The Study Of Dual Temperature/pH Sensitive Nanogels On The Construction, Drug Conjugation And Innovative Vascular Embolization Materials

Nanogels, whose structures are between branched polymers and macroscopic gels networks, are usually defined as polymeric 3D-networks within the size range of 10-1,000 nm. Due to unique temperature stimuli-responsive behavior and good biocompatibility, poly(N-isopropylacrylamide) (PNIPAM) nanogels have been widely used in biomedical field. The temperature sensitive copolymer nanogels were prepared by classical emulsion polymerization in the thesis. The sol-gel phase transition of the nanogel dispersions were detailed studied. The nanogel dispersions have been evaluated as the smart blood vessel embolic materials with X-ray screening ability for the interventional therapy of cancer. The detail work was shown as follows:1. PNIPAM, P(NIPAM-co-acrylic acid) (designated as PNA) and P(NIPAM-co-2-sulfatoethyl methacrylate) (designated as PNS) nanogels were prepared by emulsion, seminal emulsion and surfactant free emulsion polymerization (SFEP), respectively. The results showed that SDS amount had important influence on the nanogel size and size distribution. The size and PDI of PNIPAM and PNA nanogels decreased with the increasing amount of SDS. But for PNS nanogels. the increasing amount of SDS resulted in the broader distribution of size. As a consequence. PNS nanogels with good distribution of size had been prepared by SFEP. The studies on the temperature dependence of the nanogels size indicated that the increasing amount of crosslinker resulted in much denser networks of nanogels, and decreased the swelling degree of nanogels.2. PNA nanogels have dual temperature and pH sensitivity that are able to shrink with increasing temperature or decreasing pHs. Their temperature/pH dependence of size was affected by the AA content, salt concentration and nanogels structure. The concentrated dispersions of PNA nanogels successively underwent colloidal glass state, clear sol state, cloudy sol state, semisolid shrunken gel state, and phase separation state in salt-free water with the increasing temperature. Semisolid shrunken gel state, however, was not observed for PNA nanogels in buffer solutions. The phase transition temperature of PNA nanogel dispersions increased with the increase of pH, nanogel concentration and AA feeding amount. 3. PNA-8 nanogel dispersion whose concentration was 8.0%(w/v) had good flowability at pH 5.0. However, it could turn into gel at 37℃when the pH of the dispersion increased to pH 7.4 by in vitro and/or in vivo experiments. The MTT tests showed that PNA-8 nanogel dispersion had low cytotoxicity. Based on these results, PNA-8 nanogel dispersion could be developed as novel blood vessel embolic materials or injectable in situ gelling drug delivery system.4. The pH sensitive drug release was successfully implemented by the conjugation of doxorubicin (DOX, an anti-tumor drug) into PNA nanogel networks via an acid-labile hydrazone bond. MTT test and flow cytometry measure indicated that the tumor cellular uptake of PNA nanogels increased at 43℃(the temperature of tumor hyperthermia). It could be attributed to the fact that PNA nanogels occurring a hydrophilic/hydrophobic transition above their transition temperature. The increasing hydrophobility of PNA nanogels could enhance the tumor cellular uptake. Since their temperature/pH-sensitive cellular uptake behavior and pH-sensitive drug release behavior. PNA nanogels conjugated with DOX could be hopefully developed as novel temperature-targeted drug delivery system for anti-tumor drug.5. Barium sulfate. a good X-ray contrast agent, was widely applied in medical diagnosis. PNS nanogels loading Barium sulfate (PNS-Ba nanogel) were successfully prepared by using the sulfate group in the PNS nanogels. Similar to the crosslink interaction of a crosslinker. barium sulfate improved the monodisperse of nanogels. The X-ray diffraction (XRD) data indicated barium sulfate was amorphous in nanogels network. PNS-Ba nanogels had very low Ba2- ion release, and good biocompatibility.6. High concentration PNS-Ba suspensions had temperature induced sol-gel phase transition, which can be used for embolization in the body.32%of the PNS-3:1-Ba nanogels suspensions had a proper phase transition temperature, and a good embolization effect in vivo. The in vivo imaging effect of Ba-loaded PNS nanogels. however, was too poor due to the too low barium content, which need to be improved in future experiments.