CN111840546A - 一种低氧激活前药联合光治疗靶向纳米粒 - Google Patents

一种低氧激活前药联合光治疗靶向纳米粒 Download PDF

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CN111840546A
CN111840546A CN201910288533.7A CN201910288533A CN111840546A CN 111840546 A CN111840546 A CN 111840546A CN 201910288533 A CN201910288533 A CN 201910288533A CN 111840546 A CN111840546 A CN 111840546A
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calcium carbonate
hypoxia
polydopamine
nanoparticle
targeting
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陈彦佐
黄夏钦
高峰
张苗
王研
王钰婕
孙玲娜
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East China University of Science and Technology
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Abstract

本发明涉及一种低氧激活前药联合光治疗靶向纳米粒，具体涉及一种联合化疗、光动力和光热疗法的具有酸敏感性和靶向作用的载光敏剂和低氧激活前药的碳酸钙‑聚多巴胺纳米粒，属于生物医药技术领域。本发明通过将低氧激活前药载于碳酸钙内核，在其表面包裹聚多巴胺，装载光敏剂，并修饰含聚乙二醇长链的两亲性分子和肿瘤靶向多肽头基，制备得到具有长循环性、酸敏感性和主动靶向性的多功能纳米粒，实现肿瘤光动力治疗、光热治疗和化疗的联用，提高肿瘤的治疗效率。

Description

一种低氧激活前药联合光治疗靶向纳米粒
技术领域
本发明涉及一种低氧激活前药联合光治疗靶向纳米粒，具体涉及一种联合化疗、光动力和光热疗法的具有酸敏感性和靶向作用的载光敏剂和低氧激活前药的碳酸钙-聚多巴胺纳米粒，属于生物医药技术领域。
背景技术
恶性肿瘤作为全球范围内引起死亡的重要因素之一，已经成为影响人类健康的第二大疾病。在诸多抗肿瘤治疗手段中，光动力疗法以其毒性小、几乎无耐药性、选择性破坏和时间可控性等优势而备受关注，成为世界肿瘤治疗领域的研究热点之一，并已应用于多种恶性肿瘤的临床治疗。将纳米技术与光动力疗法结合，开发出包载光敏剂的纳米药物传递系统，可有效提高光敏剂的稳定性，延长其体内血液循环半衰期，增加其在肿瘤组织的蓄积，从而提高光动力疗法的肿瘤治疗效果。
尽管如此，随着氧气的消耗和近红外光敏剂的光漂白损耗，光动力疗法抗肿瘤作用逐渐减弱。近年来，采用多种疗法联合治疗恶性肿瘤已成为肿瘤治疗的主流策略，其抗肿瘤疗效较单一疗法显著提高。光热疗法作为一种与光动力疗法类似的新型抗肿瘤技术，常与光动力疗法联合发挥协同治疗作用。光热疗法杀伤肿瘤组织的两个基本要素是光热转换剂和激发光源。波长700～1000nm的近红外光能穿透皮下1cm厚的组织而对正常组织无影响，因而常用来作为光热疗法的激发光源。光热转换剂可分为无机光热材料类和有机光热材料类，其中有机光热材料因具有更高的生物安全性而备受关注。聚多巴胺是一种新型的共轭高分子类有机光热转换剂，其光热转换效率超过金纳米棒达到40％；且作为天然黑色素的主要成分，聚多巴胺具有良好的生物相容性和生物可降解性，显示出极大的研究和发展潜力。聚多巴胺纳米粒可通过多巴胺在碱性环境下氧化自聚合得到，反应条件简单易控制。此外，聚多巴胺纳米粒表面存在羟基、氨基和大π键，可同时作为多功能载药平台，用来递送一些小分子药物和修饰其它功能基团，从而实现光热疗法与其它疗法的联合作用。
绝大多数实体瘤存在缺氧微环境，且光动力疗法治疗会进一步消耗肿瘤组织中的氧分子生成活性氧簇，如单线态氧、超氧阴离子自由基、羟基自由基等，导致肿瘤组织缺氧状况加剧，限制光动力疗法的抗肿瘤作用。为了克服这一缺点，人们尝试了许多方法，如共同输送氧分子或开发低氧依赖甚至不依赖氧的光敏剂等。然而由于肿瘤的异质性和复杂的病理生理环境，这些方法在制剂学和临床转化上存在一定困难。作为一种简便且可操作性强的策略，将抗肿瘤低氧激活前药与光动力疗法联用，可显著增强整体抗肿瘤效果。低氧激活前药本身无毒性作用，但其会被肿瘤低氧细胞中的还原酶触发，生成自由基代谢产物，破坏周围生物大分子的结构，从而选择性杀伤低氧肿瘤细胞。目前国内外对低氧激活前药治疗恶性肿瘤的实验研究已取得可喜进展，但在研究中人们发现大多低氧激活前药在肿瘤组织中的渗透性较差，代谢速度快以至于难以到达肿瘤深处。对此，通过构建靶向纳米药物传递系统包载低氧激活前药，可有效增加其在肿瘤部位的蓄积，提高其体内稳定性，并实现化疗与肿瘤光动力疗法、光热疗法的结合，发挥协同抗肿瘤作用。
发明内容
针对现有技术的缺陷，本发明将低氧激活化疗药和光敏剂载于具有酸敏感性和光热效应的碳酸钙-聚多巴胺纳米粒，并修饰含聚乙二醇长链的两亲性分子和肿瘤靶向多肽头基，制备得到联合光疗和化疗的多功能纳米粒，来提高肿瘤治疗效率。
本发明的目的是制备新型的联合光动力疗法、光热疗法和化疗的具有酸敏感性和靶向作用的载光敏剂和低氧激活前药的碳酸钙-聚多巴胺纳米粒，通过以下技术方案实现：
一种低氧激活前药联合光治疗靶向纳米粒，其特征在于，所述的靶向纳米粒为表面修饰两亲性分子和靶向头基的聚多巴胺包裹碳酸钙双载药纳米粒，是通过以下方法制备而成，具体包括如下步骤：
1)将氯化钙水合物与低氧激活前药溶于无水乙醇，氯化钙在无水乙醇中的浓度为0.005～0.03M，低氧激活前药在无水乙醇中的浓度为0.005～0.05mg/mL，与2～10g碳酸氢铵一同放入真空密闭干燥容器内，室温放置8～36h，得到载药碳酸钙纳米粒；
2)将步骤1)的载药碳酸钙纳米粒离心、复溶于质量百分比0.10～0.15％的十二烷基苯磺酸钠水溶液，载药碳酸钙纳米粒复溶浓度为0.5～5mg/mL，再次离心，分散于pH 8.0～9.0、质量百分比为0.1～0.2％的多巴胺三羟甲基氨基甲烷缓冲液，载药碳酸钙纳米粒分散浓度为0.5～3.0mg/mL，室温搅拌6～24h，离心得到聚多巴胺包裹的载药碳酸钙纳米粒；
3)将步骤2)的聚多巴胺包裹的载药碳酸钙纳米粒以1～10mg/mL均匀分散于纯水中，搅拌加入含大π键的光敏剂水溶液，聚多巴胺包裹的载药碳酸钙纳米粒在光敏剂中的浓度为0.05～1mg/mL，避光搅拌1～6h，使光敏剂载于聚多巴胺表面，透析除去未装载的光敏剂；
4)将含有聚乙二醇链的两亲性分子和靶向头基修饰的两亲性分子的水溶液搅拌滴入步骤3)所得的溶液中，使聚乙二醇链的两亲性分子和靶向头基修饰的两亲性分子在步骤3)所得的溶液中的浓度分别为0.2～1mg/mL和0.06～0.6mg/mL，在0～30℃条件下避光搅拌4～24h，离心得到载低氧激活前药和光敏剂的碳酸钙-聚多巴胺靶向纳米粒，即低氧激活前药联合光治疗靶向纳米粒。
所述步骤1)中的低氧激活前药为选自替拉扎明、艾伏磷酰胺、巴诺蒽醌中的一种；氯化钙水合物为一水或六水合氯化钙的一种或两种。
所述步骤(2)中的载药碳酸钙纳米粒的离心条件为1～6℃，8000～10000rpm。
所述步骤3)的含大π键的光敏剂为选自吲哚菁绿、替莫泊芬、二氢卟吩e6中的一种。
所述步骤4)的含有聚乙二醇链的两亲性分子为选自聚乙二醇维生素E琥珀酸酯、聚氧乙烯脂肪酸酯、聚氧乙烯脂肪醇醚、聚氧乙烯-聚氧丙烯共聚物中的一种或几种；靶向头基为选自RGD肽、叶酸、转铁蛋白、茴香酰胺中的一种或几种。
本发明的优点：利用气体分散法和多巴胺的氧化自聚合，制备了一种具有酸敏感性和光热效应的碳酸钙-聚多巴胺纳米粒，并以其作为多功能载药平台包载光敏剂和低氧激活前药，同时在其表面修饰含聚乙二醇链的两亲性分子和肿瘤靶向多肽头基，得到联合光动力疗法、光热疗法和低氧激活化疗的纳米粒，并赋予该纳米粒体内长循环和对肿瘤的靶向功能。
附图说明：
图1-A为RGD肽修饰的载吲哚菁绿和替拉扎明的碳酸钙-聚多巴胺纳米粒(ICG-PDA-TPZ NPs)的粒径分布；图1-B1、图1-B2和图1-B3为载替拉扎明的碳酸钙纳米粒(TPZNPs)、聚多巴胺包裹的载替拉扎明碳酸钙纳米粒(PDA-TPZ NPs)和ICG-PDA-TPZNPs的形态。RGD肽修饰的载吲哚菁绿和替拉扎明的碳酸钙-聚多巴胺纳米粒的粒径小于200nm，分布均一，呈圆整的球形，纳米粒间无粘连和聚集现象。
图2-A为聚多巴胺包裹碳酸钙纳米粒(PDA NPs)的电子顺磁共振波谱，PDA NPs的电子顺磁共振波谱呈现单峰，其g因子接近于2.0，表明PDA NPs中形成不规则交联的网状结构，且该单醌残基网络上交替排列着共价键和自由基；图2-B为多巴胺和PDA NPs的傅里叶变换红外光谱，PDA NPs中-NH2的伸缩振动峰(3344.2cm-1和3217.5cm-1)和-N-H-的拉伸振动峰(2720.7cm-1、2640.0cm-1、2539.1cm-1和2433.9cm-1)消失，而在1625.3cm-1和1470.3cm-1处出现了吲哚结构的特征峰。
图3为RGD肽修饰的载吲哚菁绿和替拉扎明的碳酸钙-聚多巴胺纳米粒(ICG-PDA-TPZNPs)在pH 7.4和pH 5.5的磷酸盐缓冲液中的累积释药特性。其中，吲哚菁绿在两种不同pH环境下从纳米粒中释放的情况无明显差别。而替拉扎明在pH 7.4的释放介质中，48h的累积释放率仅为35.2％；在pH 5.5条件下，其48h的累积释放率增加为73.2％。因此肿瘤酸性微环境同样会促进ICG-PDA-TPZ NPs中替拉扎明的释放，可增强纳米粒对肿瘤的杀伤作用。
图4-A1、图4-A2、图4-A3、图4-A4为采用荧光探针1,3-二苯基异苯并呋喃(DPBF)测定对照组纯水、碳酸钙-聚多巴胺纳米粒(PDA NPs)、游离ICG和载吲哚菁绿的碳酸钙-聚多巴胺纳米粒(ICG-PDA NPs)的单线态氧的产生，游离ICG和ICG-PDA NPs组溶液中DPBF的吸收峰强度随光照时间的延长逐渐减弱，说明溶液中有单线态氧产生，消耗DPBF使溶液的颜色消失。图4-B为ICG-PDA NPs水溶液光热效应的考察，在光照下，载吲哚菁绿的碳酸钙-聚多巴胺纳米粒(ICG-PDA NPs)溶液的温度随光照时间的延长和纳米粒浓度的增加而升高，呈现出时间和浓度依赖的光热转换性质。
图5：加入游离吲哚菁绿或载吲哚菁绿的碳酸钙-聚多巴胺纳米粒(ICG-PDA NPs)孵育2h后，U87MG细胞内活性氧的产生情况，证明了载ICG纳米粒在U87MG细胞内光照后能够有效产生ROS。
图6-A和图6-B分别为载吲哚菁绿的碳酸钙-聚多巴胺纳米粒(ICG-PDA NPs)和RGD肽修饰的载吲哚菁绿和替拉扎明的碳酸钙-聚多巴胺纳米粒(ICG-PDA-TPZ NPs)对U87MG细胞的毒性。联合了光动力治疗、光热治疗和低氧激活化疗的载吲哚菁绿和替拉扎明的碳酸钙-聚多巴胺纳米粒使U87MG细胞的存活率显著减低，具有更强的体外抗肿瘤效果，三者联用后显示出协同增效作用。
图7-A为尾静脉注射游离吲哚菁绿、无RGD修饰的ICG-PDA NPs和RGD肽修饰的ICG-PDA NPs后6h、24h和48h时皮下荷U87MG瘤小鼠的活体荧光图像，图7-B和7-C为48h后离体主要脏器和肿瘤组织的荧光分布图及其荧光强度定量分析。给药后24h和48h，RGD肽修饰的ICG-PDA NPs荧光信号主要集中于肿瘤部位，且明显强于其他各组肿瘤荧光信号，说明经RGD修饰的纳米粒更有利于肿瘤部位的蓄积，表明本发明制备的靶向头基修饰的载药纳米粒具有良好的肿瘤靶向性。
图8-A、8-B、8-C和8-D为RGD肽修饰的载吲哚菁绿和替拉扎明的碳酸钙-聚多巴胺纳米粒(ICG-PDA-TPZ NPs)对皮下荷U87MG瘤小鼠(8-A，8-B)和原位荷B16F10瘤小鼠(8-C，8-D)的体内抗肿瘤作用；其中图8-A和8-C分别为治疗期各组的肿瘤生长曲线；图8-B和8-D分别为治疗结束后各组离体肿瘤的重量。结果表明联合了光动力治疗、光热治疗和低氧激活化疗的纳米粒，在两种肿瘤模型上均具有更强的体内抗肿瘤效果，可有效抑制肿瘤生长。
图9-A和9-B为治疗后各组肿瘤组织缺氧免疫荧光切片图及荧光定量分析。实验结果证实了经光动力治疗、光热治疗和低氧激活化疗后肿瘤组织缺氧状况的加剧，可进一步激活替拉扎明的化疗作用。
具体实施方式
通过下列实施实例进一步说明本发明的技术方案，但本发明的保护范围，不局限于此。
实施例1：
将150mg CaCl2·H2O和2mg低氧激活前药替拉扎明加入盛有100mL无水乙醇的烧杯中，搅拌使之充分溶解，并在烧杯口覆盖带孔的锡箔纸，置于干燥器中，同时放置装有6g碳酸氢铵的敞口西林瓶，并将无水硫酸铜置于干燥器下层，于抽真空状态下室温放置24h，即得载替拉扎明碳酸钙纳米粒无水乙醇溶液。离心上述纳米粒溶液，离心沉淀加入0.1％的十二烷基苯磺酸钠水溶液复溶，冰浴下探头超声20min。再次离心后，通过多巴胺的氧化自聚合制备聚多巴胺包裹的载替拉扎明碳酸钙纳米粒：取10mg离心所得的载替拉扎明碳酸钙纳米粒分散于20mL含有多巴胺的三羟甲基氨基甲烷缓冲液(1.5mg/mL，pH 8.5)，室温搅拌12h，离心即得聚多巴胺包裹的载替拉扎明碳酸钙纳米粒。取5mg上述聚多巴胺包裹的载替拉扎明碳酸钙纳米粒均匀分散于5mL去离子水中，边搅拌边滴入1mL吲哚菁绿水溶液(1mg/mL)，于20℃避光搅拌2h使吲哚菁绿通过π-π共轭连接于聚多巴胺表面，避光透析除去未连接的吲哚菁绿。最后在纳米粒外层修饰PEG长链和靶向头基：向上述纳米粒溶液中加入0.5mL TPGS水溶液和0.1mL TPGS-RGD水溶液(浓度均为5mg/mL)，室温避光搅拌4h，离心即得低氧激活前药联合光疗靶向纳米粒。
实施例2：
将220mg CaCl2·6H2O和3mg低氧激活前药巴诺蒽醌加入盛有100mL无水乙醇的烧杯中，搅拌使之充分溶解，并在烧杯口覆盖带孔的锡箔纸，置于干燥器中，同时放置装有8g碳酸氢铵的敞口西林瓶，并将无水硫酸铜置于干燥器下层，于抽真空状态下室温放置24h，即得载巴诺蒽醌碳酸钙纳米粒无水乙醇溶液。离心上述纳米粒溶液，离心沉淀加入0.15％的十二烷基苯磺酸钠水溶液复溶，冰浴下探头超声20min。再次离心后，通过多巴胺的氧化自聚合制备聚多巴胺包裹的载巴诺蒽醌碳酸钙纳米粒：取10mg离心所得的载巴诺蒽醌碳酸钙纳米粒分散于20mL含有多巴胺的三羟甲基氨基甲烷缓冲液(1.0mg/mL，pH 8.5)，室温搅拌10h，离心即得聚多巴胺包裹的载巴诺蒽醌碳酸钙纳米粒。取4mg上述聚多巴胺包裹的载巴诺蒽醌碳酸钙纳米粒均匀分散于5mL纯水中，边搅拌边滴入1mL吲哚菁绿水溶液(1mg/mL)，于20℃避光搅拌1h使吲哚菁绿通过π-π共轭连接于聚多巴胺表面，避光透析除去未连接的吲哚菁绿。最后在纳米粒外层修饰PEG长链和靶头：向上述纳米粒溶液中加入1.0mLTPGS水溶液和0.2mL TPGS-叶酸水溶液(浓度均为3mg/mL)，室温避光搅拌6h，离心即得低氧激活前药联合光疗靶向纳米粒。
实施例3：
将110mg CaCl2·H2O和1mg低氧激活前药替拉扎明加入盛有100mL无水乙醇的烧杯中，搅拌使之充分溶解，并在烧杯口覆盖带孔的锡箔纸，置于干燥器中，同时放置装有8g碳酸氢铵的敞口西林瓶，并将无水硫酸铜置于干燥器下层，于抽真空状态下室温放置24h，即得载替拉扎明碳酸钙纳米粒无水乙醇溶液。离心上述纳米粒溶液，离心沉淀加入0.4％的十二烷基苯磺酸钠水溶液复溶，冰浴下探头超声20min。再次离心后，通过多巴胺的氧化自聚合制备聚多巴胺包裹的载替拉扎明碳酸钙纳米粒：取10mg离心所得的载替拉扎明碳酸钙纳米粒分散于20mL含有多巴胺的三羟甲基氨基甲烷缓冲液(1.2mg/mL，pH 8.0)，室温搅拌11h，离心即得聚多巴胺包裹的载替拉扎明碳酸钙纳米粒。取6mg上述聚多巴胺包裹的载替拉扎明碳酸钙纳米粒均匀分散于5mL纯水中，边搅拌边滴入1mL替莫泊芬水溶液(1mg/mL)，于25℃避光搅拌3h使Ce6通过π-π共轭连接于聚多巴胺表面，避光透析除去未连接的替莫泊芬。最后在纳米粒外层修饰PEG长链和靶头：向上述纳米粒溶液中加入0.6mL TPGS水溶液和0.6mL TPGS-RGD水溶液(浓度均为4mg/mL)，室温避光搅拌8h，离心即得低氧激活前药联合光疗靶向纳米粒。
实施例4：
将330mg CaCl2·6H2O和4mg低氧激活前药替拉扎明加入盛有150mL无水乙醇的烧杯中，搅拌使之充分溶解，并在烧杯口覆盖带孔的锡箔纸，置于干燥器中央，同时放置装有8g干燥碳酸氢铵的敞口西林瓶，并将无水硫酸铜置于干燥器下层，于抽真空状态下室温放置24h，即得载替拉扎明碳酸钙纳米粒无水乙醇溶液。离心上述纳米粒溶液，离心沉淀加入0.26％的十二烷基苯磺酸钠水溶液复溶，冰浴下探头超声20min。再次离心后，通过多巴胺的氧化自聚合制备聚多巴胺包裹的载替拉扎明碳酸钙纳米粒：取10mg离心所得的载替拉扎明碳酸钙纳米粒分散于20mL含有多巴胺的三羟甲基氨基甲烷缓冲液(2.0mg/mL，pH 8.6)，室温搅拌16h，离心即得聚多巴胺包裹的载替拉扎明碳酸钙纳米粒。取8mg上述聚多巴胺包裹的载替拉扎明碳酸钙纳米粒均匀分散于5mL纯水中，边搅拌边滴入1mL吲哚菁绿水溶液(1mg/mL)，于30℃避光搅拌6h使吲哚菁绿通过π-π共轭连接于聚多巴胺表面，避光透析除去未连接的吲哚菁绿。最后在纳米粒外层修饰PEG长链和靶头：向上述纳米粒溶液中加入0.6mL普朗尼克P105水溶液和0.2mL普朗尼克P105-RGD水溶液(浓度均为4mg/mL)，室温避光搅拌10h，离心即得低氧激活前药联合光疗靶向纳米粒。
实施例5：
将128mg CaCl2·H2O和2mg低氧激活前药替拉扎明加入盛有50mL无水乙醇的烧杯中，搅拌使之充分溶解，并在烧杯口覆盖带孔的锡箔纸，置于干燥器中，同时放置装有8g碳酸氢铵的敞口西林瓶，并将无水硫酸铜置于干燥器下层，于抽真空状态下室温放置12h，即得载替拉扎明碳酸钙纳米粒无水乙醇溶液。离心上述纳米粒溶液，离心沉淀加入0.05％的十二烷基苯磺酸钠水溶液复溶，冰浴下探头超声20min。再次离心后，通过多巴胺的氧化自聚合制备聚多巴胺包裹的载替拉扎明碳酸钙纳米粒：取10mg离心所得的载替拉扎明碳酸钙纳米粒分散于20mL含有多巴胺的三羟甲基氨基甲烷缓冲液(1.3mg/mL，pH 8.7)，室温搅拌12h，离心即得聚多巴胺包裹的载替拉扎明碳酸钙纳米粒。取6mg上述聚多巴胺包裹的载替拉扎明碳酸钙纳米粒均匀分散于5mL纯水中，边搅拌边滴入1mL吲哚菁绿水溶液(1mg/mL)，于40℃避光搅拌5h使吲哚菁绿通过π-π共轭连接于聚多巴胺表面，避光透析除去未连接的吲哚菁绿。最后在纳米粒外层修饰PEG长链和靶头：向上述纳米粒溶液中加入0.4mL TPGS水溶液和0.1mL TPGS-转铁蛋白水溶液(浓度均为6mg/mL)，室温避光搅拌18h，离心即得低氧激活前药联合光疗靶向纳米粒。
实施例6：
将280mg CaCl2·6H2O和3mg低氧激活前药替拉扎明加入盛有120mL无水乙醇的烧杯中，搅拌使之充分溶解，并在烧杯口覆盖带孔的锡箔纸，置于干燥器中，同时放置装有8g碳酸氢铵的敞口西林瓶，并将无水硫酸铜置于干燥器下层，于抽真空状态下室温放置24h，即得载替拉扎明碳酸钙纳米粒无水乙醇溶液。离心上述纳米粒溶液，离心沉淀加入0.3％的十二烷基苯磺酸钠水溶液复溶，冰浴下探头超声20min。再次离心后，通过多巴胺的氧化自聚合制备聚多巴胺包裹的载替拉扎明碳酸钙纳米粒：取10mg离心所得的载替拉扎明碳酸钙纳米粒分散于20mL含有多巴胺的三羟甲基氨基甲烷缓冲液(2.0mg/mL，pH 9.0)，室温搅拌8h，离心即得聚多巴胺包裹的载替拉扎明碳酸钙纳米粒。取5mg上述聚多巴胺包裹的载替拉扎明碳酸钙纳米粒均匀分散于5mL纯水中，边搅拌边滴入1mL吲哚菁绿水溶液(1mg/mL)，于37℃避光搅拌4h使吲哚菁绿通过π-π共轭连接于聚多巴胺表面，避光透析除去未连接的吲哚菁绿。最后在纳米粒外层修饰PEG长链和靶头：向上述纳米粒溶液中加入0.8mL普朗尼克F127水溶液和0.6mL普朗尼克F127-茴香酰胺水溶液(浓度均为3mg/mL)，室温避光搅拌16h，离心即得低氧激活前药联合光疗靶向纳米粒。
通过上述实施例和各个附图可以看出，该载药纳米粒具有良好的光动力单线态氧产生能力和增强的光热效应；可有效增加药物在肿瘤部位的蓄积；并具有显著增强的体内外抗肿瘤效果。

Claims (5)

1.一种低氧激活前药联合光治疗靶向纳米粒，其特征在于，所述的靶向纳米粒为表面修饰两亲性分子和靶向头基的聚多巴胺包裹碳酸钙双载药纳米粒，是通过以下方法制备而成，具体包括如下步骤：
1)将氯化钙水合物与低氧激活前药溶于无水乙醇，氯化钙在无水乙醇中的浓度为0.005～0.03M，低氧激活前药在无水乙醇中的浓度为0.005～0.05mg/mL，与2～10g碳酸氢铵一同放入真空密闭干燥容器内，室温放置8～36h，得到载药碳酸钙纳米粒；
2)将步骤1)的载药碳酸钙纳米粒离心、复溶于质量百分比0.10～0.15％的十二烷基苯磺酸钠水溶液，载药碳酸钙纳米粒复溶浓度为0.5～5mg/mL，再次离心，分散于pH8.0～9.0、质量百分比为0.1～0.2％的多巴胺三羟甲基氨基甲烷缓冲液，载药碳酸钙纳米粒分散浓度为0.5～3.0mg/mL，室温搅拌6～24h，离心得到聚多巴胺包裹的载药碳酸钙纳米粒；
3)将步骤2)的聚多巴胺包裹的载药碳酸钙纳米粒以1～10mg/mL均匀分散于纯水中，搅拌加入含大π键的光敏剂水溶液，聚多巴胺包裹的载药碳酸钙纳米粒在光敏剂中的浓度为0.05～1mg/mL，避光搅拌1～6h，使光敏剂载于聚多巴胺表面，透析除去未装载的光敏剂；
4)将含有聚乙二醇链的两亲性分子和靶向头基修饰的两亲性分子的水溶液搅拌滴入步骤3)所得的溶液中，使聚乙二醇链的两亲性分子和靶向头基修饰的两亲性分子在步骤3)所得的溶液中的浓度分别为0.2～1mg/mL和0.06～0.6mg/mL，在0～30℃条件下避光搅拌4～24h，离心得到载低氧激活前药和光敏剂的碳酸钙-聚多巴胺靶向纳米粒，即低氧激活前药联合光治疗靶向纳米粒。
2.如权利要求1所述的低氧激活前药联合光治疗靶向纳米粒，其特征在于，所述步骤1)中的低氧激活前药为选自替拉扎明、艾伏磷酰胺、巴诺蒽醌中的一种；氯化钙水合物为一水或六水合氯化钙的一种或两种。
3.如权利要求1所述的低氧激活前药联合光治疗靶向纳米粒，其特征在于，所述步骤(2)中的载药碳酸钙纳米粒的离心条件为1～6℃，8000～10000rpm。
4.如权利要求1所述的低氧激活前药联合光治疗靶向纳米粒，其特征在于，所述步骤3)的含大π键的光敏剂为选自吲哚菁绿、替莫泊芬、二氢卟吩e6中的一种。
5.如权利要求1所述的低氧激活前药联合光治疗靶向纳米粒，其特征在于，所述步骤4)的含有聚乙二醇链的两亲性分子为选自聚乙二醇维生素E琥珀酸酯、聚氧乙烯脂肪酸酯、聚氧乙烯脂肪醇醚、聚氧乙烯-聚氧丙烯共聚物中的一种或几种；靶向头基为选自RGD肽、叶酸、转铁蛋白、茴香酰胺中的一种或几种。
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