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 5 40) underwent 40 min of middle cerebral artery occlusion. After 15 min of reperfusion, the rats (n 5 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 Tchexamethylpropyleneamine 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 Tchexamethylpropyleneamine 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 factorpositive 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 5 0.742, P 5 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.

Liposomal angiogenic peptides for ischemic limb perfusion: comparative study between different administration methods

“…The results support our hypothesis that PEGylated liposomes loaded with angiogenic peptides are efficacious for treating hindlimb ischemia, as evidenced by improved ischemic limb perfusion and increased expression of proteins related to angiogenesis. These findings are consistent with a previous study reporting the therapeutic effectiveness of liposomes loaded with angiogenic factors for treating cerebral ischemia (Hwang et al, 2015). That previous study showed the efficacy of a liposomal delivery system without surface PEG modification.…”

“…Liposomes encapsulated with angiogenic peptides were prepared as described previously with a slight modification (Hwang et al, 2015). A mixture of L-a-phosphatidylcholine (Egg PC), cholesterol, and 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[Methoxy(polyethylene glycol)-2000] (DSPE-PEG2000) (the molar ratio of 50:40:10; Sigma-Aldrich, St. Louis, MO) was dissolved in chloroform/methanol (7:3; Duck San Pure Chemical, Gyunggi-do, South Korea).…”

“…The film was completely hydrated (1.5 h, 37 C). With this approach, the loading efficiency of the angiogenic peptides obtained after extrusion and purification was 65% (Hwang et al, 2015). Angiogenic peptides (MRIKPHQGQHI) were derived from vascular endothelial growth factor (VEGF, sequence 81-91; Peptron, Daejeon, Korea), which have been demonstrated to have the angiogenic capability of the protein (Muller et al, 1998;Garcia-Aranda et al, 2011a;Garcia-Aranda et al, 2011b).…”

“…Liposomes with no known toxicity are clinically proven for cancer therapy. An experimental study also showed the therapeutic potential of liposomes to treat cerebral ischemia (Luk et al, 2004;Hwang et al, 2015). Maintaining a drug plasma concentration is essential to facilitate drug delivery to the target site.…”

Getting into the brain: liposome-based strategies for effective drug delivery across the blood–brain barrier

“…Several studies reported in the literature suggest the efficacy of Hb liposomes in the treatment of stroke by enhancing the biodistribution of Hb liposomes within the ischemic area in the brain. 144,145,147,[160][161][162][163][164]167,171,191,193,194 In the same way, liposomes for the delivery of angiogenic peptides 140 and VEGF 157 to promote angiogenesis in ischemic tissue were developed, and both formulations effectively promoted vascular regeneration. 140,157 Over the years, many liposomal formulations have been developed for the treatment of stroke.…”