發(fā)布時間：2021-04-06 04:28

　　根據(jù)世界衛(wèi)生統(tǒng)計年鑒數(shù)據(jù)顯示,癌癥是目前致病率和死亡率最高的疾病,因此,研究和開發(fā)更為有效的抗癌療法成為了人類健康發(fā)展的迫切需求。在各種新興的抗癌療法中,如免疫療法和基因療法,光動力療法（PDT）是利用小分子光敏劑（PSs）結(jié)合水分子,將光能轉(zhuǎn)化為具有細胞毒性的活性氧族（ROS）的治療策略,并且對多種類型癌癥的治療都表現(xiàn)出了抗癌有效性、無輻射性和重復治療的微創(chuàng)性。目前,PDT已在臨床試驗研究中用于對部分癌癥的診斷和治療。并且可與其他治療方案結(jié)合,產(chǎn)生協(xié)同抗癌效應。然而,PDT的臨床在體應用還有存在局限性:例如,PSs的水溶解性差,在血液循環(huán)中的半衰期時間短,對于腫瘤細胞的靶向性差,并且由于PSs的全身分布,會對正常組織中產(chǎn)生光毒性;另外,光在組織中的穿透力有限,無法達到深部組織,只能對淺表的或管腔的腫瘤進行治療。因此,本研究通過設計不同的新型納米載體介導的藥物遞送系統(tǒng)來改善PSs在體內(nèi)的生物分布,并且使用與其他治療方法與PDT的聯(lián)合療法來增強治療效果。研究內(nèi)容主要包括:（i）設計尺寸在10 nm以下的具有殼-核結(jié)構的二氧化硅納米顆粒（PSDs）,能夠有效地遞送水溶性卟啉分子（TPPS<... 

【文章來源】：北京大學北京市 211工程院校 985工程院校 教育部直屬院校

【文章頁數(shù)】：157 頁

【學位級別】：博士

【文章目錄】：
摘要
ABSTRACT
List of Acronyms
Chapter1 Introduction
    1.1 Challenges in cancer therapy
    1.2 Photodynamic therapy
        1.2.1 Tumor destruction mechanism
        1.2.2 Photosensitizers（PSs）
        1.2.3 Current limitations of PDT
    1.3 Sonodynamic therapy
        1.3.1 Mechanisms regulating the SDT
        1.3.2 Sonosensitizers
    1.4 Chemotherapy
    1.5 Nanomedicines enhance cancer therapeutic efficacy
        1.5.1 Lipid-based nanocarriers
        1.5.2 Silica Nanoparticles
        1.5.3 Functional core-shell silica nanoparticles（Cornell dots）
    1.6 Nanoformulations for enhancing photo-and sonodynamic therapy
        1.6.1 Role of NPs in PDT
        1.6.2 Role of NPs in SDT
    1.7 Porphyrin-based nanoformulations as sensitizer for photodynamic therapy and sonodynamic therapy
    1.8 Enhancing the therapeutic outcomes via combination therapy
        1.8.1 Chemotherapy-photodynamic therapy
        1.8.2 Sono-photodynamic therapy
    1.9 Research Objectives
Chapter2 Photodynamic therapy of breast cancer with porphyrin loaded silica dots
    1.10 Experimental Section
        1.10.1 Chemicals and Materials
2">        1.10.2 Synthesis of water-soluble TPPS3-NH2

        1.10.3 Synthesis of sub-10nm porphyrin-silica dots
        1.10.4 Characterization of porphyrin-silica dots
        1.10.5 Loading efficiency of porphyrin in porphyrin-silica dots
1O₂）in solution">        1.10.6 Generation of singlet oxygen（¹O₂）in solution
        1.10.7 Cellular uptake of porphyrin-silica dots
        1.10.8 Cellular ROS detection
        1.10.9 Photodynamic treatment and cytotoxicity assessment
        1.10.10 Establishment of a tumor model
        1.10.11 Pharmacokinetics and biodistribution analysis
        1.10.12 In vivo antitumor efficacy
        1.10.13 Histological analysis
        1.10.14 Toxicology profile
        1.10.15 Statistical analysis
    1.11 Result and Discussion
2）">        1.11.1 Synthesis of hydrophilic porphyrin（TPPS3-NH₂）
        1.11.2 Synthesis of sub-10nm Porphyrin-silica dots
        1.11.3 Characterization of porphyrin-silica dots
1O₂）in solution">        1.11.4 Generation of singlet oxygen（¹O₂）in solution
1O₂）in cancer cells">        1.11.5 Detection of singlet oxygen（¹O₂）in cancer cells
        1.11.6 Cellular Uptake of porphyrin-silica dots
        1.11.7 Evaluation of in vitro photodynamic therapy
        1.11.8 Pharmacokinetics and biodistribution profile of porphyrin-silica dots
        1.11.9 In vivo antitumor efficacy of porphyrin-silica dots
    1.12 Summary
Chapter3 Sono-photodynamic therapy with porphyrin-silica dots
    1.13 Experimental Section
1O₂-generation ability of PSDs via SDT">        1.13.1 ¹O₂-generation ability of PSDs via SDT
1O₂ generation ability of PSDs via SPDT">        1.13.2 ¹O₂ generation ability of PSDs via SPDT
1O₂ generation ability of PSDs via SPDT">        1.13.3 Intracellular ¹O₂ generation ability of PSDs via SPDT
    1.14 Result and Discussion
1O₂-generation ability of PSDs via SDT">        1.14.1 ¹O₂-generation ability of PSDs via SDT
1O₂-generation ability of PSDs via SPDT">        1.14.2 ¹O₂-generation ability of PSDs via SPDT
1O₂ generation ability of PSDs via SPDT">        1.14.3 Intracellular ¹O₂ generation ability of PSDs via SPDT
    1.15 Summary
Chapter4 Lipidic porphyrin nanoparticles encapsulating doxorubicin for chemo-photodynamic therapy
    1.16 Experimental Section
        1.16.1 Materials
        1.16.2 Synthesis of PGL NPs
        1.16.3 Synthesis of PGL-DOX NPs
        1.16.4 Characterization of PGL-DOX NPs
        1.16.5 Drug loading efficiency and drug loading content
        1.16.6 DOX release profile in vitro
        1.16.7 Singlet oxygen generation in aqueous solution
        1.16.8 Cellular uptake of PGL-DOX NPs
        1.16.9 Detection of cellular singlet oxygen upon irradiation
        1.16.10 In vitro chemo-photodynamic cytotoxicity
        1.16.11 Efficacy of chemo-photodynamic therapy by visual observation
        1.16.12 Tumor model establishment
        1.16.13 Pharmacokinetics and biodistribution
        1.16.14 In vivo chemo-photodynamic combination therapy
        1.16.15 Statistical analysis
    1.17 Results and discussion
        1.17.1 Preparation of PGL-DOX NPs
        1.17.2 Characterization of PGL-DOX NPs
        1.17.3 DOX release profile in vitro
        1.17.4 Investigation of singlet oxygen generation in aqueous solution
        1.17.5 Cellular uptake of PGL-DOX NPs
        1.17.6 Light-triggered lysosomal escape of PGL-DOX NPs
        1.17.7 Detection of cellular singlet oxygen upon irradiation
        1.17.8 In vitro chemo-photodynamic cytotoxicity study
        1.17.9 Efficacy of chemo-photodynamic therapy by visual observation
        1.17.10 Pharmacokinetics and biodistribution
        1.17.11 In vivo chemo-photodynamic combination therapy
    1.18 Summary
Chapter5 Concluding Remarks and Future Outlook
References
List of Publications
Acknowledgements


【參考文獻】：
期刊論文
[1]Sonodynamic therapy（SDT）: a novel strategy for cancer nanotheranostics[J]. Xueting Pan,Hongyu Wang,Shunhao Wang,Xiao Sun,Lingjuan Wang,Weiwei Wang,Heyun Shen,Huiyu Liu.  Science China（Life Sciences）. 2018(04)



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