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Drug repurposing for the treatment of alveolar echinococcosis: in vitro and in vivo effects of silica nanoparticles modified with dichlorophen

Published online by Cambridge University Press:  28 August 2019

Julia Fabbri ,
Patricia E. Pensel ,
Clara M. Albani ,
Valeria B. Arce ,
Daniel O. Mártire  and
María C. Elissondo Open the ORCID record for María C. Elissondo [Opens in a new window]
Julia Fabbri
Affiliation:
Laboratorio de Zoonosis Parasitarias, Instituto de Investigaciones en Producción, Sanidad y Ambiente (IIPROSAM), Facultad de Ciencias Exactas y Naturales, Universidad Nacional de Mar del Plata, Funes 3250, 7600, Mar del Plata, Argentina Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina
Patricia E. Pensel
Affiliation:
Laboratorio de Zoonosis Parasitarias, Instituto de Investigaciones en Producción, Sanidad y Ambiente (IIPROSAM), Facultad de Ciencias Exactas y Naturales, Universidad Nacional de Mar del Plata, Funes 3250, 7600, Mar del Plata, Argentina Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina
Clara M. Albani
Affiliation:
Laboratorio de Zoonosis Parasitarias, Instituto de Investigaciones en Producción, Sanidad y Ambiente (IIPROSAM), Facultad de Ciencias Exactas y Naturales, Universidad Nacional de Mar del Plata, Funes 3250, 7600, Mar del Plata, Argentina Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina
Valeria B. Arce
Affiliation:
Centro de Investigaciones Ópticas (CIOp), (CONICET La Plata – CIC – UNLP), Camino Parque Centenario e/505 y 508, Gonnet, Argentina
Daniel O. Mártire
Affiliation:
Instituto de Investigaciones Fisicoquímicas Teóricas y Aplicadas (INIFTA), CCT-La Plata-CONICET, Universidad Nacional de La Plata, Diagonal 113 y 64, CP 1900, La Plata, Buenos Aires, Argentina
María C. Elissondo*
Affiliation:
Laboratorio de Zoonosis Parasitarias, Instituto de Investigaciones en Producción, Sanidad y Ambiente (IIPROSAM), Facultad de Ciencias Exactas y Naturales, Universidad Nacional de Mar del Plata, Funes 3250, 7600, Mar del Plata, Argentina Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina
*
Author for correspondence: María C. Elissondo, E-mail: c.elissondo@gmail.com
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Abstract

Alveolar echinococcosis is a neglected parasitic zoonosis caused by the metacestode Echinococcus multilocularis, which grows as a malignant tumour-like infection in the liver of humans. Albendazole (ABZ) is the antiparasitic drug of choice for the treatment of the disease. However, its effectiveness is low, due to its poor absorption from the gastro-intestinal tract. It is also parasitostatic and in some cases produces side-effects. Therefore, an alternative to the treatment of this severe human disease is necessary. In this context, the repositioning of drugs combined with nanotechnology to improve the bioavailability of drugs emerges as a useful, fast and inexpensive tool for the treatment of neglected diseases. The in vitro and in vivo efficacy of dichlorophen (DCP), an antiparasitic agent for intestinal parasites, and silica nanoparticles modified with DCP (NP-DCP) was evaluated against E. multilocularis larval stage. Both formulations showed a time and dose-dependent in vitro effect against protoscoleces. The NP-DCP had a greater in vitro efficacy than the drug alone or ABZ. In vivo studies demonstrated that the NP-DCP (4 mg kg−1) had similar efficacy to ABZ (25 mg kg−1) and greater activity than the free DCP. Therefore, the repurposing of DCP combined with silica nanoparticles could be an alternative for the treatment of echinococcosis.

Keywords

Albendazolealveolar echinococcosisdichlorophenEchinococcus multilocularissilica nanoparticles
Type
Research Article
Information
Parasitology , Volume 146 , Issue 13 , November 2019 , pp. 1620 - 1630
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Copyright
Copyright © Cambridge University Press 2019 

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References

Adams, ARD and Seaton, DR (1959) Treatment of Taenia saginata infection with dichlorophen. Transactions of the Royal Society of Tropical Medicine and Hygiene 53, 5.Google Scholar
Albani, CM and Elissondo, MC (2014) Efficacy of albendazole in combination with thymol against Echinococcus multilocularis protoscoleces and metacestodes. Acta Tropica 140, 61–67.Google Scholar
Albani, CM, Pensel, PE, Elissondo, N, Gambino, G and Elissondo, MC (2015) In vivo activity of albendazole in combination with thymol against Echinococcus multilocularis. Veterinary Parasitology 212, 193–199.Google Scholar
Arce, VB, Bertolotti, SG, Oliveira, FJ, Airoldi, C, Arques, A, Santos-Juanes, L, Gonzalez, MC, Cobos, CJ, Allegretti, PE and Mártire, DO (2012) Triplet state of 4-methoxybenzyl alcohol chemisorbed on silica nanoparticles. Photochemical & Photobiological Sciences 11, 1032–1040.Google Scholar
Ayres, M, Ayres, M Jr, Ayres, DL and Santos, AS (2007) BioEstat 5.0 – Aplicações estatísticas nas áreas das ciências bio-médicas, 5th Edn. Belém, Pará, Brazil: Imprensa Oficial do Estado do Pará.Google Scholar
Baker, NC, Ekins, S, Williams, AJ and Tropsha, A (2018) A bibliometric review of drug repurposing. Drug Discovery Today 23, 661–672.Google Scholar
Barik, TK, Kamaraju, R and Gowswami, A (2012) Silica nanoparticle: a potential new insecticide for mosquito vector control. Parasitology Research 111, 1075–1083.Google Scholar
Biagi, FF, Gómez Orozco, L and Robledo, E (1959) Efficacy of dichlorophen against Hymenolepis nana. Boletín Médico del Hospital Infantil 16, 113–116.Google Scholar
Daniel-Mwambete, K, Torrado, S, Cuesta-Bandera, C, Ponce-Gordo, F and Torrado, JJ (2004) The effect of solubilization on the oral bioavailability of three benzimidazole carbamate drugs. International Journal of Pharmaceutics 272, 29–36.Google Scholar
Deplazes, P, Rinaldi, L, Alvarez Rojas, CA, Torgerson, PR, Harandi, MF, Romig, T, Antolova, D, Schurer, JM, Lahmar, S, Cringoli, G, Magambo, J, Thompson, RCA and Jenkins, EJ (2017) Global distribution of alveolar and cystic echinococcosis. In Thompson, RCA, Deplazes, P and Lymbery, AJ (eds), Advances in Parasitology. Echinococcus and Echinococcosis, Part A, vol. 95. London, United Kingdom: Academic Press, pp. 315–493.Google Scholar
Elissondo, MC, Dopchiz, M, Ceballos, L, Alvarez, L, Sánchez Bruni, S, Lanusse, C and Denegri, G (2006) In vitro effects of flubendazole on Echinococcus granulosus protoscoleces. Parasitology Research 98, 317–323.Google Scholar
Elissondo, MC, Ceballos, L, Dopchiz, M, Andresiuk, V, Alvarez, L, Sánchez Bruni, S, Lanusse, C and Denegri, G (2007) In vitro and in vivo effects of flubendazole on Echinococcus granulosus metacestodes. Parasitology Research 100, 1003–1009.Google Scholar
El-Moslemany, RM, Eissa, MM, Ramadan, AA, El-Khordagui, LK and El-Azzouni, MZ (2016) Miltefosine lipid nanocapsules: intersection of drug repurposing and nanotechnology for single dose oral treatment of pre-patent schistosomiasis mansoni. Acta Tropica 159, 142–148.Google Scholar
Escalada, JP, Arce, VB, Porcal, GV, Biasutti, MA, Criado, S, García, NA and Mártire, DO (2014) The effect of dichlorophen binding to silica nanoparticles on its photosensitized degradation in water. Water Research 50, 229–236.Google Scholar
Fukui, M (1960) Studies on Momezia expansa and its intermediate host. V. Removal of sheep, tapeworms, M. expansa and M. benedeni, with bithionol and dichlorophen. Journal of the Japan Veterinary Medical Association 13, 294–297.Google Scholar
Fukui, M, Kaneko, C and Ogawa, A (1960) Studies on equine tapeworms and their intermediate hosts. 2. Studies on removal effects of bithionol, bithionol acetate and dichlorophen for equine tapeworm, Anoplocephala perfoliata. Japanese Journal of Parasitology 9, 217–223.Google Scholar
Gemmell, MA (1958) The efficiency of dichlorophen (2, 2′-dihydroxy-5, 5-dichlorodipenyl methane) against Echinococcus granulosus infestations in dogs. Australian Veterinary Journal 34, 249–252.Google Scholar
Grinenko, NV (1964) The action of anthelmintics and their compounds on cestodes in vitro. Meditsinskaya Parazitologiya i Parazitarnye Bolezni 33, 87–92.Google Scholar
Grüner, B, Kern, P, Mayer, B, Gräter, T, Hillenbrand, A, Barth, TEF, Muche, R, Henne-Bruns, D, Kratzer, W and Kern, P (2017) Comprehensive diagnosis and treatment of alveolar echinococcosis: a single-center, long-term observational study of 312 patients in Germany. GMS Infectious Diseases 5, 1–12.Google Scholar
Gucklhorn, IR (1969) Antimicrobials in cosmetics. Part 2. Manufacturing Chemist and Aerosol News 40, 38–40.Google Scholar
Halas, NJ (2008) Nanoscience under glass: the versatile chemistry of silica nanostructures. ACS Nano 2, 179–183.Google Scholar
Hemphill, A, Stadelmann, B, Rufener, R, Spiliotis, M, Boubaker, G, Müller, J, Müller, N, Gorgas, D and Gottstein, B (2014) Treatment of echinococcosis: albendazole and mebendazole-what else? Parasite 21, 70.Google Scholar
Irache, JM, Esparza, I, Gamazo, C, Agüeros, M and Espuelas, S (2011) Nanomedicine: novel approaches in human and veterinary therapeutics. Veterinary Parasitology 180, 47–71.Google Scholar
Jackson, FC (1956) The treatment of tapeworm infestation with dichlorophen. South African Medical Journal 30, 853–854.Google Scholar
Kern, P, Menezes da Silva, A, Akhan, O, Müllhaupt, B, Vizcaychipi, KA, Budke, C and Vuitton, DA (2017) The echinococcoses: diagnosis, clinical management and burden of disease. In Thompson, RCA, Deplazes, P and Lymbery, AJ (eds), Advances in Parasitology. Echinococcus and Echinococcosus, Part B, vol. 96. London, United Kingdom: Academic Press, pp. 259–369.Google Scholar
Küster, T, Stadelmann, B, Rufener, R, Risch, C, Müller, J and Hemphill, A (2015) Oral treatments of Echinococcus multilocularis-infected mice with the antimalarial drug mefloquine that potentially interacts with parasite ferritin and cystatin. International Journal of Antimicrobial Agents 46, 546–551.Google Scholar
Llinàs, MC and Sánchez-García, D (2014) Nanopartículas de sílice: preparación y aplicaciones en biomedicina. Afinidad 71, 20–31.Google Scholar
Lundström-Stadelmann, B, Rufener, R, Ritler, D, Zurbriggen, R and Hemphill, A (2019) The importance of being parasiticidal… an update on drug development for the treatment of alveolar echinococcosis. Food and Waterborne Parasitology 12, e00040.Google Scholar
Maddison, JE, Page, SW and Church, DB (2008) Small Animal Clinical Pharmacology, vol. 5. St. Louis, Missouri, USA: Elsevier Health Sciences.Google Scholar
Miller, TA (1966) Anthelmintic activity of toluene and dichlorophen against various stages of Ancylostoma caninum in young dogs. American Journal of Veterinary Research 27, 1755–1758.Google Scholar
Naguleswaran, A, Spicher, M, Vonlaufen, N, Ortega-Mora, LM, Torgerson, P, Gottstein, B and Hemphill, A (2006) In vitro metacestodicidal activities of genistein and other isoflavones against Echinococcus multilocularis and Echinococcus granulosus. Antimicrobial Agents and Chemotherapy 50, 3770–3778.Google Scholar
National Research Council US (2011) Guide for the Care and Use of Laboratory Animals, 8th Edn. Washington, DC, USA: National Academies Press.Google Scholar
Panic, G, Duthaler, U, Speich, B and Keiser, J (2014) Repurposing drugs for the treatment and control of helminth infections. International Journal for Parasitology: Drugs and Drug Resistance 4, 185–200.Google Scholar
Rapson, EB, Jenkins, DC and Topley, P (1985) Trichostrongylus colubriformis: in vitro culture of parasitic stages and their use for the evaluation of anthelmintics. Research in Veterinary Science 39, 90–94.Google Scholar
Reuter, S, Buck, A, Grebe, O, Nüssle-Kügele, K, Kern, P and Manfras, BJ (2003) Salvage treatment with amphotericin B in progressive human alveolar echinococcosis. Antimicrobial Agents and Chemotherapy 47, 3586–3591.Google Scholar
Rufener, R, Ritler, D, Zielinski, J, Dick, L, da Silva, ET, da Silva Araujo, A, Joekel, DE, Czock, D, Goepfert, C, Moraes, AM and de Souza, MVN (2018) Activity of mefloquine and mefloquine derivatives against Echinococcus multilocularis. International Journal for Parasitology: Drugs and Drug Resistance 8, 331–340.Google Scholar
Sakamoto, T (1973) Studies on echinococcosis XXV: anthelmintic action of drugs on larval Echinococcus multilocularis in vitro. Japanese Journal of Veterinary Research 21, 73–91.Google Scholar
Sen, AB and Hawking, F (1960) Screening of cesticidal compounds on a tapeworm Hymenolepis nana in vitro. British Journal of Pharmacology and Chemotherapy 15, 436–439.Google Scholar
Siles-Lucas, M, Casulli, A, Cirilli, R and Carmena, D (2018) Progress in the pharmacological treatment of human cystic and alveolar echinococcosis: compounds and therapeutic targets. PLoS Neglected Tropical Diseases 12, e0006422.Google Scholar
Spicher, M, Roethlisberger, C, Lany, C, Stadelmann, B, Keiser, J, Ortega-Mora, LM, Gottstein, B and Hemphill, A (2008) In vitro and in vivo treatments of Echinococcus protoscoleces and metacestodes with artemisinin and artemisinin derivatives. Antimicrobial Agents and Chemotherapy 52, 3447–3450.Google Scholar
Spiliotis, M and Brehm, K (2009) Axenic in vitro cultivation of Echinococcus multilocularis metacestode vesicles and the generation of primary cell cultures. In Rupp, S and Sohn, K (eds), Host-Pathogen Interactions. Methods in Molecular Biology, vol. 470. Totowa, New Jersey, United States: Humana Press, pp. 245–262.Google Scholar
Stettler, M, Rossignol, JF, Fink, R, Walker, M, Gottstein, B, Merli, M, Theurillat, R, Thormann, W, Dricot, E, Segers, R and Hemphill, A (2004) Secondary and primary murine alveolar echinococcosis: combined albendazole/nitazoxanide chemotherapy exhibits profound anti-parasitic activity. International Journal for Parasitology 34, 615–624.Google Scholar
Tappe, D, Müller, A, Frosch, M and Stich, A (2009) Limitations of amphotericin B and nitazoxanide in the treatment of alveolar echinococcosis. Annals of Tropical Medicine and Parasitology 103, 177–181.Google Scholar
Thompson, DP and Geary, T (1995) The structure and function of helminth surfaces. In Harr, J and Muller, M (eds), Biochemistry and Molecular Biology of Parasites. London, UK: Academic, pp. 203–232.Google Scholar
Vico, TA, Arce, VB, Fangio, MF, Gende, LB, Bertran, CA, Mártire, DO and Churio, MS (2016) Two choices for the functionalization of silica nanoparticles with gallic acid: characterization of the nanomaterials and their antimicrobial activity against Paenibacillus larvae. Journal of Nanoparticle Research 18, 348.Google Scholar
Yamarik, TA (2004) Safety assessment of dichlorophene and chlorophene. International Journal of Toxicology 23, 1–27.Google Scholar