Title

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

Document Type

Article

Publication Date

12-1-2013

Publication Title

International Journal of Infectious Diseases

Keywords

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

ISSN

1201-9712

Volume

208

Issue/No.

11

First Page

1914

Last Page

1922

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.

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

DOI

10.1093/infdis/jit378

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