PLGA nanoparticles and nanosuspensions with amphotericin B: Potent in vitro and in vivo alternatives to Fungizone and AmBisome.
This paper describes the development of poly(D,L-lactide-co-glycolide) (PLGA) nanoparticles (NPs) and nanosuspensions with the polyene antibiotic amphotericin B (AmB). The nanoformulations were prepared using nanoprecipitation and were characterised with respect to size, zeta potential, morphology, drug crystallinity and content. Standard in vitro sensitivity tests were performed on MRC-5 cells, red blood cells, Leishmania infantum promastigotes and intracellular amastigotes and the fungal species Candida albicans, Aspergillus fumigatus and Trichophyton rubrum. The in vivo efficacy was assessed and compared to that of Fungizone and AmBisome in the acute A. fumigatus mouse model at a dose of 2.5 and 5.0mg/kg AmB equivalents. The developed AmB nanoformulations were equivalently or more effective against the different Leishmania stages and axenic fungi in comparison with the free drug. The in vitro biological activity, and especially hemolytic activity, clearly depended on the preparation parameters of the different nanoformulations. Further, we demonstrated that the superior in vitro antifungal activity could be extrapolated to the in vivo situation. At equivalent dose, the optimal AmB-loaded PLGA NP was about two times and the AmB nanosuspension about four times more efficacious in reducing the total burden than AmBisome. The developed AmB nanomedicines could represent potent and cost-effective alternatives to Fungizone and AmBisome.
Laboratory of Pharmaceutical Technology and Biopharmacy, University of Antwerp, Universiteitsplein 1, B-2610 Antwerp-Wilrijk, Belgium. helene.vandeven@ua.ac.be
H
H
Van de Ven
C
C
Paulussen
P B
PB
Feijens
A
A
Matheeussen
P
P
Rombaut
P
P
Kayaert
G
G
Van den Mooter
W
W
Weyenberg
P
P
Cos
L
L
Maes
A
A
Ludwig
D000666:Amphotericin B / Q000008:administration & dosage*; D000818:Animals; D000935:Antifungal Agents / Q000008:administration & dosage* / Q000737:chemistry; D001228:Aspergillosis / Q000188:drug therapy* / Q000382:microbiology; D002460:Cell Line; D015169:Colony Count, Microbial; D004912:Erythrocytes / Q000187:drug effects / Q000473:pathology; D005260:Female; D005658:Fungi / Q000187:drug effects / Q000254:growth & development / Q000302:isolation & purification; D006461:Hemolysis / Q000187:drug effects; D006801:Humans; D007668:Kidney / Q000378:metabolism; D019344:Lactic Acid / Q000008:administration & dosage* / Q000737:chemistry; D018314:Leishmania infantum / Q000187:drug effects / Q000254:growth & development; D008081:Liposomes; D008099:Liver / Q000382:microbiology; D051379:Mice; D053758:Nanoparticles / Q000008:administration & dosage* / Q000737:chemistry; D011100:Polyglycolic Acid / Q000008:administration & dosage* / Q000737:chemistry; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D013154:Spleen / Q000382:microbiology
D000935:Antifungal Agents; D008081:Liposomes; C068538:liposomal amphotericin B; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; D000666:Amphotericin B