title: RGD functionalized polymeric nanoparticles targeting periodontitis epithelial cells for the enhanced treatment of periodontitis in dogs.
abstract: Long term retention of antimicrobials with effective drug concentration in gingival crevicular fluid (GCF) is of vital importance for the treatment of chronic periodontitis. In this study, a novel epithelial cell-targeting nanoparticle drug delivery system by conjugating minocycline-loaded poly(ethylene glycol)-poly(lactic acid) (PEG-PLA) nanoparticles (NP-MIN) with RGD peptide were developed and administrated locally for targeting periodontitis epithelial cells and enhancing the treatment of periodontitis in dogs. Biodegradable NP-MIN was made with an emulsion/solvent evaporation technique. RGD peptide was conjugated to the surface of nanoparticles via Maleimide group reaction with hydrosulfide in RGD peptide (RGD-NP-MIN). Transmission electron microscopy examination and dynamic light scattering results revealed that RGD-NP-MIN had a sphere shape, with a mean diameter around 106nm. In vitro release of minocycline from RGD-NP-MIN showed that RGD modification did not change the remarkable sustained releasing characteristic of NP-MIN. To elucidate the interaction of RGD-NP and epithelial cells, RGD-NP binding, uptake and cellular internalization mechanisms by calu-3 cells were investigated. It was shown RGD modification significantly enhanced nanoparticles binding and uptake by Calu-3 cells, and RGD-NP uptake was an energy-dependent process through receptor-mediated endocytosis. Both clathrin-associated endocytosis and caveolae-dependent endocytosis pathway were involved in the RGD-NP uptake, and the intracellular transport of RGD-NP was related to lysosome and Golgi apparatus. Finally, in vivo pharmacokinetics of minocycline in the periodontal pockets and anti-periodontitis effects of RGD-NP-MIN on periodontitis-bearing dogs were evaluated. After local administration of RGD-NP-MIN, minocycline concentration in gingival crevicular fluid decreased slowly and maintained an effective drug concentration for a longer time than that of NP-MIN. Anti-periodontitis effects demonstrated that RGD-NP-MIN could significantly decrease symptoms of periodontitis, which was better than any other control group. These findings suggested that these epithelial cell-targeting nanoparticles offered a novel and effective local delivery system for the treatment of periodontitis.
authors.affiliation: Shanghai Xuhui District Dental Center, 685 Zhaojiabang Road, Shanghai 200032, China.
authors.forename: Wenxin
authors.initials: W
authors.lastname: Yao
authors.affiliation: Shanghai Xuhui District Dental Center, 685 Zhaojiabang Road, Shanghai 200032, China. Electronic address: xpc1238@126.com.
authors.forename: Peicheng
authors.initials: P
authors.lastname: Xu
authors.affiliation: Key Laboratory of Smart Drug Delivery, Ministry of Education, Department of Pharmaceutics, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai 201203, China.
authors.forename: Jingjing
authors.initials: J
authors.lastname: Zhao
authors.affiliation: Key Laboratory of Smart Drug Delivery, Ministry of Education, Department of Pharmaceutics, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai 201203, China.
authors.forename: Li
authors.initials: L
authors.lastname: Ling
authors.affiliation: Department of Pharmacology, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai 201203, China.
authors.forename: Xiaoxia
authors.initials: X
authors.lastname: Li
authors.affiliation: Key Laboratory of Smart Drug Delivery, Ministry of Education, Department of Pharmaceutics, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai 201203, China.
authors.forename: Bo
authors.initials: B
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai 201203, China.
authors.forename: Nengneng
authors.initials: N
authors.lastname: Cheng
authors.affiliation: Key Laboratory of Smart Drug Delivery, Ministry of Education, Department of Pharmaceutics, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai 201203, China. Electronic address: zqpang@fudan.edu.cn.
authors.forename: Zhiqing
authors.initials: Z
authors.lastname: Pang
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004285:Dogs; D004337:Drug Carriers / Q000737:chemistry* / Q000494:pharmacology; D016503:Drug Delivery Systems; D053758:Nanoparticles / Q000737:chemistry*; D009842:Oligopeptides / Q000737:chemistry* / Q000494:pharmacology*; D010518:Periodontitis / Q000188:drug therapy*; D011108:Polymers / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D004337:Drug Carriers; D009842:Oligopeptides; D011108:Polymers; C047981:arginyl-glycyl-aspartic acid
keywords: Local delivery; Minocycline; Polymeric nanoparticles; RGD peptide; Targeting periodontitis epithelial cells