Efficacy of a nanocochleate-encapsulated 3,5-diaryl-s-triazole derivative in a murine model of graft-versus-host disease.
We have previously demonstrated that the compound 3-(2-ethylphenyl)-5-(3-methoxyphenyl)-1H-1,2,4-triazole exerts immunosuppressive effects in several experimental models of autoimmunity. These results were achieved by subcutaneously administering ST1959 after dissolution in an oily vehicle, because of its poor water solubility. To circumvent this problem, we sought to determine whether nanocochleate technology could be successfully exploited to deliver ST1959 and protect mice undergoing lethal acute graft-versus-host disease (GVHD). Orally-administered encochleated ST1959 significantly protected animals from lethality, resulting in survival rates of 57% and 100% at doses of 2 and 10 mg/kg, respectively, whereas oral administration of 2 mg/kg ST1959, mixed with empty nanocochleates, was completely inactive. Increased survival was associated with diminished serum chemokine levels and donor CD8+ T cells in the spleen of ST1959-treated mice. Moreover, ST1959 treatment significantly counteracted GVHD-induced normocitic anemia by increasing hemoglobin, hematocrit, platelet, and red and white blood cell counts. Overall, these data show that orally-administered encochleated ST1959 significantly protects mice from GVHD.
Campo
Silvia
S
Sigma-Tau S.p.A Research and Development, Pomezia, Italy.
Arseni
Brunilde
B
Rossi
Stefania
S
D'Alessio
Valeria
V
Lu
Ruying
R
Ngoje
Joel
J
Ahl
Patrick L
PL
Bonitz
Susan
S
Mannino
Raphael
R
Di Mitri
Diletta
D
Battistini
Luca
L
Carminati
Paolo
P
De Santis
Rita
R
Ruggiero
Vito
V
D000284:Administration, Oral; D000740:Anemia / Q000209:etiology / Q000517:prevention & control; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects; D018925:Chemokines / Q000097:blood; D004195:Disease Models, Animal; D004339:Drug Compounding; D005260:Female; D006086:Graft vs Host Disease / Q000097:blood / Q000150:complications / Q000276:immunology / Q000517:prevention & control*; D006403:Hematologic Tests; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D053769:Nanocapsules; D013997:Time Factors; D014230:Triazoles / Q000008:administration & dosage / Q000494:pharmacology*
D018925:Chemokines; D007166:Immunosuppressive Agents; D053769:Nanocapsules; D014230:Triazoles; C030266:3-(2-ethylphenyl)-5-(3-methoxyphenyl)-1H-1,2,4-triazole