Improving Cerebral Blood Flow Through Liposomal Delivery of Angiogenic Peptides: Potential of ¹⁸F-FDG PET Imaging in Ischemic Stroke Treatment

Abstract

Strategies to promote angiogenesis can benefit cerebral ischemia. We determined whether liposomal delivery of angiogenic peptides with a known biologic activity of vascular endothelial growth factor benefitted cerebral ischemia. Also, the study examined the potential of (18)F-FDG PET imaging in ischemic stroke treatment.

Methods: Male Sprague-Dawley rats (n = 40) underwent 40 min of middle cerebral artery occlusion. After 15 min of reperfusion, the rats (n = 10) received angiogenic peptides incorporated into liposomes. Animals receiving phosphate-buffered solution or liposomes without peptides served as controls. One week later, (18)F-FDG PET imaging was performed to examine regional changes in glucose utilization in response to the angiogenic therapy. The following day, (99m)Tc-hexamethylpropyleneamine oxime autoradiography was performed to determine changes in cerebral perfusion after angiogenic therapy. Corresponding changes in angiogenic markers, including von Willebrand factor and angiopoietin-1 and -2, were determined by immunostaining and polymerase chain reaction analysis, respectively.

Results: A 40-min period of middle cerebral artery occlusion decreased blood perfusion in the ipsilateral ischemic cortex of the brain, compared with that in the contralateral cortex, as measured by (99m)Tc-hexamethylpropyleneamine oxime autoradiography. Liposomal delivery of angiogenic peptides to the ischemic hemisphere of the brain attenuated the cerebral perfusion defect compared with controls. Similarly, vascular density evidenced by von Willebrand factor-positive staining was increased in response to angiogenic therapy, compared with that of controls. This increase was accompanied by an early increase in angiopoietin-2 expression, a gene participating in angiogenesis. (18)F-FDG PET imaging measured at 7 d after treatment revealed that liposomal delivery of angiogenic peptides facilitated glucose utilization in the ipsilateral ischemic cortex of the brain, compared with that in the controls. Furthermore, the change in regional glucose utilization was correlated with the extent of improvement in cerebral perfusion (r = 0.742, P = 0.035).

Conclusion: Liposomal delivery of angiogenic peptides benefits cerebral ischemia. (18)F-FDG PET imaging holds promise as an indicator of the effectiveness of angiogenic therapy in cerebral ischemia.

Keywords: 18F-FDG PET imaging; angiogenic peptides; liposomes; therapy.