title: N-(2-hydroxypropyl)methacrylamide-amphotericin B (HPMA-AmB) copolymer conjugates as antileishmanial agents.
abstract: Leishmaniasis is a major health problem in many parts of the world, caused by various species of Leishmania. 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 conjugates 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)) values of 0.03 microg/mL AmB equivalent against Leishmania donovani amastigotes in PEMs and BMMs and an EC(50) of 0.57 microg/mL AmB equivalent against L. donovani in THP-1 cells. This activity was comparable with free AmB (EC(50)=0.03-0.07 microg/mL against L. donovani in PEMs and BMMs and 0.24-0.42 microg/mL against amastigotes in THP-1 cells) and Fungizone (EC(50)=0.04-0.07 microg/mL against amastigotes in PEMs). Conjugates also showed potent in vivo activity with ca. 50% inhibition of parasite burden at 1mg/kg body weight.
authors.affiliation: Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee, Sir James Black Centre, Dundee DD1 5EH, UK.
authors.forename: Salvatore
authors.initials: S
authors.lastname: Nicoletti
authors.forename: Karin
authors.initials: K
authors.lastname: Seifert
authors.forename: Ian H
authors.initials: IH
authors.lastname: Gilbert
mesh_terms: D000666:Amphotericin B / Q000494:pharmacology*; D000818:Animals; D000981:Antiprotozoal Agents / Q000494:pharmacology*; D002460:Cell Line; D002478:Cells, Cultured; D020128:Inhibitory Concentration 50; D007893:Leishmania donovani / Q000187:drug effects*; D008264:Macrophages / Q000469:parasitology; D008689:Methacrylates / Q000494:pharmacology*; D051379:Mice; D011108:Polymers / Q000138:chemical synthesis / Q000494:pharmacology*
chemical_list: D000981:Antiprotozoal Agents; D008689:Methacrylates; D011108:Polymers; D000666:Amphotericin B; C032802:hydroxypropyl methacrylate