Synthesis and Evaluation of Pegylated Dendrimeric Nanocarrier for Pulmonary Delivery of Low Molecular Weight Heparin
Synthesis and Evaluation of Pegylated Dendrimeric Nanocarrier for Pulmonary Delivery of Low Molecular Weight Heparin
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DOI：
10.1007/s11095-008-9769-y
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发表时间：
2009-03-01
影响因子：
3.7
通讯作者：
Ahsan, Fakhrul
中科院分区：
文献类型：
--
作者：
Bai, Shuhua;Ahsan, Fakhrul
本研究通过在啮齿动物模型中验证聚乙二醇化树枝状聚合物胶束延长低分子量肝素（LMWH）的半衰期并增加药物的肺吸收从而有效预防深静脉血栓形成（DVT）的假设。采用傅里叶变换红外光谱（FTIR）、核磁共振（NMR）光谱和薄层色谱（TLC）对聚乙二醇化树枝状大分子的特性和纯度进行了评价。采用Nicomp Zeta仪测定制剂的粒径分布，采用天青A法测定药物包封率。在啮齿动物模型中研究了聚乙二醇化树枝状聚合物在增强肺部吸收、延长药物半衰期和预防DVT方面的功效。FTIR、NMR和TLC数据证实PAMAM树枝状聚合物与PEG-2000缀合。LMWH在PEG-树枝状聚合物胶束中的包封率约为40%。包封LMWH后，PEG-树枝状聚合物胶束的粒径从11.7 nm增加到17.1 nm。与皮下注射LMWH相比，PEG-树枝状聚合物包埋的LMWH肺吸收显著增加，制剂的相对生物利用度为60.6%。基于PEG-树枝状聚合物的制剂的半衰期为11.9小时，这是LMWH在盐水对照制剂中的半衰期的2.4倍。当制剂以48小时间隔给药时，在啮齿动物模型中，包封在聚乙二醇化树枝状聚合物中的LMWH在减少血栓重量方面的功效与以24小时间隔皮下给药的LMWH非常相似。聚乙二醇化PAMAM树枝状聚合物可潜在地用作LMWH肺部递送的载体，用于DVT的长期管理。
This study tests the hypothesis that pegylated dendrimeric micelles prolong the half-life of low molecular weight heparin (LMWH) and increase the drug's pulmonary absorption, thereby efficacious in preventing deep vein thrombosis (DVT) in a rodent model.Pegylated PAMAM dendrimer was synthesized by conjugating G3 PAMAM dendrimer with methyl ester of polyethylene glycol 2000 (PEG-2000). Fourier transform infrared (FTIR), nuclear magnetic resonance (NMR) spectra and thin layer chromatography (TLC) were used to evaluate the identity and purity of pegylated dendrimer. The particle size distributions of the formulations were measured by using a Nicomp Zeta meter, and drug entrapment efficiency was studied by azure A assay. The efficacy of pegylated dendrimers in enhancing pulmonary absorption, prolonging drug half-life, and preventing DVT was studied in a rodent model.FTIR, NMR and TLC data confirmed that PAMAM dendrimer was conjugated to PEG-2000. The entrapment efficiency of LMWH in PEG-dendrimer micelles was about 40%. Upon encapsulation of LMWH, the particle size of PEG-dendrimer micelles increased from 11.7 to 17.1 nm. LMWH entrapped in PEG-dendrimer produced a significant increase in pulmonary absorption and the relative bioavailability of the formulation was 60.6% compared to subcutaneous LMWH. The half-life of the PEG-dendrimer-based formulation was 11.9 h, which is 2.4-fold greater than the half-life of LMWH in a saline control formulation. When the formulation was administered at 48-h intervals, the efficacy of LMWH encapsulated in pegylated dendrimers in reducing thrombus weight in a rodent model was very similar to that of subcutaneous LMWH administered at 24-h intervals.Pegylated PAMAM dendrimer could potentially be used as a carrier for pulmonary delivery of LMWH for the long-term management of DVT.