Positional Isomerism Influences pH-Responsive Release Kinetics in Methacryloyloxybenzoic Acid Polymeric Prodrugs

Polymeric prodrugs capable of pH-responsive drug release are promising platforms for localized and controlled drug delivery. While positional isomerism is known to affect the physicochemical properties of MBA polymers, a comparative evaluation of its effect on drug release kinetics and biological activity is lacking. In this study, three methacryloyloxybenzoic acid (MBA) polymeric prodrugs derived from ortho-, meta-, and para-hydroxybenzoic acid (HBA) isomers were synthesized to comparatively evaluate the influence of substituent position on HBA release profiles and biological performance. The o-, m-, and p-MBA monomers and their corresponding polymers were synthesized and structurally characterized by FTIR-ATR, 1H-NMR and UV-Vis spectroscopy. HBA release profiles investigated under physiologically relevant pH conditions revealed markedly distinct release profiles among the polymers. Poly(o-MBA) exhibited rapid and near-complete release at intestinal and physiological pH, poly(p-MBA) showed sustained and intermediate release, and poly(m-MBA) displayed minimal release under all tested conditions, indicating that substituent position strongly influences HBA release, likely through differences in ester accessibility and hydrolytic susceptibility. The polymers also exhibited planktonic antibacterial activity against Escherichia coli, Staphylococcus aureus, and Pseudomonas aeruginosa, while BALB/3T3 fibroblast viability remained above 70% at a concentration of 0.5 mg/mL. These findings indicate that positional isomerism is a key structural determinant of pH-responsive release kinetics in MBA polymers and highlight their potential as versatile platforms for pharmaceutical and biomedical applications, particularly in the design of localized and controlled drug delivery systems.