Overcoming the Mucosal Barrier: Tetraether Lipid‐Stabilized Liposomal Nanocarriers Decorated with Cell‐Penetrating Peptides Enable Oral Delivery of Vancomycin
Overcoming the Mucosal Barrier: Tetraether Lipid‐Stabilized Liposomal Nanocarriers Decorated with Cell‐Penetrating Peptides Enable Oral Delivery of Vancomycin
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克服粘膜屏障：用细胞穿透肽修饰的四醚脂质稳定脂质体纳米载体可实现万古霉素的口服递送
DOI：
10.1002/adtp.202000247
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发表时间：
2021
影响因子：
4.6
通讯作者：
... Fricker
中科院分区：
文献类型：
--
作者：
Sauter;Hertlein;Witzigmann;Laffleur;Hofhaus;... Fricker
尽管对口服肽递送有很高的医学需求，但胃肠道中的不稳定性和低粘膜渗透性仍然阻碍了这种优选的施用途径。在本文中，报告了一种脂质体纳米载体，其结合了两种自力更生的策略来克服这些递送障碍。这种方法能够设计具有协同特性的纳米载体系统：将源自古细菌的四醚脂质掺入脂质体中，以提供具有穿过胃所需的稳定性的颗粒。当所得惰性颗粒的表面用细胞穿透肽修饰时，可以实现粘膜渗透。设计的纳米载体被证明是有效的高粘膜摄取的糖肽类抗生素万古霉素在Ussing室研究。在未处理大鼠中证明了体内疗效，其中万古霉素的口服生物利用度大幅增加，万古霉素是一种已知吸收最低的药物。相比之下，施用具有单一修饰的脂质体（四醚脂质）导致显著较低的生物利用度。万古霉素在大蜡螟和全身感染小鼠模型中的抗微生物活性证明了其治疗功效。在不存在细胞毒性作用的情况下的高口服生物利用度表明，这种纳米载体递送策略通常可以促进大分子药物的口服应用。
Despite the high medical need for oral peptide delivery, instability in the gastrointestinal tract and low mucosal permeation still impede this preferred route of administration. Herein, a liposomal nanocarrier combining two self‐reliant strategies to overcome these delivery barriers is reported. This approach enables the design of a nanocarrier system with synergistic properties: tetraether lipids derived from archaea are incorporated into liposomes to provide the particles with the stability required to traverse the stomach. When the surface of the resulting inert particles is modified with cell‐penetrating peptides, mucosal permeation can be achieved. The designed nanocarrier is proven effective by the high mucosal uptake of the glycopeptide antibiotic vancomycin in Ussing chamber studies. Efficacy in vivo is demonstrated in naïve rats, where a highly increased oral bioavailability is obtained for vancomycin, a drug known to be minimally absorbed. In contrast, administration of liposomes with single modification (tetraether lipids) leads to a substantially lower bioavailability. Therapeutic efficacy is proven by the antimicrobial activity of vancomycin in aGalleria mellonellaand a systemic infection mouse model. The high oral bioavailability in absence of cytotoxic effects demonstrates that this nanocarrier delivery strategy might boost the oral application of macromolecular drugs in general.