Fabrication Of PH And Near-infrared Responsive Inorganic Nanocarrier And The Applications For Tumor Therapy

Constructing an effective drug delivery system is one of the most importantprogress in tumor chemotherapy. By using functional nanomaterials as deliveryvehicles, drugs can be bound to the surfaces or encapsulated in the hollow interior ofthese nanomaterials. Upon exposure to the appropriate stimuli, preloaded drugs can bereleased at tumor location in a controllable fashion. As a result, the nanomaterial baseddelivery was found to be an effective method for protecting the entrapped drugs frompremature release and reducing the adverse side effects of the drugs. Thus, usingstimuli-responsive nanocarrier based drug delivery systems have led to new andexciting developments with enormous potential in tumor treatments. Aiming atinorganic nanocarrier based drug delivery, this thesis mainly focuses on thedevelopment of pH and NIR responsive nanocarrier for drug controlled release andtumor therapy.1. pH-responsive polymer/mesoporous silica (MSN) nanocarrier through an acidcleavable linker for drug controlled release and tumor therapyThis section proposed a pH-responsive polymer/MSN nanocarrier through an acidcleavable linker for drug controlled release and tumor therapy. In this system, the poly(acrylic acid) homopolymer (PAA), as a nanoscopic cap, was grafted onto the MSNthrough an acid cleavable linker (PAA-ACL-MSN). Doxorubicin (DOX), as a modeldrug, was used to assess the drug release behaviors and tumor therapy. At neutral pH,the linker was intact, resulting in blockage of pores and package of DOX. By thedegradation of linker at acidic pH, the grafted PAA was removed, which gave rise touncapping and the subsequent pH-responsive controlled release of DOX. In vitrostudies using nasopharyngeal carcinoma cell line (HNE-1) proved that DOX loadedPAA-ACL-MSN (DOX@PAA-ACL-MSN) was endocytosed and demonstratedefficient operation at lysosomal pH, leading to significant cytotoxicity. As apreliminary tumor therapy in vivo, the progressive tumor development and inhibitionfollowing DOX@PAA-ACL-MSN treatment was monitored using bioluminescentimaging. By the examinations of cell proliferation in tumor tissues and the comparisonof body weight, it was revealed that the DOX@PAA-ACL-MSN was superior to freeDOX in terms of therapy efficacy and side effects due to the enhanced permeabilityand retention effects and lower pH in tumor areas.2. pH-responsive folate acid/MSN nanocarrier through an acid cleavable linker for drug controlled release and tumor targeted therapyCompared with expression at very low levels in most normal cells, folate receptorsare expressed at high levels in numerous cancer cells. Thus, modification of folate acidas tumor targeted agent on the nanocarrier surface can promote its targeted delivery.Basis on the above studies, this section proposed a pH-responsive folate acid/MSNnanocarrier through an acid cleavable linker for drug controlled release and tumortargeted therapy. Folate acid was used as gate keeper and grafted onto the MSN throughan acid cleavable linker, and then it was also performed well in the pH responsivecontrolled release in buffer. In vitro studies showed that this constructed nanocarriercould specific recognize HNE-1with overexpression folate receptors, and then wasendocytosed and demonstrated efficient operation at lysosomal pH, leading to drugcontrolled release and significant cytotoxicity.3. Non-Watson-Crick secondary structure of coralyne/poly(A) modified MSN forpH-and near-infrared-responsive (NIR) controlled release and tumor therapyPoly(A) can specifically bind with planar alkaloid, such as coralyne, leading tothe formation of non-Watson-Crick secondary structures and the cooperative bindingof poly(A) strands. Under high-temperature or low-pH conditions, the interactionbetween poly(A) and coralyne was reduced, leading to the dehybridization of thecooperative binding structure and coralyne release. Herein, a dual pH-and NIR-responsive controlled release system for tumor therapy was achieved by co-loadingcoralyne and indocyanine green (ICG) into poly(A) modified MSN. In this system,alkyne-modified poly(A) was immobilized at the pore mouth of MSN by a clickchemistry approach. Coralyne and ICG were loaded into MSN at50°C for6h and thencooled to room temperature. In these process, coralyne not only could be loaded intothe pore of MSN, but also could bind with poly(A) through non-Watson-Cricksecondary structures and then resulted the pore capping by the cooperative binding ofpoly(A) strands. Under low-pH or high-temperature conditions, the non-Watson-Cricksecondary structures was unstable, leading to the dehybridization of the cooperativebinding structure and open-gate state. ICG, the other cargo co-loaded into MSN,showed a high-efficiency for the conversion of NIR light into heat, which couldpromote the pore opening upon NIR irradiation. The in buffer and in vitro studiesdemonstrated that this system could load with coralyne and ICG with high capacity,and the pH and NIR dual-stimuli showed the higher controlled release than respectivemono-stimulus. In addition, the research also found that the combination ofphotothermal property of ICG and chemotherapeutic agents of coralyne could result in synergistic effects for tumor therapy.4. Non-Watson-Crick secondary structure of coralyne/poly(A) modified AuNR forpH-and NIR-responsive controlled release and tumor therapyThe pH and NIR dual-stimuli controlled release systems are more feasible for thehigher release effect in the practical application. Menawhile, the conversion of NIRlight into heat not only can be used in the controlled release, but also can provide thefundamental basis of hyperthermal cancer therapy with synergistic effects. Herein, adual pH-and NIR-responsive nanotherapeutic system for chemothermal treatment ofcancer cells was achieved by using non-Watson-Crick secondary structure ofcoralyne/poly(A) modified AuNR. In this system, thiolated poly(A) could be self-assembled onto AuNR, and provide the ability in loading coralyne, an anti-cancer drug,through the specific binding with non-Watson-Crick secondary structure. Under low-pH or high-temperature conditions, the non-Watson-Crick secondary structure wouldbe unstable, leading to stimuli-responsive release of coralyne for cancer chemotherapy.AuNR showed high efficiency for conversion of NIR light into heat, providing thefundamental basis of hyperthermal cancer therapy, and also promoting the triggeredrelease of coralyne from poly(A) upon NIR irradiation. In vitro studies using humanhepatoma SMMC-7721cells demonstrated that coralyne loaded poly(A)/AuNR couldbe endocytosed and demonstrated efficient operation at cellular acidic environment andNIR irradiation, leading to significant cytotoxicity through the excellent chemothermalsynergistic effects.