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.

Increased Body Exposure to New Anti-Trypanosomal Through Nanoencapsulation

“…However, in the plasma LYC may remain associated to NC for longer periods and be only partially released. This assumption is in agreement with the low cardiotoxicity of LYC in NC formulation 11 . In addition, the total LYC plasma levels do not necessarily represent the levels of free LYC available to exert pharmacological activity, considering that part of the LYC detected in the plasma can be associated to plasma proteins or remain encapsulated, as suggested by our release experiment.…”

“…We developed and validated a simple bioanalytical method based on high performance liquid chromatography with ultraviolet detection (HPLC-UV) for the quantification of LYC in plasma samples, applicable to perform in vitro release kinetic studies and to compare the pharmacokinetics of LYC in mice after intravenous administration of the formulations. The data reported here provide the foundations to explain and correlate the recently reported enhanced efficacy 6 , 7 and reduced toxicity 11 of this new candidate in NC dosage form for the treatment of Chagas disease.…”

“…The ability of polymeric NC to improve the biopharmaceutical properties of lipophilic substances has been extensively demonstrated 10 . Recently, the association of LYC with polymeric NC was reported to modify the release properties of LYC in vitro 8 , improve its efficacy in the acute 6 and chronic phases of the experimental infection and prevent cardiotoxicity 11 in mice by the intravenous and oral routes 7 .…”

Mechanisms of artemether toxicity on single cardiomyocytes and protective effect of nanoencapsulation

“…Sarcomere length (SL) shortening, an index of contraction, and intracellular Ca 2+ transients of left ventricular (LV) myocytes loaded with fluorescent ratiometric Ca 2+ indicator Indo-1AM (2 mM, Invitrogen Grand Island, NY, USA) were monitored with an IonOptix system (Milton, MA, USA) as described before (Branquinho, Roy, et al, 2017).…”

Ravuconazole self-emulsifying delivery system: in vitro activity against <em>Trypanosoma cruzi</em> amastigotes and in vivo toxicity

“…In addition, our group recently reported that nanostructured formulation is a strategy that can make a marked difference in vivo with improved efficacy and reduced toxicity of active compounds, including in the treatment of experimental Chagas disease by the oral route. [23][24][25] In this work, a RAV-SEDDS formulation for oral administration was developed and characterized. The safety of the formulation was evaluated in vivo in a 20-day treatment protocol in healthy mice and in T. cruzi-infected mice.…”