Amphotericin B in poly(lactic-co-glycolic acid) (PLGA) and dimercaptosuccinic acid (DMSA) nanoparticles against paracoccidioidomycosis.
OBJECTIVE
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.
Amaral
André C
AC
Biological Sciences Institute, Universidade de Brasília, Brasília DF 70910-900, Brazil.
Bocca
Anamélia L
AL
Ribeiro
Alice M
AM
Nunes
Janayna
J
Peixoto
Danielle L G
DL
Simioni
Andreza R
AR
Primo
Fernando L
FL
Lacava
Zulmira G M
ZG
Bentes
Ricardo
R
Titze-de-Almeida
Ricardo
R
Tedesco
Antonio C
AC
Morais
Paulo C
PC
Felipe
Maria Sueli S
MS
D000666:Amphotericin B / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D000818:Animals; D001835:Body Weight; D001853:Bone Marrow / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D015169:Colony Count, Microbial; D003840:Deoxycholic Acid / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D004338:Drug Combinations; D005260:Female; D007668:Kidney / Q000187:drug effects / Q000502:physiology; D019344:Lactic Acid / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D008099:Liver / Q000187:drug effects / Q000382:microbiology / Q000502:physiology; D008168:Lung / Q000382:microbiology / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D053758:Nanoparticles / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D010228:Paracoccidioides / Q000187:drug effects*; D010229:Paracoccidioidomycosis / Q000188:drug therapy*; D011100:Polyglycolic Acid / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D004113:Succimer / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D016896:Treatment Outcome
D004338:Drug Combinations; D003840:Deoxycholic Acid; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; D000666:Amphotericin B; C059765:amphotericin B, deoxycholate drug combination; D004113:Succimer