Abstract 9200: Targeted Delivery of Slow-Releasing Form of A Prostacyclin Analogue, ONO-1301®, Enhances Recruitment of Bone Marrow Derived Cell and Yields Functional Benefits in Acute Myocardial Infarction in Mice
Background: Prostacyclin is an endogenous factor having a variety of protective effects against ischemic pathologies. We have generated ONO-1301®, which is a synthetic prostacyclin analog characterized by chemically stable structure and enhances stromal cell derived factor-1 (SDF-1), hepatocyte growth factor (HGF), and vascular endothelial growth factor (VEGF) secretion. Here, we hypothesized that sustained delivery of ONO-1301® may induce therapeutic effects mediated by the recruited bone marrow derived cells into the injured myocardium in acute MI mouse.
Methods and Results: ONO-1301® was conjugated with poly-DL-lactic-co-glycolic acid microsphere to generate a biodegradable controlled-release form. Either the atelocollagen-sheet with ONO-1301® microsphere eluted (ONO group; n=28) or ONO-1301® free microsphere eluted (control group; n=40) was implanted on the left ventricular anterior wall at 15 minutes following permanent LCA occlusion in C57BL6/N mice (male, 8-weeks old). ONO-1301® was still present in the plasma at 1 month (134±26 pg/ml; n=5). Expression levels of SDF-1, HGF, and VEGF in the infarct-border area were significantly elevated for 1 month in the ONO group. Recruitment of bone marrow cell induced by ONO-1301® was investigated using the acute-MI model in GFP-expressing bone marrow-transplanted chimera mice. Two months after LCA ligation followed by ONO-1301® treatment, there was a greater retention of the GFP+ cells in the infarct area. Some of the GFP+ cells were differentiated into the capillary components. In the ONO-1301® treated hearts, LV anterior wall thickness was significantly greater and infarct size was lower at 1 month. Cardiac performance was significantly greater in the ONO group (fractional area change: 24±1%; n=18) than the control group (20±1%; n=22; P=0.011), associated with greater 1 month survival in the ONO group (61±9 vs. 36±8%; P=0.052).
Conclusions: Targeted delivery of the slow-releasing form of ONO-1301® possibly up-regulates protective factors, and recruits bone marrow cells into the infarct area, leading to the functional and survival benefits, indicating promising strategy to be translated into the clinical arena.
- © 2011 by American Heart Association, Inc.