Construction Of Dual Environmental Responsive Controlled Drug Delivery Based On Bimodal Mesopores Silicas

In recent years,with the deep research of nano-drug carriers,the environmental responsive inorganic-organic composite nanoparticles have been widely applied in drug delivery systems.These intelligent nano-drug carriers possessed unique advantages.Nano-drug carriers not only effectively enhanced the solubility and chemical stability of hydrophobic drugs,but also with the various physiological environment?pH and temperature?could control drug release behavior to achieve the targeted drug delivery in the lesion site,thereby enhancing the efficacy and reducing its toxicity for normal tissue.Mesoporous silica nanoparticles?MSNs?as an excellent nano-drug carrier are due to their biocompatibility and low toxicity,high surface areas and pore volume to effectively improve drug loading capacity.Bimodal mesoporous materials?BMMs?is a new mesoporous material consisting of worm-like mesopores of3 nm as well as large inter-particles pores around 10-30 nm with the unique characteristics such as the controllable structure and particles size.BMMs with rich silicon hydroxyl,can be carried out assembly or surface modification through physical or chemical method to introduce the functional object and form mesoporous nanocomposites with environmental sensitivity.Based on the such research background,in this thesis,we developed p H-and temperature-dual stimuli responsive nano-drug delivery system.BMMs core as“storage”achieved the high drug loading capability,and the pH-and temperature-dual stimuli responsive copolymer shell as“valve”controlled the drug release behaviors.In addition,the influence of composition and content of shell and the particle size of core on the properties of drug loading and release has been investigated.The main results of the research contents are summarized as follows:1.ThepH-andtemperature-dualstimuliresponsivepoly?N-isopropylacrylamide-co-acrylic acid??P?NIPAM-co-AA??nanoparticles with different contents of acrylic acid were synthesized via free radical polymerization route.The morphology,structure and swelling properties of the copolymers particles were investigated in details.The results indicated that their swollen/shrunken behaviors of spherical copolymers were strongly dependent on the various parameters,including content of acrylic acid monomers,the pH value of solution,temperature and the salt concentration.Essentially,the electrical repulsive force,Van der Waals forces and hydrogen bonding derived from the interaction between copolymer molecules and solution were thought to determine the sensitive properties of obtained P?NIPAM-co-AA?copolymer.Meanwhile,ibuprofen as model drug,the effect of composition of copolymer on the properties of drug loading and release were investigated under different external environment?pH and temperature?.The results implied that the introduction of AA chains into PNIPAM framework enhanced the loading of IBU and the maximum loading capability of P?NIPAM-co-AA?-3 was reached up to 7.9 wt%.The release behaviors of IBU-loaded copolymers exhibited highly responsive to temperature and p H values,whereas the responsive performance are relevant with the composition of copolymer.The amount of drug release exhibited a high cumulative release at 37 ^oC/pH 7.4,but a significant decrease at 37 ^oC/pH 2.0.The IBU release mechanism was proposed,whereas the IBU diffusion contribution from P?NIPAM-co-AA?was thoroughly elucidated using three empirical equations,namely Korsmeyer-Peppas model,modified Korsmeyer-Peppas model and Higuchi model,respectively.The obtained results demonstrated that the release procedure of P?NIPAM-co-AA?was driven by typical non-Fickian diffusion mechanism in the basic medium,while in acid medium two stage release mechanism was observed due to their aggregation behaviors.2.On the basis of the previous work,environmental stimuli?pH/temperature?copolymer P?NIPAM-co-AA?coated on the modified bimodal mesoporous silica?BMMs?with vinyl groups via seed polymerization method and obtained the pH-and temperature-dual stimuli responsive composite nanoparticles with core-shell structure.The results indicated that the ordered mesoporous structures were retained after coated copolymer.However,the microstructure has been changed,in which,the mass fractal was increased from 2.36 for BMMs to 2.51 for P@BMMs.Meanwhile,the drug loading capability of P@BMMs was greatly improved,compared with that of copolymer.The IBU molecules were loaded into the P@BMMs composite nanoparticles,which exhibited exothermic process and the existences of hydrogen-bond interaction between IBU molecules and P?NIPAM-co-AA?-coated surfaces.The mesoporous nanocomposites of P@BMMs could control the drug release behaviors.3.On the basis of the above research,the effects of coating amount and composition of P@BMMs composite nanoparticles on the properties of drug loading and release were investigated.The results indicated that with the increase of the amount of coating polymer,the surface area and the pore volume of P@BMMs decreased,while the mass fractal dimension increased and the corresponding drug loading capacity decreases.After drug loaded,the surface and pore volume of sample decreased sharply,the fractal dimension was transformed from the mass fractal to the surface fractal,suggesting the successful encapsulation of IBU.The release performances of serial P@BMMs were investigated under different pH and temperature conditions.The results showed that the IBU-releasing rate of P@BMMs was decreased with the increasing amount of coated copolymer.Besides,the sensitive performance presented low temperature-response and high pH-response with the increasing of AA content in the copolymer shell.The kinetic behaviors of IBU releasing from P@BMMs followed Korsemeyer-Peppas model.The trend of fractal dimension during the release process of P@BMMs were successfully traced by SAXS technique.The results indicated that the high equilibrium release amount was presented under high temperature and acidic conditions and the fractal dimension was transformed from surface fractal to mass fractal.Subsequently,the values of mass fractal dimension?D_m?were gradually decreased from 2.89 to 2.56 with the increase of IBU-release amount.However the decrease equilibrium release amount was found in basic solution and the surface fractal was maintained.4.Taken account into the effect of the size of nanoparticles on the properties of drug loading and release,a series of pH-and temperature-responsive composite nanoparticles?P@MSNs-x?with different particle size were prepared,referring to the synthesis method of P@BMMs composite nanoparticles.The results showed that the size of MSNs have a great influence on the distribution state of copolymer on the MSNs.The surface and pore volume of P@MSNs-x were decreased with the size of MSNs.In addition,the drug release properties of blank MSNs indicated that the drug release rate depended on particle size and dispersion state,but these blank MSNs exhibited non-intelligence.After coated copolymer on the surface of MSNs,the drug release rate presented non-linear relationship with the particle size of MSNs.With the increase of the particle size,the sensitivity of the drug release was significantly decreased,compared with that of P@BMMs.These results implied that the particle size had a great effect on the surface state of the polymer wrapped on the MSNs,leading to the different responsive behaviors of drug release.5.All the copolymers,mesoporous materials before and after modification,and related drug loaded samples were characterized by means of X-ray diffraction,scanningelectronmicroscopy,transmissionelectronmicroscopy,N₂adsorption-desorption,thermogravimetric analyses,hydrodynamic diameters/Zeta potential analysis,elemental analysis,Raman spectra,¹H NMR,solid ¹³C NMR,²⁹Si NMR,Small angle X-ray scattering technology,Fourier transform-infrared spectroscopy,High performance liquid chromatography and UV-vis spectra.