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Therapeutic effect of apatinib-loaded nanoparticles on diabetes-induced retinal vascular leakage.

Jeong JH, Nguyen HK, Lee JE, Suh W - Int J Nanomedicine (2016)

Bottom Line: In addition, they substantially reduced the VEGF-induced junctional loss and internalization of vascular endothelial-cadherin, a major component of endothelial junction complexes.These in vitro and in vivo data indicated that Apa-HSA-PEG nanoparticles efficiently blocked VEGF-induced breakdown of the blood-retinal barrier.These results demonstrated, for the first time, that apatinib-loaded nanoparticles may be a promising therapeutic agent for the prevention and treatment of diabetes-induced retinal vascular disorders.

View Article: PubMed Central - PubMed

Affiliation: School of Pharmacy, Sungkyunkwan University, Suwon.

ABSTRACT
Apatinib, a novel and selective inhibitor of vascular endothelial growth factor (VEGF) receptor 2, has been demonstrated recently to exhibit anticancer efficacy by inhibiting the VEGF signaling pathway. Given the importance of VEGF in retinal vascular leakage, the present study was designed to investigate whether apatinib-loaded polymeric nanoparticles inhibit VEGF-mediated retinal vascular hyperpermeability and block diabetes-induced retinal vascular leakage. For the delivery of water-insoluble apatinib, the drug was encapsulated in nanoparticles composed of human serum albumin (HSA)-conjugated polyethylene glycol (PEG). In vitro paracellular permeability and transendothelial electric resistance assays showed that apatinib-loaded HSA-PEG (Apa-HSA-PEG) nanoparticles significantly inhibited VEGF-induced endothelial hyperpermeability in human retinal microvascular endothelial cells. In addition, they substantially reduced the VEGF-induced junctional loss and internalization of vascular endothelial-cadherin, a major component of endothelial junction complexes. In vivo intravitreal injection of Apa-HSA-PEG nanoparticles in mice blocked VEGF-induced retinal vascular leakage. These in vitro and in vivo data indicated that Apa-HSA-PEG nanoparticles efficiently blocked VEGF-induced breakdown of the blood-retinal barrier. In vivo experiments with streptozotocin-induced diabetic mice showed that an intravitreal injection of Apa-HSA-PEG nanoparticles substantially inhibited diabetes-induced retinal vascular leakage. These results demonstrated, for the first time, that apatinib-loaded nanoparticles may be a promising therapeutic agent for the prevention and treatment of diabetes-induced retinal vascular disorders.

No MeSH data available.


Related in: MedlinePlus

Intravitreal injection of Apa-HSA-PEG nanoparticles inhibits diabetes-induced retinal vascular leakage in STZ-induced diabetic mice.Notes: (A) STZ-induced diabetic mice received an intravitreal injection of Apa-HSA-PEG nanoparticles (61 ng for the low-dose group [Low], 610 ng for the high-dose group [High]). An equal volume of PBS was injected into the contralateral eye as a control. One day after injection, retinal vascular leakage of EB dye was measured and expressed relative to that in each contralateral control eye (means ± SEM, **P<0.01 vs contralateral PBS control, n=8). (B) Blood glucose and body weights of mice used in this experiment were measured before (Nondiabetes) and 2 weeks after (Diabetes) the initial STZ injection (*P<0.05 vs Nondiabetes, n=8).Abbreviations: Apa-HSA-PEG, apatinib-loaded human serum albumin-conjugated polyethylene glycol; STZ, streptozotocin; PBS, phosphate-buffered saline; EB, Evans Blue; SEM, standard error of the mean.
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f5-ijn-11-3101: Intravitreal injection of Apa-HSA-PEG nanoparticles inhibits diabetes-induced retinal vascular leakage in STZ-induced diabetic mice.Notes: (A) STZ-induced diabetic mice received an intravitreal injection of Apa-HSA-PEG nanoparticles (61 ng for the low-dose group [Low], 610 ng for the high-dose group [High]). An equal volume of PBS was injected into the contralateral eye as a control. One day after injection, retinal vascular leakage of EB dye was measured and expressed relative to that in each contralateral control eye (means ± SEM, **P<0.01 vs contralateral PBS control, n=8). (B) Blood glucose and body weights of mice used in this experiment were measured before (Nondiabetes) and 2 weeks after (Diabetes) the initial STZ injection (*P<0.05 vs Nondiabetes, n=8).Abbreviations: Apa-HSA-PEG, apatinib-loaded human serum albumin-conjugated polyethylene glycol; STZ, streptozotocin; PBS, phosphate-buffered saline; EB, Evans Blue; SEM, standard error of the mean.

Mentions: VEGF has been considered as a primary factor in the pathogenesis of diabetes-induced retinal vascular diseases. Because increased expression of VEGF contributes to early retinal vascular hyperpermeability and subsequent macular edema during the progression of diabetic retinopathy and diabetic macular edema, we determined whether Apa-HSA-PEG nanoparticles could inhibit diabetes-induced retinal vascular hyperpermeability using STZ-induced diabetic mice. Two weeks after STZ injection, diabetic mice with elevated serum glucose levels (>300 mg/dL) and reduced body weights were selected and intravitreally injected with Apa-HSA-PEG nanoparticles or PBS. Vascular leakage of EB in Apa-HSA-PEG nanoparticles-injected retinas was significantly lower than that of the PBS-injected contralateral controls (Figure 5A). Serum glucose levels and body weights of mice used in this experiment were measured before and after STZ injection (Figure 5B).


Therapeutic effect of apatinib-loaded nanoparticles on diabetes-induced retinal vascular leakage.

Jeong JH, Nguyen HK, Lee JE, Suh W - Int J Nanomedicine (2016)

Intravitreal injection of Apa-HSA-PEG nanoparticles inhibits diabetes-induced retinal vascular leakage in STZ-induced diabetic mice.Notes: (A) STZ-induced diabetic mice received an intravitreal injection of Apa-HSA-PEG nanoparticles (61 ng for the low-dose group [Low], 610 ng for the high-dose group [High]). An equal volume of PBS was injected into the contralateral eye as a control. One day after injection, retinal vascular leakage of EB dye was measured and expressed relative to that in each contralateral control eye (means ± SEM, **P<0.01 vs contralateral PBS control, n=8). (B) Blood glucose and body weights of mice used in this experiment were measured before (Nondiabetes) and 2 weeks after (Diabetes) the initial STZ injection (*P<0.05 vs Nondiabetes, n=8).Abbreviations: Apa-HSA-PEG, apatinib-loaded human serum albumin-conjugated polyethylene glycol; STZ, streptozotocin; PBS, phosphate-buffered saline; EB, Evans Blue; SEM, standard error of the mean.
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Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4940015&req=5

f5-ijn-11-3101: Intravitreal injection of Apa-HSA-PEG nanoparticles inhibits diabetes-induced retinal vascular leakage in STZ-induced diabetic mice.Notes: (A) STZ-induced diabetic mice received an intravitreal injection of Apa-HSA-PEG nanoparticles (61 ng for the low-dose group [Low], 610 ng for the high-dose group [High]). An equal volume of PBS was injected into the contralateral eye as a control. One day after injection, retinal vascular leakage of EB dye was measured and expressed relative to that in each contralateral control eye (means ± SEM, **P<0.01 vs contralateral PBS control, n=8). (B) Blood glucose and body weights of mice used in this experiment were measured before (Nondiabetes) and 2 weeks after (Diabetes) the initial STZ injection (*P<0.05 vs Nondiabetes, n=8).Abbreviations: Apa-HSA-PEG, apatinib-loaded human serum albumin-conjugated polyethylene glycol; STZ, streptozotocin; PBS, phosphate-buffered saline; EB, Evans Blue; SEM, standard error of the mean.
Mentions: VEGF has been considered as a primary factor in the pathogenesis of diabetes-induced retinal vascular diseases. Because increased expression of VEGF contributes to early retinal vascular hyperpermeability and subsequent macular edema during the progression of diabetic retinopathy and diabetic macular edema, we determined whether Apa-HSA-PEG nanoparticles could inhibit diabetes-induced retinal vascular hyperpermeability using STZ-induced diabetic mice. Two weeks after STZ injection, diabetic mice with elevated serum glucose levels (>300 mg/dL) and reduced body weights were selected and intravitreally injected with Apa-HSA-PEG nanoparticles or PBS. Vascular leakage of EB in Apa-HSA-PEG nanoparticles-injected retinas was significantly lower than that of the PBS-injected contralateral controls (Figure 5A). Serum glucose levels and body weights of mice used in this experiment were measured before and after STZ injection (Figure 5B).

Bottom Line: In addition, they substantially reduced the VEGF-induced junctional loss and internalization of vascular endothelial-cadherin, a major component of endothelial junction complexes.These in vitro and in vivo data indicated that Apa-HSA-PEG nanoparticles efficiently blocked VEGF-induced breakdown of the blood-retinal barrier.These results demonstrated, for the first time, that apatinib-loaded nanoparticles may be a promising therapeutic agent for the prevention and treatment of diabetes-induced retinal vascular disorders.

View Article: PubMed Central - PubMed

Affiliation: School of Pharmacy, Sungkyunkwan University, Suwon.

ABSTRACT
Apatinib, a novel and selective inhibitor of vascular endothelial growth factor (VEGF) receptor 2, has been demonstrated recently to exhibit anticancer efficacy by inhibiting the VEGF signaling pathway. Given the importance of VEGF in retinal vascular leakage, the present study was designed to investigate whether apatinib-loaded polymeric nanoparticles inhibit VEGF-mediated retinal vascular hyperpermeability and block diabetes-induced retinal vascular leakage. For the delivery of water-insoluble apatinib, the drug was encapsulated in nanoparticles composed of human serum albumin (HSA)-conjugated polyethylene glycol (PEG). In vitro paracellular permeability and transendothelial electric resistance assays showed that apatinib-loaded HSA-PEG (Apa-HSA-PEG) nanoparticles significantly inhibited VEGF-induced endothelial hyperpermeability in human retinal microvascular endothelial cells. In addition, they substantially reduced the VEGF-induced junctional loss and internalization of vascular endothelial-cadherin, a major component of endothelial junction complexes. In vivo intravitreal injection of Apa-HSA-PEG nanoparticles in mice blocked VEGF-induced retinal vascular leakage. These in vitro and in vivo data indicated that Apa-HSA-PEG nanoparticles efficiently blocked VEGF-induced breakdown of the blood-retinal barrier. In vivo experiments with streptozotocin-induced diabetic mice showed that an intravitreal injection of Apa-HSA-PEG nanoparticles substantially inhibited diabetes-induced retinal vascular leakage. These results demonstrated, for the first time, that apatinib-loaded nanoparticles may be a promising therapeutic agent for the prevention and treatment of diabetes-induced retinal vascular disorders.

No MeSH data available.


Related in: MedlinePlus