CN110882387A - 一种肿瘤内靶向释放石墨烯阿霉素的方法 - Google Patents

一种肿瘤内靶向释放石墨烯阿霉素的方法 Download PDF

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CN110882387A
CN110882387A CN201910906293.2A CN201910906293A CN110882387A CN 110882387 A CN110882387 A CN 110882387A CN 201910906293 A CN201910906293 A CN 201910906293A CN 110882387 A CN110882387 A CN 110882387A
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沈智勇
沈贝颀
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Abstract

本发明公开了一种破坏肿瘤微血管管壁的方法，包括以下步骤：a.静脉注射微泡；b.低频超声辐照肿瘤部位。采用上述方法可靶向释放石墨烯阿霉素，静脉注射氧化石墨烯阿霉素于低频超声辐照后的生物体即可。本发明通过低频超声联合微泡，产生空化效应，致肿瘤局部微血管损伤、破裂，增加肿瘤血管内皮的通透性，而在血管中循环的石墨烯阿霉素通过肿瘤部位破裂的血管，进入肿瘤，杀死癌细胞，达到靶向高效微创治疗肿瘤的目的。

Description

一种肿瘤内靶向释放石墨烯阿霉素的方法
技术领域
本发明涉及纳米材料领域，具体是一种肿瘤内靶向释放石墨烯阿霉素的方法。
背景技术
2004 年英国科学家发现了石墨烯。其后，人们对石墨烯及其衍生物进行了广泛的研究。研究领域涉及化学化工、功能材料、催化反应、污染物去除及环境保护等。近年来，石墨烯的研究开始进入医药领域，主要包括疾病诊断如生物检验、生物成像；疾病治疗如药物载体、基因载体，光动力学治疗等。
石墨烯具有非常特殊的化学结构，是目前发现的最薄的二维纳米材料，基本结构为有机材料中最稳定的苯六元环。氧化石墨烯是其衍生物，为一种功能化的石墨烯 (GO)。GO表面带有功能化基团，如羟基、羧基和环氧基等，这些添加的功能基团改善了石墨烯的水溶性、稳定性，不仅可以通过酰化反应和酯化反应将其他基团或生物分子修饰到GO表面，也可以通过氢键等非共价键作用对GO进行修饰。研究发现GO对荧光材料有较强的猝灭作用，可作为良好的能量受体应用于荧光共振能量转移体系，为生物传感器提供了发展平台。同时，GO是由单层碳原子构成的，具有较大比表面积，可通过H-键的叠加作用与含有芳环类的药物进行物理吸附，具有较高的负载效率。因此，近年来GO被广泛地应用于生物分子的检测及抗肿瘤药物的传递。
阿霉素又称多柔比星(DOX)， 为桔红色的冻干粉剂，可溶于水，是一种抗肿瘤抗生素，可抑制RNA 和DNA的合成，抗瘤谱较广，对多种肿瘤均有作用，属周期非特异性药物，对各种生长周期的肿瘤细胞都有杀灭作用。适用于急性白血病、乳腺癌、肝癌、卵巢癌等。
用修饰后的透明质酸(HA)包覆，GO通过物理吸附、氢键负载抗肿瘤药物DOX，形成HA-GO-DOX稳定复合物，体外药物释放实验表明，HA-GO-DOX在pH 5.3环境中释放DOX的速度高于在pH 7.4的环境，为肿瘤部位（微酸环境）的药物释放提供了基础。
除了上述积极作用外，石墨烯产生的可能的负面作用也不可忽视。有报道指出，石墨烯可以与人体血红细胞产生强烈相互作用，导致血细胞破裂，对人体健康造成极大威胁，氧化石墨烯的浓度以及自身的尺寸也同样影响其自身对细胞的毒性。除了物理穿刺破坏以外，氧化行为损坏细胞也是石墨烯细胞毒性的一种普遍体现。纯石墨烯可以影响线粒体膜电位，增加胞内 ROS 含量，通过激发线粒体机制（激活信号蛋白）导致细胞凋亡，以上情况说明石墨烯对不同的细胞作用存在显著差异。然而，石墨烯的细胞毒性及其机理还需要深入研究。
化疗是治疗肿瘤的一种重要和有效的方法。然而，大部分化疗药往往缺乏靶向性，真正到达肿瘤部位的有效量很少，在杀伤癌细胞的同时也对正常细胞产生损害，使得药物在肿瘤治疗过程中产生很大的毒副作用。因此，提高药物对肿瘤部位的选择性，使药物靶向性地进攻肿瘤细胞，减少其在正常组织细胞部位的富集，从而提高药物疗效就成为肿瘤治疗中迫切解决的现实问题。
低频超声通常是指频率20-100kHz的声波，由于频率低，波长长，低频超声较高频超声穿透力更远、更深。低频超声较少应用于疾病诊断，而更多用于治疗，其主要生物学作用包括机械效应、空化效应、热效应及化学效应等，其中最重要的是空化效应。空化是在一定的声场条件下，液体中的微小气泡经历脉动、膨胀、收缩、崩溃破灭的现象，可以引发一系列物理、化学效应。空化效应可分为稳态空化及瞬态空化。前者是指微泡在声场作用下多次低幅而不破裂震荡。后者是指微泡高幅震荡，开始膨胀、接着迅速压缩，最终破裂。对于瞬态空化，声场频率越低，微泡膨胀时间越长，膨胀直径越大，在随后的压缩相微泡破裂越剧烈，空化效应亦越明显。超声空化泡具有很高的聚能能力。在压缩至最小半径前后，空化泡内部有罕见的高温高压，最高温度达数千开氏度、压力达数千帕，空化泡崩溃时，产热发光，产生自由基、冲击波，可以引起二次生物效应。
临床肿瘤化疗时常规给药途径主要包括口服和静脉注射，血液中的药物需克服血管内皮屏障，穿过肿瘤组织间隙和肿瘤细胞膜进入肿瘤细胞才能发挥相应的抗癌效果。为使化疗药物在肿瘤靶区达到有效浓度必须增大给药剂量，这可能破坏正常组织和细胞，进而造成全身毒副作用。如何克服血管内皮屏障，增加肿瘤血管内皮的通透性，是目前治疗肿瘤的热点和难点。
发明内容
本发明就是为了解决上述技术问题，所提出一种肿瘤内靶向释放石墨烯阿霉素的方法。
本发明是按照以下技术方案实现的。
一种破坏肿瘤微血管管壁的方法，通过低频超声联合微泡，产生空化效应，致肿瘤局部微血管损伤、破裂，增加肿瘤血管内皮的通透性。
进一步的，一种破坏肿瘤微血管管壁的方法，包括以下步骤：
a. 静脉注射微泡；
b. 低频超声辐照肿瘤部位。
进一步的，所述微泡为一种超声造影剂，微泡的注射剂量为SonoVue微泡0.2 mL /次。
进一步的，所述低频超声辐照的照射时间为每天1 分钟，占空比40%（开2 s，关3s）隔天进行，共2周；照射强度为声强2 W/cm2，超声频率为20 kHz。
一种肿瘤内靶向释放石墨烯阿霉素的方法，包括以下步骤：
a. 静脉注射微泡；
b. 低频超声辐照肿瘤部位；
c. 静脉注射氧化石墨烯阿霉素液体。
进一步的，所述氧化石墨烯阿霉素液体的注射剂量为阿霉素负载于氧化石墨烯表面，其载药效率为100%，即氧化石墨烯、阿霉素均为浓度40μg/ml、0.3ml/次，即12μg/次；隔天进行注射，共2周。
本发明获得了如下的有益效果。
本发明解决了单纯向肿瘤注射药物，药物在体内血管内循环，难以进入肿瘤内部的问题。本发明通过低频超声联合微泡，产生空化效应，致肿瘤局部微血管损伤、破裂，增加肿瘤血管内皮的通透性，而在血管中循环的石墨烯阿霉素通过肿瘤部位破裂的血管，进入肿瘤，杀死癌细胞，达到靶向高效微创治疗肿瘤的目的。
附图说明
图1是本发明石墨烯阿霉素的结构示意图。
具体实施方式
下面结合附图及实施例对本发明进行进一步说明。
实施例1 ：裸鼠皮下肝癌
一种肿瘤内靶向释放石墨烯阿霉素的方法，包括以下步骤：
步骤1：裸鼠尾静脉注射微泡（声诺维，一种超声造影剂）；
步骤2：低频超声辐照裸鼠皮下肝癌，通过超声空化效应，破坏肿瘤微血管；
步骤3：尾静脉注射氧化石墨烯阿霉素黑色液体通过破坏的微血管，进入肿瘤组织，促进肿瘤细胞凋亡，达到靶向发送纳米颗粒化疗药的作用。
氧化石墨烯阿霉素参考文献：Shen A-J, Li D-L, Cai X-J, Dong C-Y, Dong H-Q, Wen H-Y, Dai G-H, Wang P-J, Li Y-Y. 2012. Multifunctional nanocompositebased on graphene oxide for in vitro hepatocarcinoma diagnosis and treatment.J Biomed Mater Res Part A 2012:00A）
氧化石墨烯、阿霉素来自于西北大学化工学院，将石墨（0.5 g）、纳米3（0.5 g）和23 ml浓硫酸混合并在冰浴中搅拌1小时，然后将1.5 g KMNO4缓慢添加到溶液中并在35℃搅拌1天。接下来，缓慢添加23 ml去离子水以防止反应温度超过98°C，并搅拌30分钟。最后，向混合物中添加5 ml的H2O2（30%）和70 ml去离子水。反应混合物经重力过滤过滤，产物用盐酸溶液（3%）和去离子水连续洗涤。这些过程在离心过程中重复了几次。采用冷冻干燥法防止凝胶聚集。
构建GO-DOX：在280w 超声处理下，将盐酸阿霉素（40μg/ml）溶解于磷酸缓冲盐水（PBS）溶液（pH=8）（含40μg/ml GO）中0.5小时。然后，在温和的磁力搅拌下，反应在室温黑暗中保持24小时。通过对去离子水进行透析来纯化所得产物。
氧化石墨烯（GO）与阿霉素（DOX）结合的原因：单纯DOX毒性大，GO与DOX结合后，毒性减低，却GO的表面积大，载药量大。
超声空化效应与GO-DOX联合的原因：GO-DOX悬浮液的颗粒直径在1微米左右，而裸鼠肝癌微血管的血管内皮细胞间隙是300-800nm之间，单纯注射GO-DOX，药物在肿瘤组织血管内运输，进入肿瘤间隙的少，通过超声辐照后，空化效应产生的能量破坏肿瘤微血管，血管内皮细胞间隙增大，进入肿瘤组织及癌细胞的DOX增多，发回抗癌作用，促进肿瘤细胞凋亡，抑制肿瘤生长。
肿瘤细胞凋亡率：对照组、超声微泡组、氧化石墨烯-阿霉素组和超声微泡+氧化石墨烯阿霉素组肿瘤细胞的平均凋亡率分别为8.2±3.49、40±9.51、48.6±8.96和62.4±7.27%。超声微泡+氧化石墨烯阿霉素组与对照组、超声微泡组和氧化石墨烯-阿霉素组之间有显著性差异，t=15.03，p<0.0001；t=4.18，p=0.0031；t=2.67，p=0.0282。

Claims (6)

1.一种破坏肿瘤微血管管壁的方法，其特征在于：通过低频超声联合微泡，产生空化效应，致肿瘤局部微血管损伤、破裂，增加肿瘤血管内皮的通透性。
2.根据权利要求1所述的一种破坏肿瘤微血管管壁的方法，其特征在于：包括以下步骤：
a. 静脉注射微泡；
b. 低频超声辐照肿瘤部位。
3. 根据权利要求2所述的一种破坏肿瘤微血管管壁的方法，其特征在于：所述微泡为一种超声造影剂，微泡的注射剂量为0.2 mL /次,所述微泡的浓度为1.8×109 MBs/mL。
4. 根据权利要求2所述的一种破坏肿瘤微血管管壁的方法，其特征在于：所述低频超声辐照的照射时间为每天1 分钟，占空比40%，开2 s，关3 s，隔天进行，共2周；照射强度为声强2 W/cm2，超声频率为20 kHz。
5.一种肿瘤内靶向释放石墨烯阿霉素的方法，其特征在于：包括以下步骤：
a. 静脉注射微泡；
b. 低频超声辐照肿瘤部位；
c. 静脉注射氧化石墨烯阿霉素液体。
6.根据权利要求5所述的一种肿瘤内靶向释放石墨烯阿霉素的方法，其特征在于：所述氧化石墨烯阿霉素液体的注射剂量为阿霉素负载于氧化石墨烯表面，其载药效率为100%；即氧化石墨烯和阿霉素均为浓度40μg/ml、0.3ml/次，即12μg/次，隔天进行注射，共2周。
CN201910906293.2A 2019-09-24 2019-09-24 一种肿瘤内靶向释放石墨烯阿霉素的方法 Pending CN110882387A (zh)

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