PLGA-based macrophage-mediated drug targeting for the treatment of visceral leishmaniasis

Introduction Visceral leishmaniasis (VL), also known as kala-azar, is a systemic disease that is lethal when left untreated and is caused by species of the Leishmania donovani, namely L. donovani and L. infantum (Old World) and L. chagasi (New World). The causative agents could have two ways of transmission, zoonotic i.e. which means that it is transmitted from animal to vector to human or anthroponotic, which means that is transmitted from human to vector to human. The development of the disease is an importance of the dissemination of VL causing species to internal organs such as the liver, spleen and bone marrow (1). Drug resistance and drug toxicity are the two major obstacles closely associated with most microbial infectious diseases. Macrophages play a key role in driving the progression of several microbial diseases affecting visceral organs such as liver and spleen. Studies on VL revealed that organs such as spleen and liver serve as safe havens for parasites residing inside the macrophages. Most of the antileishmanial drugs presently in use, fail to penetrate macrophages within which parasite creep and that derives researchers to pursue delivery systems and their engineered versions in order to be therapeutically effective (2). Currently surviving therapies for leishmaniasis are very toxic and also started exhibiting emergence of drug-resistant parasitic strains. For instance, pentavalent antimonials (sodium stibogluconate) and pentamidine were potent drugs used against VL; however, it proved to be ineffective due to the emergence of several unresponsive strains of the leishmanial parasite (3). Miltefosine is a relatively new anti-VL drug which holds significant potential in treating VL along with other first-line therapeutics however, the clinical relevance and possible of Miltefosine are yet to be finalized. Despite all research initiatives and pre-clinical studies, active therapy for VL still remains challenge holding direct negative implications with respect to better drug targeting and overcoming drug resistance (4). Some lipid-based amphotericin formulations are currently in clinical trials. Amphotericin B (AmB) provides substantial leishmanicidal activity as well, and its use results in fewer treatment failures and relapses. However, the important side effects, mainly nephrotoxicity, produced by this drug at therapeutic doses have often directed to its refusal as a firstchoice treatment (5). Novel drug delivery systems, such as liposomes, nanospheres, and microspheres can result in higher concentrations of AmB in the liver and spleen but lower concentrations in the kidney and lungs (1) thus declining the toxicity of AmB. Furthermore, the administration of AmB Abstract The potential of PLGA-nanoparticles as a carrier of amphotericin B and doxorubicin against visceral leishmaniasis was evaluated by macrophage-mediated drug targeting approach. PLGA-nanoparticles were modified by coating them with macrophagespecific ligand-lectin. Prior to in-vitro studies, characterization studies were carried out systematically include particle size, surface morphology, percent drug entrapment and percent drug release. In vitro studies were carried out in J774.1 in order to evaluate the effective endocytotic uptake of nanoparticles by macrophages. The antileishmanial activity of PLGA-nanoparticles and lectin-PLGA-nanoparticles was tested in-vitro in leishmania donovani infected macrophage-amastigote system (J774A.1 cells), which showed higher efficacy of lectin grafted PLGA-nanoparticles over plain PLGA-nanoparticles. The prepared plain and lectin grafted PLGA-Nanoparticles based systems showed excellent potential for passive and active intra-macrophage targeting, respectively and the approach could be an effective alternative to the currently available drug regimens against VL.