CN109420181A - 一种用于肿瘤荧光成像及光热/光动力治疗的多功能纳米粒子 - Google Patents
一种用于肿瘤荧光成像及光热/光动力治疗的多功能纳米粒子 Download PDFInfo
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Abstract
本发明涉及一种用于肿瘤荧光成像及光热/光动力治疗的多功能纳米粒子,涉及这类多功能纳米粒子的制备方法及其在肿瘤诊疗方面的用途。此用于肿瘤荧光成像及光热/光动力治疗的多功能纳米粒子的结构示意图如附图所示,其膜成份包括用于荧光成像和光热治疗的近红外染料、用于光动力治疗的含光敏剂功能基团的脂质以及常规磷脂,光热和光敏药物的比例可根据需要进行调控,载药量大大提高;在近红外荧光的引导下,光热/光动力联合抑制肿瘤的生长,提高了肿瘤治疗效率。
Description
技术领域
本发明属于生物医用材料领域,具体涉及一种用于肿瘤荧光成像及光热/光动力治疗的多功能纳米粒子,以及其在肿瘤诊疗方面的用途。
背景技术
荧光成像是分子生物学和医学研究极为重要的手段。其中近红外区域(波长600~900nm)生物分子的光吸收最低,而自发荧光最弱,大量的红外光可以穿过组织和皮肤而被检测到。因此,其波长范围被认为是光学成像的“诊断窗”。其独特优势为:①敏感性高;②可通过不同荧光探针的设计实现各种肿瘤的靶向性成像;③可提供实时动态的肿瘤活体成像。
肿瘤的光治疗(phototherapy)因其治疗成本低、组织创伤小、副作用小及高效性逐渐成为继手术、放疗、化疗后肿瘤治疗的又一有效手段。光治疗主要包括光热治疗(photothermal therapy,PTT)和光动力治疗(photodynamic therapy,PDT)。PTT主要是通过使用在近红外区有强吸收的光热治疗剂,通过特定波长的光照射富集于肿瘤部位中的光热剂使其局部温度升高来杀伤肿瘤细胞。PDT是指将光敏剂药物输送到肿瘤细胞,通过光照使其产生“高活性”的单线态氧和自由基(ROS),从而诱导癌细胞发生凋亡。
虽然单纯的PTT和PDT用于肿瘤的治疗已取得了显著的进步,但是能够同时结合PTT和PDT两种治疗方式的纳米材料仍比较少见。如能通过微纳米技术实现PTT和PDT的结合,将有望进一步提高治疗的效果。因此,需要开发新型材料联合光动力和光热疗法来实现协同抗癌作用。另外,理想的光治疗应在杀伤肿瘤组织的同时尽可能不损伤周围的正常组织,以保证治疗的有效性和安全性。对于光治疗而言,光敏剂/光热治疗试剂是光治疗的核心要素,只有在光敏剂/光热治疗试剂存在的部位才能产生光治疗效应而对细胞产生损伤;由于治疗时所用激光能量一般较低,在缺乏光敏剂的情况下单纯的激光辐照对细胞并无杀伤效果。因此提高纳米粒子的载药量及减少在血液循环过程中的治疗试剂的泄露很重要。
基于以上考虑,我们开发出了一种用于肿瘤荧光成像及光热/光动力治疗的多功能纳米粒子,其特点是用于光热治疗的近红外染料、用于光动力治疗的具有光敏剂功能基团的脂质和常规磷脂一起自组装到超声造影剂的膜成分中,形成纳米粒子。与常规的包载药物的形式相比,共同自组装的结合方式,可以提高载药量并且减少治疗试剂在体内循环中的泄露。随后在荧光成像引导下,在肿瘤部位实施光热和光动力联合治疗。
发明内容
本发明的目的是提供一种用于肿瘤荧光成像及光热/光动力治疗的多功能纳米粒子的制备方法。
本发明的另一目的是提供上述用于肿瘤荧光成像及光热/光动力治疗的多功能纳米粒子在肿瘤诊疗中的应用。
本发明所述的一种用于肿瘤荧光成像及光热/光动力治疗的多功能纳米粒子的结构如附图1所示。
本发明中多功能纳米粒子,其特征在于该纳米粒子的壳层是由脂质双分子层构成,其组成同时包括:用于光热治疗的近红外染料、用于光动力治疗的含有光敏功能基团的脂质及各类常规磷脂,这几种成分共同自组装成类似脂质体的具有双层膜结构的纳米粒子。
其中所述近红外染料首选生物相容性好、光热转换效率高的具有疏水长链或者双亲性的染料,一般其结构如下:
其中R1,R2=C6~18烷基,R3,R4=H或SO3H-;n=2或3;X=H,CH3,CH3O,CI-,Br-,I-,对位吡啶环,吡嗪等;例如1,1-dioctadecyl-3,3,3,3-tetramethylindotricarbocyanine iodide(DiR)、吲哚菁绿(ICG)及其衍生物等。所述的染料与常规磷脂自组装形成纳米粒子,染料和磷脂通过静电作用力或范德华力结合。
所述的含有光敏功能基团的脂质一般指光敏功能基团共价连接到脂质上,其结构一般如下:
其中R1=H或C6~18烷基,R2=C6~18烷基;a,b=2或3;X=N或O,即光敏剂和脂质的连接方式是酯键或酰胺键;所述的含光敏功能基团的脂质经溶胶凝胶过程后在水溶液中能自组装形成脂质体。光敏功能基团包括血卟啉、原卟啉、四苯基卟啉、焦脱镁叶绿酸(pyropheophorbide)、细菌叶绿素、叶绿素a、苯并卟啉衍生物、四氢苯基二氢卟吩、苯并二氢卟吩、萘并二氢卟吩、酞菁或萘酞菁等。
本发明所述的一种用于肿瘤荧光成像及光热/光动力治疗的多功能纳米粒子的制备方法,包括以下步骤:
1)将一定比例的磷脂、含有光敏剂功能基团的脂质及近红外染料于乙醇中溶解混合均匀(含有光敏剂功能基团的脂质比例0~50%,近红外染料比例0~30%)。
2)采用乙醇注入法,将混匀的上述体系滴加到生理盐水中,40-60℃水浴超声15-30分钟。
3)使用8000~14000KD的透析袋将得到的体系2)在生理盐水中室温下透析2~4h。分离提纯后得到用于肿瘤荧光成像及光热/光动力治疗的多功能纳米粒子。
在步骤l)中,所述的磷脂包含12~24个碳的碳链长度以及包括磷脂酰胆碱、磷脂酰基乙醇胺、磷脂酸和磷脂酰基甘油,例如1,2-二硬脂酰基-sn-甘油基-3-磷酸胆碱(DSPC)、1,2-二棕榈酰基-sn-甘油基-3-磷脂酰胆碱(DPPC)、二硬脂酰磷脂酰乙醇胺-聚乙二醇2000(DSPE-PEG2000)、二硬脂酰磷脂酰乙醇胺-聚乙二醇2000(DSPE-PEG5000)等。
本发明中用于肿瘤荧光成像及光热/光动力治疗的多功能纳米粒子,其光热治疗试剂/具有光敏剂功能基团的脂质和磷脂共成膜,光热和光敏药物的比例可根据需要进行调控,载药量大大提高;同时,可在荧光成像引导下,精准定位肿瘤位置;光热和光动力联合治疗肿瘤,优于单独的光热治疗或者光动力治疗效果,有效改善了疗效。
附图说明
图1是本发明所描述的多功能纳米粒子的结构图;图2是具体实施例1制备得到的多功能纳米粒子的透射电镜图;图3是具体实施例1制备得到的多功能纳米粒子的动态光散射的粒径分布图;图4是具体实施例3中多功能纳米粒子在近红外光照射下的升温曲线;图5是具体实施例4中多功能纳米粒子体外在激光照射下产生单线态氧能力的测定;图6是具体实施例5中纳米粒子在动物肿瘤组织处的荧光成像的图像;图7是具体实施例6中纳米粒子在动物肿瘤组织处经激光照射后肿瘤组织的热成像图;图8是具体实施例7中多功能纳米粒子用于光热和光动力联合治疗下的动物肿瘤生长曲线。
具体实施方式
通过以下具体实施方式将有助于理解本发明,但并不限制本发明的内容。
实施例1
将二硬脂酰基磷脂酰胆碱(DSPC)、二硬脂酰基磷脂酰乙醇胺-聚乙二醇2000(DSPE-PEG2000)、卟啉脂质(PGL)和近红外染料DiR按照一定摩尔比混合(20%:10%:50%:20%),然后采用乙醇注入法,在50℃水浴超声条件下,将上述混合物注入到0.8ml水中;将上述所得到的溶液置于截留分子量8000-14000Da的透析袋中,透析2~4h,分离提纯后得到用于肿瘤荧光成像及光热/光动力治疗的多功能纳米粒子(PGL-DiR NPs)。纳米粒子的形态及粒径分布如附图2、3所示,纳米粒子在水溶液中分散良好,粒径100nm左右。
实施例2
将二硬脂酰基磷脂酰胆碱(DSPC)、二硬脂酰基磷脂酰乙醇胺-聚乙二醇2000(DSPE-PEG2000)、卟啉脂质(PGL)和近红外染料DiR按照一定摩尔比混合(10%:10%:50%:30%),然后采用乙醇注入法,在50℃水浴超声条件下,将上述混合物注入到0.8ml水中;将上述所得到的溶液置于截留分子量8000-14000Da的透析袋中,透析2~4h,分离提纯后得到用于肿瘤荧光成像及光热/光动力治疗的多功能纳米粒子(PGL-DiR NPs)。
实施例3
为了评价实施例1-2中获得的多功能纳米粒子的光热转化能力,将不同浓度纳米粒子经过760nm激光辐照(1W/cm2,5min)后,记录其温度随时间的变化情况。附图4显示PBS和PGL NPs经过激光照射5min后温度基本没有明显的升高,20μmol的PGL-DiR NPs(DiR当量)经过激光辐照5min后温度可以分别升高大概12℃,说明DiR有很高的光热转换效率。
实施例4
以ADPA(disodium salt of 9,10-anthracene dipropionic acid;Sigma)作为单线态氧探针,其最高吸收峰在378nm,与单线态氧发生化学反应后吸收峰吸收会逐渐下降。实验分两组:(PGL-DiR NPs+Laser 650,PGL-DiR NPs+Laser 760+Laser 650)分别检测不同组单线态氧产生情况。各个样品用650nm激光照射时,每5分钟用紫外-可见光分光光度计测量一次吸收光谱,随着激光照射时间延长,ADPA的吸收不断下降,反应了单线态氧产生不断增加。ADPA的吸收变化值与时间的关系如图5所示,可以看出PGL-DiR NPs直接被650nm激光照射25分钟内,并没有大量产生单线态氧,但是如果先经过760nm激光照射,再用650nm去激发,则卟啉基团会产生大量的单线态氧,这是因为DiR会淬灭卟啉基团,760nm激光辐照降解了DiR后,卟啉产生单线态氧的能力恢复。
实施例5
为了评估实施例1-2中获得的多功能纳米粒子在体内对肿瘤进行荧光成像的能力,对接种了皮下PC3肿瘤细胞的裸鼠进行荧光成像。裸鼠尾静脉注射100ul纳米粒子,然后0h、3h、6h、8h、12h、24h分别对小鼠进行近红外荧光成像。体内活体荧光成像图像如附图6示,纳米粒子体内注射后,3小时后即可见肿瘤部位有明显的荧光信号,大概6小时后,肿瘤组织荧光强度达到峰值,可以至少持续到24小时。
实施例6
体内治疗实验中进一步考察了实施例1-2中获得的多功能纳米粒子是否能对癌细胞进行有效的光热消融。接种了皮下PC3肿瘤细胞的裸鼠尾静脉注射纳米粒子200ul,24h后760nm激光(1W/cm2,10min)照射肿瘤部位,利用红外照相机对其肿瘤部位的温度进行监测(对照组:PBS)。肿瘤部位温度变化情况见附图7,激光照射10min后,肿瘤组织的温度高达65.0℃,可有效杀伤肿瘤细胞。
实施例7
体内光热和光动力联合治疗实验考察了实施例1-2中获得的多功能纳米粒子是否能对肿瘤生长进行有效抑制。将携带PC3皮下肿瘤的裸鼠随机分为4组,分别用(i)PBS,(ii)PTT,(iii)PDT,and(iv)PTT+PDT处理,其中给药方式均为尾静脉注射200ul。每组小鼠治疗后,每天记录其肿瘤体积及体重变化(肿瘤体积=长*宽^2/2)。光热和光动力联合治疗组的肿瘤体积增长速率远小于单纯光热或单纯光动力组的肿瘤体积增长速率,即联合治疗的效果要比单纯光热或光动力治疗效果要好。由此可见,用于肿瘤荧光成像及光热/光动力治疗的多功能纳米粒子,可以抑制肿瘤生长,发挥有效的治疗作用。结果如附图8所示。
Claims (7)
1.一种用于肿瘤荧光成像及光热/光动力治疗的多功能纳米粒子,其特征在于该纳米粒子的壳层是由脂质双分子层构成,其组成同时包括:用于光热治疗的近红外染料、用于光动力治疗的含有光敏功能基团的脂质及各类常规磷脂,这几种成分共同自组装成类似脂质体的具有双层膜结构的纳米粒子。
2.根据权利要求1所述的用于肿瘤荧光成像及光热/光动力治疗的多功能纳米粒子,其特征在于所述近红外染料首选生物相容性好、光热转换效率高的具有疏水长链或者双亲性的染料,一般其结构如下:
其中R1,R2=C6~18烷基,R3,R4=H或SO3H-;n=2或3;X=H,CH3,CH3O,CI-,Br-,I-,对位吡啶环,吡嗪等;例如1,1-dioctadecyl-3,3,3,3-tetramethylindotricarbocyanineiodide(DiR)、吲哚菁绿(ICG)及其衍生物等。所述的染料与常规磷脂自组装形成纳米粒子,染料和磷脂通过静电作用力或范德华力结合。
3.根据权利要求1所述的用于肿瘤荧光成像及光热/光动力治疗的多功能纳米粒子,其特征在于光敏功能基团共价连接到脂质上,其结构一般如下:
其中R1=H或C6~18烷基,R2=C6~18烷基;a,b=2或3;X=N或O,即光敏剂和脂质的连接方式是酯键或酰胺键;所述的含光敏功能基团的脂质经溶胶凝胶过程后在水溶液中能自组装形成脂质体。
4.根据权利要求3所述的光敏功能基团包括血卟啉、原卟啉、四苯基卟啉、焦脱镁叶绿酸(pyropheophorbide)、细菌叶绿素、叶绿素a、苯并卟啉衍生物、四氢苯基二氢卟吩、苯并二氢卟吩、萘并二氢卟吩、酞菁或萘酞菁等。
5.如权利要求1所述的用于肿瘤荧光成像及光热/光动力治疗的多功能纳米粒子的制备方法,其特征在于包括以下步骤:
1)将一定比例的磷脂、含有光敏剂功能基团的脂质及近红外染料于乙醇中溶解混合均匀(含有光敏剂功能基团的脂质比例0~50%,近红外染料比例0~30%)。
2)采用乙醇注入法,将混匀的上述体系滴加到生理盐水中,40-60℃水浴超声15-30分钟。
3)使用8000~14000KD的透析袋将得到的体系2)在生理盐水中室温下透析2~4h。分离提纯后得到用于肿瘤荧光成像及光热/光动力治疗的多功能纳米粒子。
6.根据权利要求7所述的磷脂包含12~24个碳的碳链长度以及包括磷脂酰胆碱、磷脂酰基乙醇胺、磷脂酸和磷脂酰基甘油,例如1,2-二硬脂酰基-sn-甘油基-3-磷酸胆碱(DSPC)、1,2-二棕榈酰基-sn-甘油基-3-磷脂酰胆碱(DPPC)、二硬脂酰磷脂酰乙醇胺-聚乙二醇2000(DSPE-PEG2000)、二硬脂酰磷脂酰乙醇胺-聚乙二醇2000(DSPE-PEG5000)等。
7.根据权利要求1所述的用于肿瘤荧光成像及光热/光动力治疗的多功能纳米粒子,其特征在于该纳米粒子可用于肿瘤的诊断和治疗。
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Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN110368504A (zh) * | 2019-08-23 | 2019-10-25 | 北京大学第三医院 | 一种产气-热敏性硅质体及其制备方法和应用 |
CN112168981A (zh) * | 2019-07-02 | 2021-01-05 | 西安电子科技大学 | 一种开关型脂质体纳米荧光探针及其制备方法和用途 |
CN113599520A (zh) * | 2020-08-26 | 2021-11-05 | 北京大学 | 一种卟啉脂质-全氟化碳纳米制剂及其制备方法和用途 |
CN114712523A (zh) * | 2022-01-25 | 2022-07-08 | 齐鲁工业大学 | 用于三模态成像引导的化疗-光疗的多功能铂(iv)和花菁染料基高聚物 |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102573914A (zh) * | 2009-10-16 | 2012-07-11 | 大学健康网络 | 卟啉纳米囊泡 |
CN104840422A (zh) * | 2014-02-18 | 2015-08-19 | 北京大学 | 一种长循环硅质体及其制备方法 |
CN105012970A (zh) * | 2015-07-21 | 2015-11-04 | 福州市传染病医院 | 用于肿瘤早期诊断与光学治疗的多功能纳米胶束及其应用 |
WO2016165006A1 (en) * | 2015-04-17 | 2016-10-20 | University Health Network | Texaphyrin-phospholipid conjugates and methods of preparing same |
-
2017
- 2017-08-23 CN CN201710731054.9A patent/CN109420181A/zh active Pending
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102573914A (zh) * | 2009-10-16 | 2012-07-11 | 大学健康网络 | 卟啉纳米囊泡 |
CN104840422A (zh) * | 2014-02-18 | 2015-08-19 | 北京大学 | 一种长循环硅质体及其制备方法 |
WO2016165006A1 (en) * | 2015-04-17 | 2016-10-20 | University Health Network | Texaphyrin-phospholipid conjugates and methods of preparing same |
CN105012970A (zh) * | 2015-07-21 | 2015-11-04 | 福州市传染病医院 | 用于肿瘤早期诊断与光学治疗的多功能纳米胶束及其应用 |
Non-Patent Citations (5)
Title |
---|
CHENG S. JIN等: "Ablation of Hypoxic Tumors with Dose-Equivalent Photothermal, but Not Photodynamic, Therapy Using a Nanostructured Porphyrin Assembly", 《ACS NANO》 * |
HYUNAH CHO等: "In vivo cancer imaging by poly(ethylene glycol)-b-poly(ɛ-caprolactone) micelles containing a near-infrared probe", 《NANOMEDICINE: NANOTECHNOLOGY, BIOLOGY, AND MEDICINE》 * |
JONATHAN F. LOVELL等: "Porphysome nanovesicles generated by porphyrin bilayers for use as multimodal biophotonic contrast agents", 《NATURE MATERIALS》 * |
柯亨特等: "多模态分子影像纳米探针介导的癌症可视化光热治疗", 《生物产业技术》 * |
野吕俊一: "《药物新制剂的设计与开发-DDS系列制剂的设计》", 31 December 1991, 中国医药科技出版社 * |
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CN110368504A (zh) * | 2019-08-23 | 2019-10-25 | 北京大学第三医院 | 一种产气-热敏性硅质体及其制备方法和应用 |
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