Henan Key Laboratory for Pharmacology of Liver Diseases, Institute of Medical and Pharmaceutical Sciences, Zhengzhou University, No. 40 Daxue Road, Zhengzhou, Henan Province 450052, China.
Henan Key Laboratory of Targeting Therapy and Diagnosis for Critical Diseases, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, Henan Province 450001, China; Collaborative Innovation Center of New Drug Research and Safety Evaluation, Zhengzhou 450001, Henan Province, China.
J Control Release. 2022 Jan;341:31-43. doi: 10.1016/j.jconrel.2021.11.020. Epub 2021 Nov 16.
Oral protein drug delivery using nano-based systems remains challenging, as contradictory surface properties are required for efficient navigation through the intestinal mucus and epithelium barriers. Therefore, new nanoplatforms with tunable surface properties in vivo are urgently needed. Inspired by the slightly acidic microclimate of the jejunal epithelial surface, we report a novel epithelium microenvironment-adaptive nanoplatform that undergoes a hydrophilicity-hydrophobicity transition at the epithelial surface. First, we synthesized and characterized a biodegradable copolymer consisting of PEG and PLGA building blocks linked by a hydrazone bond (PLGA-Hyd-PEG) to fabricate the pH-sensitive core-shell architecture of an oral insulin system. Then we loaded the system as a freeze-dried powder into enteric-coated capsules. PLGA-Hyd-PEG nanoparticles showed excellent drug protection and rapid mucus penetration owing to the high stability of the PEG coating in jejunal fluid. In the acidic microenvironment of the jejunal epithelial surface (pH ~5.5), PEG was rapidly cleaved and the hydrazone bond was hydrolyzed, converting the nanoparticle surface from hydrophilic to hydrophobic, thereby facilitating internalization into cells. Pharmacodynamic studies showed that PLGA-Hyd-PEG nanoparticles resulted in significant decrease in blood glucose level after intrajejunal administration in both normal and diabetic rats relative to control nanoparticles. In addition, enteric-coated capsules containing PLGA-Hyd-PEG nanoparticles reduced blood glucose by 35% for up to 10 h after oral administration to diabetic rats. Our findings provide a new strategy for regulating the surface properties of nanoparticles for efficient oral drug delivery.
利用基于纳米的系统进行口服蛋白药物传递仍然具有挑战性，因为需要具有相反表面特性的纳米载体才能有效地穿过肠道黏液和上皮屏障。因此，迫切需要具有体内可调表面特性的新型纳米平台。受空肠上皮表面微酸性微环境的启发，我们报告了一种新型上皮微环境适应性纳米平台，该纳米平台在上皮表面经历亲水性-疏水性转变。首先，我们合成并表征了一种由 PEG 和 PLGA 结构单元通过腙键连接而成的可生物降解共聚物（PLGA-Hyd-PEG），以构建口服胰岛素系统的 pH 敏感核壳结构。然后，我们将该系统作为冻干粉末载入肠溶胶囊中。PLGA-Hyd-PEG 纳米粒由于在空肠液中具有较高的 PEG 稳定性，因此表现出出色的药物保护和快速的黏液穿透能力。在空肠上皮表面的酸性微环境（pH~5.5）下，PEG 迅速被切断，腙键被水解，纳米粒表面从亲水转变为疏水，从而促进了细胞内化。药效学研究表明，与对照纳米粒相比，PLGA-Hyd-PEG 纳米粒经空肠内给药后，在正常和糖尿病大鼠体内均能显著降低血糖水平。此外，肠溶胶囊中含有 PLGA-Hyd-PEG 纳米粒，可使糖尿病大鼠口服后长达 10 小时内降低 35%的血糖。我们的研究结果为有效口服药物传递提供了一种调节纳米粒表面特性的新策略。
