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JAC Advance Access originally published online on November 12, 2003
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Journal of Antimicrobial Chemotherapy (2003) 52, 904-910
© 2003 The British Society for Antimicrobial Chemotherapy

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*

L.P.B.C. (UMR CNRS 7033), Université Pierre et Marie Curie, 4 place Jussieu, F-75252 Cedex 05, France

Received 27 March 2003; returned 23 May 2003; revised 18 August 2003; accepted 21 August 2003

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: amphotericin B, macrophages, serum, lipoproteins, toxicity

* Corresponding author. Present address. Régulation des équilibres fonctionnels du foie normal et pathologique, INSERM U522, Centre Hospitalier Pontchaillou, F-35033, Rennes Cedex, France. Tel: +33-2-99-54-74-02; Fax: +33-2-99-54-01-37; E-mail: francois.gaboriau{at}univ-rennes1.fr


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