title: Multifunctional properties of organic-inorganic hybrid nanocomposites based on chitosan derivatives and layered double hydroxides for ocular drug delivery.
abstract: To improve the ocular bioavailability of the model drug of pirenoxine sodium (PRN), organic-inorganic hybrid nanocomposites including layered double hydroxides (LDH) and chitosan derivatives (chitosan-glutathione (CG), chitosan-glutathione-valine (CG-V) and chitosan-glutathione-valine-valine (CG-VV)) were designed and characterized. In vivo precorneal retention study on rabbits showed that mean residence time (MRT) and area under the curve (AUC0-6h) of CG-PRN-LDH nanocomposite eye drop was up to 2.1-fold and 6.3-fold higher than those of commercial product, respectively. In vitro corneal penetration on rabbits demonstrated that the cumulative permeation of CG-VV-PRN-LDH nanocomposite dispersion was increased by 5.2 folds compared to that of commercial product, which may be due to the active transport effect of the nanocomposites by peptide transporter-1 (PepT-1). In addition, the ex vivo fluorescence imaging showed that fluorescent intensity of crystalline lens in rabbits was increased after the administration of PRN-LDH, CG-PRN-LDH, CG-V-PRN-LDH and CG-VV-PRN-LDH (in increasing order) nanocomposite eye drop. Finally, in vivo distribution evaluation in ocular tissues of rabbits revealed that AUC0-8h and MRT in crystalline lens exhibited 14.7-fold and 2.2-fold increase in CG-VV-PRN-LDH nanocomposite eye drop group than those of commercial group, respectively. In summary, the organic-inorganic hybrid nanocomposites with multifunctional properties may be a promising ocular drug delivery system to achieve prolonged precorneal retention, better corneal permeability and enhanced ocular bioavailability.
  
  
  
  Due to several structural and physiological intraocular barriers, drug delivery to the ocular mid-posterior segments still faces great challenges. In this manuscript, organic-inorganic hybrid nanocomposites based on chitosan derivatives and layered double hydroxides (LDH) were designed and constructed. Multifunctional properties of these hybrid nanocomposites were due to the possible active targeting to the peptide transporter-1 on the corneal epithelial cells, the bioadhesive ability and permeation enhancement of chitosan derivatives, and the electrostatic adsorption of LDH. Prolonged precorneal retention, better corneal permeability and enhanced ocular bioavailability of the model drug pirenoxine sodium were observed. Chitosan derivatives-LDH hybrid nanocomposites may be a promising ophthalmic drug system for the treatment of ocular diseases of mid-posterior segments.
authors.affiliation: School of Pharmacy, China Pharmaceutical University, 24 Tongjia Xiang, Nanjing 210009, China.
authors.forename: Tingting
authors.initials: T
authors.lastname: Xu
authors.affiliation: School of Pharmacy, China Pharmaceutical University, 24 Tongjia Xiang, Nanjing 210009, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Zhang
authors.affiliation: School of Pharmacy, China Pharmaceutical University, 24 Tongjia Xiang, Nanjing 210009, China.
authors.forename: Huibo
authors.initials: H
authors.lastname: Chi
authors.affiliation: School of Pharmacy, China Pharmaceutical University, 24 Tongjia Xiang, Nanjing 210009, China. Electronic address: cpufengc@163.com.
authors.forename: Feng
authors.initials: F
authors.lastname: Cao
mesh_terms: D060433:Administration, Ophthalmic; D000818:Animals; D000838:Anions; D048271:Chitosan / Q000737:chemistry*; D003315:Cornea / Q000187:drug effects; D016503:Drug Delivery Systems; D065546:Drug Liberation; D005453:Fluorescence; D006878:Hydroxides / Q000737:chemistry*; D007287:Inorganic Chemicals / Q000737:chemistry*; D008297:Male; D053761:Nanocomposites / Q000737:chemistry* / Q000648:ultrastructure; D009930:Organic Chemicals / Q000737:chemistry*; D010078:Oxazines / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D010539:Permeability / Q000187:drug effects; D066244:Proton Magnetic Resonance Spectroscopy; D011817:Rabbits; D017550:Spectroscopy, Fourier Transform Infrared; D013997:Time Factors; D014018:Tissue Distribution / Q000187:drug effects; D014961:X-Ray Diffraction
chemical_list: D000838:Anions; D006878:Hydroxides; D007287:Inorganic Chemicals; D009930:Organic Chemicals; D010078:Oxazines; C004580:pirenoxine; D048271:Chitosan
keywords: Chitosan derivatives; Corneal permeability; Layered double hydroxides; Peptide transporter-1; Pirenoxine sodium; Precorneal retention