From lipid biophysics to first-in human test: topical liposomal treatment for cutaneous leishmaniasis

Cutaneous leishmaniasis (CL) remains a major neglected disease with limited therapeutic op-tions and expanding geographic distribution. To develop a safe, accessible local treatment, we formulated topical Miltefosine gels incorporating different types of liposomes. Preclinical tests using low-dose Miltefosine (0.015% w/v) and ultrafluid liposomes were ineffective, leading us to increase the drug concentration and revise the liposomal design. At 0.5% w/v, Miltefosine—whether used alone or with fluid liposomes—produced complete lesion healing in a murine L. amazonensis model, with no relapse and sterile lesions at 30 days. Liposomes further accelerated the healing process. A first-in-human compassionate-use case with a patient refractory to standard therapies confirmed good local tolerance and eventual clinical cure using 0.5–1% Miltefosine gels + short Amphotericin B treatment. The experience also showed that ultrafluid liposomes are unsuitable for open ulcers, informing future optimization. Overall, topical Miltefosine at adequate concentration is a promising local treatment for CL, and liposomes can enhance therapeutic performance.