Hostname: page-component-5d59c44645-jb2ch Total loading time: 0 Render date: 2024-02-20T15:13:36.637Z Has data issue: false hasContentIssue false

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

Published online by Cambridge University Press:  04 May 2020

Ariane J. Sousa-Batista*
Affiliation:
Carlos Chagas Filho Biophysics Institute, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil Nanotechnology Engineering Program, Alberto Luiz Coimbra Institute for Graduate Studies and Research in Engineering – COPPE, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
Natalia Arruda-Costa
Affiliation:
Carlos Chagas Filho Biophysics Institute, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
Douglas O. Escrivani
Affiliation:
Carlos Chagas Filho Biophysics Institute, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
Franceline Reynaud
Affiliation:
Faculty of Pharmacy, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
Patrick G. Steel
Affiliation:
Department of Chemistry, Durham University, Durham, UK
Bartira Rossi-Bergmann
Affiliation:
Carlos Chagas Filho Biophysics Institute, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
*
Author for correspondence: Ariane J. Sousa-Batista, E-mail: ariane@pent.coppe.ufrj.br

Abstract

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.

Type
Research Article
Copyright
Copyright © The Author(s), 2020. Published by Cambridge University Press

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

Footnotes

*

These authors contributed equally to this work.

References

Amslinger, S, Al-Rifai, N, Winter, K, Wörmann, K, Scholz, R, Baumeistera P and Wild, M (2013) Reactivity Assessment of Chalcones by a Kinetic Thiol Assay. Organic & Biomolecular Chemistry 11, 549554.CrossRefGoogle ScholarPubMed
Aronson, NE and Joya, CA (2019) Cutaneous leishmaniasis: updates in diagnosis and management. Infectious Disease Clinics of North America 33, 101117.CrossRefGoogle ScholarPubMed
Boeck, P, Bandeira Falcão, CA, Leal, PC, Yunes, RA, Filho, VC, Torres-Santos, EC and Rossi-Bergmann, B (2006) Synthesis of chalcone analogues with increased antileishmanial activity. Bioorganic and Medicinal Chemistry 14, 15381545.CrossRefGoogle ScholarPubMed
Costa, SS, Golim, MA, Rossi-Bergmann, B, Costa, FTM and Giorgio, S (2011) Use of in vivo and in vitro systems to select Leishmania amazonensis expressing green fluorescent protein. Korean Journal of Parasitology 49, 357364.CrossRefGoogle Scholar
De Castro, CCB, Costa, PS, Laktin, GT, De Carvalho, PHD, Geraldo, RB, De Moraes, J, Pinto, PLS, Couri, MRC, Pinto, PDF and Da Silva Filho, AA (2015) Cardamonin, a schistosomicidal chalcone from Piper aduncum L. (Piperaceae) that Inhibits Schistosoma Mansoni ATP Diphosphohydrolase. Phytomedicine 22, 921928.CrossRefGoogle ScholarPubMed
de Mello, TFP, Bitencourt, HR, Pedroso, RB, Aristides, SMA, Lonardoni, MVC and Silveira, TGV (2014) Leishmanicidal activity of synthetic chalcones in Leishmania (Viannia) braziliensis. Experimental Parasitology 136, 2734.CrossRefGoogle ScholarPubMed
Demicheli, C, Ochoa, R, da Silva, JBB, Falcão, CAB, Rossi-Bergmann, B, de Melo, AL, Sinisterra, RD and Frézard, F (2004) Oral delivery of meglumine antimoniate-beta-cyclodextrin complex for treatment of leishmaniasis. Antimicrobial Agents and Chemotherapy 48, 100103.CrossRefGoogle ScholarPubMed
Herencia, F, Ferrándiz, ML, Ubeda, A, Guillén, I, Dominguez, JN, Charris, JE, Lobo, GM and Alcaraz, MJ (1999) Novel anti-inflammatory chalcone derivatives inhibit the induction of nitric oxide synthase and cyclooxygenase-2 in mouse peritoneal macrophages. FEBS Letters 453, 129134.CrossRefGoogle ScholarPubMed
Kayser, O and Kiderlen, AF (2001) In vitro leishmanicidal activity of aurones. Phytotherapy Research 15, 148152.CrossRefGoogle Scholar
Kumar, CV, Ramaiah, D, Das, PK and George, MV (1985) Photochemistry of aromatic .alpha.,.beta.-epoxy ketones. Substituent effects on oxirane ring-opening and related ylide behavior. The Journal of Organic Chemistry 50, 28182825.CrossRefGoogle Scholar
Kunthalert, D, Baothong, S, Khetkam, P, Chokchaisiri, S and Suksamrarn, A (2014) A chalcone with potent inhibiting activity against biofilm formation by nontypeable Haemophilus influenzae. Microbiology and Immunology 58, 581589.CrossRefGoogle ScholarPubMed
Łacka, I, Konieczny, MT, Bulłakowska, A, Rzymowski, T and Milewski, S (2011) Antifungal action of the oxathiolone-fused chalcone derivative. Mycoses 54, 407414.CrossRefGoogle ScholarPubMed
Li, H, Chen, Y, Zhang, B, Niu, X, Song, M, Luo, Z, Lu, G, Liu, B, Zhao, X, Wang, J and Deng, X (2016) Inhibition of sortase A by chalcone prevents Listeria monocytogenes infection. Biochemical Pharmacology 106, 1929.CrossRefGoogle ScholarPubMed
Lima, HC, Bleyenberg, JA and Titus, RG (1997) A simple method for quantifying Leishmania in tissues of infected animals. Parasitology Today 13, 8082.CrossRefGoogle ScholarPubMed
Luo, Y, Song, R, Li, Y, Zhang, S, Liu, Z-J, Fu, J and Zhu, H-L (2012) Design, synthesis, and biological evaluation of chalcone oxime derivatives as potential immunosuppressive agents. Bioorganic & Medicinal Chemistry Letters 22, 30393043.CrossRefGoogle ScholarPubMed
Luzardo-Alvarez, A, Blarer, N, Peter, K, Romero, JF, Reymond, C, Corradin, G and Gander, B (2005) Biodegradable microspheres alone do not stimulate murine macrophages in vitro, but prolong antigen presentation by macrophages in vitro and stimulate a solid immune response in mice. Journal of Controlled Release 109, 6276.CrossRefGoogle Scholar
Meeus, J, Scurr, DJ, Amssoms, K, Davies, MC, Roberts, CJ and Van Den Mooter, G (2013) Surface characteristics of spray-dried microspheres consisting of PLGA and PVP: relating the influence of heat and humidity to the thermal characteristics of these polymers. Molecular Pharmaceutics 10, 32133224.CrossRefGoogle ScholarPubMed
Meeus, J, Scurr, DJ, Appeltans, B, Amssoms, K, Annaert, P, Davies, MC, Roberts, CJ and Van Den Mooter, G (2015) Influence of formulation composition and process on the characteristics and in vitro release from PLGA-based sustained release injectables. European Journal of Pharmaceutics and Biopharmaceutics 90, 2229.CrossRefGoogle ScholarPubMed
Nielsen, SF, Christensen, SB, Cruciani, G, Kharazmi, A and Liljefors, T (1998) Antileishmanial chalcones: statistical design, synthesis, and three-dimensional quantitative structure–activity relationship analysis. Journal of Medicinal Chemistry 41, 48194832.CrossRefGoogle ScholarPubMed
Oliveira-Neto, MP, Schubach, A, Mattos, M, da Costa, SC and Pirmez, C (1997) Intralesional therapy of American cutaneous leishmaniasis with pentavalent antimony in Rio de Janeiro, Brazil – an area of Leishmania (V.) braziliensis transmission. International Journal of Dermatology 36, 463468.CrossRefGoogle Scholar
Ortalli, M, Ilari, A, Colotti, G, De Ionna, I, Battista, T, Bisi, A, Gobbi, S, Rampa, A, Di Martino, RM, Gentilomi, GA, Varani, S and Belluti, F (2018) Identification of chalcone-based antileishmanial agents targeting trypanothione reductase. European Journal of Medicinal Chemistry 152, 527541.CrossRefGoogle ScholarPubMed
Ortega-Oller, I, Padial-Molina, M, Galindo-Moreno, P, O'Valle, F, Jódar-Reyes, AB and Peula-García, JM (2015) Bone regeneration from PLGA Micro-Nanoparticles. BioMed Research International 2015, 118.CrossRefGoogle ScholarPubMed
Patterson, S and Wyllie, S (2014) Nitro drugs for the treatment of trypanosomatid diseases: past, present, and future prospects. Trends in Parasitology 30, 289298.CrossRefGoogle ScholarPubMed
Sivakumar, PM, Prabhakar, PK and Doble, M (2011) Synthesis, antioxidant evaluation, and quantitative structure-activity relationship studies of chalcones. Medicinal Chemistry Research 20, 482492.CrossRefGoogle Scholar
Sousa-Batista, AJ and Rossi-Bergmann, B (2018). Nanomedicines for cutaneous leishmaniasis. In Afrin F (ed.), Leishmaniases as Re-Emerging Diseases. UK: IntechOpen, pp. 181197.Google Scholar
Sousa-Batista, AJ, Escrivani-Oliveira, D, Falcão, CAB, Da Silva Philipon, CIM and Rossi-Bergmann, B (2018 a) Broad spectrum and safety of oral treatment with a promising nitrosylated chalcone in murine leishmaniasis. Antimicrobial Agents and Chemotherapy 62, 15.CrossRefGoogle ScholarPubMed
Sousa-Batista, AJ, Pacienza-Lima, W, Arruda-Costa, N, Falcão, CAB and Rossi-Bergmann, B (2018 b) Depot subcutaneous injection with chalcone CH8-loaded PLGA microspheres aiming at a single-dose treatment of cutaneous leishmaniasis. Antimicrobial Agents and Chemotherapy 62, e01822–17.Google Scholar
Sousa-Batista, AJ, Arruda-Costa, N, Rossi-Bergmann, B and , MI (2018 c) Improved drug loading Via Spray drying of a chalcone implant for local treatment of cutaneous leishmaniasis. Drug Development and Industrial Pharmacy 18, 18.Google Scholar
Sousa-Batista, AJ, Pacienza-Lima, W, , MI and Rossi-Bergmann, B (2019) Novel and safe single-dose treatment of cutaneous leishmaniasis with implantable amphotericin B-loaded microspheres. International Journal for Parasitology: Drugs and Drug Resistance 11, 148155.Google Scholar
Tiwari, B, Pratapwar, A, Tapas, A, Butle, S and Vatkar, B (2010) Synthesis and antimicrobial activity of some chalcone derivatives and their copper complexes. International Journal of ChemTech Research 2, 499503.Google Scholar
Torres-Santos, EC, Moreira, DL, Kaplan, MAC, Meirelles, MN and Rossi-Bergmann, B (1999a) Selective effect of 2’,6’-dihydroxy-4’-methoxychalcone isolated from Piper aduncum on Leishmania amazonensis. Antimicrobial Agents and Chemotherapy 43, 12341241.CrossRefGoogle Scholar
Torres-Santos, EC, Rodrigues, JM, Moreira, DL, Kaplan, MAC and Rossi-Bergmann, B (1999b) Improvement of in vitro and in vivo antileishmanial activities of 2’,6’- dihydroxy-4’-methoxychalcone by entrapment in poly(D,L-lactide) nanoparticles. Antimicrobial Agents and Chemotherapy 43, 17761778.CrossRefGoogle Scholar
Uliana, SRB, Trinconi, CT and Coelho, AC (2017) Chemotherapy of leishmaniasis: present challenges. Parasitology 20, 117.Google Scholar
Wan, F and Yang, M (2015) Design of PLGA-based depot delivery systems for biopharmaceuticals prepared by spray drying. International Journal of Pharmaceutics 498, 8295.CrossRefGoogle ScholarPubMed
WHO (2017) Global leishmaniasis update, 2006–2015: a turning point in leishmaniasis surveillance. Weekly Epidemiological Record 92, 557572.Google Scholar