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 (EC50 = 0.034 μM for both strains) and amastigote forms (EC50 = 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/cm2 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.
摘要：
皮肤利什曼病（CL）是由利什曼原虫寄生虫引起的一种被忽视的疾病。口服药物米替福辛是有效的，但是耐药性问题日益严重，这导致了治疗失败率和感染复发的增加。光动力疗法（PDT）结合了光源和光敏药物，以通过氧化应激促进细胞死亡。虽然PDT对几种病原体有效，它对耐药的利什曼原虫寄生虫的使用仍有待探索。在这里，我们研究了有机发光二极管（OLED）作为可穿戴光源的潜力，这将使CL能够在家使用或门诊治疗。我们还评估了其对对抗利什曼原虫诱导的小鼠CL中的米替福辛抗性的影响。与1,9-二甲基-亚甲基蓝（DMMB）（OLED-PDT）结合的OLED的体外活性针对野生型和耐米膦的亚马逊乳杆菌菌株（两种菌株的EC50=0.034μM）和amastigote形式（EC50=0.052μM和0.077μM，分别)。还评估了巨噬细胞和成纤维细胞中的细胞毒性。在体内,我们研究了OLED-PDT与米替福辛结合使用不同协议的潜力。我们的结果表明，OLED-PDT可以通过增加活性氧和刺激一氧化氮的产生来有效杀死两种亚马逊乳杆菌。此外，OLED-PDT在体内表现出极大的抗利什曼酶活性，允许使用7.8J/cm2的光剂量和15μM的DMMB浓度在感染的小鼠中将米替福辛剂量减少一半。总之,OLED-PDT成为家庭护理的新途径，并允许联合疗法克服皮肤利什曼病的耐药性。
