本文主要研究内容
作者宋娇（2019）在《近红外光触发纳米粒用于小鼠乳腺肿瘤多模成像和光热治疗的实验研究》一文中研究指出：第一部分 近红外光触发纳米粒(NP-IR780)的制备和表征目的制备载全氟溴辛烷(perfluorooctyl bromide,PFOB)和碘化IR780(IR780 iodide,IR780)的脂质近红外光触发纳米粒(NP-IR780)并检测其一般性质。方法通过薄膜水化和声震的方法制备纳米粒,并对其一般性质进行检测:形态、分散性、超微结构、粒径、电位、IR780载药量。将NP-IR780稀释成不同浓度,通过小动物活体成像系统、光声成像系统、计算机断层扫描(computed tomography,CT)成像系统检测其近红外荧光/光:声/CT成像能力。通过激光辐照,热成像仪监测温度变化评估NP-IR780的光热转化效应。通过细胞增殖活性监测(Cell counting kit-8,CCK-8)法检测纳米粒对表达荧光素酶(Luciferase,Luc)乳腺癌细胞(4T1/Luc)的毒性;通过共聚焦显微镜和流式细胞术检测纳米粒对4T1/Luc细胞的靶向性。结果NP-IR780呈球形壳核结构,大小均一,水溶液中分散性好,粒径266.0±50.2 nm，电位-23.97±4.40 mV,IR780 载药量 4.37±0.5%,在体外表现出良好的近红外荧光/光声/CT成像能力及光热转换效应。NP-IR780在浓度为5-30μg/mL范围内无明显细胞毒性;共聚焦显微镜观察和流式细胞术检测证明与不携带IR780纳米粒(nanoparticles,NP)相比,NP-IR780有更好的肿瘤靶向性。结论通过薄膜水化和声震的方法成功合成了一般性质良好的NP-IR780脂质纳米粒,该纳米粒在体外具有近红外荧光/光声/CT多模成像能力和光热转换效应,并且对4TI/Luc细胞表现出良好的靶向性。第二部分近红外光触发纳米粒(NP-IR780)体内多模成像实验研究目的评估近红外光触发纳米粒(NP-IR780)在小鼠体内的安全性,并通过小鼠原位乳腺癌模型研究其在体内对肿瘤的靶向性,探讨其作为近红外荧光成像、光声成像和CT成像多模造影剂在体内显示肿瘤的效果。方法1.安全性评估:健康雌性BALB/c小鼠分为3组(每组5只):对照组、NP-IR780 低剂量组(25mg/kg)、NP-IR780 高剂量组(50mg/kg)。:尾静脉给药14天后检测血常规,肝、肾、心功能的生化指标和心、肝、脾、肺、肾病理变化。2.成功建立4T1/Luc小鼠原位乳腺癌模型后,评估NP-IR780的近红外荧光成像能力及其在体内的靶向性。荷瘤小鼠随机分为两组(每组 3 只):游离 IR780 组(1.1mg/kg)和 NP-IR780(25mg/kg,IR780 的剂量l.1mg/kg)。尾静脉给药后通过小动物活体成像系统分别采集小鼠生物发光图像和注射前、注射后(1小时、3小时、24小时、48小时)近红外荧光图像;在48小时处死两组小鼠,采集游离心、肝、脾、肺、肾、肿瘤组织的近红外荧光图像。荷瘤小鼠随机分为两组(每组3只):分别经尾静脉注射红色荧光染.料(1，Γ-Dioctadecy1-3,3,3’,3’-tetramethylindocarbocyanineperchlorate,DiI)标记的NP和NP-IR780,48小时后取肿瘤组织冰冻切片并在荧光显微镜下观察NP和NP-IR780在肿瘤组织中分布的差异,进一步评估纳米粒在组织学水平的靶向性。确定NP-IR780在荷瘤小鼠体内的安全性和肿瘤靶向性后,分别于注射前、注射后(3小时、24小时)通过光声成像系统和CT成像系统采集图像,评估NP-IR780作为造影剂的光声成像和CT成像效果。结果与对照组相比,两组注射了 NP-IR780(25mg/kg和50mg/kg)小鼠的红细胞、白细胞、血小板、生化指标(ALT、AST、TPBL、CK、LDH、CR、BUN)以及组织器官(心、肝、脾、肺、肾)病理无明显变化,证实该纳米粒在剂量小于等于50mg/kg时在小鼠体内的生物安全性。通过小动物活体成像系统采集的近红外荧光图像显示游离的IR780和NP-IR780对肿瘤组织都具有靶向性,但是与游离的IR780相比,NP-IR780组荧光强度不仅有明显的升高,而且在24小时达到高峰后可以维持至48小时。48小时离体器官和肿瘤组织的荧光图像显示NP-IR780和游离的IR780在肿瘤组织中的聚集高于心、肝、脾、肺、肾组织;而NP-IR780组的整体荧光强度远远高于游离IR780组。进一步比较NP和NP-IR780在肿瘤组织中的分布差异,发现注射DiI标记的NP-IR780和NP至荷瘤小鼠48小时后,荧光显微镜观察NP-IR780组的肿瘤组织横断面荧光强度明显高于NP组,有明显的统计学差异,提示NP-IR780在肿瘤组织中的聚集明显优于NP。光声成像系统采集小鼠肿瘤部位NP-IR780注射前,注射后3小时和24小时后的图像显示,随着时间的延长,肿瘤组织中的光声信号逐渐增加,24小时后光声信号约为注射前的3倍,提示NP-IR780可以通过光声成像显示肿瘤。CT成像系统采集荷瘤小鼠NP-IR780注射前,注射后3小时、24小时的CT图像,显示肿瘤部位的CT信号在注射后3小时,24小时增强,且在24小时CT信号值增加了约1.3倍,提示NP-IR780可以作为CT成像造影剂增强显示肿瘤。结论NP-IR780对小鼠4TI/Luc乳腺癌组织具有良好的靶向作用,且可以作为近红外荧光成像、光声成像、CT成像造影剂显示小鼠肿瘤组织。第三部分近红外光触发纳米粒(NP-IR780)术中近红外荧光导航肿瘤切除和光热治疗的实验研究目的研究NP-IR780术中近红外荧光成像显示原发肿瘤和淋巴结转移瘤的能力和术中介导光热消融残留病灶的治疗效果。方法原位乳腺癌小鼠经尾静脉注射NP-IR780后,在不同时间点(0天,1天.,2天,3天,4天,5天;每组3只)通过手术将肿瘤区域暴露于体式荧光显微镜下,并实时采集手术区域白光和近红外荧光图像,术中图像引导下切除肿瘤组织后行病理学检查。在耳廓皮下注射4TI/Luc肿瘤细胞,建立小鼠颈部淋巴结转移瘤模型,通过小动物活体成像系统监测成瘤过程。建立小鼠颈部淋巴结转移瘤模型后,经尾静脉注射NP-IR780，并于注射前、注射后2天(每组3只)采集术中颈部淋巴结转移瘤区域白光和近红外光图像,术中图像引导下切除转移瘤组织后行病理学检查。原位乳腺癌小鼠随机分为6组(每组5只):1.对照组、2.NP-IR780组、3.激光组、4.光热组、5.手术组、6.手术+光热组。第4组给药(NP-IR780)48小时后,肿瘤区域给予激光辐照;第5组给药(NP-IR780)48小时后,行不完全肿瘤切除术;第6组给药(NP-IR780)48小时后,行不完全肿瘤切除术,术中对残余肿瘤行激光辐照。经过不同的处理后,观察小鼠肿瘤体积和生存时间的改变以及小鼠体重的变化。治疗后24小时,各组随机处死3只小鼠,取肿瘤组织做苏木精伊红(hematoxylin-eosin,H&E)染色、细胞凋亡(TdT-mediated dUTP nick-end labeling,TUNEL)和增:殖细胞核抗原(proliferating cell nuclear antigen,PCNA)检查。结果静脉注射NP-IR780两天后,通过近红外荧光成像实时清晰显示了小于lcm肿瘤组织的边界,其大小与白光显示的肿瘤组织一致。通过图像软件进一步分析在注射纳米粒2天后可同时获得较高的肿瘤与正常组织荧光信号强度比(tumor-to-background fluorescence signal intensity ratio,TBR)和肿瘤区域平均荧光强度。冰冻切片病理分析显示NP-IR780在肿瘤组织中的聚集明显高于周围正常组织。通过小动物活体成像系统监测,耳廓皮下接种4T1/LuC细胞25天左右成功建立小鼠颈部淋巴结转移瘤模型。经尾静脉注射NP-IR780至颈部淋巴结转移瘤小鼠体内，两天后通过术.中近红外荧光成像清晰的显示转移的淋巴结位置、边界和大小,转移瘤与周围组织的平均荧光强度比值为2.94±0.21。术后病理结果提示为恶性转移瘤组织。原位乳腺癌小鼠随机分为6组,接受不同治疗后,结果显示:激光组和NP-IR780组与对照组相比,肿瘤体积和生存时间无明显改变;而手术和光热治疗(激光+NP-IR780)不同程度对肿瘤起了治疗作用,肿瘤体积缩小,小鼠生存时间延长,但所有的小鼠在后期出现了肿瘤复发。光热治疗+手术治疗组对荷瘤小鼠的疗效最好,完全治愈率达到80%,只有1只小鼠出现了肿瘤的复发。治疗后2周内各组小鼠的体重无明显差别。治疗后24小时的病理切片分析显示对照组、激光组、NP-IR780组和手术组中以增殖旺盛的PCNA阳性细胞为主,而光热组和手术+光热组以显示凋亡的TUNEL 阳性细胞为主,其中光热组中也可以见到少量PCNA 阳性的肿瘤细胞,H&E染色显示光热组和手术+光热组中有大量坏死的细胞。结论NP-IR780可以作为近红外荧光成像造影剂在术中实时引导肿瘤及淋巴结转移瘤切除术,并在术中介导光热治疗清除残留病灶,改善荷瘤小鼠的预后。光热治疗是通过诱导细胞凋亡和高热坏死两种途径杀死肿瘤细胞。
Abstract
di yi bu fen jin gong wai guang chu fa na mi li (NP-IR780)de zhi bei he biao zheng mu de zhi bei zai quan fu xiu xin wan (perfluorooctyl bromide,PFOB)he dian hua IR780(IR780 iodide,IR780)de zhi zhi jin gong wai guang chu fa na mi li (NP-IR780)bing jian ce ji yi ban xing zhi 。fang fa tong guo bao mo shui hua he sheng zhen de fang fa zhi bei na mi li ,bing dui ji yi ban xing zhi jin hang jian ce :xing tai 、fen san xing 、chao wei jie gou 、li jing 、dian wei 、IR780zai yao liang 。jiang NP-IR780xi shi cheng bu tong nong du ,tong guo xiao dong wu huo ti cheng xiang ji tong 、guang sheng cheng xiang ji tong 、ji suan ji duan ceng sao miao (computed tomography,CT)cheng xiang ji tong jian ce ji jin gong wai ying guang /guang :sheng /CTcheng xiang neng li 。tong guo ji guang fu zhao ,re cheng xiang yi jian ce wen du bian hua ping gu NP-IR780de guang re zhuai hua xiao ying 。tong guo xi bao zeng shi huo xing jian ce (Cell counting kit-8,CCK-8)fa jian ce na mi li dui biao da ying guang su mei (Luciferase,Luc)ru xian ai xi bao (4T1/Luc)de du xing ;tong guo gong ju jiao xian wei jing he liu shi xi bao shu jian ce na mi li dui 4T1/Lucxi bao de ba xiang xing 。jie guo NP-IR780cheng qiu xing ke he jie gou ,da xiao jun yi ,shui rong ye zhong fen san xing hao ,li jing 266.0±50.2 nm，dian wei -23.97±4.40 mV,IR780 zai yao liang 4.37±0.5%,zai ti wai biao xian chu liang hao de jin gong wai ying guang /guang sheng /CTcheng xiang neng li ji guang re zhuai huan xiao ying 。NP-IR780zai nong du wei 5-30μg/mLfan wei nei mo ming xian xi bao du xing ;gong ju jiao xian wei jing guan cha he liu shi xi bao shu jian ce zheng ming yu bu xie dai IR780na mi li (nanoparticles,NP)xiang bi ,NP-IR780you geng hao de zhong liu ba xiang xing 。jie lun tong guo bao mo shui hua he sheng zhen de fang fa cheng gong ge cheng le yi ban xing zhi liang hao de NP-IR780zhi zhi na mi li ,gai na mi li zai ti wai ju you jin gong wai ying guang /guang sheng /CTduo mo cheng xiang neng li he guang re zhuai huan xiao ying ,bing ju dui 4TI/Lucxi bao biao xian chu liang hao de ba xiang xing 。di er bu fen jin gong wai guang chu fa na mi li (NP-IR780)ti nei duo mo cheng xiang shi yan yan jiu mu de ping gu jin gong wai guang chu fa na mi li (NP-IR780)zai xiao shu ti nei de an quan xing ,bing tong guo xiao shu yuan wei ru xian ai mo xing yan jiu ji zai ti nei dui zhong liu de ba xiang xing ,tan tao ji zuo wei jin gong wai ying guang cheng xiang 、guang sheng cheng xiang he CTcheng xiang duo mo zao ying ji zai ti nei xian shi zhong liu de xiao guo 。fang fa 1.an quan xing ping gu :jian kang ci xing BALB/cxiao shu fen wei 3zu (mei zu 5zhi ):dui zhao zu 、NP-IR780 di ji liang zu (25mg/kg)、NP-IR780 gao ji liang zu (50mg/kg)。:wei jing mai gei yao 14tian hou jian ce xie chang gui ,gan 、shen 、xin gong neng de sheng hua zhi biao he xin 、gan 、pi 、fei 、shen bing li bian hua 。2.cheng gong jian li 4T1/Lucxiao shu yuan wei ru xian ai mo xing hou ,ping gu NP-IR780de jin gong wai ying guang cheng xiang neng li ji ji zai ti nei de ba xiang xing 。he liu xiao shu sui ji fen wei liang zu (mei zu 3 zhi ):you li IR780 zu (1.1mg/kg)he NP-IR780(25mg/kg,IR780 de ji liang l.1mg/kg)。wei jing mai gei yao hou tong guo xiao dong wu huo ti cheng xiang ji tong fen bie cai ji xiao shu sheng wu fa guang tu xiang he zhu she qian 、zhu she hou (1xiao shi 、3xiao shi 、24xiao shi 、48xiao shi )jin gong wai ying guang tu xiang ;zai 48xiao shi chu si liang zu xiao shu ,cai ji you li xin 、gan 、pi 、fei 、shen 、zhong liu zu zhi de jin gong wai ying guang tu xiang 。he liu xiao shu sui ji fen wei liang zu (mei zu 3zhi ):fen bie jing wei jing mai zhu she gong se ying guang ran .liao (1，Γ-Dioctadecy1-3,3,3’,3’-tetramethylindocarbocyanineperchlorate,DiI)biao ji de NPhe NP-IR780,48xiao shi hou qu zhong liu zu zhi bing dong qie pian bing zai ying guang xian wei jing xia guan cha NPhe NP-IR780zai zhong liu zu zhi zhong fen bu de cha yi ,jin yi bu ping gu na mi li zai zu zhi xue shui ping de ba xiang xing 。que ding NP-IR780zai he liu xiao shu ti nei de an quan xing he zhong liu ba xiang xing hou ,fen bie yu zhu she qian 、zhu she hou (3xiao shi 、24xiao shi )tong guo guang sheng cheng xiang ji tong he CTcheng xiang ji tong cai ji tu xiang ,ping gu NP-IR780zuo wei zao ying ji de guang sheng cheng xiang he CTcheng xiang xiao guo 。jie guo yu dui zhao zu xiang bi ,liang zu zhu she le NP-IR780(25mg/kghe 50mg/kg)xiao shu de gong xi bao 、bai xi bao 、xie xiao ban 、sheng hua zhi biao (ALT、AST、TPBL、CK、LDH、CR、BUN)yi ji zu zhi qi guan (xin 、gan 、pi 、fei 、shen )bing li mo ming xian bian hua ,zheng shi gai na mi li zai ji liang xiao yu deng yu 50mg/kgshi zai xiao shu ti nei de sheng wu an quan xing 。tong guo xiao dong wu huo ti cheng xiang ji tong cai ji de jin gong wai ying guang tu xiang xian shi you li de IR780he NP-IR780dui zhong liu zu zhi dou ju you ba xiang xing ,dan shi yu you li de IR780xiang bi ,NP-IR780zu ying guang jiang du bu jin you ming xian de sheng gao ,er ju zai 24xiao shi da dao gao feng hou ke yi wei chi zhi 48xiao shi 。48xiao shi li ti qi guan he zhong liu zu zhi de ying guang tu xiang xian shi NP-IR780he you li de IR780zai zhong liu zu zhi zhong de ju ji gao yu xin 、gan 、pi 、fei 、shen zu zhi ;er NP-IR780zu de zheng ti ying guang jiang du yuan yuan gao yu you li IR780zu 。jin yi bu bi jiao NPhe NP-IR780zai zhong liu zu zhi zhong de fen bu cha yi ,fa xian zhu she DiIbiao ji de NP-IR780he NPzhi he liu xiao shu 48xiao shi hou ,ying guang xian wei jing guan cha NP-IR780zu de zhong liu zu zhi heng duan mian ying guang jiang du ming xian gao yu NPzu ,you ming xian de tong ji xue cha yi ,di shi NP-IR780zai zhong liu zu zhi zhong de ju ji ming xian you yu NP。guang sheng cheng xiang ji tong cai ji xiao shu zhong liu bu wei NP-IR780zhu she qian ,zhu she hou 3xiao shi he 24xiao shi hou de tu xiang xian shi ,sui zhao shi jian de yan chang ,zhong liu zu zhi zhong de guang sheng xin hao zhu jian zeng jia ,24xiao shi hou guang sheng xin hao yao wei zhu she qian de 3bei ,di shi NP-IR780ke yi tong guo guang sheng cheng xiang xian shi zhong liu 。CTcheng xiang ji tong cai ji he liu xiao shu NP-IR780zhu she qian ,zhu she hou 3xiao shi 、24xiao shi de CTtu xiang ,xian shi zhong liu bu wei de CTxin hao zai zhu she hou 3xiao shi ,24xiao shi zeng jiang ,ju zai 24xiao shi CTxin hao zhi zeng jia le yao 1.3bei ,di shi NP-IR780ke yi zuo wei CTcheng xiang zao ying ji zeng jiang xian shi zhong liu 。jie lun NP-IR780dui xiao shu 4TI/Lucru xian ai zu zhi ju you liang hao de ba xiang zuo yong ,ju ke yi zuo wei jin gong wai ying guang cheng xiang 、guang sheng cheng xiang 、CTcheng xiang zao ying ji xian shi xiao shu zhong liu zu zhi 。di san bu fen jin gong wai guang chu fa na mi li (NP-IR780)shu zhong jin gong wai ying guang dao hang zhong liu qie chu he guang re zhi liao de shi yan yan jiu mu de yan jiu NP-IR780shu zhong jin gong wai ying guang cheng xiang xian shi yuan fa zhong liu he lin ba jie zhuai yi liu de neng li he shu zhong jie dao guang re xiao rong can liu bing zao de zhi liao xiao guo 。fang fa yuan wei ru xian ai xiao shu jing wei jing mai zhu she NP-IR780hou ,zai bu tong shi jian dian (0tian ,1tian .,2tian ,3tian ,4tian ,5tian ;mei zu 3zhi )tong guo shou shu jiang zhong liu ou yu bao lou yu ti shi ying guang xian wei jing xia ,bing shi shi cai ji shou shu ou yu bai guang he jin gong wai ying guang tu xiang ,shu zhong tu xiang yin dao xia qie chu zhong liu zu zhi hou hang bing li xue jian cha 。zai er kuo pi xia zhu she 4TI/Luczhong liu xi bao ,jian li xiao shu geng bu lin ba jie zhuai yi liu mo xing ,tong guo xiao dong wu huo ti cheng xiang ji tong jian ce cheng liu guo cheng 。jian li xiao shu geng bu lin ba jie zhuai yi liu mo xing hou ,jing wei jing mai zhu she NP-IR780，bing yu zhu she qian 、zhu she hou 2tian (mei zu 3zhi )cai ji shu zhong geng bu lin ba jie zhuai yi liu ou yu bai guang he jin gong wai guang tu xiang ,shu zhong tu xiang yin dao xia qie chu zhuai yi liu zu zhi hou hang bing li xue jian cha 。yuan wei ru xian ai xiao shu sui ji fen wei 6zu (mei zu 5zhi ):1.dui zhao zu 、2.NP-IR780zu 、3.ji guang zu 、4.guang re zu 、5.shou shu zu 、6.shou shu +guang re zu 。di 4zu gei yao (NP-IR780)48xiao shi hou ,zhong liu ou yu gei yu ji guang fu zhao ;di 5zu gei yao (NP-IR780)48xiao shi hou ,hang bu wan quan zhong liu qie chu shu ;di 6zu gei yao (NP-IR780)48xiao shi hou ,hang bu wan quan zhong liu qie chu shu ,shu zhong dui can yu zhong liu hang ji guang fu zhao 。jing guo bu tong de chu li hou ,guan cha xiao shu zhong liu ti ji he sheng cun shi jian de gai bian yi ji xiao shu ti chong de bian hua 。zhi liao hou 24xiao shi ,ge zu sui ji chu si 3zhi xiao shu ,qu zhong liu zu zhi zuo su mu jing yi gong (hematoxylin-eosin,H&E)ran se 、xi bao diao wang (TdT-mediated dUTP nick-end labeling,TUNEL)he zeng :shi xi bao he kang yuan (proliferating cell nuclear antigen,PCNA)jian cha 。jie guo jing mai zhu she NP-IR780liang tian hou ,tong guo jin gong wai ying guang cheng xiang shi shi qing xi xian shi le xiao yu lcmzhong liu zu zhi de bian jie ,ji da xiao yu bai guang xian shi de zhong liu zu zhi yi zhi 。tong guo tu xiang ruan jian jin yi bu fen xi zai zhu she na mi li 2tian hou ke tong shi huo de jiao gao de zhong liu yu zheng chang zu zhi ying guang xin hao jiang du bi (tumor-to-background fluorescence signal intensity ratio,TBR)he zhong liu ou yu ping jun ying guang jiang du 。bing dong qie pian bing li fen xi xian shi NP-IR780zai zhong liu zu zhi zhong de ju ji ming xian gao yu zhou wei zheng chang zu zhi 。tong guo xiao dong wu huo ti cheng xiang ji tong jian ce ,er kuo pi xia jie chong 4T1/LuCxi bao 25tian zuo you cheng gong jian li xiao shu geng bu lin ba jie zhuai yi liu mo xing 。jing wei jing mai zhu she NP-IR780zhi geng bu lin ba jie zhuai yi liu xiao shu ti nei ，liang tian hou tong guo shu .zhong jin gong wai ying guang cheng xiang qing xi de xian shi zhuai yi de lin ba jie wei zhi 、bian jie he da xiao ,zhuai yi liu yu zhou wei zu zhi de ping jun ying guang jiang du bi zhi wei 2.94±0.21。shu hou bing li jie guo di shi wei e xing zhuai yi liu zu zhi 。yuan wei ru xian ai xiao shu sui ji fen wei 6zu ,jie shou bu tong zhi liao hou ,jie guo xian shi :ji guang zu he NP-IR780zu yu dui zhao zu xiang bi ,zhong liu ti ji he sheng cun shi jian mo ming xian gai bian ;er shou shu he guang re zhi liao (ji guang +NP-IR780)bu tong cheng du dui zhong liu qi le zhi liao zuo yong ,zhong liu ti ji su xiao ,xiao shu sheng cun shi jian yan chang ,dan suo you de xiao shu zai hou ji chu xian le zhong liu fu fa 。guang re zhi liao +shou shu zhi liao zu dui he liu xiao shu de liao xiao zui hao ,wan quan zhi yu lv da dao 80%,zhi you 1zhi xiao shu chu xian le zhong liu de fu fa 。zhi liao hou 2zhou nei ge zu xiao shu de ti chong mo ming xian cha bie 。zhi liao hou 24xiao shi de bing li qie pian fen xi xian shi dui zhao zu 、ji guang zu 、NP-IR780zu he shou shu zu zhong yi zeng shi wang cheng de PCNAyang xing xi bao wei zhu ,er guang re zu he shou shu +guang re zu yi xian shi diao wang de TUNEL yang xing xi bao wei zhu ,ji zhong guang re zu zhong ye ke yi jian dao shao liang PCNA yang xing de zhong liu xi bao ,H&Eran se xian shi guang re zu he shou shu +guang re zu zhong you da liang huai si de xi bao 。jie lun NP-IR780ke yi zuo wei jin gong wai ying guang cheng xiang zao ying ji zai shu zhong shi shi yin dao zhong liu ji lin ba jie zhuai yi liu qie chu shu ,bing zai shu zhong jie dao guang re zhi liao qing chu can liu bing zao ,gai shan he liu xiao shu de yu hou 。guang re zhi liao shi tong guo you dao xi bao diao wang he gao re huai si liang chong tu jing sha si zhong liu xi bao 。
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