PDF(Pubmed)
Abstract：
The clinical utility of gemcitabine, an antimetabolite antineoplastic agent applied in various chemotherapy treatments, is limited due to the required intravenous injection. Although chemical structure modifications of gemcitabine result in enhanced oral bioavailability, these modifications compromise complex synthetic routes and cause unexpected side effects. In this study, gemcitabine-loaded glycocholic acid-modified micelles (Gem-PPG) were prepared for enhanced oral chemotherapy. The in vitro transport pathway experiments revealed that intact Gem-PPG were transported across the intestinal epithelial monolayer via an apical sodium-dependent bile acid transporter (ASBT)-mediated pathway. In mice, the pharmacokinetic analyses demonstrated that the oral bioavailability of Gem-PPG approached 81%, compared to less than 20% for unmodified micelles. In addition, the antitumor activity of oral Gem-PPG (30 mg/kg, BIW) was superior to that of free drug injection (60 mg/kg, BIW) in the xenograft model. Moreover, the assessments of hematology, blood chemistry, and histology all indicated the hypotoxicity profile of the drug-loaded micelles.
摘要：
吉西他滨的临床应用，一种应用于各种化疗治疗的抗代谢抗肿瘤剂，是有限的，由于需要静脉注射。尽管吉西他滨的化学结构修饰可提高口服生物利用度，这些修饰破坏了复杂的合成路线并引起意想不到的副作用。在这项研究中,制备装载吉西他滨的甘氨胆酸修饰的胶束（Gem-PPG）用于增强的口服化疗。体外转运途径实验表明，完整的Gem-PPG通过顶端钠依赖性胆汁酸转运蛋白（ASBT）介导的途径转运穿过肠上皮单层。在老鼠身上,药代动力学分析表明，Gem-PPG的口服生物利用度接近81%，相比之下，未改性的胶束不到20%。此外,口服Gem-PPG的抗肿瘤活性（30mg/kg，白车身)优于游离药物注射(60mg/kg，BIW）在异种移植模型中。此外，血液学评估，血液化学,和组织学都表明载药胶束的低毒性特征。
