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