Postacute Ischemia Vascular Endothelial Growth Factor Transfer by Transferrin-Targeted Liposomes Attenuates Ischemic Brain Injury After Experimental Stroke in Rats

Abstract

Our objective was to achieve the enhanced delivery of vascular endothelial growth factor (VEGF) to ischemically disordered brain through transferrin-coupled liposomes (Tf-PLs) via intravenous administration, and to observe the effect of Tf-VEGF-PLs on ischemic brain neuroprotection and angiogenesis. Cerebral VEGF overexpression was achieved with Tf-PLs by intravenous injection 48 hr after an acute stroke. β-Galactosidase expression was monitored; saline was injected as a control. The success of postischemic gene transduction was confirmed by β-galactosidase staining and by increased VEGF mRNA and protein in ischemic brain. Vascular density, neurological recovery, and ischemic area calculation were performed to evaluate the effect of Tf-VEGF-PLs. The positive expression of β-galactosidase indirectly indicated that VEGF was successfully delivered into brain by Tf-VEGF-PLs. VEGF mRNA in the Tf-VEGF-PL group 24 hr after injection was significantly higher than in the control group (p < 0.05). Western blot analysis showed that postischemic Tf-VEGF-PLs resulted in increased VEGF protein levels compared with VEGF-PLs and saline-administered rats (p < 0.05) 48 hr after administration. At 21 days after drug injection, we observed a significant decrease in infarct volume and better neurological function in the Tf-VEGF-PL-treated group, compared with the VEGF-PL group. FITC-dextran marking showed increased vascular density in the penumbra of Tf-VEGF-PL-treated hemispheres (245,873.9, number of microvessels per field) compared with that in VEGF-PL-treated hemispheres (139,801.3) or saline-treated hemispheres (102,175.5) (p < 0.05). The remainder of the cerebral blood flow after ischemia in the Tf-VEGF-PL group was significantly more than in the control groups (0.35 vs. 0.29, 0.21; p < 0.05). We conclude that the VEGF gene can be delivered noninvasively into the brain by Tf-VEGF-PLs. Postischemic treatment with Tf-VEGF-PLs effectively promoted neuroprotection and vascular regeneration in the chronic stage of cerebral infarction.

Getting into the brain: liposome-based strategies for effective drug delivery across the blood&ndash;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.…”

Predictive Value of Circulating Vascular Endothelial Growth Factor-1 Level Measured Repeatedly During Long-Term Follow-Up in Patients with Arterial Hypertension after Acute Ischemic Stroke

“…We explored that an increase in the circulating VEGF-1 level appears to be associated with the accumulation of cardiovascular events before achieving the optimal predictive cutoff point of circulating VEGF-1 during a sixth-month follow-up. Many recent clinical trials failed to indicate a predictive value of VEGF-1 peak concentrations among symptomatic atherosclerotic patients atherosclerotic carotid plaque patients after stroke [12], while theoretical backgrounds of such hypothesis are very attractive [22,23]. In particular, the VEGF-1 secretion due to focal brain ischemia was found to be able to create a neuroprotection, to improve neo angiogenesis and neurogenesis [24,25].…”

Predictive Value of Circulating Vascular Endothelial Growth Factor-1 in Arterial Hypertension Patients

“…Many recent clinical trials did not indicate predictive value of VEGF-1 peak concentrations among symptomatic atherosclerotic carotid plaque patients after stroke [13], while theoretical backgrounds for such hypotheses are very attractive [23,24]. In particular, it was found that VEGF-1 secretion due to focal brain ischemia mediates to realize a neuroprotection, to improve neoangiogenesis and neurogenesis [25,26].…”