CN110935038B - 长余辉纳米复合物及其在肿瘤多模态成像和协同治疗中的应用 - Google Patents
长余辉纳米复合物及其在肿瘤多模态成像和协同治疗中的应用 Download PDFInfo
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Abstract
本发明公开了一种长余辉纳米复合物,由人血清白蛋白负载近红外吸收染料和Fe3+,并包裹在长余辉纳米材料的表面制得,为核壳结构,所述长余辉纳米材料为核,负载有近红外吸收染料和Fe3+的人血清白蛋白为壳。使用后,能够实现多模态成像,获得更全面的生物组织特性,从而对生物组织结构、功能特性及早期病变进行成像;能够实现多模态成像与多手段协同治疗一体化。
Description
【技术领域】
本发明属于生物医学技术领域,尤其涉及长余辉纳米复合物及其在肿瘤多模态成像和协同治疗中的应用。
【背景技术】
癌症已成为威胁人类健康和生命的重大疾病之一。目前临床上采用核磁 (MRI)、X射线断层扫描(CT)、正电子发射型计算机断层显像(PET)等影像学检查手段结合组织病理分析和肿瘤标志物检测进行确诊。这些检测方法往往成本较高,周期较长且灵敏度较低,无法满足临床需求。肿瘤的临床治疗手段主要有手术切除、放疗、化疗等,这些治疗手段难以根除肿瘤细胞,靶向性很差且机体损伤较大,病人非常痛苦。因此发展更有效的诊疗手段是生命医学、分析科学等领域极具有挑战和机遇的重要课题。
近年来纳米材料在生物医学中的研究和应用受到人们的广泛关注,为了避免在实际诊断和治疗过程中多次给药的缺点,科学家们研制出了多种肿瘤诊疗一体化探针,有效的实现了肿瘤组织的成像和治疗。光学成像方式具有较高的灵敏度,波长选择广且成本较低。常用的光学探针有量子点、上转换纳米材料、碳点、贵金属纳米簇等,由于其良好的光学性能和光化学稳定性在癌症的光学诊断领域展现了广阔的应用前景。然而这些纳米材料还是有很多固有问题难以解决,例如诊断时须有外源激发光持续激发,导致在成像中会受到较强的组织背景荧光干扰,无法实现较深、较小肿瘤组织的高灵敏成像。
光动力治疗(PDT)、光热治疗(PTT)等治疗方法与目前临床上采用的手术、化疗、放疗等常规治疗手段相比,展现出创伤小、毒性低、适用性好、治疗时间短、可重复治疗、保护重要器官功能等诸多优点。光动力治疗是利用光敏剂在氧气和激发光照射下产生单线态氧杀死肿瘤细胞,但由于肿瘤组织一般氧气含量较低,光敏剂的稳定性有限,因此实际治疗效果很难达到预期。目前也无法较好的实现光热、光动力和化学动力协同治疗,增强肿瘤治疗效果。
【发明内容】
本发明的目的是提供长余辉纳米复合物及其在肿瘤多模态成像和协同治疗中的应用,能够实现多模态成像,获得更全面的生物组织特性,从而对生物组织结构、功能特性及早期病变进行成像;能够实现多模态成像与多手段协同治疗一体化。
本发明采用以下技术方案:一种长余辉纳米复合物,由人血清白蛋白负载近红外吸收染料和Fe3+,并包裹在长余辉纳米材料的表面制得,为核壳结构,所述长余辉纳米材料为核,负载有近红外吸收染料和Fe3+的人血清白蛋白为壳。
进一步地,上述长余辉纳米材料、近红外染料、人血清白蛋白和Fe3+的质量比为2:3:10:1。
进一步地,上述长余辉纳米材料的粒径为30.5±5.2nm。
进一步地,上述长余辉纳米材料为Zn1.1Ga1.8Ge0.1O4:0.5%Cr3+,0.5%Eu3+。
进一步地,上述近红外吸收染料为IR780。
本发明公开了上述一种长余辉纳米复合物的制备方法,该制备方法如下:称取长余辉纳米材料、人血清白蛋白、近红外吸收染料和FeCl3,将长余辉纳米材料溶解在含有人血清白蛋白的超纯水中,超声处理,然后搅拌;然后依次加入 FeCl3水溶液、NaCl水溶液和NaOH水溶液,再次搅拌;然后,逐滴加入含有IR780 的乙醇溶液,再加入戊二醛水溶液,再次搅拌,收集固体产物,即为长余辉纳米复合物。
进一步地,长余辉纳米材料为2mg,加入的FeCl3水溶液为浓度为100mM,加入量为200μL,NaCl水溶液的浓度为1M,加入量为10μL;NaOH水溶液的浓度为2M,加入量为10μL,乙醇溶液中IR780的量为3mg,加入量为14mL。
本发明还公开了上述一种长余辉纳米复合物或上述的制备方法制备的长余辉纳米复合物,在肿瘤多模态成像中的应用;所述多模态成像包括余辉成像、核磁成像和光声成像。
本发明还公开了上述一种长余辉纳米复合物或上述的制备方法制备的长余辉纳米复合物,在制备协同光热治疗、化学动力治疗和光动力治疗的抗肿瘤药物中的应用。
本发明还公开了上述一种长余辉纳米复合物或上述的制备方法制备的长余辉纳米复合物,用于肿瘤光热、化学动力和光动力协同治疗。
本发明的有益效果是:1.避免单一成像的缺陷,提高肿瘤成像灵敏度。如图 7-9所示,通过余辉成像、核磁和光声三模态成像,可以更加精确的给出肿瘤的结构、大小和位置信息,肿瘤成像的灵敏度有了很大的提高。2.长余辉纳米复合物是,添加治疗不同的肿瘤的药物,以实现对不同肿瘤的同时诊断和治疗,实时动态监测药物的分布及治疗效果,利于随时调整治疗方案。3.PHFI可以同时实现对肿瘤的光学、核磁、光声多模态成像和化学动力、光动力、光热协同治疗,通过成像手段可以实时探测注射的PHFI所在活体的位置及含量,从而可以随时调整后续注射剂量或者治疗方案。4.极大的降低给药剂量,降低毒副作用,避免了成像和治疗需要分别注射药物,PHFI同时集合了成像与治疗功能。5.对进一步开拓多功能、特异性、安全高效的新型长余辉纳米复合物具有重要意义。
【附图说明】
图1透射电镜下PHFI的形态表征图;
图2长余辉纳米材料PLNP在紫外灯照射5min后,发射700nm处长余辉衰减曲线图;
图3长余辉纳米材料PLNP的激发-发射光谱图,其中λem=700nm;
图4长余辉纳米材料PLNP的余辉和LED重复激发光谱图;
图5尾静脉注射长余辉纳米复合物PHFI后的荷瘤小鼠分别在5min、1h和 4h的活体余辉成像图,及其在6h后主要脏器及肿瘤的余辉成像图;
图6图6a.为不同长余辉纳米复合物PHFI浓度水溶液的T1加权的核磁共振图像
图6b.T1弛豫率和静脉注射过长余辉纳米复合物PHFI后的荷瘤小鼠分别在0h 和6h的核磁共振影像图;
图7未经静脉注射过长余辉纳米复合物PHFI的荷瘤小鼠和静脉注射后1h、 6h与24h的小鼠光声成像图;
图8不同浓度长余辉纳米复合物PHFI水溶液的紫外-可见光吸收光谱图;
图9不同浓度长余辉纳米复合物PHFI的光热效果及其水溶液的升温曲线表征图;
图10长余辉纳米复合物PHFI类芬顿反应活性表征图;
图11在不同pH下对苯二甲酸氧化产物2-羟基对苯二甲酸的荧光强度验证羟基自由基的产生;
图12长余辉纳米材料PLNP@HSA-Fe和HSA-Fe在持续或间歇的650nm 激光照射下的类芬顿催化活性表征图;
图13不同浓度长余辉纳米复合物PHFI的水溶液的光动力治疗效果图;
图14光增强长余辉纳米复合物PHFI类芬顿催化活性增强光动力效果图;
图15长余辉纳米复合物PHFI的细胞内标记图;
图16不同处理后4T1细胞用Calcein-AM和PI共染色的激光共聚焦荧光显微镜成像图;
图17细胞存活CCK-8检测试剂盒评价PHFI在不同条件下对4T1细胞的杀伤效果图;
图18不同浓度PHFI的溶血分析;
图19给长余辉纳米复合物PHFI后第30天的PHFI阳性小鼠和正常小鼠主要脏器的苏木精-伊红染色图像;
图20长余辉纳米复合物PHFI的体内治疗效果图;
图21不同治疗方式下的肿瘤体积在治疗期内的变化,*p<0.01。
【具体实施方式】
下面结合附图和具体实施方式对本发明进行详细说明。
近红外发光长余辉纳米材料,用PLNP指代,具有突出的免原位激发的优点,能够有效的避免生物组织本身的自发光或者背景干扰。在实际成像应用方面,当余辉较弱时可以用白光或者红光LED灯进行重复激发,使得成像时间不再局限于材料的余辉时间,进一步扩展了长余辉纳米材料的应用范围,通过调控掺杂的离子组成、材料的粒径分布和表面修饰,赋予长余辉纳米材料多方面的功能,可用于生物检测、医学成像、疾病治疗等多个领域。
本实施例中,人血清白蛋白,用HAS指代;长余辉纳米材料,用PLNP指代;长余辉纳米复合物用PHFI指代。
本发明实施例公开了一种长余辉纳米复合物,由人血清白蛋白负载近红外吸收染料和Fe3+,并包裹在长余辉纳米材料的表面制得,为核壳结构,所述长余辉纳米材料为核,负载有近红外吸收染料和Fe3+的人血清白蛋白为壳。Fe3+可用Mn2+代替,但化学动力治疗的效果会损失,核磁成像能力也会减弱。
上述长余辉纳米材料、近红外染料、人血清白蛋白和Fe3+的质量比为2:3:10:1。
上述长余辉纳米材料的粒径为30.5±5.2nm。
上述长余辉纳米材料为Zn1.1Ga1.8Ge0.1O4:0.5%Cr3+,0.5%Eu3+。可以换成其他长余辉纳米材料,但需保证其同样具有较长的余辉时间和远红外激发效果。
上述近红外吸收染料为IR780。可以换成其他近红外激发的染料,但需保证其同样具有光热/光动力治疗的能力。
本实施例公开了上述的一种长余辉纳米复合物的制备方法,该制备方法如下:称取长余辉纳米材料、人血清白蛋白、近红外吸收染料和FeCl3,将长余辉纳米材料溶解在含有人血清白蛋白的超纯水中,超声处理,然后搅拌;然后依次加入FeCl3水溶液、NaCl水溶液和NaOH水溶液,再次搅拌;然后,逐滴加入含有IR780的乙醇溶液,再加入戊二醛水溶液,再次搅拌,收集固体产物,即为长余辉纳米复合物。
上述长余辉纳米材料为2mg,加入的FeCl3水溶液为浓度为100mM,加入量为200μL,NaCl水溶液的浓度为1M,加入量为10μL;NaOH水溶液的浓度为2M,加入量为10μL,乙醇溶液中IR780的量为3mg,加入量为14mL。
上述的一种长余辉纳米复合物或上述制备方法制备的长余辉纳米复合物,在肿瘤多模态成像中的应用。多模态成像包括余辉成像、核磁成像和光声成像。
首先合成近红外吸收染料IR780。通过四步有机反应分离纯化得到。步骤(1) 将苯肼在搅拌下与3-甲基-2-丁酮反应,得到棕红色液体;向所得红色液体中加入冰醋酸,最终得到淡黄色油状液体。步骤(2)2,3,3-三甲基-3H-吲哚及溴丙酸乙酯于单口瓶中,加少量乙腈搅拌,最后纯化得到淡黄色油状液体。步骤(3)两口瓶中加入N,N-二甲基甲酰胺(DMF),滴加三氯氧磷和二氯甲烷的混合液。再缓慢滴加环己酮,得到淡黄色固体。步骤(4)将步骤(2)和步骤(3)所得到的化合物溶于DMF中,最终得到墨绿色液体,纯化浓缩后得到深绿色目标固体染料IR780。可通过核磁和质谱的分析确定每一步反应是否成功。
合成PHFI:步骤2.1.取PLNP粉末2mg置于0.8mL水中,加入10mgHSA 超声分散均匀;步骤2.2.加入0.2mL0.02mol/L的FeCl3;步骤2.3.加入0.01mL 1mol/L的NaCl以及0.01mL2mol/L的NaOH;步骤2.4.室温搅拌5min,同时滴加14mL无水乙醇;步骤2.5.加入0.0235mL戊二醛,体积分数8%;步骤2.6. 室温搅拌约24h,离心10000rpm,10min收产物,并用无水乙醇、去离子水各洗涤一次,得到产物PHFI。室温指的是25℃。通过透射电镜观察,如图1所示,所制备的PHFI有明显的核壳结构,且壳层包覆完好。可得制备的PHFI结构、形貌合格。在HSA基础上通过一步法自聚集合成了纳米级的长余辉纳米复合物,可以增加生物相容性,降低材料毒性。
长余辉纳米材料为纳米颗粒状,为Zn1.1Ga1.8Ge0.1O4:0.5%Cr3+,0.5%Eu3+,余辉时间超过1600s,如附图2所示,表明所合成的PLNP材料具有较好的余辉性能,具有700nm左右近红外区的余辉发射。如图3所示,为PLNP的激发-发射光谱图,由图可知,表明所合成的PLNP材料能够被较宽的激发光所激发,发射在近红外区域,适合活体肿瘤光学成像。
如图4,将PLNP粉末在紫外灯下照射5min,观察其余辉的衰减至24h,然后每天用红色LED灯重新激发1min,并观察激发后1h的余辉情况。发现PLNP 在紫外灯照射后具有较强的余辉,24h后仍能够检测到该余辉信号。此外,PLNP 能够被LED灯重复激发,并且激发1h后仍具有较强的余辉。说明PLNP具有较好的余辉强度和余辉时间,有利于实现免原位激发成像,避免背景荧光干扰,且成像时间可以不再局限于余辉时间,在活体水平具有较高的应用价值。
为进一步验证长余辉纳米复合物PHFI具有余辉成像能力,进行如下实验,将荷瘤小鼠尾静脉注射PHFI,得到其分别在5min、1h和4h的活体余辉成像图,以及其在6h后主要脏器及肿瘤的余辉成像图,如图5所示,由图中可知,长余辉纳米复合物PHFI经静脉注射进入小鼠体内后,随时间推移逐渐向肿瘤部位富集,经过1小时余辉成像可以清晰地分辨出肿瘤部位的信号富集。
为验证PHFI在肿瘤中的成像效果,进行如下验证:选不同PHFI浓度,得不同PHFI浓度下溶液T1加权的核磁共振图像,如图6中的6a,并做了T1弛豫率和静脉注射过PHFI后的荷瘤小鼠分别在0h和6h的核磁共振影像图6b,9b 中,圆圈处为肿瘤,由图6可知,随着长余辉纳米复合物PHFI进入小鼠肿瘤部位,Fe3+浓度增加,小鼠肿瘤组织的T1加权核磁共振成像信号明显增强,使肿瘤部位更加明晰。
上述PHFI可作为一种良好的光声成像造影剂,将未经静脉注射过PHFI的荷瘤小鼠和静脉注射过PHFI后1h、6h与24h的小鼠进行广声成像检测,如图 7所示,随着时间的推移,肿瘤部位光声信号逐渐增强,表明PHFI具有较好的肿瘤组织成像效果。
由以上验证可知,PHFI可应用于多模态成像,可以弥补单一成像方式的局限和缺点,获得更全面的生物组织特性,从而对生物组织结构、功能特性及早期病变进行成像。
对不同浓度PHFI水溶液进行紫外-可见光吸收检测,得图8,由图8可知,从紫外光到近红外区域,PHFI有一个很宽的吸收带,特别是染料分子IR780在 780nm左右有一个近红外吸收峰。这说明在808nm激光照射下,PHFI具有较强的光热和光动力转换的潜力。并且,在808nm激光辐照下,PHFI表现出浓度依赖性的温度升高,如图9所示。说明PHFI在光的照射下能够升温且产生单线态氧,而较高的温度和单线态氧均具有杀死肿瘤细胞的作用。在1mg/mL的浓度下辐照10min后温度升高至59.4℃,而纯溶剂,即水的温度无明显升高。
进一步验证PLNP中Fe3+的作用,即由于Fe3+的存在,PHFI纳米粒子表现出类芬顿催化的活性。如图10所示,以不同浓度PHFI催化TMB显色的程度表征了该活性,TMB显色程度明显地随PHFI浓度升高而升高,最大吸收峰在652nm 附近。而类芬顿效果是分解肿瘤组织较多的双氧水,产生羟基自由基,羟基自由基具有较大的毒性,能够杀死肿瘤细胞。
图11为以不同pH下对苯二甲酸(TA)氧化产物2-羟基对苯二甲酸(HA) 的荧光强度来验证羟基自由基的产生,在反应管中产生了羟基自由基,产生的羟基自由基与样品管内的对苯二甲酸反应生成有荧光的2-羟基对苯二甲酸,通过检测荧光强度的改变间接证明有羟基自由基的产生。由图11可知,在PHFI的催化下,过氧化氢确实分解产生了具有强氧化性、能杀伤癌细胞的羟基自由基,并在富含过氧化氢且偏酸的肿瘤微环境中产率更高。随后,使用PLNP@HSA-Fe和 HSA-Fe纳米复合材料分别研究了在650nmLED光照射下的光增强催化性能,如图12所示,不同材料在持续或间歇的650nm激光照射下的类芬顿催化活性,以催化氧化四甲基联苯胺(TMB)显色的程度表征;可得,在持续或间隔的650nm LED光照射下,PLNP@HSA-Fe比HSA-Fe更能增强类芬顿活性。这些结果表明, PHFI能表现出化学动力治疗效果,且能在650nm光照射下增强催化效果。
为了研究PHFI增强光动力治疗效果的机理,进行如下验证:以二苯基苯并呋喃(DPBF)荧光猝灭程度表征不同浓度PHFI下单线态氧的产生量,如图13 所示,为可见PHFI在808nm激光照射下,使DPBF荧光强度呈浓度依赖性下降。即使在一个极低的浓度下,如5μg/m),当过氧化氢和650nm单色光共存时,也能观察到DPBF的荧光强度显著降低,如图14所示。这是由于在偏酸性的肿瘤微环境下,由于类芬顿反应产生更多的O2,使得DPBF的猝灭能力明显增强。上述结果表明,PHFI具有较好的光热和光动力转换能力,同时光增强类芬顿反应可显著提高PDT的协同治疗效果。
为了验证PHFI具有肿瘤细胞杀伤效果,进行如下细胞实验:分别用DAPI 蓝色和LysotrackerGreen绿色对细胞核和溶酶体进行染色,PHFI的荧光信号标尺大小为10μm,得PHFI的细胞内标记图,如图15所示。由图15可得,绝大部分纳米粒子富集在溶酶体中,只有少量游离在细胞质内。
图16为不同处理后4T1细胞用Calcein-AM和PI共染色的激光共聚焦荧光显微镜成像图,标尺大小为250μm,可得在不同处理手段中,单独施加PHFI 和单独施加双激光对小鼠乳腺癌细胞4T1细胞的杀伤效果都很弱,表现出强烈的绿色荧光,说明细胞呈存活状态。只有当同时施加PHFI和双激光才能造成癌细胞的大量死亡,表现强烈红色荧光,这表明了PHFI介导的CDT/PDT/PTT协同治疗具有良好疗效。如图17是细胞存活CCK-8检测试剂盒评价PHFI在不同条件下对4T1细胞的杀伤效果图,PHFI浓度为100μg/mL,*p<0.01,**p<0.001。可见PHFI加双激光处理的细胞存活率为25%,远低于分别用650nm和808nm 激光照射的细胞的46.3%和30%。对照组细胞存活率高于90%,说明激光对细胞几乎无损伤。这些结果证实了PHFI具有显著的光增强治疗效果。并应用于靶向肿瘤成像和CDT/PTT/PDT联合治疗。
为验证长余辉纳米复合物PHFI具有良好的生物相容性,进行溶血实验。在溶血实验中,即使在100μg/mL的高浓度,PHFI的溶血率也低于2.5%,如图17 所示。图18给出了给PHFI后第30天的PHFI阳性小鼠和正常小鼠主要脏器的苏木精-伊红染色图像,标尺为50μm;由图可知,小鼠的各脏器均未出现明显的炎症或组织损伤。这展现了PHFI优秀的生物相容性,证明了PHFI在体内应用方面具有足够的安全性。
为验证长余辉纳米复合物PHFI小鼠体内的活体实验效果,进行如下实验:将小鼠分成6组,分别给予不同治疗方式,不接受治疗和分别接受PHFI、双激光照射以及PHFI和双激光照射治疗的荷瘤小鼠在治疗前、治疗7天后、治疗14天后的照片;接受PHFI与两种单激光照射治疗荷瘤小鼠分别在治疗前、治疗7天后、治疗14天后的比较照片;检测治疗不同时间其肿瘤的相对大小。与PBS对照组相比,单独PHFI组和双激光照射组治疗效果不明显,抗肿瘤作用可忽略不计,如图20左所示。在650nm或808nm光照射下,PHFI处理组的肿瘤生长均被严重抑制,如图20中右所示。而PHFI在650nm和808nm双激光照射后,由于CDT/PDT/PTT的协同治疗作用,肿瘤几近消失,如图20中左所示。通过图21 中肿瘤相对体积大小的变化,可以更加直观的得出,没有进行处理的荷瘤小鼠肿瘤体积在第18天增加了10倍左右,注射PHFI或者肿瘤组织用光照射的小鼠肿瘤与未经任何处理的小鼠一样,肿瘤体积增加明显,18天内也增加了近10倍。而注射了PHFI并用650nm光照射后的小鼠肿瘤体积的增长有了明显的抑制,18 天内肿瘤体积只增加了近5倍。注射PHFI并用808nm光照后小鼠肿瘤体积增加了近3倍,也具有十分明显的抑制。而注射PHFI并用650nm和808nm双光照射后的小鼠肿瘤在18天后几乎完全消失,肿瘤得到治愈。证明在双光照射下PHFI 具有很好的肿瘤协同治疗的效果。
使用本发明中的长余辉纳米复合物,构建多模态成像与多手段协同治疗一体化,在制备长余辉纳米复合物时,可直接添加不同肿瘤治疗的药物,药物与负载有近红外吸收染料和Fe3+的人血清白蛋白混合,共同形成外壳,以实现对不同肿瘤的同时诊断和治疗,实时动态监测药物的分布及治疗效果,诊断与治疗不存在时空差异。
Claims (7)
1.一种长余辉纳米复合物,其特征在于,由人血清白蛋白负载近红外吸收染料和Fe3+,并包裹在长余辉纳米材料的表面制得,为核壳结构,所述长余辉纳米材料为核,负载有近红外吸收染料和Fe3+的人血清白蛋白为壳;
所述长余辉纳米材料为Zn1.1Ga1.8Ge0.1O4:0.5%Cr3+,0.5%Eu3+;
所述近红外吸收染料为IR780。
2.根据权利要求1所述的一种长余辉纳米复合物,其特征在于,所述长余辉纳米材料、近红外染料、人血清白蛋白和Fe3+的质量比为2:3:10:1。
3.根据权利要求1或2所述的一种长余辉纳米复合物,其特征在于,所述长余辉纳米材料的粒径为30.5±5.2nm。
4.根据权利要求1、2或3所述的一种长余辉纳米复合物的制备方法,其特征在于,该制备方法如下:称取长余辉纳米材料、人血清白蛋白、近红外吸收染料和FeCl3,将长余辉纳米材料溶解在含有人血清白蛋白的超纯水中,超声处理,然后搅拌;然后依次加入FeCl3水溶液、NaCl水溶液和NaOH水溶液,再次搅拌;然后,逐滴加入含有IR780的乙醇溶液,再加入戊二醛水溶液,再次搅拌,收集固体产物,即为长余辉纳米复合物。
5.根据权利要求4所述的一种长余辉纳米复合物的制备方法,其特征在于,所述长余辉纳米材料为2mg,加入的FeCl3水溶液为浓度为100mM,加入量为200μL,NaCl水溶液的浓度为1M,加入量为10μL;NaOH水溶液的浓度为2M,加入量为10μL,乙醇溶液中IR780的量为3mg,加入量为14mL。
6.根据权利要求1-3中任一项所述的一种长余辉纳米复合物或权利要求4或5中的制备方法制备的长余辉纳米复合物在制备肿瘤多模态成像药物中的应用;所述多模态成像包括余辉成像、核磁成像和光声成像。
7.根据权利要求1-3中任一项所述的一种长余辉纳米复合物或权利要求4或5中的制备方法制备的长余辉纳米复合物在制备协同光热治疗、化学动力治疗和光动力治疗的抗肿瘤药物中的应用。
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