Synthesis and Assessment of First-Generation Polyamidoamine Dendrimer Prodrugs to Enhance the Cellular Permeability of P-gp Substrates
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- 作者：Mohammad Najlah ; Sally Freeman ; David Attwood ; Antony D'Emanuele
- 刊名：Bioconjugate Chemistry
- 出版年：2007
- 出版时间：May 2007
- 年：2007
- 卷：18
- 期：3
- 页码：937 - 946
- 全文大小：185K
- 年卷期：v.18,no.3(May 2007)
- ISSN：1520-4812
文摘
The aim of this study is to evaluate the potential use of first-generation (G1) polyamidoamine (PAMAM) dendrimersas drug carriers to enhance the permeability, hence oral absorption, of drugs that are substrates for P-glycoprotein(P-gp) efflux transporters. G1 PAMAM dendrimer-based prodrugs of the water-insoluble P-gp substrate terfenadine(Ter) were synthesized using succinic acid (suc) or succinyl-diethylene glycol (suc-deg) as a linker/spacer (toyield G1-suc-Ter and G1-suc-deg-Ter, respectively). In addition, the permeability of G1-suc-deg-Terwas enhanced by attaching two lauroyl chains (L) to the dendrimer surface (L2-G1-suc-deg-Ter). All of theG1 dendrimer-terfenadine prodrugs were more hydrophilic than the parent drug, as evaluated by drug partitioningbetween 1-octanol and phosphate buffer at pH 7.4 (log Kapp). The influence of the dendrimer prodrugs on theintegrity and viability of human Caucasian colon adenocarcinoma cells (Caco-2) was determined by measuringthe transepithelial electrical resistance (TEER) and leakage of lactate dehydrogenase (LDH) enzyme, respectively.The LDH assay indicated that the dendrimer prodrugs had no impact on the viability of Caco-2 cells up to aconcentration of 1 mM. However, the IC50 of the prodrugs was lower than that of G1 PAMAM dendrimer becauseof the high toxicity of terfenadine. Measurements of the transport of dendrimer prodrugs across monolayers ofCaco-2 cells showed an increase of the apparent permeability coefficient (Papp) of terfenadine in both apical-to-basolateral (A 
B) and basolateral-to-apical (B A) directions after its conjugation to G1 PAMAM dendrimer.The A B Papp of the dendrimer prodrugs was significantly greater than B A Papp. The surface-modifieddendrimer prodrug L2-G1-suc-deg-Ter showed the highest A B permeability among the conjugates.
B) and basolateral-to-apical (B A) directions after its conjugation to G1 PAMAM dendrimer.The A B Papp of the dendrimer prodrugs was significantly greater than B A Papp. The surface-modifieddendrimer prodrug L2-G1-suc-deg-Ter showed the highest A B permeability among the conjugates.