Success in Navigating Hurdles to Oral Delivery of a Bioactive Peptide Complement Antagonist through Use of Nanoparticles to Increase Bioavailability and In Vivo Efficacy

被引：5

作者：

Xu, Weizhi ^{[1
,2
]}

Kumar, Vinod ^{[1
]}

Cui, Cedric S. ^{[1
]}

Li, Xaria X. ^{[1
]}

Whittaker, Andrew K. ^{[2
]}

Xu, Zhi Ping ^{[2
]}

Smith, Maree T. ^{[1
]}

Woodruff, Trent M. ^{[1
]}

Han, Felicity Y. ^{[1
,2
]}

机构：

[1] Univ Queensland, Fac Med, Sch Biomed Sci, Brisbane, Qld 4072, Australia

[2] Univ Queensland, Australian Inst Bioengn & Nanotechnol, Brisbane, Qld 4072, Australia

来源：

ADVANCED THERAPEUTICS | 2022年 / 5卷 / 12期

基金：

澳大利亚国家健康与医学研究理事会;

关键词：

bioactive peptide; blood-brain barrier; C5aR1; antagonists; nanoparticles; oral bioavailability; pharmacokinetics; poly(lactic-co-glycolic) acid; BLOOD-BRAIN-BARRIER; C5A RECEPTOR ANTAGONISTS; FUTURE; INHIBITION; PARAMETERS; INTEGRITY; PMX205; MODEL;

D O I：

10.1002/adtp.202200109

中图分类号：

R9 [药学];

学科分类号：

1007 ;

摘要：

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 approximate to 25% to approximate to 50%), and therapeutic potential (approximate to 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.

引用

页数：12