Photoactivity of Pluronic® F-127 nanoencapsulated hypericin against Leishmania: A promising approach for cutaneous leishmaniasis.

Hypericin (HYP) is a naturally occurring naphthodianthrone that has been extensively studied, particularly in combination with photodynamic therapy (PDT), for its therapeutic properties. Encapsulation of HYP with Pluronic® F-127 nanoparticles enhances its bioavailability. Leishmaniasis is a neglected disease and a global health problem, with varying clinical forms caused by Leishmania parasites. Current treatments are limited by high toxicity and relapse, highlighting the need for alternative therapeutics. We investigated the activity of free HYP and that encapsulated with Pluronic® F-127 (HYPF127) in association with PDT against Leishmania (Leishmania) amazonensis. These compounds demonstrated high anti-Leishmania activity when associated with PDT, with IC50 values for promastigote forms of 18 ± 3 μM for HYP and 16 ± 5 μM for HYPF127. Moderate activity against amastigotes was observed at lower concentrations, and prominent macrophage cytotoxicity was detected in the compounds following irradiation, with CC50 of 0.6 ± 0.2 μM for HYPF127 and 0.2 ± 0.1 μM for HYP in murine macrophages. Phosphatidylserine externalization, mitochondrial membrane depolarization, and DNA fragmentation were observed in promastigotes treated with PDT, suggesting the induction of apoptosis. These results are slightly superior to those obtained for HYPF127. In silico evaluation demonstrated the affinity of HYP for trypanothione reductase (TR), suggesting a possible target and mechanism of action through redox homeostasis inhibition in Leishmania. In conclusion, nanoencapsulated photoactivated HYP exhibited promising antileishmanial activity against L. amazonensis, with F-127 enhancing its potential. Therefore, TR inhibition may be involved in the mechanism of action.