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

作者：Daftarian Pirouz M^*; Stone Geoffrey W; Kovalski Leticia; Kumar Manoj; Vosoughi Aram; Urbieta Maitee; Blackwelder Pat; Dikici Emre; Serafini Paolo; Duffort Stephanie; Boodoo Richard; Rodriguez Cortes Alheli; Lemmon Vance; Deo Sapna; Alberola Jordi; Perez Victor L; Daunert Sylvia; Ager Arba L

来源：Journal of Infectious Diseases, 2013, 208(11): 1914-1922.

DOI：10.1093/infdis/jit378

• 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. %26lt;br%26gt;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. %26lt;br%26gt;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. %26lt;br%26gt;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.

• 出版日期2013-12-1