Journal Article

Heat-induced reformulation of amphotericin B-deoxycholate favours drug uptake by the macrophage-like cell line J774

Monique Chéron, Caroline Petit, Jacques Bolard and François Gaboriau

in Journal of Antimicrobial Chemotherapy

Published on behalf of British Society for Antimicrobial Chemotherapy

Volume 52, issue 6, pages 904-910
Published in print December 2003 | ISSN: 0305-7453
Published online December 2003 | e-ISSN: 1460-2091 | DOI:
Heat-induced reformulation of amphotericin B-deoxycholate favours drug uptake by the macrophage-like cell line J774

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Aim: Heat treatment of deoxycholate-amphotericin B (AmB-DOC) leads to a therapeutically interesting supramolecular rearrangement (h-AmB-DOC); this reformulation improves the therapeutic index of AmB-DOC by reducing amphotericin B (AmB) toxicity in mammalian cell lines from 3- to 10-fold. Its activity in experimentally induced fungal infection in mice remains unchanged compared with AmB-DOC, whereas its activity is 2.5 times higher in Leishmania donovani-infected mice. This work investigates the in vitro mechanism that allows this improvement.

Methods: In this study, we analysed the role of serum components on the interaction of h-AmB-DOC with two cultured cell lines: murine peritoneal macrophage cells (J774) and kidney epithelial cells (LLCPK1). The methods used were: spectrophotometry for AmB uptake; MTT assay for cell viability; and lactate dehydrogenase release for membrane damage.

Results: In the presence of 10% fetal calf serum (FCS), the toxicity of AmB-DOC or h-AmB-DOC for both cell lines was null or weak. Interestingly, in J774 cells, the uptake of AmB in the form of h-AmB-DOC was much higher. In LLCPK1 cells, AmB uptake was more limited in both cases but remained higher with h-AmB-DOC. In the absence of FCS, no toxicity for either cell line was observed with h-AmB-DOC.

Conclusions: These findings confirm the importance of serum proteins in AmB biodistribution and suggest that, in vivo, the reduced toxicity and the improved antileishmanial activity of AmB-DOC after moderate heating may be the result of its increased uptake by macrophages.

Keywords: Keywords: amphotericin B, macrophages, serum, lipoproteins, toxicity

Journal Article.  3869 words.  Illustrated.

Subjects: Medical Oncology ; Critical Care

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