Design And Evaluation Of Nanoporous Silica Drug Carriers With Underlying Structural Chirality

Compared with traditional materials,chiral mesoporous silica nanoparticles(CMSs)with helical morphology and unique textural properties have integrated the advantages of both nanomaterials and chiral fabrications.On the basis of the distinctive properties of CMSs,they are considered as excellent candidates in delivering drugs.In the present study,three kinds of CMSs was synthesized using biomimetic technology and applied as drug carriers.Creatively,the fundamental capacities of CMSs in being drug carriers were also studied to explore the formation-structure-property relationship of mesoporous silicas and establishing deep theoretical guidance for designing biomaterials as nanocarrier with expected performances.CMSs(His-CMSs,Pro-CMSs and Trp-CMSs)were biomimetic synthetized on various initial synthesis conditions at room temperature through sol-gel reaction by using three kinds of synthesized heterocyclic amino acid derivatives(C16-L-histidine,C16-L-proline and C16-L-tryptophan)as templates,APTES as CSDA and TEOS as silica source.The formation mechanism of CMSs and effect of initial synthesis conditions,including surfactant type,basicity and co-solvents on structure of CMSs were systematically investigated.In brief,the interactions taken place on the organic/inorganic hybrid interface(including interaction between APTES and surfactant and between APTES and TEOS)favored the helical packing of surfactants,thus resulting in curved mesoscopic structure.CMSs were characterized by TEM,SAXD,FTIR and BET test,the results showed that CMSs were spherical nanoparticles with curved channels.Surfactant structure was the dominant factor to direct the final morphology and structure of CMSs.Besides,lower NaOH concentration resulted in construction of nanochannels with higher ordered and lower curvature degree.The addition of organic alcohol was found to facilitate the formation of CMSs with larger particle size.It was convincible that the principle had important meaning for precisely control of mesoporous silicas and lay fundamental for the design of nanomaterials.To evaluate the suitability of CMSs in being drug carrier and explore the structureproperty relationship of mesoporous silicas,the fundamental capacity of CMSs that covered structure,wettability,degradation,toxicity and hemocompatibility were systematically studied.The results showed that CMSs were kinds of silica materials with good biocompatibility and low toxicity.Interestingly,the biological properties of CMSs including hemocompatibility,toxicity and degradation were mainly dominated by the physicochemical characteristics,such as structure and wettability.CMSs can degrade completely under simulated gastric fluid(SGF,pH 1.0),simulated intestinal fluid(SIF,pH 6.8)and simulated body fluid(SBF,pH 7.4)through a time period of 2-13 weeks.Among them,Trp-CMS with the best wettability exhibited the fastest degradation rate.Besides,His-CMS and Pro-CMS were proved to be safe both in intro and in vivo,whereas Trp-CMS was found to induce severe hemolysis at high concentration when they were circulating into the blood and might cause cell cycle arrest when incubating with HepG2 cells.The results implied that His-CMS and Pro-CMS were better candidates in delivering drugs.It is believed that,these findings would make efforts in understanding the relationship between physicochemical characteristic and biological properties.His-CMS was employed as poorly water-soluble drug nimodipine(NMP)carrier.Characteristics of His-CMS and its application as drug carrier were intensively investigated and compared with MCM41.The results showed that His-CMS was spherical nanoparticles with curved disordered nanospace,while MCM41 was nanospheres with ordered lattice fringes.By using solvent deposition method,NMP was respectively loaded into His-CMS and MCM41.Benefiting from the chiral pore architectures,His-CMS was able to load NMP with high capacity.Structural features of NMP before and after drug loading were systemically investigated using FTIR,DSC and XRD studies.The results showed that hydrogen bonds were formed between carriers and NMP during drug loading process.After that crystalline state of NMP effectively changed to modification L and amorphous state,and the first form turned out to be easily removed by washing.As a result,drug dissolution rate was significantly improved after drug loading,and the best result came from NMP loaded His-CMS sample(NMP-C3).It was able to release 71.88%of drug within 1 h,which was 5.8-fold higher than the release amount of pure NMP.Undoubtedly,after loading into His-CMS,NMP presented the highest relative bioavailability(386.22%),and the best therapeutic effect.Besides,after being loaded into His-CMS,NMP showed improvement of brain distribution.NMP-C3 also significantly prolonged the survival time of cerebral anoxia induced by NaNO2 in mice compared to pure NMP.In short,the novel His-CMS-based drug delivery system was effective in controlling the drug release rate and improving the oral bioavailability of poorly water-soluble drugs.Pro-CMS was also biomimetic synthesized using proline derivative and applied as poorly water-soluble drug diazepam(DZP)and nimesulide(NMS)carriers.Drugs can be incorporated into Pro-CMS with high efficiency.As evidenced by XRD analysis,infrared analysis(FTIR and in situ FTIR)and thermal analysis(DSC and TGA),during this process,drugs effectively transformed from crystalline state to amorphous state.As a result,the dissolution rate of the hydrophobic drug was significantly improved.The biodistribution study suggested that after loaded into Pro-CMS,DZP distribution in mice had been changed and showed the tendency of brain distribution and lung distribution.45 min post administration,1:3 DZP/CMS concentrations in plasma,lung and brain were about 8.57-fold,124.94-fold and 19.55-fold higher than that of pure DZP respectively.90 min post administration,the content of 1:3 DZP/CMS in brain was 62.31-fold higher than that of pure DZP.Besides,the pharmacodynamic experiment demonstrated that,the anti-inflammation effect of NMS was obviously improved by incorporating into Pro-CMS,the inhibition rates of 1:3 NMS/CMS in all pharmacodynamics tests varied from 102.2%to 904.3%.Undoubtedly,these findings will provide useful information on biological application of chiral mesoporous silica nanoparticles and are of great importance for controlled drug delivery and release system of nanoporous silica based drug carriers.