Studies On Phenylboronic Acid-Containing Bioadhesive Materials As Carriers For Mucosal Transport Of Insulin

Protein and peptide drugs possess biological activities that mark them as potential therapeutics in diagnosis, medical treatment for various diseases. Therapeutic peptides and proteins are typically administered by injection due to their fragile nature and the low bioavailability. Thus, chronic treatment brings incontinences and pains to the patient. Recently, researchers have paid more attention to adhesive polymers. The polymers as carriers could prolong the retention time of drugs on the mucous membrane, improve the permeability of drug epithelial barrier and the bioavailability of drugs. In this work, we focus to offer the mucosal drugs delivery systems, in order to find the protein drug carriers with mucoadhesion which could promote the transport of drugs across the membrane1) Amphiphilic glycopolymer nanoparticles as vehicles for nasal delivery of insulinBoronic acid and its derivatives are known to possess the ability to reversibly interact with diols, sugars, and glycoproteins, and transport saccharide across lipid bilayers. Since all cell membranes virtually include glycoproteins and/or glycolipids, which facilitates compounds containing boronic acid groups to bind to cell surfaces. In this work, we propose to design new drug delivery vehicles based poly (2-lactobionamidoethyl methacrylate-r-3-acrylamidophenylboronic acid). The glycopolymer could assemble into the nanoparticles with the size in the range of289～353nm, and zeta potential was-22～27mV. Insulin, as a model drug, was efficiently encapsulated within the nanoparticles, and loading capacity was up to12%. In vitro study revealed that the insulin release could be controlled by modifying the composition of glycopolymers. Cell viability test showed that p(LAMA-r-AAPBA) nanoparticles had good cytocompatibility. Moreover, the mechanism of nanoparticle internalization into Calu-3cells was a combination mechanism of clathrin-mediated endocytosis and lipid raft/caveolae-mediated endocytosis. Importantly, there was a significant decrease in the blood glucose levels after the nasal administration of p(LAMA-r-AAPBA) nanoparticles to diabetic rats. Therefore, p(LAMA-r-AAPBA) glycopolymers have a potential application as a nasal delivery systems for proteins and peptides.2) Biodegrable phenylboronic acid-containing Dextran as vehicles for nasal delivery of insulinThe main chain of the p(LAMA-r-AAPBA) is made up by the C-C bonds, and it is non-degradation in the body. In order to improve the degradation of polymer with phenylboronic acid, we further synthesized phenylboronic acid-graft-Dextran (Dex-PBA). Dex-PBA could assemble into the nanoparticles with size about300nm. Insulin could be efficiently encapsulated within the nanoparticles, and loading capacity was up to22%. The mucoadhesion test show that the Dex-PBA nanoparticles could interact with mucin, and the DSC test demonstrated the interaction between the Dex-PBA nanoparticles and mucin. Cell viability test showed that Dex-PBA nanoparticles had good cytocompatibility. Moreover, the mechanism of nanoparticle internalization into Calu-3cells was a combination mechanism of clathrin-mediated endocytosis and lipid raft/caveolae-mediated endocytosis. Importantly, there was a significant decrease in the blood glucose levels after the nasal administration of Dex-PBA nanoparticles to diabetic rats. Therefore, Dex-PBA glycopolymers have a potential application as nasal carrier for proteins and peptides.In summary, the phenylboronic acid-contained polymer carriers possess the good biocompatibility and mucoadhesion, could protect the protein drugs from being degraded and deliver them into cells or tissues with high bioavailability.