Design And Fabrication Of Carriers For Targeting Anticancer Drug Delivery And Dual Responsive Controlled Release

Mesoporous silica nanoparticles (MSNs) have significant applications inthe construction of targeting and controlled-release drug carriers due to theirunique characteristics. By introducing targeting ligand and stimuli-responsiveunit into MSNs, the targeting delivery and controlled release of anticancerdrug under redox and pH-stimuli can be realized.In our works, redox response of MSNs system (PEI-MSNs) coated withpolyethyleneimine (PEI) are designed and fabricated. Disulfide dithio acid(DDA) is covalently attached to the MSNs surface as redox response units,and then PEI is grafted on DDA and encased in MSNs surface to constructPEI-MSNs. The redox responsive MSNs are used for targeting delivery andcontrolled release of5-fluorouracil because PEI can promote passivetargeting.In order to target more efficiently for cancer cells, folic acid (FA) is usedas the active targeting ligand based on PEI-MSNs and complex FA-PEI-MSNsare formed for redox responsive controlled release of pirarubicin. Cell testdemonstrated that HepG2cells have a clearly higher endocytosis rate thanhuman umbilical vein endothelial cells. This system with targeting release andredox response has potential applications in autonomously controlled releaseof cells.In addition to redox response and targeting release, the pH responsivegroup can be introduced into MSNs surface. MSNs with redox response areend-capped with pH responsive chitosan to achieve targeting FA-CS-MSNs,which displays redox and pH dual responsive controlled release throughadjusting pH and the reducing agents. This pH responsive function based onthe acidic environment of cancer cells can enhance the targeting efficiencydue to synergistic effect of passive and active targeting of FA. Therefore themultiple responses and controllable release of pirarubicin in vivo are achieved. Furthermore, we prepare monodisperse polyer microspheres using themicrofluidic chip. A new and simple modified method for superhydrophilicPDMS chip is developed, and monodisperse paclitaxel (PTX) loaded poly(L-lactic acid) microspheres are prepared, in which PTX has a smaller initialburst and more sustained-release. The method to prepare monodispersepolymer microspheres lays the foundation for the accurately study ofrelationship between the microspheres size, morphology and microspheresdegration, pharmacokinetics, and provide useful information for clinicalmedication.By the introduction of stimuli-responsive groups and FA as a targetingligand into MSNs, in this thesis, three stimuli-responsive controlled-releasesystems for targeted drug delivery are constructed and studied. A simplemethod for preparation of monodisperse polymer microspheres usingmicrofluidic droplet was developed. The work will facilitate the design andconstruction of new system for targeting anticancer drug delivery, in vivocontrolled release and clinical therapy of cancer.