Preparation Of Fluorescent PH-Responsive Mesoporous SiO₂ And Its Performance For Controlled Ibuprofen Delivery

The pH-responsive drug delivery system has attracted the attention of many researchers,because it released the drug in control manner on basis of different pH values at various body sites in normal and pathological conditions.Among them,the applications of pH-responsive mesoporous silica-based hybrid materials in drug delivery system have made great progress,beside improving drug loading capacity it also achieved the targeted release for pathological tissues.However,monitoring of the exact sites or specific time of drug release in vivo is a big challenge,which need to be addressed urgently.Based on our previous works,the fluorescent molecules（1,8-naphthalic anhydride）and pH-sensitive poly（acrylic acid）（PAA）were grafted onto the surface of mesoporous silica nanomaterials by hybridization to prepare a series of fluorescent pH-responsive mesoporous silica composites.And using ibuprofen（IBU）as model drugs,the fluorescent performance and fractal evolution of mesoporous composites during drug delivery were investigated in detail.The main research content and results are as follows:1.A series of fluorescent pH-responsive hybrid P@BMMs-II-n（n=1,4,7,10,20）were prepared by grafting the polymer doped with fluorescent molecules（PID-PAA-II）synthesized by two-step hybridization of PAA and 3-aminopropyltriethoxysilane modified 1,8-naphthalic anhydride（3-1,8-naphthalenediamido-propyltriethoxysilane,PID）on the surface of vinyl-modified bimodal mesoporous materials（BMMs）,in which,II represents the two-step method and n represents the mass percentage of PID and PAA.The results elucidated that the surface modification of vinyl and the encapsulation of PID-PAA-II did not destroy the double mesoporous structure of BMMs（the most probabilistic pore diameters are about 3 nm and 20 nm）.The as synthesized hybrid material was used as a carrier and IBU was successfully loaded into the mesoporous channels of BMMs,however,under the existing conditions,the amount of PID had little effect on the drug loading capacity of P@BMMs-II-n.The release experiments in vitro showed that the IBU-releasing equilibrium amount for P@BMMs-II under acidic conditions（pH 2.0）was much higher than alkaline conditions（pH 7.4）,indicating that the strong pH dependence.Additionally,the PID amount have no effect on it,as the pH response of P@BMMs-II-n（n=1,4,7,10,20）showed almost no change.2.The results of the small angle X-ray scattering（SAXS）measurements indicated that the mesoporous hybrid materials（P@BMMs-II-20）possessed typical fractal features before drug loading and after drug release.At the same time,the distance distribution functions from SAXS data further proved that it had the feature of the core-shell structure.In particular,the mass fractal dimension of the hybrid P@BMMs-II-20coated with PID-PAA-II increased from 2.60 to 2.79 compared with t-BMMs-MPS before coating,while the fractal feature of P@BMMs-II-20 was transformed from mass fractal to surface fractal after drug loading,indicating the mesoporous structure evolved from high porosity to densification,especially with the prolongation of drug loading time,the surface fractal dimension gradually increased from 2.78 to 2.88.In the alkaline release environments,the fractal features of drug-loaded samples（I/P@BMMs-II-20）changed from surface fractal to mass fractal,and with the extension of drug release time,the mass fractal dimension gradually decreased from 2.79 to 2.61,however,under acidic conditions,the drug-loaded samples（I/P@BMMs-II-20）always maintained the features of surface fractal.3.Photoluminescence（PL）emission spectra showed that with the increase of the amount of PID,the position of the characteristic emission peak of I/P@BMMs-II was gradually red-shifted from 395 nm to 450 nm approximately.The results indicated that PID molecules were gradually distributed from monodispersed state to aggregated state in hybrid P@BMMs-II-n（n=1,4,7,10,20）.Especially,when the amount of PID was less than 10%P@BMMs-II-n（n=1,4,7,10）as carriers in different pH release environments always maintained strong fluorescent performance near 395 nm,while in case of 20%（PID）,the position of the characteristic emission peak shifted from the initial 450 nm to around 400 nm with strong fluorescence.In addition,the fluorescence decay curves showed that the decay lifetimes of hybrid P@BMMs-II-7 and P@BMMs-II-10 were 2.53 and 18.78 ns,2.64 and 18.80 ns,respectively,longer than that of pure PID（2.37 and 14.97 ns）.4.The PID-PAA-I were synthesized by adding PID molecules directly into the synthesis of PAA via one-step method,and then immobilized on the surface of vinyl modified BMMs to prepare a series of fluorescent pH responsive hybrid P@BMMs-I-n（n=1,4,7,10,20）,in which,I stands for one-step method.Using the synthesized hybrid material as a carrier,IBU was mainly loaded in the mesoporous channels of BMMs（about 3 nm）,and the drug loading capacity of P@BMMs-I-n（n=1,4,7,10,20）was 10.78%,12.47%,10.84%,11.51%,12.58%,respectively.The release experiments in vitro showed that the P@BMMs-I had strong pH dependence similar to P@BMMs-II,and it did not change with increasing the amount of PID,as the pH response of P@BMMs-I-n（n=1,4,7,10,20）almost did not change.5.The fractal evolution of hybrid P@BMMs-I-20 before drug loaded and after drug release was analyzed by SAXS technique.The mass fractal dimension of the hybrid P@BMMs-I-20 encapsulated with PID-PAA-I increased from 2.60 to 2.75compared with t-BMMs-MPS before wrapping.After the drug loading,the fractal features of P@BMMs-I-20 was changed from mass fractal to surface fractal,which was consistent with the results of the two-step method,especially with the increase of drug loading time,the surface fractal dimension gradually increased from 2.76 to 2.89.In alkaline and acidic release environments,the surface fractal was transformed into mass fractal for drug-loaded samples（I/P@BMMs-I-20）at the initial time,and with the extension of the release time,the mass fractal dimension gradually decreased from 2.88and 2.89 to 2.71 and 2.74,respectively.6.The PL emission spectra showed that the fluorescent intensity of the characteristic emission peak around 450 nm for I/P@BMMs-I synthesized by one-step method was higher than the fluorescent intensity of the emission peak around 395 nm,and the fluorescent intensity increased with the increasing the PID amount.In particular,when the amount of PID was less than 7%,P@BMMs-I-n（n=1,4,7）as carriers in different pH release environments always maintained strong fluorescence near 395 nm;while when the amount of PID was more than 10%,P@BMMs-I-10 and P@BMMs-I-20 maintained strong fluorescence around 400 nm.In addition,the fluorescence decay curves showed that the decay lifetimes of the hybrid P@BMMs-I-7 and P@BMMs-I-10 prepared by one-step method were 3.50 and 18.70 ns,3.53 and 18.86 ns,respectively,not only longer than that of pure PID,but also longer than that of P@BMMs-II-7 and P@BMMs-II-10.Therefore,the hybrid P@BMMs synthesized in this paper is a promising drug carrier and has a potential application for controlled drug release.7.The structure and properties of the hybrid P@BMMs were characterized by X-ray diffraction（XRD）,scanning electron microscopy（SEM）,transmission electron microscopy（TEM）,N₂ sorption analysis,thermogravimetric analysis（TG）,Photoluminescence（PL）spectroscopy,high performance liquid chromatography（HPLC）,ultraviolet visible spectroscopy（UV-vis）,time-resolved fluorescence spectroscopy（TRFS）,and SAXS.In particular,the fractal structure of BMMs after organic modification and drug loading was further clarified by SAXS technique.