Thermo-sensitive polyethylene glycol-based hydrogel for controlled peptide decoy release: a novel therapy for bladder fibrosis in male mice with partial outlet obstruction

Abstract

A novel thermo-sensitive polyethylene glycol (PEG)-based hydrogel formulation combining KCF18—a peptide decoy that inhibits receptor binding of tumor necrosis factor-α, interleukin-1β, and interleukin-6—was developed to enable controlled release of KCF18 for the treatment of bladder fibrosis resulting from partial bladder outlet obstruction (BOO). The hydrogel, composed of methyl PEG–poly(lactic-co-glycolic acid) (mPEG–PLGA, diblock copolymer) and PLGA–PEG–PLGA (triblock copolymer) at a 5:5 wt ratio, was mixed with KCF18 (1.5 mg/kg) to produce a 20 % KCF-hydrogel solution (100 μL). Pharmacokinetic analysis revealed a peak plasma KCF18 concentration on Day 1, sustained through Day 2, with an estimated half-life of 3.5 days. In an adult male mouse model of BOO-induced bladder fibrosis, weekly subcutaneous administration of the KCF-hydrogel for seven weeks improved bladder function, reduced fibrosis, and downregulated transforming growth factor-β and fibrosis-related markers, including collagen I, vimentin, and α-smooth muscle actin. Therapeutic benefits were observed when treatment was initiated during the early or mid-disease stages (Day 7 or 14 post-BOO), but not in the late stage (Day 28). This thermo-sensitive PEG-based hydrogel enables controlled KCF18 release, offering a promising therapeutic strategy for BOO-induced bladder fibrosis when administered in the early or mid-disease stages.