Photodynamic therapy offers a novel approach to managing miltefosine-resistant cutaneous leishmaniasis
Fernanda V. Cabral, Mina Riahi, Saydulla Persheyev, Cheng Lian, Mauro Cortéz, Ifor D W Samuel, Martha S. Ribeiro
Abstract
Cutaneous leishmaniasis (CL) is a neglected disease caused by Leishmania parasites. The oral drug miltefosine is effective, but there is a growing problem of drug resistance, which has led to increasing treatment failure rates and relapse of infections. Photodynamic therapy (PDT) combines a light source and a photoactive drug to promote cell death by oxidative stress. Although PDT is effective against several pathogens, its use against drug-resistant Leishmania parasites remains unexplored. Herein, we investigated the potential of organic light-emitting diodes (OLEDs) as wearable light sources, which would enable at-home use or ambulatory treatment of CL. We also assessed its impact on combating miltefosine resistance in Leishmania amazonensis -induced CL in mice. The in vitro activity of OLEDs combined with 1,9-dimethyl-methylene blue (DMMB) (OLED-PDT) was evaluated against wild-type and miltefosine-resistant L. amazonensis strains in promastigote (EC 50 = 0.034 μM for both strains) and amastigote forms (EC 50 = 0.052 μM and 0.077 μM, respectively). Cytotoxicity in macrophages and fibroblasts was also evaluated. In vivo , we investigated the potential of OLED-PDT in combination with miltefosine using different protocols. Our results demonstrate that OLED-PDT is effective in killing both strains of L. amazonensis by increasing reactive oxygen species and stimulating nitric oxide production. Moreover, OLED-PDT showed great antileishmanial activity in vivo , allowing the reduction of miltefosine dose by half in infected mice using a light dose of 7.8 J/cm 2 and 15 μM DMMB concentration. In conclusion, OLED-PDT emerges as a new avenue for at-home care and allows a combination therapy to overcome drug resistance in cutaneous leishmaniasis. • A new approach to treating cutaneous leishmaniasis is proposed. • A combination of photodynamic therapy and miltefosine is shown to be effective against drug resistant L. amazonensis. • OLEDs are shown to be novel wearable light sources suitable for at-home care of cutaneous leishmaniasis. • Photodynamic therapy combined with oral miltefosine promotes complete healing. • Photodynamic therapy reduces the miltefosine dose by half, preventing the emergence of drug resistance.