CN112043682B - 一种基于多孔钆掺杂氧化铁纳米簇的磁性纳米药物载体及其制备方法 - Google Patents

一种基于多孔钆掺杂氧化铁纳米簇的磁性纳米药物载体及其制备方法 Download PDF

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CN112043682B
CN112043682B CN202010990496.7A CN202010990496A CN112043682B CN 112043682 B CN112043682 B CN 112043682B CN 202010990496 A CN202010990496 A CN 202010990496A CN 112043682 B CN112043682 B CN 112043682B
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iron oxide
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金珍
李佳
解琳艳
常金龙
赵俊强
于毅
任武
于勉
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Abstract

本发明涉及医用纳米材料技术领域，具体涉及一种基于多孔钆掺杂氧化铁纳米簇的磁性纳米药物载体及其制备方法。本发明磁性纳米结构药物载体由钆掺杂氧化铁纳米簇为核心，钆掺杂氧化铁纳米簇的表面积大且其表面富含羟基，尤其是合成介孔结构的钆掺杂氧化铁纳米簇，可负载高含量的抗癌药物。外围可降解壳层可有效的防止抗癌药物的非特异性释放，在药物达到靶向作用部位后，通过酸碱度和外部近红外光刺激使壳层材料降解，暴露出负载有药物的钆掺杂氧化铁纳米簇，实现药物释放。同时，钆掺杂氧化铁纳米簇由于其亚纳米粒子紧密集中于一体的特征表现出优秀的磁化强度，可应用于T1‑T2磁共振影像造影剂。

Description

一种基于多孔钆掺杂氧化铁纳米簇的磁性纳米药物载体及其 制备方法
技术领域
本发明涉及医用纳米材料技术领域，具体涉及一种基于多孔钆掺杂氧化铁纳米簇的磁性纳米药物载体及其制备方法。
背景技术
癌症是当前威胁人类生命健康的主要疾病之一，化疗是最常用的治疗方法。但是传统的化疗在杀死肿瘤细胞的同时，也会杀死正常细胞、破坏人体免疫系统，并且具有容易复发的缺点。因此研发具有靶向杀伤癌细胞的化疗药物递送、药物释放系统，能够降低放疗对正常细胞的副作用，提高治疗效果，对实现高效、安全的肿瘤治疗具有重要意义。本发明是基于纳米粒子的磁性靶向抗癌药物传递系统。
纳米粒子作为药物递送载体在尺寸、实现靶向功能等具有优势，其中设计合理有效的药物载体尤为关键。最理想的药物载体应该具备良好的空间、时间和剂量控制功能等特点。当药物载体随血液在人体内流动时，应保持药物分子的稳定性。当药物载体到达癌症部位时，可以迅速通过某种手段靶向释放药物，以达到治疗效果最大化和减少对正常细胞的伤害。
要获得在空间、时间和剂量上有效控制的药物载体，首先需要解决的是对药物靶向作用的有效监测。医学影像技术在肿瘤治疗过程中扮演着重要角色，如疾病的早期诊断，手术过程汇总的实时成像以及治疗后的效果跟踪等，这些技术都可以大大提高疾病的治愈率，对于临床治疗方案的制定和疗效的准确评估具有重要的指导意义。但由于每种成像方式自身的局限性，单一的成像模式不能完全提供肿瘤的形态和功能信息。所以发展多模态成像技术可以发挥各个成像模式的长处，大大提高肿瘤诊断的精度。
光热治疗是利用近红外光和光敏材料，在肿瘤部位产生热而治疗癌症的方法，结合光热疗法和靶向药物传递技术，可进一步提高癌症治疗效果，现有技术中存在利用光敏作用靶向药物传递技术的同时实现药物的控释，例如中国专利CN109453378A，通过设置光响应性聚合物外壳结构，在光的作用下控释药物，但是该专利公开的药物载体不能用作多模态成像造影剂。
因此，需研发具备负载药物、可控药物释放、多模态成像造影剂等多功能药物载体，使癌症治疗可形成治疗和诊断一体化，可提高治疗效果、减轻副作用，降低治疗成本和患者的生存质量。
韩国专利(1020180128936)；Porous magnetic nanoparticle based drugdelivery system and preparation method thereof)、日本专利(JP23003993)；SUPERPARAMAGNETIC CLUSTER-NANO PARTICLE-POROUS COMPOSITE BEAD AND FABRICATIONMETHOD THEREOF及美国专利(US9533045号；Photo-thermal therapy using magneticnanoparticles。这些专利是关于制备多孔磁性纳米粒子和多孔磁性纳米簇及设计用于光热治疗的纳米粒子的内容。但现有的这些纳米粒子只涉及到研发多孔结构的纳米粒子或光热治疗应用。缺乏提高影像诊断精确度的考虑。因此，需研发结合多模态影像造影剂、光热和化疗功能、合理的药物控释的多功能纳米粒子，提高疾病早期诊断精确度及药物利用度和治疗效果。
发明内容
为了克服现有技术的缺陷，本发明的目的之一在于提供一种基于多孔钆掺杂氧化铁纳米簇的磁性纳米药物载体，有效控制药物释放，避免药物提前释放，提高药物利用度，具有磁化增强作用，可用作T1-T2磁共振影像造影剂。
本发明的目的之二在于提供一种基于多孔钆掺杂氧化铁纳米簇的磁性纳米药物载体的制备方法。
一种基于多孔钆掺杂氧化铁纳米簇的磁性纳米药物载体，所述药物载体为核壳结构；其中核心为负载有药物的钆掺杂氧化铁纳米簇，围绕核心的壳体结构为可降解壳层。
可选的，所述壳体结构为生物可降解高分子壳层。
可选的，所述壳体结构为光热作用可降解高分子壳层。
可选的，所述可降解高分子壳层材料选自聚多巴胺(polydopamine)、透明质酸(hyaluronic acid)、二氧化硅(silica)、聚(N-异丙基丙烯酰胺)(NIPAM)、多吡咯(polypyrrole)和以上物质的衍生物中的一种或多种。作为优选的，所述可降解高分子壳层材料为聚多巴胺。
可选的，所述钆掺杂氧化铁纳米簇是GdxFeyOz，x为0.1到3的正数；y为0.1到3的正数；z为1到5的正数；所述钆掺杂氧化铁纳米簇为具有介孔的纳米结构体，所述药物负载在介孔结构中。
可选的，所述钆掺杂氧化铁纳米簇的直径为20～500nm。
可选的，所述可降解壳层聚乙二醇化；所述可降解壳层上还修饰有靶向配体分子结构。
可选的，所述靶向配体分子为抗体、多肽或适配体。作为优选的，所述靶向配体分子为叶酸。
可选的，所述的抗癌药物选自阿霉素(doxorubicine)、表柔比星(Epirubicin)、吉西他滨(Gemsitabin)、顺铂(Cisplatin)、卡铂(Carboplatin)、甲基苄肼(Procarbazine)、环磷酰胺(Cyclophosphamide)、更生霉素(Dactinomycin)、柔红霉素(Daunorubicin)、依托泊苷(Etoposide)、他莫昔芬(Tamoxifen)、丝裂霉素(Mitomycin)、博莱霉素(Bleomycin)、普卡(Plicamycin)、长春碱(Vinblastine)、甲氨蝶呤(Methotrexate)中的一种或多种。
本发明磁性纳米结构药物载体由钆掺杂氧化铁纳米簇为核心，钆掺杂氧化铁纳米簇的表面积大且其表面富含羟基，尤其是合成介孔结构的钆掺杂氧化铁纳米簇，可负载高含量的抗癌药物。外围可降解壳层可有效的防止抗癌药物的非特异性释放，在药物达到靶向作用部位后，通过酸碱度和外部近红外光刺激使壳层材料降解，暴露出负载有药物的钆掺杂氧化铁纳米簇，实现药物释放。同时，钆掺杂氧化铁纳米簇由于其亚纳米粒子紧密集中于一体的特征表现出优秀的磁化强度，可应用于T1-T2磁共振影像造影剂。
本发明药物载体可通过高通透性和滞留效应富集在肿瘤部位，并可通过酸碱度和外部近红外光刺激控制药物释放来克服目前化疗局限性之一的多药耐性。
上述基于多孔钆掺杂氧化铁纳米簇的磁性纳米药物载体，包括以下操作步骤：
1)制备多孔钆掺杂氧化铁纳米簇；
2)步骤1)制备的多孔结构钆掺杂氧化铁纳米簇中负载药物；
3)在步骤2)制备的负载有药物的多孔结构钆掺杂氧化铁纳米簇表面形成可降解壳层；
4)在壳层表面修饰聚乙二醇分子。
可选的，步骤1)制备多孔钆掺杂氧化铁纳米簇的具体方法为：将一定比例的FeCl3·6H2O和GdCl3·6H2O溶解于乙二醇和聚乙醇混合溶液，搅拌反应后，在反应体系中加入一定比例的聚谷氨酸(PGA)或聚乙烯亚胺(PEI)和乙酸铵(NH4OAc)，在氮气保护下搅拌加热反应，获得均匀透明溶液，然后升高温度加热熟化后冷却至室温，用乙醇和去离子水反复洗涤，获得黑色的PGIONC，为钆掺杂氧化铁纳米簇。
其中FeCl3·6H2O和GdCl3·6H2O质量比为1:10到10:1；乙二醇和聚乙醇为体积比为1:2到1:10；聚乙醇的分子量为300～1000；聚谷氨酸(PGA)或聚乙烯亚胺(PEI)和乙酸铵(NH4OAc)根据实际情况需要可以过量，加入的含量可微调多孔钆掺杂氧化铁纳米簇的大小。
其中搅拌反应的温度为80℃，时间为30分钟；搅拌加热反应的温度为120℃，时间为1小时；升高温度加热熟化为加热至200℃，熟化8小时。
可选的，步骤2)多孔结构钆掺杂氧化铁纳米簇中负载药物的具体方法为：将一定量的多孔钆掺杂氧化铁纳米簇分散到PBS缓冲液(pH 7.4)中，加入阿霉素(DOX)搅拌反应，并反复洗涤和磁铁收集得到DOX负载的多孔钆掺杂氧化铁纳米簇。
其中搅拌过程中，搅拌温度可以是4～40℃，搅拌速度可以是400到1000rpm/min。
可选的，步骤3)中负载有药物的多孔结构钆掺杂氧化铁纳米簇表面形成可降解壳层的具体方法为：取负载有药物的多孔钆掺杂氧化铁纳米簇并超声分散于PDA Tris缓冲液溶液(50ml，pH 8.5)室温搅拌反应，用磁选法反复洗涤并收集DOX-PGIONC@PDA纳米粒子，即为钆掺杂氧化铁纳米簇的磁性纳米药物载体。其中形成的PDA作为一种可降解高分子聚合物，是为了形成可降解壳层，应当可以理解的是还可以使用其他材料形成可降解壳层；其中负载有药物的多孔钆掺杂氧化铁纳米簇与PDA的浓度和反应时间影响所形成的PDA的厚度，作为优选的，负载有药物的多孔钆掺杂氧化铁纳米簇与PDA的浓度相等，反应时间为4小时。
根据需要，还可以进一步在壳层材料表面修饰聚乙二醇分子和靶向分子(如；叶酸)，具体步骤如下；将一定比率的PGIONC@PDA纳米粒子或负载有药物的PGIONC@PDA纳米粒子分散于Tris缓冲液溶液(20ml，pH 8.5)，加入聚乙二醇二胺(PEG-diamine,MW2000),室温搅拌，反应2小时候，用磁选法洗条并收集PGIONC@PDA/PEG纳米粒子。
FA表面修饰可通过羧基与氨基的化学偶联反应实现，具体步骤如下；将一定量的FA溶解于DMSO溶液，并按比例加入EDC和NHS进行行羧基催化，随后逐步滴入到PGIONC@PDA/PEG分散的溶液中Tris溶液中，在室温下反应2小时后，磁选法反复洗条并收集PGIONC@PDA/PEG/FA纳米粒子。
附图说明
图1为本发明实施例中制备多孔钆掺杂氧化铁纳米簇的整体结构及工艺过程示意图；
图2为本发明实施例制备的多孔钆掺杂氧化铁纳米簇的磁性纳米药物载体透射电镜图；
图3为本发明实施例制备的多孔钆掺杂氧化铁纳米簇的磁性纳米药物载体的药物负载和药物控释结果图；
图4为本发明实施例制备的多孔钆掺杂氧化铁纳米簇的磁性纳米药物载体的T1-T2MR成像结果图。
具体实施方式
下面结合具体实施例对本发明做进一步的详细说明。除特殊说明的之外，各实施例及试验例中所用的设备和试剂均可从商业途径得到。
实施例
本实施例制备基于多孔钆掺杂氧化铁纳米簇的磁性纳米药物载体，具体制备方法为：
1)制备多孔钆掺杂氧化铁纳米簇(PGIONC)
采用改良的溶剂热法合成尺寸均一、稳定性高的PGIONC，具体步骤如下；将一定比例的FeCl3·6H2O和GdCl3·6H2O溶解于乙二醇(15ml)和聚乙醇(30ml)混合溶液并在80℃搅拌30分钟，在反应体系中加入一定比例的聚谷氨酸(PGA)和乙酸铵(NH4OAc)，在120℃氮气保护下搅拌加热1小时，获得均匀透明溶液。随后，封入内衬特氟隆不锈钢高压釜内，加热至200℃，熟化8小时后冷却至室温，并用乙醇和去离子水反复洗涤，获得黑色的PGIONC；整体结构及工艺过程指示图如图1所示。
其中根据实际需要选择FeCl3·6H2O和GdCl3·6H2O的用量比例，可调整范围为1:10到10:1；可以根据所需要获得的多孔钆掺杂氧化铁纳米簇的大小调整聚谷氨酸(PGA)和乙酸铵(NH4OAc)的用量，其用量调整范围为0.5～2g。
2)多孔钆掺杂氧化铁纳米簇孔内负载抗癌药物(DOX-PGIONC纳米粒子)
由于PGIONC的多孔结构且其表面富含羟基，PGIONC介孔内可封装较高含量的抗癌药物(DOX)，DOX负载步骤具体如下；将PGIONC分散到PBS缓冲液(pH 7.4)中。加入DOX进行反应4小时，反复洗涤和磁铁收集得到DOX-PGIONC纳米粒子；
其中需要通过实验确定纳米簇的封装率和最大载药量，具体方法为，将PGIONC分散到PBS缓冲液(pH 7.4)中，加入一系列不同比例的DOX进行反应4小时，并反复洗条和磁铁收集得到DOX-PGIONC纳米粒子，利用紫外可见吸收光谱仪(UV-vis)确定封装率并确定其最大药物装载量，结合确定的封装率和最大载药量，结合实际制备药物的药效需求，选择合适的PGIONC和DOX用量；
另外，应当可以理解的是，本实施例中以DOX作为药物成分仅作为举例说明，可以根据实际需要选用其他药物成分，按照上述方法负载在多孔钆掺杂氧化铁纳米簇孔内；
3)在负载药物的多孔钆掺杂氧化铁纳米簇表面形成生物可降解高分子聚合物壳层：
利用PDA在碱性pH下自聚合特性，在DOX-PGIONC表面形成一定厚度的PDA层，PDA层的厚度可通过PDA反应浓度和反应时间调整。具体步骤如下，取一定量的PGIONC超生分散于同浓度的PDA溶解Tris缓冲液溶液(50ml，pH 8.5)室温搅拌4h，用磁选法反复洗涤并收集DOX-PGIONC@PDA纳米粒子，即为多孔钆掺杂氧化铁纳米簇的磁性纳米药物载体，其透射电镜图如图2所示。
另外，需要解释的是，为了提高纳米粒子在血液中的分散性，本发明多孔钆掺杂氧化铁纳米簇的磁性纳米药物载体的表面还可进行聚乙二醇化，将一定比率的DOX-PGIONC@PDA纳米粒子分散于Tris缓冲液溶液(20ml，pH 8.5)，加入聚乙二醇二胺(PEG-diamine,MW2000),室温搅拌，反应2小时候，用磁选法洗条并收集DOX-PGIONC@PDA/PEG纳米粒子。
结合实际的靶向作用需求，还可以选择在其表面修饰靶向配体分子，例如叶酸(FA)，将一定量的FA溶解于DMSO溶液，并按比例加入EDC和NHS进行行羧基催化，随后逐步滴入到DOX-PGIONC@PDA/PEG分散的溶液中Tris溶液中，在室温下反应2小时后，磁选法反复洗条并收集DOX-PGIONC@PDA/PEG/FA纳米粒子。
试验例利用近经红外光(波长；808nm)和酸碱度药物控释
试验方法及结果：
1)分别取相应的样品，分别分散在5mLPBS溶液(pH；5.0和7.4)中，并分别转移至透析袋(MWCO：3500Da)中，将透析袋分别置于装有50mLPBS(pH；5.0和7.4)的容器中，NIR处理5分钟后在37度的温度下150rpm摇动，从每个样品中分别取出1mL处理后的样品，并保存在无光的环境中进行进一步分析，将1mL新鲜PBS加回容器中以保持恒定体积；使用紫外可见分光光度计分析每个实验组样品中的DOX浓度，计算释放DOX的累积速率作为时间的函数。并按照上述同样的方法处理对照组样品，不进行近红外光作用，结果如图3所示，由于PGIONC@PDA的介孔结构，该药物载体的药物负载率高达38.6％，该纳米药物载体因PDA和药物的π-π堆垛作用，可在正常的生理环境(pH 7.4)中很好的封存药物，但在酸性(肿瘤部位pH 5.0)环境下，由于π-π堆垛作用的减弱，迅速释放药物。此外，通过近红外光作用下产生的热效应，进一步提升药物释放，通过酸碱度和近红外的双重刺激下该纳米药物载体可在24小时内释放37.8％药物。
试验例体外T1-T2 MR成像实验
试验方法及结果：
所有的MR成像研究均在Philips Achieva 3.0T MRI扫描仪上进行，将磁性纳米气泡加入PBS(pH＝7.4)稀释获得不同浓度的PGIONC@PD样品(Gd；0、0.05、0.1、0.15、0.25mM,Fe；0、0.1、0.2、0.3、0.5mM)，并置于直径1厘米的离心管中，使用以下参数获得T1和T2加权的图像，T1图像(TR/TE＝1000/11ms),T2图像(TR/TE＝4000/72ms).其结果如图4所示。
最后应说明的是：以上实施例仅用以说明本发明的技术方案，而非对其限制；尽管参照前述实施例对本发明进行了详细的说明，本领域的普通技术人员应当理解：其依然可以对前述各实施例所记载的技术方案进行修改，或者对其中部分技术特征进行等同替换；而这些修改或者替换，并不使相应技术方案的本质脱离本发明各实施例技术方案的精神和范围。

Claims (7)

1.一种基于多孔钆掺杂氧化铁纳米簇的磁性纳米药物载体，其特征在于，所述药物载体为核壳结构；其中核心为负载有药物的钆掺杂氧化铁纳米簇，围绕核心的壳体结构为可降解壳层；其中钆掺杂氧化铁纳米簇为具有介孔的纳米结构体，药物负载在介孔结构中；可降解壳层由聚多巴胺形成。
2.如权利要求1所述的基于多孔钆掺杂氧化铁纳米簇的磁性纳米药物载体，其特征在于，所述钆掺杂氧化铁纳米簇是GdxFeyOz，x为0.1到3的正数；y为0.1到3的正数；z为1到5的正数。
3.如权利要求2所述的基于多孔钆掺杂氧化铁纳米簇的磁性纳米药物载体，其特征在于，所述钆掺杂氧化铁纳米簇的直径为20~500nm。
4.如权利要求1~3任一项所述的基于多孔钆掺杂氧化铁纳米簇的磁性纳米药物载体，其特征在于，所述可降解壳层聚乙二醇化；所述可降解壳层上还修饰有靶向配体分子结构。
5.如权利要求4所述的基于多孔钆掺杂氧化铁纳米簇的磁性纳米药物载体，其特征在于，所述靶向配体分子为抗体、多肽或适配体。
6.如权利要求1~3任一项所述的基于多孔钆掺杂氧化铁纳米簇的磁性纳米药物载体，其特征在于，所述的药物选自阿霉素（doxorubicin）、表柔比星（Epirubicin）、吉西他滨（Gemcitabine）、顺铂（Cisplatin）、卡铂（Carboplatin）、甲基苄肼（Procarbazine）、环磷酰胺（Cyclophosphamide）、更生霉素（Dactinomycin）、柔红霉素（Daunorubicin）、依托泊苷（Etoposide）、他莫昔芬（Tamoxifen）、丝裂霉素（Mitomycin）、博莱霉素（Bleomycin）、普卡霉素（Plicamycin）、长春碱（Vinblastine）、甲氨蝶呤（Methotrexate）中的一种或多种。
7.一种如权利要求6所述的基于多孔钆掺杂氧化铁纳米簇的磁性纳米药物载体，其特征在于，包括以下操作步骤：
1）制备多孔钆掺杂氧化铁纳米簇；
2）步骤1）制备的多孔结构钆掺杂氧化铁纳米簇中负载药物；
3）在步骤2）制备的负载有药物的多孔结构钆掺杂氧化铁纳米簇表面形成可降解壳层；
4）在壳层表面修饰聚乙二醇分子。
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