CN115006523A - 一种近红外二区响应性纳米颗粒的制备方法 - Google Patents

一种近红外二区响应性纳米颗粒的制备方法 Download PDF

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CN115006523A
CN115006523A CN202111210380.8A CN202111210380A CN115006523A CN 115006523 A CN115006523 A CN 115006523A CN 202111210380 A CN202111210380 A CN 202111210380A CN 115006523 A CN115006523 A CN 115006523A
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黄彬
柯诗祺
柯静
倪卓娜
苏燕青
何燕彬
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Fujian Nanping Green Pine Chemical Co ltd
Fujian University of Traditional Chinese Medicine
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Fujian University of Traditional Chinese Medicine
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Abstract

本发明公开了一种近红外二区响应性纳米颗粒的制备方法，其包括如下步骤：将聚乙烯吡咯烷酮、没食子酸和氯化铜溶解于超纯水中，混匀后，加入硫化钠，反应后，得到硫化铜纳米颗粒；将卵磷脂、二硬脂酰磷脂酰乙醇胺‑聚乙二醇和所述硫化铜纳米颗粒溶解于水中，在50℃下加入相变材料、单萜敏化剂和乙醇，在0℃下进行反应，得到所述近红外二区响应性纳米颗粒。本发明通过将单萜敏化剂冰片和硫化铜(CuS NPs)结合作为光热剂，响应纳米材料，直接靶向转移恶性细胞，避免化疗药物对正常细胞的损伤，从而减缓患者接受药物治疗的痛苦。

Description

一种近红外二区响应性纳米颗粒的制备方法
技术领域
本发明涉及一种近红外二区响应性纳米颗粒的制备方法，属于抗肿瘤药物技术领域。
背景技术
目前临床针对肿瘤治疗上主要以手术切除辅助化疗药物、通路阻断剂类药物或抗体类药物进行。但是上述治疗方式面临患者创伤面积大、毒副作用大、组织靶向选择性差以及药物代谢消耗等问题。
作为一种适应性反应，肿瘤细胞可以提高其抗氧化能力，例如，肿瘤细胞中谷胱甘肽(GSH)水平的升高，进一步赋予肿瘤细胞抗凋亡和耐药性。更糟糕的是，肿瘤细胞中GSH水平的升高作为一种活性氧类(ROS)清除剂，不仅大大降低了ROS类药物治疗的疗效，而且促进了肿瘤的转移，从而使肿瘤死亡率高，难以治愈。
作为典型的非侵入性光激发治疗策略，光动力治疗(PDT)已经被批准应用于临床并且在治疗食道癌、皮肤癌与非小细胞肺癌等方面取得了很大的成功。这是目前临床上出现等一种新型治疗方法，利用光动力效应，特定波长照射肿瘤部位，能使选择性聚集在肿瘤组织的光敏药物活化，引发光化学反应破坏肿瘤。
光动力疗法中的光敏药物会将能量传递给周围的氧，生成活性很强的单态氧，产生细胞毒性进而杀伤肿瘤细胞。PDT包含三个要素：光、光敏剂与氧气。在特定波长光的激发下，光敏剂可以被选择性地激活并产生具有细胞毒性的ROS，它可以造成核内DNA的破坏进而诱导癌细胞死亡。
肿瘤光热治疗是一种借助光源热源来杀灭癌细胞的物理疗法，基本原理是在激光照射条件下，利用光热转换产生的高热量来破坏、消除癌细胞。相较于手术和放化疗等传统治疗，光热疗法理论上可以做到更精准、更可控、更高效，并可降低对正常组织的损伤。
当前肿瘤光热治疗是利用光热试剂(即吸光纳米材料)在激光照射下产生的热量来直接杀灭肿瘤细胞，其核心在于发展具有良好生物安全性与高速率的光热转化效率的光热试剂；光热治疗作为一种新兴的治疗肿瘤的手段受到研究人员广泛的关注。纳米光热治疗技术具有适用范围广、非侵入、选择性强、过程简单、正常组织损伤小等优点，在肿瘤治疗、药物释控、光控植入材料等领域展现出巨大的应用价值。然而，目前制约肿瘤光热治疗临床转化的主要问题有以下几个方面：
1、光热试剂的体内滞留时间长且难以分解代谢；
2、以金、银、铂和钯等为代表的贵金属纳米粒子，成本较高、光热稳定性较差，且有一定的毒性；
3、单纯激发光的功率来提高肿瘤光热治疗的效果，势必将会对肿瘤周边组织造成较为明显的损伤，故光热试剂的光热转化效率有待优化与提高；
4、光热试剂的肿瘤递送效果较低且存在明显的个体差异；
5、激发光的组织穿透深度有限(<1cm)且易造成周边正常组织损伤等；
6、光热疗法会因光源穿透组织容易逐步衰减，而无法消融较大体积的肿瘤。
发明内容：
本发明的目的在于提供一种具有近红外二区响应性纳米颗粒的制备方法，以解决现有技术中所存在的上述问题。
为了实现上述目的，本发明的技术方案如下：
一种近红外二区响应性纳米颗粒的制备方法，其包括如下步骤：
将聚乙烯吡咯烷酮、没食子酸和氯化铜溶解于超纯水(Milli-Q)中，混匀后，加入硫化钠，反应后，得到硫化铜纳米颗粒；
将卵磷脂、二硬脂酰磷脂酰乙醇胺-聚乙二醇和所述硫化铜纳米颗粒溶解于水中，在50℃下加入相变材料、单萜敏化剂和乙醇，在0℃下进行反应，得到所述近红外二区响应性纳米颗粒。
作为优选方案，所述相变材料和单萜敏化剂的重量比为1：1。
作为优选方案，所述单萜敏化剂为冰片。
作为优选方案，所述相变材料为1-十六醇和油酸的混合物。
作为优选方案，所述1-十六醇和油酸的质量比为3.5：1。
一种由前述的任意一种制备方法得到的近红外二区响应性纳米颗粒。
一种如前述的近红外二区响应性纳米颗粒在光热治疗药物中的用途。
本发明的实现原理为：以中药作载体合成的高分子材料，以不同的形式与药物分子通过化学键合、物理吸附或包裹，构成药物控制系统。在不降低原有药效并抑制其副作用的情况下，以合适的浓度和时间将药物控释系统导向至病患的部位，然后通过一系列的物理、化学及生物控制，将药物等以最佳剂量和时间释放出来，达到定时、定位、定量发挥药物的疗效。
更具体地体现在以下几个方面：
1、本发明提供了一个近红外二区(NIR-II)激活的纳米平台用于光热治疗和细胞内氧化稳态干扰；
2、该纳米平台使用相变材料(PCM)用于包装硫化铜纳米颗粒(CuS NPs)和冰片(NB)，其中，PCM可以在1060nm激光照射下通过高温熔化，实现NB和CuS NPs的热响应释放；
3、在酸性肿瘤环境下，从CuS@NPs解离的铜离子通过消耗GSH被还原为Cu+；
4、肿瘤内的H2O2被转化为高毒的羟基自由基，破坏细胞内氧化稳态；
5、NB可以增加细胞内ROS的含量以增强化学动力学疗法的治疗效果。
与现有技术相比，本发明具有如下的有益效果：
1、本发明通过将单萜敏化剂冰片和硫化铜(CuS)纳米颗粒结合作为光热剂，响应纳米材料，直接靶向转移恶性细胞，避免化疗药物对正常细胞的损伤，从而减缓患者接受药物治疗的痛苦；
2、光热效应更具灵活性，通过改变入射角度和偏振方向，将带来更多的温度分布的可能性，实现更加灵活的局域温度控制。相变材料(PCM)用于封装CuS纳米颗粒和NB，会直接破坏细胞内氧化还原稳态和热失活肿瘤细胞。NIR-II光热剂具有GSH消除的特性，用于干扰细胞内氧化还原稳态的NB/CuS@PCM，光热疗法在体外和体内均显示出明显的抗肿瘤作用。
附图说明
通过阅读参照以下附图对非限制性实施例所作的详细描述，本发明的其它特征、目的和优点将会变得更明显：
图1 CuS@PCM纳米颗粒和NB/CuS@PCM纳米颗粒的吸收光谱。
图2 NB/CuS@PCM纳米颗粒在扫描电镜下的结构呈像。
图3 1W/cm功率的1064nm激光照射下，含有不同浓度的NB/CuS@PCM纳米颗粒溶液的温度情况。
图4 100μg/ml的NB/CuS@PCM纳米颗粒在不同功率的激光照射下的纳米颗粒溶液的温度情况。
图5 NB/CuS@PCM核磁共振谱的光热稳定性测定
图6不同浓度下而实验表明NB/CuS@PCM纳米颗粒的羟基自由基的生成能力。
图7 NB/CuS@PCM纳米颗粒的GSH清除能力。
图8 NB/CuS@PCM纳米颗粒的冰片释放能力。
图9无远红外刺激下，NB/CuS@PCM纳米颗粒与传统的CuS@PCM纳米颗粒杀伤乳腺癌4T1细胞的能力差异。
图10远红外刺激下，NB/CuS@PCM纳米颗粒与传统的CuS@PCM纳米颗粒杀伤乳腺癌4T1细胞的能力差异。
图11在有、无热刺激下，NB/CuS@PCM纳米颗粒清除GSH的能力差异
图12 NB/CuS@PCM纳米颗粒与传统的CuS@PCM纳米颗粒，在有、无远红外光激发条件下，促进细胞产生活性氧的能力差异。
图13不同浓度冰片对乳腺癌4T1的细胞毒性作用。
具体实施方式
下面结合具体实施例对本发明进行详细说明。以下实施例将有助于本领域的技术人员进一步理解本发明，但不以任何形式限制本发明。应当指出的是，对本领域的普通技术人员来说，在不脱离本发明构思的前提下，还可以做出若干变形和改进。这些都属于本发明的保护范围。
实施例1
本实施例提供了一种近红外二区响应性纳米颗粒的制备方法，具体包括如下步骤：
将100mg聚乙烯吡咯烷酮、20mg没食子酸和86mg CuCl2溶解在10mLMilli-Q水中。搅拌1小时后，加入200mg硫化钠。溶液颜色将在几秒钟内变为黑色，搅拌4小时后，所得产物用10000Da分子量截留透析袋透析，并使用0.22μm注射器过滤器过滤，得到硫化铜纳米颗粒，记为CuS NPs；
将20mg卵磷脂、10mgDSPE-PEG和10mgCuS NPs溶解在10mL水中并加热至50℃。在超声处理条件下，将PCM(10mg)和NB(10mg)的乙醇混合物快速注入上述溶液中。然后将所得溶液在冰浴中冷却。通过透析和过滤纯化后，得到近红外二区响应性纳米颗粒，记为NB/CuS@PCMNPs。
将含冰片的相变材料滴加到硫酸铜纳米颗粒悬浮液中，在冰水浴中冷却，可制备NB/CuS@PCM纳米颗粒。该图片说明含有冰片的NB/CuS@PCM纳米颗粒的吸收光谱与传统的不含冰片的CuS@PCM纳米颗粒相比没有显著差异，如图1所示。
表征通过以下几个方式进行测定：
通过动态光散射仪、扫描电子显微镜和透射电子显微镜分析纳米颗粒的尺寸分布和形貌。粉末X射线衍射(XRD)图案通过D8 Advance X射线衍射仪实现。
扫描电镜图像如图2所示，NB/CuS@PCM纳米颗粒的形状为球形，平均直径为52.9nm。
UV-3600UV-vis-NIR光谱仪用于收集吸收光谱。采用E50红外相机测量样品温度变化。NB的释放行为是使用香兰素作为显色试剂监测的。(将一定量的含有10mg·mL-1香草醛的浓硫酸溶液加入到250μL样品或NB标准溶液中。所得溶液在室温下放置10分钟。最后，在监测吸收光谱变化之前，用水稀释(1:1)所得溶液。)
光热测通过以下几个方式进行测定：
不同浓度的NB/CuS@PCM NPs暴露于1060nm激光(1W·cm-2)。并且使用FLIR红外相机确定样品的温度变化。为了评估光热稳定性，在五个激光开关循环期间监测NB/CuS@PCMNPs的温度变化。
GSH耗竭包括以下几个步骤：
将不同浓度的NB/CuS@PCM NPs溶液(pH＝6.5)与GSH和DTNB探针混合。GSH和DTNB探针的浓度分别为10mM和100mM。然后使用UVvis-NIR光谱仪收集样品的吸收光谱。
化学动力学活性测定包括以下几个步骤：
将用1060nm激光(1mg·mL-1)处理的NB/CuS@PCM NPs溶液与不同的溶液(pH＝6.5)孵育，例如，NB/CuS@PCM+MB，NB/CuS@PCM+MB+H2O2。MB和H2O2的浓度分别为10μg·mL-1和10mM。孵育3小时后，用紫外-可见光谱仪对样品进行表征以监测吸收光谱的变化。
细胞活力测试包括以下步骤：
每孔(96孔板)中加入150μL4T1细胞(5×105个细胞每mL)，孵育16小时。然后用NB/CuS@PCM NPs和CuS@PCM NPs处理细胞。为了评估纳米颗粒的光热治疗性能，用1060nm激光照射细胞。为了评估纳米颗粒的暗毒性，在没有激光处理的情况下培养细胞。再培养12小时后，进行常规细胞毒性试验。
细胞内ROS检测包括以下步骤：
首先，用1060nm激光处理NB/CuS@PCM NPs和CuS@PCM NPs。所得分散液(pH＝6.5，H2O2＝50μM)与4T1细胞共培养1天。然后用DCFH-DA探针染色细胞，然后使用X71倒置荧光显微镜(Olympus，日本)记录荧光图像。
NB/CuS@PCM纳米颗粒的色散温度变化具有剂量依赖性：在同样的激光照射时间下，剂量越大，纳米颗粒的温度越高。比如，1060nm激光照射10分钟后，50μg/ml的CuS/NB@PCM纳米颗粒的温度可提高到42.6℃，如图3所示。
NB/CuS@PCM纳米颗粒的色散温度变化具有激光功率依赖性：在同样的纳米颗粒浓度液体中，照射激光的功率越大，纳米颗粒的温度越高。比如，随着激光功率密度从0.4w/cm2增加到1w/cm2，100μg/ml的NB/CuS@PCM纳米颗粒的最终温度由31.3℃增加到50.4℃，如图4所示。
光热稳定性分析表明，NB/CuS@PCM纳米颗粒在经过五次激光辐照后仍具有较高的光热稳定性，如图5所示。
谷胱甘肽(GSH)可以帮助中肿瘤细胞抵御活性氧类(ROS)的杀伤作用，清除肿瘤组织中的GSH可以帮助杀灭肿瘤细胞。而实验表明，在酸性环境中，NB/CuS@PCM纳米颗粒可以消耗并逐步耗尽环境中的GSH，并且呈现纳米颗粒浓度依赖性，如图6所示。
利用亚甲基蓝(MB)与羟基自由基发生反应后蓝色消失这一原理，可以验证羟自由基的存在。通过本研究证实，在热条件下NB/CuS@PCM纳米颗粒可以促进羟基自由基的生成，如图7所示。
在激光照射下，随着激光照射时间的延长，NB/CuS@PCM纳米颗粒释放的冰片含量升高，表明NB/CuS@PCM纳米在应用上可以按需释放冰片，如图8所示。
在黑暗环境，无外界远红外光刺激条件下，传统的Cus@PCM纳米颗粒和本项目新研发的NB/CuS@PCM纳米颗粒均未表现出优异的抗肿瘤活力，即使纳米颗粒浓度高达100μg/ml,乳腺癌4T1细胞的细胞活力仍高于78％，如图9所示。
在具有1060nm的激光照射下，传统的Cus@PCM纳米颗粒和本项目新研发的NB/CuS@PCM纳米颗粒均表现出一定的抗肿瘤细胞活性，并且随着纳米颗粒浓度的升高，乳腺癌4T1细胞的细胞活力急剧下降，并且NB/CuS@PCM纳米颗粒抗肿瘤细胞的能力大于传统的Cus@PCM纳米颗粒：当浓度在50μg/ml时CuS@PCM组的肿瘤细胞活力为53.1％，而NB/CuS@PCM的为33.4％，如图10所示。
在热刺激条件下，NB/CuS@PCM纳米颗粒处理的乳腺癌4T1细胞中GSH的含量显著降低，并且纳米颗粒清除GSH的能力呈现剂量浓度依赖，如图11所示。
冰片可以通过增加活性氧(ROS)含量来提高机体对抗癌药物的吸收和增强抗癌药物的治疗效果。在远红外光刺激下，NB/CuS@PCM纳米颗粒能够促进细胞产生大量的活性氧。并且，NB/CuS@PCM纳米颗粒促进活性氧产生的效果远高于传统的CuS@PCM纳米颗粒，如图12所示。
单独的冰片对4T1肿瘤细胞并未出现明显的细胞毒性作用，如图13所示。
实施例2
本实施例提供了一种近红外二区响应性纳米颗粒的制备方法，具体包括如下步骤：
将100mg聚乙二醇、20mg没食子酸和86mg CuCl2溶解在10mLMilli-Q水中。搅拌1小时后，加入200mg硫化钠。溶液颜色将在几秒钟内变为黑色，搅拌4小时后，所得产物用10000Da分子量截留透析袋透析，并使用0.22μm注射器过滤器过滤，得到硫化铜纳米颗粒，记为CuS NPs；
将20mg卵磷脂、10mgDSPE-PEG和10mgCuS NPs溶解在10mL水中并加热至50℃。在超声处理条件下，将PCM(10mg)和NB(10mg)的乙醇混合物快速注入上述溶液中。然后将所得溶液在冰浴中冷却。通过透析和过滤纯化后，得到近红外二区响应性纳米颗粒，记为NB/CuS@PCM NPs。
实施例3
本实施例提供了一种近红外二区响应性纳米颗粒的制备方法，具体包括如下步骤：
将100mg聚乙烯吡咯烷酮、20mg单宁酸和86mg CuCl2溶解在10mL Milli-Q水中。搅拌1小时后，加入200mg硫化钠。溶液颜色将在几秒钟内变为黑色，搅拌4小时后，所得产物用10000Da分子量截留透析袋透析，并使用0.22μm注射器过滤器过滤，得到硫化铜纳米颗粒，记为CuS NPs；
将20mg卵磷脂、10mgDSPE-PEG和10mgCuS NPs溶解在10mL水中并加热至50℃。在超声处理条件下，将PCM(10mg)和NB(10mg)的乙醇混合物快速注入上述溶液中。然后将所得溶液在冰浴中冷却。通过透析和过滤纯化后，得到近红外二区响应性纳米颗粒，记为NB/CuS@PCM NPs。
实施例4
本实施例提供了一种近红外二区响应性纳米颗粒的制备方法，具体包括如下步骤：
将100mg聚乙二醇、20mg单宁酸和86mg CuCl2溶解在10mLMilli-Q水中。搅拌1小时后，加入200mg硫化钠。溶液颜色将在几秒钟内变为黑色，搅拌4小时后，所得产物用10000Da分子量截留透析袋透析，并使用0.22μm注射器过滤器过滤，得到硫化铜纳米颗粒，记为CuSNPs；
将20mg卵磷脂、10mgDSPE-PEG和10mgCuS NPs溶解在10mL水中并加热至50℃。在超声处理条件下，将PCM(10mg)和NB(10mg)的乙醇混合物快速注入上述溶液中。然后将所得溶液在冰浴中冷却。通过透析和过滤纯化后，得到近红外二区响应性纳米颗粒，记为NB/CuS@PCM NPs。
对比例1
本对比例与实施例1的区别在于，在1060nm的激光照射下，传统的Cus@PCM纳米颗粒和本项目新研发的NB/CuS@PCM纳米颗粒均表现出一定的抗肿瘤细胞活性，但是NB/CuS@PCM纳米颗粒抗肿瘤细胞的能力大于传统的Cus@PCM纳米颗粒：当浓度在50μg/ml时CuS@PCM组的肿瘤细胞活力为53.1％，而NB/CuS@PCM的为33.4％。此外，在远红外光刺激下，NB/CuS@PCM纳米颗粒能够促进细胞产生大量的活性氧，并且，NB/CuS@PCM纳米颗粒促进活性氧产生的效果远高于传统的CuS@PCM纳米颗粒。
对比例2
本对比例与实施例1的区别仅在于，仅仅用冰片作为光热治疗药物，单萜敏化剂冰片(NB)不具有显著性的杀伤乳腺癌肿瘤细胞的能力。
以上对本发明的具体实施例进行了描述。需要理解的是，本发明并不局限于上述特定实施方式，本领域技术人员可以在权利要求的范围内做出各种变形或修改，这并不影响本发明的实质内容。

Claims (7)

1.一种近红外二区响应性纳米颗粒的制备方法，其特征在于，包括如下步骤：
将聚乙烯吡咯烷酮、没食子酸和氯化铜溶解于超纯水中，混匀后，加入硫化钠，反应后，得到硫化铜纳米颗粒；
将卵磷脂、二硬脂酰磷脂酰乙醇胺-聚乙二醇和所述硫化铜纳米颗粒溶解于水中，在50℃下加入相变材料、单萜敏化剂和乙醇，在0℃下进行反应，得到所述近红外二区响应性纳米颗粒。
2.如权利要求1所述近红外二区响应性纳米颗粒的制备方法，其特征在于，所述相变材料和单萜敏化剂的重量比为1：1。
3.如权利要求1或2所述近红外二区响应性纳米颗粒的制备方法，其特征在于，所述单萜敏化剂为冰片。
4.如权利要求1所述近红外二区响应性纳米颗粒的制备方法，其特征在于，所述相变材料为1-十六醇和油酸的混合物。
5.如权利要求4所述近红外二区响应性纳米颗粒的制备方法，其特征在于，所述1-十六醇和油酸的质量比为3.5：1。
6.一种由权利要求1～5中所述的任意一种制备方法得到的近红外二区响应性纳米颗粒。
7.一种如权利要求6所述的近红外二区响应性纳米颗粒在光热治疗药物中的用途。
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