The traditional subcutaneous or intravenous injection of insulin can not effectively control the release of insulin, resulting in an unregulated the blood glucose levels on diabetic patients. It is urgently to develop a self-controllable insulin delivery system with high sensitivity to the change of blood glucose levels in vivo. In this work, polymer microneedles (MNs) integrated with glucose-responsive mesoporous bioactive glass nanoparticles (BGNs) for transdermal delivery of insulin had been developed for the self-regulate and painless transdermal administration. The hypoglycaemic drug (insulin) was loaded in the mesoporous BGNs that surface premodification by a composite enzyme layer (CEL). The CEL was consisted of polyethyleneimine (PEI), glucose oxidase (GOx) and catalase (CAT). The formed CEL could be used as the glucose-sensitive layer and 'gatekeeper' for the release of encapsulated insulin from mesoporous of BGNs. The glucose in CEL that diffused and penetrated from body fluids could be catalyzed to gluconic acid by GOx/CAT which caused the pH decrease in the CEL, resulting the structure destruction of CEL and leading to release of preloaded insulin from the BGNs. After the treatment of the as-prepared MNs on diabetic rats, a highly hypoglycemic effect and lower risk of hypoglycemia could be obtained. This study demonstrated that as-designed glucose-sensitive and pH-triggered transdermal delivery system was a promising strategy for the treatment of the diabetes.
Near-infrared (NIR) light-triggered and separable segmented microneedles (MNs), consisting of lauric acid and polycaprolactone (LA/PCL) arrowheads and poly(vinyl alcohol) and polycaprolactone (PVA/PVP) supporting bases, have been fabricated. A hypoglycemic drug (metformin) and photothermal conversion factor (Cu7S4 nanoparticles) are encapsulated into LA/PCL arrowheads. Due to the dissolution of soluble supporting bases after the absorption of tissue fluid, the separable MNs arrowheads can be embedded into skin after insertion. Under the NIR-light irradiation, the LA/PCL arrowheads exhibit an excellent thermal-ablation change with a low amount of Cu7S4 nanoparticles (0.1 wt %) due to the low melting point of LA and PCL, thus enabling the release behavior of the encapsulated model drug to be photothermally triggered. Compared to the hypodermic injection of metformin, the thermal ablation of separable MNs triggered by NIR irradiation in the current research exhibit an excellent hypoglycemic effect in vivo. It suggests that the NIR-induced thermal-ablation MNs comprise a prospective transdermal drug-delivery system for the precise control of the timing and dosage of a drug that is dependent on NIR administration.
A glucose-mediated insulin delivery system would be highly satisfactory for diabetes diagnosis dependent on the concentration of blood glucose in the body. Herein, a novel microneedle (MN) delivery device integrated with insulin-loaded and H2O2-responsive mesoporous silica nanoparticles (MSNs) was designed to achieve fast and painless administration. The MSNs were obtained by the modification by 4-(imidazoyl carbamate)phenylboronic acid pinacol ester (ICBE) and following a host-guest complexation between ICBE and α-cyclodextrin (α-CD). A drug and a glucose-responsive factor, namely insulin and glucose oxidase (GOx), were encapsulated into the MSNs. GOx in the MSNs could convert glucose to gluconic acid and generate hydrogen peroxide (H2O2). The phenylboronic ester on the surface of the MSNs could be oxidized in the presence of H2O2, which resulted in the destruction of host-guest complexation, leading to the disassembly of the drug-loaded MSNs and subsequent release of the preloaded insulin. After transdermal administration to diabetic rats, an effective hypoglycemic effect was obtained by detection over time compared with that of subcutaneous injection. This work suggests that the as-prepared glucose-mediated and H2O2-responsive MN systems have promising applications in diabetes treatment.
A self-responsive insulin delivery system is highly desirable because of its high sensitivity dependent on blood glucose levels. Herein, a smart pH-triggered and glucose-mediated transdermal delivery system, insulin-loaded and ZnO quantum dots (ZnO QDs) capped mesoporous bioactive glasses (MBGs) integrated with microneedles (MNs), was developed to achieve control and painless administration. ZnO QDs as a promise pH-responsive switch were employed to cap the nanopores of MBGs via electrostatic interaction. The drug (insulin) and glucose-responsive factor (glucose oxidase/catalase, GOx/CAT) were sealed into the pores of MBGs. GOx/CAT in the MBGs could catalyze glucose to form gluconic acid, resulting decrease in the local pH. The ZnO QDs on the surface of the MBGs could be dissolved in the acidic condition, leading to disassembly of the pH-sensitive MBGs and then release of preloaded insulin from the MBGs. As a result of administration in a diabetic model, an excellent hypoglycemic effect and lower hypoglycemia risk were obtained. These results indicate that as-prepared pH-triggered and glucose-mediated transdermal delivery systems have hopeful applications in the treatment of diabetes.
The separable microneedles (MNs), consisted of upper metformin-loaded PCL arrowheads and lower PVA/PCL supporting array, have been fabricated by separately molding method. The metformin-loaded and thermal ablation MNs arrowheads were capped on dissolving solid supporting array. The as-fabricated MNs exhibited an excellent thermal ablation change due to the low melting point of PCL. After insertion into the skin, the upper separable MNs arrowheads could be embedded into the skin. When the separable MNs arrowheads were exposed to thermal stimulus, causing the PCL MNs arrowheads to melt and enabling the release of encapsulated metformin to be thermally modulated.
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