title: Biodegradable Polymeric Nanocapsules Prevent Cardiotoxicity of Anti-Trypanosomal Lychnopholide.
abstract: Chagas disease is a neglected parasitic disease caused by the protozoan Trypanosoma cruzi. New antitrypanosomal options are desirable to prevent complications, including a high rate of cardiomyopathy. Recently, a natural substance, lychnopholide, has shown therapeutic potential, especially when encapsulated in biodegradable polymeric nanocapsules. However, little is known regarding possible adverse effects of lychnopholide. Here we show that repeated-dose intravenous administration of free lychnopholide (2.0 mg/kg/day) for 20 days caused cardiopathy and mortality in healthy C57BL/6 mice. Echocardiography revealed concentric left ventricular hypertrophy with preserved ejection fraction, diastolic dysfunction and chamber dilatation at end-stage. Single cardiomyocytes presented altered contractility and Ca2+handling, with spontaneous Ca2+waves in diastole. Acute in vitro lychnopholide application on cardiomyocytes from healthy mice also induced Ca2+handling alterations with abnormal RyR2-mediated diastolic Ca2+release. Strikingly, the encapsulation of lychnopholide prevented the cardiac alterations induced in vivo by the free form repeated doses. Nanocapsules alone had no adverse cardiac effects. Altogether, our data establish lychnopholide presented in nanocapsule form more firmly as a promising new drug candidate to cure Chagas disease with minimal cardiotoxicity. Our study also highlights the potential of nanotechnology not only to improve the efficacy of a drug but also to protect against its adverse effects.
authors.affiliation: Pharmaceutical Sciences Post-graduation Program (CiPharma), Escola de Farmácia, Universidade Federal de Ouro Preto, Minas Gerais, Brazil.|PHYMEDEXP, Inserm U1046, CNRS UMR 9214, Université de Montpellier - Montpellier, France.
authors.forename: Renata Tupinambá
authors.initials: RT
authors.lastname: Branquinho
authors.affiliation: PHYMEDEXP, Inserm U1046, CNRS UMR 9214, Université de Montpellier - Montpellier, France.
authors.forename: Jérôme
authors.initials: J
authors.lastname: Roy
authors.affiliation: PHYMEDEXP, Inserm U1046, CNRS UMR 9214, Université de Montpellier - Montpellier, France.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Farah
authors.affiliation: Pharmaceutical Sciences Post-graduation Program (CiPharma), Escola de Farmácia, Universidade Federal de Ouro Preto, Minas Gerais, Brazil.|PHYMEDEXP, Inserm U1046, CNRS UMR 9214, Université de Montpellier - Montpellier, France.
authors.forename: Giani Martins
authors.initials: GM
authors.lastname: Garcia
authors.affiliation: PHYMEDEXP, Inserm U1046, CNRS UMR 9214, Université de Montpellier - Montpellier, France.
authors.forename: Franck
authors.initials: F
authors.lastname: Aimond
authors.affiliation: PHYMEDEXP, Inserm U1046, CNRS UMR 9214, Université de Montpellier - Montpellier, France.
authors.forename: Jean-Yves
authors.initials: JY
authors.lastname: Le Guennec
authors.affiliation: Pharmaceutical Sciences Post-graduation Program (CiPharma), Escola de Farmácia, Universidade Federal de Ouro Preto, Minas Gerais, Brazil.
authors.forename: Dênia Antunes
authors.initials: DA
authors.lastname: Saude-Guimarães
authors.affiliation: Pharmaceutical Sciences Post-graduation Program (CiPharma), Escola de Farmácia, Universidade Federal de Ouro Preto, Minas Gerais, Brazil.
authors.forename: Andrea
authors.initials: A
authors.lastname: Grabe-Guimaraes
authors.affiliation: Pharmaceutical Sciences Post-graduation Program (CiPharma), Escola de Farmácia, Universidade Federal de Ouro Preto, Minas Gerais, Brazil.
authors.forename: Vanessa Carla Furtado
authors.initials: VC
authors.lastname: Mosqueira
authors.affiliation: Pharmaceutical Sciences Post-graduation Program (CiPharma), Escola de Farmácia, Universidade Federal de Ouro Preto, Minas Gerais, Brazil.
authors.forename: Marta
authors.initials: M
authors.lastname: de Lana
authors.affiliation: PHYMEDEXP, Inserm U1046, CNRS UMR 9214, Université de Montpellier - Montpellier, France.
authors.forename: Sylvain
authors.initials: S
authors.lastname: Richard
mesh_terms: D000818:Animals; D001672:Biocompatible Materials / Q000737:chemistry; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects; D002316:Cardiotonic Agents / Q000737:chemistry / Q000494:pharmacology*; D066126:Cardiotoxicity; D014355:Chagas Disease / Q000175:diagnosis / Q000188:drug therapy / Q000401:mortality / Q000469:parasitology; D004452:Echocardiography; D007783:Lactones / Q000009:adverse effects*; D008297:Male; D051379:Mice; D057054:Molecular Imaging; D009026:Mortality; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism; D053769:Nanocapsules / Q000737:chemistry; D011108:Polymers / Q000737:chemistry; D012717:Sesquiterpenes / Q000009:adverse effects*; D014344:Trypanocidal Agents / Q000009:adverse effects*; D014349:Trypanosoma cruzi / Q000187:drug effects*
chemical_list: D001672:Biocompatible Materials; D002316:Cardiotonic Agents; D007783:Lactones; D053769:Nanocapsules; D011108:Polymers; D012717:Sesquiterpenes; D014344:Trypanocidal Agents; C427603:lychnopholide; D002118:Calcium