Cargando…

Supplementation of host response by targeting nitric oxide to the macrophage cytosol is efficacious in the hamster model of visceral leishmaniasis and adds to efficacy of amphotericin B

We investigated efficacy of nitric oxide (NO) against Leishmania donovani. NO is a mediator of host response to infection, with direct parasiticidal activity in addition to its role in signalling to evoke innate macrophage responses. However, it is short-lived and volatile, and is therefore difficul...

Descripción completa

Detalles Bibliográficos
Autores principales: Pandya, Sanketkumar, Verma, Rahul Kumar, Khare, Prashant, Tiwari, Brajendra, Srinivasarao, Dadi A., Dube, Anuradha, Goyal, Neena, Misra, Amit
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4919251/
https://www.ncbi.nlm.nih.gov/pubmed/27183429
http://dx.doi.org/10.1016/j.ijpddr.2016.01.001
_version_ 1782439220806156288
author Pandya, Sanketkumar
Verma, Rahul Kumar
Khare, Prashant
Tiwari, Brajendra
Srinivasarao, Dadi A.
Dube, Anuradha
Goyal, Neena
Misra, Amit
author_facet Pandya, Sanketkumar
Verma, Rahul Kumar
Khare, Prashant
Tiwari, Brajendra
Srinivasarao, Dadi A.
Dube, Anuradha
Goyal, Neena
Misra, Amit
author_sort Pandya, Sanketkumar
collection PubMed
description We investigated efficacy of nitric oxide (NO) against Leishmania donovani. NO is a mediator of host response to infection, with direct parasiticidal activity in addition to its role in signalling to evoke innate macrophage responses. However, it is short-lived and volatile, and is therefore difficult to introduce into infected cells and maintain inracellular concentrations for meaningful periods of time. We incorporated diethylenetriamine NO adduct (DETA/NO), a prodrug, into poly(lactide-co-glycolide) particles of ∼200 nm, with or without amphotericin B (AMB). These particles sustained NO levels in mouse macrophage culture supernatants, generating an area under curve (AUC(0.08-24h)) of 591.2 ± 95.1 mM × h. Free DETA/NO resulted in NO peaking at 3 h and declining rapidly to yield an AUC of 462.5 ± 193.4. Particles containing AMB and DETA/NO were able to kill ∼98% of promastigotes and ∼76% of amastigotes in 12 h when tested in vitro. Promastigotes and amastigotes were killed less efficiently by particles containing a single drug– either DETA/NO (∼42%, 35%) or AMB (∼90%, 50%) alone, or by equivalent concentrations of drugs in solution. In a pre-clinical efficacy study of power >0.95 in the hamster model, DETA/NO particles were non-inferior to Fungizone® but not Ambisome®, resulting in significant (∼73%) reduction in spleen parasites in 7 days. Particles containing both DETA/NO and AMB were superior (∼93% reduction) to Ambisome®. We conclude that NO delivered to the cytosol of macrophages infected with Leishmania possesses intrinsic activity and adds significantly to the efficacy of AMB.
format Online
Article
Text
id pubmed-4919251
institution National Center for Biotechnology Information
language English
publishDate 2016
publisher Elsevier
record_format MEDLINE/PubMed
spelling pubmed-49192512016-06-30 Supplementation of host response by targeting nitric oxide to the macrophage cytosol is efficacious in the hamster model of visceral leishmaniasis and adds to efficacy of amphotericin B Pandya, Sanketkumar Verma, Rahul Kumar Khare, Prashant Tiwari, Brajendra Srinivasarao, Dadi A. Dube, Anuradha Goyal, Neena Misra, Amit Int J Parasitol Drugs Drug Resist Article We investigated efficacy of nitric oxide (NO) against Leishmania donovani. NO is a mediator of host response to infection, with direct parasiticidal activity in addition to its role in signalling to evoke innate macrophage responses. However, it is short-lived and volatile, and is therefore difficult to introduce into infected cells and maintain inracellular concentrations for meaningful periods of time. We incorporated diethylenetriamine NO adduct (DETA/NO), a prodrug, into poly(lactide-co-glycolide) particles of ∼200 nm, with or without amphotericin B (AMB). These particles sustained NO levels in mouse macrophage culture supernatants, generating an area under curve (AUC(0.08-24h)) of 591.2 ± 95.1 mM × h. Free DETA/NO resulted in NO peaking at 3 h and declining rapidly to yield an AUC of 462.5 ± 193.4. Particles containing AMB and DETA/NO were able to kill ∼98% of promastigotes and ∼76% of amastigotes in 12 h when tested in vitro. Promastigotes and amastigotes were killed less efficiently by particles containing a single drug– either DETA/NO (∼42%, 35%) or AMB (∼90%, 50%) alone, or by equivalent concentrations of drugs in solution. In a pre-clinical efficacy study of power >0.95 in the hamster model, DETA/NO particles were non-inferior to Fungizone® but not Ambisome®, resulting in significant (∼73%) reduction in spleen parasites in 7 days. Particles containing both DETA/NO and AMB were superior (∼93% reduction) to Ambisome®. We conclude that NO delivered to the cytosol of macrophages infected with Leishmania possesses intrinsic activity and adds significantly to the efficacy of AMB. Elsevier 2016-01-14 /pmc/articles/PMC4919251/ /pubmed/27183429 http://dx.doi.org/10.1016/j.ijpddr.2016.01.001 Text en © 2016 Published by Elsevier Ltd on behalf of Australian Society for Parasitology. http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Article
Pandya, Sanketkumar
Verma, Rahul Kumar
Khare, Prashant
Tiwari, Brajendra
Srinivasarao, Dadi A.
Dube, Anuradha
Goyal, Neena
Misra, Amit
Supplementation of host response by targeting nitric oxide to the macrophage cytosol is efficacious in the hamster model of visceral leishmaniasis and adds to efficacy of amphotericin B
title Supplementation of host response by targeting nitric oxide to the macrophage cytosol is efficacious in the hamster model of visceral leishmaniasis and adds to efficacy of amphotericin B
title_full Supplementation of host response by targeting nitric oxide to the macrophage cytosol is efficacious in the hamster model of visceral leishmaniasis and adds to efficacy of amphotericin B
title_fullStr Supplementation of host response by targeting nitric oxide to the macrophage cytosol is efficacious in the hamster model of visceral leishmaniasis and adds to efficacy of amphotericin B
title_full_unstemmed Supplementation of host response by targeting nitric oxide to the macrophage cytosol is efficacious in the hamster model of visceral leishmaniasis and adds to efficacy of amphotericin B
title_short Supplementation of host response by targeting nitric oxide to the macrophage cytosol is efficacious in the hamster model of visceral leishmaniasis and adds to efficacy of amphotericin B
title_sort supplementation of host response by targeting nitric oxide to the macrophage cytosol is efficacious in the hamster model of visceral leishmaniasis and adds to efficacy of amphotericin b
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4919251/
https://www.ncbi.nlm.nih.gov/pubmed/27183429
http://dx.doi.org/10.1016/j.ijpddr.2016.01.001
work_keys_str_mv AT pandyasanketkumar supplementationofhostresponsebytargetingnitricoxidetothemacrophagecytosolisefficaciousinthehamstermodelofvisceralleishmaniasisandaddstoefficacyofamphotericinb
AT vermarahulkumar supplementationofhostresponsebytargetingnitricoxidetothemacrophagecytosolisefficaciousinthehamstermodelofvisceralleishmaniasisandaddstoefficacyofamphotericinb
AT khareprashant supplementationofhostresponsebytargetingnitricoxidetothemacrophagecytosolisefficaciousinthehamstermodelofvisceralleishmaniasisandaddstoefficacyofamphotericinb
AT tiwaribrajendra supplementationofhostresponsebytargetingnitricoxidetothemacrophagecytosolisefficaciousinthehamstermodelofvisceralleishmaniasisandaddstoefficacyofamphotericinb
AT srinivasaraodadia supplementationofhostresponsebytargetingnitricoxidetothemacrophagecytosolisefficaciousinthehamstermodelofvisceralleishmaniasisandaddstoefficacyofamphotericinb
AT dubeanuradha supplementationofhostresponsebytargetingnitricoxidetothemacrophagecytosolisefficaciousinthehamstermodelofvisceralleishmaniasisandaddstoefficacyofamphotericinb
AT goyalneena supplementationofhostresponsebytargetingnitricoxidetothemacrophagecytosolisefficaciousinthehamstermodelofvisceralleishmaniasisandaddstoefficacyofamphotericinb
AT misraamit supplementationofhostresponsebytargetingnitricoxidetothemacrophagecytosolisefficaciousinthehamstermodelofvisceralleishmaniasisandaddstoefficacyofamphotericinb