Preparation of Glucose-Responsive Phenylboronic Acid-Containing Polymers and Their Application to Artificial Pancreas

点击翻译按钮获取中文摘要

A new "Intelligent" polymer system sensitive to glucose concentration have been studied as a candidate material for chemically regulated insulin release system. Phenylboronic acid is capable to form reversible binding with cis-diol substances. Glucose responsive insulin release system has been studied with utilization of phenylboronic acid polymers for the key material to exchange reaction between gluconic acid modified insulin (G-Ins) and glucose molecule. CompIexation of various diol-containing molecules with PBA gel beads [poly (3-methacrylamidophenylboronic acid-co-acrylamide-co-N,N'-methylenebis- (acrylamide)] was evaluated using frontal chromatography at pH 8.5. The structural features of the diol-containing molecules strongly influenced their binding to PBA gel beads. In particular, open-chain mono saccharides demonstrated higher association constants (ca. 9.5X10X^2 to 5.1X10X^3 l/mol) than glucose (ca. 6.3X10X^2 l/mol). G-Ins was synthesized, and was bound onto PBA gel column. … More Then, the G-Ins release profile in response to varying glucose concentrations was investigated at pH 8.5. The released concentration of G-Ins from the polymer was pulsatile in response to the repeated stepwise concentration changes of glucose. Other remarkable results are that the linearity between glucose concentration and peak height of released G-lns, and that the release response have no lag time to change of glucose concentration. To enhance binding between PBA and glucose under physiological pH 7.4, an amine component was incorporated into the polymer chain along with PBA [poly (3-methacrylamidophenylboronic acid-co-N,N-dimethylaminopropylacrylamide-co-acrylamide-co-N,N'-methylenebis (acrylamide)]. The proportion of the amount of PBA groups complexed with glucose versus total amount of PBA groups was determined by batch method. Compared to PBA copolymer synthesized without the amine component, the proportion increased as a function of the amine content and the pH of the buffer. These results confirm that the interaction of neighboring amines (unprotonated) with PBA strengthens the binding with glucose, especially at pH 7.4 and above. Release property of G-Ins from the amine-containing PBA gel beads at pH 7.4 was evaluated using a liquid chromatography system. Amine-containing PBA gel showed less rapid decrease of G-Ins in the column under buffer-rinse over PBA gel. The released amount of G-Ins from amine-containing PBA gel is much greater than for the PBA gel, responding to the addition of glucose at physiological pH.The results from long-term release studies demonstrate that the amine-containing PBA gel has the capability to respond to glucose challenge over 120 hours. Furthermore, a linearity of released G-Ins was observed with glucose concentration. These results demonstrate the feasibility of an insulin-responsive system to achieve insulin release in response to glucose under physiological conditions. Less