Theranostics 2018; 8(7):1869-1878. doi:10.7150/thno.20524

Research Paper

Targeting regenerative exosomes to myocardial infarction using cardiac homing peptide

Adam Vandergriff1,2*, Ke Huang2*, Deliang Shen3✉*, Shiqi Hu1,2, Michael Taylor Hensley2, Thomas G. Caranasos4, Li Qian5, Ke Cheng1,2✉

1. Joint Department of Biomedical Engineering at University of North Carolina at Chapel Hill and North Carolina State University,
2. Department of Molecular and Biomedical Sciences and Comparative Medicine Institute, North Carolina State University, Raleigh, North Carolina
3. Department of Cardiovascular Medicine, First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
4. Department of Cardiothoracic Surgery, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
5. Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
* Equal Contributions

Abstract

Rationale: Cardiac stem cell-derived exosomes have been demonstrated to promote cardiac regeneration following myocardial infarction in preclinical studies. Recent studies have used intramyocardial injection in order to concentrate exosomes in the infarct. Though effective in a research setting, this method is not clinically appealing due to its invasive nature. We propose the use of a targeting peptide, cardiac homing peptide (CHP), to target intravenously-infused exosomes to the infarcted heart.

Methods: Exosomes were conjugated with CHP through a DOPE-NHS linker. Ex vivo targeting was analyzed by incubating organ sections with the CHP exosomes and analyzing with fluorescence microscopy. In vitro assays were performed on neonatal rat cardiomyocytes and H9C2 cells. For the animal study, we utilized an ischemia/reperfusion rat model. Animals were treated with either saline, scramble peptide exosomes, or CHP exosomes 24 h after surgery. Echocardiography was performed 4 h after surgery and 21 d after surgery. At 21 d, animals were sacrificed, and organs were collected for analysis.

Results: By conjugating the exosomes with CHP, we demonstrate increased retention of the exosomes within heart sections ex vivo and in vitro with neonatal rat cardiomyocytes. In vitro studies showed improved viability, reduced apoptosis and increased exosome uptake when using CHP-XOs. Using an animal model of ischemia/reperfusion injury, we measured the heart function, infarct size, cellular proliferation, and angiogenesis, with improved outcomes with the CHP exosomes.

Conclusions: Our results demonstrate a novel method for increasing delivery of for treatment of myocardial infarction. By targeting exosomes to the infarcted heart, there was a significant improvement in outcomes with reduced fibrosis and scar size, and increased cellular proliferation and angiogenesis.

Keywords: Targeting, exosomes, cardiac regeneration, heart disease, myocardial infarction

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How to cite this article:
Vandergriff A, Huang K, Shen D, Hu S, Hensley MT, Caranasos TG, Qian L, Cheng K. Targeting regenerative exosomes to myocardial infarction using cardiac homing peptide. Theranostics 2018; 8(7):1869-1878. doi:10.7150/thno.20524. Available from http://www.thno.org/v08p1869.htm