Tissue uptake of docetaxel loaded hydrophobically derivatized hyperbranched polyglycerols and their effects on the morphology of the bladder urothelium
Tissue uptake of docetaxel loaded hydrophobically derivatized hyperbranched polyglycerols and their effects on the morphology of the bladder urothelium
复制标题
DOI：
10.1016/j.biomaterials.2011.09.081
复制
发表时间：
2012-01-01
期刊：
影响因子：
14
通讯作者：
Burt, Helen M.
中科院分区：
文献类型：
--
作者：
Mugabe, Clement;Raven, Peter A.;Burt, Helen M.
最近，我们报道了多西他赛（DTX）负载，胺封端的超支化聚甘油（HPG-C-8/10-MePEG-NH 2）纳米粒子显着增加药物在小鼠膀胱组织中的摄取，是最有效的制剂，以显着抑制原位模型中的膀胱癌的肿瘤生长。本研究的目的是研究HPG-C-8/10-MePEG-NH 2纳米颗粒对膀胱尿路上皮形态和完整性、膀胱组织中的DTX摄取和渗透性以及在暴露于HPG-C-8/10-MePEG-NH 2纳米颗粒然后冲洗之后膀胱尿路上皮恢复的程度的影响。HPG-C-8/10-MePEG-NH 2纳米颗粒在离体猪膀胱以及活小鼠膀胱组织中均显著增加了DTX的摄取。此外，HPG-C-8/10-MePEG-NH 2纳米颗粒被证明通过引起尿道上皮屏障功能和形态的变化而增加膀胱壁的渗透性，所述尿道上皮屏障功能和形态通过紧密连接的打开和浅表伞细胞的脱落而改变。这些数据表明，脱落可能是由细胞凋亡机制触发的，随后在HPG-C-8/10-MePEG-NH 2纳米颗粒滴注后24小时内尿激酶迅速恢复。HPG-C-8/10-MePEG-NH 2纳米颗粒引起膀胱尿路上皮形态学的显著但可快速恢复的变化，我们认为这可能使它们适合于增加膀胱组织的药物渗透性和膀胱内药物递送。(C)2011爱思唯尔有限公司保留所有权利。
Recently, we have reported that docetaxel (DTX) loaded, amine terminated hyperbranched polyglycerol (HPG-C-8/10-MePEG-NH2) nanoparticles significantly increased drug uptake in mouse bladder tissues and was the most effective formulation to significantly inhibit tumor growth in an orthotopic model of bladder cancer. The objective of this study was to investigate the effects of HPG-C-8/10-MePEG-NH2 nanoparticles on bladder urothelial morphology and integrity, DTX uptake and permeability in bladder tissue and the extent of bladder urothelial recovery following exposure to, and then washout of, HPG-C-8/10-MePEG-NH2 nanoparticles. HPG-C-8/10-MePEG-NH2 nanoparticles significantly increased the uptake of DTX in both isolated pig bladder as well as in live mouse bladder tissues. Furthermore, HPG-C-8/10-MePEG-NH2 nanoparticles were demonstrated to increase the permeability of the urinary bladder wall by causing changes to the urothelial barrier function and morphology through opening of tight junctions and exfoliation of the superficial umbrella cells. These data suggest that exfoliation may be triggered by an apoptosis mechanism, which was followed by a rapid recovery of the urothelium within 24 h post-instillation of HPG-C-8/10-MePEG-NH2 nanoparticles. HPG-C-8/10-MePEG-NH2 nanoparticles cause significant but rapidly recoverable changes in the bladder urothelial morphology, which we believe may make them suitable for increasing drug permeability of bladder tissue and intravesical drug delivery. (C) 2011 Elsevier Ltd. All rights reserved.