Coating of PLA-nanoparticles with cyclic, arginine-rich cell penetrating peptides enables oral delivery of liraglutide.
Coating of PLA-nanoparticles with cyclic, arginine-rich cell penetrating peptides enables oral delivery of liraglutide.
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DOI：
10.1016/j.nano.2019.102132
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发表时间：
2019-11
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影响因子：
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通讯作者：
P. Uhl;C. Grundmann;M. Sauter;P. Storck;A. Tursch;S. Özbek;K. Leotta;R. Roth;D. Witzigmann;J. Kulkarni;V. Fidelj;C. Kleist;P. Cullis;G. Fricker;W. Mier
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文献类型：
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作者：
P. Uhl;C. Grundmann;M. Sauter;P. Storck;A. Tursch;S. Özbek;K. Leotta;R. Roth;D. Witzigmann;J. Kulkarni;V. Fidelj;C. Kleist;P. Cullis;G. Fricker;W. Mier
直到今天，由于多肽药物在胃肠道中的不稳定性和低粘膜穿透性，口服给药受到阻碍。为了克服这些障碍，PLA（聚乳酸）纳米颗粒被包裹了一个环状的、富含聚精氨酸的细胞穿透肽（环状R9-CPP）。这些表面修饰的纳米颗粒显示出与标准pla纳米颗粒相当的尺寸和多分散性指数。zeta电位显著增加，表明cpp成功偶联到纳米颗粒表面。低温电镜图证实了改性纳米颗粒的大小和形态。利拉鲁肽具有较高的包封率。体外测试使用Caco-2细胞显示高活力，表明这种新制剂的耐受性。通过Caco-2结合和摄取试验证明了粘膜结合和渗透的强烈增强。在Wistar大鼠中，新型纳米颗粒显示利拉鲁肽的口服生物利用度显著提高4.5倍，显示出肽药物口服递送的巨大潜力。
Until today, the oral delivery of peptide drugs is hampered due to their instability in the gastrointestinal tract and low mucosal penetration. To overcome these hurdles, PLA (polylactide acid)-nanoparticles were coated with a cyclic, polyarginine-rich, cell penetrating peptide (cyclic R9-CPP). These surface-modified nanoparticles showed a size and polydispersity index comparable to standard PLA-nanoparticles. The zeta potential showed a significant increase indicating successful CPP-coupling to the surface of the nanoparticles. Cryo-EM micrographs confirmed the appropriate size and morphology of the modified nanoparticles. A high encapsulation efficiency of liraglutide could be achieved. In vitro tests using Caco-2 cells showed high viability indicating the tolerability of this novel formulation. A strongly enhanced mucosal binding and penetration was demonstrated by a Caco-2 binding and uptake assay. In Wistar rats, the novel nanoparticles showed a substantial, 4.5-fold increase in the oral bioavailability of liraglutide revealing great potential for the oral delivery of peptide drugs.