Coating doxorubicin-loaded nanocapsules with alginate enhances therapeutic efficacy against Leishmania in hamsters by inducing Th1-type immune responses.

Abstract

BACKGROUND AND PURPOSE:

The aim of the present study was to evaluate the immunomodulatory and chemotherapeutic potential of alginate-(SA) coated nanocapsule (NCs) loaded with doxorubicin (SA-NCs-DOX) against visceral leishmaniasis in comparison with nano-emulsions containing doxorubicin (NE-DOX).

EXPERIMENTAL APPROACH:

NE-DOX was prepared using low-energy emulsification methods. Stepwise addition of protamine sulphate and SA in a layer-by-layer manner was used to form SA-NCs-DOX. SA-NCs-DOX, NE-DOX and Free DOX were compared for their cytotoxicity against Leishmania donovani-infected macrophages in vitro and generation of T-cell responses in infected hamsters in vivo.

KEY RESULTS:

Size and ζ potential of the NE-DOX and SA-NCs-DOX formulations were 310 ± 2.1 nm and (-)32.6 ± 2.1 mV, 342 ± 4.1 nm and (-)29.3 ± 1.2 mV respectively. SA-NCs-DOX was better (1.5 times) taken up by J774A.1 macrophages compared with NE-DOX. SA-NCs -DOX showed greater efficacy than NE-DOX against intramacrophagic amastigotes. SA-NCs-DOX treatment exhibited enhanced apoptotic efficiency than NE-DOX and free DOX as evident by cell cycle analysis, decrease in mitochondrial membrane potential, ROS and NO production. T-cell responses, when assessed through lymphoproliferative responses, NO production along with enhanced levels of iNOS, TNF-α, IFN-γ and IL-12 were found to be up-regulated after SA-NCs-DOX, compared with responses to NE-DOX in vivo. Parasitic burden was decreased in Leishmania-infected hamsters treated with SA-NCs-DOX, compared with NE-DOX.

CONCLUSIONS AND IMPLICATIONS:

Our results provide insights into the development of an alternative approach to improved management of leishmaniasis through a combination of chemotherapy with stimulation of the innate immune system.

• Authors: S Kansal, R Tandon, A Verma, P Misra, A K Choudhary, R Verma, P R P Verma, A Dube, P R Mishra
• Journal: British journal of pharmacology (Br J Pharmacol) Vol. 171 Issue 17 Pg. 4038-50 (Sep 2014) ISSN: 1476-5381 [Electronic] England
• PMID: 24837879 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2014 The British Pharmacological Society.

Chemical References

• Alginates
• Antiprotozoal Agents
• Coated Materials, Biocompatible
• Hexuronic Acids
• Nanocapsules
• Glucuronic Acid
• Daunorubicin

Topics

• Alginates (administration & dosage, chemistry, pharmacology)
• Animals
• Antiprotozoal Agents (administration & dosage, chemistry, pharmacology)
• Cell Line
• Coated Materials, Biocompatible (administration & dosage, chemistry, pharmacology)
• Cricetinae
• Daunorubicin (administration & dosage, chemistry, pharmacology)
• Glucuronic Acid (administration & dosage, chemistry, pharmacology)
• Hexuronic Acids (administration & dosage, chemistry, pharmacology)
• Leishmania donovani (drug effects, immunology)
• Macrophages (drug effects, immunology, parasitology)
• Male
• Mice
• Nanocapsules (chemistry)
• Th1 Cells (drug effects, immunology)