H2O2-responsive mPEG-2-mercapto-1-methylimidazole prodrug nanosystem for enhanced therapeutic efficacy against hyperthyroidism

Abstract

Methimazole (MMI) is a widely used anti-hyperthyroidism drug. To improve the therapeutic effect of MMI and reduce its side effects on thyroid and liver, a new hydrogen peroxide (H₂O₂) responsive prodrug nanosystem for the therapy of hyperthyroidism was constructed via thiol-Michael addition between MMI and propiolic acid and followed by esterification with polyethylene glycol monomethyl ether (mPEG) and then ultrasonic dispersion. The α, β-unsaturated C = C double bond (−SCH = CHCOO–) in the prodrug could be cleaved by high concentrations of H₂O₂ (0.3 mM or above) to release MMI, which was verified by ¹H nuclear magnetic resonance (¹H NMR) and electrospray ionization mass spectrometry (ESI MS). Esterase and weakly acidic pH stimulation could also enhance the drug release. The cell experiment demonstrated that the nanoparticles (NPs) could significantly elevate diseased cell-selective drug release and the released amount could be adjusted according to the level of H₂O₂ in the diseased cells. In addition, due to the synergy of H₂O₂-stimulated drug release and H₂O₂-deprivation, the NPs showed a more noticeable inhibition effect on lactoperoxidase (LPO) and were more effective in hyperthyroidism treatment than MMI. More importantly, in vitro cell culture studies and in vivo evaluations demonstrated that the system had markedly reduced thyroid toxicity and hepatotoxicity compared with MMI. It also possessed a prolonged circulating half-life, and could significantly reduce the oxidative damage of thyroid and liver tissues caused by hyperthyroidism. Thus, this nanosystem provides a novel strategy for improving the therapeutic efficacy of MMI against hyperthyroidism.