Diabetes is one of the major social health problems in the world. Subcutaneous injection of insulin is the traditional administration in the diabetes treatment, which is inconvenient and painful. Moreover, subcutaneous injection of insulin might result in hypoglycemia. In addition to oral insulin, controlled drug delivery systems are able to improve efficiency and safety of therapy by optimizing the duration and kinetics of release, and it also becomes the current hotspot. The smart insulin delivery system with glucose-sensitive characteristics attract considerable attention. The smart insulin delivery system stimulates the endogenous pancreatic β cells and releases an appropriate amount of insulin at the right time according to the patient's blood glucose level. According to the glucose sensitive unit, the smart insulin delivery system can be divided into three categories, glucose oxidase (GOx), concanavalin A (ConA) and phenylboronic acid (PBA). When the blood glucose concentration changes, the carrier structure changes or the competition of binding site between glucose and insulin triggers drug release.
1. Drug delivery system based on glucose oxidase
Glucose reacts with oxygen to form gluconolactone and H2O2 under the catalysis of glucose oxidase (GOx), and then glucolactone is rapidly hydrolyzed to gluconic acid in an aqueous environment. Therefore, insulin delivery system based on GOx can be divided into pH trigger and H2O2 trigger types.
The pH-triggered insulin release system utilizes the gluconic acid produced when GOx oxidizes glucose to reduce the local pH, which leads to the change of carrier structure (dissociation, swelling or collapse), and ultimately leads to drug release. Peptide hydrogel is an excellent carrier for insulin delivery, but its application is limited by the inconvenient use of cross-linking agent and implantation. The self-assembling peptide hydrogel avoids the use of cross-linking agents. It has good biocompatibility properties, and the advantage of injectable administration. An injectable pH-sensitive peptide hydrogel containing GOx, catalase (CAT) and insulin has been developed by some researchers. The oxidation of glucose by GOx causes a decrease in local pH, which leads to the rejection of the adjacent alkaline amino acid side chains in the peptide hydrogel, the opening of the hairpin structure and the decomposition of the peptide hydrogel to release insulin. It is the most common and simple way to physically coat GOx in nanoparticles, but the loss of GOx during the drug release process will cause the glucose sensitivity of the system to decrease. In addition, microspheres could provide more durable drug delivery than nanoparticles. Microneedle is a minimally invasive drug delivery system that can be administered by patients themselves. It can be temporarily inserted into the stratum corneum to penetrate the epidermis and prevent damage to deeper tissues.
The insulin release system is triggered by H2O2 to use H2O2 generated when GOx oxidizes glucose to trigger insulin release. For example, a multilayer film of shikimic acid modified poly allylamine hydrochloride (SA-PAH) and phenylboronic acid modified poly allylamine hydrochloride (PBA-PAH) is constructed by alternately depositing on calcium carbonate microspheres. The H2O2 produced by the oxidation of glucose by GOx causes the carbon boron bond of PBA-PAH to break and decompose. The drug-loaded particles remain stable at a glucose concentration of 0.9mg·ml﹣1, and insulin is released only at a glucose concentration of more than 1.8mg·ml﹣1. A core-shell microneedle patch is composed of cross-linked polyvinyl alcohol (PVA) gel. The core of the microneedle is 4-nitrophenyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborocine-2-yl) benzyl carbonate immobilizes insulin on the PVA matrix, and then produces H2O2 to trigger the release. CAT is added to the shell to reduce the risk of inflammation caused by H2O2. When glucose reacts with GOx to produce H2O2, the core gel is triggered to dissociate and release insulin. The patch can effectively reduce the blood glucose level in mice with diabetes. The blood glucose level is reduced to 1mg·ml-1 within 2 hours, and maintained at 2mg·ml-1 for 6 hours. In addition, colloidal particle integration microneedle is another strategy to realize the intellectualization of microneedles.
2. Drug delivery s...
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