Dual-responsive Drug Delivery System Based On Hollow Mesoporous Silica Nanoparticles And Its Biological Evaluations In Vitro And In Vivo

Tumor is one of the most lethal diseases worldwide in the 21 st century. The conventional chemotherapy and radiation therapy etc. had severe toxic side effects on the patients. With the development of nano-biomedicine, intelligent responsive nanomedicine delivery system provides convinence for solving those problems above. Due to their relatively good biocomapatibility, tunable dimension and mesopore size, high surface area and pore volume, and easy to be modified, hollow mesoporous silicon nanoparticles(HMSNs) were widely uased as carriers for intelligent drug delivery.In order to target tumor for intelligent responsive therapy, we designed and constructed a redox/pH dual-responsive drug delivery system(HMSNs-S-S-CPA-CytC-LA) by using CytC as end-capping agent, redox-cleavable disulfide bonds and pH-disassociation boronate ester bonds as intermediate linkers, lactobionic acid as targeting moiety and HMSNs as drug carrier. The results of scanning electron microscopy(SEM), transmittance electron microscopy(TEM), dynamic light scattering(DLS), Zeta potential measurements, fourier transform infrared spectroscopy(FTIR), thermogravimeric analysis(TGA), BET/BJH analysis confirmed that disulfide bonds, boronate ester bonds and lactobionic acid modified CytC were successfully conjugated to the surface of HMSNs, i.e., the HMSNs-S-S-CPA-CytC-LA system was successfully constructed.The in vitro results revealed that HMSNs-S-S-CPA-CytC-LA@DOX system has redox and pH dual responsive drug release property. The HMSNs-S-S-CPA-CytC-LA system has good cytocompatibility, and HMSNs-S-S-CPA-CytC-LA@DOX could effectively inhibit the proliferation of Hep G2 cells. TEM, flow cytometry analysis and confocal laser scanning microscopy(CLSM) observations demonstrated that HMSNs-S-S-CPA-CytC-LA@ DOX system could be endocytosed by HepG2 cells via targeting recognition, and mainly distributed in cytoplasm, while not penetrating into cell nuclei. Furthermore, the specific microenvironments of tumor cells(overexpressed GSH and acidic environment) triggered the breakage of the-S-S- and boronate ester bonds of the system, leading to rapid DOX release for the inhibition of tumor cells growth. Meanwhile, dissociative CytC could synergistically induced cell apoptosis by activating caspase in the presence of dATP.The in vivo tumor experiments suggested that HMSNs-S-S-CPA-CytC-LA@DOX system could efficiently induce tomor cells apoptosis and inhibit tumor growth. Tunel staining of tumor tissues and H&E staining assays of main organs of nude mice suggested that HMSNs-S-S-CPA-CytC-LA@DOX system had higher tumor inhibition effect than those of free DOX group and HMSNs@DOX group, while with reltively low toxic side effect.In summary, the constructed dual-responsive drug delivery system in this study potentially improved the drug utilization efficiency and synergistically induced cells apoptosis by means of the caspase activation via dissociative cytochrome C. This study affords a new concept for the development of dual-responsive drug delivery system for synergistical tumor therapy.