Multifunctional Nanomaterials Loading SiRNA For Overcoming Multidrug Resistance And Polyoxometalate Inhibit The Aggregation Of Aβ Associated With Alzheimer’s Disease

Multidrug resistance(MDR) is one of the most common and intractable problem in the process of chemotherapy, which often leads to poor therapeutic effect, recurrence or death. The mechanisms of MDR were diverse and complex, which combined involvement of multiple genes and a variety of biological processes. Nowadays, reversal MDR of malignant tumor has been regarded as the most important task, which can significantly improve the sensitivity of tumor cells and overcome multidrug resistance in biochemistry and clinical medicine.RNA interference(RNAi) is a powerful tool for sequence-speci?c suppression of genes and has potential applications for targeted gene therapy. To date, various co-delivery platforms for si RNA and chemotherapy agents have been developed to reverse MDR in cancer cells. A variety of si RNA delivery approaches have been developed, including cationic polymer(PEI), chitosan, peptides, mesoporous Silica, virus-based vectors, and dendriworms. These methods have been suggested to improve the intracellular delivery of small interfering RNA(si RNA) and ef?ciently silence targeted genes, and some of them have achieved exciting results in experiments to limit tumor growth.Alzheimer’s disease(AD) is a kind of progressive neurodegenerative diseases that cause memory and cognitive dysfunction. A neuropathological hallmark of AD is aggregation of a forty-residue peptide known asamyloid beta forty(Aβ40). While past work has indicated that blocking Aβ40 aggregation could be an effective strategy for the treatment of AD.In this thesis we synthesized a series of functionalized nanomaterials and delivering si RNA for reversal of multidrug resistance, and study its drug loading, release and anti-tumor and anti-AD activities. This thesis consists of four 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 nanomaterials 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, a dinuclear Ru(II) complex was synthesized to functionalized chiral Se NPs(L-Se NPs and D-Se NPs) to act as a multifunctional nanocarrier-based delivery system(NDS) in order to deliver si RNA targeting the MDR1 gene, which is responsible for MDR in cancer cells. We evaluated the efficiency of gene silencing and cytotoxicity of these drug delivery systems in A549 and A549 R cells. To clarify a possible mechanism of cell death, we investigated the internalization effect of Ru@L-Se NPs-si RNA. Further, we treated nude mice that received A549 R xenografts with Ru@L-Se NPs-si RNA to examine its biodistribution by ?uorescent imaging and anti-tumor effects in vivo. The results suggest that cisplatin-resistant A549 R cells treated with Ru@L-Se NPs-si RNA demonstrated significant downregulation of P-glycoprotein(P-gp) expression, resulting in unprecedented enhanced cytotoxicity through the induction of apoptosis with the involvement of phosphorylation of p53, MAPK and PI3K/Akt signaling pathways. In vivo investigation confirmed that Ru@L-Se NPs-si RNA nanoparticles exhibited high tumor-targeted fluorescence, enhanced anti-tumor efficacy, and decreased systemic toxicity.In chapter 3, we present herein a new method for direct and selective coordination of cysteine to CUSs in MIL-101, the cysteine served as the linkage and in situ reduction selenite/ruthenium to form Se NPs/Ru NPs functionalized MIL-101. We have shown that Se@MIL-101 and Ru@MIL-101 with high porosity and surface binding sites represent a unique nanocarrier platform for the delivery of pooled(P-gp and VEGF) si RNAs to drugresistant MCF-7/T cells. The Se@MIL-101 and Ru@MIL-101 can significantly protects si RNAs from nuclease degradation, enhances si RNA cellular uptake, and promotes si RNA escape from endosomes to silence MDR genes, leading to unprecedented enhanced cytotoxicity through the induction of apoptosis with the involvement of the dynamic instability of MTs and disrupting normal mitotic spindle formation.In chapter 4, based on our previous work, peptide modified Mo polyoxometallat(Mo-POMs) nanoparticles were synthesized by the self-assembly of Aβ target peptide and Mo-POMs. We studied the interactions between the Peptide@Mo-POMs nanoparticle and Aβ40 in the presence of Zn2+, and the results showed that Peptide@Mo-POMs was capable of inhibiting Aβ40 aggregation and disaggregating Aβ fibrils. In vitro experiments revealed that Peptide@Mo-POMs could target and be well absorbed by PC12 cells, which led to the inhibition of intracellular Aβ aggregation and reduced cytotoxicity induced by Aβ aggregates.