胶质瘤纳米治疗技术的研究现状与发展前景

涂艳阳，祁 婧，张永生,杨宏伟

(第四军医大学：1唐都医院实验外科，2唐都医院，陕西 西安 710038；3哈佛医学院布列根与妇女医院神经外科，美国 波士顿 02115)

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胶质瘤纳米治疗技术的研究现状与发展前景

涂艳阳1，祁 婧1，张永生2,杨宏伟3

(第四军医大学：1唐都医院实验外科，2唐都医院，陕西 西安 710038；3哈佛医学院布列根与妇女医院神经外科，美国 波士顿 02115)

神经胶质瘤是颅内最常见的恶性肿瘤，占所有颅内肿瘤的46%. 由于神经胶质瘤呈侵润性生长，故仅通过传统手术难以做到全部切除，因此，采用新技术手段提高现有早期诊断、疗效预测以及有效治疗策略是亟待解决的首要问题. 随着纳米生物医学的飞速发展，纳米技术已经在胶质瘤的预测、诊断、影像及治疗等领域显示出巨大的优势. 本研究综述了纳米载体、胶质瘤纳米治疗机理以及胶质瘤纳米诊断和治疗领域的主要研究进展.

胶质瘤;纳米载体;化疗药物

0 引言

长期以来,恶性肿瘤的诊断和治疗一直是医学和生命科学研究领域的热点和难点. 神经胶质瘤是颅内最常见的恶性肿瘤，约占所有颅内肿瘤的46%，诊断后的胶质瘤患者生存期仅有12～14个月. 由于神经胶质瘤呈侵润性生长，故仅通过传统手术无法有效治愈，难以做到肿瘤的全部切除，故多采用联合治疗，配以放疗和化疗来降低复发率，延长生存期[1]. 但是，目前的化疗药物和放疗主要针对生长期细胞，而对处于非生长期的神经胶质瘤干癌细胞几乎没有作用[1]. 所以侵润性极强的神经胶质瘤具有低治愈、高复发的特点，这也成为至今无法攻克的一大难题[1].

目前，对于恶性胶质瘤，临床上面临的主要问题是肿瘤的诊断与治疗的分离. 集多种性能于一体的诊疗剂(Theranostics)的设计和应用有望解决这个难题[2]. 智能化的诊疗剂能有效提高治疗疾病的选择和特异性，达到高的局部毒性和低的副作用. 因此，针对胶质瘤的诊断与治疗分离这一临床主要问题，能够利用磁性纳米粒子、金纳米棒[3]实现恶性胶质瘤的分子影像和个性化治疗. 随着纳米生物医学的快速发展，纳米技术已经在胶质瘤的预防、诊断、影像和治疗等领域作出巨大的贡献. 本研究综述了纳米载体、胶质瘤纳米治疗机理以及胶质瘤纳米诊断和治疗领域的主要研究进展.

1 纳米载体

纳米载体来源于生物、有机和无机物，用以探究各种生物学机制和解决生物学问题. 纳米载体多为脂类和聚合材料构成，另外还开发出各种潜在新材料包括巨噬细胞特异的纳米粒子[4]，靶向磁纳米粒子[5-6]、金纳米材料[7]、功能化的碳纳米管[8]、二氧化硅颗粒[9-10]及修饰的植物病毒[11]等.

聚合物材料是纳米材料中的最大的一类，包括许多亚型，如核-壳粒子、可生物降解的聚乳酸-共-羟基乙酸(PLGA)纳米颗粒、水凝胶纳米粒子. 聚合物胶束是非交联粒子，涉及共聚物颗粒、单一聚合物链包含不止一个相同分子. 一个简单的聚合物胶束包含许多二亲聚合物，模拟胶束的尾巴和头部. 这些聚合物在疏水性药物周围自发形成胶束. 具有受控尺寸和形状的聚合物纳米粒子允许细胞附着同时可以防止内在化，从而使细胞对药物的有效载荷携带到递送第二个站点. 因此针对循环肿瘤细胞，就可以使用具有长循环时间的聚合物. 水凝胶纳米粒子，也被称为纳米凝胶，在亲水环境中接触水时交联在接触时膨胀[12]. 纳米凝胶可以共价或非共价结合的药物或靶向配体，还可以响应于环境因素膨胀或缩小，如pH或温度.

脂类是可以自组织囊泡(脂质双分子层和脂质体)的二亲性小分子、胶束或脂质复合物(无定形颗粒[13]. 这些载体可以修饰为靶向递送水溶性和不溶性的治疗剂. 尺寸、承载能力和定位功能等属性也可以被修饰. 再加上适当的目标配体，如整联蛋白结合肽，脂质体可在血管生成过程在肿瘤血管系统积累[14]且可递送有效治疗载荷. 金纳米颗粒已经被用于热烧蚀治疗[15]，通过以热的形式释放能量至近红外光响应诱导肿瘤血管的凝结以及可协同增加其他靶向疗法的治疗效果[16]. 金纳米颗粒也可以作为支架连接多个配体[17]. 其他纳米材料类，如纳米铁颗粒和碳纳米颗粒，也同样应用到药物递送治疗[18].

2 治疗机理

纳米粒子治疗剂从小分子药物或生物大分子的载体(如蛋白质或siRNA)[19-28]到成像和热吸收载体. 纳米颗粒装载药物的优点包括疾病位点靶向药物、触发药物在身体的特定位置释放[29-30]以及改变药物的药代动力学特性以增加其在疾病部位的半衰期[31]. 这些能力会减少脱靶效应和降低药物剂量[32-33]. 纳米粒子具备更多复杂的药物递送能力，例如递送含有调节血管系统分子的药物[34-35]，药物前体以及其激活酶[36-37]或靶向配体免疫治疗[38-41]. 同时，生理微环境[42-43]或可替代的外部刺激(超声[44-46]、光[47-49]或射频电磁场[50])也可以触发局部药物释放.

纳米粒子的治疗作用不仅仅是药物的封装和递送. Thermoablative治疗(加热组织以杀死肿瘤细胞)、磁场、红外线和无线电频率等技术可以通过激活纳米材料局部增强对患病组织的作用[15,51-53]. 但是所有这些外部触发作用既有优点也有局限性. 例如，电磁场能深入(>15 cm)渗透，但它们难以聚焦. 高强度聚焦超声(HIFU)能深入组织且可聚焦到几个毫米的体积，但是当应用到骨骼或气体填充的器官时其功能则会减弱[54]. 红外灯的波长范围为750～1300 nm，穿透组织且可达1 cm的深度，之后渗透大幅减小[55]. 因此红外线主要适用于病变靠近皮肤表面的情况.

3 胶质瘤纳米治疗技术

随着纳米技术在20世纪80年代的迅速发展，医学领域便利用这一新的技术开发出新的治疗剂. 对于脑肿瘤，纳米技术方法可以通过血脑屏障便于药物递送[56-57]. 纳米颗粒类似生物大分子，不能像生物小分子一样随意扩散到组织[58]. 该纳米粒子在肿瘤内积累的能力是由于增强的渗透性和滞留效果. 增强的渗透性并且保留效果是由活跃的血管生成和血管结构改变而部分介导的，这导致即使在血清水平下降的情况下，纳米颗粒仍滞留在肿瘤组织[59]. 此外，纳米颗粒可以“保护”递送的目标免于周围环境的干扰而到达靶位. 例如，静脉注射时亚甲蓝很快会被高铁血红蛋白还原酶催化失活. 这种现象可以通过利用纳米颗粒递送亚甲蓝到肿瘤组织的方法来避免[60-62]. 纳米颗粒也可以用于递送化疗药物穿过血脑屏障，如阿霉素[63-64]. 纳米颗粒递送阿霉素的疗法具有降低毒性与改善多形性成胶质细胞瘤的异种移植物模型中抗肿瘤细胞的功效[63-65].

在神经外科领域，正在研究纳米粒子用于脑成像[66]. 另外，氧化铁纳米颗粒可装载荧光染料，实现肿瘤的可视化外科手术[58,67-69].

纳米颗粒用于药物递送的能力是未来治疗脑肿瘤的方向. 某些化疗药物，如阿霉素和紫杉醇，可利用固体脂质纳米粒封装，对于肿瘤组织有较高的可利用性并尽量减少全身性毒性[70]. 由于病毒载体的免疫反应以及脂质体效率较低，研究人员也正在研究纳米粒子用于基因治疗[58]. 例如，含APO2/TRAIL质粒装载到纳米颗粒可以在肿瘤组织中累积，增加C6胶质瘤小鼠生存率[71].

4 展望

纳米医学开创了胶质瘤早期诊断与靶向治疗策略的新时代. 胶质瘤的纳米治疗是利用纳米材料靶向识别并杀灭恶性胶质瘤细胞的个性化治疗. 利用纳米材料特性，同时结合脑胶质瘤干细胞的特异靶点及其所特异的分子信号通路来设计纳米治疗探针已经成为一个新的热点研究. 但是胶质瘤纳米治疗所面临的许多问题还有待于进一步的研究；如何构建体内靶向分子探针、放大信号、消除探针潜在毒性正是当今胶质瘤纳米治疗需要解决的关键问题；另外，纳米探针作为小分子或多肽探针连接在纳米粒子表面后，作为信号源的纳米粒子较高的表面可能会改变其分子构象或者屏蔽其结合基团，所以两者相互作用的长期机制还不明确，仍需进一步的探究进行验证. 因此，纳米治疗技术在人体应用还有很多值得挖掘和深究的方向. 如今的胶质瘤纳米诊断和治疗技术正飞速发展，纳米科技也为攻克胶质瘤提供了一种全新的治疗策略.

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The current situation and prospect of treating glioma with nanotechnology

TUYan-Yang1,QIJing1,ZHANGYong-Sheng2，YANGHong-Wei3

The Fourth Military Medical University:1Department of Experimental Surgery,2Tangdu Hospital, Xi’an 710038, China;3Neurosurgerons, Brigham and Women’s Hospital, Haward Medical Shool, Boston 02115, America

Neuroglioma is the most common malignancy, accounting for nearly half of all human brain tumors. Operation is still difficult to completely remove because of its invasive growth. Thus, the introduction of new technology to improve current diagnosticis, curative effect forecast and treatment strategies is the major problems to be solved. With the rapid development of nano-biomedicine, nanotechnology has demonstrated its great advantages in the prevention, diagnosis, imaging and treatment of gliomas and other areas. This paper reviews the progress of major nanocarrier, nanoparticle therapy treatment mechanism and nanoparticle diagnostic and therapeutic areas for glioma.

glioma; nanocarrier; chemotherapy drugs

2016-07-18;接受日期:2016-08-04

国家自然科学基金资助项目(No.81572983,No.81272419)

涂艳阳. 博士,副教授,副主任医师. Tel: 029-84777469 E-mail:tu.fmmu@gmail.com

张永生. 教授,主任医师,院长. E-mail:zhangys@fmmu.edu.cn

2095-6894(2016)09-01-04

R739.4

A