Polymer-Nanoparticle Hybrids For Drug Delivery Applications

摘要

Combination of nanoparticles (NPs) and pharmaceutically active compounds like drug molecules are very effective in drug delivery systems due to their superior performance and selectivity. These advanced nanostructured drug carriers are also employed to deliver nucleic acids and proteins to the diseased site. Drug targeting and release to the infected site have now become popular both in {in vitro} and {in vivo} research areas. Multifunctional NPs used in drug delivery applications offers several advantages such as increase stability of NPs, modify optical, magnetic, electronic properties as well as incorporate biocompatibility and stimuli responsive behaviour within a single framework.Several studies have been done with inorganic NPs and polymeric NPs and combination of these, for example conjugation of thermoresponsive polymers with gold nanoparticles (Aunps) were studied and properties of these constructs were compared with the free polymer drug carrier system.System used in this work is comparatively unique and different in the sense that Fe@Au NPs conjugated with hydrogels have not studied prior to this study. In this research, inorganic (Fe@Au) and polymeric NPs (pNIPAm/AAc and PEG) are gelled together, to from a multifunctional drug carrier. Most important attribute which these nano-constructs should have is stability and effective release kinetics of the loaded drug.The master thesis has focused primarily on the loading and release of drug and protein molecules. First, Fe@Au were synthesized from previously established method at Ugelstad laboratory, NTNU. These NPs were then characterized using DLS (Dynamic Light Scattering), zeta-size, UV-vis (Ultra-violet spectroscopy) and S(T)EM. In order to investigate the variations of the sizes and zeta potentials as a function of temperature and pH (in case of size) as well as structural framework and UV-vis spectra of formed NPs respectively. Thereafter these NPs were coated with pNIMPm/AAc hydrogels (which were optimized previously at Ugelstad laboratory, NTNU), PEG and the combination of these polymers. Coated sample were also characterized with the same techniques as used for Fe@Au NPs. Loading studies were performer with three drugs L-dopa, coumarin and cytochrome c and estimated with UV-vis using calibration curves for the drugs. Drug loading was optimized and concentration of drug and NP which gives maximum loading efficiency was used for the release studies. Release of the loaded drugs were observed at high temperature (40oC) and low pH (3.3). Drug release was also measured with UV-vis.Two methods were used for coating of Fe@Au NPs, method 1 and method 2. Method 2 provides better loading efficiencies compared to method 1 and therefore used in this study. Size of pNIMAm/AAc based hydrogels decreased at higher temperature due to transition from hydrophilic to a hydrophobic state. VPPT for heating and cooling shown by hydrogels alone is 38 oC, which indicated their reversibility. Size increased for Fe@Au NPs coated with the hydrogel probably due to the cross-linking effect provided by Fe@Au NPs. VPTT is observed when for heating and cooling is calculated as 39.8 oC and 39.5 oC for coated samples. Fe@Au _PEG _Hydrogel system shows appreciable reversibility with VPPT values for heating and cooling reported as 37.1 oC and 36.7 oC. pH Effect on size is similar to temperature effect. Cytochrome C loading shows high loading efficiencies of 31.66 % and 32.57 % for Fe@Au_Hydrogel and Fe@Au_PEG_Hydrogel respectively. Highest release of 87.20 % was obtained from Fe@Au_Hydrogel system, while Fe@Au_PEG_Hydrogel system shows fastest release rate. In case of Cytochrome C, both highest and fastest release were given by Fe@Au_PEG. However, Fe@Au_PEG_Hydrogel system also shows almost identical t^1/2 in comparison to Fe@Au_PEG.Polymer-NPs hybrids shows promising loading and release of the drugs with change in temperature and pH. Which highlight their superiority as a drug carrier compared to only polymeric and inorganic system. Further studies with these systems can be developed in which two drugs at the same time can be loaded and released from this nanocarrier system.