Targeting regenerative exosomes to myocardial infarction using cardiac homing peptide

Vandergriff, Adam; Huang, Ke; Shen, Deliang; Hu, Shiqi; Hensley, Michael Taylor; Caranasos, Thomas G.; Qian, Li; Cheng, Ke

The nano-scale size of exosomes has a dichotomous effect on the therapeutic potential of exosomes. Their small size allows exosomes to traverse capillary beds in the lungs and other tissues, which can trap cells or larger particles, but simultaneously reduces the rate of extravasation of the exosomes to the hypothesized target tissue [60] . When delivered intravenously, large amounts of exosomes have been shown to accumulate in off target organs such as the liver [22] [23] [24] . Thus far, no studies have definitively shown any side effects of excess exosome injection, though one study did report death of one animal when receiving large doses of intravenous exosomes, possibly due to pulmonary embolism [60] . Drug targeting has primarily been studied as a means to reduce the negative off-target effects of chemotherapeutic drugs [61] [62] [63] , although there has been an increased interest in drug targeting for cardiac regeneration [64] [65] [66] [67] [68] [69] [70] [71] [72] [73] . Following myocardial infarction, the myocardium undergoes several changes that can be exploited for targeting. One such change is an increase in vascular permeability, analogous to the enhanced permeability and retention (EPR) effect in cancer, allowing for increased extravasation of liposomes [74] . Changes in protein expression as well as exposure of normally intracellular proteins such as myosin have been utilized for targeting. Due to their high specificity, antibodies and antibody fragments have been the targeting molecule of choice [75] . Recent studies also showed that platelet membranes could be utilized to target cells to the infarct heart [76] . Recent developments in phage display have yielded many new targeting molecules such as the CHP [26, 27] . Though the exact mechanism by which CHP interacts with the myocardium is unknown, by conjugating it to exosomes it amplifies the regenerative effects of the exosomes. A limitation of our study is that the mechanisms underlying the regenerative properties of exosomes were not fully elucidated. Nevertheless, recent studies from our group and others have demonstrated pro-angiogenic, pro-myogeneic, antiapoptotic, and anti-inflammatory roles of stem cell secretome [77, 78] .