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JAC Advance Access originally published online on April 24, 2006
Journal of Antimicrobial Chemotherapy 2006 58(1):66-75; doi:10.1093/jac/dkl153
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© The Author 2006. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

Lipid-covered drug particles: combined action of dioctadecyldimethylammonium bromide and amphotericin B or miconazole

Nilton Lincopan and Ana M. Carmona-Ribeiro*

Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo CP 26077, Avenida Lineu Prestes 748–Butantã, CEP 05513-970, São Paulo-SP, Brazil

Received 8 February 2006; returned 13 March 2006; revised 27 March 2006; accepted 30 March 2006

*Corresponding author. Tel: +55-11-30912164; Fax: +55-11-38155579; E-mail: mcribeir{at}iq.usp.br

Objectives: Coverage of antifungal drug particles (miconazole and amphotericin B) with cationic lipid and evaluation of a synergistic action between lipid and drug.

Methods: Miconazole and amphotericin B were mixed with cationic bilayer fragments (BF) of dioctadecyldimethylammonium bromide (DODAB) at extreme drug to lipid molar proportions (P). Light scattering for particle sizing and zeta-potential analysis evaluated effects of cationic lipid on drug particle size and charge. Colony counts evaluated viability of Candida spp. and Cryptococcus neoformans over a range of P.

Results: BF loading capacity for monomeric amphotericin B is 0.1 mM amphotericin B at 2 mM DODAB (P = 1:20). Above this low P, amphotericin B aggregates in the dispersion. At high P, addition of chaotropic K2HPO4 (0.2–2 mM) converts miconazole or amphotericin B aggregates into negatively charged particles with affinity for cationic lipid, which then surrounds each drug particle with a cationic layer. The combined in vitro action of lipid-covered drug particles against Candida and C. neoformans depends on P and interaction time. DODAB by itself kills C. neoformans and Candida at 2 and 2 to >250 mg/L minimal fungicidal concentration (MFC). In combination, over the first hour, fungicidal activity is due to DODAB with lipid capsules retarding drug action. At 48 h interaction time and 104 cfu/mL, MFC (mg/L) against Candida albicans is reduced from 4 to 1 amphotericin B (at 2 DODAB), and from 8 to 1 miconazole (at 1 DODAB).

Conclusions: DODAB may be a suitable candidate for use in combination with miconazole for antifungal therapy.

Keywords: antifungal activity , synergism , chaotropic effect , bilayer-covered drug particle


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