Benznidazole-loaded multiparticulate drug delivery systems improve experimental Chagas disease pharmacotherapy

GARCÍA, MÓNICA C; EBERHARDT, NATALIA; SANMARCO, LILIANA; PONCE, NICOLÁS; JIMENEZ KAIRUZ, ALVARO; AOKI, MARÍA P.

Congreso; Reunión Conjunta de Sociedades de Biociencias; 2017

Benznidazole (BZ) is the selected drug for Chagas disease treatment, showing a parasitological cure rate of 60-80% during the acute phase. High frequency of administration, long-term treatment, and several side effects are issues that negatively affect therapeutic success. We have developed BZ-loaded multiparticulate drug delivery systems (MDDS) that showed modified release of BZ. These pharmaceutical strategies would reduce side effects of BZ and/or allow reducing its frequency of administration. The present work aimed to evaluate the efficacy and safety of BZ-loaded MDDS compared to the reference treatment (BZ 100 mg/kg daily) in a murine model of Chagas disease. BALB/c mice were ip infected with 1000 Tulahuen trypomastigotes, and after 15 days post-infection (dpi) were orally treated with BZ-loaded MDDS or pure BZ at 50 and 100 mg/kg daily or intermittent (2 or 5 day intervals). In order to accurately assess efficacy, at 105 dpi mice were immunosuppressed with 4 doses of cyclophosphamide at 3 day intervals. Then, mice were sacrificed and parasitemia, parasite heart-load, relative weight of spleens, livers and hearts, and tissue injury biomarkers were analyzed. Treated animals presented a survival higher than 80% compared to mice infected and non-treated (INT) which showed a survival of 9% (p<0.001). At different schemes of therapies, both pure BZ or loaded in the MDDS at 100 mg/kg, were able to override the parasitemia in comparison to INT mice (p<0.001), and at 50 mg/kg the treatments allow reducing the parasitemia levels (p<0.05). Before immunosuppression, the percentage of ROS-producing circulating cells was higher at 50 mg/kg (p<0.001) compared with BZ at 100 mg/kg, which could be explained due to parasite persistence. BZ-loaded MDDS treatments showed a significant reduction in heart damage (p<0.05) compared to the reference treatment. Thus, BZ-loaded MDDS seems to be safer than pure BZ at 100 mg/kg preserving the efficacy for the treatment of Chagas disease.