Department of Pharmaceutics, School of Pharmacy, Jinan University, Guangzhou 510632, China.
Department of Pharmacy, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan 250014, Shandong, China.
Int J Pharm. 2019 Sep 10;568:118508. doi: 10.1016/j.ijpharm.2019.118508. Epub 2019 Jul 9.
Imatinib (IMT) is a selective tyrosine kinase inhibitor clinically used for treating chronic myeloid leukemia and malignant gastrointestinal stromal tumors. However, oral administration of IMT is challenged by its high oral dose, low intestinal solubility and adverse reactions. This work aimed to investigate the effect of galactose ligand on polymeric nanoparticles-facilitated oral absorption of IMT. N-oleoyl-D-galactosamine was synthesized for fabricating biomimetic galactose-modified nanoparticles (GNPs) in an attempt to improve the oral bioavailability of IMT. IMT-loaded GNPs (IMT-GNPs) were prepared using a solvent diffusion technique and characterized by particle size, morphology, and entrapment efficiency (EE). The in vitro release and in vivo oral bioavailability of IMT-GNPs were comparatively studied with bulk IMT and IMT-loaded nanoparticles (IMT-NPs), respectively. The resultant IMT-GNPs were 122.0 nm around in particle size with a polydispersity index (PDI) of 0.201. IMT-GNPs possessed a high EE (93.06%) and exhibited a sustained effect on drug release. After oral administration, IMT-GNPs significantly enhanced the oral bioavailability of IMT, up to 152.3% relative to IMT suspensions, whereas IMT-NPs merely resulted in an increase to 115.2%. Cellular uptake and ex vivo intestinal transport imaging demonstrated that GNPs were armed with higher cellular affinity and intestinal epithelial permeability compared with galactose-free IMT-NPs. These results provide solid evidence that galactose modification has great potential to ulteriorly promote the oral absorption of IMT on the base of nanoparticles, which may be conducive to achieve the synergy and attenuation of IMT.
伊马替尼（IMT）是一种选择性酪氨酸激酶抑制剂，临床上用于治疗慢性髓性白血病和恶性胃肠道间质瘤。然而，IMT 的口服给药受到其高口服剂量、低肠道溶解度和不良反应的挑战。本工作旨在研究半乳糖配体对聚合物纳米粒促进 IMT 口服吸收的影响。合成了 N-油酰-D-半乳糖胺，用于制备仿生半乳糖修饰的纳米粒（GNPs），试图提高 IMT 的口服生物利用度。采用溶剂扩散技术制备载伊马替尼的 GNPs（IMT-GNPs），并对其粒径、形态和包封效率（EE）进行了表征。分别用 bulk IMT 和载伊马替尼的纳米粒（IMT-NPs）比较研究了 IMT-GNPs 的体外释放和体内口服生物利用度。所得 IMT-GNPs 的粒径约为 122.0nm，多分散指数（PDI）为 0.201。IMT-GNPs 具有较高的 EE（93.06%），并表现出药物释放的持续效果。口服给药后，IMT-GNPs 显著提高了 IMT 的口服生物利用度，相对于 IMT 混悬液提高了 152.3%，而 IMT-NPs 仅提高了 115.2%。细胞摄取和离体肠转运成像表明，与不含半乳糖的 IMT-NPs 相比，GNPs 具有更高的细胞亲和力和肠上皮通透性。这些结果为半乳糖修饰在纳米粒基础上进一步促进 IMT 的口服吸收提供了确凿的证据，这可能有助于实现 IMT 的协同作用和减毒作用。
