Synthesis, biodistribution, and imaging of PEGylated-acetylated polyamidoamine dendrimers.
Synthesis, biodistribution, and imaging of PEGylated-acetylated polyamidoamine dendrimers.
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DOI：
10.1166/jnn.2014.7995
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发表时间：
2014-05
影响因子：
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通讯作者：
Jianfeng Liu;Jinjian Liu;Liping Chu;Lingling Tong;Hongjun Gao;Cuihong Yang;De-zhi Wang;Linqi Shi;Deling Kong;Zongjin Li
中科院分区：
文献类型：
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作者：
Jianfeng Liu;Jinjian Liu;Liping Chu;Lingling Tong;Hongjun Gao;Cuihong Yang;De-zhi Wang;Linqi Shi;Deling Kong;Zongjin Li
聚酰胺胺（PAMAM）树枝状聚合物已广泛用作药物载体、非病毒基因载体和显像剂。然而，由于固有的毒性和器官积累，树枝状聚合物在生物系统中的使用受到限制。在本研究中，采用乙酰化和聚乙二醇化-乙酰化策略来最大限度地减少 PAMAM 树枝状聚合物的毒性，并改善其生物分布和药代动力学，以用于医疗应用。通过用乙酸酐和聚乙二醇 (PEG) 3.4 k 对第 4 代乙酰化 PAMAM 树枝状聚合物 (G4) 进行聚乙二醇化，合成了聚乙二醇化乙酰化 PAMAM (G4-Ac-PEG) 树枝状聚合物。为了研究缀合物的细胞毒性和体内生物分布，进行了体外细胞活力分析、碘 125 (125I) 成像、组织分布和苏木精-伊红 (HE) 染色。我们发现乙酰化和聚乙二醇化-乙酰化基本上消除了体外树枝状聚合物固有的细胞毒性。平面伽马（gamma）相机成像显示，所有缀合物均缓慢从体内消除，并且观察到乙酰化 PAMAM 树枝状聚合物在较高的腹部积聚。组织分布分析表明，与非聚乙二醇化乙酰化树枝状大分子相比，聚乙二醇化乙酰化树枝状大分子在血液中的滞留时间更长，在肾脏和肝脏等器官中的积累更低，但乙酰化仅能显着增加G4在肾脏中的积累并降低血液中的浓度。组织学结果显示，高剂量给药后各组均未观察到明显损伤。本研究表明，聚乙二醇化-乙酰化可以改善血液滞留，减少器官蓄积，改善药代动力学特征，这表明聚乙二醇化-乙酰化为PAMAM树枝状大分子修饰提供了一种替代方法。
Polyamidoamine (PAMAM) dendrimers have been widely used as drug carriers, non-viral gene vectors and imaging agents. However, the use of dendrimers in biological system is constrained because of inherent toxicity and organ accumulation. In this study, the strategy of acetylation and PEGylation-acetylation was used to minimize PAMAM dendrimers toxicities and to improve their biodistribution and pharmacokinetics for medical application. PEGylated-acetylated PAMAM (G4-Ac-PEG) dendrimers were synthesized by PEGylation of acetylated PAMAM dendrimer of generation 4 (G4) with acetic anhydride and polyethylene glycol (PEG) 3.4 k. To investigate the cytotoxicity and in vivo biodistribution of the conjugates, in vitro cell viability analysis, Iodine-125 (125I) imaging, tissue distribution and hematoxylin-eosin (HE) staining were performed. We find that acetylation and PEGylation-acetylation essentially eliminates the inherent dendrimer cytotoxicity in vitro. Planar gamma (gamma) camera imaging revealed that all the conjugates were slowly eliminated from the body, and higher abdominal accumulation of acetylation PAMAM dendrimer was observed. Tissue distribution analysis showed that PEGylated-acetylated dendrimers have longer blood retention and lower accumulation in organs such as the kidney and liver than the non-PEGylated-acetylated dendrimers, but acetylation only can significantly increase the accumulation of G4 in the kidney and decrease the concentration in blood. Histology results reveal that no obvious damage was observed in all groups after high dose administration. This study indicates that PEGylation-acetylation could improve the blood retention, decrease organ accumulation, and improve pharmacokinetic profile, which suggests that PEGylation-acetylation provides an alternative method for PAMAM dendrimers modification.