Enhanced Oral Delivery of Paclitaxel Using Acetylcysteine Functionalized Chitosan-Vitamin E Succinate Nanomicelles Based on a Mucus Bioadhesion and Penetration Mechanism

• Published in: Molecular pharmaceutics Vol. 10; no. 9; pp. 3447 - 3458
• Main Authors: Lian, He, Zhang, Tianhong, Sun, Jin, Liu, Xiaohong, Ren, Guolian, Kou, Longfa, Zhang, Youxi, Han, Xiaopeng, Ding, Wenya, Ai, Xiaoyu, Wu, Chunnuan, Li, Lin, Wang, Yongjun, Sun, Yinghua, Wang, Siling, He, Zhonggui
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 03.09.2013
• Subjects: Acetylcysteine - chemistry; Animals; Chitosan - chemistry; Drug Carriers - chemistry; Micelles; Mucus; Paclitaxel - administration & dosage; Paclitaxel - chemistry; Rats; Rats, Sprague-Dawley; Spectrometry, X-Ray Emission; Thermogravimetry; Vitamin E - chemistry; paclitaxel; mucoadhesion; chitosan-vitamin E succinate-N-acetyl-l-cysteine; permeation enhancer; oral absorption
• ISSN: 1543-8384; 1543-8392
• DOI: 10.1021/mp400282r

In addition to being a physiological protective barrier, the gastrointestinal mucosal membrane is also a primary obstacle that hinders the oral absorption of many therapeutic compounds, especially drugs with a poor permeability. In order to resolve this impasse, we have designed multifunctional nanomicelles based on the acetylcysteine functionalized chitosan-vitamin E succinate copolymer (CS-VES-NAC, CVN), which exhibit marked bioadhesion, possess the ability to penetrate mucus, and enhance the oral absorption of a hydrophobic drug with a poor penetrative profile, paclitaxel. The intestinal absorption (K a = 0.38 ± 0.04 min–1, P app = 0.059 cm·min–1) of CVN nanomicelles was greatly improved (4.5-fold) in comparison with paclitaxel solution, and CLSM (confocal laser scanning microscope) pictures also showed not only enhanced adhesion to the intestinal surface but improved accumulation within intestinal villi. The in vivo pharmacokinetics indicated that the AUC0–t (586.37 ng/mL·h) of CVN nanomicelles was markedly enhanced compared with PTX solution. In summary, the novel multifunctional CVN nanomicelles appear to be a promising nanocarrier for insoluble and poorly permeable drugs due to their high bioadhesion and permeation-enhancing capability.