Folate coupled poly(ethyleneglycol) conjugates of anionic poly(amidoamine) dendrimer for inflammatory tissue specific drug delivery
Folate coupled poly(ethyleneglycol) conjugates of anionic poly(amidoamine) dendrimer for inflammatory tissue specific drug delivery
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DOI：
10.1002/jbm.a.31122
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发表时间：
2007-07-01
影响因子：
4.9
通讯作者：
Diwan, Prakash V.
中科院分区：
文献类型：
--
作者：
Chandrasekar, Durairaj;Sistla, Ramakrishna;Diwan, Prakash V.
叶酸受体在动物模型和患有自然发生的类风湿性关节炎的人类患者中的活化（但不是静止）巨噬细胞上过表达。本研究的目的是制备叶酸靶向聚乙二醇（PEG）偶联阴离子树枝状大分子（G3.5 PAMAM）作为炎症靶向给药系统，并研究其在关节炎大鼠体内的生物分布模式。叶酸-聚乙二醇-聚酰胺-胺偶联物，具有不同程度的取代，通过两步反应，通过阿托伐他汀介导的偶联反应合成和负载吲哚美辛。叶酸-PEG缀合物使药物负载效率增加10- 20倍，并且体外释放曲线表明药物的控制释放。血浆药代动力学参数表明叶酸-PEG缀合物的AUC、循环半衰期和平均停留时间增加。组织分布研究显示，叶酸-PEG缀合物的胃摄取显著较少，从而限制了胃相关的副作用。对于叶酸-PEG缀合物，爪中药物的时间平均相对药物暴露（re）范围为1.81至2.37。当与天然树枝状聚合物（1.72）相比时，叶酸-PEG缀合物（3.44）的总体药物靶向效率（T-e）最高。叶酸-PEG-PAMAM偶联物是将抗关节炎药物靶向递送至炎症的理想选择，具有降低的副作用和更高的靶向效率。(c)2007 Wiley Periodicals，Inc.
Folate receptor is overexpressed on the activated (but not quiescent) macrophages in both animal models and human patients with naturally occurring rheumatoid arthritis. The aim of this study was to prepare folate targeted poly (ethylene glycol) (PEG) conjugates of anionic dendrimer (G3.5 PAMAM) as targeted drug delivery systems to inflammation and to investigate its biodistribution pattern in arthritic rats. Folate-PEG-PAMAM conjugates, with different degrees of substitution were synthesized by a two-step reaction through a carbodiimide-mediated coupling reaction and loaded with indomethacin. Folate-PEG conjugation increased the drug loading efficiency by 10- to 20-fold and the in vitro release profile indicated controlled release of drug. The plasma pharmacokinetic parameters indicated an increased AUC, circulatory half-life and mean residence time for the folate-PEG conjugates. The tissue distribution studies revealed significantly lesser uptake by stomach for the folate-PEG conjugates, thereby limiting gastric-related side effect. The time-averaged relative drug exposure (re) of the drug in paw for the folate-PEG conjugates ranged from 1.81 to 2.37. The overall drug targeting efficiency (T-e) was highest for folate-PEG conjugate (3.44) when compared to native dendrimer (1.72). The folate-PEG-PAMAM conjugates are the ideal choice for targeted delivery of antiarthritic drugs to inflammation with reduced side-effects and higher targeting efficiency. (c) 2007 Wiley Periodicals, Inc.