卟啉纳米载体用于肿瘤光动力联合声动力/化疗的研究

发布时间：2021-04-06 04:28

　　根据世界卫生统计年鉴数据显示,癌症是目前致病率和死亡率最高的疾病,因此,研究和开发更为有效的抗癌疗法成为了人类健康发展的迫切需求。在各种新兴的抗癌疗法中,如免疫疗法和基因疗法,光动力疗法（PDT）是利用小分子光敏剂（PSs）结合水分子,将光能转化为具有细胞毒性的活性氧族（ROS）的治疗策略,并且对多种类型癌症的治疗都表现出了抗癌有效性、无辐射性和重复治疗的微创性。目前,PDT已在临床试验研究中用于对部分癌症的诊断和治疗。并且可与其他治疗方案结合,产生协同抗癌效应。然而,PDT的临床在体应用还有存在局限性:例如,PSs的水溶解性差,在血液循环中的半衰期时间短,对于肿瘤细胞的靶向性差,并且由于PSs的全身分布,会对正常组织中产生光毒性;另外,光在组织中的穿透力有限,无法达到深部组织,只能对浅表的或管腔的肿瘤进行治疗。因此,本研究通过设计不同的新型纳米载体介导的药物递送系统来改善PSs在体内的生物分布,并且使用与其他治疗方法与PDT的联合疗法来增强治疗效果。研究内容主要包括:（i）设计尺寸在10 nm以下的具有壳-核结构的二氧化硅纳米颗粒（PSDs）,能够有效地递送水溶性卟啉分子（TPPS<... 

【文章来源】：北京大学北京市 211工程院校 985工程院校 教育部直属院校

【文章页数】：157 页

【学位级别】：博士

【文章目录】：
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


【参考文献】：
期刊论文
[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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