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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

Preparation and characterization of Apa-HSA-PEG nanoparticles.Notes: (A) Schematic diagram of the preparation of Apa-HSA-PEG nanoparticles. (B) TEM images and (C) particle size distribution of Apa-HSA-PEG nanoparticles. All scale bars =500 µm.Abbreviations: Apa-HSA-PEG, apatinib-loaded human serum albumin-conjugated polyethylene glycol; TEM, transmission electron microscope; NHS, N-hydroxysuccinimide; RT, room temperature; THF, tetrahydrofuran.
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f1-ijn-11-3101: Preparation and characterization of Apa-HSA-PEG nanoparticles.Notes: (A) Schematic diagram of the preparation of Apa-HSA-PEG nanoparticles. (B) TEM images and (C) particle size distribution of Apa-HSA-PEG nanoparticles. All scale bars =500 µm.Abbreviations: Apa-HSA-PEG, apatinib-loaded human serum albumin-conjugated polyethylene glycol; TEM, transmission electron microscope; NHS, N-hydroxysuccinimide; RT, room temperature; THF, tetrahydrofuran.

Mentions: The HSA-PEG conjugate was synthesized by conjugating mPEG-NHS (MW 5,000 Da) to the primary amines of HSA. The average molecular weight of the conjugate was 125 kDa, suggesting that about 12 PEG molecules were conjugated to one HSA molecule, as determined by GPC analysis (data not shown). The preparation of Apa-HSA-PEG nanoparticles is presented schematically in Figure 1A. The HSA-PEG conjugate and apatinib were dissolved in a 50% tetrahydrofuran aqueous solution. The solvent was then evaporated under reduced pressure at 100°C, forming a thin and transparent film. Apa-HSA-PEG nanoparticles were generated by dissolving the film in deionized water. The nano-particles showed spherical morphology with a diameter of 267.5±0.97 nm (Figure 1B and C). High-performance liquid chromatography analysis revealed that the loading amount and entrapping efficiency of Apa-HSA-PEG nanoparticles were 5.4 (w/w) and 77.1%, respectively.


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

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

Preparation and characterization of Apa-HSA-PEG nanoparticles.Notes: (A) Schematic diagram of the preparation of Apa-HSA-PEG nanoparticles. (B) TEM images and (C) particle size distribution of Apa-HSA-PEG nanoparticles. All scale bars =500 µm.Abbreviations: Apa-HSA-PEG, apatinib-loaded human serum albumin-conjugated polyethylene glycol; TEM, transmission electron microscope; NHS, N-hydroxysuccinimide; RT, room temperature; THF, tetrahydrofuran.
© Copyright Policy
Related In: Results  -  Collection

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

f1-ijn-11-3101: Preparation and characterization of Apa-HSA-PEG nanoparticles.Notes: (A) Schematic diagram of the preparation of Apa-HSA-PEG nanoparticles. (B) TEM images and (C) particle size distribution of Apa-HSA-PEG nanoparticles. All scale bars =500 µm.Abbreviations: Apa-HSA-PEG, apatinib-loaded human serum albumin-conjugated polyethylene glycol; TEM, transmission electron microscope; NHS, N-hydroxysuccinimide; RT, room temperature; THF, tetrahydrofuran.
Mentions: The HSA-PEG conjugate was synthesized by conjugating mPEG-NHS (MW 5,000 Da) to the primary amines of HSA. The average molecular weight of the conjugate was 125 kDa, suggesting that about 12 PEG molecules were conjugated to one HSA molecule, as determined by GPC analysis (data not shown). The preparation of Apa-HSA-PEG nanoparticles is presented schematically in Figure 1A. The HSA-PEG conjugate and apatinib were dissolved in a 50% tetrahydrofuran aqueous solution. The solvent was then evaporated under reduced pressure at 100°C, forming a thin and transparent film. Apa-HSA-PEG nanoparticles were generated by dissolving the film in deionized water. The nano-particles showed spherical morphology with a diameter of 267.5±0.97 nm (Figure 1B and C). High-performance liquid chromatography analysis revealed that the loading amount and entrapping efficiency of Apa-HSA-PEG nanoparticles were 5.4 (w/w) and 77.1%, respectively.

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