JAC Advance Access published online on November 12, 2003
Journal of Antimicrobial Chemotherapy, doi:10.1093/jac/dkg455
© 2003 by The British Society for Antimicrobial Chemotherapy
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Original article
1 L.P.B.C. (UMR CNRS 7033), Université Pierre et
Marie Curie, 4 place Jussieu, F-75252 Cedex 05, France
* Corresponding author. E-mail: francois.gaboriau{at}univ-rennes1.fr.
Received 27 March 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
Heat-induced reformulation of amphotericin B-deoxycholate
favours drug uptake by the macrophage-like cell line J774
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