Preparation Of PEGlyted Stimuli Responsive Nanohydrogels For Controlled Release Of Drug

In order to reduce the side effects of drug and improve drug distribution in human bodies and therapeutic effects, the study and develop of biocompatible and biodegradable stimuli responsive drug delivery systems which could better control the release of drug in lesion site through active or passive targeting have attracted more and more attention. Due to many unique advantages of nanohydrogels, such as good biocompatibility, larger specific surface area for multivalent modification and bioconjugation, complex internal networks suitable for drug loading and hydrophilic surface and crosslinking structure for prolonged circulation time, they have shown powerful potential in the application as drug carriers. Poor biodegradability and biocompatibility of synthetic nanohydrogels are key obstacles that hold back their further application in drug delivery systems; meanwhile, nanohydrogels prepared from natural polysaccharides with excellent biocompatibility also have defects of lower drug loading content and lack of biodegradability.In view of the above questions, this article was focused on the preparation of biocompatible and biodegradable single or double stimuli responsive nanohydrogels with high performance of drug loading efficiency and good effect on the controlled drug release. Chemically synthesized methacrylic acid(MAA) and modified natural polymeric sodium alginate(SA) were used as raw materials respectively, and the introduction of well-known biocompatible polymer polyethylene glycol(PEG) which derivatives with many other advantages into the backbone of the nanohydrogels could further improve the biocompatibility of the nanohydrogels. The structure of the nanohydrogels were characterized by fourier transform infrared(FTIR) spectroscopy, morphology and size of them were investigated by transmission electron microscope(TEM) and dynamic light scattering(DLS), and finally studied their loading and controlled release behaviors of an anti-cancer drug(DOX). The research contents and main achievements of this dissertation comprised three parts as follows:1. Monodisperse biodegradable nanohydrogels were synthesized by one-step distillation precipitation polymerization with MAA and poly(ethylene glycol) methyl ether methacrylate as monomers and N,N-bis(acryloyl)cystamine(BACy) as crosslinker. The chemical structures of the nanohydrogels were investigated by FTIR spectrometer. TEM and digital camera were used to observe the disintegration behavior of the nanohydrogels under reductive media, the result showed that the fragments after disintegration can be rarely seen in the vision of TEM and most of the nanohydrogels degraded into linear polymer chains. DOX served as a model drug for the investigation of the loading performance of the nanohydrogels, the drug encapsulation efficiency(DEE) were all as high as 95%. The drug release experiments demonstrated that the nanohydrogels had obvious pH and redox responsive release properties. Finally, the cytocompatibility of the nanohydrogels was evaluated on HepG2 cells through MTT assay.2. A facile approach was developed to prepare oxidized alginate-graft-poly(ethylene glycol)(OSA-g-mPEG) nanohydrogels with crosslinker cystamine under the activation of carbodiimide(EDC), the obtained nanohydrogels have good biocompatibility compared with those synthetic nanohydrogels. The OSA-mPEG nanohydrogels with higher oxidation degree(DO%=20%) were featured of relative regular morphology, narrow size distribution and small particle size of 45 nm under TEM. The nanohydrogels expressed favorable size distribution and the size of DOX-loaded nanohydrogels was 110 nm by DLS. We varied the amount of drug, proportion of solvent and the amount of acetic acid to investigate their impacts on the formation of the drug-loaded nanohydrogels, drug and carriers were mainly connected through Schiff base bonds. The nanohydrogels(DO%=20%) had preferable drug loading property and showed better pH-sensitive release performance. In cells experiments, the nanohydrogels exhibited benign cytocompatibility, confocal laser scanning microscopy observation verified that DOX-loaded nanohydrogels were efficiently internalized into cells via endocytosis, and the released DOX could effectively kill cells.3. A calcium ionic crosslinking method was utilized to prepare in situ drug-loaded SA, OSA and OSA-g-mPEG nanohydrogels with dried particle size about 50 nm for controlled release of DOX. This method was simple, and the nanohydrogels were prepared as DOX was loaed into the nanohydrogels. The experimentation process not only was simplified, but also the distribution of the drug in the nanohydrogels was improved. The hydrodynamic diameter of the OSA-g-mPEG nanohydrogels was 135 nm which was conducive to their transportation in vivo. The DEE values of these nanohydrogels were all over 90%, and the drug loading content was about 26%. Their drug release experiments were conducted under different pH respectively, the nanohydrogels with different composition presented different levels of pH-triggered DOX release. The OSA-g-mPEG nanohydrogels showed the best pH-responsive controlled release performance, and they could release DOX sustainedly for three days under pH 5.0.