Reducing the toxicity of amphotericin B by encapsulation using methoxy poly(ethylene glycol)-b-poly(l-glutamic acid-co-l-phenylalanine)

Abstract

Amphotericin B (AmB) is an antifungal drug used for serious fungal infections and leishmaniosis. However, its clinical application is limited because of its high toxicity. To resolve this problem, herein we loaded AmB into methoxy poly(ethylene glycol)-b-poly(L-glutamic acid-co-L-phenylalanine) (mPEG-b-P(Glu-co-Phe)) nanoparticles (L-AmB) via electrostatic, hydrophobic and π–π interactions. The L-AmB has excellent stability both in PBS and in plasma and shows a remarkably reduced hemolysis (17.1 ± 1.5%, 6 h) compared to the free AmB (94.2 ± 5.3%, 6 h). The nephrotoxicity of L-AmB is significantly lower than that of free AmB. The maximum tolerance dose (MTD) of L-AmB is 3.0 mg kg⁻¹, which is 3.75 fold that of free AmB (MTD = 0.8 mg kg⁻¹). The antimicrobial activity of the conjugate was retained in vivo, with L-AmB proving to be a more protective treatment for Aspergillus fumigatus infections in mice than AmB alone. These indicate that L-AmB is a formulation of AmB with low side effects.