Na Wen,Chunmei Gao,Shaoyu Lü,Xiubin Xu,Xiao Bai,Can Wu,Piao Ning,Shaofei Zhang,Mingzhu Liu
The high pKa (8.26 to 8.6) of PBA has restricted its glucose-responsiveness in physiological conditions, and the high cytotoxicity of polymers is also a limiting problem in their potential application for insulin delivery. Novel amphiphilic glucose-sensitive dialdehyde starch polymers containing 3-aminophenylboronic acid (APBA) as a glucose-responsive group and mPEGylated dialdehyde starch (mPEG-DAS) with hydrophobic 7-hydroxycoumarin-4-acetic acid (Cou) were synthesized. This dialdehyde starch derivative can self-assemble into mPEG-DAS–APBA–Cou micelles with “shell–core” structures in phosphate-buffered saline solution (PBS). In addition, the drug-loaded micelles can release insulin rapidly in response to hyperglycemia in a physiological environment. The results demonstrated that the mPEG-DAS–APBA–Cou micelles showed notable glucose responsive behavior near the physiological range. The insulin release from the nanocarriers is sensitive to different concentrations of glucose, releasing insulin rapidly under the conditions of 3 mg mL−1 glucose while demonstrating comparatively inert release at 1 mg mL−1 glucose (pH 7.4). MTT assays and hemolysis studies both confirmed that the mPEG-DAS–APBA–Cou micelles have low cytotoxic activity to A549 cells and low blood toxicity. These results suggest that the glucose-sensitive dialdehyde starch micelles (mPEG-DAS–APBA–Cou) have potential applications as a glucose-responsive material for insulin delivery.
Low adhesion to skin remains a significant challenge for most hydrogel based transdermal drug delivery systems. Meanwhile, most of the methods to improve bio-adhesion often ignore the effect of the cohesion. Inspired by the adhesion mechanism of natural mussels and the synergistic balance theory based on cohesion and adhesion, we designed a poly (acrylamide- co -hydroxyethyl acrylate)-polydopamine-polyvinylpyrrolidone (PAHDP) quaternary composite hydrogel to enhance the cohesion and adhesion through the synergistic effect of multiple hydrogen bonds to achieve strong bio-adhesion to skin. The structure of PAHDP was characterized by FTIR, 1 H NMR, SEM and TGA . The peeling adhesion force of PAHDP on porcine skin was improved by 9-fold compared with PAH hydrogel. At the same time, the adhesion force of drug-loaded PAHDP was 1.3 times that of Voltaren® EX . The rheological test further demonstrated that the synergistic hydrogen bonding can significantly improve the PAHDP cohesion. In addition, in vitro release, skin permeation and pharmacokinetics test of PAHDP hydrogel containing diclofenac sodium (DIC) showed that monomer dopamine (DA) could promote drug release. FTIR and molecular modeling were utilized to further demonstrate the enhanced drug release mechanism of DA. MTT assay, H&E staining and skin erythema analysis demonstrated that PAHDP was non-irritant to the skin. In conclusion, the innovatively prepared PAHDP hydrogel exhibits high skin adhesion, excellent mechanical properties, non-irritation and high drug release ability. This study also provides a simple and efficient strategy and theoretical basis for the preparation of high adhesion and high drug release hydrogels for transdermal drug delivery system.
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