【作者】 张浩；

【导师】 李桢；

【作者基本信息】 苏州大学 ， 放射医学， 2019， 博士

【摘要】 脑胶质瘤的治疗因其发病部位的特殊性及复杂性至今仍然是全人类最具挑战性的肿瘤之一,具有诊断难、治疗难的特点。血脑屏障对维持大脑中枢神经系统内环境的稳定具有极其重要的作用,其独特的结构是人体内最严格的屏障,一方面阻止了脑部血液中有害物质进入脑部组织,维持大脑内部正常的生理环境;另一方面也妨碍了大约98%的小分子药物及几乎全部的大分子药物进入脑部,使药物无法达到有效的治疗浓度,严重影响治疗效果。因此,如何安全、无创、靶向的使诊疗试剂穿过血脑屏障,到达病灶部位,是目前亟待解决的问题。本论文工作主要集中于聚焦超声辅助开启血脑屏障后,利用超小Cu2-xSe纳米颗粒穿过血脑屏障,通过非侵入式成像手段,监测血脑屏障开启后可逆修复性;负载药物的Cu2-xSe纳米颗粒载近红外二区1064nm激光照射下,用于原位脑胶质瘤的光动力治疗和化学治疗。研究所得主要结果如下:本课题第一章,简要概述血脑屏障相关研究进展。首先系统总结了脑部疾病诊断的成像方式,其次概述药物进入到大脑的各种途径,然后具体介绍了增强血脑屏障通透性的策略,本章最后阐明了本课题的选题依据与研究内容。本课题第二章,聚焦超声辅助不同尺寸Cu2-xSe纳米颗粒脑部光声成像研究。合成尺寸粒径在3 nm、20 nm和100 nm左右的Cu2-xSe纳米颗粒,在聚焦超声开启血脑屏障后,尾静脉注射三种尺寸Cu2-xSe纳米颗粒,通过脑部光声成像研究发现聚焦超声开启血脑屏障后,Cu2-xSe纳米颗粒尺寸越大,光声成像效果越差。结果表明:本实验中,3 nm Cu2-xSe纳米颗粒在血脑屏障开启后,光声成像效果最好。本课题第三章,可代谢超小Cu2-xSe纳米颗粒监测血脑屏障的开启与修复。以超小3 nm Cu2-xSe纳米颗粒为造影剂,通过非侵入式光声和SPECT/CT双模态成像监测聚焦超声诱导的血脑屏障开启和修复。超小3 nm Cu2-xSe纳米颗粒有较长的血液循环时间,有利于其穿过血脑屏障,用于光声和SPECT/CT成像,监测聚焦超声对血脑屏障的开启和修复。通过生物分布、组织切片和血常规分析证明在体内的3 nm Cu2-xSe纳米颗粒可在15天后从脑部及其它主要脏器代谢排出体外而不会引起副作用。本章以超小3 nm Cu2-xSe纳米颗粒作为造影剂,结合非侵入式成像和聚焦超声的优点,在脑部疾病的诊治方面具有很大潜力。本课题第四章,近红外二区激发超小Cu2-xSe纳米颗粒在原位脑胶质瘤光动力治疗和化疗中的研究。由于超小Cu2-xSe纳米颗粒在近红外二区具有很强的吸收,并且与近红外二区激光的深层组织穿透能力相结合,使得超小Cu2-xSe纳米颗粒在1064 nm激光照射下表现出良好的光动力治疗性能。进一步研究发现超小CU2-xSe纳米颗粒可通过电子转移(Ⅰ型光动力反应)和能量转移(Ⅱ型光动力反应)机制产生大量的·OH和1O2。在聚焦超声辅助下,负载化疗药物的超小Cu2-xSe纳米颗粒可穿越血脑屏障聚集到脑胶质瘤部位,结合1064 nm激光照射,可实现脑胶质瘤的光动力治疗和化学治疗,结果发现脑胶质瘤生长得到有效抑制。本章研究发现载药超小Cu2-xSe纳米颗粒在原位脑胶质瘤治疗中具有很大意义。更多还原

【Abstract】 Brain tumor,which represents a deadly disease that has been difficult to be identified and treated,is one of the most challenging diseases due to its particularity and complexity.The Blood-Brain Barrier(BBB)plays an important role in maintaining the stability of central nervous system(CNS).The unique structure of BBB is the most stringent barrier in the human body.On one hand,it prevents harmful substances from entering the CNS and maintains the normal physiological microenvironment in the brain,on the other hand,it prevents about 98%of small molecule drugs and all of the macromolecular drugs entering the CNS.The existence of BBB affects the therapeutic effect of brain diseases seriously.Therefore,how to safely,non-invasively and targeted transport the therapeutic agents across the BBB and reach the target site is an urgent problem to be solved at present.The work of this thesis mainly focuses on the focused ultrasound-assisted opening of the BBB,using the ultra-small Cu2-xSe NPs as therapeutic agent for noninvasively monitoring the opening and recovery of the BBB.The ultra-small Cu2-xSe NPs loaded with chemotherapeutic drugs were developed for photodynamic therapy and chemotherapy of orthotopic brain tumor under the irradiation of 1064 nm laser with the assistance of focused ultrasound.The main results of the study are as follows:Chapter 1:A brief overview of the research progress of the BBB.Firstly,the imaging methods of brain diseases diagnosis are summarized systematically,and then the various ways of therapeutic reagents to enter the CNS are outlined.The strategies to enhance the permeability of the BBB and the basis and research content of this dissertation are introduced at last.Chapter 2:PA imaging of different size Cu2-xSe nanoparticles in brain with the assistant of focused ultrasound.Cu2-xSe NPs with the different sizes of 3 nm,20 nm and 100 nm were synthesized.After the BBB opening mice were administrated with Cu2-xSe NPs(3 nm,20 nm and 100 nm),The PA imaging of the BBB opening mice were captured after treatment with various size of Cu2-xSe NPs.The results showed that the size of 3 nm Cu2-xSe NPs were the best for PA imaging of the opening BBB.Chapter 3:Monitoring the opening and recovery of the BBB with noninvasive molecular imaging by biodegradable ultra-small Cu2-xSe NPs.Dual-modal PA and SPECT/CT imaging based on ultra-small Cu2-xSe NPs(3 nm)were used to noninvasively monitor the opening and recovery of the BBB induced by focused ultrasound.The ultra-small Cu2-xSe NPs exhibited a long blood circulation time.Both small size and long blood circulation time enable them to efficiently penetrate into the brain with the assistance of ultrasound,which resulted in a strong signal at the sonicated site and allowed for PA and SPECT/CT imaging monitoring the recovery of the opened BBB.The results of biodistribution,histological staining and blood routine examination indicate that the accumulated Cu2-xSe NPs could be excreted from the brain and other major organs after 15 days without causing side effects.By the combination of the advantages of noninvasive molecular imaging and focused ultrasound,the ultra-small biocompatible Cu2-xSe NPs hold great potential for the diagnosis and therapeutic treatment of brain diseases.Chapter 4:Second near-infrared window photodynamic therapy and chemotherapy of orthotopic brain tumor with ultra-small Cu2-xSe NPs.Ultra-small Cu2-xSe NPs possess a strong absorbance in the NIR-Ⅱ window.Their strong NIR-Ⅱ absorbance and the deeper-tissue penetration of NIR-Ⅱ light ensure excellent photodynamic therapy performance under irradiation by a 1064 nm laser.We also demonstrate that ultra-small Cu2-xSe NPs can produce vast amounts of reactive oxygen species via electron transfer(for ·OH generation)and energy transfer(for 1O2 generation)mechanisms under irradiation.In addition,these NPs can be effectively and locally transported into orthotopic brain tumor with the assistance of focused ultrasound.The results show that the tumor growth can be significantly suppressed.This work demonstrates the great potential of drug-loaded ultra-small Cu2-xSe NPs as a promising therapeutic agent for treatment of orthotopic brain tumor.更多还原