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

Abstract

BACKGROUND AND PURPOSEThe 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 APPROACHNE-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 RESULTSSize 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 IMPLICATIONSOur 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.

PEGylated Dendritic Polyglycerol Conjugate Delivers Doxorubicin to the Parasitophorous Vacuole in Leishmania infantum Infections

“…Several DOX‐conjugated nanosystems have been used against intracellular leishmania infections, resulting in an almost twofold higher antileishmanial effect than free DOX . Despite the fact that our results showed a decrease in the antiparasitic effect after DOX conjugation, the EC 50 values obtained are in the micromolar order similar to those obtained by others.…”

Doxorubicin-Immersed Skeletal Muscle Grafts Promote Peripheral Nerve Regeneration Across a 10-mm Defect in the Rat Sciatic Nerve

“…[31][32][33] Additionally, macrophages expressed the specific receptor to bind the apoptotic cells to phagocyte them, and induced antiinflammatory responses. 34,35 Further studies are needed to assess the relationships among doxorubicin, macrophages, and peripheral nerve regeneration.…”

Leishmaniasis treatment update of possibilities for drug repurposing

“…Doxorubicin, an anthraquinone used in the treatment of a wide variety of tumors with a mechanism of action on topoisomerase II and an ability to intercalate in DNA, has potent activity in vitro and in an experimental model of visceral leishmaniasis. The development of doxorubicin-loaded microparticles and nanocapsules showed promising results in the experimental model of visceral leishmaniasis (84)(85)(86).…”