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.
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. majormouse 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.
Authors: Adriana M do Nascimento; Mateus Gonçalves Soares; Fernanda K V da Silva Torchelsen; Jorge A Viana de Araujo; Paula S Lage; Mariana C Duarte; Pedro H R Andrade; Tatiana G Ribeiro; Eduardo A F Coelho; Andréa M do Nascimento Journal: World J Microbiol Biotechnol Date: 2015-08-29 Impact factor: 3.312
Authors: Tahereh Zadeh Mehrizi; Mehdi Shafiee Ardestani; Ali Khamesipour; Mostafa Haji Molla Hoseini; Nariman Mosaffa; Ali Anissian; Amitis Ramezani Journal: J Mater Sci Mater Med Date: 2018-07-28 Impact factor: 3.896
Authors: Jessica Hersh; David Broyles; José Manuel Condor Capcha; Emre Dikici; Lina A Shehadeh; Sylvia Daunert; Sapna Deo Journal: ACS Appl Bio Mater Date: 2020-12-24
Authors: Zhao-Jun Liu; Pirouz Daftarian; Letícia Kovalski; Bo Wang; Runxia Tian; Diego M Castilla; Emre Dikici; Victor L Perez; Sapna Deo; Sylvia Daunert; Omaida C Velazquez Journal: PLoS One Date: 2016-04-22 Impact factor: 3.240