A Targeted and Adjuvanted Nanocarrier Lowers the Effective Dose of Liposomal Amphotericin B and Enhances Adaptive Immunity in Murine Cutaneous Leishmaniasis

Authors

Pirouz M. Daftarian, University of Miami
Geoffrey W. Stone, University of Miami
Leticia Kovalski, University of Miami
Manoj Kumar, University of Miami
Aram Vosoughi, University of Miami
Maitee Urbieta, University of Miami
Patricia Blackwelder, University of MiamiFollow
Emre Dikici, University of Miami
Stephanie Duffort, University of Miami
Richard Boodoo, University of Miami
Alheli Rodriguez-Cortes, Universität Autonoma de Barcelona - Italy
Vance Lemmon, University of Miami
Sapna Deo, University of Miami
Jordi Alberola, Universität Autonoma de Barcelona - Italy
Victor L. Perez, University of Miami
Sylvia Daunert, University of Miami
Arba L. Ager, University of Miami

Document Type

Article

Publication Title

International Journal of Infectious Diseases

ISSN

1201-9712

Publication Date

12-1-2013

Keywords

Immunochemotherapy, Nanocarrier, Adoptive immunity, Intracellular, Obligate intracellular parasites, Leishmaniasis, Vaccine

Abstract

Background: Amphotericin B (AmB), the most effective drug against leishmaniasis, has serious toxicity. As Leishmania species are obligate intracellular parasites of antigen presenting cells (APC), an immunopotentiating APC-specific AmB nanocarrier would be ideally suited to reduce the drug dosage and regimen requirements in leishmaniasis treatment. Here, we report a nanocarrier that results in effective treatment shortening of cutaneous leishmaniasis in a mouse model, while also enhancing L. major specific T-cell immune responses in the infected host.

Methods: We used a Pan-DR-binding epitope (PADRE)-derivatized-dendrimer (PDD), complexed with liposomal amphotericin B (LAmB) in an L. major mouse model and analyzed the therapeutic efficacy of low-dose PDD/ LAmB vs full dose LAmB.

Results: PDD was shown to escort LAmB to APCs in vivo, enhanced the drug efficacy by 83% and drug APC targeting by 10-fold and significantly reduced parasite burden and toxicity. Fortuitously, the PDD immunopotentiating effect significantly enhanced parasite-specific T-cell responses in immunocompetent infected mice.

Conclusions: PDD reduced the effective dose and toxicity of LAmB and resulted in elicitation of strong parasite specific T-cell responses. A reduced effective therapeutic dose was achieved by selective LAmB delivery to APC, bypassing bystander cells, reducing toxicity and inducing antiparasite immunity.

DOI

10.1093/infdis/jit378

Volume

208

Issue

11

First Page

1914

Last Page

1922

Comments

©The Author 2013. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved.

Additional Comments

DOD grant #: DAMD 17-03-20021; National Institutes of Health grant #: P30AI073961

NSUWorks Citation

Pirouz M. Daftarian, Geoffrey W. Stone, Leticia Kovalski, Manoj Kumar, Aram Vosoughi, Maitee Urbieta, Patricia Blackwelder, Emre Dikici, Stephanie Duffort, Richard Boodoo, Alheli Rodriguez-Cortes, Vance Lemmon, Sapna Deo, Jordi Alberola, Victor L. Perez, Sylvia Daunert, and Arba L. Ager. 2013. A Targeted and Adjuvanted Nanocarrier Lowers the Effective Dose of Liposomal Amphotericin B and Enhances Adaptive Immunity in Murine Cutaneous Leishmaniasis .International Journal of Infectious Diseases , (11) : 1914 -1922. https://nsuworks.nova.edu/occ_facarticles/446.