TY - JOUR
T1 - Sertraline Delivered in Phosphatidylserine Liposomes Is Effective in an Experimental Model of Visceral Leishmaniasis
AU - Romanelli, Maiara Maria
AU - da Costa-Silva, Thais Alves
AU - Cunha-Junior, Edezio
AU - Dias Ferreira, Daiane
AU - Guerra, Juliana M.
AU - Galisteo, Andres Jimenez
AU - Pinto, Erika Gracielle
AU - Barbosa, Leandro R. S.
AU - Torres-Santos, Eduardo Caio
AU - Tempone, Andre Gustavo
N1 - This work was funded by grants provided by the São Paulo State Research Foundation (FAPESP 2018/10279-6, 2015/23403-9, 2015/15822-1, and 2013/07275-5) and Conselho Nacional de Pesquisa e Desenvolvimento (CNPq) 306305/2017-8, 306943/2015-8, and 420567/2016-0.
PY - 2019/10/29
Y1 - 2019/10/29
N2 - Liposomes containing phosphatidylserine (PS) has been used for the delivery of drugs into the intramacrophage milieu. Leishmania (L.) infantum parasites live inside macrophages and cause a fatal and neglected viscerotropic disease, with a toxic treatment. Sertraline was studied as a free formulation (SERT) and also entrapped into phosphatidylserine liposomes (LP-SERT) against intracellular amastigotes and in a murine model of visceral leishmaniasis. LP-SERT showed a potent activity against intracellular amastigotes with an EC50 value of 2.5 μM. The in vivo efficacy of SERT demonstrated a therapeutic failure. However, when entrapped into negatively charged liposomes (-58 mV) of 125 nm, it significantly reduced the parasite burden in the mice liver by 89% at 1 mg/kg, reducing the serum levels of the cytokine IL-6 and upregulating the levels of the chemokine MCP-1. Histopathological studies demonstrated the presence of an inflammatory infiltrate with the development of granulomas in the liver, suggesting the resolution of the infection in the treated group. Delivery studies showed fluorescent-labeled LP-SERT in the liver and spleen of mice even after 48 h of administration. This study demonstrates the efficacy of PS liposomes containing sertraline in experimental VL. Considering the urgent need for VL treatments, the repurposing approach of SERT could be a promising alternative.
AB - Liposomes containing phosphatidylserine (PS) has been used for the delivery of drugs into the intramacrophage milieu. Leishmania (L.) infantum parasites live inside macrophages and cause a fatal and neglected viscerotropic disease, with a toxic treatment. Sertraline was studied as a free formulation (SERT) and also entrapped into phosphatidylserine liposomes (LP-SERT) against intracellular amastigotes and in a murine model of visceral leishmaniasis. LP-SERT showed a potent activity against intracellular amastigotes with an EC50 value of 2.5 μM. The in vivo efficacy of SERT demonstrated a therapeutic failure. However, when entrapped into negatively charged liposomes (-58 mV) of 125 nm, it significantly reduced the parasite burden in the mice liver by 89% at 1 mg/kg, reducing the serum levels of the cytokine IL-6 and upregulating the levels of the chemokine MCP-1. Histopathological studies demonstrated the presence of an inflammatory infiltrate with the development of granulomas in the liver, suggesting the resolution of the infection in the treated group. Delivery studies showed fluorescent-labeled LP-SERT in the liver and spleen of mice even after 48 h of administration. This study demonstrates the efficacy of PS liposomes containing sertraline in experimental VL. Considering the urgent need for VL treatments, the repurposing approach of SERT could be a promising alternative.
KW - drug delivery
KW - drug repurposing
KW - leishmania
KW - liposomes
KW - neglected diseases
KW - sertraline
UR - http://www.scopus.com/inward/record.url?scp=85075115445&partnerID=8YFLogxK
U2 - 10.3389/fcimb.2019.00353
DO - 10.3389/fcimb.2019.00353
M3 - Article
C2 - 31737574
AN - SCOPUS:85075115445
SN - 2235-2988
VL - 9
SP - 1
EP - 12
JO - Frontiers in Cellular and Infection Microbiology
JF - Frontiers in Cellular and Infection Microbiology
M1 - 353
ER -
