Effects of γ- and hydroxypropyl-γ-cyclodextrins on the transport of doxorubicin across an in vitro model of blood-brain barrier
Effects of γ- and hydroxypropyl-γ-cyclodextrins on the transport of doxorubicin across an in vitro model of blood-brain barrier
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DOI：
10.1124/jpet.104.071845
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发表时间：
2004-12-01
影响因子：
3.5
通讯作者：
Tilloy, S
中科院分区：
文献类型：
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作者：
Monnaert, V;Betbeder, D;Tilloy, S
阿霉素（DOX）和γ -环糊精（γ - cd）或羟丙基- γ - cd （hp - γ - cd）之间的关联已被研究，以增加这种抗肿瘤药物向大脑的递送。采用紫外可见光谱法测定了γ - cd或hp - γ - cd与DOX配合物在生理介质中的化学计量学和稳定常数。通过体外血脑屏障（BBB）模型，观察DOX、γ - cd和hp - γ - cd对脑毛细血管内皮细胞的通透性和毒性。对于每个CD，内皮通透性相对较低，分别在20 mM、20 mM和50 mM DOX、γ -CD和hp - γ -CD时发生血脑屏障破坏。在固定的DOX浓度中加入越来越多的CDs。γ - cd或hp - γ - cd的添加，分别达到15和35 mM，减少了DOX的递送，可能是由于复合物穿过血脑屏障的渗透降低和自由DOX浓度的降低。较高的CD浓度增加了DOX向大脑的输送，但这种影响是由于血脑屏障完整性的丧失。与各种药物在Caco-2细胞模型上观察到的结果相反，CDs不能增加DOX在体外血脑屏障模型中的传递。
Association between doxorubicin (DOX) and gamma-cyclodextrin (gamma-CD) or hydroxypropyl-gamma-CD (HP-gamma-CD) has been examined to increase the delivery of this antitumoral agent to the brain. The stoichiometry and the stability constant of gamma-CD or HP-gamma-CD and DOX complexes were determined in physiological medium by UV-visible spectroscopy. By using an in vitro model of the blood-brain barrier (BBB), endothelial permeability and toxicity toward the brain capillary endothelial cells of DOX, gamma-CD, and HP-gamma-CD were performed. For each CD, endothelial permeability was relatively low and a disruption of the BBB occurred at 20 muM, 20 mM, and 50 mM DOX, gamma-CD, and HP-gamma-CD, respectively. Increasing amounts of CDs were added to a fixed DOX concentration. Addition of gamma-CD or HP-gamma-CD, up to 15 and 35 mM, respectively, decreased the DOX delivery, probably due to the low complex penetration across the BBB and the decrease in free DOX concentration. Higher CD concentrations increased the DOX delivery to the brain, but this effect is due to a loss of BBB integrity. In contrast to what was observed on Caco-2 cell model with various drugs, CDs are not able to increase the delivery of DOX across our in vitro model of BBB.