惡性腫瘤是嚴重威脅人類健康的多發(fā)病之一,目前主要的臨床治療手段是化療。但傳統(tǒng)小分子藥物往往腫瘤特異性不高,加上藥物本身的理化性質(zhì)缺陷如水難溶,藥效受到限制。納米遞藥系統(tǒng)可以有效提高藥物的靶向性,在遞送疏水性藥物中發(fā)揮獨特的優(yōu)勢,相關研究取得了很大的進展。無機納米藥物傳遞平臺(具有金屬核心的NDDPs)已成為靶向抗癌治療中有前途的載藥載體。在各種無機納米粒子中,介孔二氧化硅納米粒子(MSNs)和金納米粒子(Au NPs)具有巨大的抗癌治療潛力。首先,本課題開發(fā)了一種既具有CD44靶向性又具有線粒體靶向性的新型酶響應型多級靶向抗癌藥物傳遞系統(tǒng)。將線粒體靶向化合物三苯基膦(TPP)接枝到MSN表面,而后進行阿霉素(DOX)的裝載,最后用腫瘤靶向分子透明質(zhì)酸(HA)封端,形成最終的納米體系(MSN-DPH)。體外實驗結果表明,腫瘤細胞通過CD44受體介導的內(nèi)吞作用優(yōu)先吸收MSN-DPH。此外,由于TPP的線粒體靶向能力,MSN-DPH主要聚集在線粒體中。透明質(zhì)酸酶對透明質(zhì)酸的降解促進了癌細胞中DOX的釋放。因此,MSN-DPH能有效地殺死癌細胞,同時對正常細胞的細胞毒性要低得多。接下來,本論文...

【文章頁數(shù)】：98 頁

【學位級別】：博士

【文章目錄】：
ACKNOWLEDGEMENTS
DEDICATION
LIST OF ABBREVIATIONS
ABSTRACT
摘要
Chapter 1:General Introduction and Review of Literature
    1.1 Introduction
    1.2 Doxorubicin(DOX):A Potential Anti-Cancer Drug
    1.3 Inorganic NDDPs Implicated in Anti-Cancer Therapy
        1.3.1 MSNs based NDDPs Implicated in Anti-Cancer Therapy
        1.3.2 AuNPs Based NDDPs Implicated in Anti-Cancer Therapy
    1.4 Glycosaminoglycans(GAGs)and Their Implications in Anti-Cancer Therapy
    1.5 Significance of Reserch
    1.6 Objectives
Chapter 2:Enzyme Responsive Mesoporous Silica Nanoparticles for Tumor Cells and Mitochondria Multistage-Targeted Drug Delivery
    2.1 Introduction
    2.2 Materials and Methods
        2.2.1 Materials
        2.2.2 Characterizations
        2.2.3 Synthesis and Ammonization of MSNs(MSN-NH2)
        2.2.4 Synthesis of Triphenylphosphine Propionic Acid and Preparation of MSN-NH2-TPP
        2.2.5 Preparation of DOX Loaded MSNs(MSN-DPH)
        2.2.6 Release of DOX from MSN-DOX and MSN-DPH
        2.2.7 Cellular Uptake and Intracellular Localization of MSN-DPH
        2.2.8 In Vitro Cytotoxicity of MSN-DPH
        2.2.9 Statistical Analysis
    2.3 Results and Discussion
        2.3.1 Preparation and Characterization Analysis of MSN-DPH
        2.3.2 FTIR Analysis of Synthesised MSN-DPH
        2.3.3 HAase-responsive DOX Release from MSN-DPH
        2.3.4 Multistage Targeting Capability of MSN-DPH
        2.3.5 In Vitro Antitumor Effect of MSN-DPH
Chapter 3:Study of Prepration and Characterization of Au@MSNs and Glycosaminoglycans(GAGs)Modified Au@MSNs Nanoparticles
    3.1 Introduction
    3.2 Materials and Methods
        3.2.1 Reagents
        3.2.2 Instruments Used
        3.2.3 Preparation of Au@MSNs
        3.2.4 Modification of Au@MSNs to Prepare Au@MSNs-SH
        3.2.5 Modification of Hyaluronic Acid,Heparin Sodium and Heparan Sulfate
        3.2.6 Measuring the Amount of Thiol Grafted on Surface GAGs
        3.2.7 Characterization of Modified GAGs
    3.3 Results and Discussion
        3.3.1 Characterization of Au@MSNs
        3.3.2 Particle Size of Au@MSNs
        3.3.3 Characterization of Au@MSNs-SH
        3.3.4 The Amount of Grafted Thiol Group on Surface of GAGs
        3.3.5 FTIR Analysis of Thiolated GAGs
Chapter 4: Study of Preparation, Drug Release Profiles and Anti-Cancer Activity of Au@MSNs@GAGs Nanoparticles
    4.1 Introduction
    4.2 Materials and Methods
        4.2.1 Reagents
        4.2.2 Instruments Used
        4.2.3 Plotting the Standard Curve of DOX
        4.2.4 Au@MSNs-SH Drug Loading
        4.2.5 Bonding between Au@MSNs-SH and GAG-SH
        4.2.6 Drug Release from Au@MSNs@GAGs
        4.2.7 Photothermal Effect of Au@MSNs@GAGs
        4.2.8 In Vitro Cytotoxicity of Analysis of Au@MSNs@GAGs on HepG2 cells
        4.2.9 In Vitro Cytotoxicity of Analysis of Au@MSNs@GAGs on Cos7 cells
        4.2.10 Synergistic Effects of Au@MSNs@GAGs and Photothermal Therapy
        4.2.11 Cellular Uptake and Intracellular Localization of Au@MSNs@GAGs
    4.3 Results and Discussion
        4.3.1 Drug Loading and Entrapment Efficiency of Au@MSNs-SH
        4.3.2 Characterization of Au@MSNs@GAGs
        4.3.3 Particle Size Measurements
        4.3.4 Transmission Electron Microscopy Analysis
        4.3.5 Drug Release Profiles from Au@MSNs@GAGs
        4.3.6 Photothermal Effect of Au@MSNs@GAGs
        4.3.7 Cytotoxic Assay of Au@MSNs@GAGs
        4.3.8 Synergistic Effect of Au@MSNs@GAGs and Photothermal Therapy
        4.3.9 Cellular Uptake of Au@MSNs@GAG by HepG2 Cells
Chapter 5:General Conclusion,Key innovations and Future Research
    5.1 General Conclusions
    5.2 Key innovations
    5.3 Future Research
Bibliography
List of Publications



本文編號：3804095