Substantial preclinical data have validated cyclic hexapeptide complement C5a receptor 1 antagonists (C5aRAs) that target immune cells, as novel therapies for a range of inflammatory diseases that currently have limited effective treatment options. However, like most small-molecule peptides, their poor oral bioavailability and short circulation half-life are major hurdles that have limited their clinical translation. Here, a single emulsion technique is employed to produce poly(lactic-co-glycolic) acid nanoparticles (NPs) with exceptionally high peptide C5aRA (PMX205) loading efficiency (over 50%). Strikingly, the PMX205-NPs not only facilitate prolonged release of the encapsulated PMX205 but also dramatically increase its oral bioavailability (from ≈25% to ≈50%), and therapeutic potential (≈95% inhibition of C5a induces neutrophilia in mice and maintenance of neuroprotective barrier integrity). The enhanced in vivo pharmacological activity of PMX205 in the form of NPs opens an exciting opportunity for the clinical application of peptide C5aRAs and possibly other therapeutic peptides.

中文翻译：

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通过使用纳米颗粒提高生物利用度和体内功效，成功克服口服递送生物活性肽补体拮抗剂的障碍

大量临床前数据已经验证了靶向免疫细胞的环状六肽补体 C5a 受体 1 拮抗剂 (C5aRAs)，作为目前有效治疗选择有限的一系列炎症性疾病的新疗法。然而，与大多数小分子肽一样，它们的口服生物利用度差和循环半衰期短是限制其临床转化的主要障碍。在这里，采用单一乳液技术生产聚（乳酸-co-乙醇酸纳米粒子 (NPs) 具有极高的肽 C5aRA (PMX205) 负载效率（超过 50%）。引人注目的是，PMX205-NPs 不仅促进封装的 PMX205 的延长释放，而且显着增加其口服生物利用度（从 ≈25% 到 ≈50%）和治疗潜力（≈95% 的 C5a 抑制诱导小鼠中性粒细胞增多和维持神经保护屏障完整性）。NPs 形式的 PMX205 增强的体内药理活性为肽 C5aRAs 和可能的其他治疗肽的临床应用打开了一个令人兴奋的机会。