title: Therapeutic effect of apatinib-loaded nanoparticles on diabetes-induced retinal vascular leakage.
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.
authors.affiliation: School of Pharmacy, Sungkyunkwan University, Suwon.
authors.forename: Ji Hoon
authors.initials: JH
authors.lastname: Jeong
authors.affiliation: College of Pharmacy, Chung-Ang University, Seoul, Korea.
authors.forename: Hong Khanh
authors.initials: HK
authors.lastname: Nguyen
authors.affiliation: School of Pharmacy, Sungkyunkwan University, Suwon.
authors.forename: Jung Eun
authors.initials: JE
authors.lastname: Lee
authors.affiliation: College of Pharmacy, Chung-Ang University, Seoul, Korea.
authors.forename: Wonhee
authors.initials: W
authors.lastname: Suh
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D001813:Blood-Retinal Barrier / Q000187:drug effects; D015820:Cadherins / Q000378:metabolism; D048909:Diabetes Complications / Q000503:physiopathology; D003921:Diabetes Mellitus, Experimental / Q000150:complications; D004337:Drug Carriers / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D058449:Intravitreal Injections; D008810:Mice, Inbred C57BL; D053758:Nanoparticles / Q000008:administration & dosage* / Q000737:chemistry; D011725:Pyridines / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D012164:Retinal Diseases / Q000188:drug therapy* / Q000209:etiology; D012171:Retinal Vessels / Q000187:drug effects* / Q000503:physiopathology; D012709:Serum Albumin / Q000737:chemistry; D000099152:Cadherin 5
chemical_list: D015703:Antigens, CD; D015820:Cadherins; D004337:Drug Carriers; D011725:Pyridines; D012709:Serum Albumin; D000099152:Cadherin 5; C553458:apatinib
keywords: permeability; retinal vascular endothelial cells; vascular endothelial growth factor