Nanomaterial-Mediated Photodynamic Therapy for the Destruction of Tumors

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研究生：	瓦竺 Poliraju Kalluru
論文名稱：	Nanomaterial-Mediated Photodynamic Therapy for the Destruction of Tumors Nanomaterial-Mediated Photodynamic Therapy for the Destruction of Tumors
指導教授：	黃國柱 Hwang, Kuo Chu
口試委員:	袁俊傑 Yuan, Chiun-Jye 吳淑褓 Wu, Shu-pao 江啟勳 Chiang, Chi-Shiun 宋信文 Sung, Hsing-Wen
學位類別：	博士 Doctor
系所名稱：	理學院 - 化學系 Department of Chemistry
論文出版年：	2016
畢業學年度：	104
語文別：	英文
論文頁數：	178
中文關鍵詞：	奈米材料、光動力治療、腫瘤、癌症
外文關鍵詞：	Nanomaterials, Photodynamic Therapy, Tumors, Cancer
相關次數：	點閱：1 下載：0
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近年來光療法已經被發現能夠用在治療多種的癌症上面，比起其他的治療，它主要的優點如：非侵入性治療、高穿深度、低副作用以及低成本等。光動力治療（PDT）是一種光療法中的重要方法，主要是使用有機感光劑(PS)吸光後將光子能量轉移到組織中的氧氣(3O2)，產生單重態的氧氣（1O2），進而毒殺癌細胞。大部分臨床上的PDT只能使用在治療表皮的腫瘤，因為大部分的有機PS吸收UV光或是可見光，而這兩波段的光對組織的穿深度低，加上有機PS通常水溶性較差，導致較差的吸光能力。此外，有機PS也容易被光分解（Photobleaching）或被酵素分解，因此PDT在臨床上還有許多的問題必須去克服。然而，奈米材料的優點為PDT帶來了許多契機。在合成具有高吸光係數、近紅外光的吸收、高光學穩定性、高表面積、磁性和螢光等等性質的奈米材料是不易的，在本論文中，將探討幾種不含有機PS的奈米材料在PDT的應用，以及其使用近紅外光驅動的皮膚癌和肺癌的治療。
第一章中，我們合成了摻雜鑭系金屬矽中孔洞奈米材料（EuGd@MCF），並將抗癌藥物Doxorubicin(DOX)修飾在表面，此材料具有磁振造影、螢光顯影及紅外光驅動單重態氧氣生成等性質，能夠同時使用化療及 PDT來對癌細胞/腫瘤進行毒殺。第二章中，我們發表PEGylated氧化鎢奈米線（PEG-W18O49NWs）作為PDT光敏材料，應用在單重態氧對癌細胞/腫瘤細胞的毒殺; 我們使用低功率的雷射（980nm, 200mW/cm2）對HeLa細胞進行光療實驗，此結果顯示細胞凋亡PDT的貢獻遠大於光熱治療（PTT），直接的證據包含：單重態氧形成、活性氧物種（ROS）及Heat shock protein(HSP70)表現。在in vivo實驗，在低劑量的雷射治療下，結果顯示，PDT毒殺B16F0黑色素瘤遠大於PTT。
第三章中，我們合成上轉換奈米粒子（UCNPs），由於UCNPs有上轉換螢光散射，在低強度的雷射（70~360 mW/cm2）下能夠產生單重態氧並可以作為PDT的PS。將UCNPs結合靜默基因（silencing gene）,superoxide dismutase (SOD1)，能夠提升材料對肺癌細胞毒殺的效率提升。最後在第四章中，我們使用PEGylated 氧化石墨烯修飾上葉酸（GO-PEG-folate）作為PDT的試劑，使用980nm雷射照射下毒殺黑色素瘤細胞。綜觀本論文介紹多種奈米材料，探討在不使用有機的感光劑的情況下，PDT毒殺癌細胞的效果。綜觀，我們發現了奈米材料光動力治療領域(NmPDT)，且能夠取代使用有機感光劑的PDT以及奈米材料光熱治療(NmPTT)在臨床上癌症治療。

In the recent clinical scenario, phototherapies are widely explored for the treatment of various types of cancers. The major advantages of phototherapies include non-invasiveness, superior tissue penetration, reduced side effects and cost-effective treatment strategies than other modalities. Photodynamic therapy (PDT) is one of the very important phototherapeutic approaches which involve the use of an organic photosensitizer (PS) molecule to absorb and transfer the photon energy to the normal tissue oxygen (3O2) to generate cytotoxic singlet oxygen (1O2), which is able to kill cancer cells. Most of the clinical PDT treatments are restricted to surface tumors, because most of organic PS can only be photochemically excited by either UV or visible light, which have very short tissue penetration depths. The organic PS molecules are usually insoluble in water, possesses very poor light absorbing capabilities, and also prone to severe photobleaching and enzymatic degradation. Therefore, it leaves a grand challenge to develop a novel and exciting treatment modality which can overcome the drawbacks of conventional PDT. In this regard, the advent of nanotechnology brings a lot of hope to the clinical biomedicine. Fabrication of nanomaterials with extra-ordinary light absorbing capabilities extending the visible to near infra-red regions, excellent photostabilities, high surface area, magnetic and fluorescent properties are actually very rare and limited. In this thesis, we have explored such variety of nanomaterials which can mediate the photodynamic therapeutic effects without any co-presence of organic photosensitizers and capable of activation by NIR light for the treatments of skin and lung cancers.
In the first chapter, we have developed a theranostic nanoconstruct based on lanthanide doped mesoporous silica nanoparticles (EuGd@MCF) loaded with an anticancer drug, doxorubicin (DOX) can facilitate simultaneous magnetic resonance (MR) / fluorescence imaging and can also sensitize formation of singlet oxygen (1O2) upon near-infra red (NIR) light irradiation to exert the combination of chemo-photodynamic therapeutic (PDT) effects to kill the cancer cells/solid tumors. In the second chapter, we have presented an unprecedented phenomenon of photosensitization of singlet oxygen and its photodynamic therapeutic (PDT) effects mediated by PEGylated tungsten oxide nanowires (PEG-W18O49 NWs) on destruction of cancer cells/malignant tumors. In the PEG-W18O49 NWs internalized HeLa cells, we show that at low laser intensity (980 nm, 200 mW/cm2), cancer cells die from PDT-initiated apoptosis with a very minor contribution coming from the photothermal therapy (PTT) effect-initiated apoptosis. Direct evidences such as, singlet oxygen, reactive oxygen species (ROS) formation and heat shock protein (HSP 70) expression were also provided to show the existence of PDT and PTT pathways. In the in vivo experiments, the PEG-W18O49 NWs-mediated PDT effects are far more effective in destructing B16F0 melanoma tumors than the corresponding PEG-W18O49 NWs -mediated PTT effects at low doses of NIR light irradiation.
In the third chapter, we have showed that upconversion nanoparticles (UCNPs) can sensitize formation of singlet oxygen (1O2) and exert in vivo photodynamic therapeutic effects upon NIR (980 nm) light excitation at very low laser doses (70~360 mW/cm2), in addition to the upconversion fluorescence emission. In combination with the silencing gene, superoxide dismutase (SOD1), the upconversion nanoparticles-mediated combination therapeutic modality can effectively kill lung tumors. Further, in the chapter four, we have extended the similar study to PEGylated nano graphene oxide conjugated with the folate (GO-PEG-folate) to develop as a nanomaterial-mediated PDT reagent for the destruction of melanoma tumors upon activation by 980 nm NIR light. Overall, the current thesis provides an overview of how the intrinsic nanomaterials can be used as photodynamic therapeutic reagents in killing cancer cells without the use of any organic photosensitizers. Taken altogether, we have discovered the field of nanomaterial-mediated photodynamic therapy (NmPDT), as an exciting alternative to organic PS-mediated PDT and nanomaterial-mediated photothermal therapy (NmPTT) for the clinical cancer treatments.

Chapter 1: Unprecedented Multi-Functional Lanthanide-Doped Mesoporous 
Silica Frameworks for Bimodal Imaging and Chemo-Photodynamic Therapy 
Of Tumors

1 Background and Introduction……………………………………………. …1

1.1.Cancer Chemo-Phototherapy using Nanomaterials………………………......1
2 Experimental Section………………………………………………………...5

2.1 Synthesis of EuGd@MCF................................................................................5 
2.2 Synthesis of EuGd@MCF-PEG-folate.............................................................6
2.3 DOX loading on EuGd@MCF.........................................................................6 
2.4 Percentage of drug loading efficiency (DLE) of EuGd@MSF-DOX..............7
2.5 DOX release from EuGd@MCF at different pH……………………………..8
2.6 Quantum yield calculations…………………………………………………..8
2.7 In vitro fluorescence imaging of EuGd@MCF using confocal laser scanning microscopy (CLSM)………………………………………………………………..9
2.8 In vitro cellular uptake studies of EuGd@MCF-DOX using confocal laser scanning microscopy (CLSM)…………………………………………………….10
2.9 In vivo magnetic resonance imaging (MRI)………………………………...11
2.10 In vitro DOX release measured using MTT assay………………………...11
2.11 Singlet oxygen phosphorescence measurements…………………………..12 
2.12 DPBF experiments…………………………………………………………12 
2.13 EPR measurements………………………………………………………...13
2.14 Phototoxicity of EuGd@MCF and EuGd@MCF-DOX..............................13
2.15 Reactive oxygen species (ROS) experiments……………………………...14 
2.16 Singlet oxygen sensor green (SOSG) experiments………………………...14
2.17 Heat shock protein expression analysis……………………………………15
2.18 In vitro confocal imaging for EuGd@MSF-DOX in MCF-7/MDR.………15
2.19 Phototoxicity of EuGd@MSF and EuGd@MSF-DOX in MCF-7/MDR using MTT assay………………………………………………………………….16
2.20 P-glycoprotein (P-gp) expression analysis.………………………………..16
2.21 In vivo fluorescence imaging of EuGd@MCF-PEG-folate........................17
2.22 In vivo tumor growth study.……………………………………………….17
2.23 Tissue sectioning and caspase 3 staining………………………………….18
3 Results and Discussion………………………………………………………18

3.1 Synthesis and Characterization of Lanthanide-doped Mesoporous Silica Frameworks (EuGd@MSF)..................................................................................18
3.2 EuGd@MSF-DOX for in vitro combination of 
chemo-photodynamic therapy…………………………………………………….25
3.3 EuGd@MSF-DOX for in vivo combination of 
chemo-photodynamic therapy…………………………………………………….39
4 Conclusions......................................................................................................50

5 References........................................................................................................52

Chapter 2: Photosensitization of Singlet Oxygen and In vivo Photodynamic Therapeutic Effects Mediated by PEGylated W18O49 Nanowires   

1 Background and Introduction………………………………………………58

2 Experimental Section………………………………………………………..60
2.1 Synthesis of ultrathin PEG-W18O49 NWs..………………………………..60
2.2 Singlet oxygen phosphorescence measurements..…………………………..60 
2.3 Cell culture, materials and reagent.…………………………………………61
2.4 Cytotoxicity assays.………………………………………………………....61
2.5 Reactive oxygen species (ROS) experiment.…………………………….....62
2.6 Singlet oxygen sensor green (SOSG) experiment.……………………….....63
2.7 Heat-shock protein expression analysis.…………………………………….63 
2.8 In vivo tumor growth study…………………………………………………63
2.9 Tissue sectioning and caspase 3 staining……………………………………64
2.10 In vivo monitoring tumor temperature…………………………………….65
2.11 Quantum yield calculations……………………………………………......65

3 Results and Discussion………………………………………………………66

4 Conclusions......................................................................................................85

5 References…………………………………………………………………….87


Chapter 3: Conquering Multidrug Resistant Lung Cancer by Upconversion Nanoparticles-Mediated Photodynamic Therapy Combined with Gene Silencing
1 Background and Introduction.......................................................................90

2 Experimental Section..………………………………………………………93

2.1 Synthesis of UCNPs….……………………………………………………..93
2.2  Synthesis of citrate-capped UCNPs…….…………………………………..93
2.3 Synthesis of anti-EGFR conjugated UCNPs………………………………..94
2.4 Singlet oxygen phosphorescence emission measurements…………………94
2.5 Cellular uptake studies using multi-photon confocal laser scanning microscopy (CLSM)………………………………………………………………95
2.6 Preparation of siRNA-anti-EGFR-UCNPs………………………………….95
2.7 Isolation of total RNA from siRNA-anti EGR-UCNPs 
internalized NCIH23 cells………………………………………………………...96
2.8 Polymerase chain reaction (PCR) of total RNA to complimentary DNA…..97
2.9 Real-time quantitative PCR (RT-qPCR) experiment…………………….....97
2.10 Cytotoxicity assays………………………………………………………..98
2.11 ROS experiments……………………………………………………….....99
2.12 SOSG experiments………………………………………………………...99
2.13 In vitro apoptosis detection using Annexin V……………………………100
2.14 In vivo tumor growth study………………………………………………100
2.15 HE and Caspase 3 staining……………………………………………….101
2.16 Determination of upconversion photoluminescence quantum yield of as synthesized UCNPs and citrate capped UCNPs…………………………………101
2.17 Singlet O2 phosphorescence Quantum yield measurements……………...103
3 Results and Discussion..................................................................................105

3.1 Synthesis, characterization and optical properties of UCNPs……………..105
3.2 In vitro UCNPs-mediated PDT and gene silencing experiments………….113
3.3 In vivo UCNPs-mediated PDT and gene silencing experiments………….118 
4 Conclusions………………………………………………………………….126

5 References…………………………………………………………………...127

Chapter 4: Nano-Graphene Oxide-mediated In vivo Fluorescence Imaging 
and Bimodal Photodynamic and Photothermal Destruction of Tumors

1 Background and Introduction…………………………………………….133

2 Experimental Section…..…………………………………………………..138

2.1 Synthesis of nano-graphene oxide…………………………………………138
2.2 Synthesis of GO-PEG-folate.......................................................................138
2.3 Generation of 1O2 phosphorescence……………………………………….139
2.4 DPBF quenching experiment………………………………………………139
2.5 In vitro cellular uptake experiments……………………………………….139
2.6 Cytotoxicity assays………………………………………………………...139
2.7 In vitro detection of reactive oxygen species (ROS) experiments………...140
2.8 Intracellular detection of 1O2 using singlet oxygen sensor green (SOSG)..140
2.9 Intracellular detection of heat-shock protein (HSP70) expression levels…141
2.10 In vivo tumor growth study using GO-PEG-folate………………………141
2.11 In vivo fluorescence imaging using GO-PEG-folate……………………..142
2.12 Calculation of fluorescence emission quantum yields 
of GO-PEG-folate………………………………………………………………..142
2.13 Singlet O2 phosphorescence Quantum yield measurements.……………..144

3 Results and Discussion…..…………………………………………………145

3.1 Synthesis and characterization of GO and GO-PEG-folate.……………….145
3.2 Calculation of photothermal conversion efficiency of GO-PEG-folate.…..149
3.3  GO-PEG-folate as intrinsic in vitro fluorescent cellular marker………….154
3.4 In vitro NmPDT and NmPTT experiments using GO-PEG-folate………..156
3.5 Determination of NmPDT vs. NmPTT ratio………………………………158
4 In vivo GO-PEG-folate-mediated NmPDT and NmPTT experiment……….164
4 Conclusions………………………………………………………………….170

5 References…………………………………………………………………...171

1 Summary……………………………………………………………………176 





                                

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