N-(2-hydroxypropyl)methacrylamide-amphotericin B (HPMA-AmB) copolymer conjugates as antileishmanial agents

摘要

Leishmaniasis is a major health problem in many parts of the world, caused by various species of Leish_mania. Amastigotes are the clinically relevant form of the parasite in the human host and reside in the parasitophorous vacuole within macrophages. Polymer-drug conjugates have been used for lysosomotropic drug delivery and have already shown potential in anticancer and antileishmanial chemotherapy. We synthesised N-(2-hydroxypropyl)methacrylamide-amphotericin B (HPMA-AmB) copolymer con_jugates in which the AmB was attached to the polymer through a degradable GlyPheLeuGly linker. Antileishmanial activity was assessed in vitro against intracellular amastigotes in host macrophages [murine peritoneal exudate macrophages (PEMs), murine bone marrow-derived macrophages (BMMs) and differentiated THP-1 cells]. The most potent copolymers had 50% effective concentration (EC_(50)) val_ues of 0.03 _g/mL AmB equivalent against Leishmania donovani amastigotes in PEMs and BMMs and an EC50 of 0.57 _g/mL AmB equivalent against L. donovani in THP-1 cells. This activity was comparable with free AmB (EC_(50) =0.03-0.07 _g/mL against L. donovani in PEMs and BMMs and 0.24-0.42 _g/mL against amastigotes in THP-1 cells) and Fungizone~_ (EC_(50) = 0.04-0.07 _g/mL against amastigotes in PEMs). Conjugates also showed potent in vivo activity with ca. 50% inhibition of parasite burden at 1 mg/kg body weight.