In vitro evaluation of dendrimer prodrugs for oral drug delivery
In vitro evaluation of dendrimer prodrugs for oral drug delivery
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DOI：
10.1016/j.ijpharm.2006.11.047
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发表时间：
2007-05-04
影响因子：
5.8
通讯作者：
D'Emanuele, Antony
中科院分区：
文献类型：
--
作者：
Najlah, Mohammad;Freeman, Sally;D'Emanuele, Antony
基于树枝状聚合物的前药用于增强低溶解度模型药物萘普生的跨上皮渗透性。评估树枝状聚合物-萘普生连接的稳定性。萘普生通过酰胺键或酯键与G 0聚酰胺胺（PAMAM）树枝状聚合物缀合。在80%人血浆和50%大鼠肝匀浆中评价G 0前药的稳定性。测定缀合物对Caco-2细胞的细胞毒性，并报道缀合物穿过Caco-2单层（37 ℃）的转运。此外，一个月桂酰基链（L）连接到二甘醇酯缀合物（G 0-deg-NAP）的G 0 PAMAM树枝状聚合物的表面基团以增强渗透性。乳酸酯缀合物G 0-Tact-NAP在80%人血浆和50%大鼠肝匀浆中缓慢水解（t（1/2）= 180 min）。G 0-deg-NAP在80%人血浆中水解更快（t（1/2）=51 min），在50%肝匀浆中快速裂解（t（1/2）=4.7 min）。当暴露于Caco-2细胞3小时时，缀合物是无毒的。渗透性研究表明，显着增强时，结合到树枝状聚合物的运输napoleen; L-G 0-deg-NAP产生最高的渗透性。具有适当连接基的基于树枝状聚合物的前药具有作为低溶解度药物如萘普生的口服递送的载体的潜力。(C)2006 Elsevier B. V.保留所有权利。
Dendrimer-based prodrugs were used to enhance the transepithelial permeability of naproxen, a low solubility model drug. The stability of the dendrimer-naproxen link was assessed. Naproxen was conjugated to G0 polyamidoamine (PAMAM) dendrimers either by an amide bond or an ester bond. The stability of G0 prodrugs was evaluated in 80% human plasma and 50% rat liver homogenate. The cytotoxicity of conjugates towards Caco-2 cells was determined and the transport of the conjugates across Caco-2 monolayers (37 degrees C) was reported. In addition, one lauroyl chain (L) was attached to the surface group of G0 PAMAM dendrimer of the diethylene glycol ester conjugate (G0-deg-NAP) to enhance permeability. The lactic ester conjugate, G0-Tact-NAP, hydrolyzed slowly in 80% human plasma and in 50% rat liver homogenate (t(1/2) = 180 min). G0-deg-NAP was hydrolyzed more rapidly in 80% human plasma (t(1/2)=51 min) and was rapidly cleaved in 50% liver homogenate (t(1/2) =4.7 min). The conjugates were non-toxic when exposed to Caco-2 cells for 3 h. Permeability studies showed a significant enhancement in the transport of naproxen when conjugated to dendrimers; L-G0-deg-NAP yielding the highest permeability. Dendrimer-based prodrugs with appropriate linkers have potential as carriers for the oral delivery of low solubility drugs such as naproxen. (C) 2006 Elsevier B.V. All rights reserved.