Novel Multifunctional Drug Delivery Systems Based On Nanoparticles For Cancer Diagnosis And Therapy

Cancer is one of serious diseases that threaten human being. Nowadays, the common methods adopted for cancer therapy are chemotherapy, radiation and surgey. As each treatment method has its drawbacacks, cancer therapy still doesn’t reach an optimal result. Thus, it’s very necessary to develop new technology for cancer diagnosis and therapy. Nanotechnology has been used for cacer detection, diagnosis and treatment widely. The size of materials developed by nanotechnology is at nanosacle levels, which allows the nanomaterials to penetrate in the depth of tumors specifically. Nanoparticles prefer to accumulate in tumors tissues through enhanced permeability and retention (EPR) effect. Thus, the drugs delivered by nanocarriers can have a high drug concentration in tumors and a low concentration in normal tissues. Therefore, the anticancer efficiency of the drugs can be improved along with the side effects reduced. The circulation time of hydrophobic drugs can be enhanced by using nanoparticles as carriers, leading to the improvement of the anticancer efficiency of drugs. The stimuli-responsive nanocarriers can overcome the bodily and intracellular delivery barriers, and have special physical-chemical changes in the diseased sites which may be beneficial to the cancer treatment. Meanwhile, such nanocarrieres can also reduce the side effects of drugs and improve their efficiency. In addition, nanoparticles can be adopted as contrast agenets for biomedical imaging, which can noninvasively detect the disease in the incubation period. However, different diagnosis and therapy techniques usually require different nanoparticles to perform. In order to make the application of nanotechnology in clinic possible, combining different functions of diagnosis and therapy into a single system is significantly needed.The common clinical chemotherapy drugs always have serious side effects. Thus, much attention has been paid to the development of natural ancticancer drugs. Artemisinin (ART) is a sesquiterpene lactone derived from herbal medicine with anticancer activities against many kinds of human cancers. ART has low side effects and is a promising anticancer drug. However, ART has poor water solubiltiy and quick metabolism in body. Such drawbacks preclude the clinical application of the drug. Thus, employing nanotechnology to alleviate the problems and improve the anticancer efficiency of ART is challengeable and necessary.In this dissertation, we adopted different chemosynthetic methods to develop several types of nanoparticles which simultaneously have diagnosis and treatment functions. And then, we employed the nanoparticles to deliver ART and investigate their anticancer ability in vitro and in vivo. The specific researches are shown as follows:(1) A pH-responsive T1-T2*dual-modal contrast agent of iron manganese silicate hollow nanospheres (FeMn(SiO4)) has been synthesized. Cytotoxicity study and histology analysis showed excellent biocompatibility of these hollow nanospheres, which is necessary for their in vivo imaging application. MRI experiments in vivo showed that only10min after intravenous injection of the contrast agents, obvious distinction between the tumors and normal tissues can be observed easily through both T1and T2*signals, with the assistance of their pH-responsive property. Though MR images for reticuloendothelial system (RES) organs demonstrated that the hollow nanospheres were mainly distributed in liver finally, the histology analysis showed that no pathophysiological changes could be observed from liver36h after intravenous administration of the nanospheres.(2) Multifunctional nanocarriers (Fe3O4@C@Ag nanoparticles) have been prepared. The loading content of997mg/g for doxorubicin (DOX) is achieved not only via hydrogen bonding and physical absorption relying on carbon shell, but also through the formation of chemical bonds between carboxyl of Fe3O4@C@Ag nanoparticles and hydroxy of DOX under NIR radiation. Photo-regulated drug release could be realized due to the photothermal effect in localized surface plasmon resonance of Ag nanoparticles to break the chemical bonds. And cells uptake the DOX loaded nanocarriers are almost normal when incubated in the dark. However, they tend to be apoptosis when cultured under NIR radiation. This excellent property of NIR-responsive drug delivery can reduce the damage of DOX to the normal cells and simultaneously improve the efficiency of drug. The in vitro cell viability tests reveal that the obtained hybrid nanoparticles possess good biocompatibility. More importantly, the Fe3O4@C@Ag nanoparticles enable dual-modal imaging of two-photon fluorescence (TPF) imaging and magnetic resonance imaging (MRI). The multifunctional Fe3O4@C@Ag nanoparticles show the potential biomedical applications in simultaneous diagnosis and therapy.(3) pH-responsive nanocarriers Fe3O4/Ag@mSiO2(FCA@mSiO2) have been prepared. It is well suited to carry hydrophobic anti-cancer drug Artemisinin (ART) and Fe2+ions into cancer cells and enhance cell killing. ART can be effectively stored in the mesoporous silica shells with a loading content of484mg/g, while Fe2+ions can be liberated due to the low pH value in acidic organelles and act non-enzymatically to cleave endoperoxide bridges of ART, generating organic radicals to kill cancer cells efficiently. The toxicity of ART-loaded FCA@mSiO2nanoparticles was significantly increased compared with free drug ART, which showed that the pH-responsive core-shell nanoparticles as Fe2+ions and ART delivery vehicles value will be promising candidates for cancer therapy.(4) It is found that Mn2+could substitute for Fe2+to react with ART and generate toxic products, inducing a much higher anticancer efficiency. On this basis, pH-responsive Fe3O4@MnSiO3-Folate (Fe3O4@MnSiO3-FA) nanospheres which can efficiently deliver hydrophobic ART into tumors in mice models have been prepared. The anticancer efficiency of ART-loaded Fe3O4@MnSiO3-FA nanospheres is very high. And the ART dosage adopted for the therapy is much lower than the dosage used in the other reported ART or derivates in vivo antitumor experiments. Such high efficiency is ascribed to the synergistic effect between the released Mn2+and ART, and further studies are still needed to reveal the mechanism of the interaction between Mn2+and ART for killing cancer cells. Compared with the commercial anticancer drugs, ART has much lower side effects. And the histological analysis demonstrated that the drug-loaded nanocarriers have low toxicity to major organs. Thus, the combination of ART and Mn2+based on the carriers Fe3O4@MnSiO3-FA nanospheres provides a promising way for clinical tumor therapy.