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      Development of mannose-anchored thiolated amphotericin B nanocarriers for treatment of visceral leishmaniasis

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          Abstract

          Aim:

          Our goal was to improve treatment outcomes for visceral leishmaniasis by designing nanocarriers that improve drug biodistribution and half-life. Thus, long-acting mannose-anchored thiolated chitosan amphotericin B nanocarrier complexes (MTC AmB) were developed and characterized.

          Materials & methods:

          A mannose-anchored thiolated chitosan nanocarrier was manufactured and characterized. MTC AmB was examined for cytotoxicity, biocompatibility, uptake and antimicrobial activities.

          Results:

          MTC AmB was rod shaped with a size of 362 nm. MTC AmB elicited 90% macrophage viability and 71-fold enhancement in drug uptake compared with native drug. The antileishmanial IC 50 for MTC AmB was 0.02 μg/ml compared with 0.26 μg/ml for native drug.

          Conclusion:

          These studies show that MTC can serve as a platform for clearance of Leishmania in macrophages.

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          Mechanism of amphotericin B resistance in clinical isolates of Leishmania donovani.

          Joana de Oliveira, Dharmendra Singh, Ashish Kumar … (2012)
          The clinical value of amphotericin B, the mainstay therapy for visceral leishmaniasis in sodium antimony gluconate-nonresponsive zones of Bihar, India, is now threatened by the emergence of acquired drug resistance, and a comprehensive understanding of the underlying mechanisms is the need of the hour. We have selected an amphotericin B-resistant clinical isolate which demonstrated 8-fold-higher 50% lethal doses (LD(50)) than an amphotericin B-sensitive strain to explore the mechanism of amphotericin B resistance. Fluorimetric analysis demonstrated lower anisotropy in the motion of the diphenylhexatriene fluorescent probe in the resistant strain, which indicated a higher fluidity of the membrane for the resistant strain than for the sensitive strain. The expression patterns of the two transcripts of S-adenosyl-l-methionine:C-24-Δ-sterol methyltransferase and the absence of ergosterol, replaced by cholesta-5,7,24-trien-3β-ol in the membrane of the resistant parasite, indicate a decreased amphotericin B affinity, which is evidenced by decreased amphotericin B uptake. The expression level of MDR1 is found to be higher in the resistant strain, suggesting a higher rate of efflux of amphotericin B. The resistant parasite also possesses an upregulated tryparedoxin cascade and a more-reduced intracellular thiol level, which helps in better scavenging of reactive oxygen species produced by amphotericin B. The resistance to amphotericin B was partially reverted by the thiol metabolic pathway and ABC transporter inhibitors. Thus, it can be concluded that altered membrane composition, ATP-binding cassette transporters, and an upregulated thiol metabolic pathway have a role in conferring amphotericin B resistance in clinical isolates of Leishmania donovani.
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            Thiolated polymers--thiomers: development and in vitro evaluation of chitosan-thioglycolic acid conjugates.

            Constantia Kast, Andreas Bernkop-Schnürch (2001)
            The aim of this study was to improve mucoadhesive properties of chitosan by the covalent attachment of thiol moieties to this cationic polymer. Mediated by a carbodiimide, thioglycolic acid (TGA) was covalently attached to chitosan. This was achieved by the formation of amide bonds between the primary amino groups of the polymer and the carboxylic acid group of TGA. Dependent on the pH-value and the weight ratio of polymer to TGA during the coupling reaction the resulting thiolated polymers, the so-called thiomers, displayed 6.58, 9.88, 27.44, and 38.23 micromole thiol groups per gram polymer. Tensile studies carried out with these chitosan-TGA conjugates on freshly excised porcine intestinal mucosa demonstrated a 6.3-, 8.6-, 8.9-, and 10.3-fold increase in the total work of adhesion (TWA) compared to the unmodified polymer, respectively. In contrast, the combination of chitosan and free unconjugated TGA showed almost no mucoadhesion. These data were in good correlation with further results obtained by another mucoadhesion test demonstrating a prolonged residence time of thiolated chitosan on porcine mucosa. The swelling behavior of all conjugates was thereby exactly in the same range as for an unmodified polymer pretreated in the same way. Furthermore, it could be shown that chitosan-TGA conjugates are still biodegradable by the glycosidase lysozyme. According to these results. chitosan-TGA conjugates represent a promising tool for the development of mucoadhesive drug delivery systems.
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              Mannose-conjugated chitosan nanoparticles loaded with rifampicin for the treatment of visceral leishmaniasis.

              Brahmeshwar Mishra, Pramila Chaubey (2014)
              The aim of current research work was to develop and investigate the potential of rifampicin (RIF) loaded mannose-conjugated chitosan nanoparticulate system for selective delivery to the macrophages in the management of visceral leishmaniasis (VL). RIF loaded mannose-conjugated chitosan nanoparticles (mCNPs) were prepared and characterized for shape, size, entrapment efficiency and in vitro drug release. The in vivo bio-distribution in albino rats and ex vivo drug uptake by macrophage were also evaluated. It was observed that extent of accumulation of mCNPs in macrophage rich organs, particularly in liver and spleen, were significantly higher compared to free drug. Ex vivo uptake of mCNPs was 2.31 times higher compared to unconjugated chitosan nanoparticles (CNPs). The macrophage uptake of mCNPs was inhibited significantly on pre-incubation with 0.05 M mannose in a parallel experiment, being suggestive of receptor mediated uptake of mannosylated nanoparticles. Our results indicate that mCNPs could be a promising carrier for selective delivery of RIF to macrophages for effective management of VL.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Nanomedicine (Lond)
                Journal ID (iso-abbrev): Nanomedicine (Lond)
                Journal ID (publisher-id): NNM
                Title: Nanomedicine
                Publisher: Future Medicine Ltd (London, UK )
                ISSN (Print): 1743-5889
                ISSN (Electronic): 1748-6963
                Publication date (Print): January 2017
                Publication date (Electronic): 23 November 2016
                Volume: 12
                Issue: 2
                Pages: 99-115
                Affiliations
                [1 ]Department of Pharmacy, Quaid-i-Azam University Islamabad, 45320, Pakistan
                [2 ]Department of Pharmacology & Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198, USA
                [3 ]Department of Entomology, University College of Agriculture & Environmental Sciences, The Islamia University, Bahawalpur, Pakistan
                [4 ]Nuclear Medicine, Oncology & Radiotherapy Institute, Islamabad, Pakistan
                [5 ]Department of Animal Sciences, Quaid-i-Azam University, Islamabad, 45320, Pakistan
                [6 ]Centre for Interdisciplinary Research in Basic Sciences, International Islamic University, Islamabad, Pakistan
                Author notes
                *Author for correspondence: benson.edagwa@ 123456unmc.edu
                Article
                DOI: 10.2217/nnm-2016-0325
                PMC ID: 5144491
                PubMed ID: 27879160
                SO-VID: 43fa6066-0f92-4027-acd3-1051e86384f9
                Copyright © © Benson Edagwa
                License:

                This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 Unported License

                History
                Date received : 02 September 2016
                Date accepted : 26 October 2016
                Categories
                Subject: Research Article

                Keywords: amphotericin b,macrophage nanoparticle targeting,mannose receptors,thiolated chitosan,visceral leishmaniasis
                Data availability:
                Keywords: amphotericin b, macrophage nanoparticle targeting, mannose receptors, thiolated chitosan, visceral leishmaniasis

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