Wheat germ agglutinin modified mixed micelles overcome the dual barrier of mucus/enterocytes for effective oral absorption of shikonin and gefitinib.

The combination of shikonin (SKN) and gefitinib (GFB) can reverse the drug resistance of lung cancer cells by affecting energy metabolism. However, the poor solubility of SKN and GFB limits their clinical application because of low bioavailability. Wheat germ agglutinin (WGA) can selectively bind to sialic acid and N-acetylglucosamine on the surfaces of microfold cells and enterocytes, and is a targeted biocompatible material. Therefore, we created a co-delivery micelle system called SKN/GFB@WGA-micelles with the intestinal targeting functions to enhance the oral absorption of SKN and GFB by promoting mucus penetration for nanoparticles via oral administration. In this study, Caco-2/HT29-MTX-E12 co-cultured cells were used to simulate a mucus/enterocyte dual-barrier environment, and HCC827/GR cells were used as a model of drug-resistant lung cancer. We aimed to evaluate the oral bioavailability and anti-tumor effect of SKN and GFB using the SKN/GFB@WGA-micelles system. In vitro and in vivo experimental results showed that WGA promoted the mucus penetration ability of micelles, significantly enhanced the uptake efficiency of enterocytes, improved the oral bioavailability of SKN and GFB, and exhibited good anti-tumor effects by reversing drug resistance. The SKN/GFB@WGA-micelles were stable in the gastrointestinal tract and provided a novel safe and effective drug delivery strategy.
Competing Interests: Declarations. Competing interests: The authors have no relevant financial or non-financial interests to disclose. Ethics approval: Male Sprague–Dawley rats weighing 180–200 g were provided by Shanghai Slack Laboratory Animal Co., Ltd. (Shanghai, China) and raised at the Shanghai University of Traditional Chinese Medicine (permit SCXK [Hu] 2017-0005) under the ethics number PZSHUTCM211213013. Male BALB/c nude mice weighing 18–20 g were provided by Vital River Laboratory Animal Technology Co., Ltd. (Beijing, China) and raised at Shanghai Southern Model Biotechnology Co., Ltd. (permit SCXK [Jing] 2016–0011) under the ethics number 2019-W9-5297. Before the experiments, all animals were raised in a controlled environment with a relative humidity of 55 ± 10% and a temperature of 23 ± 2 °C for at least one week, strictly adhering to the guidelines set forth by the Animal Ethical Committee. Consent for publication: The authors declare that all authors have been actively involved in the work leading to this paper and all take responsibility for the published work.
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