Efficacy of CG(3)R(6)TAT nanoparticles self-assembled from a novel antimicrobial peptide for the treatment of Candida albicans meningitis in rabbits.
BACKGROUND
Candidal meningitis is a common clinical manifestation of invasive candidiasis in neonates. The aim of this study was to evaluate the in vivo antifungal efficacy of CG(3)R(6)TAT nanoparticles, novel core-shell structures self-assembled from cationic antimicrobial peptides, in a rabbit model of candidal meningitis.


METHODS
In vitro activity of CG(3)R(6)TAT nanoparticles against Candida albicans was assessed by determining the minimum inhibitory concentration and kill-time curves. In vivo, intravenous treatment with CG(3)R(6)TAT nanoparticles (n = 6; 0.25 mg/kg/day) or fluconazole (n = 6; 100 mg/kg/day) began 3 days after infection and continued for 11 consecutive days; the efficacy was assessed following 11 days of treatment by yeast counting in cerebrospinal fluid (CSF), the leukocyte concentrations in CSF and the histopathology of brain parenchyma.


RESULTS
At a concentration three times higher than the minimum inhibitory concentration (8.1 μmol/l), the nanoparticles complete- ly sterilized C. albicans after 5 h of incubation. In addition, there was a significant reduction in fungal counts and leukocyte concentrations in the CSF from rabbits treated with CG(3)R(6)TAT nanoparticles or fluconazole versus those from untreated control rabbits (p < 0.05, ANCOVA). The median number of days of treatment required to sterilize CSF cultures was 8.5 days for CG(3)R(6)TAT nanoparticle therapy (p = 0.022, vs. control) and 9.7 days for fluconazole therapy (p > 0.05, vs. control). The histopathologic severity of rabbits was significantly attenuated after CG(3)R(6)TAT treatment (p = 0.001, vs. control).


CONCLUSIONS
This study suggests that CG(3)R(6)TAT nanoparticles may be a promising therapeutic agent for candidal meningitis.
State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, PR China.
Kaijin
K
Xu
Huaying
H
Wang
Lihong
L
Liu
Wei
W
Xu
Jifang
J
Sheng
Weimin
W
Fan
Yi-Yan
YY
Yang
Lanjuan
L
Li
D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000008:administration & dosage* / Q000494:pharmacology; D002176:Candida albicans / Q000187:drug effects*; D002177:Candidiasis / Q000188:drug therapy* / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D008297:Male; D016921:Meningitis, Fungal / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D008813:Mice, Inbred ICR; D008826:Microbial Sensitivity Tests; D053758:Nanoparticles / Q000008:administration & dosage* / Q000737:chemistry; D011817:Rabbits
D023181:Antimicrobial Cationic Peptides