title: Multi-ion-crosslinked nanoparticles with pH-responsive characteristics for oral delivery of protein drugs.
abstract: pH-Responsive nanoparticles composed of chitosan (CS) and poly-gamma-glutamic acid (gamma-PGA) blended with tripolyphosphate (TPP) and MgSO(4) (multi-ion-crosslinked NPs) were prepared and characterized to determine their effectiveness in the oral delivery of insulin. Their counterparts without TPP and MgSO(4) (NPs) were used as a control. FT-IR and XRD results indicated that the spontaneous interaction between CS, insulin, gamma-PGA, MgSO(4) and TPP can form an ionically crosslinked network-structure, leading to the formation of nanoparticles. Multi-ion-crosslinked NPs were more compact than NPs, while their zeta potential values were comparable. During storage, multi-ion-crosslinked NPs suspended in deionized water were stable for at least 10 weeks. Multi-ion-crosslinked NPs had a superior stability over a broader pH range than NPs. In the in vitro release study, NPs failed to provide an adequate retention of loaded insulin in dissolution media compared to multi-ion-crosslinked NPs. Transepithelial-electrical-resistance and transport experiments demonstrated that multi-ion-crosslinked NPs significantly more effectively transported insulin than NPs; confocal visualization further validated the enhanced permeation of insulin via the paracellular pathway. The aforementioned results suggest that multi-ion-crosslinked NPs are a promising carrier for improved transmucosal delivery of insulin in the small intestine.
authors.affiliation: Department of Chemical Engineering, National Tsing Hua University, Hsinchu, Taiwan, ROC.
authors.forename: Yu-Hsin
authors.initials: YH
authors.lastname: Lin
authors.forename: Kiran
authors.initials: K
authors.lastname: Sonaje
authors.forename: Kurt M
authors.initials: KM
authors.lastname: Lin
authors.forename: Jyuhn-Huarng
authors.initials: JH
authors.lastname: Juang
authors.forename: Fwu-Long
authors.initials: FL
authors.lastname: Mi
authors.forename: Han-Wen
authors.initials: HW
authors.lastname: Yang
authors.forename: Hsing-Wen
authors.initials: HW
authors.lastname: Sung
mesh_terms: D000284:Administration, Oral; D018938:Caco-2 Cells; D048271:Chitosan / Q000737:chemistry; D004337:Drug Carriers / Q000737:chemistry*; D016503:Drug Delivery Systems / Q000379:methods; D017097:Electric Impedance; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007328:Insulin / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics; D007477:Ions / Q000737:chemistry; D008278:Magnesium Sulfate / Q000737:chemistry; D053758:Nanoparticles / Q000737:chemistry*; D010316:Particle Size; D011099:Polyglutamic Acid / Q000737:chemistry; D011122:Polyphosphates / Q000737:chemistry; D011506:Proteins / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D017550:Spectroscopy, Fourier Transform Infrared; D019108:Tight Junctions / Q000378:metabolism; D014961:X-Ray Diffraction
chemical_list: D004337:Drug Carriers; D007328:Insulin; D007477:Ions; D011122:Polyphosphates; D011506:Proteins; D011099:Polyglutamic Acid; D008278:Magnesium Sulfate; D048271:Chitosan; C005692:triphosphoric acid