Accelerated Mucopermeation and Penetration of the Polypeptide Antibiotic Colistin via Ionic Complexation with Polyphosphazene Carriers

Abstract The mucus barrier plays a vital protective role for nonkeratinized epithelia in the body, yet its complex structure poses a significant obstacle to effective noninvasive, topical drug delivery. Here, we synthesize chain-end-labeled poly(α-glutamic acid) (PGA) and poly[di(carboxylatophenoxy)phosphazene] (PCPP) and use an artificial pulmonary mucus to evaluate the mucopermeation of the polymers compared with the established mucus-penetrating polymer poly(ethylene glycol) (PEG). The biodegradable polyacids PGA and PCPP exhibited mucus permeability similar to that of the biopersistent PEG, even at high polymer concentrations (up to 50 mg/mL). To enable drug loading, PGA and PCPP were further examined for their ability to electrostatically complex the antibiotic lipopeptide Colistin (Polymyxin E) at different polymer-to-Colistin ratios. Colistin binding studies in PBS confirmed effective encapsulation by both polymers with PCPP-Colistin complexes exhibiting the highest stability. Mucopermeation studies of the polymer-Colistin complexes revealed enhanced Colistin mucopermeation for both polyacids, with an enhanced effect observed for PCPP complexes. Furthermore, the broth microdilution assay revealed no differences in the minimum inhibitory concentrations (MICs) of Colistin, PGA-Colistin, or PCPP-Colistin. Overall, PCPP showed significantly superior performance due to its higher Colistin encapsulation efficiency, attributed to its unique chemical structure, thereby highlighting its potential as a biodegradable mucus-penetrating carrier for cationic therapeutic peptides.