Colon-targeted complement C5a₁ receptor inhibition using pH-sensitive nanoparticles ameliorates experimental colitis

The complement system is associated with inflammatory bowel disease (IBD) pathology. Complement activation induces C5a production, which signals through the C5a₁ receptor (C5aR1) to drive inflammatory responses that may underlie IBD.

We examined mucosal biopsies from ulcerative colitis patients and identified C5a₁ receptor up-regulated in active lesions, supporting the C5a₁ receptor as a target for therapeutic intervention. Cyclic peptide C5a₁ receptor antagonists such as PMX205 are orally efficacious in preclinical colitis models; however, their clinical application may be limited by rapid metabolism. We therefore encapsulated PMX205 within pH-sensitive polymers to target drug for colon delivery following oral administration.

PMX205 nanoparticles were non-toxic and released bioactive PMX205 in simulated colon fluid. In vivo imaging of Cy5-labelled nanoparticles demonstrated rapid entry and persistence in the mouse colon for up to 48 h. Next, we utilised the dextran sodium sulphate-induced colitis model to examine efficacy of the C5a₁ receptor-antagonist formulation. We show that oral administration of PMX205 nanoparticles every 2 days from symptom onset significantly mitigated weight loss, clinical illness, colon length reduction and epithelial damage to a similar degree as C5a₁ receptor^-/- mice. Notably, unformulated PMX205 was markedly less effective in this dosing regimen.

This novel colon-targeted formulation therefore offers a potent therapeutic strategy for translating C5a₁ receptor antagonists for IBD conditions such as ulcerative colitis.