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Functional Stimuli-Responsive Nanogel-particles for Oral Peptide Delivery: Preparation, Drug-Release Behaviors and in Vitro Cellular Interaction

H. Ichikawa, Y. Fukumori and H. Kamiya
Kobe Gakuin University, JP

oral peptide delivery, stimuli-responsive hydrogel, nanoparticle, caco-2 cell,

The present study involves preparation and evaluation of novel core-shell nanoparticles (CSNPs) consisting of thermo-responsive poly(N-isopropylacrylamide) (p(NIPAAm)) hydrogel core with pH-responsive poly(methacrylic acid-grafted-poly(ethylene glycol)) (p(MAA-g-EG)) shell layer as a carrier for oral peptide delivery. The CSNPs were structurally designed to provide specific functions such as protecting chemically unstable peptide drugs from harsh manufacturing and physiological environments and enhancing the drug absorption at the preferable sites in the gastrointestinal tract. It was confirmed that the CSNPs exhibited both thermo- and pH-sensitive swelling properties, which allowed two types of model peptides, i.e., bovine insulin and vancomycin hydrochloride (VCH), to be incorporated into the CSNPs by simple equilibrium partitioning method at low temperature and neutral pH. The peptide-incorporated CSNPs showed pH-dependent release behaviors. Release of VCH and insulin was significantly suppressed in a simulated gastric fluid (pH 1.2). On the other hand, prolonged release of VCH was obtained in a simulated intestinal fluid (pH 6.8), whereas relatively rapid release occurred in the case of insulin. Moreover, the CSNPs were found to possess cellular tight-junction opening effect against Caco-2 cell monolayers because of calcium-chelating ability of the p(MAA-g-EG) shell, which is essential for enhancing intestinal absorption of such peptide drugs.

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