OpiCa1-PEG-PLGA nanomicelles antagonize acute heart failure induced by the cocktail of epinephrine and caffeine

Jun Li; Fei Wang; Xinyan Liu; Zhixiao Yang; Xiaoyu Hua; Hongqiao Zhu; Carmen R Valdivia; Li Xiao; Songyu Gao; Héctor H Valdivia; Liang Xiao; Jinming Wang

doi:10.1016/j.mtbio.2023.100859

OpiCa1-PEG-PLGA nanomicelles antagonize acute heart failure induced by the cocktail of epinephrine and caffeine

Mater Today Bio. 2023 Nov 8:23:100859. doi: 10.1016/j.mtbio.2023.100859. eCollection 2023 Dec.

Authors

Jun Li^{1

2}, Fei Wang², Xinyan Liu³, Zhixiao Yang^{2

4}, Xiaoyu Hua², Hongqiao Zhu³, Carmen R Valdivia⁵, Li Xiao^{5

6}, Songyu Gao², Héctor H Valdivia⁵, Liang Xiao², Jinming Wang¹

Affiliations

¹ College of Veterinary Medicine, Shanxi Agricultural University, ShanXi, TaiGu, 030801, China.
² Department of Occupational and Environmental Health, Faculty of Naval Medicine, Naval Medical University (Second Military Medical University), Shanghai, 200433, China.
³ Department of Traditional Chinese Medicine Surgery, The First Affiliated Hospital of the Navy Medical University (Changhai Hospital), Shanghai, 200433, China.
⁴ Teaching and Research Department of Chinese Pharmacy, Yunnan Traditional Chinese Medicine, YunNan, KunMing, 650500, China.
⁵ Department of Medicine and Cardiovascular Research Center, University of Wisconsin-Madison School of Medicine and Public Health, Madison, WI, USA.
⁶ Department of Forensic Toxicological Analysis, West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu, 610065, China.

Abstract

Background: Reducing Ca²⁺ content in the sarcoplasmic reticulum (SR) through ryanodine receptors (RyRs) by calcin is a potential intervention strategy for the SR Ca²⁺ overload triggered by β-adrenergic stress in acute heart diseases.

Methods: OpiCal-PEG-PLGA nanomicelles were prepared by thin film dispersion, of which the antagonistic effects were observed using an acute heart failure model induced by epinephrine and caffeine in mice. In addition, cardiac targeting, self-stability as well as biotoxicity were determined.

Results: The synthesized OpiCa1-PEG-PLGA nanomicelles were elliptical with a particle size of 72.26 nm, a PDI value of 0.3, and a molecular weight of 10.39 kDa. The nanomicelles showed a significant antagonistic effect with 100 % survival rate to the death induced by epinephrine and caffeine, which was supported by echocardiography with significantly recovered heart rate, ejection fraction and left ventricular fractional shortening rate. The FITC labeled nanomicelles had a strong membrance penetrating capacity within 2 h and cardiac targeting within 12 h that was further confirmed by immunohistochemistry with a self-prepared OpiCa1 polyclonal antibody. Meanwhile, the nanomicelles can keep better stability and dispersibility in vitro at 4 °C rather than 20 °C or 37 °C, while maintain a low but stable plasma OpiCa1 concentration in vivo within 72 h. Finally, no obvious biotoxicities were observed by CCK-8, flow cytometry, H&E staining and blood biochemical examinations.

Conclusion: Our study also provide a novel nanodelivery pathway for targeting RyRs and antagonizing the SR Ca²⁺ disordered heart diseases by actively releasing SR Ca²⁺ through RyRs with calcin.

Keywords: Acute heart failure; Ca2+; OpiCa1-PEG-PLGA nanomicelle; RyR2; β-adrenergic stress.