A targeted and adjuvanted nanocarrier lowers the effective dose of liposomal amphotericin B and enhances adaptive immunity in murine cutaneous leishmaniasis.
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.
['Daftarian|Pirouz M|PM|', 'Stone|Geoffrey W|GW|', 'Kovalski|Leticia|L|', 'Kumar|Manoj|M|', 'Vosoughi|Aram|A|', 'Urbieta|Maitee|M|', 'Blackwelder|Pat|P|', 'Dikici|Emre|E|', 'Serafini|Paolo|P|', 'Duffort|Stephanie|S|', 'Boodoo|Richard|R|', 'Rodríguez-Cortés|Alhelí|A|', 'Lemmon|Vance|V|', 'Deo|Sapna|S|', 'Alberola|Jordi|J|', 'Perez|Victor L|VL|', 'Daunert|Sylvia|S|', 'Ager|Arba L|AL|']
D056704:Adaptive Immunity D000666:Amphotericin B D000818:Animals D000938:Antigen-Presenting Cells D000981:Antiprotozoal Agents D050091:Dendrimers D004195:Disease Models, Animal D004337:Drug Carriers D000939:Epitopes D005260:Female D007274:Injections, Intraperitoneal D018320:Leishmania major D054332:Leishmaniasis Vaccines D016773:Leishmaniasis, Cutaneous D017737:Macrophages, Peritoneal D017780:Malaria Vaccines D051379:Mice D008807:Mice, Inbred BALB C D008810:Mice, Inbred C57BL D046529:Microscopy, Electron, Transmission D053758:Nanoparticles
nanocarrier leishmaniasis obligate intracellular parasites intracellular adoptive immunity immunochemotherapy vaccine