Calycosin-triblock copolymer nanomicelles attenuate doxorubicin-induced cardiotoxicity through upregulation of ERp57

Abstract It has been indicated that doxorubicin (Dox) can induce some unwanted cardiotoxicity through different signaling pathways. In the present study, calycosin-PEG-PPG-PEG copolymer nanomicelles were developed and well-characterized by different techniques. Afterwards, the protective effects of calycosin-triblock copolymer nanomicelles against Dox-stimulated cardiotoxicity in H9C2 cardiomyocytes was explored by viability, reactive oxygen species (ROS), and reactive nitrogen species (RNS) assays. Also, the expression level of ERp57, p53, Bax, and Bcl-2 at both mRNA and protein levels were assessed by qPCR and western blot assays, respectively. It was seen that synthesized calycosin-triblock copolymer nanomicelles had a size of around 20-30 nm with good colloidal stability, sustained drug release and improved dissolution rate. Also, it was shown that calycosin-triblock copolymer nanomicelles can penetrate into the nucleus of H9C2 cells and mitigate Dox-induced cardiotoxicity through a remarkable reduction in ROS and RNS generation. Also, it was found that calycosin-triblock copolymer nanomicelles resulted in the downregulation of Bax and P53 and overexpression of Bcl-2 and ERp57 at both mRNA and proteins level and these protective effects were inhibited in the presence of ERp57–siRNA silencing. Therefore, this study may provide useful information about the development of drug-loaded nanomicelles for mitigation of Dox-induced toxicity.