Study On The In Situ Gelable Thermosensitive Nanogel Based On Poly(N-isopropylacrylamide)

Injectable thermosensitive aqueous polymer solution can be transformed into (semi-) solid gel at a desired position posterior to being introduced into body through a microcatheter without adding any organic solvent and crosslinker, naming undergoing sol-gel transition at body temperature. As an implant, injectable thermosensitive aqueous polymer solution is a promising drug carrier, embolic materials and scaffolds for tissue engineering because it can load various therapeutic pharmaceutical formulations by simply solution mixing, and avoiding the need for patient specific scaffold prefabrication. Nowadays, various kinds of temperature-induced in situ-forming gel polymer solution have been exploited. But these systems usually have rather high viscosity, slow temperature-responding or high critical gelation concentration, which limited their applications in biomedical field.Nanogels are crosslinked polymer gel particles possessing an average diameter in the range of 1?1000 nm. The nanogel dispersions often have low viscosity and shear thinning property. In addition, thermosensitive nanogel dispersions often possess stronger temperature sensitivities and faster temperature response compared with thermosensitve polymer solution, which make an attractive potential to be applied in biomedical engineering. In this thesis, the thermosensitive phase behaviors of temperature-sensitive nanogel dispersions have been investigated and the main contents and results are as follows:(1) Poly(N-isopropylacrylamide-co-acrylamide) (poly(NIPAAm-co-AAm), named as PNIP/AAm) nanogels were prepared by precipitation polymerization in the presence of various amount of crosslinker. The sizes of microgels were narrow distributions with diameters of 200~300 nm characterized by dynamic light scattering (DLS). The vial inverting with visual method was employed to study the thermosensitive behaviors of PNIP/AAm nanogel dispersions. The nanogel dispersions usually experienced four phases when temperature increased: semitranslucent swollen gel, clear suspension, cloud suspension and white shrunken gel. The related phase transition temperatures were influenced by the content of crosslinker and the concentration of the nanogel dispersions. Herein, gelation temperature (GT) was changed exceeding 20℃, shrunken temperature (ST) was slightly changed about 3℃, and cloud point temperature (CPT) was nearly no change.(2) The volume phase transition temperature (VPTT), kinetics of the thermosensitive volume phase transitions of PNIP/AAm nanogel particles and rheological behavior of PNIP/AAm nanogel dispersions were investigated by DLS, time-course UV-vis spectroscopy and rheological analysis, respectively. With the increasing of the AAm content in the copolymer nanogels, VPTT of nanogel and the time required for equilibrium de-swelling increased while the time required for equilibrium swelling decreased, the CPT and ST of the nanogel dispersions increased and GT decreased. The nanogel dispersions were typical pseudoplastic liquids at room temperature and turned into elastic solid near 37℃, namely, the sol-gel phase transition of the nanogel dispersions occurred in the process of temperature increasing. The sol-gel transition was reversible but with hysteresis.(3) The thermosensitive drug-loading to PNIP/AAm nanogel and drug release profile of in situ gelable PNIP/AAm nanogel dispersion were studied. The results indicated that the thermosensitivity of PNIP/AAm nanogels couldn't be destroyed by drug-loading. The crosslinker content had little effect on the drug-loading capability of these nanogels and the drug release profile of in situ-forming gel of the nanogel dispersion. On the other hand, in situ-forming gel of the nanogel dispersion with biggish diameter of nanogel particles had a faster drug release rate. In addition, the release from in situ-forming gel of nanogel dispersion for 5-Fluorouracil was rapid and complete while slow and incomplete release for bovine serum albumin. (4) The high content of Iohexol, a contrast media, in nanogel based on PNIPAAm dispersion had a profound effect on the volume phase transition of nanogel particles and thermosensitive phase behavior of nanogel dispersion, which mainly due to the presence of Iohexol with polyhydroxy group changed the micro-environment of nanogel particles. The presence of Iohexol made the nanogel particles became shrunken at lower temperature and led to the VPTT of nanogel increased about 10℃in compared with that absence of Iohexol dispersion. And the nanogel dispersion with high Iohexol concentration didn't turn into shrunken gel as expected but semitranslucent swollen gel near body temperature.(5) The PNIP/AAm nanogel dispersion with the nanogel concentration of 6.0 wt/v% in phosphate-buffered saline (PBS) solution was sol at room temperature and turned into white gel rapidly at 37℃. This dispersion had the ability of in situ-forming gel by hypodermic injection and occluding the vein after intravenous injection into the tail of rats with tolerable cell toxicity tested in vitro.(6) A biodegradable thermosensitive chitosan/glycerphosphate (CS/GPS) hydrogel was also prepared. The fast gelable CS/GPS solutions at 37℃can be obtained by increasing the concentration of GPS and pH of solutions through dissolved GPS into dilute NaOH solution. The obtained CS/GPS hydrogel showed thermosensitivity and sustained release of drug.In a word, the prepared thermosensitive nanogel based on PNIPAAm dispersion was a novel kind of temperature-induced in situ-forming gel system which was sol with low viscosity and turned into gel at body temperature. These studies on the thermosensitive phase behavior of nanogel dispersions have great signification both in theory and in application.