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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

Apa-HSA-PEG nanoparticles block VEGF-induced retinal vascular leakage in vivo.Notes: (A) Representative images of FITC-dextran-perfused retinal whole mounts. (B) Quantitative analysis of extravasated EB dye in the retinal tissues after intravitreal injection of rhVEGF (100 ng) and/or Apa-HSA-PEG nanoparticles (580 ng). Vascular leakage of EB dye in treated eyes was normalized relative to that in each contralateral control eye (means ± SEM, *P<0.05 vs PBS control, #P<0.05 vs VEGF, n=5). Scale bar =200 µm.Abbreviations: Apa-HSA-PEG, apatinib-loaded human serum albumin-conjugated polyethylene glycol; VEGF, vascular endothelial growth factor; FITC, fluorescein isothiocyanate; EB, Evans Blue; rhVEGF, recombinant human VEGF; SEM, standard error of the mean; PBS, phosphate-buffered saline.
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f4-ijn-11-3101: Apa-HSA-PEG nanoparticles block VEGF-induced retinal vascular leakage in vivo.Notes: (A) Representative images of FITC-dextran-perfused retinal whole mounts. (B) Quantitative analysis of extravasated EB dye in the retinal tissues after intravitreal injection of rhVEGF (100 ng) and/or Apa-HSA-PEG nanoparticles (580 ng). Vascular leakage of EB dye in treated eyes was normalized relative to that in each contralateral control eye (means ± SEM, *P<0.05 vs PBS control, #P<0.05 vs VEGF, n=5). Scale bar =200 µm.Abbreviations: Apa-HSA-PEG, apatinib-loaded human serum albumin-conjugated polyethylene glycol; VEGF, vascular endothelial growth factor; FITC, fluorescein isothiocyanate; EB, Evans Blue; rhVEGF, recombinant human VEGF; SEM, standard error of the mean; PBS, phosphate-buffered saline.

Mentions: To further demonstrate the role of Apa-HSA-PEG nanoparticles in VEGF-triggered vascular leakage, we performed an in vivo retinal vascular permeability assay with intravitreal injection of VEGF and/or Apa-HSA-PEG nanoparticles (Figure 4A). VEGF treatment induced substantial leakage of systemically injected FITC-dextran in the retinal vasculature with consequent perivascular hyper-fluorescence. However, co-injection of Apa-HSA-PEG nanoparticles and VEGF resulted in a significant inhibition of VEGF-induced extravasation of FITC-dextran. Quantification analyses of retinal vascular leakage using EB dye showed an approximately twofold increase of EB deposition in VEGF-treated retinal tissues. This increase was significantly reduced by treatment with Apa-HSA-PEG nanoparticles (Figure 4B). These data support that Apa-HSA-PEG nanoparticles effectively prevent VEGF-induced disruption of the BRB in vivo.


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

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

Apa-HSA-PEG nanoparticles block VEGF-induced retinal vascular leakage in vivo.Notes: (A) Representative images of FITC-dextran-perfused retinal whole mounts. (B) Quantitative analysis of extravasated EB dye in the retinal tissues after intravitreal injection of rhVEGF (100 ng) and/or Apa-HSA-PEG nanoparticles (580 ng). Vascular leakage of EB dye in treated eyes was normalized relative to that in each contralateral control eye (means ± SEM, *P<0.05 vs PBS control, #P<0.05 vs VEGF, n=5). Scale bar =200 µm.Abbreviations: Apa-HSA-PEG, apatinib-loaded human serum albumin-conjugated polyethylene glycol; VEGF, vascular endothelial growth factor; FITC, fluorescein isothiocyanate; EB, Evans Blue; rhVEGF, recombinant human VEGF; SEM, standard error of the mean; PBS, phosphate-buffered saline.
© Copyright Policy
Related In: Results  -  Collection

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

f4-ijn-11-3101: Apa-HSA-PEG nanoparticles block VEGF-induced retinal vascular leakage in vivo.Notes: (A) Representative images of FITC-dextran-perfused retinal whole mounts. (B) Quantitative analysis of extravasated EB dye in the retinal tissues after intravitreal injection of rhVEGF (100 ng) and/or Apa-HSA-PEG nanoparticles (580 ng). Vascular leakage of EB dye in treated eyes was normalized relative to that in each contralateral control eye (means ± SEM, *P<0.05 vs PBS control, #P<0.05 vs VEGF, n=5). Scale bar =200 µm.Abbreviations: Apa-HSA-PEG, apatinib-loaded human serum albumin-conjugated polyethylene glycol; VEGF, vascular endothelial growth factor; FITC, fluorescein isothiocyanate; EB, Evans Blue; rhVEGF, recombinant human VEGF; SEM, standard error of the mean; PBS, phosphate-buffered saline.
Mentions: To further demonstrate the role of Apa-HSA-PEG nanoparticles in VEGF-triggered vascular leakage, we performed an in vivo retinal vascular permeability assay with intravitreal injection of VEGF and/or Apa-HSA-PEG nanoparticles (Figure 4A). VEGF treatment induced substantial leakage of systemically injected FITC-dextran in the retinal vasculature with consequent perivascular hyper-fluorescence. However, co-injection of Apa-HSA-PEG nanoparticles and VEGF resulted in a significant inhibition of VEGF-induced extravasation of FITC-dextran. Quantification analyses of retinal vascular leakage using EB dye showed an approximately twofold increase of EB deposition in VEGF-treated retinal tissues. This increase was significantly reduced by treatment with Apa-HSA-PEG nanoparticles (Figure 4B). These data support that Apa-HSA-PEG nanoparticles effectively prevent VEGF-induced disruption of the BRB in vivo.

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