JAC Advance Access originally published online on January 16, 2009
Journal of Antimicrobial Chemotherapy 2009 63(3):526-533; doi:10.1093/jac/dkn539
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Original research |
Amphotericin B in poly(lactic-co-glycolic acid) (PLGA) and dimercaptosuccinic acid (DMSA) nanoparticles against paracoccidioidomycosis
1 Biological Sciences Institute, Universidade de Brasília, Brasília DF 70910-900, Brazil 2 Genomic Science and Biotechnology, Universidade Católica de Brasília, Brasília DF 70790-160, Brazil 3 Chemistry Institute, Universidade de São Paulo, Ribeirão Preto SP 14040-901, Brazil 4 Faculty of Agronomy and Veterinary Medicine, Universidade de Brasília, Brasília DF 70910-900, Brazil 5 Physics Institute, Universidade de Brasília, Brasília DF 70910-900, Brazil
Received 3 July 2008; returned 3 October 2008; revised 5 December 2008; accepted 12 December 2008
* Corresponding author. Universidade de Brasília, Departamento de Biologia Celular, Laboratório de Biologia Molecular, Campus Darcy Ribeiro, Asa Norte, Brasília DF 70910-900, Brazil. Tel: +55-61-33072423; Fax: +55-61-33498411; E-mail: msueliunb{at}gmail.com
Objectives: The present study reports on the preparation and testing of a desoxycholate amphotericin B (D-AMB) sustained delivery system based on poly(lactic-co-glycolic acid) (PLGA) and dimercaptosuccinic acid (DMSA) polymeric blends (Nano-D-AMB) aimed at reducing the number of AMB administrations required to treat mycosis.
Methods: BALB/c mice were infected with the yeast Paracoccidioides brasiliensis intravenously to mimic the chronic form of paracoccidioidomycosis. At 30 days post-infection, the animals were treated with Nano-D-AMB [6 mg/kg of encapsulated D-AMB, intraperitoneally (ip), interval of 72 h] or D-AMB (2 mg/kg, ip, interval of 24 h). Drug efficacy was investigated by the fungal burden recovery from tissues. Toxicity was assessed by renal and hepatic biochemical parameters, physical appearance of the animals and haematological investigation. The control groups used were non-infected and the infected mice mock treated with PBS.
Results: Nano-D-AMB presented results comparable to free D-AMB, with a marked antifungal efficacy. The Nano-D-AMB-treated group presented lower loss of body weight and absence of stress sign (piloerection and hypotrichosis) observed after D-AMB treatment. No renal [blood urea nitrogen (BUN), creatinine] or hepatic (pyruvic and oxalacetic glutamic transaminases) biochemical abnormalities were found. The micronucleus assay showed no significant differences in both the micronucleus frequency and percentage of polychromatic erythrocytes for Nano-D-AMB, indicating the absence of genotoxicity and cytotoxic effects.
Conclusions: The D-AMB-coated PLGA–DMSA nanoparticle showed antifungal efficacy, fewer undesirable effects and a favourable extended dosing interval. Nano-D-AMB comprises an AMB formulation able to lessen the number of drug administrations. Further studies would elucidate whether Nano-D-AMB would be useful to treat systemic fungal infections such as paracoccidioidomycosis, candidiasis, aspergillosis and cryptococcosis.
Keywords: nanobiotechnology , antifungal , polymers , drug delivery