Single-dose treatment for cutaneous leishmaniasis with an easily synthesized chalcone entrapped in polymeric microparticles

TY - JOUR

T1 - Single-dose treatment for cutaneous leishmaniasis with an easily synthesized chalcone entrapped in polymeric microparticles

AU - Sousa-Batista, Ariane J.

AU - Arruda-Costa, Natalia

AU - O. Escrivani, Douglas

AU - Reynaud, Franceline

AU - Steel, Patrick G.

AU - Rossi-Bergmann, Bartira

N1 - Funding Information: The authors thank the Brazilian agencies FAPERJ (E-26/202.402/2017 – BBP) and CNPq for financial support and The Royal Society London for an International Collaboration Award for Research Professors (#IC160044 to BRB and PGS). Publisher Copyright: Copyright © The Author(s), 2020. Published by Cambridge University Press. Copyright: Copyright 2020 Elsevier B.V., All rights reserved.

PY - 2020/8

Y1 - 2020/8

N2 - Cutaneous leishmaniasis (CL) is a major health problem in many countries and its current treatment involves multiple parenteral injections with toxic drugs and requires intensive health services. Previously, the efficacy of a single subcutaneous injection with a slow-release formulation consisting of poly(lactide-co-glycolide) (PLGA) microparticles loaded with an antileishmanial 3-nitro-2-hydroxy-4,6-dimethoxychalcone (CH8) was demonstrated in mice model. In the search for more easily synthesized active chalcone derivatives, and improved microparticle loading, CH8 analogues were synthesized and tested for antileishmanial activity in vitro and in vivo. The 3-nitro-2′,4′,6′-trimethoxychalcone (NAT22) analogue was chosen for its higher selectivity against intracellular amastigotes (selectivity index = 1489, as compared with 317 for CH8) and more efficient synthesis (89% yield, as compared with 18% for CH8). NAT22 was loaded into PLGA / polyvinylpyrrolidone (PVP) polymeric blend microspheres (NAT22-PLGAk) with average diameter of 1.9 μm. Although NAT22-PLGAk showed similar activity to free NAT22 in killing intracellular parasites in vitro (IC50 ~ 0.2 μm), in vivo studies in Leishmania amazonensis - infected mice demonstrated the significant superior efficacy of NAT22-PLGAk to reduce the parasite load. A single intralesional injection with NAT22-PLGAk was more effective than eight injections with free NAT22. Together, these results show that NAT22-PLGAk is a promising alternative for single-dose localized treatment of CL.

AB - Cutaneous leishmaniasis (CL) is a major health problem in many countries and its current treatment involves multiple parenteral injections with toxic drugs and requires intensive health services. Previously, the efficacy of a single subcutaneous injection with a slow-release formulation consisting of poly(lactide-co-glycolide) (PLGA) microparticles loaded with an antileishmanial 3-nitro-2-hydroxy-4,6-dimethoxychalcone (CH8) was demonstrated in mice model. In the search for more easily synthesized active chalcone derivatives, and improved microparticle loading, CH8 analogues were synthesized and tested for antileishmanial activity in vitro and in vivo. The 3-nitro-2′,4′,6′-trimethoxychalcone (NAT22) analogue was chosen for its higher selectivity against intracellular amastigotes (selectivity index = 1489, as compared with 317 for CH8) and more efficient synthesis (89% yield, as compared with 18% for CH8). NAT22 was loaded into PLGA / polyvinylpyrrolidone (PVP) polymeric blend microspheres (NAT22-PLGAk) with average diameter of 1.9 μm. Although NAT22-PLGAk showed similar activity to free NAT22 in killing intracellular parasites in vitro (IC50 ~ 0.2 μm), in vivo studies in Leishmania amazonensis - infected mice demonstrated the significant superior efficacy of NAT22-PLGAk to reduce the parasite load. A single intralesional injection with NAT22-PLGAk was more effective than eight injections with free NAT22. Together, these results show that NAT22-PLGAk is a promising alternative for single-dose localized treatment of CL.

KW - Chalcone

KW - chemotherapy

KW - drug delivery systems

KW - Leishmania

KW - local treatment

UR - https://www.scopus.com/pages/publications/85085120337

U2 - 10.1017/S0031182020000712

DO - 10.1017/S0031182020000712

M3 - Article

C2 - 32364107

AN - SCOPUS:85085120337

SN - 0031-1820

VL - 147

SP - 1032

EP - 1037

JO - Parasitology

JF - Parasitology

IS - 9

ER -