribution studies could be confirmed by the PET imaging, which provides a reliable way to evaluate in vivo pharmacokinetic properties of peptoids noninvasively and in real time. The pharmacokinetic data presented here can provide an insight for further development of the antimicrobial peptoids as pharmaceuticals.
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影响因子：
3.2
作者：
Fowler SA;Blackwell HE
通讯作者：
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影响因子：
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作者：
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DOI：
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发表时间：
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影响因子：
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