Biomacromolecules 2005, 6, 1829-1834
1829
Design of Hybrid Hydrogels with Self-Assembled Nanogels as Cross-Linkers: Interaction with Proteins and Chaperone-Like Activity Nobuyuki Morimoto,† Takao Endo,‡ Yasuhiko Iwasaki,† and Kazunari Akiyoshi*,†,§ Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, 2-3-10, Kanda-surugadai, Chiyoda-ku, Tokyo 101-0062, Japan, Department of Biomolecular Science, Faculty of Science, Toho University, 2-2-1 Miyama, Funabashi-shi, Chiba 274-8510, Japan, and Center of Excellence Program for Frontier Research on Molecular Destruction and Reconstruction of Tooth and Bone, Tokyo Medical and Dental University, 2-3-10, Kanda-surugadai, Chiyoda-ku, Tokyo 101-0062, Japan Received March 2, 2005; Revised Manuscript Received April 26, 2005
New hybrid hydrogels with nanogel domains were obtained by using polymerizable self-assembled nanogels as cross-linkers. Methacryloyl groups were introduced to cholesteryl group-bearing pullulan (CHP). The methacryloyl group-bearing CHPs (CHPMAs) formed nanogels by their self-association in water (Rg ) 14-17 nm). CHPMA nanogels were polymerized with 2-methacryloyloxyethyl phosphorylcholine (MPC) by radical polymerization in a semidilute aqueous solution. CHPMA nanogels acted as effective crosslinkers for gelation. TEM observation showed that the nanogel structure was retained after gelation and that the nanogels were well dispersed in the macrogel. The hybrid hydrogels showed two well-defined networks such as a nanogel intranetwork structure of less than 10 nm (physically cross-linking) and an internetwork structure of several hundred nanometers (chemically cross-linking). The immobilized nanogels retained their ability to trap and release protein (insulin was used as a model protein) by host-guest interaction of the cholesteryl group and cyclodextrin and also showed high chaperone-like activity for refolding of chemically denatured protein. Introduction Polymer hydrogels have been widely used as functional materials in biotechnological and biomedical applications.1 Recently, hydrogels with unique cross-linking points have been reported. Dendrimers,2 microspheres,3 and nanoparticles4 have all been used as cross-linkers in preparing chemically cross-linked gels. Stimuli-responsive hydrogels with antibodies5 and artificial protein motifs6 as physically cross-linked points and topological hydrogels with cyclodextrin units as movable cross-linking points7 have been developed. Control of the network structure of gels and the design of hydrogels with a well-controlled nanodomain structure are still challenging problems.8 We report here polymerizable nanogels (physically cross-linked) as functional cross-linkers for preparing hybrid hydrogels. Nanometer-sized (
