The Preparation, Characterization And Biological Evaluation Of Concentrated PNIP/BMA Nanogel Dispersions For Interventional Therapy Of Liver Cancer

Poly(N-isopropylacrylamide-co-Butyl methacrylate) (PNIP/BMA) nanogel Iohexol dispersions with high concentration exhibit reversible thermosensitive phase behaviors while temperature changes. Nanogel concentration, Iohexol concentration and temperature play important roles in the thermosensitive phase behaviors of nanogel Iohexol dispersions. In this thesis, the size and zeta potential of PNIP/BMA nanogel is 270+-20nm and -10mV respectively. The cocentrated nanogel Iohexol dispersions exibited good shear thinning behavior and fast temperature response. Main contents and results are as follows:(1) PNIP/BMA nanogel were prepared by soap-free emulsion polymerization. Characterized by dynamic light scattering (DLS), nearly monodisperse PNIP/BMA nanogel had the average size of 270+-20nm. The zeta potential of PNIP/BMA nanogel was -10±3mv, which obviously decreased as temperature increased. The microscopic morphology of PNIP/BMA nanogel was characterized by Transmission Electron Microscope (TEM). DLS was employed to determine the effect of Iohexol concentration on the diameter of nanogel particles as temperature changed. In water, the diameter of the nanogel particles decreased while temperature increased; In contrast, it increased with the increasing temperature in Iohexol solution.(2) The vial inverting with visual method was employed to study the thermosensitive behaviors of concentrated PNIP/BMA nanogel Iohexol dispersion. The concentrated PNIP/BMA nanogel Iohexol dispersion usually underwent four phases when temperature increased: semitranslucent swollen gel, semitranslucent fluid, cloud suspension and white shrunken gel. The related phase transition temperatures were influenced by the content of Iohexol and the concentration of the nanogel dispersions. The gelation temperature (GT) was increased as the concentration of the nanogel dispersions and Iohexol were increased, but shrunken temperature (ST) was slightly decreased, and cloud point temperature (CPT) was nearly no change. The PNIP/BMA nanogel dispersion with the nanogel concentration of 6.0 wt/v% in Iohexol solution was sol at room temperature and turned into white gel rapidly at 37℃, which we can use as injectable in situ-forming gel stuff. On the contrary , the PNIP/BMA nanogel dispersion in water can not turned into stable white gel at the same nanogel concentration.(3) The kinetics of the thermosensitive volume phase transitions of PNIP/BMA nanogel particles were evaluated by measuring the relative turbidity of nanogel aqueous dispersions under varying temperature. With the increasing of the temperature range of in vitro and in vivo, the time required for equilibrium de-swelling increased while the content of Iohexol and nanogel were slightly affect. Meanwhile, effect of the content of Iohexol and nanogel on the time required for equilibrium de-swelling was slightly. The viscosity of nanogel dispersions was affect by temperature, shear rate and the concentration of the nanogels. The influence of temperature on viscosity of nanogel dispersion was in coincidence with thermosensitive phase behaviors under temperature changes. The cocentrated nanogel Iohexol dispersions exibited good shear thinning behavior.(4) Iohexol release profile of in situ gelable PNIP/BMA nanogel Iohexol dispersion was studied by UV-vis spectroscopy. The results indicated that Iohexol had a faster release rate, the cumulative release reached 90% after 6h.(5) The PNIP/ BMA nanogel Iohexol dispersion with the nanogel concentration of 6.0 wt/v% was sol at room temperature and turned into white gel rapidly at 37℃. This dispersion had the ability of in situ-forming gel by catheter injection and occluding the vein of cancer after arterial injection. The hemolysis test indicated that the haemolysis rate of The PNIP/BMA nanogel Iohexol dispersion with the nanogel concentration of 6.0 wt/v% was 0.3%, which met the ISO standard(no more than 5%). The PNIP/BMA and PNIP nanogel water dispersions were tolerable cell toxicity tested in vitro, but the level of cytotoxicity of the PNIP/BMA nanogel Iohexol dispersion reached grade 2 after 24h.In a word, the resultant cocentrated PNIP/BMA nanogel Iohexol dispersions were novel thermosensitive material which exhibited reversible thermosensitive phase behaviors with the change of temperature, and has the characteristic of autoradiography. The studies on its thermosensitive behavior and biocompatibility are very important on its application.