A targeted and adjuvanted nanocarrier lowers the effective dose of liposomal amphotericin B and enhances adaptive immunity in murine cutaneous leishmaniasis

Pirouz M. Daftarian, Geoffrey Stone, Leticia Kovalski, Manoj Kumar, Aram Vosoughi, Maitee Urbieta, Pat Blackwelder, Emre Dikici, Paolo Serafini, Stephanie Duffort, Richard Boodoo, Alhelí Rodríguez-Cortés, Vance Lemmon, Sapna K Deo, Jordi Alberola, Victor L Perez Quinones, Sylvia Daunert, Arba L Ager

Research output: Contribution to journalArticle

28 Citations (Scopus)

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 APCspecific 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.

Original languageEnglish
Pages (from-to)1914-1922
Number of pages9
JournalJournal of Infectious Diseases
Volume208
Issue number11
DOIs
StatePublished - Dec 1 2013

Fingerprint

Cutaneous Leishmaniasis
Dendrimers
Adaptive Immunity
Parasites
Antigen-Presenting Cells
Leishmaniasis
Amphotericin B
T-Lymphocytes
Pharmaceutical Preparations
Leishmania
Therapeutics
liposomal amphotericin B
Epitopes
Immunity

Keywords

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

ASJC Scopus subject areas

  • Infectious Diseases
  • Immunology and Allergy

Cite this

A targeted and adjuvanted nanocarrier lowers the effective dose of liposomal amphotericin B and enhances adaptive immunity in murine cutaneous leishmaniasis. / Daftarian, Pirouz M.; Stone, Geoffrey; Kovalski, Leticia; Kumar, Manoj; Vosoughi, Aram; Urbieta, Maitee; Blackwelder, Pat; Dikici, Emre; Serafini, Paolo; Duffort, Stephanie; Boodoo, Richard; Rodríguez-Cortés, Alhelí; Lemmon, Vance; Deo, Sapna K; Alberola, Jordi; Perez Quinones, Victor L; Daunert, Sylvia; Ager, Arba L.

In: Journal of Infectious Diseases, Vol. 208, No. 11, 01.12.2013, p. 1914-1922.

Research output: Contribution to journalArticle

Daftarian, PM, Stone, G, Kovalski, L, Kumar, M, Vosoughi, A, Urbieta, M, Blackwelder, P, Dikici, E, Serafini, P, Duffort, S, Boodoo, R, Rodríguez-Cortés, A, Lemmon, V, Deo, SK, Alberola, J, Perez Quinones, VL, Daunert, S & Ager, AL 2013, 'A targeted and adjuvanted nanocarrier lowers the effective dose of liposomal amphotericin B and enhances adaptive immunity in murine cutaneous leishmaniasis', Journal of Infectious Diseases, vol. 208, no. 11, pp. 1914-1922. https://doi.org/10.1093/infdis/jit378
Daftarian, Pirouz M. ; Stone, Geoffrey ; Kovalski, Leticia ; Kumar, Manoj ; Vosoughi, Aram ; Urbieta, Maitee ; Blackwelder, Pat ; Dikici, Emre ; Serafini, Paolo ; Duffort, Stephanie ; Boodoo, Richard ; Rodríguez-Cortés, Alhelí ; Lemmon, Vance ; Deo, Sapna K ; Alberola, Jordi ; Perez Quinones, Victor L ; Daunert, Sylvia ; Ager, Arba L. / A targeted and adjuvanted nanocarrier lowers the effective dose of liposomal amphotericin B and enhances adaptive immunity in murine cutaneous leishmaniasis. In: Journal of Infectious Diseases. 2013 ; Vol. 208, No. 11. pp. 1914-1922.
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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 APCspecific 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.",
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T1 - A targeted and adjuvanted nanocarrier lowers the effective dose of liposomal amphotericin B and enhances adaptive immunity in murine cutaneous leishmaniasis

AU - Daftarian, Pirouz M.

AU - Stone, Geoffrey

AU - Kovalski, Leticia

AU - Kumar, Manoj

AU - Vosoughi, Aram

AU - Urbieta, Maitee

AU - Blackwelder, Pat

AU - Dikici, Emre

AU - Serafini, Paolo

AU - Duffort, Stephanie

AU - Boodoo, Richard

AU - Rodríguez-Cortés, Alhelí

AU - Lemmon, Vance

AU - Deo, Sapna K

AU - Alberola, Jordi

AU - Perez Quinones, Victor L

AU - Daunert, Sylvia

AU - Ager, Arba L

PY - 2013/12/1

Y1 - 2013/12/1

N2 - 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 APCspecific 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.

AB - 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 APCspecific 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.

KW - Adoptive immunity

KW - Immunochemotherapy

KW - Intracellular

KW - Leishmaniasis

KW - Nanocarrier

KW - Obligate intracellular parasites

KW - Vaccine

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