title: Enhancement of scutellarin oral delivery efficacy by vitamin B12-modified amphiphilic chitosan derivatives to treat type II diabetes induced-retinopathy.
abstract: BACKGROUND
  Diabetic retinopathy is the most common complication in diabetic patients relates to high expression of VEGF and microaneurysms. Scutellarin (Scu) turned out to be effective against diabetes related vascular endothelial cell dysfunction. However, its clinical applications have been limited by its low bioavailability. In this study, we formulated and characterized a novel intestinal target nanoparticle carrier based on amphiphilic chitosan derivatives (Chit-DC-VB12) loaded with scutellarin to enhance its bioavailability and then evaluated its therapeutic effect in experimental diabetic retinopathy model.
  
  
  RESULTS
  Chit-DC-VB12 nanoparticles showed low toxicity toward the human colon adenocarcinoma (Caco-2) cells and zebra fish within concentration of 250 μg/ml, owing to good biocompatibility of chitosan. The scutellarin-loaded Chit-DC-VB12 nanoparticles (Chit-DC-VB12-Scu) were then prepared by self-assembly in aqueous solution. Scanning electron microscopy and dynamic light scattering analysis indicated that the Chit-DC-VB12-Scu nanoparticles were spherical particles in the sizes ranging from 150 to 250 nm. The Chit-DC-VB12-Scu nanoparticles exhibited high permeation in Caco-2 cell, indicated it could be beneficial to be absorbed in humans. We also found that Chit-DC-VB12 nanoparticles had a high cellular uptake. Bioavailability studies were performed in Sprague-Dawley rats, which present the area under the curve of scutellarin of Chit-DC-VB12-Scu was two to threefolds greater than that of free scutellarin alone. Further to assess the therapeutic efficacy of diabetic retinopathy, we showed Chit-DC-VB12-Scu down-regulated central retinal artery resistivity index and the expression of angiogenesis proteins (VEGF, VEGFR2, and vWF) of retinas in type II diabetic rats.
  
  
  CONCLUSIONS
  Chit-DC-VB12 nanoparticles loaded with scutellarin have better bioavailability and cellular uptake efficiency than Scu, while Chit-DC-VB12-Scu nanoparticles alleviated the structural disorder of intraretinal neovessels in the retina induced by diabetes, and it also inhibited the retinal neovascularization via down-regulated the expression of angiogenesis proteins. In conclusion, the Chit-DC-VB12 nanoparticles enhanced scutellarin oral delivery efficacy and exhibited potential as small intestinal target promising nano-carriers for treatment of type II diabetes induced-retinopathy.
authors.affiliation: Research Center of Translational Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China.
authors.forename: Jingnan
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Polymer and Material Science, School of Chemistry, Key Laboratory for Polymeric Composite and Functional Materials of Ministry of Education, Guangdong Provincial Key Laboratory for High Performance Polymer-based Composites, Sun Yat-sen University, Guangzhou, 510275, China.
authors.forename: Jiayun
authors.initials: J
authors.lastname: Tan
authors.affiliation: Department of Polymer and Material Science, School of Chemistry, Key Laboratory for Polymeric Composite and Functional Materials of Ministry of Education, Guangdong Provincial Key Laboratory for High Performance Polymer-based Composites, Sun Yat-sen University, Guangzhou, 510275, China.
authors.forename: Jiahao
authors.initials: J
authors.lastname: Luo
authors.affiliation: Institute of Biomaterial, Department of Applied Chemistry, College of Materials and Energy, South China Agricultural University, Guangzhou, 510642, China.
authors.forename: Peilin
authors.initials: P
authors.lastname: Huang
authors.affiliation: Institute of Biomaterial, Department of Applied Chemistry, College of Materials and Energy, South China Agricultural University, Guangzhou, 510642, China.
authors.forename: Wuyi
authors.initials: W
authors.lastname: Zhou
authors.affiliation: Yale University, New Haven, CT, 06511, USA.
authors.forename: Luming
authors.initials: L
authors.lastname: Chen
authors.affiliation: Research Center of Translational Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China.
authors.forename: Lingli
authors.initials: L
authors.lastname: Long
authors.affiliation: Department of Polymer and Material Science, School of Chemistry, Key Laboratory for Polymeric Composite and Functional Materials of Ministry of Education, Guangdong Provincial Key Laboratory for High Performance Polymer-based Composites, Sun Yat-sen University, Guangzhou, 510275, China.
authors.forename: Li-Ming
authors.initials: LM
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, 510080, China.
authors.forename: Banghao
authors.initials: B
authors.lastname: Zhu
authors.affiliation: Department of Polymer and Material Science, School of Chemistry, Key Laboratory for Polymeric Composite and Functional Materials of Ministry of Education, Guangdong Provincial Key Laboratory for High Performance Polymer-based Composites, Sun Yat-sen University, Guangzhou, 510275, China. yanglq@mail.sysu.edu.cn.
authors.forename: Liqun
authors.initials: L
authors.lastname: Yang
authors.affiliation: Research Center of Translational Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China. dengyub@mail.sysu.edu.cn.|Guangdong Provincial Key Laboratory of Orthopedics and Traumatology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China. dengyub@mail.sysu.edu.cn.
authors.forename: David Y B
authors.initials: DY
authors.lastname: Deng
mesh_terms: D000284:Administration, Oral; D000818:Animals; D047310:Apigenin / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D001682:Biological Availability; D018938:Caco-2 Cells; D048271:Chitosan / Q000031:analogs & derivatives*; D003924:Diabetes Mellitus, Type 2 / Q000150:complications; D003930:Diabetic Retinopathy / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology; D004337:Drug Carriers / Q000737:chemistry*; D004365:Drugs, Chinese Herbal / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D049919:Erigeron / Q000737:chemistry; D005965:Glucuronates / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D006801:Humans; D008297:Male; D053758:Nanoparticles / Q000737:chemistry*; D017207:Rats, Sprague-Dawley; D012171:Retinal Vessels / Q000187:drug effects / Q000473:pathology; D042461:Vascular Endothelial Growth Factor A / Q000032:analysis; D014805:Vitamin B 12 / Q000737:chemistry*; D015027:Zebrafish
chemical_list: D004337:Drug Carriers; D004365:Drugs, Chinese Herbal; D005965:Glucuronates; D042461:Vascular Endothelial Growth Factor A; C484876:scutellarin; D047310:Apigenin; D048271:Chitosan; D014805:Vitamin B 12
keywords: Chitosan; Diabetic retinopathy; Human colon adenocarcinoma cells; Nanoparticle; Scutellarin; Vascular endothelial growth factor