Construction And Evaluation Of Biomimetic Regulated Nanoporous Silica Drug Delivery Systems

On the basis of huge application ability of nanoporou silica in delivering drugs and unique advantages of porous materials synthesized using biomimetic technology(including mild synthesized conditions,abundant templates and self-assemble process with flexible regulation),the present work adopted biomimetic technology to creatively prepare nanoporous silica@PEI xerogel(NSX),amino modified nanoporous silica xerogel(ANSX),chiral mesoporous silica and its amino modification(B-CMS and Amino-B-CMS),bimodal nanoporous silica(B-BNS)and dual functionalized mesoporous silica nanoparticles(Dual-MSN),explored the relationship between formation mechanism and characterizations of carriers by taking advantages of biomimetic technology,and constructed drug loading systems to lay deep theoretical basis for designing nanoporous drug delivery systems with expected performances.NSX-1,NSX-2 and NSX-3 were synthesized with ingredients of TEOS,PEI aggregate solution prepared by three proportions of methanol,and absolute ethyl alcohol.The results showed that NSX was amorphous carrier with nanopores.NSX synthesized with lower proportion of methanol in PEI aggregate solution had higher degree of porosity.One step method was used to prepare PNH loaded NSX.The results indicated that the repository type of NSX can control drug release slowly,and the order of release was NSX-3>NSX-2>NSX-1,demonstrating that the property of NSX can be regulated by changing the proportion of methanol in PEI aggregate solution thus controlling drug release.This principle has important meaning for designing drug loaded NSX system.Amino modified NSX named ANSX was prepared using polycondensation method.IMC loading systems,which were IMC-NSX and IMC-ANSX,were constructed using one step method.The results showed that hydrogen bonding forces were formed between drug and carriers.Drug was encorporated in IMC-NSX and IMC-ANSX with amorphous phase.SBET?Vt and WBJH of ANSX were lower than NSX,also SBET and Vt of drug loaded carriers were smaller than carriers,while WBJH of IMC-ANSX was higher than IMC-NSX.Both IMC-NSX and IMC-ANSX can significantly improve drug dissolution,and the release rate of IMC-ANSX was faster than IMC-NSX.The pore enlarging phenomenon of IMC-ANSX indicated that the IMC distribution in IMC-ANSX can be regulated spontaneously in the synthesized process of IMC-ANSX,which controlled drug release and improved drug dissolution.B-CMS1,B-CMS2 and B-CMS3 with supramolecular chirality were synthesized using amino acid derivative of C16-L-alanine,and synthesis conditions of pH and stirring rate were studied.It can be concluded that pH and stirring rate impacted morphology,SBET and Vt significantly.Afterwards,IMC loaded B-CMS was constructed by solvent evaporation method.The research found that drug was encorporated in carrier with amorphous state.Compared to raw drug,the cumulative release of IMC at 90 min was enhanced from 40%to more than 80%.The release order was in consistent with the order of WBJH demonstrating that B-CMS was an excellent carrier for controlling drug release.Then Amino-B-CMS was prepared on the basis of B-CMS.TEM and BET analysis results confirmed that the porous channels of Amino-B-CMS were denser than B-CMS,also SBET and Vt of Amino-B-CMS was lower than B-CMS.IMC loaded Amino-B-CMS was obtained by solvent evaporation method.The drug distribution of Amino-B-CMS was superior to B-CMS,resulting in its faster release.In addition,rat pharmacokinetics result indicated that IMC loaded B-CMS and IMC loaded Amino-B-CMS significantly advanced relative bioavailability.B-BNS was unexpected obtained using C16-L-serine as biomimetic template under pH 13.Its formation mechanism relied on the dynamic behavior of C16-L-serine.TEM and BET test results demonstrated that B-BNS was meso-meso amorphous carrier.IBU loaded B-BNS was constructed then the drug state of existence in carrier together with functions of carrier was studied.The differences of release rate between small mesopores and large mesopores led to the "double stair" phenomenon of cumulative release profile in simulated gastric fluid,and co-existence of burst release and sustained release in simulated intestinal fluid,which realized bimodal control release.The present study lays fundamental for the development of bimodal nanoporous silica drug delivery system.Dual-MSN with molecular chirality and carboxyl function was synthesized with polyamine biomimetic condition.It showed that Dual-MSN was nanoparticles with thick core and thin shell.Compared to MSN,SBET and Vt were reduced,and surface roughness was also lowered.DOX loaded Dual-MSN was established and it was discovered that the advantages of Dual-MSN in delivering DOX were as follows.Firstly,the carboxyl functional groups of carrier presented strong electrostatic repulsion under weak acid pH condition,thus triggering pH stimuli of DOX release.Secondly,Dual-MSN with molecular chiral function had ordered channels on the nanoparticle shell,which lowered surface roughness of nanoparticles,thus enhancing the amount of DOX loaded Dual-MSN uptaken by MCF-7 cells then improved the ability of DOX loaded Dual-MSN in killing MCF-7 cells.