Preparation Of The Mussel-inspired Adhesive Hydrogels And Their Applications For Drug Delivery

Marine mussels can adhere to a variety of substrate surfaces in wet conditions. Studies have found that an unusual amino acid,3,4-dihydroxyphenyl-L-alanine (Dopa), is important for the formation of hydrogel-like adhesive pads. Research has also revealed that inorganic ions, especially Fe3+, are abundant in their adhesive pads. The catechol group, side chain of Dopa, is the key to mussel adhesion, and exhibits strong adhesion to various organic and inorganic surfaces. Hydrogels with catechol-containing polymers could be formed by the oxidation of catechol groups, or coordination between metal ions (e.g., Fe3+) and catechol groups, which could provide a highly biocompatible 3D matrix for drug loading.In this study, sodium alginate (SA) and chitosan (CS) were used to prepare derivatives for the preparation of the Fe3+- or IO4--induced mussel-inspired adhesive hydrogels. A novel Fe3+-induced mussel-inspired CCS-NACCS hydrogel with good biocompatibility was selected as a drug carrier for the sustained and controlled release of drugs. The details are as follows:1. Two kinds of polysaccharide, SA and CS, were used to synthesiz mussel-inspired adhesive materials, and the products were confirmed by 1H-NMR. The highest degree of substitution (DS) of DSA and CCS was 29.1% and 77.7%, while the DS of CSA and NACCS was 29.3% and 24.5%.2. Two kinds of mussel-inspired adhesive hydrogels, DSA-CSA and CCS-NACCS, were prepared using the materials synthesized above. Each of the DSA-CSA and CCS-NACCS hydrogels were induced by Fe3+ and IO4- to form crosslinking structure. The influence of DS, the molar ratio of IO4- or Fe3+ and catechol, and thiol concentration on the gelation time of hydrogels were studied. From those hydrogels, we selected out a novel Fe3+-induced mussel-inspired CCS-NACCS hydrogel with a fast gelation rate (it can gel within 12 s).3. The physical properties and the crosslinking mechanism of the hydrogel were characterized by a rotational rheometer, Raman spectroscopy, UV-vis spectroscopy, and SEM. It demonstrated that the Fe3+-induced mussel-inspired CCS-NACCS hydrogel was a dual covalent-coordination crosslinking system with porous structure (the average pore size was 48 ?m).4. Doxorubicin (DOX) was loaded into Fe3+-induced mussel-inspired CCS-NACCS hydrogels to evaluate their in vitro release properties. At pH 7.4, the drug loading capacity and drug loading efficiency were 0.998 mg DOX/g hydrogel and 99.5%, and within 60 h,44.9% of the loaded DOX was released from hydrogel. When the pH was decreased to 5.0, the cumulative release of DOX increased to 61.1%. The release curves were fitted to the Ritger-Peppas model to describe the drug release mechanism to be Fickian diffusion. The hydrogel showed no obvious toxicity and can be used for the sustained and controlled release of DOX. During the whole process, the potency of DOX was maintained and the DOX released from the hydrogel could effectively inhibit the proliferation of several kinds of tumor cells. The intercellular distribution of DOX was investigated using a confocal laser scanning microscope.In conclusion, a novel Fe3+ -induced mussel-inspired CCS-NACCS injectable hydrogel with good biocompatibility was prepared in this study, which can be used as a drug carrier for the sustained and controlled release of drugs. The gelation time and its mechanism, the drug loading capacity, the drug release property and its mechanism, and the cell cytotoxicity were investigated in this study. The results demonstrated that Fe3+-induced mussel-inspired CCS-NACCS injectable hydrogel was a biocompatible and controllable system that would be appropriate for biomedical applications.