Notoginsenoside R1-loaded mesoporous silica nanoparticles targeting the site of injury through inflammatory cells improves heart repair after myocardial infarction
Han Li,
Jing Zhu,
Yan-wu Xu,
Fang-fang Mou,
Xiao-li Shan,
Qiang-li Wang,
Bao-nian Liu,
Ke Ning,
Jia-jia Liu,
Ya-chao Wang,
Jin-xia Mi,
Xiaohui Wei,
Shui-jin Shao,
Guo-hong Cui,
Rong Lu,
Hai-dong Guo
Affiliations
Han Li
Academy of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China; Department of Anatomy, School of Basic Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
Jing Zhu
Department of Anatomy, School of Basic Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
Yan-wu Xu
Department of Biochemistry, School of Basic Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
Fang-fang Mou
Department of Anatomy, School of Basic Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
Xiao-li Shan
School of Basic Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
Qiang-li Wang
Department of Histoembryology, School of Basic Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
Bao-nian Liu
Department of Anatomy, School of Basic Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
Ke Ning
Department of Physiology, School of Basic Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
Jia-jia Liu
Academy of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China; Department of Anatomy, School of Basic Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
Ya-chao Wang
Academy of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China; Department of Anatomy, School of Basic Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
Jin-xia Mi
Science and Technology Center, Shanghai University of Traditional Chinese Medicine, Shanghai, China
Xiaohui Wei
The MOE Key Laboratory for Standardization of Chinese Medicines and the SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
Shui-jin Shao
Department of Anatomy, School of Basic Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
Guo-hong Cui
Department of Neurology, Shanghai No. 9 People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200011, China; Corresponding author.
Rong Lu
School of Basic Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China; Corresponding author.
Hai-dong Guo
Academy of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China; Department of Anatomy, School of Basic Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China; Corresponding author. Academy of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
Notoginsenoside R1 (NGR1) is the main monomeric component extracted from the dried roots and rhizomes of Panax notoginseng, and exerts pharmacological action against myocardial infarction (MI). Owing to the differences in compound distribution, absorption, and metabolism in vivo, exploring a more effective drug delivery system with a high therapeutic targeting effect is crucial. In the early stages of MI, CD11b-expressing monocytes and neutrophils accumulate at infarct sites. Thus, we designed a mesoporous silica nanoparticle-conjugated CD11b antibody with loaded NGR1 (MSN-NGR1-CD11b antibody), which allowed NGR1 precise targeted delivery to the heart in a noninvasively manner. By increasing targeting to the injured myocardium, intravenous injection of MSN-NGR1-CD11b antibody nanoparticle in MI mice improved cardiac function and angiogenesis, reduced cell apoptosis, and regulate macrophage phenotype and inflammatory factors and chemokines. In order to further explore the mechanism of NGR1 protecting myocardium, cell oxidative stress model and oxygen-glucose deprivation (OGD) model were established. NGR1 protected H9C2 cells and primary cardiomyocytes against oxidative injury induced by H2O2 and OGD treatment. Further network pharmacology and molecular docking analyses suggested that the AKT, MAPK and Hippo signaling pathways were involved in the regulation of NGR1 in myocardial protection. Indeed, NGR1 could elevate the levels of p-Akt and p-ERK, and promote the nuclear translocation of YAP. Furthermore, LY294002 (AKT inhibitor), U0126 (ERK1/2 inhibitor) and Verteporfin (YAP inhibitor) administration in H9C2 cells indicated the involvement of AKT, MAPK and Hippo signaling pathways in NGR1 effects. Meanwhile, MSN-NGR1-CD11b antibody nanoparticles enhanced the activation of AKT and MAPK signaling pathways and the nuclear translocation of YAP at the infarcted site. Our research demonstrated that MSN-NGR1-CD11b antibody nanoparticle injection after MI enhanced the targeting of NGR1 to the infarcted myocardium and improved cardiac function. More importantly, our pioneering research provides a new strategy for targeting drug delivery systems to the ischemic niche.
