Stimuli-Responsive Controlled Drug Delivery Systems Based On Mesoporous Silica Nanoparticles Capping With Peptides

On a worldwide basis, cancer is considered to be the number one leading cause of death to human lives. Conventional methods for cancer treatment, such as chemotherapy, radiotherapy and surgery, have been unable to satisfy the development and demand for cancer therapy, owing to the following deficiencies:low drug biocompatibility and bioavailability, the significant systemic toxicity and lack of specific recognition in tumor tissue. Thus, scientists paid much attention to develop novel stimuli-reponsive nanocarriers for tumor cancer therapy. Peptides, as a kind of attractive biological material, have been extensively exploited for controlled drug delivery, owing to their well biocompatibility, biodegradability and more flexibility in functionality. In this study, we designed novel stimuli-responsive drug delivery systems based on mesoporous silica nanoparticles (MSNs) capping with peptide shells, and researched the target effect and microenvironment responsive drug release profiles of these drug delivery systems in tumor tissue. The work of this thesis is mainly focused on the following issues:In chapter 1, the very recent progress of peptides in functionality was reviewed and the development and application of drug delivery systems based on mesoporous silica nanoparticles (MSNs) capping with peptide shells as gatekeeper was summarized.In chapter 2, a novel pH- and redox- dual-responsive tumor-triggered targeting mesoporous silica nanoparticle (TTTMSN) was designed as the drug carrier. Once the drug loaded TTTMSN reached tumor sites, the MPEG chains in the outer layer of TTTMSN would be removed due to the hydrolyzation of benzoic-imine bond at the acidic tumor extracellular environment. Then the exposed RGD ligand could enhance the uptake of nanoparticles by tumor cells through recognizing and binding to specific receptors/integrins overexpressed on the surface of tumor cells. After the internalization by tumor cells of TTTMSN, the loaded DOX would be released rapidly from TTTMSN since the gatekeeper RGDFFFFC moiety on the surface of silica nanoparticles was switched on due to the cleavage of disulfide linkages in the presence of disulfide reducing agents glutathione (GSH) secreted by tumor cells or dithiothreitol (DTT) added factitiously.In chapter 3, a redox-responsive mesoporous silica nanoparticle (RRMSN) was developed as a drug nanocarrier capping with amphiphilic peptides (AP) by self-assembly for cancer targeting therapy. The alkyl chain stearic acid (C18-Cys) with thiol terminal group was anchored on the surface of MSNs via disulfide bond, and antineoplastic drug DOX was loaded in the pore of MSNs. The pore was capping by amphiphilic peptide Cis-DSDSDSDSRGDS through hydrophobic interactions between the octadecyl groups of MSNs and alkyl chains of AP. It was found that after the internalization of MSNs by cancer cells via the receptor-mediated endocytosis, the surface amphiphilic peptides and alkyl chain of RRMSN/DOX were removed to induce rapid drug release intracellularly after the cleavage of disulfide bond, triggered by GSH secreted in cancer cells and DOX diffused into the cytoplasm and the nuclei, causing cell apoptosis.In chapter 4, a novel redox-responsive nanocarrier based on MSNs, capping with a therapeutic peptide was designed for tumor targeting synergy therapy (TTSTMSN). The therapeutic peptide (RGDWWW)2KC was anchored on the surface of mesoporous silica nanoparticles via disulfide bond, and antineoplastic drug DOX was loaded in the pore of MSNs. The pore was capping by the rich tryptophans in two branched chains throug ?-? stacking or hydrophobic interactions between the indole rings. In vitro drug release profiles of the nanocarrier were studied and the redox-responsive property and tumor targeting synergy therapy effect were also evaluated. Once the drug loaded nanoparticles were accumulated in cancer cells via the receptor-mediated endocytosis, the peptide capping shells on the surface of MSNs were removed to induce rapid drug release intracellularly after the cleavage of disulfide bond, triggered by GSH secreted in cancer cells and DOX diffused into cytoplasm and nuclei. At the same time, the falling therapeutic rich tryptophans in the branched chains interacted with DNA due to the indole rings, leading to the disturbing of DNA structure through strong ? interactions and causing cell apoptosis.