Research Article For reprint orders, please contact: reprints@futuremedicine.com Mannosylated thiolated paromomycin-loaded PLGA nanoparticles for the oral therapy of visceral leishmaniasis Iqra Afzal 1 , Hafz Shoaib Sarwar 1,2 , Muhammad Farhan Sohail 1,2 , Sanjay Varikuti 3 , Sarwat Jahan 4 , Sohail Akhtar 5 , Masoom Yasinzai 6 , Abhay R Satoskar* ,3 & Gul Shahnaz** ,1,3 1 Department of Pharmacy, Quaid-I-Azam University, Islamabad 44000, Pakistan 2 Riphah Institute of Pharmaceutical Science, Riphah International University, Lahore Campus, Lahore, Pakistan 3 Department of Pathology, Ohio State University Medical Center, Columbus, OH 43201, USA 4 Department of Animal Sciences, Quaid-I-Azam University, Islamabad 44000, Pakistan 5 Department of Entomology, University College of Agriculture & Environmental Sciences, The Islamia University, Bahawalpur, Pakistan 6 Centre for Interdisciplinary Research in Basic Sciences, International Islamic University, Islamabad, Pakistan *Author for correspondence: Tel.: +1 614 366 3417; Fax: +1 614 292 7072; Abhay.Satoskar@osumc.edu **Author for correspondence: Tel.: +92 51 9064 4137; gshahnaz@qau.edu.pk Aim: The present study evaluates the effcacy of paromomycin (PM)-loaded mannosylated thiomeric nanoparticles for the targeted delivery to pathological organs for the oral therapy of visceral leishma- niasis. Materials & methods: Mannosylated thiolated chitosan (MTC)-coated PM-loaded PLGA nanopar- ticles (MTC-PLGA-PM) were synthesized and evaluated for morphology, drug release, permeation en- hancing and antileishmanial potential. Results: MTC-PLGA-PM were spherical in shape with a size of 391.24 ± 6.91 nm and an encapsulation effciency of 67.16 ± 14%. Ex vivo permeation indicated 12.73-fold higher permeation of PM with MTC-PLGA-PM against the free PM. Flow cytometry indicated enhanced macrophage uptake and parasite killing in Leishmania donovani infected macrophage model. In vitro an- tileishmanial activity indicated 36-fold lower IC 50 for MTC-PLGA-PM as compared with PM. The in vivo studies indicated 3.6-fold reduced parasitic burden in the L. donovani infected BALB/c mice model. Con- clusion: The results encouraged the concept of MTC-PLGA-PM nanoparticles as promising strategy for visceral leishmaniasis. First draft submitted: 3 February 2018; Accepted for publication: 2 October 2018; Published online: 28 January 2019 Keywords: L. donovani • macrophage targeting • mannose receptors • oral therapy • paromomycin • thiolated chitosan • visceral leishmaniasis Visceral leishmaniasis (VL) is a fatal tropical disease caused by parasite Leishmania donovani, transmitted to the human by the bite of an infected sandfly [1]. Upon inoculation the leishmania parasite is readily taken up by mononuclear phagocyte system (monocytes and tissue macrophages) [2]. Inside the macrophages the leishmania parasite survives the macrophage-induced killing mechanism and replicates inside phagolysosomes and propagates the infection [3,4]. Current chemotherapeutic modalities failed to elicit the effective parasitic clearance due to decreased macrophage permeability, drug resistance, lack of oral bioavailability, toxicity, longer duration of treatment and cost–effectiveness [5]. The development of wide spread resistance against the first-line drugs, the antimonial compounds have limited their use [6]. The amphotericin B is effective in clearing the parasitic burden but its use is associated with severe toxicity and high cost, causing a burden of the limited health budget of developing countries [7]. Paromomycin (PM) is aminoglycoside antibiotic with significant antileishmanial activity with wide range of safety and is new recommended drug for the treatment of leishmaniasis [8]. However, the full therapeutic potential of PM is jeopardized by its decreased accumulation inside the macrophages due to decreased permeability across macrophages cell membrane and lack of oral bioavailability [9,10]. Therefore, it will be a promising strategy to enhance the intracellular accumulation and oral bioavailability of PM to be used as highly efficient antileishmanial agent. Nanomedicine (Lond.) (Epub ahead of print) ISSN 1743-5889 10.2217/nnm-2018-0038 C  2019 Future Medicine Ltd