Xing Yabing, Li Xiao, Cui Weiwei, Xue Meng, Quan Yanan, Guo Xinhong
Department of Pharmacy, Children's Hospital Affiliated to Zhengzhou University, Zhengzhou 450018, China.
School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China.
Pharmaceutics. 2022 Jun 27;14(7):1361. doi: 10.3390/pharmaceutics14071361.
Based on glucose (G) transporters (GLUTs), structuring nanoparticles with G as a target are an effective strategy to enhance oral bioavailability and anti-tumor effects of drugs. A novel drug delivery system using G-modified zein (GZ) nanoparticles loaded with docetaxel (DTX) (DTX-GNPs) was prepared and characterized and via assessment of cellular uptake, absorption site, pharmacokinetics, distribution, and anti-tumor effects. The DTX-GNPs were approximately 120 nm in size. Compared with DTX-NPs, G modification significantly enhanced cellular uptake of DTX-GNPs by 1.22 times in CaCo-2 cells, which was related to GLUT mediation and the enhancement of endocytosis pathways clathrin, micropinocytosis, and caveolin. Compared to DTX-NPs, G modification significantly enhanced DTX-NP absorption in the jejunum and ileum, delayed plasma concentration peak time, prolonged the average residence time , and increased oral bioavailability (from 43.82% to 96.04%). Cellular uptake and oral bioavailability of DTX were significantly affected by the G modification ratio. Compared with DTX-NPs, G modification significantly reduced drug distribution in the liver, lungs, and kidneys and increased tumor distribution and tumor growth inhibition rate without obvious systemic toxicity. This study demonstrated the potential of GZ-NPs as nanocarriers for DTX to enhance oral bioavailability and anti-tumor effects.
基于葡萄糖（G）转运蛋白（GLUTs），以G为靶点构建纳米颗粒是提高药物口服生物利用度和抗肿瘤效果的有效策略。制备了一种新型药物递送系统，即载有多西他赛（DTX）的G修饰玉米醇溶蛋白（GZ）纳米颗粒（DTX-GNPs），并通过细胞摄取、吸收部位、药代动力学、分布和抗肿瘤效果评估对其进行了表征。DTX-GNPs的大小约为120nm。与DTX-NPs相比，G修饰显著增强了CaCo-2细胞对DTX-GNPs的细胞摄取，是DTX-NPs的1.22倍，这与GLUT介导以及网格蛋白、微胞饮作用和小窝蛋白等内吞途径的增强有关。与DTX-NPs相比，G修饰显著增强了DTX-NPs在空肠和回肠的吸收，延迟了血药浓度峰值时间，延长了平均驻留时间，并提高了口服生物利用度（从43.82%提高到96.04%）。DTX的细胞摄取和口服生物利用度受G修饰率的显著影响。与DTX-NPs相比，G修饰显著降低了药物在肝脏、肺和肾脏中的分布，增加了肿瘤分布和肿瘤生长抑制率，且无明显的全身毒性。本研究证明了GZ-NPs作为DTX纳米载体在提高口服生物利用度和抗肿瘤效果方面的潜力。
