title: Orally Targeted Delivery of Tripeptide KPV via Hyaluronic Acid-Functionalized Nanoparticles Efficiently Alleviates Ulcerative Colitis.
abstract: Overcoming adverse effects and selectively delivering drug to target cells are two major challenges in the treatment of ulcerative colitis (UC). Lysine-proline-valine (KPV), a naturally occurring tripeptide, has been shown to attenuate the inflammatory responses of colonic cells. Here, we loaded KPV into hyaluronic acid (HA)-functionalized polymeric nanoparticles (NPs). The resultant HA-KPV-NPs had a desirable particle size (∼272.3 nm) and a slightly negative zeta potential (∼-5.3 mV). These NPs successfully mediated the targeted delivery of KPV to key UC therapy-related cells (colonic epithelial cells and macrophages). In addition, these KPV-loaded NPs appear to be nontoxic and biocompatible with intestinal cells. Intriguingly, we found that HA-KPV-NPs exert combined effects against UC by both accelerating mucosal healing and alleviating inflammation. Oral administration of HA-KPV-NPs encapsulated in a hydrogel (chitosan/alginate) exhibited a much stronger capacity to prevent mucosa damage and downregulate TNF-α, thus they showed a much better therapeutic efficacy against UC in a mouse model, compared with a KPV-NP/hydrogel system. These results collectively demonstrate that our HA-KPV-NP/hydrogel system has the capacity to release HA-KPV-NPs in the colonic lumen and that these NPs subsequently penetrate into colitis tissues and enable KPV to be internalized into target cells, thereby alleviating UC.
authors.affiliation: Institute for Clean Energy and Advanced Materials, Faculty of Materials and Energy, Southwest University, Chongqing 400715, People's Republic of China; Institute for Biomedical Sciences, Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, GA 30302, USA. Electronic address: bxiao@gsu.edu.
authors.forename: Bo
authors.initials: B
authors.lastname: Xiao
authors.affiliation: Institute for Clean Energy and Advanced Materials, Faculty of Materials and Energy, Southwest University, Chongqing 400715, People's Republic of China.
authors.forename: Zhigang
authors.initials: Z
authors.lastname: Xu
authors.affiliation: Institute for Biomedical Sciences, Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, GA 30302, USA.
authors.forename: Emilie
authors.initials: E
authors.lastname: Viennois
authors.affiliation: Institute for Biomedical Sciences, Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, GA 30302, USA.
authors.forename: Yuchen
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Institute for Biomedical Sciences, Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, GA 30302, USA.
authors.forename: Zhan
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Institute for Biomedical Sciences, Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, GA 30302, USA.
authors.forename: Mingzhen
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Institute for Biomedical Sciences, Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, GA 30302, USA.
authors.forename: Moon Kwon
authors.initials: MK
authors.lastname: Han
authors.affiliation: Institute for Clean Energy and Advanced Materials, Faculty of Materials and Energy, Southwest University, Chongqing 400715, People's Republic of China.
authors.forename: Yuejun
authors.initials: Y
authors.lastname: Kang
authors.affiliation: Institute for Biomedical Sciences, Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, GA 30302, USA; Atlanta Veterans Affairs Medical Center, Decatur, GA 30033, USA.
authors.forename: Didier
authors.initials: D
authors.lastname: Merlin
mesh_terms: D000284:Administration, Oral; D000464:Alginates / Q000737:chemistry; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D048271:Chitosan / Q000737:chemistry; D003093:Colitis, Ulcerative / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D004337:Drug Carriers; D004339:Drug Compounding; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D015870:Gene Expression; D020723:Glucuronic Acid / Q000737:chemistry; D006603:Hexuronic Acids / Q000737:chemistry; D006801:Humans; D006820:Hyaluronic Acid / Q000737:chemistry*; D020100:Hydrogels / Q000737:chemistry; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D009074:Melanocyte-Stimulating Hormones / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D051379:Mice; D058990:Molecular Targeted Therapy; D053758:Nanoparticles / Q000008:administration & dosage / Q000737:chemistry*; D010316:Particle Size; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D000067996:RAW 264.7 Cells; D012967:Sodium Dodecyl Sulfate; D055672:Static Electricity; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
chemical_list: D000464:Alginates; D000893:Anti-Inflammatory Agents; D004337:Drug Carriers; D006603:Hexuronic Acids; D020100:Hydrogels; D010446:Peptide Fragments; D014409:Tumor Necrosis Factor-alpha; D012967:Sodium Dodecyl Sulfate; C043156:MSH (11-13); D020723:Glucuronic Acid; D009074:Melanocyte-Stimulating Hormones; D006820:Hyaluronic Acid; D048271:Chitosan
keywords: nanoparticle; oral administration; targeted delivery; tripeptide KPV; ulcerative colitis