Liu Jianfeng, Liu Jinjian, Chu Liping, Tong Lingling, Gao Hongjun, Yang Cuihong, Wang Dezhi, Shi Linqi, Kong Deling, Li Zongjin
J Nanosci Nanotechnol. 2014 May;14(5):3305-12. doi: 10.1166/jnn.2014.7995.
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.
聚酰胺-胺（PAMAM）树枝状大分子已被广泛用作药物载体、非病毒基因载体和成像剂。然而，由于其固有的毒性和器官蓄积性，树枝状大分子在生物系统中的应用受到限制。在本研究中，采用乙酰化和聚乙二醇化-乙酰化策略来降低PAMAM树枝状大分子的毒性，并改善其在医学应用中的生物分布和药代动力学。通过用乙酸酐和3.4k聚乙二醇（PEG）对第4代乙酰化PAMAM树枝状大分子（G4）进行聚乙二醇化反应，合成了聚乙二醇化-乙酰化PAMAM（G4-Ac-PEG）树枝状大分子。为了研究这些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大分子固有的细胞毒性。平面γ相机成像显示，所有缀合物都从体内缓慢清除，并且观察到乙酰化PAMAM树枝状大分子在腹部的蓄积更高。组织分布分析表明，与未聚乙二醇化-乙酰化的树枝状大分子相比，聚乙二醇化-乙酰化树枝状大分子在血液中的保留时间更长，在肾脏和肝脏等器官中的蓄积更低，但仅乙酰化就能显著增加G4在肾脏中的蓄积并降低血液中的浓度。组织学结果显示，高剂量给药后所有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保留，减少器官蓄积，并改善药代动力学特征，这表明聚乙二醇化-乙酰化提供了一种修饰PAMAM树枝状大分子的替代方法。
