| Multidrug resistance(MDR) is the most common and intractable problem in the chemotherapy of malignant tumor, which often leads to poor therapeutic effect, recurrence or death. The mechanisms of MDR were diverse and complex, which combined actions of multiple genes and multiple signaling pathways. Now MDR has attracted much attention in cancer treatment. It will be an important task to improve the sensitivity of tumor cells and overcome multidrug resistance in biochemistry and clinical medicine.Selenium is an essential trace element for humans. Owing to low toxicity, high biological activity and wide application for anti-tumor, selenium nanoparticles(Se NPs) has been a research hotspot in the field of nanomaterial drugs. It has been reported that Se NPs can regulate the expression of cancer gene, induce intracellular ROS generation and induce cell apoptosis. Meanwhile, Se NPs also play roles as gene/drug carrier, and overcome multidrug resistance through RNA interference, which are rarely reported.Therefore, this paper attempts to synthesize a series of functionalized nano selenium, and study its drug loading, release and anti-tumor activities. Based on the previous work, two functionalized selenium nanoparticles were prepared through different reducing agents and modifiers in aqueous solution. And the therapeutic ability to overcome tumor MDR was studied, aiming to find the potential drugs that target to MDR. The full paper is divided into three chapters.In chapter 1, we first describe the mechanism of MDR and the approaches to overcome MDR, and then focus on the present research methods and progress development of nanoparticles in overcoming MDR. Finally, we point out the challenges, difficulties and future prospects of the current treatment of MDR and give the purpose and significance of this thesis.In chapter 2, multifunctional poyamidoamine(PAMAM) modified selenium(Se NPs) nanoparticles were synthesized, then loaded with cisplatin(DDP), and finally complexed with MDR1 si RNA through electrostatic force(G5@Se-DDPNPs). The drug release and gene silencing effect induced by si RNA were investigated. The results showed that G5@Se NPs can enhance the load and release of si RNA, and gene silencing efficiency. When complexed with mdr1 si RNA, the expression of P-glycoprotein and multidrug resistance-associated protein was significantly down-regulated; G5@Se-DDP-si RNA arrested cells at G1 phase and led to enhanced cytotoxicity in A549/DDP cells through AKT and ERK signaling pathways. Animal studies also demonstrated that the G5@Se-DDP-si RNA significantly enhanced the anti-tumor effect on tumor-bearing nude mice, with no appreciable abnormality in the major organs.In chapter 3, layered double hydroxides(LDHs) supported Se NPs were first prepared and characterized, and then complexed with multiple therapeutic si RNAs(P-gp and β-tubulin III). We studied the interaction between Se@LDH and tublin, and regulation of specific si RNAs on the intracellular protein. The results suggested that Se@LDH showed excellent abilities to deliver si RNA into cells, including enhancing si RNA internalization, and promoting si RNA escape from endosomes. Moreover, Se@LDH may be a microtubule(MT) stabilizing agent which could inhibit cell proliferation by blocking cell cycle at G2/M phase, disrupting normal mitotic spindle formation and inducing cell apoptosis. Compared with different si RNA delivery systems, Se@LDH-pooled si RNAs could significantly downregulate the expression of P-gp and β-tubulin III, and exhibit better gene silencing efficiency. |
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