Abstract 14202: Targeted Therapeutics Delivery to Ischemia/reperfusion Injured Cardiomyocytes Using Genetically Engineered Exosomes
Introduction: Traditional vectors for gene therapy are associated with various side effects including low delivery and/or transduction efficiency, immunogenicity, carcinogenicity, inability to pass biological barriers, and non-targeting capability among others. Exosomes are naturally secreted nanosized particles that carry many signal molecules of the producer cells, which upon fusion with recipient cells unload their cargos that modulate the functions of the recipient cells. Exosomes, generated through two consecutive plasma invaginations, were selectively enriched transmembrane proteins.
Hypothesis: Transmembrane proteins can be utilized to display a homing peptide on their surface, which confers the targeting capability and thus realizes targeted therapeutics delivery.
Methods: A peptide homing to ischemia/reperfusion injured cardiomyocytes (IR-iCMs) was successfully displayed on the surface of exosomes by fusion to the N-terminus of lysosome associated membrane glycoprotein-2b (LAMP-2b) by genetic engineering, and the targeted delivery to IR-iCMs was evaluated both in vitro and in vivo.
Results: Exosomes isolated from HEK293 cells transfected with plasmids encoding the fusion LAMP-2b were preferentially internalized into hypoxia/re-oxygenated neonatal cardiomyocytes relative to CMs under normoxia in vitro. When administered systemically, these exosomes were selectively enriched in the area of IR-iCMs elative to CMs.
Conclusions: A peptide homing to IR-iCMs was successfully displayed on the surface of exosomes. These genetic engineered exosomes preferentially internalize into IR-iCMs relative to cadiomyocytes under normoxia both in vivo and in vitro, and thus can be exploited for targeted therapeutics delivery in cardiac ischemia/reperfusion injury.
Author Disclosures: L. Mao: None. X. Li: None. X. Fan: None. L. Huang: None. X. Zeng: None. X. Dang: None.
- © 2016 by American Heart Association, Inc.