用于肿瘤光动力疗法的新型水溶性光敏剂的研究
摘要
恶性肿瘤是目前医药界急待攻克的难题,尽管现有的治疗手段如：手术、放化疗和免疫疗法一直在不断进步,可是我们仍需继续寻找对付肿瘤的新方法。光动力疗法(Photodynamic Therapy, PDT)是一种基于光敏剂、氧和激发光的微创肿瘤治疗技术,其中光敏剂是PDT治疗的关键。针对目前临床常用光敏剂存在的细胞摄取量低、代谢缓慢、缺乏靶向性和滞后的光毒性等问题,我们开展了新型光敏剂的研究。本论文涉及两个体系的新型水溶性光敏剂：氨基多羧酸修饰四苯基卟啉系列和糖基修饰氟硼二吡咯系列,研究它们的理化性质、体内外抗肿瘤活性和作用机制,以期开发高效、低毒的光动力抗肿瘤候选新药。
第一部分：氨基多羧酸修饰四苯基卟啉化合物的研究
化合物A1-9：①我们利用高效液相色谱法测定化合物A1-9的含量,结果表明化合物A1-9的含量均大于95%；②用紫外分光光度法测定化合物A1-9的光漂白速率、单线态氧产率和脂水分配系数,结果表明化合物A1-9的光稳定性好,单线态氧产率在0.41-0.61范围内,脂水分配系数在1.79-2.96之间；③用荧光分光光度法测定人肝癌细胞Hep G2、人胃癌细胞HGC-27、人胃腺癌细胞BGC：823和人非小细胞肺癌细胞A549对化合物A1-9的吸收量,结果表明给药浓度为201μM时,四种肿瘤细胞对化合物A1-9的药物吸收量均在0.1-0.4μM/1×104cells范围内；④用荧光显微镜和激光共聚焦显微镜观察化合物A1-9在上述四种肿瘤细胞中的定位情况,结果显示化合物A1-9主要定位于细胞溶酶体；⑤以上述四种肿瘤细胞为研究对象,用MTT法检测化合物A1-9对肿瘤细胞的光动力杀伤作用,结果表明化合物A1-9在1.25-20μM剂量范围内的暗毒性较小,而在光照条件下能显著抑制体外培养的人肝癌、胃癌和肺癌细胞的增殖,其中化合物A7效果最好,对四种肿瘤细胞的最大抑制率大于84%,IC50值小于0.89gM。
苗头化合物A10：①我们以人大细胞肺癌细胞NCI-H460、人骨肉瘤细胞U-2OS、人脐静脉内皮细胞ECV-304、人增生性瘢痕成纤维细胞FB和人永生化表皮细胞HaCat为研究对象,评价苗头化合物A10对肿瘤细胞和正常细胞的选择性杀伤作用,结果表明苗头化合物A10对两种肿瘤细胞的光毒性强,最大抑制率大于71%,IC50值小于6μM,对三种正常细胞的光毒性小,最大抑制率小于24%,IC50值大于20μM；②以人肝癌细胞Hep G2和人胃腺癌细胞BGC-823为研究对象,用流式细胞仪检测A10-PDT对肿瘤细胞凋亡和细胞周期的影响,结果表明A10-PDT可诱导人肝癌细胞Hep G2和人胃腺癌细胞BGC-823发生凋亡,将人肝癌细胞Hep G2阻滞于Go/Gl期,并且呈剂量依赖关系；③用等温滴定量热法和圆二色谱法探讨苗头化合物A10与牛血清白蛋白(BSA)的相互作用,结果表明苗头化合物A10与蛋白质BSA的作用力类型以氢键、范德华力和静电引力为主,可诱导BSA二级结构单元a-Helix的含量减少,β-Turn的含量增加；④用最大给药量法测试A10-PDT的急性毒性,结果表明A10-PDT无严重急性中毒的危险性；⑤以移植性Lewis肺癌小鼠、移植性肝癌H22小鼠、移植性人胃腺癌BGC-823裸小鼠为模型,评价苗头化合物A10的体内光动力治疗效果,结果表明给药剂量为20mg/kg时,A10-PDT对移植性Lewis肺癌小鼠的最大肿瘤抑制率为81.52%,对肝癌H22小鼠的最大肿瘤抑制率为95.15%,给药剂量为1Omg/kg和5mg/kg时,A10-PDT对人胃腺癌BGC-823裸小鼠的肿瘤生长有明显的抑制作用；⑥用荧光成像法和冰冻切片法探讨苗头化合物A10在荷瘤动物体内的组织分布情况,结果表明尾静脉注射24h,苗头化合物A10在各组织中的浓度大致为肿瘤>肝>肺>肾>脾>心,给药后12-48h肿瘤组织中的药物浓度处于较高水平。
第二部分：糖基修饰氟硼二吡咯化合物的研究
化合物B1-6：①我们用紫外分光光度法测定化合物B1-6的光漂白速率、单线态氧产率和脂水分配系数,结果表明化合物B1-6的光漂白速率较慢,单线态氧产率在0.073-0.29范围内,脂水分配系数在0.37-2.69之间；②用荧光显微镜和激光共聚焦显微镜观察化合物B1-6在入肝癌细胞Hep G2、人胃癌细胞HGC-27、人大细胞肺癌细胞NCI-H460和人肝细胞L02中的定位情况,结果显示化合物B1-6在细胞线粒体和溶酶体中均有分布；③以上述四种细胞为研究对象,用MTT法检测化合物B1-6对细胞的光动力杀伤作用,结果表明化合物B1-6在1.25-20μM剂量范围内结合激光照射能显著抑制体外培养的人肝癌、胃癌和肺癌细胞的增殖,对肝细胞的杀伤作用较肿瘤细胞小,其中化合物B3具有特殊的暗毒性,对肿瘤细胞的最大抑制率大于80%,IC50值小于0.18gM。
苗头化合物B3：①用寇氏法测试苗头化合物B3的小鼠急性毒性,结果表明B3的半数致死量为149.70mg/kg;②以移植性肝癌H22小鼠、移植性人肝癌Hep G2裸小鼠为模型,评价苗头化合物B3的体内抗肿瘤效果,结果表明给药剂量为10mg/kg时,B3对移植性肝癌H22小鼠的最大肿瘤抑制率为69.21%,给药剂量为10mg/kg和5mg/kg时,B3对人肝癌Hep G2裸小鼠的肿瘤生长有明显的抑制作用。
Tumor is a difficult problem for the medicinal world to conquer. Though a lot of progress have been achieved in traditional cancer therapeutic methods such as surgery, radiotherapy, chemotherapy and immunotherapy, however the practice demands more novel efficient approaches for caner treatment. Photodynamic therapy (PDT), a newly emerging non-invasive cancer treatment method is based on the combined interaction of photosensitizer, oxygen and light. While in this modality the crucial element is photosensitizer. Up to now the clinical photosensitizers still have some shortcomings, such as low cell uptake, slow metabolism, poor targeting and retarded phototoxicity, etc. Two new series of water-soluble photosensitive compounds synthesized in our laboratory are evaluated in this thesis:aminopolycarboxylic acid conjugated with tetraphenyl-porphyrins and saccharide conjugated with boron dipyrromethenes (BODIPY). The studies covers physical and chemical properties, in vitro and in vivo antitumor activity, antitumor mechanism. The goal of this work is to reveal structure-activity relationship of photosensitizers in these two chemical systems and to find high efficiency and low toxicity drug candidates for PDT.
Part one:Aminopolycarboxglic acid complexes with tetraphenylporphyrins
Compounds A1-9:①High performance liquid chromatography(HPLC) was exployed to perform the quantitative analysis of compounds A1-9, the results indicated that the purity of compound A1-9were over95%.②The photobleaching rate, singlet oxygen yield and lipid-water partition coefficient were studied by UV spectrophotometry, the results showed compound A1-9was stable to light illumination, singlet oxygen yield was among0.41-0.61and lipid-water partition coefficient was among1.79-2.96.③The cell uptake experiment was conducted for compound A1-9in cell line Hep G2(human hepatoma), cell line HGC-27(human gastric cancer), cell line BGC-823(human gastric cancer) and cell line A549(human non-small cell lung cancer) by the spectrofluorimetry, the results showed that they were similar in the four tumor cell lines at condition of0.1-0.4μM/1×104cells in20μM dosage.④Cellular localization of compound A1-9in the four tumor cell lines were observed by fluorescence microscopy and confocal laser scanning microscope, the results showed they mainly located in the lysosomes.⑤MTT experiments in above four tumor cell lines showed dark toxicity of compound A1-9was low during1.25-20μM, however followed with laser irradiation, these compounds could significantly inhibit the proliferation of liver, gastric and lung cancer cells, the best phototoxicity compound was A7, whose maximum inhibition rate in the four tumor cells were above84%and IC50below0.89μM respectively.
Compound A10is studied in more details as the hit compound:①The selective killing effect among tumor cells and normal cells were evaluated on cell line NCI-H460(human large cell lung cancer), cell line U-2OS (human osteosarcoma), cell line ECV-304(human umbilical vein endothelial), FB (human hypertrophic scar fibroblasts) and cell line HaCat (immortalized human epidermal), the results showed that A10-PDT could selectively kill tumor cells, whose maximum inhibition rates were above71%and IC50below6μM on two tumor cells, while maximum inhibition rates less than24%and IC50above20μM on three normal cells.②A10-PDT influenced on cell apoptosis and cell cycle were detected by flow cytometry, the results showed A10-PDT could make Hep G2cells blocked in G0/G1phase and induce cell line Hep G2and cell line BGC-823cells to apoptosis with dose-dependent relationship.③Generally pharmaceutical acts via interaction with protein, here BSA as model protein was chosen to investigate this interaction with hit compound A10by ITC and CD spectrum, the results showed hit compound A10could lead to the BSA secondary structural elements alpha-Helix content decrease and beta-Turn content increase via ensemble effect of hydrogen bonding, van der Waals force and electrostatic attraction.④Maximum dose as the index of acute toxicity on medicines was usually reported, here A10-PDT at2000mg/kg dose in Kunming mice showed A10-PDT had no risk of severe acute toxicity effects, while the working dose was20mg/kg. These results demonstrated A10-PDT is good enough for clinical application.⑤Mice bearing either H22liver cancer or Lewis lung cancer, nude mice bearing BGC-823respectively were used as animal model to evaluate A10-PDT in vivo, the results showed maximum tumor inhibition rate of A10-PDT on mice bearing Lewis lung cancer was81.52%, on H22liver cancer was95.15%at20mg/kg dosage. It could inhibit the tumor proliferation of nude mice bearing human gastric cancer BGC-823at5,10mg/kg respectively.⑥The tissue distribution of hit compound A10in tumor-bearing mice was explored by fluorescence imaging and frozen section method, the results showed after intravenous injection24h, the concentration of hit compound A10in the different organs decrease in the following order:tumor>liver>lung>kidney> spleen>heart, during12-48h the concentration of hit compound A10in tumor was at a high level.
Part two:Saccharide group complexes with boron dipyrromethenes
Compounds B1-6:①The photobleaching rate, singlet oxygen yield and lipid-water partition coefficient were studied by UV spectrophotometry, the results showed compound B1-6was stable to light illumination, singlet oxygen yield was among0.073-0.29and lipid-water partition coefficient was among0.37-2.69.②Cellular localization of compound B1-6in in cell line NCI-H460(human large cell lung cancer), cell line Hep G2(human hepatoma), cell line HGC-27(human gastric cancer), cell line LO2(human liver cell) were observed by fluorescence microscopy and confocal laser scanning microscope, the results showed these compounds located in both mitochondria and lysosomes.③MTT experiments in above four tumor cell lines showed compound B1-6followed with laser irradiation could significantly inhibit the proliferation of liver, gastric and lung cancer cells over80%at20μM dosage, while less than80%for liver cells. The above experiments indicated compound B3had special dark toxicity, whose maximum inhibition rate in the four tumor cells were above80%and IC50below0.18μM.
Compound B3is studied in more details as the antitumor chemical agent:①The acute toxicity of hit compound B3was tested by karber method, the results showed LD50of hit compound B3was149.70mg/kg.②Mice bearing H22liver cancer and nude mice bearing Hep G2were used as animal model to evaluate hit compound B3in vivo, the results showed maximum tumor inhibition rate of hit compound B3on mice bearing H22liver cancer was69.21%at10mg/kg dosage, and it could inhibit the tumor proliferation of nude mice bearing human liver cancer Hep G2at5,10mg/kg dosage respectively.
第一部分：氨基多羧酸修饰四苯基卟啉化合物的研究
化合物A1-9：①我们利用高效液相色谱法测定化合物A1-9的含量,结果表明化合物A1-9的含量均大于95%；②用紫外分光光度法测定化合物A1-9的光漂白速率、单线态氧产率和脂水分配系数,结果表明化合物A1-9的光稳定性好,单线态氧产率在0.41-0.61范围内,脂水分配系数在1.79-2.96之间；③用荧光分光光度法测定人肝癌细胞Hep G2、人胃癌细胞HGC-27、人胃腺癌细胞BGC：823和人非小细胞肺癌细胞A549对化合物A1-9的吸收量,结果表明给药浓度为201μM时,四种肿瘤细胞对化合物A1-9的药物吸收量均在0.1-0.4μM/1×104cells范围内；④用荧光显微镜和激光共聚焦显微镜观察化合物A1-9在上述四种肿瘤细胞中的定位情况,结果显示化合物A1-9主要定位于细胞溶酶体；⑤以上述四种肿瘤细胞为研究对象,用MTT法检测化合物A1-9对肿瘤细胞的光动力杀伤作用,结果表明化合物A1-9在1.25-20μM剂量范围内的暗毒性较小,而在光照条件下能显著抑制体外培养的人肝癌、胃癌和肺癌细胞的增殖,其中化合物A7效果最好,对四种肿瘤细胞的最大抑制率大于84%,IC50值小于0.89gM。
苗头化合物A10：①我们以人大细胞肺癌细胞NCI-H460、人骨肉瘤细胞U-2OS、人脐静脉内皮细胞ECV-304、人增生性瘢痕成纤维细胞FB和人永生化表皮细胞HaCat为研究对象,评价苗头化合物A10对肿瘤细胞和正常细胞的选择性杀伤作用,结果表明苗头化合物A10对两种肿瘤细胞的光毒性强,最大抑制率大于71%,IC50值小于6μM,对三种正常细胞的光毒性小,最大抑制率小于24%,IC50值大于20μM；②以人肝癌细胞Hep G2和人胃腺癌细胞BGC-823为研究对象,用流式细胞仪检测A10-PDT对肿瘤细胞凋亡和细胞周期的影响,结果表明A10-PDT可诱导人肝癌细胞Hep G2和人胃腺癌细胞BGC-823发生凋亡,将人肝癌细胞Hep G2阻滞于Go/Gl期,并且呈剂量依赖关系；③用等温滴定量热法和圆二色谱法探讨苗头化合物A10与牛血清白蛋白(BSA)的相互作用,结果表明苗头化合物A10与蛋白质BSA的作用力类型以氢键、范德华力和静电引力为主,可诱导BSA二级结构单元a-Helix的含量减少,β-Turn的含量增加；④用最大给药量法测试A10-PDT的急性毒性,结果表明A10-PDT无严重急性中毒的危险性；⑤以移植性Lewis肺癌小鼠、移植性肝癌H22小鼠、移植性人胃腺癌BGC-823裸小鼠为模型,评价苗头化合物A10的体内光动力治疗效果,结果表明给药剂量为20mg/kg时,A10-PDT对移植性Lewis肺癌小鼠的最大肿瘤抑制率为81.52%,对肝癌H22小鼠的最大肿瘤抑制率为95.15%,给药剂量为1Omg/kg和5mg/kg时,A10-PDT对人胃腺癌BGC-823裸小鼠的肿瘤生长有明显的抑制作用；⑥用荧光成像法和冰冻切片法探讨苗头化合物A10在荷瘤动物体内的组织分布情况,结果表明尾静脉注射24h,苗头化合物A10在各组织中的浓度大致为肿瘤>肝>肺>肾>脾>心,给药后12-48h肿瘤组织中的药物浓度处于较高水平。
第二部分：糖基修饰氟硼二吡咯化合物的研究
化合物B1-6：①我们用紫外分光光度法测定化合物B1-6的光漂白速率、单线态氧产率和脂水分配系数,结果表明化合物B1-6的光漂白速率较慢,单线态氧产率在0.073-0.29范围内,脂水分配系数在0.37-2.69之间；②用荧光显微镜和激光共聚焦显微镜观察化合物B1-6在入肝癌细胞Hep G2、人胃癌细胞HGC-27、人大细胞肺癌细胞NCI-H460和人肝细胞L02中的定位情况,结果显示化合物B1-6在细胞线粒体和溶酶体中均有分布；③以上述四种细胞为研究对象,用MTT法检测化合物B1-6对细胞的光动力杀伤作用,结果表明化合物B1-6在1.25-20μM剂量范围内结合激光照射能显著抑制体外培养的人肝癌、胃癌和肺癌细胞的增殖,对肝细胞的杀伤作用较肿瘤细胞小,其中化合物B3具有特殊的暗毒性,对肿瘤细胞的最大抑制率大于80%,IC50值小于0.18gM。
苗头化合物B3：①用寇氏法测试苗头化合物B3的小鼠急性毒性,结果表明B3的半数致死量为149.70mg/kg;②以移植性肝癌H22小鼠、移植性人肝癌Hep G2裸小鼠为模型,评价苗头化合物B3的体内抗肿瘤效果,结果表明给药剂量为10mg/kg时,B3对移植性肝癌H22小鼠的最大肿瘤抑制率为69.21%,给药剂量为10mg/kg和5mg/kg时,B3对人肝癌Hep G2裸小鼠的肿瘤生长有明显的抑制作用。
Tumor is a difficult problem for the medicinal world to conquer. Though a lot of progress have been achieved in traditional cancer therapeutic methods such as surgery, radiotherapy, chemotherapy and immunotherapy, however the practice demands more novel efficient approaches for caner treatment. Photodynamic therapy (PDT), a newly emerging non-invasive cancer treatment method is based on the combined interaction of photosensitizer, oxygen and light. While in this modality the crucial element is photosensitizer. Up to now the clinical photosensitizers still have some shortcomings, such as low cell uptake, slow metabolism, poor targeting and retarded phototoxicity, etc. Two new series of water-soluble photosensitive compounds synthesized in our laboratory are evaluated in this thesis:aminopolycarboxylic acid conjugated with tetraphenyl-porphyrins and saccharide conjugated with boron dipyrromethenes (BODIPY). The studies covers physical and chemical properties, in vitro and in vivo antitumor activity, antitumor mechanism. The goal of this work is to reveal structure-activity relationship of photosensitizers in these two chemical systems and to find high efficiency and low toxicity drug candidates for PDT.
Part one:Aminopolycarboxglic acid complexes with tetraphenylporphyrins
Compounds A1-9:①High performance liquid chromatography(HPLC) was exployed to perform the quantitative analysis of compounds A1-9, the results indicated that the purity of compound A1-9were over95%.②The photobleaching rate, singlet oxygen yield and lipid-water partition coefficient were studied by UV spectrophotometry, the results showed compound A1-9was stable to light illumination, singlet oxygen yield was among0.41-0.61and lipid-water partition coefficient was among1.79-2.96.③The cell uptake experiment was conducted for compound A1-9in cell line Hep G2(human hepatoma), cell line HGC-27(human gastric cancer), cell line BGC-823(human gastric cancer) and cell line A549(human non-small cell lung cancer) by the spectrofluorimetry, the results showed that they were similar in the four tumor cell lines at condition of0.1-0.4μM/1×104cells in20μM dosage.④Cellular localization of compound A1-9in the four tumor cell lines were observed by fluorescence microscopy and confocal laser scanning microscope, the results showed they mainly located in the lysosomes.⑤MTT experiments in above four tumor cell lines showed dark toxicity of compound A1-9was low during1.25-20μM, however followed with laser irradiation, these compounds could significantly inhibit the proliferation of liver, gastric and lung cancer cells, the best phototoxicity compound was A7, whose maximum inhibition rate in the four tumor cells were above84%and IC50below0.89μM respectively.
Compound A10is studied in more details as the hit compound:①The selective killing effect among tumor cells and normal cells were evaluated on cell line NCI-H460(human large cell lung cancer), cell line U-2OS (human osteosarcoma), cell line ECV-304(human umbilical vein endothelial), FB (human hypertrophic scar fibroblasts) and cell line HaCat (immortalized human epidermal), the results showed that A10-PDT could selectively kill tumor cells, whose maximum inhibition rates were above71%and IC50below6μM on two tumor cells, while maximum inhibition rates less than24%and IC50above20μM on three normal cells.②A10-PDT influenced on cell apoptosis and cell cycle were detected by flow cytometry, the results showed A10-PDT could make Hep G2cells blocked in G0/G1phase and induce cell line Hep G2and cell line BGC-823cells to apoptosis with dose-dependent relationship.③Generally pharmaceutical acts via interaction with protein, here BSA as model protein was chosen to investigate this interaction with hit compound A10by ITC and CD spectrum, the results showed hit compound A10could lead to the BSA secondary structural elements alpha-Helix content decrease and beta-Turn content increase via ensemble effect of hydrogen bonding, van der Waals force and electrostatic attraction.④Maximum dose as the index of acute toxicity on medicines was usually reported, here A10-PDT at2000mg/kg dose in Kunming mice showed A10-PDT had no risk of severe acute toxicity effects, while the working dose was20mg/kg. These results demonstrated A10-PDT is good enough for clinical application.⑤Mice bearing either H22liver cancer or Lewis lung cancer, nude mice bearing BGC-823respectively were used as animal model to evaluate A10-PDT in vivo, the results showed maximum tumor inhibition rate of A10-PDT on mice bearing Lewis lung cancer was81.52%, on H22liver cancer was95.15%at20mg/kg dosage. It could inhibit the tumor proliferation of nude mice bearing human gastric cancer BGC-823at5,10mg/kg respectively.⑥The tissue distribution of hit compound A10in tumor-bearing mice was explored by fluorescence imaging and frozen section method, the results showed after intravenous injection24h, the concentration of hit compound A10in the different organs decrease in the following order:tumor>liver>lung>kidney> spleen>heart, during12-48h the concentration of hit compound A10in tumor was at a high level.
Part two:Saccharide group complexes with boron dipyrromethenes
Compounds B1-6:①The photobleaching rate, singlet oxygen yield and lipid-water partition coefficient were studied by UV spectrophotometry, the results showed compound B1-6was stable to light illumination, singlet oxygen yield was among0.073-0.29and lipid-water partition coefficient was among0.37-2.69.②Cellular localization of compound B1-6in in cell line NCI-H460(human large cell lung cancer), cell line Hep G2(human hepatoma), cell line HGC-27(human gastric cancer), cell line LO2(human liver cell) were observed by fluorescence microscopy and confocal laser scanning microscope, the results showed these compounds located in both mitochondria and lysosomes.③MTT experiments in above four tumor cell lines showed compound B1-6followed with laser irradiation could significantly inhibit the proliferation of liver, gastric and lung cancer cells over80%at20μM dosage, while less than80%for liver cells. The above experiments indicated compound B3had special dark toxicity, whose maximum inhibition rate in the four tumor cells were above80%and IC50below0.18μM.
Compound B3is studied in more details as the antitumor chemical agent:①The acute toxicity of hit compound B3was tested by karber method, the results showed LD50of hit compound B3was149.70mg/kg.②Mice bearing H22liver cancer and nude mice bearing Hep G2were used as animal model to evaluate hit compound B3in vivo, the results showed maximum tumor inhibition rate of hit compound B3on mice bearing H22liver cancer was69.21%at10mg/kg dosage, and it could inhibit the tumor proliferation of nude mice bearing human liver cancer Hep G2at5,10mg/kg dosage respectively.
引文
[1]Agostinis P, Berg K, Cengel K A, et al. Photodynamic therapy of cancer:an update[J]. CA Cancer J Clin,2011,61(4):250-281.
[2]Badawi A M. Important facts about cancer prevention[M]. Bloomington:Trafford Publishing,2012:17.
[3]Jemal A, Bray F, Center M M, et al. Global cancer statistics[J]. CA Cancer J Clin, 2011,61(2):69-90.
[4]Siegel R, Naishadham D, Jemal A. Cancer Statistics,2012[J]. CA Cancer J Clin, 2012,62(1):10-29.
[5]赫洁,赵平,陈万清.2012中国肿瘤登记年报[M].北京：军事医学科学出版社,2012：1-5.
[6]Dougherty T J, Kaufman J E, Goldfarb A, et al. Photoradiation therapy for the treatment of malignant tumors[J]. Cancer Res,1978,38 (8):2628-2635.
[7]Dougherty T J, Boyle D G, Weishaupt K R, et al. Photoradiation therapy—clinical and drug advances[J]. Adv Exp Med Biol,1983,160:3-13.
[8]Dougherty T J. Photodynamic therapy(PDT) of malignant tumors[J]. Crit Rev Oncol Hematol,1984,2(2):83-116.
[9]Dougherty T J. An overview of the status of photoradiation therapy [J]. Prog Clin Biol Res,1984,170:75-87.
[10]Dougherty T J. Photodynamic therapy[J]. Photochem Photobiol,1993,58(6):895-900.
[11]Dolmans D E, Fukumura D, Jain R K. Photodynamic therapy for cancer[J]. Nat Rev Cancer,2003,3(5):380-387.
[12]Kato H. History of photodynamic therapy--past, present and future[J]. Gan To Kagaku Ryoho,1996,23(1):8-15.
[13]Dougherty T J, Gomer C J, Henderson B W, et al. Photodynamic therapy[J]. J Natl Cancer Inst,1998,90(12):889-905.
[14]Dougherty T J. An update on photodynamic therapy applications[J]. J Clin Laser Med Surg,2002,20(1):3-7.
[15]Moan J, Peng Q. An outline of the hundred-year history of PDT[J]. Anticancer Res, 2003,23(5A):2591-3600.
[16]Kessel D. Adventures in photodynamic therapy:1976-2008[J]. J Porphyr Phthalocyanines,2008,12(8):877-880.
[17]刘凡光,李晓松.光动力疗法在中国[J].中国激光医学杂志,2005,14(1)：72.
[18]李黎波,李文敏,项蕾红,等.光动力疗法在中国的应用与临床研究[J].中国激光医学杂志,2012,21(5)：278-307.
[19]范开华,陈军.光敏剂在光动力学疗法中的研究进展[J].中国药房,2010,21(30)：2870-2873.
[20]廖旺军.临床肿瘤光动力治疗学[M].北京：人民军医出版社,2006：1-6.
[21]Wilson B C. Photodynamic therapy for cancer:principles [J]. Can J Gastroenterol, 2002,16(6):393-396.
[22]Juarranz A, Jaen P, Sanz-Rodriquez F, et al. Photodynamic therapy of cancer. Basic principles and applications[J]. Clin Transl Oncol,2008,10(3):148-154.
[23]Juzeniene A, Nielsen K P, Moan J. Biophysical aspects of photodynamic therapy[J]. J Environ Pathol Toxicol Oncol,2006,25(1):7-28.
[24]Niedre M, Patterson M S, Wilson B C. Direct near-infrared luminescence detection of singlet oxygen generated by photodynamic therapy in cells in vitro and tissues in vivo [J]. Photochem Photobiol,2002,75(4):382-391.
[25]Wright A, Bubb W A, Hawkins C L, et al. Singlet oxygen-mediated protein oxidation:evidence for the formation of reactive side chain peroxides on tyrosine residues[J]. Photochem Photobiol,2002,76(1):35-46.
[26]Castano A P, Mroz P, Hamblin M R. Photodynamic therapy and anti-tumor immunity[J]. Nat Rev Cancer,2006,6(7):535-545.
[27]Korbelik M. PDT-associated host response and its role in the therapy outcome[J]. Lasers Surg Med,2006,38(5):500-508.
[28]Buytaert E, Dewaele M, Agostinis P. Molecular effectors of multiple cell death pathways initiated by photodynamic therapy[J]. Biochim Biophys Acta,2007,1176(1): 86-107.
[29]Vrouenraets M B, Visser G W, Snow G B, et al. Basic principles, applications in oncology and improved selectivity of photodynamic therapy[J]. Anticancer Res, 2003,23(1B):505-522.
[30]Gudgin-Dickson E F, Goyan R L, Pottier R H. New directions in photodynamic therapy[J]. Cell Mol Biol,2002,42(8):939-954.
[31]顾瑛.光动力疗法[M].北京：人民卫生出版社,2012：1-10.
[32]Zheng H. A Review of progress in clinical photodynamic therapy[J]. Technol Cancer Res Treat,2005,4(3):283-293.
[33]Moser J G. Photodynamic tumor therapy.2nd and 3rd generation photosensitizers [M]. London:Harwood Academic Publishers,1997:3-8.
[34]Wohrle D, Hirth A, Bogdahn-Rai T, et al. Photodynamic therapy of cancer:second and third generations of photosensitizers [J]. Russ Chem Bull,1998,47(5):807-816.
[35]Detty M R, Gibson S L, Wagner S J. Current clinical and preclinical photosensitizers for use in photodynamic therapy[J]. J Med Chem,2004,47(16):3897-3915.
[36]Allison R R, Downie G H, Cuenca R, et al. Photosensitizer in clinical PDT[J]. Photodiag Photodyn Therapy,2004,1(1):27-42.
[37]Savellano M D, Hasan T. Photochemical targeting of epidermal growth factor receptor:a mechanistic study[J]. Clin Cancer Res,2005,11(4):1658-1668.
[38]Mallikaratchy P, Tang Z W, Tan W H. Cell specific aptamer-photosensitizer conjugates as a molecular tool in photodynamic therapy [J]. Chem Med Chem,2008,3(3): 425-428.
[39]Pushpan S K, Venkatraman S, Anand V G, et al. Porphyrins in photodynamic therapy---a search for ideal photosensitizers[J]. Curr Med Chem Anticancer Agents, 2002,2(2):187-207.
[40]Shuler M F, Borrillo J L, Ho A C. Photodynamic therapy update[J]. Curr Opin Ophthalmol,2001,12(3):202-206.
[41]Ormrod D, Jarvis B. Topical aminolevulinic acid HC1 photodynamic therapy [J]. Am J Clin Dermatol,2000,1(2):133-141.
[42]陶然,顾瑛,刘凡光,等.血啉甲醚体外光敏反应机制研究[J].中国激光医学杂志,2002,11(3)：149-152.
[43]Boch R, Canaan A J, Cho A, et al. Cellular and antitumor activity of a new diethylene glycol benzoporphyrin derivative (Lemuteporfin)[J]. Photochem Photobiol, 2006,82(1):219-224.
[44]Hunt D W, Boivin W A, Fairley L A, et al. Ultraviolet B light stimulates interleukin-20 expression by human epithelial keratinocytes[J]. Photochem Photobiol, 2006,82(5):1292-1300.
[45]Lim S H, Thivierge C, Nowak-Sliwinska P, et al. In vitro and in vivo photocytotoxicity of boron dipyrromethene derivatives for photodynamic therapy [J]. J Med Chem,2010,53(7):2865-2874.
[46]He H, Lo P C, Yeung S L, et al. Synthesis and vitro photodynamic activities of pegylated distyryl boron dipyrromethene derivatives [J]. J Med Chem,2011,54(8): 3097-3102.
[47]Deng H, Liu X, Xie J, et al. Quantitative and site-directed chemical modification of hypocrellins toward direct drug delivery and effective photodynamic activity[J]. J Med Chem,2012,55(5):1910-1919.
[48]De Rosa F S, Bentley M V. Photodynamic therapy of skin cancers:sensitizers, clinical studies and future directives [J]. Pharm Res,2000,17(12):1447-1455.
[49]Castano A P, Demidova T N, Hamblin M R. Mechanisms in photodynamic therapy: Part one-photosensitizers, photochemistry and cellular localization[J]. Photodiagnosis Photodyn Ther,2004,1(4):279-293.
[50]陈杰波,欧敏锐,李忠琴,等.光动力治疗药物——光敏剂的研究进展[J].海峡药学,2003,15(6)：8-12.
[51]史宏敏.激光医学基础[M].广州：华南理工大学出版社,1990：32-62.
[52]黄卓正,李俊亨.现代激光医学[M].广西：广西科学技术出版社,1996：116-130.
[53]Verdaasdonk R M, van Swol C F. Laser light delivery systems for medical applications[J]. Phys Med Biol,1997,42(5):869-894.
[54]van den Bergh H. On the evolution of some endoscopic light delivery systems for photodynamic therapy [J]. Endoscopy,1998,30(4):392-407.
[55]Nichols M G, Foster T H. Oxygen diffusion and reaction kinetics in the photodynamic therapy of multicell tumor spheroids[J]. Phys Med Biol,1994,39(12): 2161-2181.
[56]Schunck T, Poulet P. Oxygen consumption through metabolish and photodynamic reactions in cells cultured on microbeads[J]. Phys Med Biol,2000,45(1):103-119.
[57]Foote C S. Definition of type Ⅰ and type Ⅱ photosensitized oxidation[J]. Photochem Photobiol,1991,54(5):659.
[58]Coulter A. The status of photodynamic therapy research:an overview of current and future cancer clinical treatments[J]. J Clin Laser Med Surg,1990,8(4):2-11.
[59]Keller S M. Photodynamic therapy. Biology and clinical application[J]. Chest Surg Clin N Am,1995,5(1):121-137.
[60]Qiang Y G, Zhang X P, Li J, et al. Photodynamic therapy for malignant diseases: clinical investigation and application[J]. Chin Med J,2006,119(10):845-857.
[1]郭江红.新型两亲性光敏剂的合成与光学性质研究[D].北京：北京协和医学院,2012：12-27.
[2]Bhaumik J, Weissleder R, McCarthy J R. Synthesis and photophysical properties of sulfonamidophenyl porphyrins as models for activatable photosensitizers[J]. J Org Chem, 2009,74(16):5894-5901.
[3]Banfi S, Caruso E, Buccafurni L, et al. Comparison between 5,10,15,20-tetraaryl-and 5,15-diarylporphyrins as photosensitizers:synthesis, photodynamic activity, and quantitative structure-activity relationship modeling[J]. J Med Chem,2006,49(11): 3293-3304.
[4]Peng C L, Lai P S, Chang C C, et al. The synthesis and photodynamic properties of meso-substituted, cationic porphyrin derivatives in HeLa cells[J]. Dyes Pigm,2010,84(1): 140-147.
[5]韩锐.抗癌药物研究与实验技术[M].北京：北京医科大学中国协和医科大学联合出版社,1997：271-273.
[6]Zheng X, Morgan J, Pandey S K, et al. Conjugation of 2-(1'-hexyloxyethyl)-2-devinylpyrophephorbide-a (HPPH) to carbohydrates changes its subcellular distribution and enhances photodynamic activity in vivo[J], J Med Chem,2009,52(14):4306-4318.
[7]Huang Y Y, Mroz P, Zhiyentayev T, et al. In vitro photodynamic therapy and quantitative structure-activity relationship studies with stable synthetic near-infrared-absorbing bacteriochlorin photosensitizers[J]. J Med Chem,2010,53(10):4018-4027.
[8]Hammer N D, Lee S, Vesper B J, et al. Charge dependence of cellular uptake and selective antitumor activity of porphyrazines[J]. J Med Chem,2005,48(26):8125-8133.
[9]Schmitt F, Govindaswamy P, Suss-Fink G, et al. Ruthenium porphyrin compounds for photodynamic therapy [J]. J Med Chem,2008,51(6):1811-1816.
[10]魏伟,吴希美,李元建.药理实验方法学[M].北京：人民卫生出版社,2010：1566-1569.
[11]Lei W, Xie J, Hou Y, et al. Mitochondria-targeting properties and photodynamic activities of porphyrin derivatives bearing cationic pendant[J]. J Photochem Photobiol, 2010,98(2):167-171.
[12]Shi Z H, Wang Y H, Fu C G. Study on retention behavior of metal-tetraphenyl porphine chelates in reverse-phase high performance liquid chromatography[J]. Se Pu, 2000,18(1):27-29.
[13]夏梅君,申琦,郭九吉,等.取代四苯基卟啉的紫外、荧光光谱及电化学性质[J].郑州大学学报(理学版),2010,42(4)：83-87.
[14]左国防,雷新有,杜捷,等.系列卟啉化合物的合成及其光谱和电化学性质的研究[J].光谱实验室,2008,25(3)：290-296.
[15]顾瑛.光动力疗法[M].北京：人民卫生出版社,2012：224-240.
[16]Kogan B Y. Nonlinear photodynamic therapy. Saturation of a photochemical dose by photosensitizer bleaching[J], Photochem Photobiol Sci,2003,2(6):673-676.
[17]Dysart J S, Patterson M S. Characterization of Photofrin photobleaching for singlet oxygen dose estimation during photodynamic therapy of MLL cells in vitro [J]. Phys Med Biol,2005,50(11):2597-2616.
[18]Dysart J S, Patterson M S. Photobleaching kinetics, photoproduct formation, and dose estimation during ALA induced PpIX PDT of MLL cells under well oxygenated and hypoxic conditions[J]. Photochem Photobiol Sci,2006,5(1):73-81.
[19]Kochevar I E. Singlet Oxygen signaling:from intimate to global[J]. Sci STKE,2004, 221:7.
[20]吕庆銮,张苗,岳宁宁,等.单线态氧的检测及分析应用研究进展[J].化学分析计量,2008,17(3)：74-77.
[21]黄显雯,吕汪洋,姚玉元,等.pH敏感锌酞菁聚合物的制备及光活性[J].浙江理工大学学报,2010,27(1)：1-5.
[22]Hirakawa K, Hirano T, Nishimura Y, et al. Dynamics of singlet oxygen generation by DNA-binding photosensitizers[J]. J Phys Chem B,2012,116(9):3037-3044.
[23]Yuan J, Mahama-Relue P A, Fournier R L, et al. Predictions of mathematical models of tissue oxygenation and generation of singlet oxygen during photodynamic therapy[J]. RadiatRes,1997,148(4):386-394.
[24]Box K J, Comer J E. Using measured pKa, LogP and solubility to investigate supersaturation and predict BCS class[J]. Curr Drug Metab,2008,9(9):869-878.
[25]Igarashi K, Kashiwaqi K. Modulation of cellular function by polyamines[J]. Int J Biochem Cell Biol,2010,42(1):39-51.
[26]Chan W S, Svensen R, Phillips D, et al. Cell uptake, distribution and response to aluminium chloro sulphonated phthalocyanine, a potential anti-tumour photosensitizer[J]. Br J Cancer,1986,53(2):255-263.
[27]Daly R, Vaz G, Davies A M, et al. Synthesis and biological evaluation of a library of glycoporphyrin compounds[J]. Chemistry,2012,18(46):14671-14679.
[28]Glidden M D, Celli J P, Massodi I, et al. Image-Based Quantification of Benzoporphyrin Derivative Uptake, Localization, and Photobleaching in 3D Tumor Models, for Optimization of PDT Parameters[J]. Theranostics,2012,2(9):827-839.
[29]Nakayama K, Katoh Y, Tamura M. "Triple Observation Method (TOM)" to discriminate optically autofluorescence from porphyrins versus that from copper-metallothioneins[J]. J Fluoresc,2011,21(2):835-839.
[30]Lassalle H P, Wagner M, Bezdetnaya L, et al. Fluorescence imaging of Foscan and Foslip in the plasma membrane and in whole cells[J]. J Photochem Photobiol B, 2008,92(1):47-53.
[31]Kinzler I, Haseroth E, Hauser C, et al. Role of mitochondria in cell death induced by Photofrin-PDT and ursodeoxycholic acid by means of SLIM[J]. Photochem Photobiol Sci,2007,6(12):1332-1340.
[32]Maftoum-Costa M, Naves K T, Oliveira A L, et al. Mitochondria, endoplasmic reticulum and actin filament behavior after PDT with chloroaluminum phthalocyanine liposomal in HeLa cells[J]. Cell Biol Int,2008,32(8):1024-1028.
[33]Caruso J A, Mathieu P A, Joiakim A, et al. Differential susceptibilities of murine hepatoma lclc7 and Tao cells to the lysosomal photosensitizer NPe6:influence of aryl hydrocarbon receptor on lysosomal fragility and protease contents[J]. Mol Pharmacol, 2004,65(4):1016-1028.
[34]戴维德,王雷,刘凡光,等.高分辨率荧光显微成像技术在光敏剂亚细胞定位研究中的应用[J].中国激光医学杂志,2004,13(4)：240-245.
[35]Edwards B K, Brown M L, Wingo P A, et al. Annual report to the nation on the status of cancer,1975-2002, featuring population-based trends in cancer treatment[J]. J Natl Cancer Inst,2005,97(19):1407-1427.
[36]Van M J, Kaspers G J, Cloos J. Cell sensitivity assays:the MTT assay [J]. Methods Mol Biol,2011,731:237-245.
[37]陈靖京,王玉茂,刘天军.新型卟啉类光敏药物介导的PDT对两种胃癌细胞HGC27和MGC803的杀伤效应[J].国际生物医学工程杂志,2011,34(3)：154-166.
[38]陈靖京.卟啉类光敏抗肿瘤化合物评价[[)].北京：北京协和医学院,2011：23-44.
[39]曹波.新型水溶性光敏剂的评价和机制研究[D].北京：北京协和医学院,2012：20-50.
[40]Sieuwerts A M, Klijn J G, Peters H A, et al. The MTT tetrazolium salt assay scrutinized:how to use this assay reliably to measure metabolic activity of cell cultures in vitro for the assessment of growth characteristics, IC50-values and cell survival[J]. Eur J Clin Chem Clin Biochem,1995,33(11):813-823.
[1]陈靖京,王玉茂,刘天军.新型卟啉类光敏药物介导的PDT对两种胃癌细胞HGC27和MGC803的杀伤效应[J].国际生物医学工程杂志,2011,34(3)：154-166.
[2]陈靖京.卟啉类光敏抗肿瘤化合物评价[D].北京：北京协和医学院,2011：23-44.
[3]陈靖京,魏武,纪爱芳,等.新型光敏药物对胃癌MGC803细胞的光动力治疗研究[J].中华胃肠外科杂志,2012,15(12)：1291-1295.
[4]曹波.新型水溶性光敏剂的评价和机制研究[D].北京：北京协和医学院,2012：20-50.
[5]Gollnick S O, Owczarczak B, Maier P. Photodynamic therapy and antitumor immunity[J]. Lasers Surg Med,2006,38(5):509-515.
[6]Kralova J, Briza T, Moserova I, et al. Glycol porphyrin derivatives as potent photodynamic inducers of apoptosis in tumor cells[J]. J Med Chem,2008,51(19): 5964-5973.
[7]Lv F, Cao B, Cui Y, et al. Zinc phthalocyanine labelled polyethylene glycol: preparation, characterization, interaction with bovine serum albumin and near infrared fluorescence imaging in vivo[J]. Molecules,2012,17(6):6348-6361.
[8]王冬冬,孙德志,李林尉,等.5-氟尿嘧啶与牛血清白蛋白的相互作用[J].物理化学学报,2007,23(10)：1627-1630.
[9]魏伟,吴希美,李元建.药理实验方法学[M].北京：人民卫生出版社,2010：1566-1569.
[10]Pecaut M J, Dutta-Roy R, Smith A L, et al. Acute effects of iron-particle radiation on immunity. Part I Population distribution[J]. Radiat Res,2006,165(1):68-77.
[11]郑景存CDHS801光动力学杀伤膀胱癌机理的试验研究[D].上海：复旦大学,2005：55-60.
[12]Chen L, He Z, Qin L, et al. Antitumor effect of malaria parasite infection in a murine Lewis lung cancer model through induction of innate and adaptive immunity [J]. PLoS One,2011,6(9):24407.
[13]Zhang H, Ma W, Li Y. Generation of effective vaccines against liver cancer by using photodynamic therapy[J]. Lasers Med Sci,2009,24(4):549-552.
[14]Jin I, Yuji M, Yoshinori N, et al. Anti-tumor effect of PDT using Photofrin in a mouse angiosarcoma model[J]. Arch Dermatol Res,2008,300(4):161-166.
[15]Lv F, Li Y, Cao B, et al. Galactose substituted zinc phthalocyanines as near infrared fluorescence probes for liver cancer imaging[J]. J Mater Sci Mater Med,2013,24(3): 811-819.
[16]Gultekin E, Gultekin O E, Cingillioglu B, et al. The value of frozen section evaluation in the management of borderline ovarian tumors[J]. J Cancer Res Ther, 2011,7(4):416-420.
[17]Wyld L, Reed M W, Brown N J. Differential cell death response to photodynamic therapy is dependent on dose and cell type[J]. Br J Cancer,2001,84(10):1384-1386.
[18]Dahl T A. Direct exposure of mammalian cells to pure exogenous singlet oxygen (1 delta gO2)[J]. Photochem Photobiol,1993,57(2):248-254.
[19]Pedersen B W, Sinks L E, Breitenbach T, et al. Single cell responses to spatially controlled photosensitized production of extracellular singlet oxygen[J]. Photochem Photobiol,2011,87(5):1077-1091.
[20]Agarwal M L, Clay M E, Harvey E J, et al. Photodynamic therapy induces rapid cell death by apoptosis in L5178Y mouse lymphoma cells[J]. Cancer Res,1991 51(21): 5993-5996.
[21]Bourre L, Rousset N, Thibaut S, et al. PDT effects of m-THPC and ALA, phototoxicity and apoptosis[J]. Apoptosis,2002,7(3):221-230.
[22]杨铭.抗肿瘤抗病毒药物与核酸相互作用的分子机制[M].北京：北京大学医学出版社,2009：359-361.
[23]Fan F, Nie S, Yang D, et al. Labeling lysosomes and tracking lysosome-dependent apoptosis with a cell-permeable activity-based probe[J]. Bioconjug Chem,2012,23(6): 1309-1317.
[24]瑞菲尔·努纳兹.流式细胞术原理与科研应用简明手册[M].北京：化学工业出版社,2005：27-32.
[25]刘力华,黄明辉,张宏波,等.血卟琳单甲醚光敏剂光动力学疗法对人乳腺肿瘤细胞生长周期的阻滞作用及其凋亡研究[J].中国综合临床,2011,27(9)：945-947.
[26]Komatsu T, Nakagawa A, Qu X. Structural and mutagenic approach to create human serum albumin-based oxygen carrier and photosensitizer[J]. Drug Metab Pharmacokinet, 2009,24(4):287-299.
[27]高岭,曹洪玉,刘阁.4种金属卟啉配合物与血清白蛋白作用的光谱研究[J].化学试剂,2012,34(2)：108-112.
[28]Singh SK, Kishore N. Calorimetric and spectroscopic studies on the interaction of methimazole with bovine serum albumin[J]. J Pharm Sci,2008,97(6):2362-2372.
[29]Zhao P, Huang J W, Ji L N. Cationic pyridinium porphyrins appending different peripheral substituents:spectroscopic studies on their interactions with bovine serum albumin[J]. Spectrochim Acta A Mol Biomol Spectrosc,2012,88:130-136.
[30]顾瑛.光动力疗法[M].北京：人民卫生出版社,2012：224-240.
[1]Frimannsson D O, Grossi M, Murtagh J, et al. Light induced antimicrobial properties of a brominated boron difluoride (BF2) chelated tetraarylazadipyrromethene photosensitizer[J]. J Med Chem,2010,53(20):7337-7343.
[2]Yogo T, Urano Y, Ishitsuka Y, et al. Highly efficient and photostable photosensitizer based on BODIPY chromophore[J]. J Am Chem Soc,2005,127(35):12162-12163.
[3]Caruso E, Banfi S, Barbieri P, et al. Synthesis and antibacterial activity of novel cationic BODIPY photosensitizers[J], J Photochem Photobiol B,2012,114:44-51.
[4]Lim S H, Thivierge C, Nowak-Sliwinska P, et al. In vitro and in vivo photocytotoxicity of boron dipyrromethene derivatives for photodynamic therapy [J]. J Med Chem,2010,53(7):2865-2874.
[5]He H, Lo P C, Yeung S L, et al. Synthesis and in vitro photodynamic activities of pegylated distyryl boron dipyrromethene derivatives[J]. J Med Chem,2011,54(8): 3097-3102.
[6]顾瑛.光动力疗法[M].北京：人民卫生出版社,2012：224-240.
[7]Kamkaew A, Lim S H, Lee H B, et al. BODIPY dyes in photodynamic therapy[J]. Chem Soc Rev,2013,42(1):77-88.
[1]Ronny P, Justin R G, Janelle N L, et al. Synthesis of aza-BODIPY boron difluoride PDT agents to promote apoptosis in HeLa cells[J]. Lett Org Chem,2011,8(6):368-373.
[2]Shukla S, Skoumbourdis A P, Walsh M J, et al. Synthesis and characterization of a BODIPY conjugate of the BCR-ABL kinase inhibitor Tasigna (nilotinib):evidence for transport of Tasigna and its fluorescent derivative by ABC drug transporters [J]. Mol Pharm,2011,8(4):1292-1302.
[3]Ono M, Watanabe H, Kimura H, et al. BODIPY-based molecular probe for imaging of cerebral β-amyloid plaques[J]. ACS Chem Neurosci,2012,3(4):319-324.
[4]陈美娟,肖顺汉,冯文宇,等.青银注射液静脉、腹腔注射对小鼠半数致死量(LDso)的测定[J].泸州医学院学报,2007,30(5)：349-351.
[5]深泽天,杨觅,禹立霞,等.紫杉类药物温敏纳米胶束的小鼠LD50及其毒性差异[J].江苏医药,2008,34(1)：56-58.
[6]魏伟,吴希美,李元建.药理实验方法学[M].北京：人民卫生出版社,2010：1566-1569.
[2]Badawi A M. Important facts about cancer prevention[M]. Bloomington:Trafford Publishing,2012:17.
[3]Jemal A, Bray F, Center M M, et al. Global cancer statistics[J]. CA Cancer J Clin, 2011,61(2):69-90.
[4]Siegel R, Naishadham D, Jemal A. Cancer Statistics,2012[J]. CA Cancer J Clin, 2012,62(1):10-29.
[5]赫洁,赵平,陈万清.2012中国肿瘤登记年报[M].北京：军事医学科学出版社,2012：1-5.
[6]Dougherty T J, Kaufman J E, Goldfarb A, et al. Photoradiation therapy for the treatment of malignant tumors[J]. Cancer Res,1978,38 (8):2628-2635.
[7]Dougherty T J, Boyle D G, Weishaupt K R, et al. Photoradiation therapy—clinical and drug advances[J]. Adv Exp Med Biol,1983,160:3-13.
[8]Dougherty T J. Photodynamic therapy(PDT) of malignant tumors[J]. Crit Rev Oncol Hematol,1984,2(2):83-116.
[9]Dougherty T J. An overview of the status of photoradiation therapy [J]. Prog Clin Biol Res,1984,170:75-87.
[10]Dougherty T J. Photodynamic therapy[J]. Photochem Photobiol,1993,58(6):895-900.
[11]Dolmans D E, Fukumura D, Jain R K. Photodynamic therapy for cancer[J]. Nat Rev Cancer,2003,3(5):380-387.
[12]Kato H. History of photodynamic therapy--past, present and future[J]. Gan To Kagaku Ryoho,1996,23(1):8-15.
[13]Dougherty T J, Gomer C J, Henderson B W, et al. Photodynamic therapy[J]. J Natl Cancer Inst,1998,90(12):889-905.
[14]Dougherty T J. An update on photodynamic therapy applications[J]. J Clin Laser Med Surg,2002,20(1):3-7.
[15]Moan J, Peng Q. An outline of the hundred-year history of PDT[J]. Anticancer Res, 2003,23(5A):2591-3600.
[16]Kessel D. Adventures in photodynamic therapy:1976-2008[J]. J Porphyr Phthalocyanines,2008,12(8):877-880.
[17]刘凡光,李晓松.光动力疗法在中国[J].中国激光医学杂志,2005,14(1)：72.
[18]李黎波,李文敏,项蕾红,等.光动力疗法在中国的应用与临床研究[J].中国激光医学杂志,2012,21(5)：278-307.
[19]范开华,陈军.光敏剂在光动力学疗法中的研究进展[J].中国药房,2010,21(30)：2870-2873.
[20]廖旺军.临床肿瘤光动力治疗学[M].北京：人民军医出版社,2006：1-6.
[21]Wilson B C. Photodynamic therapy for cancer:principles [J]. Can J Gastroenterol, 2002,16(6):393-396.
[22]Juarranz A, Jaen P, Sanz-Rodriquez F, et al. Photodynamic therapy of cancer. Basic principles and applications[J]. Clin Transl Oncol,2008,10(3):148-154.
[23]Juzeniene A, Nielsen K P, Moan J. Biophysical aspects of photodynamic therapy[J]. J Environ Pathol Toxicol Oncol,2006,25(1):7-28.
[24]Niedre M, Patterson M S, Wilson B C. Direct near-infrared luminescence detection of singlet oxygen generated by photodynamic therapy in cells in vitro and tissues in vivo [J]. Photochem Photobiol,2002,75(4):382-391.
[25]Wright A, Bubb W A, Hawkins C L, et al. Singlet oxygen-mediated protein oxidation:evidence for the formation of reactive side chain peroxides on tyrosine residues[J]. Photochem Photobiol,2002,76(1):35-46.
[26]Castano A P, Mroz P, Hamblin M R. Photodynamic therapy and anti-tumor immunity[J]. Nat Rev Cancer,2006,6(7):535-545.
[27]Korbelik M. PDT-associated host response and its role in the therapy outcome[J]. Lasers Surg Med,2006,38(5):500-508.
[28]Buytaert E, Dewaele M, Agostinis P. Molecular effectors of multiple cell death pathways initiated by photodynamic therapy[J]. Biochim Biophys Acta,2007,1176(1): 86-107.
[29]Vrouenraets M B, Visser G W, Snow G B, et al. Basic principles, applications in oncology and improved selectivity of photodynamic therapy[J]. Anticancer Res, 2003,23(1B):505-522.
[30]Gudgin-Dickson E F, Goyan R L, Pottier R H. New directions in photodynamic therapy[J]. Cell Mol Biol,2002,42(8):939-954.
[31]顾瑛.光动力疗法[M].北京：人民卫生出版社,2012：1-10.
[32]Zheng H. A Review of progress in clinical photodynamic therapy[J]. Technol Cancer Res Treat,2005,4(3):283-293.
[33]Moser J G. Photodynamic tumor therapy.2nd and 3rd generation photosensitizers [M]. London:Harwood Academic Publishers,1997:3-8.
[34]Wohrle D, Hirth A, Bogdahn-Rai T, et al. Photodynamic therapy of cancer:second and third generations of photosensitizers [J]. Russ Chem Bull,1998,47(5):807-816.
[35]Detty M R, Gibson S L, Wagner S J. Current clinical and preclinical photosensitizers for use in photodynamic therapy[J]. J Med Chem,2004,47(16):3897-3915.
[36]Allison R R, Downie G H, Cuenca R, et al. Photosensitizer in clinical PDT[J]. Photodiag Photodyn Therapy,2004,1(1):27-42.
[37]Savellano M D, Hasan T. Photochemical targeting of epidermal growth factor receptor:a mechanistic study[J]. Clin Cancer Res,2005,11(4):1658-1668.
[38]Mallikaratchy P, Tang Z W, Tan W H. Cell specific aptamer-photosensitizer conjugates as a molecular tool in photodynamic therapy [J]. Chem Med Chem,2008,3(3): 425-428.
[39]Pushpan S K, Venkatraman S, Anand V G, et al. Porphyrins in photodynamic therapy---a search for ideal photosensitizers[J]. Curr Med Chem Anticancer Agents, 2002,2(2):187-207.
[40]Shuler M F, Borrillo J L, Ho A C. Photodynamic therapy update[J]. Curr Opin Ophthalmol,2001,12(3):202-206.
[41]Ormrod D, Jarvis B. Topical aminolevulinic acid HC1 photodynamic therapy [J]. Am J Clin Dermatol,2000,1(2):133-141.
[42]陶然,顾瑛,刘凡光,等.血啉甲醚体外光敏反应机制研究[J].中国激光医学杂志,2002,11(3)：149-152.
[43]Boch R, Canaan A J, Cho A, et al. Cellular and antitumor activity of a new diethylene glycol benzoporphyrin derivative (Lemuteporfin)[J]. Photochem Photobiol, 2006,82(1):219-224.
[44]Hunt D W, Boivin W A, Fairley L A, et al. Ultraviolet B light stimulates interleukin-20 expression by human epithelial keratinocytes[J]. Photochem Photobiol, 2006,82(5):1292-1300.
[45]Lim S H, Thivierge C, Nowak-Sliwinska P, et al. In vitro and in vivo photocytotoxicity of boron dipyrromethene derivatives for photodynamic therapy [J]. J Med Chem,2010,53(7):2865-2874.
[46]He H, Lo P C, Yeung S L, et al. Synthesis and vitro photodynamic activities of pegylated distyryl boron dipyrromethene derivatives [J]. J Med Chem,2011,54(8): 3097-3102.
[47]Deng H, Liu X, Xie J, et al. Quantitative and site-directed chemical modification of hypocrellins toward direct drug delivery and effective photodynamic activity[J]. J Med Chem,2012,55(5):1910-1919.
[48]De Rosa F S, Bentley M V. Photodynamic therapy of skin cancers:sensitizers, clinical studies and future directives [J]. Pharm Res,2000,17(12):1447-1455.
[49]Castano A P, Demidova T N, Hamblin M R. Mechanisms in photodynamic therapy: Part one-photosensitizers, photochemistry and cellular localization[J]. Photodiagnosis Photodyn Ther,2004,1(4):279-293.
[50]陈杰波,欧敏锐,李忠琴,等.光动力治疗药物——光敏剂的研究进展[J].海峡药学,2003,15(6)：8-12.
[51]史宏敏.激光医学基础[M].广州：华南理工大学出版社,1990：32-62.
[52]黄卓正,李俊亨.现代激光医学[M].广西：广西科学技术出版社,1996：116-130.
[53]Verdaasdonk R M, van Swol C F. Laser light delivery systems for medical applications[J]. Phys Med Biol,1997,42(5):869-894.
[54]van den Bergh H. On the evolution of some endoscopic light delivery systems for photodynamic therapy [J]. Endoscopy,1998,30(4):392-407.
[55]Nichols M G, Foster T H. Oxygen diffusion and reaction kinetics in the photodynamic therapy of multicell tumor spheroids[J]. Phys Med Biol,1994,39(12): 2161-2181.
[56]Schunck T, Poulet P. Oxygen consumption through metabolish and photodynamic reactions in cells cultured on microbeads[J]. Phys Med Biol,2000,45(1):103-119.
[57]Foote C S. Definition of type Ⅰ and type Ⅱ photosensitized oxidation[J]. Photochem Photobiol,1991,54(5):659.
[58]Coulter A. The status of photodynamic therapy research:an overview of current and future cancer clinical treatments[J]. J Clin Laser Med Surg,1990,8(4):2-11.
[59]Keller S M. Photodynamic therapy. Biology and clinical application[J]. Chest Surg Clin N Am,1995,5(1):121-137.
[60]Qiang Y G, Zhang X P, Li J, et al. Photodynamic therapy for malignant diseases: clinical investigation and application[J]. Chin Med J,2006,119(10):845-857.
[1]郭江红.新型两亲性光敏剂的合成与光学性质研究[D].北京：北京协和医学院,2012：12-27.
[2]Bhaumik J, Weissleder R, McCarthy J R. Synthesis and photophysical properties of sulfonamidophenyl porphyrins as models for activatable photosensitizers[J]. J Org Chem, 2009,74(16):5894-5901.
[3]Banfi S, Caruso E, Buccafurni L, et al. Comparison between 5,10,15,20-tetraaryl-and 5,15-diarylporphyrins as photosensitizers:synthesis, photodynamic activity, and quantitative structure-activity relationship modeling[J]. J Med Chem,2006,49(11): 3293-3304.
[4]Peng C L, Lai P S, Chang C C, et al. The synthesis and photodynamic properties of meso-substituted, cationic porphyrin derivatives in HeLa cells[J]. Dyes Pigm,2010,84(1): 140-147.
[5]韩锐.抗癌药物研究与实验技术[M].北京：北京医科大学中国协和医科大学联合出版社,1997：271-273.
[6]Zheng X, Morgan J, Pandey S K, et al. Conjugation of 2-(1'-hexyloxyethyl)-2-devinylpyrophephorbide-a (HPPH) to carbohydrates changes its subcellular distribution and enhances photodynamic activity in vivo[J], J Med Chem,2009,52(14):4306-4318.
[7]Huang Y Y, Mroz P, Zhiyentayev T, et al. In vitro photodynamic therapy and quantitative structure-activity relationship studies with stable synthetic near-infrared-absorbing bacteriochlorin photosensitizers[J]. J Med Chem,2010,53(10):4018-4027.
[8]Hammer N D, Lee S, Vesper B J, et al. Charge dependence of cellular uptake and selective antitumor activity of porphyrazines[J]. J Med Chem,2005,48(26):8125-8133.
[9]Schmitt F, Govindaswamy P, Suss-Fink G, et al. Ruthenium porphyrin compounds for photodynamic therapy [J]. J Med Chem,2008,51(6):1811-1816.
[10]魏伟,吴希美,李元建.药理实验方法学[M].北京：人民卫生出版社,2010：1566-1569.
[11]Lei W, Xie J, Hou Y, et al. Mitochondria-targeting properties and photodynamic activities of porphyrin derivatives bearing cationic pendant[J]. J Photochem Photobiol, 2010,98(2):167-171.
[12]Shi Z H, Wang Y H, Fu C G. Study on retention behavior of metal-tetraphenyl porphine chelates in reverse-phase high performance liquid chromatography[J]. Se Pu, 2000,18(1):27-29.
[13]夏梅君,申琦,郭九吉,等.取代四苯基卟啉的紫外、荧光光谱及电化学性质[J].郑州大学学报(理学版),2010,42(4)：83-87.
[14]左国防,雷新有,杜捷,等.系列卟啉化合物的合成及其光谱和电化学性质的研究[J].光谱实验室,2008,25(3)：290-296.
[15]顾瑛.光动力疗法[M].北京：人民卫生出版社,2012：224-240.
[16]Kogan B Y. Nonlinear photodynamic therapy. Saturation of a photochemical dose by photosensitizer bleaching[J], Photochem Photobiol Sci,2003,2(6):673-676.
[17]Dysart J S, Patterson M S. Characterization of Photofrin photobleaching for singlet oxygen dose estimation during photodynamic therapy of MLL cells in vitro [J]. Phys Med Biol,2005,50(11):2597-2616.
[18]Dysart J S, Patterson M S. Photobleaching kinetics, photoproduct formation, and dose estimation during ALA induced PpIX PDT of MLL cells under well oxygenated and hypoxic conditions[J]. Photochem Photobiol Sci,2006,5(1):73-81.
[19]Kochevar I E. Singlet Oxygen signaling:from intimate to global[J]. Sci STKE,2004, 221:7.
[20]吕庆銮,张苗,岳宁宁,等.单线态氧的检测及分析应用研究进展[J].化学分析计量,2008,17(3)：74-77.
[21]黄显雯,吕汪洋,姚玉元,等.pH敏感锌酞菁聚合物的制备及光活性[J].浙江理工大学学报,2010,27(1)：1-5.
[22]Hirakawa K, Hirano T, Nishimura Y, et al. Dynamics of singlet oxygen generation by DNA-binding photosensitizers[J]. J Phys Chem B,2012,116(9):3037-3044.
[23]Yuan J, Mahama-Relue P A, Fournier R L, et al. Predictions of mathematical models of tissue oxygenation and generation of singlet oxygen during photodynamic therapy[J]. RadiatRes,1997,148(4):386-394.
[24]Box K J, Comer J E. Using measured pKa, LogP and solubility to investigate supersaturation and predict BCS class[J]. Curr Drug Metab,2008,9(9):869-878.
[25]Igarashi K, Kashiwaqi K. Modulation of cellular function by polyamines[J]. Int J Biochem Cell Biol,2010,42(1):39-51.
[26]Chan W S, Svensen R, Phillips D, et al. Cell uptake, distribution and response to aluminium chloro sulphonated phthalocyanine, a potential anti-tumour photosensitizer[J]. Br J Cancer,1986,53(2):255-263.
[27]Daly R, Vaz G, Davies A M, et al. Synthesis and biological evaluation of a library of glycoporphyrin compounds[J]. Chemistry,2012,18(46):14671-14679.
[28]Glidden M D, Celli J P, Massodi I, et al. Image-Based Quantification of Benzoporphyrin Derivative Uptake, Localization, and Photobleaching in 3D Tumor Models, for Optimization of PDT Parameters[J]. Theranostics,2012,2(9):827-839.
[29]Nakayama K, Katoh Y, Tamura M. "Triple Observation Method (TOM)" to discriminate optically autofluorescence from porphyrins versus that from copper-metallothioneins[J]. J Fluoresc,2011,21(2):835-839.
[30]Lassalle H P, Wagner M, Bezdetnaya L, et al. Fluorescence imaging of Foscan and Foslip in the plasma membrane and in whole cells[J]. J Photochem Photobiol B, 2008,92(1):47-53.
[31]Kinzler I, Haseroth E, Hauser C, et al. Role of mitochondria in cell death induced by Photofrin-PDT and ursodeoxycholic acid by means of SLIM[J]. Photochem Photobiol Sci,2007,6(12):1332-1340.
[32]Maftoum-Costa M, Naves K T, Oliveira A L, et al. Mitochondria, endoplasmic reticulum and actin filament behavior after PDT with chloroaluminum phthalocyanine liposomal in HeLa cells[J]. Cell Biol Int,2008,32(8):1024-1028.
[33]Caruso J A, Mathieu P A, Joiakim A, et al. Differential susceptibilities of murine hepatoma lclc7 and Tao cells to the lysosomal photosensitizer NPe6:influence of aryl hydrocarbon receptor on lysosomal fragility and protease contents[J]. Mol Pharmacol, 2004,65(4):1016-1028.
[34]戴维德,王雷,刘凡光,等.高分辨率荧光显微成像技术在光敏剂亚细胞定位研究中的应用[J].中国激光医学杂志,2004,13(4)：240-245.
[35]Edwards B K, Brown M L, Wingo P A, et al. Annual report to the nation on the status of cancer,1975-2002, featuring population-based trends in cancer treatment[J]. J Natl Cancer Inst,2005,97(19):1407-1427.
[36]Van M J, Kaspers G J, Cloos J. Cell sensitivity assays:the MTT assay [J]. Methods Mol Biol,2011,731:237-245.
[37]陈靖京,王玉茂,刘天军.新型卟啉类光敏药物介导的PDT对两种胃癌细胞HGC27和MGC803的杀伤效应[J].国际生物医学工程杂志,2011,34(3)：154-166.
[38]陈靖京.卟啉类光敏抗肿瘤化合物评价[[)].北京：北京协和医学院,2011：23-44.
[39]曹波.新型水溶性光敏剂的评价和机制研究[D].北京：北京协和医学院,2012：20-50.
[40]Sieuwerts A M, Klijn J G, Peters H A, et al. The MTT tetrazolium salt assay scrutinized:how to use this assay reliably to measure metabolic activity of cell cultures in vitro for the assessment of growth characteristics, IC50-values and cell survival[J]. Eur J Clin Chem Clin Biochem,1995,33(11):813-823.
[1]陈靖京,王玉茂,刘天军.新型卟啉类光敏药物介导的PDT对两种胃癌细胞HGC27和MGC803的杀伤效应[J].国际生物医学工程杂志,2011,34(3)：154-166.
[2]陈靖京.卟啉类光敏抗肿瘤化合物评价[D].北京：北京协和医学院,2011：23-44.
[3]陈靖京,魏武,纪爱芳,等.新型光敏药物对胃癌MGC803细胞的光动力治疗研究[J].中华胃肠外科杂志,2012,15(12)：1291-1295.
[4]曹波.新型水溶性光敏剂的评价和机制研究[D].北京：北京协和医学院,2012：20-50.
[5]Gollnick S O, Owczarczak B, Maier P. Photodynamic therapy and antitumor immunity[J]. Lasers Surg Med,2006,38(5):509-515.
[6]Kralova J, Briza T, Moserova I, et al. Glycol porphyrin derivatives as potent photodynamic inducers of apoptosis in tumor cells[J]. J Med Chem,2008,51(19): 5964-5973.
[7]Lv F, Cao B, Cui Y, et al. Zinc phthalocyanine labelled polyethylene glycol: preparation, characterization, interaction with bovine serum albumin and near infrared fluorescence imaging in vivo[J]. Molecules,2012,17(6):6348-6361.
[8]王冬冬,孙德志,李林尉,等.5-氟尿嘧啶与牛血清白蛋白的相互作用[J].物理化学学报,2007,23(10)：1627-1630.
[9]魏伟,吴希美,李元建.药理实验方法学[M].北京：人民卫生出版社,2010：1566-1569.
[10]Pecaut M J, Dutta-Roy R, Smith A L, et al. Acute effects of iron-particle radiation on immunity. Part I Population distribution[J]. Radiat Res,2006,165(1):68-77.
[11]郑景存CDHS801光动力学杀伤膀胱癌机理的试验研究[D].上海：复旦大学,2005：55-60.
[12]Chen L, He Z, Qin L, et al. Antitumor effect of malaria parasite infection in a murine Lewis lung cancer model through induction of innate and adaptive immunity [J]. PLoS One,2011,6(9):24407.
[13]Zhang H, Ma W, Li Y. Generation of effective vaccines against liver cancer by using photodynamic therapy[J]. Lasers Med Sci,2009,24(4):549-552.
[14]Jin I, Yuji M, Yoshinori N, et al. Anti-tumor effect of PDT using Photofrin in a mouse angiosarcoma model[J]. Arch Dermatol Res,2008,300(4):161-166.
[15]Lv F, Li Y, Cao B, et al. Galactose substituted zinc phthalocyanines as near infrared fluorescence probes for liver cancer imaging[J]. J Mater Sci Mater Med,2013,24(3): 811-819.
[16]Gultekin E, Gultekin O E, Cingillioglu B, et al. The value of frozen section evaluation in the management of borderline ovarian tumors[J]. J Cancer Res Ther, 2011,7(4):416-420.
[17]Wyld L, Reed M W, Brown N J. Differential cell death response to photodynamic therapy is dependent on dose and cell type[J]. Br J Cancer,2001,84(10):1384-1386.
[18]Dahl T A. Direct exposure of mammalian cells to pure exogenous singlet oxygen (1 delta gO2)[J]. Photochem Photobiol,1993,57(2):248-254.
[19]Pedersen B W, Sinks L E, Breitenbach T, et al. Single cell responses to spatially controlled photosensitized production of extracellular singlet oxygen[J]. Photochem Photobiol,2011,87(5):1077-1091.
[20]Agarwal M L, Clay M E, Harvey E J, et al. Photodynamic therapy induces rapid cell death by apoptosis in L5178Y mouse lymphoma cells[J]. Cancer Res,1991 51(21): 5993-5996.
[21]Bourre L, Rousset N, Thibaut S, et al. PDT effects of m-THPC and ALA, phototoxicity and apoptosis[J]. Apoptosis,2002,7(3):221-230.
[22]杨铭.抗肿瘤抗病毒药物与核酸相互作用的分子机制[M].北京：北京大学医学出版社,2009：359-361.
[23]Fan F, Nie S, Yang D, et al. Labeling lysosomes and tracking lysosome-dependent apoptosis with a cell-permeable activity-based probe[J]. Bioconjug Chem,2012,23(6): 1309-1317.
[24]瑞菲尔·努纳兹.流式细胞术原理与科研应用简明手册[M].北京：化学工业出版社,2005：27-32.
[25]刘力华,黄明辉,张宏波,等.血卟琳单甲醚光敏剂光动力学疗法对人乳腺肿瘤细胞生长周期的阻滞作用及其凋亡研究[J].中国综合临床,2011,27(9)：945-947.
[26]Komatsu T, Nakagawa A, Qu X. Structural and mutagenic approach to create human serum albumin-based oxygen carrier and photosensitizer[J]. Drug Metab Pharmacokinet, 2009,24(4):287-299.
[27]高岭,曹洪玉,刘阁.4种金属卟啉配合物与血清白蛋白作用的光谱研究[J].化学试剂,2012,34(2)：108-112.
[28]Singh SK, Kishore N. Calorimetric and spectroscopic studies on the interaction of methimazole with bovine serum albumin[J]. J Pharm Sci,2008,97(6):2362-2372.
[29]Zhao P, Huang J W, Ji L N. Cationic pyridinium porphyrins appending different peripheral substituents:spectroscopic studies on their interactions with bovine serum albumin[J]. Spectrochim Acta A Mol Biomol Spectrosc,2012,88:130-136.
[30]顾瑛.光动力疗法[M].北京：人民卫生出版社,2012：224-240.
[1]Frimannsson D O, Grossi M, Murtagh J, et al. Light induced antimicrobial properties of a brominated boron difluoride (BF2) chelated tetraarylazadipyrromethene photosensitizer[J]. J Med Chem,2010,53(20):7337-7343.
[2]Yogo T, Urano Y, Ishitsuka Y, et al. Highly efficient and photostable photosensitizer based on BODIPY chromophore[J]. J Am Chem Soc,2005,127(35):12162-12163.
[3]Caruso E, Banfi S, Barbieri P, et al. Synthesis and antibacterial activity of novel cationic BODIPY photosensitizers[J], J Photochem Photobiol B,2012,114:44-51.
[4]Lim S H, Thivierge C, Nowak-Sliwinska P, et al. In vitro and in vivo photocytotoxicity of boron dipyrromethene derivatives for photodynamic therapy [J]. J Med Chem,2010,53(7):2865-2874.
[5]He H, Lo P C, Yeung S L, et al. Synthesis and in vitro photodynamic activities of pegylated distyryl boron dipyrromethene derivatives[J]. J Med Chem,2011,54(8): 3097-3102.
[6]顾瑛.光动力疗法[M].北京：人民卫生出版社,2012：224-240.
[7]Kamkaew A, Lim S H, Lee H B, et al. BODIPY dyes in photodynamic therapy[J]. Chem Soc Rev,2013,42(1):77-88.
[1]Ronny P, Justin R G, Janelle N L, et al. Synthesis of aza-BODIPY boron difluoride PDT agents to promote apoptosis in HeLa cells[J]. Lett Org Chem,2011,8(6):368-373.
[2]Shukla S, Skoumbourdis A P, Walsh M J, et al. Synthesis and characterization of a BODIPY conjugate of the BCR-ABL kinase inhibitor Tasigna (nilotinib):evidence for transport of Tasigna and its fluorescent derivative by ABC drug transporters [J]. Mol Pharm,2011,8(4):1292-1302.
[3]Ono M, Watanabe H, Kimura H, et al. BODIPY-based molecular probe for imaging of cerebral β-amyloid plaques[J]. ACS Chem Neurosci,2012,3(4):319-324.
[4]陈美娟,肖顺汉,冯文宇,等.青银注射液静脉、腹腔注射对小鼠半数致死量(LDso)的测定[J].泸州医学院学报,2007,30(5)：349-351.
[5]深泽天,杨觅,禹立霞,等.紫杉类药物温敏纳米胶束的小鼠LD50及其毒性差异[J].江苏医药,2008,34(1)：56-58.
[6]魏伟,吴希美,李元建.药理实验方法学[M].北京：人民卫生出版社,2010：1566-1569.