CN109568610A - 一种基于Janus药物共轭体的诊疗微泡的制备方法和用途 - Google Patents
一种基于Janus药物共轭体的诊疗微泡的制备方法和用途 Download PDFInfo
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- A61K31/7072—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid having two oxo groups directly attached to the pyrimidine ring, e.g. uridine, uridylic acid, thymidine, zidovudine
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Abstract
本发明涉及一种集超声成像及化疗于一体的多功能微泡,涉及这类多功能微泡的制备方法及其在肿瘤诊疗方面的用途。集超声成像及化疗于一体的多功能微泡的结构示意图如图所示,其膜成份包括用于化疗的Janus药物共轭体以及常规磷脂,Janus药物共轭体和常规磷脂的比例可根据需要进行调控,载药量大大提高。在超声作用下,该多功能微泡可在肿瘤部位实现定点靶向爆破转变为纳米粒子,极大提高了药物在肿瘤部位的富集及摄取,有效改善了化疗抑制肿瘤生长的效果。
Description
技术领域
本发明属于生物医用材料领域,具体涉及一种集超声成像以及化疗于一体的多功能超声微泡,以及其在肿瘤诊疗方面的用途。
背景技术
1968年Gramiak首次报道了可增强显影的小气泡,即超声微泡造影剂(UCA),它的出现开创了无创超声诊断和治疗的新领域。随着对其研究的不断深入,人们发现超声微泡造影剂不仅是一种良好的超声显像对比剂,而且是一种重要的药物递送载体。对超声微泡造影剂携带基因或药物靶向治疗在医学领域的研究日益广泛。超声微泡造影剂靶向治疗包括超声介导载药微泡的治疗及超声介导靶向载药微泡的治疗。
靶向载药微泡携带基因或化疗药物可以达到靶向结合肿瘤并有效治疗肿瘤的目的,该方法是目前肿瘤治疗的研究热点。将携有基因或细胞毒性药物的靶向微泡从外周静脉或局部注射后,当微泡特异性结合到肿瘤部位时,进行超声辐照破坏微泡,使基因或药物局部释放,达到提高局部药物或基因的浓度、保护药物避免被肝脏摄取、延缓药物的释放、减少给药次数、减小给药剂量、增加药物疗效和减轻全身的不良反应的目的,而且还可以通过改变超声仪器各个参数的设置,控制药物释放速度,进行实时监控,减少药物或基因破坏,节约用量。
目前基因或药物与超声微泡造影剂的连接方式:1、药物直接粘附在微泡的表面;2、药物镶嵌在微泡外壳膜之间,可增加微泡外壳的稳定性;3、某些药物或基因以非共价键结合在微泡表面;4、疏水性药物可以混合在一层油脂层内,形成一层薄膜包绕在微泡内,其外包被这一层稳定的膜。最近开发出一种新的方法,将载药脂质体与微泡相连实现微泡载药。以上所述的药物装载方式有一个共同的缺点,药物的载药量低且容易发生泄漏,降低治疗效果的同时,容易引起生物体的毒副作用。
基于以上考虑,本发明设计合成了一种基于季戊四醇的高度对称的Janus喜树碱-5-氟脱氧尿苷共轭药物分子(JCFC),并且开发出了一类集超声成像以及化疗于一体的多功能超声微泡。其特点是将用于化疗的Janus药物共轭体(JCFC)和普通脂质组装到超声造影剂的膜成分中,在超声引导下可在肿瘤部位定点击破微泡,使其转变为纳米粒子,在超声空化作用下,纳米粒子更多的被肿瘤细胞摄取。随后进一步在荧光成像引导下,在肿瘤部位实现高效化疗。
发明内容
本发明的目的是提供一类集超声成像以及化疗于一体的多功能超声微泡造影剂以及该类微泡的制备方法。
本发明的另一目的是提供上述集超声成像以及化疗于一体的多功能微泡造影剂在肿瘤诊疗中的应用。
本发明所述的集超声成像以及化疗于一体的多功能微泡造影剂的结构如附图1所示。Janus药物共轭体和普通磷脂按一定比例混合成膜后,通入惰性气体,在超声和机械振动作用下可组装形成微气泡,该气泡在特定强度超声波作用下可转变为纳米粒子,从而更有利于进入肿瘤组织和细胞中,在肿瘤酸性微环境和细胞中相关酯酶作用下,化疗药物可发生释放,达到高效化疗的目的。
本发明中多功能微泡造影剂,其特征在于该微泡的壳层是由脂质单分子层构成,其膜成分同时包括:用于化疗的Janus药物共轭体及各类常规磷脂,微泡内包载惰性气体或液体,其中用于化疗的Janus药物共轭体可以和常规磷脂在水溶液中共同自组装形成微泡。
其中所述的一种集超声成像以及化疗于一体的多功能微泡,其特征在于药物分子通过季戊四醇共价连接在一起得到Janus药物共轭体,其结构一般如下:
其中,A代表各种疏水性化疗药物分子,B代表各种亲水性化疗药物分子,X和Y代表各种连接基团,X和Y可以相同,也可以不同;a=2或3;b=2或3,a和b可以相同,也可以不同。所述的Janus药物共轭体经溶胶凝胶过程后在水溶液中能自组装形成脂质体。
所述的Janus药物共轭体,其特征在于化疗药物选自紫杉醇、喜树碱、五氟脱氧尿苷、阿霉素、异环磷酰胺、长春新碱、长春花碱、依托泊甙、威猛、卡铂、顺铂、丝裂霉素、长春花碱酰胺、表阿毒素、异长春花碱和甲氨蝶呤。
本发明所述的一种集超声成像以及化疗于一体的多功能微泡的制备方法,包括以下步骤:
1)将一定比例的磷脂和Janus药物共轭体于二甲基亚砜(DMSO)中溶解混合均匀(Janus药物共轭体比例0~50%)。
2)采用DMSO注入法,将混匀的上述体系滴加到生理盐水中,40-60℃水浴15-30分钟。
3)使用8000~14000KD的透析袋,将得到的体系在生理盐水中室温下透析2~4h。
4)将上述所得体系转移至西林瓶中,然后加入丙二醇、甘油作为稳定剂,混匀。
5)往西林瓶中填充惰性内包物质,封口后,使用银汞调和器剧烈震荡45s,分离提纯后得到集超声成像以及化疗于一体的多功能微泡。
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,优选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)、1,2-二棕榈酰基-sn-甘油基-3-磷脂酸(DPPA)、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)。
步骤5)中所述的惰性内包物质包含空气、氮气、二氧化碳、氟碳烃气体,液体选自C5-C12氟碳烃。
本发明所述的超声成像及化疗于一体的多功能微泡,其用于化疗的Janus药物共轭体以及常规磷脂共同成膜,Janus药物共轭体和常规磷脂的比例可根据需要进行调控,载药量大大提高,同时可有效避免药物泄漏。在超声作用下,该多功能微泡可在肿瘤部位实现定点靶向爆破转变为纳米粒子,极大提高了药物在肿瘤部位的富集及摄取,有效改善了化疗抑制肿瘤生长的效果。
附图说明
图1是本发明所描述的多功能微泡造影剂的结构图,以及在肿瘤诊疗中的应用示意图;图2是具体实施例1制备得到的多功能微泡的显微镜观察结果(包括白光通道和荧光通道);图3是具体实施例2制备得到的多功能微泡的粒径分布结构;图4是具体实施例4中微泡造影剂的体外超声造影图像;图5是具体实施例5中微泡造影剂在动物肿瘤组织处的超声造影图像。
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)和Janus药物共轭体(JCFC)按照一定摩尔比混合(80%:10%:10%),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,取出后分别加入甘油和丙二醇各100μL混合均匀。将混合液装入3.5mL西林瓶中,充入足量的全氟丙烷(C3F8)气体,振荡器震荡45s,分离提纯后得到集超声成像以及化疗于一体的多功能微泡(JCFC MBs)。将该微泡置于荧光显微镜下可观察到,微泡呈现规整的球形结构,大小在450nm到4μm之间,在荧光通道下,可明显看到微泡壳层上的喜树碱荧光,证实Janus药物共轭体成功组装到了微泡上,具体如图附图2所示。
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)和Janus药物共轭体(JCFC)按照一定摩尔比混合(45%:5%:50%),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,取出后分别加入甘油和丙二醇各100μL混合均匀。将混合液装入3.5mL西林瓶中,充入足量的全氟丁烷气体,振荡器震荡45s,分离提纯后得到集超声成像以及化疗于一体的多功能微泡(JCFC MBs)。微泡粒径分布如附图3所示,微泡大小在0.73um左右,呈现比较窄的分布,表明微泡的大小相对比较均一。
实施例3
将二硬脂酰基磷脂酰胆碱(DSPC)、1,2-二棕榈酰基-sn-甘油基-3-磷脂酸(DPPA)和Janus药物共轭体(JCFC)按照一定摩尔比混合(45%:5%:50%),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,取出后分别加入甘油和丙二醇各100μL混合均匀。将混合液装入3.5mL西林瓶中,加入足量的全氟溴辛烷,振荡器震荡45s,分离提纯后得到集超声成像以及化疗于一体的多功能微泡(JCFC MBs)。
实施例4
将实施例1-3中获得的集超声成像以及化疗于一体的多功能微泡与生理盐水按体积比1:3配置后注入乳胶管中,在水槽中放入500ml超声脱气水,将上述乳胶管置于液体中部,使用超声诊断仪contrast模式,MI:0.04(机械指数),探头频率:3-12MHz,观察微泡体外超声造影效果。体外超声造影图像见附图4所示,由于硅胶管壁本身较高的密度,导致其在超声场里呈现较高的回声效果,而硅胶管内腔在没有多功能微泡JCFC MBs存在的时候,呈现无回声状态。当注射JCFC微泡之后,在硅胶管的内腔中观察到显著的回声信号增强,从而证实了JCFC微泡具有很好的体外超声显影增强的能力。
实施例5
为了评估实施例1-3中获得的多功能微泡体内超声显影增强性能,对PC3荷瘤裸鼠进行了肿瘤超声成像。微泡的浓度为1*108/mL,按照1mL/kg的浓度尾静脉注射到裸鼠体内,紧接着注射100μL生理盐水。使用超声诊断仪contrast模式,MI:0.04(机械指数),探头频率:3-12MHz。体内超声造影图像见附图5所示,注射后10s时,超声信号接近饱和,超声击破后,肿瘤部位超声造影信号消失,说明JCFC微泡在高能超声作用下发生了破裂,20秒时,又可见微泡重新灌注到肿瘤血管,增强超声造影信号逐渐增强,然后在大概注射5min后,超声增强信号逐渐衰减至未注射微泡前水平。
Claims (9)
1.一种集超声成像以及化疗于一体的多功能微泡,其特征在于该微泡的壳层是由脂质单分子层构成,其组成同时包括:用于化疗的Janus药物共轭体及各类常规磷脂,微泡内包载惰性气体或液体,用于化疗的Janus药物共轭体可以和常规磷脂在水溶液中共同自组装形成微泡。
2.根据权利要求1所述的一种集超声成像以及化疗于一体的多功能微泡,其特征在于该多功能微泡可在超声作用下转变为纳米粒子,所述纳米粒子的粒径范围为20nm-700nm。
3.根据权利要求1所述的一种集超声成像以及化疗于一体的多功能微泡,其特征在于药物分子通过季戊四醇共价连接在一起得到Janus药物共轭体,其结构一般如下:
其中,A代表各种疏水性化疗药物分子,B代表各种亲水性化疗药物分子,X和Y代表各种连接基团,X和Y可以相同,也可以不同;a=2或3;b=2或3,a和b可以相同,也可以不同。所述的Janus药物共轭体经溶胶凝胶过程后在水溶液中能自组装形成脂质双层膜结构。
4.根据权利要求3所述的Janus药物共轭体,其特征在于化疗药物选自紫杉醇、喜树碱、五氟脱氧尿苷、阿霉素、异环磷酰胺、长春新碱、长春花碱、依托泊甙、威猛、卡铂、顺铂、丝裂霉素、长春花碱酰胺、表阿毒素、异长春花碱和甲氨蝶呤。
5.根据权利要求1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,优选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)、1,2-二棕榈酰基-sn-甘油基-3-磷脂酸(DPPA)、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)。
6.根据权利要求1所述的一种集超声成像以及化疗于一体的多功能微泡,其特征在于所述的超声造影剂由成膜材料包裹气体或液体构成,所述微泡造影剂的粒径范围为200nm-8um。
7.如权利要求1所述的一种集超声成像以及化疗于一体的多功能微泡的制备方法,其特征在于包括以下步骤:
1)将一定比例的磷脂和Janus药物共轭体于二甲基亚砜(DMSO)中溶解混合均匀(Janus药物共轭体比例0~100%)。
2)采用DMSO注入法,将混匀的上述体系滴加到生理盐水中,40-60℃水浴15-30分钟。
3)使用8000~14000KD的透析袋,将得到的体系在生理盐水中室温下透析2~4h。
4)将上述所得体系转移至西林瓶中,然后加入丙二醇、甘油作为稳定剂,混匀。
5)往西林瓶中填充惰性内包物质,封口后,使用银汞调和器剧烈震荡45s,分离提纯后得到集超声成像以及化疗于一体的多功能微泡。
8.根据权利要求7中步骤5)所述的惰性内包物质包含空气、氮气、二氧化碳、氟碳烃气体,液体选自C5-C12氟碳烃。
9.根据权利要求1所述的一种集超声成像以及化疗于一体的多功能微泡,其特征在于该微泡可用于肿瘤的诊断和治疗。
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