Polypeptide/Mesoporous Silica-Based Nano-Sized Drug Delivery Systems:Fabrication And Biomedical Application

In cancer treatment, drug delivery systems (DDSs), which can overcome the rapid blood clearance and severe side effects of chemotherapeutics, enhance the water solubility of the drugs and achieve tumor selectivity, are of significant importance. Various nano-sized DDSs, including liposomes, nanogels, polymeric nanoparticles, inorganic nanoparticles, and nano-micelles were developed to deliver anticancer drugs to tumor tissues via the enhanced permeation and retention (EPR) effect. In this thesis, a series of novel polypeptide/mesoporous silica-based nano-sized DDSs were designed and fabricated for cancer therapy.In chapter1, we discussed the history, fabrication, functionalization and biomedical application, especially for controlled release and cancer therapy, of the polypeptide/mesoporous silica-based nano-sized DDSs.In chapter2, a series of porphyrin-functionalized amphiphilic diblock copolypeptides were synthesized by ROP of Leu-NCA and Z-Lys-NCA, followed by the deprotection of Z groups, which exhibited high fluorescence quantum yields. DLS measurements and TEM observation confirmed the micellar structure formed by the self-assembly of APP-L109K186. APP-L109K186micelles exhibited no significant dark cytotoxicity and high PDT efficacy against HepG2and HeLa cells. These results indicated the micelles could be a novel carrier for cancer therapy.In chapter3, we reported the synthesis and construction of a pH-responsive, MSN-based dual-drug-delivery system, CPT@MSN-hyd-DOX. where CPT was physically loaded into MSN with chemically conjugated DOX via an acid-labile hydrazone bond. The system has following features:(1) the nanoparticles can be conveniently and easily constructed via a facile one-pot strategy;(2) the acid-labile hydrazone bond for DOX conjugation is extraordinarily sensitive to the slightly acidic tumor extracellular environment (i.e., the nanoparticles can maintain a relatively "stealth" status during circulation and release DOX triggered by the tumor acidity when they accumulate at the tumor site via the EPR effect);(3) as a hydrophobic antitumor drug, CPT loaded in the pores of MSNs can be effectively delivered to tumor cells with a sustained release, and (4) the conspicuous synergistic effect of CPT and DOX can be activated by tumor acidity and further promoted by the increased acidity in subcellular compartments such as the lyso/endosomes.In chapter4, we reported a novel multifunctional, MSN-based drug delivery system, DOX@MSN-S-S-RGD, where N3-GRGDSGRGDS-NH2was chemically conjugated onto MSN-S-S-Alkyne via the "click" chemistry. We demonstrated that:(1) the attachment of RGD peptide to the outer surface of MSN can partly prevent the uncontrolled leaching of loaded guest molecules (DOX);(2) compared with normal cells, such as COS7, DOX@MSN-S-S-RGD showed higher affinity toward a??3integrin-rich cancer cell, U87MG;(3) the tethering of the RGD peptide linked via disulfide unit to the surface of MSN was a very efficient approach to entrap DOX in the pore reservoir during circulation but to release DOX in a burst manner in response to cellular GSH which can remove the peptide by cleavage of the disulfide stalk moiety.In chapter5, a novel intelligent MSN based, multifunctional MSN-SATAT&DMAK11was prepared as a stepwise-acid-active DDS for tumor-specific nucleus-targeted drug delivery, which was proved to possess following feathers:(1) the nanoparticles can maintain a relatively "stealth" character with protein/cell resistance under normal physiological environment,(2) and then transformed into a more cell-interactive form upon arrival at the target tumor site to exhibit promoted cellular uptake via tumor-acidity-activated charge conversion of dimethylmaleic amides,(3) fast endo/lysosomal escape occurred with the facilitation of SATAT via the hydrolysis of succinyl amides for the internalized nanoparticles, and (4) the presence of regenerated TAT peptide can facilitate the active nuclear import to realize intranuclear drug delivery. We believe the MSN-SATAT&DMAK11carrier demonstrated here may have a promising potential for cancer therapy.