CN107708742B - 诊断治疗用气泡制剂(tb)及其使用方法 - Google Patents
诊断治疗用气泡制剂(tb)及其使用方法 Download PDFInfo
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- CN107708742B CN107708742B CN201680033821.2A CN201680033821A CN107708742B CN 107708742 B CN107708742 B CN 107708742B CN 201680033821 A CN201680033821 A CN 201680033821A CN 107708742 B CN107708742 B CN 107708742B
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Abstract
提供一种诊断治疗用气泡制剂,通过用诊断用超声波和低强度治疗用超声波进行超声波照射,就能够对对象组织进行诊断和治疗。该诊断治疗用气泡制剂包括外壳和气体,该外壳由脂质形成,该气体被封在外壳的内腔内。形成外壳的脂质为阴离子脂质,该阴离子脂质是由二硬脂酰基磷脂酰胆碱(DSPC)、二硬脂酰磷脂酰甘油(DSPG)和1,2‑二硬脂酰‑sn‑甘油基‑3‑磷酸乙醇胺‑N‑[甲氧基(聚乙二醇)](DSPE‑PEG)形成的。气体和混合气体为全氟丙烷或全氟丁烷。
Description
技术领域
本发明涉及一种诊断治疗用气泡制剂(TB)及该气泡制剂的使用方法,能够用该诊断治疗用气泡制剂(TB)对对象组织进行诊断(Diagnostics)和治疗(Therapeutics)。
背景技术
超声造影剂是微小气泡的悬浮液,日本国内正在使用的超声造影剂主要有Levovist(注册商标)和Sonazoid(注册商标)。当利用心血管显影进行诊断时使用Levovist;当利用库普弗(Kupffer)显影来诊断是否患有肝癌和乳腺肿瘤时使用Sonazoid。Levovist的外壳由为糖质的半乳糖形成,空气被封在该外壳内;Sonazoid的外壳由为磷脂的磷脂酰丝氨酸钠形成,全氟丁烷被封在该外壳内。
然而,这些超声造影剂不具有治疗功能,临床现场等则要求其具有更多的功能。近年来,将诊断(Diagnosis)和治疗(Therapeutics)融合在一起的诊断治疗(Theranostics)备受瞩目。其为同时进行诊断和治疗的系统,在DDS这一领域诊断治疗用(Theranostics)制剂的研发即高功能纳米载体(nanocarrier)的研发备受关注。
在应用于临床的诊断方法中,超声波具有以下优点:非侵袭性、简便、成本较低且能够实时地获取为进行诊断的图像。正因为如此,超声波诊断装置已成为很多临床领域所不可缺少的一种装置。而且,在临床现场,超声波的物理能已不仅用于诊断,还用于治疗。
例如,非专利文献1、2中所报告的方法如下:使用以血管显影等为目的且用于临床的超声造影剂即微气泡(micro bubble)并同时进行超声波照射,来将药物或基因送入细胞内。该方法从体外照射超声波而从时间上和空间上来控制微气泡的破裂(cavitation),由此而能够以良好的效率将药物或基因仅引入超声波所照射的部位。作为一种将基因、核酸特异性地引入器官、组织中的方法,该方法备受期待。还报告说,该方法在各种组织下进行体外和活体内的基因引入。
不用做外科手术就能够破坏癌细胞的高强度聚焦超声(HIGH INTENSITY FOCUSEDULTRASOUND:HIFU)治疗方法正在不断普及,该治疗方法让高强度的超声波(例如,声强为3000~5000W/cm2)从体外聚焦在体内癌组织的一点上,利用热能(热作用)和空化(非热作用)来烧灼癌细胞从而杀死癌细胞(专利文献1)。该聚焦部位的温度约达到80~90℃,上述作用就是利用该温度所具有的热能来烧灼癌细胞从而破坏癌细胞的。
然而,该HIFU治疗方法一次照射能够烧灼的范围例如为3mm×3mm×10mm,故需要边移动焦点边重复进行照射。就HIFU治疗方法而言,焦点的偏移具有很高的危险性,故要在MRI、超声波图像的引导下进行该HIFU治疗。皮肤或其周围部位的温度很高,所以既需要不停地进行精密的控制,又需要确保冷却时间。因此,通常所需要的治疗时间为2~4小时。
就这样,HIFU为非侵袭性治疗方法,非常理想。如果能够让具有治疗功能的气泡制剂进入癌组织中,就能够用低强度超声波且利用空化作用仅对存在气泡的部位进行癌症的治疗,该低强度超声波例如比HIFU中使用的高强度超声波弱1/100~1/500左右。
专利文献1:日本公表特许公报特表2009-533188号公报
非专利文献1:Mitragotri S,Healing sound:the use of ultrasound in drugdelivery and other therapeutic applications.Nature Rev.Drug Discov.2005;4:255-259.
非专利文献2:Lawrie A,Brisken AF,Francis SE,Cumberland DC,Crossman DC,Newman CM,Microbubble-enhanced ultrasound for vascular gene delivery.GeneTher.,2000;7:2023-2027.
发明内容
-发明要解决的技术问题-
本发明正是鉴于上述问题而完成的。其目的在于:提供一种能够借助低强度超声波照射来诊断和治疗对象组织的诊断治疗用气泡制剂及该气泡制剂的使用方法。
-用以解决技术问题的技术方案-
本发明所涉及的诊断治疗用气泡制剂(TB)的特征在于:包括外壳(coating)和气体,该外壳由脂质形成,该气体被封在所述外壳的内腔内,通过让低强度治疗用超声波起作用,就能够对对象组织进行诊断(Diagnostics)和治疗(Therapeutics)。形成所述外壳的脂质为阴离子脂质,该阴离子脂质是通过使二硬脂酰基磷脂酰胆碱(DSPC)、二硬脂酰磷脂酰甘油(DSPG)、1,2-二硬脂酰-sn-甘油基-3-磷酸乙醇胺-N-[甲氧基(聚乙二醇)](1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)]:DSPE-PEG)的摩尔比为22~60:30~68:4~12而形成的;所述气体含有全氟丙烷、全氟丁烷、全氟戊烷以及全氟己烷中的至少一种,或者含有全氟丙烷、全氟丁烷、全氟戊烷以及全氟己烷中的两种以上的混合气体。
本发明所涉及的诊断治疗用气泡制剂(TB)的使用方法的特征在于:将本发明所涉及的诊断治疗用气泡制剂悬浮在注射用水中而形成的悬浮液引入对象组织中,让第一频率的诊断用超声波对对象组织起作用,来利用对象组织的显影进行诊断(Diagnostics);让第二频率的低强度治疗用超声波对对象组织起作用,来利用空化现象对对象组织进行治疗(Therapeutics)。
-发明的效果-
与现有技术中的微气泡相比,本发明所涉及的诊断治疗用气泡制剂不会遭受诊断用超声波照射的破坏,能够长时间地共振和共鸣,因此,能够长时间地连续进行超声造影。根据本发明,利用低强度治疗用超声波照射就能够对对象组织进行诊断和治疗。进行低强度聚焦超声(Low Intensity Focused Ultrasound:LOFU)治疗时,聚焦部位的温度不会上升,安全性高。这样一来,就有希望建立一个高安全性的超声波诊断治疗系统,以便尽早地对血栓进行诊断和治疗,对脑功能疾患、肾脏疾患进行低侵袭性治疗。
附图说明
图1示出本发明所涉及的诊断治疗用气泡制剂的制备工序。
图2示出各种不同的外壳成分比下,气泡制剂的持续性。
图3示出示出随着时间的推移,由于Sonazoid(比较例)、封入有全氟丙烷气体的气泡制剂和封入有全氟丁烷气体的气泡制剂而能看到的、利用超声波成像出的图像。
图4示出由于Sonazoid(比较例)和封入有全氟丙烷气体的气泡制剂而能看到的、在已将肿瘤部位放大后的情况下利用超声波成像出的图像。
图5示出在活体内将荧光素酶基因引入肝脏时,荧光素酶活性的上升情况。
图6示出在活体内将荧光素酶基因引入肝脏时,荧光素酶发光而形成的图像。
图7示出在体外将荧光素酶基因引入colon26培养细胞时,荧光素酶活性的上升情况。
图8是照片,示出通过振荡制备出的气泡制剂。
图9示出用均质器制备出的cRGD修饰量为5摩尔%的被修饰气泡与HUVEC细胞的结合性。
图10示出通过振荡制备出的cRGD修饰量为5摩尔%的被修饰气泡与HUVEC细胞的结合性。
图11示出通过振荡制备出的cRGD修饰量为10摩尔%的被修饰气泡与HUVEC细胞的结合性。
图12示出本实施例所涉及的气泡制剂的抗肿瘤效果。
具体实施方式
下面,参照附图具体地说明本发明的实施方式,该实施方式只是为了易于理解本发明的原理,本发明的范围并不限于以下实施方式,本领域技术人员通过对以下实施方式的构成方式做适当的置换而得到的其它实施方式都包括在本发明的范围内。
1.<诊断治疗用气泡制剂>
本实施方式所涉及的诊断治疗用气泡制剂包括外壳和气体,该外壳由脂质形成,该气体被封在该外壳的内腔内。
形成外壳的脂质为阴离子脂质,该阴离子脂质是通过使二硬脂酰基磷脂酰胆碱(DSPC)、二硬脂酰磷脂酰甘油(DSPG)和1,2-二硬脂酰-sn-甘油基-3-磷酸乙醇胺-N-[甲氧基(聚乙二醇)](DSPE-PEG)的摩尔比为22~60:30~68:4~12而形成的。
气体是全氟代烃气体。具体而言,气体含有全氟丙烷、全氟异丁烷以及全氟正丁烷中的至少一种,或者含有全氟丙烷、全氟异丁烷以及全氟正丁烷中的两种以上的混合气体。特别是,在日本能够买到用于医疗的全氟丙烷,所以优选全氟代烃气体为全氟丙烷。需要说明的是,还可以含有除此以外的全氟代烃气体。具体而言,例如全氟甲烷、全氟乙烷、全氟异辛烷、全氟正辛烷和六氟化硫。所填充的气体压力例如为0.1~1.0MPa左右。
本发明所涉及的诊断治疗用气泡制剂,是磷脂和聚乙二醇-脂质将疏水性全氟碳气体包裹起来而形成的微小气泡,且以直径500nm~5μm的泡状存在于液体中。例如用动态光散射法测量诊断治疗用气泡制剂的直径。
使DSPC、DSPG和DSPE-PEG的摩尔比为22~60:30~68:4~12来形成外壳。这样一来,外壳对全氟代烃的保持性就会提高,在诊断用超声波的照射下,外壳不会破裂,而会持续地共振和共鸣。这样一来,就能够长时间地进行超声造影。
需要说明的是,形成外壳的DSPC、DSPG和DSPE-PEG中,DSPE能够被以下所示的磷脂取代。也就是说,二肉豆蔻酰基磷脂酰乙醇胺(DMPE)、二棕榈酰基磷脂酰乙醇胺(DPPE)、二油酰基磷脂酰乙醇胺(DOPE)、二硬脂酰基磷脂酰乙醇胺(DSPE)、二花生酰基磷脂酰乙醇胺(DAPE:diarachidoylphosphatidylethanolamine)或二月桂酰基磷脂酰乙醇胺(DLPE)等磷脂酰乙醇胺;二月桂酰基磷脂酰胆碱(DLPC)、二肉豆蔻酰磷脂酰胆碱(DMPC)、二棕榈酰磷脂酰胆碱(DPPC)、二花生酰基磷脂酰胆碱(DAPC)或二油酰基磷脂酰胆碱(DOPC)等磷脂酰胆碱;二肉豆蔻酰基磷脂酰丝氨酸(DMPS)、二花生酰基磷脂酰丝氨酸(DAPS)、二棕榈酰基磷脂酰丝氨酸(DPPS)、二硬脂酰基磷脂酰丝氨酸(DSPS)、二油酰基磷脂酰丝氨酸(DOPS)等磷脂酰丝氨酸;二棕榈酰磷脂酸(DPPA)、二肉豆蔻酰磷脂酸(DMPA)、二硬脂酰基磷脂酸(DSPA)、二花生酰基磷脂酸(DAPA:diarachidoyl phosphatidic acid)及其碱金属盐等磷脂酸衍生物;二肉豆蔻酰磷脂酰甘油(DMPG)及其碱金属盐、二棕榈酰磷脂酰甘油(DPPG)及其碱金属盐、二硬脂酰磷脂酰甘油(DSPG)及其碱金属盐、二油酰基磷脂酰甘油(DOPG)等磷脂酰甘油;二月桂酰基磷脂酰肌醇(DLPI)、二花生四烯酰磷脂酰肌醇(DAPI)、二肉豆蔻酰磷脂酰肌醇(DMPI)、二棕榈酰基磷脂酰肌醇(DPPI)、二硬脂酰基磷脂酰肌醇(DSPI)、二油酰基磷脂酰肌醇(DOPI)等磷脂酰肌醇。
在形成外壳的DSPC、DSPG和DSPE-PEG中,除了DSPE-PEG以外,还有硬脂PEG、棕榈PEG、油酸PEG、肉豆蔻PEG、月桂酰PEG等。
PEG的分子量例如为500~12000。优选的DSPE-PEG为DSPE-PEG2000、DSPE-PEG3000或DSPE-PEG5000,特别优选的是DSPE-PEG2000。
需要说明的是,外壳中除了含有DSPC、DSPG和DSPE-PEG以外,还可以含有以下所示的磷脂。亦即,二肉豆蔻酰磷脂酰胆碱(DMPC)、二月桂酰基磷脂酰胆碱(DLPC)、二棕榈酰磷脂酰胆碱(DPPC)、二油酰基磷脂酰胆碱(DOPC)、二亚油酰磷脂酰胆碱(dilinoleoylphosphatidylcholine)等磷脂酰胆碱;二月桂酰磷脂酰甘油(DLPG)、二肉豆蔻酰磷脂酰甘油(DMPG)、二棕榈酰磷脂酰甘油(DPPG)、二油酰磷脂酰甘油(DOPG)、二亚油酰磷脂酰甘油(dilinoleoylphosphatidylglycerol)等磷脂酰甘油;二月桂酰基磷脂酰乙醇胺(DLPE)、二肉豆蔻酰基磷脂酰乙醇胺(DMPE)、二棕榈酰基磷脂酰乙醇胺(DPPE)、二硬脂酰基磷脂酰乙醇胺(DSPE)、二油酰基磷脂酰乙醇胺(DOPE)、二亚油酰基磷脂酰乙醇胺(dilinoleoyl phosphatidylethanolamine)等磷脂酰乙醇胺;二月桂酰基磷脂酰丝氨酸(dilauroylphosphatidylserine)(DLPS)、二肉豆蔻酰基磷脂酰丝氨酸(DMPS)、二棕榈酰基磷脂酰丝氨酸(DPPS)、二硬脂酰基磷脂酰丝氨酸(DSPS)、二油酰基磷脂酰丝氨酸(DOPS)、二亚油酰基磷脂酰丝氨酸(dilinoleoylphosphatidylserin)等磷脂酰胆碱(phosphatidylcholine)。
外壳中除了可以含有上述磷脂以外,还可以含有例如甘油糖脂、鞘糖脂。甘油糖脂例如有:磺氧基核糖基甘油酯(sulfoxyribosylglyceride)、双糖基甘油二酯(diglycosyldiglyceride)、双半乳糖甘油二酯(digalactosyl diglyceride)、半乳糖甘油二酯(galactosyl diglyceride)、糖基甘油二酯(glycosyl diglyceride)等。鞘糖脂例如有:半乳糖脑苷脂、乳糖脑苷脂、神经节苷脂等。
能够外壳的脂质表面上修饰有靶细胞、靶组织、靶病灶的配体。血栓的配体例如有:精氨酸-甘氨酸-天冬氨酸(RGD)序列肽、西格玛蛋白等。癌细胞的配体例如有:转铁蛋白、叶酸、透明质酸、半乳糖或甘露糖。单克隆抗体、多克隆抗体也能作配体用。RGD序列为优选。RGD序列具有与存在于特定细胞或血栓上的细胞粘附因子特异性结合的功能。因此,通过让RGD序列修饰在外壳的脂质表面上,更容易地将血栓可视化。
为了让配体修饰在外壳的脂质表面上,优选外壳由二硬脂酰基磷脂酰胆碱(DSPC)、二硬脂酰磷脂酰甘油(DSPG)和二硬脂酰基磷脂酰乙醇胺-聚乙二醇(DSPE-PEG)衍生物形成。例如,优选,二硬脂酰基磷脂酰乙醇胺-聚乙二醇-马来酰亚胺(DSPE-PEG MAL)、二硬脂酰基磷脂酰乙醇胺-聚乙二醇-羧基(DSPE-PEG-COOH)、二硬脂酰基磷脂酰乙醇胺-聚乙二醇-琥珀酰亚胺(DSPE-PEG-NHS)或二硬脂酰基磷脂酰乙醇胺-聚乙二醇-氨基(DSPE-PEG-NH2)。
还可以根据需要,向外壳中添加其它物质,例如,外壳中可以含有作膜稳定剂用的谷甾醇、胆固醇、二氢胆固醇、胆固醇酯、植物甾醇类、豆甾醇、菜油甾醇、胆甾烷醇、羊毛甾醇、1-O-甾醇葡糖苷(1-O-sterolglucoside)、1-O-甾醇麦芽糖苷(1-O-sterolmaltoside)以及它们的混合物。
还能够在本发明所涉及的诊断治疗用气泡制剂的外壳的内部含有药物,或者,还能够让本发明所涉及的诊断治疗用气泡制剂的外壳的表面吸附药物。优选,能够长期维持其在血中的浓度的药物,或对特定的疾患部位或细胞具有靶向性的药物等。药物并无特别限定,例如有:抗癌剂、抗生素、抗喘药、抗血栓药、抗原生动物药、免疫增强剂、肽类药物、抗病毒剂。
抗癌剂并无特别限定。例如有:阿霉素、顺铂、丝裂霉素、博莱霉素、5-氟尿嘧啶、氨甲蝶呤、氮芥、白消安、奥沙利铂、紫杉醇、喜树碱等。抗生素例如有:sulfazen、庆大霉素、链霉素等。抗喘药例如有茶碱等。抗血栓药例如有:tPA、肝素、低分子肝素、尿激酶、血栓调节蛋白、链激酶等。抗原生动物药例如有葡甲胺锑等。免疫增强剂例如有胞壁酰肽类等。肽类药物例如有:天然型或转基因型α、β、γ-干扰素、白介素、超氧化物歧化酶等。还能列举出其它药物,例如:前列腺素等动脉硬化症治疗药、治疗动脉阻塞性疾病、血栓闭塞性脉管炎的NF卡巴-B、诱饵(decoy)等。
不仅能够在诊断治疗用气泡制剂的外壳的内部含有药物或者能够让诊断治疗用气泡制剂的外壳的表面吸附药物,还能够在诊断治疗用气泡制剂的内部含有基因或者还能够让该诊断治疗用气泡制剂的表面吸附基因。基因例如有:DNA、RNA、反义DNA、siRNA、诱饵、治疗性寡核苷酸等。
2.<诊断治疗用气泡制剂的制造方法>
如图1所示,一边搅拌脂质溶液生成悬浮液,一边使其与全氟代烃气体接触,之后,再用均质器(15000rpm、5分)将有机相乳化为水相,即能够将本发明所涉及的诊断治疗用气泡制剂作为纳米气泡悬浮液制备出来。
本发明所涉及的诊断治疗用气泡制剂不仅能够用均质器制备出来,还能够例如通过振荡制备出来。例如,将具有规定比的脂质体溶液投入小玻璃瓶中,用小玻璃瓶振荡器进行振荡,也能够制备出纳米气泡悬浮液。
3.<冻干粉末>
通过对本发明所涉及的诊断治疗用气泡制剂悬浮于海藻糖或蔗糖即糖质溶液中而形成的悬浮液进行冷冻干燥,即可得到本实施方式所涉及的冻干粉末。
冷冻干燥之际,为防止冷冻带来的破坏和/或为防止分散,还可以含有冷冻干燥添加剂。冷冻干燥添加剂例如有:甘氨酸一样的氨基酸;甘露醇、麦芽糖、葡萄糖、乳糖、菊糖、蔗糖、海藻糖或环式糊精一样的糖类;葡聚糖、壳聚糖一样的多糖;或者聚乙二醇一样的聚亚氧烷基乙二醇等。
该冻干粉末能够长期保存三个月以上,用注射用水和上述全氟丙烷等全氟代烃气体复原后,即可使用。
4.<诊断治疗用气泡制剂(TB)的使用方法>
按以下所述使用本发明所涉及的诊断治疗用气泡制剂。也就是说,将本发明所涉及的诊断治疗用气泡制剂悬浮于注射用水中而形成的悬浮液引入对象组织中。对象组织并无特别限定,例如为癌组织。
接下来,让第一频率的诊断用超声波对对象组织起作用,利用对象组织的显影进行诊断。第一频率例如为3MHz~20MHz。让第一频率起作用而产生微流(Microstreaming)现象。也就是说,超声波的声强使纳米气泡重复地扩大和缩小,局部振动。
接下来,让第二频率的低强度超声波对对象组织起作用,利用空化现象对对象组织进行治疗。第二频率例如为0.5MHz~3.0MHz。空化现象在纳米气泡破裂时释放很大的压力而产生喷流。
让第一频率的诊断用超声波作用于对象组织,就能够进行对象组织的显影。能够显影说的是,如果朝着该部位照射第二频率的低强度超声波或照射LOFU,就能够利用空化现象进行治疗。而且,仅照射低强度超声波或者仅照射LOFU的话,聚焦部位的温度不会上升,因此治疗安全性高且侵袭性低。
(实施例)
实施例1.<诊断治疗用气泡制剂的制备>
一边搅拌摩尔比为22:68:10的DSPC、DSPG和DSPE-PEG2000-OMe的阴离子脂质溶液而生成悬浮液,一边使其与全氟丙烷气体(气体流量为12ml/分)。之后,用均质器(15000rpm、5分)将气体乳化,由此即制备出气泡悬浮液。
接下来,除了如下所示改变了阴离子脂质溶液中的DSPC、DSPG和DSPE-PEG2000-OMe的摩尔比以外,其它方面都与上述一样,这样制备出气泡悬浮液。
DSPC:DSPG:DSPE-PEG2000-OMe=30:60:10
DSPC:DSPG:DSPE-PEG2000-OMe=36:54:10
DSPC:DSPG:DSPE-PEG2000-OMe=45:45:10
DSPC:DSPG:DSPE-PEG2000-OMe=54:36:10
DSPC:DSPG:DSPE-PEG2000-OMe=60:30:10
作为比较例,除了如下所示改变了阴离子脂质溶液中的DSPC、DSPG和DSPE-PEG2000-OMe的摩尔比以外,其它方面都与上述一样,这样制备出气泡悬浮液。
DSPC:DSPG:DSPE-PEG2000-OMe=0:90:10
DSPC:DSPG:DSPE-PEG2000-OMe=90:0:10
就这样,以多种不同的外壳成分比制备出多种气泡制剂。图2示出多种不同的外壳成分比下气泡制剂的持续性。需要气泡在血管内和肿瘤内具有停留性和稳定性。如图2所示,与比较例所涉及的气泡制剂相比,随着时间的推移,本发明所涉及的气泡制剂仍具有非常优良的停留性。
实施例2.<荷瘤小鼠的持续显影>
接下来,对荷瘤小鼠在诊断用超声波作用下的连续抖动情况进行了观察,拍摄下了血流成像出的图像。
一边搅拌由摩尔比为22:68:10的DSPC、DSPG和DSPE-PEG2000-OMe形成的阴离子脂质溶液生成悬浮液,一边使其与全氟丙烷气体接触,之后,用均质器(15000rpm、5分)将有机相乳化为水相,由此制备出纳米气泡。接下来,除了使用全氟丁烷气体以外,其它方面都与上述一样,这样制备出气泡制剂。
用诊断用超声波装置利用超声波成像,来判断纳米气泡是否到达了肿瘤部位。诊断用超声波装置使用的是GE Healthcare公司的LOGIQ E9。
图3示出随着时间的推移,由于Sonazoid(比较例)、封入有全氟丙烷气体的气泡制剂和封入有全氟丁烷气体的气泡制剂而能看到的利用超声波成像出的图像。如图3所示,与比较例相比,在本实施例中,从肿瘤部位观察到了较强的回声信号,因此,可确信:本气泡制剂稳定地到达了肿瘤部位。本实施例中,即使时间推移,也能够观察到较强的回声信号。
图4示出Sonazoid(比较例)和封入有全氟丙烷气体的气泡制剂在将肿瘤部位放大后且利用超声波成像出的图像。如图4所示,与比较例相比,在本实施例中,从肿瘤部位观察到了较强的回声信号。
实施例3.<利用超声波引入基因>
接下来,对同时使用封入有全氟丙烷气体的气泡制剂(TB)和低强度超声波照射引入基因的基因引入系统的功能进行了评价。在活体实验中,将本实施例所涉及的封入有全氟丙烷气体的气泡制剂(50nmol)和将报告基因(荧光素酶:Luciferase)编码后得到的pDNA一起通过尾巴静脉投入实验用小鼠体内(100μg),并马上用Sonitron探针(12nm)对肝脏部分进行了经皮性的治疗用超声波照射(US)(1MHz、50%duty、1W/cm2、60sec.)。图5示出荧光素酶活性的上升情况。在活体内发光成像的过程中,对异氟烷麻醉下的实验小鼠投入了荧光素底物(luciferin substrate)(15mg/mL、200μL)以后,用IVIS成像系统检测了发光情况并加以定量。图6示出活体内发光成像的结果。如图5和图6所示,仅从进行了治疗用超声波照射的肝脏观察到有荧光素酶显现出来。
在活体实验中,将本实施例所涉及的含有全氟丙烷气体的气泡制剂(5nmol/sample)和将报告基因(荧光素酶:Luciferase)编码后得到的pDNA(5μg/sample)一起添加到Colon26培养细胞液中,并进行了治疗用超声波照射(2MHz、50%duty、2W/cm2、60sec.)。如图7所示,仅观察到使用了封入有全氟丙烷气体的气泡制剂并进行了治疗用超声波照射的试样,基因显现得非常明显。
由此得知:靠本实施例所涉及的封入有全氟丙烷气体的气泡制剂(TB)和低强度治疗用超声波照射进行的给药系统会对癌基因、核酸治疗非常有用,这是人们可期待的。
实施例4.<通过振荡来制备气泡制剂>
实施例1中,用均质器将气体乳化,由此而制备出气泡悬浮液。实施例4中,通过振荡来制备气泡制剂。
向小玻璃瓶中投入DSPC:DSPG:DSPE-PEG2000-OMe=30:60:10(摩尔比)的脂质体(脂质浓度:0.5mM)1mL,用全氟丙烷气体置换小玻璃瓶顶部空间(headspace)的空气并进行了冰冷。之后,用小玻璃瓶振荡器振荡了45秒钟后,再次进行了冰冷。为了除去较大的气泡,将小玻璃瓶倒过来并静置15分钟,如图8所示,将下部的气泡悬浮液回收起来。
实施例5.<用均质器制备出的肽修饰气泡与靶细胞的结合性评价>
作为肽修饰脂质,准备的是由环形RGD(cRGD)修饰的DSPE-PEG3400。需要说明的是,cRGD是与过剩显现在癌组织的新生血管内皮细胞表面上的αVβ3整合素特异结合的肽序列,通过让该cRGD修饰在气泡表面上,即能够制备出能够选择性地与靶细胞结合的靶型气泡。然后,一边搅拌DSPC:DSPG:DSPE-PEG2000-OMe:cRGD修饰DSPE-PEG3400=30:60:5:5(摩尔比)的阴离子脂质溶液生成悬浮液,一边使其与全氟丙烷气体(气体流量为12ml/分)接触。之后,用均质器(15000rpm、5分)将气体乳化,由此制备出气泡悬浮液,即准备好了cRGD修饰气泡。cRGD修饰量为5摩尔%。
靶细胞使用的是人脐静脉内皮细胞(HUVEC)。该HUVEC是供cRGD结合的细胞。
另一方面,不与HUVEC结合的控制肽使用的是环形RAD(cRAD)。与cRGD修饰气泡一样,制作了cRAD修饰气泡,且cRAD修饰量为5摩尔%。
将cRGD或cRAD修饰气泡(DiI标记)添加到HUVEC细胞中,在37℃的温度下培育了10分钟。之后,对细胞进行冲洗,用流式细胞仪对气泡与细胞的结合情况进行了评价。如图9所示,与用均质器制备出的cRAD修饰量为5摩尔%的修饰气泡相比,用均质器制备出的cRGD修饰量为5摩尔%的修饰气泡对HUVEC细胞显示出优良的结合性。
实施例6.<通过振荡制备出的肽修饰气泡与靶细胞的结合性评价>
实施例5示出了用均质器制备出的肽修饰气泡与HUVEC细胞的结合性。实施例6示出了通过振荡制备出的肽修饰气泡与HUVEC细胞的结合性。
与实施例5一样,作为肽修饰脂质,准备的是由环形RGD(cRGD)修饰的DSPE-PEG3400。向小玻璃瓶中投入DSPC:DSPG:DSPE-PEG2000-OMe:cRGD修饰DSPE-PEG3400=30:60:5:5或30:60:0:10(摩尔比)的脂质体(脂质浓度:0.5mM)1mL,用全氟丙烷气体置换小玻璃瓶顶部空间的空气并进行了冰冷。之后,用小玻璃瓶振荡器振荡了45秒钟,再次进行了冰冷。为了除去较大的气泡,将小玻璃瓶倒过来并静置15分钟,将下部的气泡悬浮液回收起来,即准备好了cRGD修饰气泡。准备好了cRGD修饰量为5摩尔%的修饰气泡与cRGD修饰量为10摩尔%的修饰气泡。
与实施例5一样,控制肽使用的是环形RAD(cRAD)。与cRGD修饰气泡一样,通过振荡制备出cRAD修饰气泡,准备好了修饰量为5摩尔%的修饰气泡和修饰量为10摩尔%的修饰气泡。
将cRGD或cRAD修饰气泡(DiO标记)添加到HUVEC细胞中,在37℃的温度下培育了30分钟。之后,对细胞进行冲洗,用流式细胞仪对气泡与细胞的结合情况进行了评价。如图10所示,与通过振荡制备出的cRAD修饰量为5摩尔%的修饰气泡相比,通过振荡制备出的cRGD修饰量为5摩尔%的修饰气泡对HUVEC细胞显示出优良的结合性。而且,如图11所示,与通过振荡制备出的cRAD修饰量为10摩尔%的修饰气泡相比,通过振荡制备出的cRGD修饰量为10摩尔%的修饰气泡也对HUVEC细胞显示出优良的结合性。
实施例7.<抗肿瘤效果的评价>
一边搅拌DSPC:DSPG:DSPE-PEG2000-OMe=30:60:10(摩尔比)的阴离子脂质溶液生成悬浮液,一边使其与全氟丙烷气体(气体流量为12ml/分)接触。之后,用均质器(15000rpm、5分)将气体乳化,由此即制备出气泡悬浮液。对该气泡悬浮液进行冷冻和干燥而得到了冻干粉末。向该冻干粉末中添加2mL的超纯水(2mL MilliQ水)并让粉末悬浮在超纯水中。
接下来,将1×106/50μL/只的小鼠黑色素瘤细胞(B16BL6细胞)移植到C57BL/6j小鼠后背部皮下,癌细胞生长7天后,向肿瘤内投入已通过5μm的过滤器的气泡25μL,之后马上朝着肿瘤进行经皮超声波照射。
超声波照射条件如下。
装置:sonitron 2000(Nepa Gene股份有限公司)
频率:1MHz
声强:4W/cm2
照射时间与非照射时间之比(duty):50%
时间:120sec.
重复周期(burst rate):2Hz
肿瘤体积用(肿瘤的长径×肿瘤的短径×肿瘤的短径)×0.5(mm3)这一计算式求出,以肿瘤径为指标评价了抗肿瘤效果。如图12所示,明确可知:本实施例所涉及的气泡具有优良的抗肿瘤效果。
-产业实用性-
能够用于治疗血栓或者用于治疗癌症。
Claims (7)
1.一种诊断治疗用气泡制剂,其包括外壳和气体,该外壳由脂质形成,该气体被封在所述外壳的内腔内,通过让诊断用超声波和低强度治疗用超声波起作用,能够对对象组织进行诊断和治疗,该诊断治疗用气泡制剂的特征在于:
形成所述外壳的脂质为阴离子脂质,该阴离子脂质是通过使二硬脂酰基磷脂酰胆碱、二硬脂酰磷脂酰甘油和1,2-二硬脂酰-sn-甘油基-3-磷酸乙醇胺-N-[甲氧基(聚乙二醇)]的摩尔比为30~45:45~60:4~12而形成的,
所述气体含有全氟丙烷、全氟丁烷、全氟戊烷以及全氟己烷中的至少一种,或者含有全氟丙烷、全氟丁烷、全氟戊烷以及全氟己烷中的两种以上的混合气体。
2.根据权利要求1所述的诊断治疗用气泡制剂,其特征在于:
形成所述外壳的脂质为阴离子脂质,阴离子脂质是通过使二硬脂酰基磷脂酰胆碱、二硬脂酰磷脂酰甘油和1,2-二硬脂酰-sn-甘油基-3-磷酸乙醇胺-N-[甲氧基(聚乙二醇)]的重量比为30:60:10而形成的;
所述气体为全氟丙烷。
3.根据权利要求1或2所述的诊断治疗用气泡制剂,其特征在于:
所述低强度治疗用超声波的声强为0.03~50W/cm2。
4.根据权利要求1或2所述的诊断治疗用气泡制剂,其特征在于:
该诊断治疗用气泡制剂的直径为500nm~5μm。
5.根据权利要求1或2所述的诊断治疗用气泡制剂,其特征在于:
所述外壳含有二硬脂酰基磷脂酰胆碱、二硬脂酰磷脂酰甘油和二硬脂酰基磷脂酰乙醇胺-聚乙二醇衍生物,
所述二硬脂酰基磷脂酰乙醇胺-聚乙二醇衍生物为二硬脂酰基磷脂酰乙醇胺-聚乙二醇-马来酰亚胺、二硬脂酰基磷脂酰乙醇胺-聚乙二醇-羧基、二硬脂酰基磷脂酰乙醇胺-聚乙二醇-琥珀酰亚胺或二硬脂酰基磷脂酰乙醇胺-聚乙二醇-氨基。
6.根据权利要求5所述的诊断治疗用气泡制剂,其特征在于:
所述外壳的脂质表面上修饰有配体,
所述配体为精氨酸-甘氨酸-天冬氨酸序列肽、转铁蛋白、叶酸、透明质酸、半乳糖或甘露糖。
7.一种冻干粉末,其特征在于:
该冻干粉末,是通过对权利要求1到6中任一项所述的诊断治疗用气泡制剂悬浮在海藻糖、菊糖或蔗糖即糖质溶液中而形成的悬浮液进行冷冻和干燥而得到的。
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