CN109395106B - 一种结构稳定的纳米铋球簇及其制备方法与应用 - Google Patents
一种结构稳定的纳米铋球簇及其制备方法与应用 Download PDFInfo
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Abstract
本发明公开了纳米铋球簇和负载药物的纳米铋球簇及制备方法与应用,属于生物与医学纳米材料领域。本发明公开了一种来源于口服胃药的一步法简单快速合成高安全性的多功能纳米探针。通过紫外光照射后一步法合成了具有CT/光声双模态成像功能的纳米铋球簇。该纳米铋球簇具有尺寸均一,稳定性好,光热转换效率高,低毒性,良好的生物相容性等优点。探针吸附抗肿瘤药物后,可直接用于动物实验。探针可以通过EPR效应被肿瘤细胞吞噬,同时可利用近红外光与肿瘤的酸性环境实现负载的抗肿瘤药物可控释放,达到药物和光热联合治疗目的,且治疗效果显著优于单一模式治疗。
Description
技术领域
本发明属于生物与医学纳米材料领域,具体涉及一种结构稳定的纳米铋球簇及制备方法与应用。
背景技术
癌症严重威胁着人类的健康与生命。特别是在发展中国家,由于有效筛查技术少、早期诊断技术水平低等因素导致癌症发现时普遍偏晚,再加上肿瘤治疗效果差且副作用大、复发转移率高、精准性差等原因导致肿瘤治疗难度更大。因此探索安全、简便的诊疗技术对提高癌症患者的生存率有着非常重要的意义。
在肿瘤的诊断方面,CT、MRI、PET和超声等成像方法发挥着重要的作用。然而由于不同成像方式原理不同,每种成像模式都有自己独特的优点,同时又存在自身的局限,因此单一成像模式往往无法满足疾病诊断的全部需求。
无论是造影剂探针或光热纳米制剂,一个不容忽视的问题就是其安全性。由于这些纳米材料基本上都是来源于昂贵的化学试剂,且在合成、纯化等诸多繁琐步骤中不可避免的需要使用各种溶剂、表面活性剂等,这些试剂往往都具有一定毒性,它们的残留会给探针的在体使用带来较大的毒副作用,故探针的毒性始终是一个巨大安全隐患。
发明内容
本发明解决了现有技术中造影剂无法在多种成像条件下同时使用,负载药物的载体无法可控释放,以及现有技术中的造影剂具有毒性存在安全隐患的技术问题。
按照本发明的第一方面,提供了一种结构稳定的纳米铋球簇的制备方法,含有以下步骤:
(1)将能溶于水的铋盐和具有羟基、羧基或氨基的聚合物溶于水得到溶液A,或者将能溶于水的铋盐和多肽溶于水得到溶液B,或者将药品丽珠得乐溶于水得到溶液C;
(2)将步骤(1)得到的溶液A、溶液B或溶液C在紫外光下照射3min-4min,使所述溶液A、溶液B或溶液C中的铋盐被还原得到单质铋,所述单质铋聚集形成铋球簇,所述溶液A或溶液C中的聚合物通过分子间作用力吸附在所述铋球簇表面,或者所述溶液B中的多肽通过分子间作用力吸附在所述铋球簇表面;
(3)将步骤(2)所得产物以4000rad/min-6000rad/min的转速离心15min-20min,弃沉淀取上清,即得到结构稳定的纳米铋球簇。
优选地,所述能溶于水的铋盐为枸橼酸铋钾或柠檬酸铋;所述聚合物为羧甲基纤维素钠、聚乙烯吡咯烷酮或聚乙二醇;所述能溶于水的铋盐中的铋原子和聚合物的质量之比为1:(5-8)。
按照本发明的另一方面,提供了所述方法制备得到的结构稳定的纳米铋球簇,所述结构稳定的纳米铋球簇为铋原子聚集形成的铋球簇,具有羟基、羧基或氨基的聚合物通过分子间作用力吸附在所述铋球簇表面,或者多肽通过分子间作用力吸附在所述铋球簇表面;所述聚合物或者多肽用于使铋球簇形成结构稳定的球体。
优选地,所述结构稳定的纳米铋球簇的直径为25nm-55nm;所述聚合物为羧甲基纤维素钠、聚乙烯吡咯烷酮或聚乙二醇。
按照本发明的另一方面,提供了一种负载药物的结构稳定的纳米铋球簇,所述负载药物的结构稳定的纳米铋球簇含有权利要求3或4所述的结构稳定的纳米铋球簇和水溶性药物;所述水溶性药物通过共价键与纳米铋球簇表面的聚合物或多肽连接。
优选地,所述水溶性药物为抗肿瘤药物、抗菌药或抗血栓药;
优选地,所述抗肿瘤药物为为盐酸阿霉素、5-氟尿嘧啶或水溶性紫杉醇前药。
按照本发明的另一方面,提供了所述负载药物的结构稳定的纳米铋球簇的制备方法,其特征在于,将权利要求3或4所述的结构稳定的纳米铋球簇以及水溶性药物加入到缓冲溶液中,避光搅拌10h-12h后,然后以8000rad/min-10000rad/min的转速离心10min-15min,弃上清取沉淀,即得到负载药物的结构稳定的纳米铋球簇。
优选地,所述水溶性药物为抗肿瘤药物、抗菌药或抗血栓药;
优选地,所述抗肿瘤药物为为盐酸阿霉素、5-氟尿嘧啶或水溶性紫杉醇前药。
按照本发明的另一方面,提供了所述的结构稳定的纳米铋球簇用于光声成像和/或CT成像的造影剂的应用;
优选地,所述光声成像的激发波长为523nm-744nm。
按照本发明的另一方面,提供了所述的结构稳定的纳米铋球簇在制备药物载体中的应用。
总体而言,通过本发明所构思的以上技术方案与现有技术相比,主要具备以下的技术优点:
(1)本发明所述的纳米铋球簇具有CT和光声双模态成像的效果。光声成像提供微量癌症相关分子在组织中的分布和位置情况,CT成像提供深部组织空间结构信息,这样就能通过优势互补同时获取高灵敏度癌症相关的分子信息和高分辨率的病理组织图像,由于肿瘤的早期诊断可以大大提高患者的存活率,这种双模态成像不仅有助于减少检查次数,降低服用成像造影剂的剂量,更可获得多维度信息,因此对于提高早期诊断的准确率,降低误诊风险有着巨大帮助。
(2)本发明所述的纳米铋球簇自身具有光热效应。光热治疗利用正常组织和肿瘤细胞对温度耐受能力的差异,达到既能使肿瘤细胞凋亡,又不损伤正常组织的治疗目的;而且光热治疗不但对肿瘤细胞有直接的毒杀效应,还可以明显增强化疗的疗效,抑制和预防恶性肿瘤的复发和转移,这是由于热疗在杀死肿瘤细胞的同时,还有助于化疗药物进入肿瘤组织增加化疗药物的细胞毒性。本发明所述的纳米铋球簇的高光热转换效率可以满足深部肿瘤光热治疗,同时也减少纳米探针使用。
(3)本发明所述负载药物的纳米铋球簇为药物的可控释放。负载药物的纳米铋球簇可以通过EPR效应被肿瘤细胞吞噬,同时可利用近红外光与肿瘤的酸性环境实现负载的抗肿瘤药物DOX(盐酸阿霉素)可控释放,达到药物和光热联合治疗目的,且治疗效果显著优于单一模式治疗。负载在纳米铋球簇上的药物(盐酸阿霉素)可通过降低pH(降低的pH小于血液生理的pH)或激光照射两种手段控制药物释放,既保证了精准靶向治疗,又可保证药物对正常组织无额外伤害。
(4)本发明所述的纳米铋球簇可用具备国药准字号的口服胃药丽珠得乐制备得到,安全可靠,完全没有任何添加。而且丽珠得乐价格低廉,胃药丽珠得乐(<1RMB/g)作为唯一原料,通过紫外光照射后一步法合成了具有CT和光声双模态成像功能的纳米铋球簇,其具有光热转换效率高、尺寸均一以及稳定的特点,而且其具有低毒性和良好的生物安全性,经过简单的离心洗涤,吸附抗肿瘤药物DOX后就可直接用于动物的活体实验。小鼠主要器官H&E染色和血液生化指标监测表明,探针也具有良好的生物安全性。结果表明,该纳米铋球簇可以很好的用于肿瘤的在体双模态成像与化疗和光热联合治疗效果。
附图说明
图1是本发明负载药物的纳米铋球簇的制备流程图。
图2是本发明的纳米铋球簇的结构示意图。
图3是本发明的纳米铋球簇的透射电镜图。
图4是本发明的纳米铋球簇的光热效应图。
图5是本发明多功能探针的光声和CT双模态成像:图5(a)是多功能探针的光声成像,图5(b)是多功能探针的CT成像。
图6是本发明多功能纳米探针负载盐酸阿霉素后不同条件下的药物释放曲线:图6(a)为不同pH条件下药物的释放曲线;图6(b)为有激光照射和无激光照射条件下药物的释放曲线。
图7是将本发明的反应时间缩短至1.5min后的产物电镜图。
具体实施方式
为了使本发明的目的、技术方案及优点更加清楚明白,以下结合附图及实施例,对本发明进行进一步详细说明。应当理解,此处所描述的具体实施例仅仅用以解释本发明,并不用于限定本发明。此外,下面所描述的本发明各个实施方式中所涉及到的技术特征只要彼此之间未构成冲突就可以相互组合。
以下各个实施例中的所用的药品丽珠得乐为丽珠集团丽珠制药厂生产,国药准字为H10900086,产品批号为1709134。
实施例1:制备纳米铋球簇
将1g丽珠得乐(含有枸橼酸铋钾BPC和羧甲基纤维素钠)溶于超纯水中,定容至5mL,吸取2mL重新定容至25mL超纯水中,紫外灯照射3min后,5000rad/min离心15min取上清即可得到纳米铋球簇。
实施例2:制备载药纳米铋球簇
制备负载药物的纳米铋球簇的过程如图1所示。将实施例1中合成好的纳米铋球簇(铋原子的质量为1g)与40μg DOX(盐酸阿霉素)加入5mL PBS中避光搅拌12h,8000rad/min离心10min弃上清后沉淀重悬,重复三次即得到载药纳米铋球簇,避光保存。负载药物的纳米铋球簇的结构示意图如图2所示。
实施例3:对本发明纳米铋球簇进行透射电镜观察
将实施例1制备的本发明纳米铋球簇作透射电镜观察,透射电镜图见图3。图中即为纳米铋球簇,左上角插图为高分辨透射电子显微镜下的单质铋球,晶格清晰可见。
实施例4:对本发明纳米铋球簇进行光热效应实验
取150μL不同浓度(以铋为基准,0.25,0.5,1.0和2.0mg/mL)实施例1的纳米铋球簇,以及4mg/mL的丽珠得乐水溶液置于可拆卸酶标板孔中,使用1.0W/cm2的808nm激光照射样品5min,用红外热成像仪记录样品随激光照射的温度变化。同样方法测定浓度为1.0mg/mL实施例1的纳米铋球簇在不同激光强度(1.0,1.5和2.0W/cm2)下的温度变化。
图4是本发明的纳米铋球簇的光热效应图。当照射激光的功率一定时,纳米铋球簇的温度随着浓度的增加而增加,1mg/mL时达到饱和,作为对照4mg/mL的丽珠得乐溶液并没有明显的光热效应,证明光热效应不是来自于胃药本身。而当纳米铋球簇浓度一定时,温度随着激光功率的增加而增加。
实施例5:对本发明纳米铋球簇进行CT/光声成像
将不同浓度梯度(以铋为基准,0.3,0.6,0.9,1.2和1.5mg/mL)的探针水溶液放置于PCR管中,进行CT成像,其中CT成像系统的条件为:空间分辨率是100μm,实验中的管电压是50kV,管电流是0.800mA。同时将上述浓度梯度的探针注入软管中,检测探针的光声信号,激光波长为744nm,能量为120nJ。
图5是本发明多功能探针的光声和CT双模态成像:图5(a)是多功能探针的光声成像,图5(b)是多功能探针的CT成像。从图5中可以看出,随着Bi浓度的增加,本探针的光声与CT造影效果明显增强,且强度与探针浓度呈良好的线性关系。不仅如此,探针的CT强度约是等质量浓度碘海醇的两倍。
实施例6:对本发明载药纳米铋球簇进行可控药物释放实验
将实施例2中合成的本发明载药探针(以铋为基准0.6mg)分别溶于pH为5.4和7.4的3mL PBS中,放入分子量为500的透析袋中,透析液也调节成对应的pH,每隔一段时间取出透析液测定其中DOX含量并放回,以此考察本发明载药探针的pH响应下的药物释放。DOX的释放率为释放出的DOX总质量/载入的DOX总量×100%。
将实施例2中合成的本发明载药探针(以铋为基准0.6mg)分别分散在1mL的PBS溶液中(pH=7.4),37℃水浴12h,每隔2h取出8000rad/min离心10min,测上清中DOX的量后加入PBS重悬并用808nm激光器(1W/cm2)照射5min,同样离心测上清中DOX的量,加入PBS重悬后再放回37℃水浴锅中,前后共照射6次;另一组做同样的处理只是不用激光照射,以此考察本发明载药探针的激光响应下的药物释放。DOX的释放率为释放出的DOX总质量/载入的DOX总量×100%。
图6是本发明多功能纳米探针负载盐酸阿霉素后不同条件下的药物释放曲线:图6(a)为不同pH条件下药物的释放曲线;图6(b)为有激光照射和无激光照射条件下药物的释放曲线。由图6(a)可以得知,pH=5.4时,药物释放量要远大于pH=7.4;由图6(b)可以得知,激光照射下的药物释放速率要远高于无激光照射。
实施例7
将120mg羧甲基纤维素钠与称取120mg柠檬酸铋溶于溶于25mL水中,紫外灯照射3min后5000rad/min离心15min取上清,得到的溶液不能够稳定存在。
实施例8
将1g丽珠得乐(含有枸橼酸铋钾BPC和羧甲基纤维素钠)溶于超纯水中,定容至5mL,吸取2mL重新定容至25mL超纯水中,紫外灯照射1.5min后,5000rad/min离心15min取上清,得到的溶液不能够稳定存在,透射电子显微镜观察到的结果如图7所示。
对比例1
若加入的羧甲基纤维素钠不足或紫外照射时间小于3min,则会造成铋球大多数以单个分散形式存在,铋球簇的数量较少,且整个溶液体系不能够稳定的存在。
本领域的技术人员容易理解,以上所述仅为本发明的较佳实施例而已,并不用以限制本发明,凡在本发明的精神和原则之内所作的任何修改、等同替换和改进等,均应包含在本发明的保护范围之内。
Claims (10)
1.一种结构稳定的纳米铋球簇的制备方法,其特征在于,含有以下步骤:
(1)将能溶于水的铋盐和具有羟基、羧基或氨基的聚合物溶于水得到溶液A,或者将能溶于水的铋盐和多肽溶于水得到溶液B,或者将药品丽珠得乐溶于水得到溶液C;所述能溶于水的铋盐为枸橼酸铋钾或柠檬酸铋;所述聚合物为羧甲基纤维素钠、聚乙烯吡咯烷酮或聚乙二醇;所述能溶于水的铋盐中的铋原子和聚合物的质量之比为1:(5-8);
(2)将步骤(1)得到的溶液A、溶液B或溶液C在紫外光下照射3min-4min,使所述溶液A、溶液B或溶液C中的铋盐被还原得到单质铋,所述单质铋聚集形成铋球簇,所述溶液A或溶液C中的聚合物通过分子间作用力吸附在所述铋球簇表面,或者所述溶液B中的多肽通过分子间作用力吸附在所述铋球簇表面;
(3)将步骤(2)所得产物以4000rad/min-6000rad/min的转速离心15min-20min,弃沉淀取上清,即得到结构稳定的纳米铋球簇。
2.由权利要求1所述方法制备得到的结构稳定的纳米铋球簇,其特征在于,所述结构稳定的纳米铋球簇为铋原子聚集形成的铋球簇,具有羟基、羧基或氨基的聚合物通过分子间作用力吸附在所述铋球簇表面,或者多肽通过分子间作用力吸附在所述铋球簇表面;所述聚合物或者多肽用于使铋球簇形成结构稳定的球体。
3.如权利要求2所述的结构稳定的纳米铋球簇,其特征在于,所述结构稳定的纳米铋球簇的直径为25nm-55nm;所述聚合物为羧甲基纤维素钠、聚乙烯吡咯烷酮或聚乙二醇。
4.一种负载药物的结构稳定的纳米铋球簇,其特征在于,所述负载药物的结构稳定的纳米铋球簇含有权利要求2或3所述的结构稳定的纳米铋球簇和水溶性药物;所述水溶性药物通过共价键与纳米铋球簇表面的聚合物或多肽连接。
5.如权利要求4所述的负载药物的结构稳定的纳米铋球簇,其特征在于,所述水溶性药物为抗肿瘤药物、抗菌药或抗血栓药。
6.如权利要求5所述的负载药物的结构稳定的纳米铋球簇,其特征在于,所述抗肿瘤药物为盐酸阿霉素、5-氟尿嘧啶或水溶性紫杉醇前药。
7.如权利要求4或5所述负载药物的结构稳定的纳米铋球簇的制备方法,其特征在于,将权利要求3或4所述的结构稳定的纳米铋球簇以及水溶性药物加入到缓冲溶液中,避光搅拌10h-12h后,然后以8000rad/min-10000rad/min的转速离心10min-15min,弃上清取沉淀,即得到负载药物的结构稳定的纳米铋球簇。
8.如权利要求7所述的负载药物的结构稳定的纳米铋球簇的制备方法,其特征在于,所述水溶性药物为抗肿瘤药物、抗菌药或抗血栓药。
9.如权利要求8所述的负载药物的结构稳定的纳米铋球簇的制备方法,其特征在于,所述抗肿瘤药物为为盐酸阿霉素、5-氟尿嘧啶或水溶性紫杉醇前药。
10.权利要求2或3所述的结构稳定的纳米铋球簇在制备药物载体中的应用。
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