| Summary: | 博士 === 國立交通大學 === 材料科學與工程學系所 === 103 === Sustained drug release system has been received greatest attention in the world, especially injectable hydrogel drug delivery system. However, burst release in the initial stage of drug release limits the biomedical application in the hydrogel system. In order to efficiently suppress and control the drug release property in the initial drug release, we have developed a hydrogel composed of nanoparticles, the nanoparticles can reduce the release rate in the initial stage of drug release, and investigated the material properties and its biomedical applications. Therefore, this thesis is focused on three topics: 1. Design and characterization of a novel amphiphilc chitosan nanocapsule-based thermo-gelling hydrogel (CHC gel). 2. In-vitro characterization and in-vivo glaucoma treatment of a shear reversible injectable hydrogel. 3. Design and investigation of a highly pH-sensitive CHC-based nanogel for biomedical applications.
The first part of this thesis is to employ a modified amphiphilic chitosan polymer as a key material for fabricating hydrogel, and combine with glycerol and β-glycerophasphate to prepare a thermo-gelling hydrogel for biomedical use. The amphiphilic chitosan (carboxymethyl-hexanoyl chitosan, CHC) was successfully synthesized in this lab. The CHC demonstrated self-assembly into nanocapsules about 200 nm in size in aqueous environment, and the capsules demonstrated good drug loading properties. The hydrogel in this study was composed of CHC nanocapsules and named CHC gel. The CHC gel was investigated its rheological property, electron microscope image, drug release property and cytotoixicity. The potential as a depot drug delivery system was demonstrated in vivo through the therapeutic effect of ethosuximide (ESM) loaded CHC gel, suppressing spike wave discharges (SWDs) in Long Evan rat model. Simultaneously, the clearance of gels from the site of administration was monitored by using non-invasively MRI. Finally, this study developed a potential material for injectable depot gel for drug delivery.
To develop an injectable and long-term drug release hydrogel system, the CHC gel was merged with benzalkonium chloride (BAK) as biocide and stabilizer for protecting drugs. The BAK-containing CHC gel (CHC-BAK gel) was investigated the effects caused by BAK through rheological study, drug release property and cytotoxicity. New Zealand rabbit was employed as animal model and induced an abnormally high IOP (intraocular pressure) by intravitreal injection of triamcinolone acetonide (TA), a kind of synthetic corticosteroid. Then, we injected a latanoprost loaded BAK-CHC gel under rabbit’s eye ball for sustained release and monitored the IOP variation. In this study, the injection ability and drug preservation of injectable hydrogel system for drug delivery were investigated and discussed further. The CHC drug delivery hydrogel system was progressed in a new therapeutics and thorough study in biology.
In addition to prepare an injectable biogel for sustained release, CHC nanoparticle was modified with functional groups by chemical synthesis for increasing functions, such as thermosensitivity and pH sensitivity, and improving its value in biomedical applications. In the final part of this thesis, Acrylic acid (AA) monomer was employed as the group improving the function of CHC polymer. AA monomers were grafted on the CHC by the chemical bond between the protonated amine on CHC and the double bond of AA monomers. The macroradicals can react with the double bond of AA monomers and act as the active site to initiate chain propagation of the monomers and form poly(acrylic acid). CHC-PAA nanogel presents higher pH-responsive behavior in terms of size or volume than existing reports in the literature and are aimed to use for drug delivery application. The nanogel also presents low cell cytotoxicity for cancerous cells (MCF-7) and normal cells (BCE), which indicates the nanogel can be design as a new biomaterial for cellular-based therapeutics.
In summary, this injectable hydrogel prepared by amphiphilic chitosan and other chemicals can be loaded with multi-drugs and process in situ sustained drug release. The hydrogel can be degraded naturally without any additional invasive surgery. Burst release in the initial release of the hydrogel also conspicuously decreased because of its microstructure. Besides, the hydrogel exhibits good biocompatibility and low cell cytotoxicity, which improve the potential for using in various biomedical applications. Moreover, the amphiphilic chitosan polymer can be modified with some specific groups for improvig the functions, and be used in different biomedical applications, such as oral drug delivery.
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