At the end of this thesis, 1H and 13C{ 1H} NMR spectra for all the new compounds and the crystallographic details for the X-ray structure are given as Appendices. / Chapter 1 presents an overview of photodynamic therapy, including its historical development, photophysial and biological mechanisms, and current clinical situation. A brief review of second-generation photosensitizers and the different approaches for targeted photodynamic therapy are also given. / Chapter 2 reports the synthesis and characterization of a silicon(IV) phthalocyanine which is substituted axially with two diamino moieties, together with its di- and tetramethylated derivatives. The non-methylated analogue shows a high photocytotoxicity toward HT29 human colorectal adenocarcinoma and HepG2 human hepatocarcinoma cells with IC50 values down to 0.01 muM. Interestingly, this compound also exhibits a pH-dependent behavior. The fluorescence quantum yield increases by four folds and the singlet oxygen quantum yield increases by three folds in water when the pH decreases from 7.0 to 5.0. The preliminary results suggest that this compound is a promising photosensitizer of which the photodynamic activity can be modulated by changing the pH of the environment. Furthermore, this compound can be used as a near-infrared fluorescence probe for optical imaging of intracellular acidic level. / Chapter 3 reports a novel series of aminophenyl-substituted silicon(IV) phthalocyanines. The aminophenyl moieties in these conjugates can also modulate the photophysical and photosensitizing properties of the phthalocyanine core through changing the pH of the environment. These phthalocyanines exhibit a low photocytotoxicity under physiological conditions (pH 7.4). It is likely that the amino groups, in the free amine form, can quench the singlet excited state of phthalocyanine by a photoinduced electron transfer (PET) mechanism, and reduce the chance of intersystem crossing and the efficiency in generating singlet oxygen. The strong aggregation tendency of these compounds in this pH environment is another major reason for the low photocytotoxicity. When the pH is lower to 6.4-6.9, the amino groups are protonated so that they are no longer electron donors, and the compounds become less aggregated. These changes lead to an increase in photocytotoxicity. The results of this study are reported in this Chapter. / Chapter 4 describes a new series of silicon(IV) phthalocyanines conjugated axially with various polyamine derivatives. Polyamines are naturally occurring compounds which are involved in a number of cell processes including cell proliferation and differentiation. Their biosynthetic activity and polyamine levels in some tumor cells are significantly higher than those in normal cells. Conjugation of polyamine analogues is therefore one of the promising approaches to improve the tumor-targeting property of photosensitizers. This Chapter describes the synthesis, spectroscopic characterization, and photophysical properties of these compounds. Their photodynamic activities toward HT29 and Chinese hamster ovary (CHO) cells have also been studied in detail. Their cellular uptake, subcellular localization, cell death mechanism, and in vivo photocytotoxicity have also been studied. / In Chapter 5, we report a series of silicon(IV) phthalocyanines containing one or two cholesterol unit(s) at the axial position(s), including their synthesis, spectroscopic characterization, photophysical properties, and in vitro photodynamic activities. These cholesterol-containing photosensitizers can form stable conjugates with low-density lipoprotein (LDL), which is the major lipoprotein carrier for cholesterol in human plasma. On the basis that cancer cells generally express significantly more LDL receptors than normal cells, these cholesterol-conjugated phthalocyanines are designed with a view to enhancing their selectivity toward tumor. Unfortunately, conjugation of cholesterol reduces the photodynamic activity of the silicon(IV) phthalocyanines as a result of their higher aggregation tendency. / This thesis reports the synthesis, spectroscopic characterization, and photophysical and biological properties of several series of novel silicon(IV) phthalocyanines which are specially designed as efficient and selective photosensitizers for photodynamic therapy. / Jiang, Xiongjie. / Source: Dissertation Abstracts International, Volume: 72-01, Section: B, page: . / Thesis (Ph.D.)--Chinese University of Hong Kong, 2010. / Includes bibliographical references and index. / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. Ann Arbor, MI : ProQuest Information and Learning Company, [200-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstract also in Chinese.

Thesis (Ph. D.)--University of Hong Kong, 2007. / Title proper from title frame. Also available in printed format.

Thesis (Ph. D.)--University of Hong Kong, 2007. / Title proper from title frame. Also available in printed format.

Thesis--University of Oklahoma. / Bibliography: leaves 62-63.

The molecular design, synthesis and spectroscopic characterization of a series of ruthenium(II), metal-free and platinum(II) photosensitizers were discussed. The applications of some of these compounds in dye-sensitized solar were also outlined. To start with, a brief overview on the background of dye-sensitized solar cells (DSSCs) was presented in Chapter 1. In Chapter 2, a series of new thiocyanate-free ruthenium(II) cyclometalated complexes with different ligands were successfully synthesized and some of them were fully characterized by spectroscopic and computational methods. The nature of cyclometalating ligands effectively tunes the properties of the metal complexes and the resulting DSSC performance. In Chapter 3, new di-anchoring organic dyes have been synthesized and characterized. This molecular design strategy can significantly enhance the . value because this successfully inhibits the undesirable charge combination and prolongs the electron lifetime. The discoveries open up a new avenue to the evolution of organic sensitizers and the optimization of bridged di-anchoring dyes for highly efficient co-adsorbent-free DSSCs. In Chapter 4, a series of new thiophene-free platinum sensitizers for the application of DSSCs was developed. Four unsymmetrical platinum(II) di-acetylide complexes containing phenothiazine moiety with different donor units were designed and synthesized. These photosensitizers were fully characterized by spectroscopic as well as computational studies and also successfully employed in DSSC fabrication. These findings provided positive evidence that platinum-acetylide complexes have a great potential and prospect for the use as promising metal-based photosensitizers in DSSC applications. Finally, Chapters 5 and 6 present the concluding remarks and the experimental details of the work described in Chapters 2–4.

本論文報導了幾個系列的新型鋅酞菁配合物以及氟硼二吡咯染料的合成與表徵。 這些精心設計的化合物可作為高效的和選擇性的光敏劑應用於靶向性光動力療法和細菌的光動力失活。 / 第一章概述了光動力療法，包括歷史發展、光物理和生物機制及其臨床應用現狀。 重點介紹了用於靶向性光動力療法的第三代光敏劑，其中包括基於靶向性配體、納米載體的光敏劑以及可激活的光敏劑。 另外，本章還簡單介紹了用於抗菌光動力療法的光敏劑。 / 第二章報導了一種新型的由細胞核定位的短肽共軛修飾的鋅酞菁配合物的合成與表徵。 此短肽分子的氨基酸序列為：Gly-Gly-Pro-Lys-Lys-Lys-Arg-Lys-Val。 我們研究了該化合物的光物理性質、聚集行為以及離體光動力活性，同時與其非肽共軛修飾的化合物進行了詳細的比較。 利用HT29人結腸腺癌細胞，研究發現此多肽共軛修飾的酞菁展示了較高的細胞吸收、更高的細胞內活性氧的產生效率和光毒性。 同時活體實驗證明此化合物增加了酞菁在裸鼠腫瘤的停留時間。 這些結果在本章中均進行了詳細的報導。 / 第三章敘述了另一種多肽共軛修飾的鋅酞菁化合物的製備和光物理性質。 這個多肽包含了一個環狀的氨基酸序列，即 Arg-Gly-Asp-D-Phe-Lys，此多肽被認為能以腫瘤相關的血管新生時的高表達的跨膜受體（如 α[subscript v]β₃ 整合素）為靶向。 利用 α[subscript v]β₃ 整合素高表達的 U87-MG 人惡性膠質瘤細胞，我們研究了這個化合物的細胞吸收、細胞內活性氧的產生、離體光動力活性以及亞細胞定位。 同時，用 α[subscript v]β₃ 整合素低表達的 MCF-7 人乳腺癌細胞作為對照。 / 通常，腫瘤細胞外的pH值比正常細胞組織的低，因此，我們合成一個由酸敏感的縮醛鍵連接的酞菁二聚體。 此二聚體會發生自身淬滅且對pH有響應。 通過電子吸收和熒光光譜， 我們詳細地研究了這個化合物在不同酸性條件下的光物理性質和斷開動力學。 由於酞菁環具有強的二聚化趨勢，這個二聚體能自身淬滅，因而呈現“失活狀態。 通過降低檸檬酸緩衝液的pH值，這個化合物的乙縮醛鍵能優先斷開，並且斷開的速率隨pH值的降低而增加。 兩個酞菁環的分開增強了熒光強度和單態氧的產生。 這個二聚光敏劑還能在 HT29 細胞內被激活，從而產生較強的細胞內熒光。 相比之下，由乙二醇鏈連接的類似物基本上沒有熒光發射。 同時，這個可斷開的二聚物對HT29細胞光毒性也比不可斷開的類似物高（半致死量：IC₅₀ = 0.35 vs. 0.59 μM）。 第四章對這些結果進行了詳細的報導。 / 在第五章中，我們報導了兩種以腫瘤靶向配體葉酸共軛修飾的二（苯乙烯基）－氟硼二吡咯衍生物的合成、光譜表徵以及光物理性質。 在這兩個化合物中，葉酸和二（苯乙烯基）－氟硼二吡咯是通過不同長度的乙二醇鏈連接的。 我們研究了這兩個化合物的鏈長對KB人鼻咽癌細胞和MCF-7細胞的吸收和離體光動力活性的影響。 前者能高表達葉酸受體，而後者作為低葉酸受體表達的一個對照。 與MCF-7細胞相比，兩個化合物都展示了對KB細胞較高的吸收和光毒性（半致死量：IC₅₀ = 0.062 vs. 2.56 μM 和0.177 vs. 0.995 μM）。 此外，具有較長鏈的化合物優先定位在溶酶體中，而較短鏈的那個化合物則較多停留在細胞的內質網。 / 第六章重點開發了一系列多胺以及不同長度的聚賴氨酸（包括2、4、8個賴氨酸）共軛修飾的鋅酞菁配合物，并用於抗菌光動力療法。 我們報導了它們的合成、光物理性質以及對甲氧西林青霉素敏感的格蘭陽性金黄色釀膿葡萄球菌和格蘭陰性綠膿桿菌的光動力抗菌活性。 其中，三-N-甲基化的酞菁顯示了特別高的效果，在濃度為16 nM時，能降低大於5 log10 的金黄色釀膿葡萄球菌。 / 第七章闡述了前面幾章的實驗部份。 論文的最後附上所有新化合物的核磁共振氫譜和碳譜。 / This thesis describes the synthesis and characterization of several series of novel zinc(II) phthalocyanines and boron dipyrromethenes (BODIPYs), which are carefully designed as efficient and selective photosensitizers for targeted photodynamic therapy (PDT) and photodynamic inactivation of bacteria. / Chapter 1 presents an overview of PDT, including its historical development, photophysial and biological mechanisms, and current research directions. Emphasis is placed on the third-generation photosensitizers for targeted PDT, including targeting ligand-based photosensitizers, nanoparticle-based photosensitizers, and activatable photosensitizers. A brief review of photosensitizers that can be used for antimicrobial PDT is also given. / Chapter 2 reports the synthesis and characterization of a novel zinc(II) phthalocyanine conjugated with a short peptide with a nuclear localization sequence, namely Gly-Gly-Pro-Lys-Lys-Lys-Arg-Lys-Val. The photophysical properties, aggregation behavior, and in vitro photodynamic activity of this compound have been investigated and compared with its non-peptide-conjugated analogue. It has been found that the peptide-conjugated phthalocyanine shows an enhanced cellular uptake, higher efficiency in generating intracellular reactive oxygen species (ROS), higher photocytotoxicity against HT29 human colorectal adenocarcinoma cells, and enhanced tumor-retention property in tumor-bearing nude mice. The results are reported in detail in this chapter. / Chapter 3 describes the preparation and photophysical properties of another analogue conjugated with a peptide containing the cyclic Arg-Gly-Asp-D-Phe-Lys sequence, which is known to target the upregulated transmembrane protein receptors such as α[subscript v]β₃ integrin during angiogenesis. The cellular uptake, intracellular ROS generation, in vitro photodynamic activity, and subcellular localization of this conjugate have been investigated against U87-MG human glioblastoma cells, which have a high expression of α[subscript v]β₃ integrin. MCF-7 human breast adenocarcinoma cells, which have a low expression of α[subscript v]β₃ integrin, have been used as a negative control. / On the base that the extracellular pH in tumors is generally lower than that in normal tissues, we have developed a pH-responsive self-quenched phthalocyanine dimer connected with an acid-sensitive ketal linker. The basic photophysical properties of this compound and its cleavage kinetics upon exposure to different acidic conditions have been extensively studied by electronic absorption and fluorescence spectroscopy. Owing to the strong dimerization tendency of the phthalocyanine ring, this dimer is self-quenched and in the "OFF" state. By lowering the pH (< 6.5) in citrate buffer solutions, the linker is preferentially cleaved, and the rate of cleavage increases as the pH decreases. The separation of the phthalocyanine moieties leads to enhancement in fluorescence intensity and singlet oxygen production. This dimeric photosensitizer can also be activated inside HT29 cells causing strong intracellular fluorescence. By contrast, the fluorescence is hardly observed for the non-cleavable ethylene glycol-linked analogue. The photocytotoxicity of the cleavable dimer is also higher than that of the non-cleavable counterpart (IC₅₀ = 0.35 vs. 0.59 μM). The results are reported in detail in Chapter 4. / In Chapter 5, we describe the synthesis, characterization, and photophysical properties of two distyryl BODIPY derivatives conjugated with a folic acid as a tumor-targeting ligand via an ethylene glycol spacer with different chain length. The effects of the chain length on the cellular uptake and in vitro photodynamic activities of these compounds have been examined against KB human nasopharyngeal epidermal carcinoma cells and MCF-7 cells. The former are known to have a high expression of folate receptors, while the latter have been used as a negative control. Both compounds show enhanced cellular uptake and higher photocytotoxicity toward KB cells when compared with MCF-7 cells (IC₅₀ = 0.062 vs. 2.56 μM and 0.177 vs. 0.995 μM). The conjugate with a longer spacer shows preferential localization in the lysosomes, while the analogue with a shorter linker accumulates in the endoplasmic reticulum of the cells. / Chapter 6 focuses on the development of a series of zinc(II) phthalocyanines substituted with a polyamine moiety or a polylysine chain containing 2, 4, or 8 lysine units for antimicrobial PDT. Their synthesis, photophysical properties, and photodynamic antimicrobial activities against Gram (+) methicillin-sensitive Staphylococcus aureus and Gram (-) Pseudomonas aeruginosa are reported. The tri-N-methylated phthalocyanine is particularly potent showing a more than 5 log₁₀ reduction of the Staphylococcus aureus at 16 nM. / Chapter 7 gives the experimental details for the work described in the preceding chapters. ¹H and ¹³C{¹H} NMR of all the new compounds are given in the Appendix. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Ke, Meirong. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2012. / Includes bibliographical references (leaves 159-176). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstract also in Chinese. / Abstract --- p.i / Abstract (in Chinese) --- p.v / Acknowledgment --- p.viii / Table of Contents --- p.xi / List of Figures --- p.xvi / List of Schemes --- p.xxiv / List of Tables --- p.xxv / Abbreviations --- p.xxvi / Chapter Chapter 1 --- Introduction --- p.1 / Chapter 1.1 --- General Introduction of Photodynamic Therapy --- p.1 / Chapter 1.2 --- Mechanisms of Photodynamic Therapy --- p.2 / Chapter 1.2.1 --- Photophysical Mechanisms --- p.2 / Chapter 1.2.2 --- Biological Mechanisms --- p.4 / Chapter 1.3 --- Clinical Status of Photodynamic Therapy --- p.5 / Chapter 1.4 --- Overview of Photosensitizers --- p.7 / Chapter 1.5 --- Targeted Photodynamic Therapy --- p.13 / Chapter 1.5.1 --- Targeting Ligand-Based Photosensitizers --- p.13 / Chapter 1.5.1.1 --- Synthetic Peptides --- p.13 / Chapter 1.5.1.2 --- Proteins --- p.16 / Chapter 1.5.1.3 --- Aptamers --- p.18 / Chapter 1.5.1.4 --- Folic acid --- p.19 / Chapter 1.5.1.5 --- Other Biological Ligands --- p.20 / Chapter 1.5.2 --- Nanoparticle-Based Photosensitizers --- p.20 / Chapter 1.5.2.1 --- Biodegradable Nanoparticle-Based Photosensitizers --- p.21 / Chapter 1.5.2.2 --- Non-Biodegradable Nanoparticle-Based Photosensitizers --- p.23 / Chapter 1.5.3 --- Activatable Photosensitizers --- p.25 / Chapter 1.5.3.1 --- Environment-Activated Photosensitizers --- p.26 / Chapter 1.5.3.2 --- Enzyme-Activated Photosensitizers --- p.27 / Chapter 1.5.3.3 --- Nucleic Acid-Activated Photosensitizers --- p.29 / Chapter 1.6 --- Antimicrobial Photodynamic Therapy --- p.32 / Chapter 1.6.1 --- General Introduction --- p.32 / Chapter 1.6.2 --- Photosensitizers for Antimicrobial Photodynamic Therapy --- p.34 / Chapter Chapter 2 --- A Phthalocyanine-Peptide Conjugate with High in vitro Photodynamic Activity and Enhanced in vivo Tumor-Retention Property --- p.36 / Chapter 2.1 --- Introduction --- p.36 / Chapter 2.2 --- Results and Discussion --- p.37 / Chapter 2.2.1 --- Molecular Design and Synthesis --- p.37 / Chapter 2.2.2 --- Electronic Absorption and Photophysical Properties --- p.42 / Chapter 2.2.3 --- In Vitro Photodynamic Activities --- p.44 / Chapter 2.2.4 --- In Vivo Studies --- p.50 / Chapter 2.3 --- Conclusion --- p.52 / Chapter Chapter 3 --- Synthesis, Characterization, and Photodynamic Activity of a cylic RGD-Conjugated Phthalocyanine --- p.53 / Chapter 3.1 --- Introduction --- p.53 / Chapter 3.2 --- Results and Discussion --- p.54 / Chapter 3.2.1 --- Molecular Design and Synthesis --- p.54 / Chapter 3.2.2 --- Electronic Absorption and Photophysical Properties --- p.57 / Chapter 3.2.3 --- In Vitro Photodynamic Activities --- p.59 / Chapter 3.3 --- Conclusion --- p.67 / Chapter Chapter 4 --- A pH-Responsive Fluorescent Probe and Photosensitizer Based on the Dimerization Property of Phthalocyanines --- p.69 / Chapter 4.1 --- Introduction --- p.69 / Chapter 4.2 --- Results and Discussion --- p.70 / Chapter 4.2.1 --- Synthesis and Characterization --- p.70 / Chapter 4.2.2 --- Electronic Absorption and Photophysical Properties --- p.74 / Chapter 4.2.3 --- In Vitro Studies --- p.80 / Chapter 4.3 --- Conclusion --- p.84 / Chapter Chapter 5 --- Synthesis, Characterization, and Photodynamic Activities of BODIPY-Folate Conjugates --- p.86 / Chapter 5.1 --- Introduction --- p.86 / Chapter 5.2 --- Results and Discussion --- p.87 / Chapter 5.2.1 --- Synthesis and Characterization --- p.87 / Chapter 5.2.2 --- Electronic Absorption and Photophysical Properties --- p.92 / Chapter 5.2.3 --- In Vitro Studies --- p.94 / Chapter 5.3 --- Conclusion --- p.100 / Chapter Chapter 6 --- Synthesis, Characterization, and Antimicrobial Photodynamic Activities of Cationic Phthalocyanines --- p.102 / Chapter 6.1 --- Introduction --- p.102 / Chapter 6.2 --- Results and Discussion --- p.103 / Chapter 6.2.1 --- Synthesis and Characterization --- p.103 / Chapter 6.2.2 --- Electronic Absorption and Photophysical Properties --- p.108 / Chapter 6.2.3 --- In Vitro Photodynamic Antimicrobial Activities --- p.112 / Chapter 6.3 --- Conclusion --- p.114 / Chapter Chapter 7 --- Experimental Section --- p.115 / Chapter 7.1 --- General --- p.115 / Chapter 7.2 --- Synthesis --- p.119 / Chapter 7.2.1 --- Synthesis for Chapter 2 --- p.119 / Chapter 7.2.2 --- Synthesis for Chapter 3 --- p.125 / Chapter 7.2.3 --- Synthesis for Chapter 4 --- p.128 / Chapter 7.2.4 --- Synthesis for Chapter 5 --- p.132 / Chapter 7.2.5 --- Synthesis for Chapter 6 --- p.138 / Chapter 7.3 --- pH-Response Properties of 4.6 and 4.7 in Citrate Buffer Solutions --- p.143 / Chapter 7.4 --- In Vitro Studies --- p.144 / Chapter 7.4.1 --- Cell Lines and Culture Conditions --- p.144 / Chapter 7.4.2 --- Photocytotoxicity Assay --- p.145 / Chapter 7.4.3 --- Photodynamic Antimicrobial Inactivatoin Studies --- p.147 / Chapter 7.4.4 --- Intracellular ROS Measurements --- p.148 / Chapter 7.4.5 --- Cellular Uptake (Determined by Extraction Method) --- p.149 / Chapter 7.4.6 --- Cellular Uptake (Determined by Confocal Microscopy) --- p.150 / Chapter 7.4.7 --- Cellular Uptake (Determined by Flow Cytometry) --- p.152 / Chapter 7.4.8 --- Fluorescence Microscopic Studies --- p.153 / Chapter 7.4.9 --- Subcellular Localization Studies --- p.153 / Chapter 7.4.10 --- pH-Dependent Intracellular Fluorescence Studies --- p.155 / Chapter 7.5 --- In Vivo Imaging and Ex Vivo Organ Biodistribution --- p.156 / Chapter Chapter 8 --- Conclusion and Outlook --- p.157 / References --- p.159 / Chapter Appendix --- NMR Spectra of New Compounds --- p.177

Photodynamic therapy (PDT) is a minimally invasive treatment modality for some human diseases, including cancer. To destroy the targeted cells or tissues, PDT relies on the reactive oxygen species (ROS) generated from a series of photochemical reactions by the light-activated photosensitizers administered to the patients. Many dyes could be modified to become photosensitizers. The BODIPY-based fluorophores could be converted into potent photosensitizers with highly efficient singlet oxygen generation as well as considerable brightness of fluorescence. Some of them exhibit potent in vitro PDT effects. However, carriers are often required for an effective delivery of the BODIPY-based dyes in biological system. / Silica nanoparticles are ceramic-based materials prepared by condensation of silanes along the surfactant-based templating agents. Mesoporous silica nanoparticles (MSNs) and organically modified silica nanoparticles (OMSNs) represent two major types of silica nanocarriers used for loading of photosensitizers in PDT. Typical MSNs have a diameter of 100-500 nm and a highly ordered hexagonal porous structure for loading of guest molecules. The OMSNs are smaller in size (diameter ~20 nm). Both MSNs and OMSNs are known to be chemically inert and biocompatible. Therefore, they were selected as the carriers for BODIPY-based photosensitizers in the present study. / A BODIPY-based photosensitizer with an absorption maximum at the red region (~660 nm) was modified to carry a carboxyl group at the meso-position. This photosensitizer was conjugated to an amine-functionalized MSN of diameter 80-120 nm by a post-synthesis grafting approach. This strategy allowed the entrapment of delicate dyes by the MSN under mild reaction conditions. The resulting composites with different photosensitizer loading were all spherical and with diameter from 80-120 nm. Dispersing the composites in H₂O, the fluorescence emission was moderately quenched due to dye aggregation. However, compared with the surfactant solubilized free dye, the MSN conjugated BODIPY produced singlet oxygen more efficiently. The dye loading per the unit mass of MSN did not impose any significant effect on the photophysical properties of the composites. The in vitro PDT effects of the BODIPY-based dye entrapped in the MSN were evaluated by using the human adenocarcinoma cells HT-29. The dyes loaded in the MSNs were more cytotoxic than the free dye, but slightly less cytotoxic when compared with the surfactant-formulated dye. The rate of intracellular ROS production of the MSN entrapped dye was much higher than that of the free dye with or without surfactant, which was consistent with the results obtained in the studies of the photophysical properties. The dye in MSN was more efficient as an inducer of apoptosis than the dye in surfactant, as shown by the annexin V/PI staining. Subcellular localization studies using confocal microscopy revealed that the dye in MSN was mainly found in endoplasmic reticulum and lysosome of the cells. / This amine-functionalized MSN platform was further modified on the surface. On a batch of amine-bearing MSN (~200 nm in diameter) loaded with the BODIPY-based photosensitizer, a layer of polyethylene glycol (PEG) was grafted. The PEG layer was comprised of short PEG chains (~15 repeating units) with a methyl end and another long PEG chains (~44 repeating units) with an azide end. The alkyne-modified tLyP-1 peptide targets the cancer cell and blood vessel surface marker, neuropilin, was conjugated to the MSN via azide-alkyne Huisgen cycloaddition (click reaction). Unlike many other reported designs of photosensitizer-MSN composites utilizing only amine functionalization, this approach prevented the competition for conjugation site between the photosensitizer and the targeting ligand. The use of click reaction allowed a greater feasibility in targeting ligand design. In H₂O, the surface decorated composites could still generate singlet oxygen as effectively as the bare composite. The in vitro PDT effects toward human prostate adenocarcinoma cells PC-3 with a high level of neuropilin expression of the composites were evaluated. The peptide-bearing MSN had a faster initial uptake in cells, which could be moderately suppressed by the addition of free peptide. The peptide-linked MSN had a higher photocytotoxicity toward the PC-3 cells when compared with the MSN without the peptide due to the enhanced cellular uptake. Both composites were confined to the lysosome of the cells, which might be the consequence of lacking surface positive charge to help endosomal escape. Therefore, further optimization of the composite by adjusting the PEG loading, chain length and the amount of targeting ligand loading should be made. / OMSNs are homogenous spherical particles with a smaller size (~20 nm). The capability of OMSNs to be multi-functional dye nanocarriers was also explored. Besides a BODIPY-based photosensitizer, a phthalocyanine-based photosensitizer and an aza-BODIPY-based imaging dye were also chosen for OMSN entrapment. It was found that only those surfactant-soluble dyes could be successfully entrapped in the OMSNs. Dyes in OMSNs remained non-aggregated, thus emitting a bright fluorescence. The photosensitizers generated singlet oxygen with the same efficiency as the surfactant-formulated free dyes. The potency of the OMSN-entrapped photosensitizers toward the HeLa derived KB cells was similar to that of the surfactant-solubilized free dyes. OMSNs are hence alternative carrier to the surfactant-based emulsifiers for in vitro photosensitizer delivery. To decorate the surface of OMSN, folate was conjugated to the composite by one-pot approach. However, the resulting composite failed to exhibit any tumor targeting effect toward KB cells having a high level of folate receptor expression. Besides, in order to prevent premature dye leakage in culture media as a result of the interaction with serum proteins, an attempt was also made to prepare OMSNs with a covalently linked BODIPY-based dye. However, the conjugated dye was aggregated, which diminished the singlet oxygen generation and quenched the fluorescence of the composites, although the surface of this composite was successfully decorated with PEG or the azide-bearing silane. / In conclusion, the BODIPY-based photosensitizers could be entrapped in MSNs and OMSNs could be successfully delivered into cancer cells in vitro. The PDT effects induced by these composites were often comparable to those caused by the the surfactant-solubilized dyes. Although surface decorations could be made for the particles, further fine adjustment on the surface properties of the composites is needed to improve the specificity and potency of the composites in the future. / 光動力治療(PDT)可用作治療一些人類疾病如癌症。這種低創傷度治療模式的主要原理是先把光敏劑注入病人體內，然後以光照射患處，激活當中的光敏劑。經過一系列的光化學反應後，病患組織附近的氧分子會被光敏劑轉化成為活性氧物種，從而破壞病變的組織或細胞。在眾多可改造成光敏劑的染色劑中，氟硼二吡咯(BODIPY)熒光團可以轉成兼具高活性氧轉化率及強熒光的光敏劑。研究顯示，部份BODIPY衍生的光敏劑在細胞實驗中有強大的PDT效果。可是，這些光敏劑往往需要由載體輔助才可以送達目標組織或細胞。 / 二氧化矽納米粒子是由硅烷在介面活性劑模板上聚合而成的陶瓷基類納米粒子，其中介孔二氧化矽納米粒子(MSN)和有機改造二氧化矽納米粒子(OMSN)為兩種最常用的光敏劑載體。MSN的直徑通常介乎100至500納米，並有高度整齊排列的六角介孔以供承載客分子。OMSN則比較細小，直徑約20納米。MSN和OMSN皆為化學惰性以及生物相容的物料，所以在本研究中它們被選為BODIPY類光敏劑的載體。 / 在一個BODIPY光敏劑（它的吸收峰位於紅光，波長約660納米範圍內）上，羧基被加到中央位置上。這個帶羧基的光敏劑可以嫁接到己成形的帶胺功能團MSN上。由於後合成嫁接法可以於溫和的條件下進行，相信其亦可應用其他脆弱的染色劑及帶胺MSN的連結上。即使有不同光敏劑載入量，同一系列的合成物的直徑皆是80至120納米。當這些合成物分散在水中，MSN內光敏劑會因聚合作用，其熒光強度會明顯減弱。可是，比起沒有載體或以介面活性劑配方的光敏劑，包裹於MSN內的光敏劑能更有效的產生活性氧。在光物理的測試中，光敏劑的承載量對MSN化合物的光物理性質俱沒有明顯的影響。 / 對人工培植的人類大腸腺癌細胞HT-29而言，承載於MSN內的光敏劑的比沒有載體的具光毒性。可是對比起以介面活性劑配方的BODIPY，承載於MSN內的光敏劑還是光毒性稍弱。另外，承載於MSN內的光敏劑在細胞內產生活性氧的效率，遠高於介面活性劑配方內、或沒有載體的光敏劑，這項發現跟光物理的檢測結果類近。另外，annexin v/PI染色實驗結果顯示，MSN承載的光敏劑能更有效的引發細胞淍亡。共焦顯微鏡進行的細胞內定位法顯示，MSN承載的光敏劑主要分佈在內質網和溶酶體之中。 / 這類帶胺官能團的MSN的粒子表面可作進一步修飾。本研究嘗試用聚乙二醇層修飾一種直徑約200納米、以及載有BODIPY光敏劑的MSN。該聚乙二醇層由帶甲基端的短鏈(約15個重複單位)和帶疊氮端的長鏈(約44個重複單位)PEG組成。然後，以疊氮──炔烴Huisgen環加成法（點擊反應）將帶炔烴的tLyP-1短肽連接到PEG上。該tLYP-1短肽對在一些癌細胞和癌組織血管上常見的neuropilin有高度結合親和力，故可作靶向分子使用。另外，本研究裏採用的嫁接方法跟現時常用於只有胺官能團的MSN處理法不同：光敏劑和靶向份子是分別連接於MSN的胺和疊氮官能團上，故能避免光敏劑與靶向分子競爭。同時因為使用簡易的點擊化學反應，靶向分子的設計可以有更多選擇。 / 在水中，有和沒有表面修飾的MSN同樣有效地產生活性氧。對人工培植、並在細胞表面高度表達neuropilin的人類前列腺癌細胞PC-3而言，帶tLyP-1的MSN合成物有更高光毒性，其中的原因包括帶tLyP-1的MSN有更快的攝入初速。另外，自由的tLyP-1短肽可稍為抑制這種MSN合成物的細胞吸收，亦可見tLyP-1足以影響MSN的細胞攝入。可是，不論有沒有帶短肽，兩種以PEG修飾的MSN皆是因為沒有表面電荷而無法逃離細胞的溶酶體，以致其PDT效果改善幅度有限。所以在往後的研究，PEG的覆蓋量、長度和靶向分子的接連率需作進一步探討。 / OMSN是直徑約20納米均勻的圓形粒子。本研究亦會探討如何可以用OMSN作為多功能的染色劑載體。除了BODIPY光敏劑之外，另一個鋅酞菁和一個氮雜氟硼二吡咯的熒光顯影劑亦包裹在OMSN中。結果顯示，只有可以用介面活性劑溶解的染色劑才可以成功包進OMSN之內。OMSN內的染色劑基本上沒有聚合現象，故能發出強熒光，而包覆在光敏劑之內的光敏劑轉化氧作活性氧的效率跟介面活性劑配方的光敏劑一樣。 / 不論是鋅酞菁或BODIPY，包裹在OMSN內的光敏劑對在人工培植、及源自HeLa的KB癌細胞的PDT效果跟介面活性劑配方的光敏劑相若。因此，OMSN可替代活性介面劑作為光敏劑的載體。本研究亦嘗試在OMSN的表面上以葉酸作修飾。可是，即使用了表面上有大量的葉酸受體的KB細胞，葉酸修飾過的OMSN並沒有靶向性。另外，為了解決OMSN內吸附的染色劑會因粒子與血清蛋白的互動而漏出粒子外的問題，本研究亦嘗試將OMSN與BODIPY衍生的光敏劑以共價鍵連結。同時其表面亦以帶疊氮聚乙二醇層作修飾。可是，BODIPY光敏劑在以這些OMSN合成物內有嚴重的聚合現象，以致於活性氧產生和熒光亮度大幅度減弱。 / 總括來說，本研究內設計的BODIPY衍生的光敏劑皆可以用MSN或OMSN來承載，並成功送達至人工培植的癌細胞內。這些化合物的PDT效果往往媲美那些以介面活性劑配方的同類光敏劑。雖然證明了這些粒子表面可以予以修飾，其表面修飾層仍需要進一步的改善，以增強它們的靶向專一度和PDT功效。 / Yeung, Sin Lui. / Thesis Ph.D. Chinese University of Hong Kong 2015. / Includes bibliographical references (leaves 148-159). / Abstracts also in Chinese. / Title from PDF title page (viewed on 24, October, 2016). / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only.

published_or_final_version / abstract / Chemistry / Doctoral / Doctor of Philosophy

Organic semiconducting materials have been attracted considerable attention as a promising technology for the next generation flexible electronic devices, such as solar cells and field-effect transistors because of their advantages of low-cost, structural versatility and flexibility. Many organic semiconducting materials have been developed in recent years. In this thesis, four pi-conjugated building blocks based on benzodithiophene and quinoxalinedithienothiophene were applied to develop novel photovoltaic materials, including donor-acceptor alternating copolymers as a donor material for polymer solar cells, photosensitizers for dye sensitized solar cells, small molecule hole transporting materials for perovskite solar cells and small molecule acceptors for organic solar cells. A comprehensive review of current development of organic photovoltaic materials was presented in Chapter 1. In Chapter 2, a series of D-A copolymers (PBB-n) based on 4,7-di(thiophen-2-yl)benzo[c][1,2,5]thiadiazole and 4,5-bis((2-ethylhexyl)oxy)benzo[2,1-b:3,4-b'] dithiophene attached with different solubilizing side-chains were designed, synthesised and characterized. In general, PBB-n polymers showed good absorption in the region of visible light and UV region, indicating such polymers are a promising light harvester. Also, PBB-n exhibited suitable energy levels, suggesting that they could be applied as the donor materials in polymer solar cells. PBB-n also exhibited various extent of aggregation behaviour. Chapter 3 described syntheses and the fluorination effect of two series of fluoro-substituted PBB-n copolymers, namely PfBB-n and PffBB-n on optical, electrochemical, and optoelectronic properties. Among them, PfBB-n series was characterized with photovoltaic performance. The champion devices fabricated from PfBB-12 showed a PCE as high as 9.7%, with a Voc of 0.92 V, a Jsc of 16.60 mA/cm-2 and a FF of 63.49%. Cells fabricated from other PfBB-n copolymers also exhibited good PV performance with PCE ranging from 7.4 - 8.5%. For PffBB-n polymers, temperature-dependent aggregation behaviour was exploited by modulating the coating temperature during device fabrication. PSC devices based on PffBB-n exhibited good PV performance with PCE ranging from 7.4% to 9.9%. Among which, PffBB-14 provided the most promising PV performance with PCE of 9.9%, a Voc of 0.92 V, a Jsc of 16.8 mA/cm-2 and a FF of 64.36%. Electron deficient conjugated structure was seldom used as the π-bridge in metal-free photosensitizers. In Chapter 4, four novel organic photosensitizers, namely QC5-m and PC5-n were designed with an electron deficient π-bridge. Typical sandwich-structured DSSCs based on the newly developed photosensitizers exhibited promising photovoltaic performance with PCE ranging from 5.23 - 7.77 %, with a maximum Jsc as high as 15.63 mA cm-2. These results suggest that the use of electron deficient π-bridge provides alternative approach to construct efficient organic photosensitizers. Chapter 5 and Chapter 6 described the design, synthesis and investigation of novel hole-transporting materials and electron acceptor materials based on benzo[2,1-b:3,4-b']dithiophene-4,5-dione derived building blocks as potential organic photovoltaic materials for solar cell applications. Keywords: organic photovoltaic materials, photosensitizers, polymer solar cell, electron acceptor, hole-transporting materials.

O tratamento da doença periodontal consiste na remoção mecânica do biofilme, sendo que terapias complementares como a terapia fotodinâmica antimicrobiana (aPDT) podem melhorar os resultados obtidos. Este trabalho avaliou in vitro o efeito dos corantes azul de toluidina e azul de metileno com distintos parâmetros de laser (70; 100mW) e LED em Aggregatibacter actinomycetemcomitans (A.a) em suspensão. O primeiro experimento avaliou efeito bactericida de diferentes concentrações dos dois corantes sozinhos (0,05; 0,1; 0,5, 1,0; 2,0; 5,0; 10 mg/ml). O segundo foi dividido nos seguintes grupos: controles positivo e negativo (gentamicina), grupos somente com luz aplicada, grupos com três concentrações (0,05; 0,1; 10 mg/ml) de corante sozinhos ou associados ao laser de baixa intensidade (660 nm; 2,91 e 4,16 W/cm2; 70 e 100mW; 45 J/cm2; 0,024 cm2; 12 e 18s) e LED (627 ± 10 nm; 150mW/cm2; 10,5 mW; 20 J/cm2; 0,07cm2; 123s). Os dados foram analisados pelo teste ANOVA complementado por Tukey (p<0,05). Os resultados demonstraram que ambos os corantes na concentração de 10 mg/ml sozinhos ou associados com laser (ambas as potências) ou LED causaram 100 % de morte bacteriana semelhante ao controle negativo (p>0,05). Com isso, pode-se concluir que aPDT pode eliminar o A.a. de forma dependente da concentração do corante. / The main treatment of periodontal disease is the mechanical removal of biofilm. Adjuvant therapies as antimicrobial photodynamic therapy (aPDT) may offer better results. The aim of this in vitro study was to evaluate the effect of toluidine and methylene blue dyes, associated to red laser (70; 100mW) and LED on elimination of a suspension of Aggregatibacter actinomycetemcomitans (A.a). A first test evaluated the bactericidal effect of various concentrations of both dyes (0.05; 0.1; 0.5, 1.0; 2.0; 5.0, 10 mg/ml) in absence of light. In the second test, the experimental groups consisted of positive and negative (gentamicin) controls, groups with three concentrations (0.05; 0.1,10 mg/ml) of dyes alone of associated to low level laser (660 nm; 2.91 and 4.16 W/cm2; 70 and 100mW; 45 J/cm2; 0.024 cm2; 12 and 18s) and LED (627 ± 10 nm; 150mW/cm2; 10.5 mW; 20 J/cm2; 0.07cm2; 123s). Data were analyzed by ANOVA complemented by Tukeys test (p<0.05). The results showed that both dyes, with 10 mg/ml, alone or associated to laser and LED caused 100% of death as the negative control (p>0.05). It can be concluded that aPDT is capable of eliminate A.a depending of the dye concentration.