Polylactide Nanocapsules Attenuate Adverse Cardiac Cellular Effects of Lyso-7, a Pan-PPAR Agonist/Anti-Inflammatory New Thiazolidinedione

• Main Authors: Giani M. Garcia (Author), Jérôme Roy (Author), Ivan R. Pitta (Author), Dulcinéia S. P. Abdalla (Author), Andrea Grabe-Guimarães (Author), Vanessa C. F. Mosqueira (Author), Sylvain Richard (Author)
• Format: Book
• Published: MDPI AG, 2021-09-01T00:00:00Z.
• Subjects: article
• Online Access: Connect to this object online.
• Notes: 10.3390/pharmaceutics13091521; 1999-4923
• Keywords: peroxisome proliferator-activated receptor-γ; cardiotoxicity; metabolic syndrome; atherosclerosis; contraction; calcium transient; Pharmacy and materia medica; RS1-441
• Source: Pharmaceutics, Vol 13, Iss 9, p 1521 (2021)

Lyso-7 is a novel synthetic thiazolidinedione, which is a receptor (pan) agonist of PPAR α,β/δ,γ with anti-inflammatory activity. We investigated the cardiotoxicity of free Lyso-7 in vitro (4.5-450 nM), and Lyso-7 loaded in polylactic acid nanocapsules (NC) in vivo (Lyso-7-NC, 1.6 mg/kg). In previous work, we characterized Lyso-7-NC. We administered intravenously Lyso-7, Lyso-7-NC, control, and blank-NC once a day for seven days in mice. We assessed cell contraction and intracellular Ca²⁺ transients on single mice cardiomyocytes enzymatically isolated. Lyso-7 reduced cell contraction and accelerated relaxation while lowering diastolic Ca²⁺ and reducing Ca²⁺ transient amplitude. Lyso-7 also promoted abnormal ectopic diastolic Ca²⁺ events, which isoproterenol dramatically enhanced. Incorporation of Lyso-7 in NC attenuated drug effects on cell contraction and prevented its impact on relaxation, diastolic Ca²⁺, Ca²⁺ transient amplitude, Ca²⁺ transient decay kinetics, and promotion of diastolic Ca²⁺ events. Acute effects of Lyso-7 on cardiomyocytes in vitro at high concentrations (450 nM) were globally similar to those observed after repeated administration in vivo. In conclusion, we show evidence for off-target effects of Lyso-7, seen during acute exposure of cardiomyocytes to high concentrations and after repeated treatment in mice. Nano-encapsulation of Lyso-7 in polymeric NC attenuated the unwanted effects, particularly ectopic Ca²⁺ events known to support life-threatening arrhythmias favored by stress or exercise.