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Biomimetic Viruslike and Charge Reversible Nanoparticles to Sequentially Overcome Mucus and Epithelial Barriers for Oral Insulin Delivery
ACS Applied Materials & Interfaces ( IF 8.3 ) Pub Date : 2018-03-05 00:00:00 , DOI: 10.1021/acsami.7b16524 Jiawei Wu 1 , Yaxian Zheng 1 , Min Liu 1 , Wei Shan 1 , Zhirong Zhang 1 , Yuan Huang 1
ACS Applied Materials & Interfaces ( IF 8.3 ) Pub Date : 2018-03-05 00:00:00 , DOI: 10.1021/acsami.7b16524 Jiawei Wu 1 , Yaxian Zheng 1 , Min Liu 1 , Wei Shan 1 , Zhirong Zhang 1 , Yuan Huang 1
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Nanoparticles (NPs) for oral delivery of peptide/protein drugs are largely limited due to the coexistence of intestinal mucus and epithelial barriers. Sequentially overcoming these two barriers is intractable for a single nanovehicle due to the requirements of different or even contradictory surface properties of NPs. To solve this dilemma, a mucus-penetrating virus-inspired biomimetic NP with charge reversal ability (P-R8-Pho NPs) was developed by densely coating poly(lactic-co-glycolic acid) NPs with cationic octa-arginine (R8) peptide and specific anionic phosphoserine (Pho). The small size (81.81 nm) and viruslike neutral charged surface (−2.39 mV) of the biomimetic NPs achieved rapid mucus penetration, which was almost equal to that of the conventional PEGylated mucus-penetrating nanoparticles. The hydrolysis of surface-anchored anionic Pho was achieved by intestinal alkaline phosphatase, which led to the turnover of ζ potential to positive (+7.37 mV). This timely charge reversal behavior also exposed cationic R8 peptide and induced efficient cell-penetrating peptide (CPP)-mediated cellular uptake and transepithelial transport on Caco-2/E12 cocultured cell model. What’s more, P-R8-Pho NPs showed excellent stability in simulated gastrointestinal conditions and enhanced absorption in intestine in vivo. Finally, oral administration of insulin-loaded P-R8-Pho NPs enabled to induce a preferable hypoglycemic effect and a 1.9-fold higher oral bioavailability was achieved compared with single CPP-modified P-R8 NPs on diabetic rats. The combinative application of biomimetic mucus-penetrating strategy and enzyme-responsive charge reversal strategy in a single nanovehicle could sequentially overcome mucus and epithelial barriers, thus showing great potential for the oral peptide/protein delivery.
中文翻译：
仿生病毒样和电荷可逆纳米粒子顺序克服粘液和上皮屏障的口服胰岛素传递。
由于肠粘液和上皮屏障的共存，用于口服肽/蛋白质药物的纳米颗粒（NPs）受到很大限制。由于要求纳米颗粒具有不同甚至相互矛盾的表面特性，对于单个纳米车辆而言，相继克服这两个障碍是很棘手的。为了解决这一难题，粘液穿透病毒启发仿生NP与电荷反转能力（P-R8-来自Pho的NP）通过密集地涂布聚显影（乳酸-共-乙醇酸）NPs与阳离子八-精氨酸（R8）肽和特定的阴离子磷酸丝氨酸（Pho）。仿生NP的小尺寸（81.81 nm）和病毒样的中性带电表面（−2.39 mV）实现了快速的粘液渗透，这几乎与常规的PEG化粘液穿透纳米颗粒相等。表面固定的阴离子Pho的水解是通过肠碱性磷酸酶实现的，这导致ζ电位转换为正值（+7.37 mV）。这种及时的电荷逆转行为还暴露了阳离子R8肽，并在Caco-2 / E12共培养的细胞模型上诱导了有效的细胞穿透肽（CPP）介导的细胞摄取和跨上皮运输。此外，P-R8-Pho NP在模拟胃肠道条件下表现出出色的稳定性，并在体内肠道吸收增强。最后，与单次CPP修饰的P-R8 NP相比，口服给予胰岛素的P-R8-Pho NPs可以诱导较好的降血糖作用，口服生物利用度比糖尿病大鼠高1.9倍。仿生粘液穿透策略和酶反应性电荷逆转策略在单个纳米车辆中的组合应用可以依次克服粘液和上皮屏障，因此显示出口服肽/蛋白质递送的巨大潜力。
更新日期：2018-03-05
中文翻译：
仿生病毒样和电荷可逆纳米粒子顺序克服粘液和上皮屏障的口服胰岛素传递。
由于肠粘液和上皮屏障的共存，用于口服肽/蛋白质药物的纳米颗粒（NPs）受到很大限制。由于要求纳米颗粒具有不同甚至相互矛盾的表面特性，对于单个纳米车辆而言，相继克服这两个障碍是很棘手的。为了解决这一难题，粘液穿透病毒启发仿生NP与电荷反转能力（P-R8-来自Pho的NP）通过密集地涂布聚显影（乳酸-共-乙醇酸）NPs与阳离子八-精氨酸（R8）肽和特定的阴离子磷酸丝氨酸（Pho）。仿生NP的小尺寸（81.81 nm）和病毒样的中性带电表面（−2.39 mV）实现了快速的粘液渗透，这几乎与常规的PEG化粘液穿透纳米颗粒相等。表面固定的阴离子Pho的水解是通过肠碱性磷酸酶实现的，这导致ζ电位转换为正值（+7.37 mV）。这种及时的电荷逆转行为还暴露了阳离子R8肽，并在Caco-2 / E12共培养的细胞模型上诱导了有效的细胞穿透肽（CPP）介导的细胞摄取和跨上皮运输。此外，P-R8-Pho NP在模拟胃肠道条件下表现出出色的稳定性，并在体内肠道吸收增强。最后，与单次CPP修饰的P-R8 NP相比，口服给予胰岛素的P-R8-Pho NPs可以诱导较好的降血糖作用，口服生物利用度比糖尿病大鼠高1.9倍。仿生粘液穿透策略和酶反应性电荷逆转策略在单个纳米车辆中的组合应用可以依次克服粘液和上皮屏障，因此显示出口服肽/蛋白质递送的巨大潜力。
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