Study On Preparation And Propreties Of Thermo-responsive Nanoparticles And Nanofibers As Drug Delivry System

Nano-drug delivery system is such a kind of system which is prepared from numerous materials and whose diameter size is between50～1000nm. Drugs can be entrapped or dissolved into nanosystems, or be absorbed/scattered on the surface of systems. Nano-drug delivery systems can change the drug distribution in vivo, improve drug dissolution rate, enhanced drug property of targeting, controlled releasing, controllability, low toxicity and intelligent, so that drugs can play a better therapeutic effect or diagnostic function in medical part. Such multitude excellent performance makes nano-drug delivery system become a hot direction on drug modification research in recent decades.In nano-drug delivery systems, the intelligent materials occupy an important position because of its unique biomimetic properties. Lately, Poly (N-vinyl caprolactam)(PNVCL), the thermo responsive polymer, is attracting considerable attention from many researchers. This material has a phase transition temperature in the range of30～40℃(likes PNIPAM known to all), which is very close to the physiology temperature of human. Due to its high coordination properties, the material also owns complexation ability with different organic compounds and biocompatibility in vivo. After hydrolysis, it doesn’t product toxic amino derivatives compared to PNIPAM.The paper selected ketoprofen as the model drug, to developed two simple and convenient preparation nano drug delivery system containing thermo-responsive comonomer NVCL (including nanospheres and nanofibers). Drug-loaded nanoparticles and nano-fibers, containing thermo-responsive N-vinyl caprolactam (NVCL), were prepared by free radical polymerization. Their structure and morphology were confirmed by a variety of character means; the relationship during structure, morphology and nature of two nano-drug delivery system were researched. MTT assay detected bio compatibility of nano-fiber membrane; on this basis, in vitro drug release behavior of ketoprofen of nanoparticles and nano fibers were studied. The main research could be summarized as follows:(1) Comonomers (ketoprofen vinyl ester, KVE;6-O-vinyladipoyl-a-D-galactose, VAG) were synthesized by chemical and enzymatic methods respectively. Two novel thermo-responsive copolymers, Poly (NVCL-co-KVE) and Poly (NVCL-co-VAG), were prepared by free radical polymerization. FT-IR,]H NMR and other analytical methods confirmed products’ compound characterization. For Poly (NVCL-co-KVE) and Poly (NVCL-co-VAG) with different monomer ratios, molecular weights were confirmed by gel permeation chromatography (GPC). The lower critical solution temperature (LCST) of the copolymer was verified by UV-visible spectrophotometer.The results showed that:a) Poly (NVCL-co-KVE) with different monomer ratios all had high molecular weight and narrow dispersion,1H NMR analysis suggested drug loading content of Poly (NVCL-co-KVE) could be effectively controlled through regulating monomer ratio. LCSTs of Poly (NVCL-co-KVE) were between2～4℃. So Poly (NVCL-co-KVE) can be agglomerate not loose on human physiological temperature. LCSTs of Poly (NVCL-co-VAG) with different monomer ratios displayed that higher value of LCST with higher sugar content. When the sugar content reaches a certain amount in copolymer, LCST no more exists. Due to the experiment requirements, we selected copolymer (i) with suitable LCST as materials for next experment, to ensure that the material will be not immediately dissolved in aqueous solution. GPC of copolymer (i) also showed that it has a high molecular weight and narrow dispersion for electrospun.(2) Novel thermoresponsive nanoparticles were self-assembled from the random copolymer Poly (KVE-co-NVCL). The products were characterized by FESEM, DLS. The results showed that the shape of nanoparticles was observed as approximately spherical, and the diameter of these nanoparticles was≈50nm in a dehydrated state. But the results of DLS showed that diameter was≈150nm in aqueous solution. The distinction of two results was explained by swell phenomenon in aqueous solution. In vitro drug release studies illustrated that the drug loaded nanoparticles can avoid raw drug burst releasing, extend the releasing time, improve drug utilization rate. And the more NVCL contented, the quicker drug released.(3) Ketoprofen-loaded Poly (VAG-co-NVCL) nanofibers were successfully prepared by electro spinning method in ethanol solutions as the spinning solutions. The fabrication parameters were determined by SEM, DSC and XRD measurements. SEM was carried out to observe the morphology of the nanofibers. DSC and XRD were conducted to clarify the states of the drug. Drug release profiles were investigated using in vitro dissolution tests under different temperature conditions. Results from SEM showed that the drug was distributed evenly in Poly (VAG-co-NVCL) nanofibers. DSC and XRD results showed that ketoprofen dispersed in Poly (VAG-co-NVCL) with Noncrystalline. In vitro release study showed that temperature influenced the drug release pattern from nanofibers. As expected, the rate and amount of drug release was found to be much faster below the LCST than that above the LCST of Poly (VAG-co-NVCL). At25℃,≈100%of the drug was released within4h. In contrast, at37℃, the drug release from the nanofibers was characterized with an initial burst (approximately0-40%of the initial loading amount) followed by a sustained release (approximately40-82%of the initial loading amount) and a nonrelease phase (beyond82%of the initial loading amount). MTT assay of cell viability suggested that the incorporation of galactose within PNVCL does not compromise the biocompatibility of the PNVCL and promotes proliferation of the endothelial cells.