Water-soluble amphotericin B?polyvinylpyrrolidone complexes with maintained antifungal activity against Candida spp. and Aspergillus spp. and reduced haemolytic and cytotoxic effects - Toxicity Limits

Water-soluble amphotericin B?polyvinylpyrrolidone complexes with maintained antifungal activity against Candida spp. and Aspergillus spp. and reduced haemolytic and cytotoxic effects
16 November 2005
Ekatherina Charvalos1,2, Manolis N. Tzatzarakis3, Fran?oise Van Bambeke2, Paul M. Tulkens2, Aristidis M. Tsatsakis3, George N. Tzanakakis3 and Marie-Paule Mingeot-Leclercq2,*
Journal of Antimicrobial Chemotherapy
Objectives: Poor solubility and toxicity severely hinder the clinical use of amphotericin B (AmB), in spite of its attractive chemotherapeutic properties. Water-soluble complexes of AmB and polyvinylpyrrolidone (AmB?PVP) could display lower cytotoxicity while maintaining antifungal activity.
Methods: AmB?PVP [with PVP of 10, 24 and 40 kDa (AC1, AC2 and AC4)] were compared with free AmB for (i) activity against Candida spp. (five albicans; nine non-albicans) and Aspergillus spp. (four strains), (ii) haemolysis of sheep red blood cells, and (iii) release of lactate dehydrogenase from J774 macrophages [with further comparison with free PVP and a liposomal formulation of amphotericin (AmBisome?)].
Results: MICs and MFCs of AC1, AC2 and AC4 against Candida spp. and of AC2 and AC4 against Aspergillus spp. were similar to those of AmB (and even lower for some Candida strains). Killing kinetics (24 h) were also similar. Haemolytic activity of AC2 and AC4 was 2-fold lower than that of free AmB. Cytotoxicity of AC2 towards J774 macrophages was 8-fold lower, and that of AC4 5-fold lower than that of AmB and not significantly different from that of AmBisome?. The lower cytotoxicity of AC2, AC4 was correlated with a lower cellular accumulation of amphotericin. Spectroscopic analysis shows that the lower toxicity of AmB?PVP was not owing to significant change in the monomeric/polymeric forms ratio of the drug.
Conclusions: AmB?PVP complexes compared favourably with AmB for antifungal activity, were less haemolytic and cytotoxic than AmB, and show a similar cytotoxicity profile to AmBisome?.
Keywords: J774 macrophages , red blood cells , accumulation , lactate dehydrogenase , AmBisome?
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