CN107073142B - 用于放射成像和疗法的磷酸锶微粒 - Google Patents
用于放射成像和疗法的磷酸锶微粒 Download PDFInfo
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- CN107073142B CN107073142B CN201480083320.6A CN201480083320A CN107073142B CN 107073142 B CN107073142 B CN 107073142B CN 201480083320 A CN201480083320 A CN 201480083320A CN 107073142 B CN107073142 B CN 107073142B
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Abstract
本发明涉及多孔微颗粒载体,其掺入放射性同位素以形成用于放射疗法和成像的放射性微粒。本发明还提供制备微粒的方法和使用放射性微粒的治疗方法。
Description
本发明的领域是用于医学疗法和成像的放射性微粒,且特别是用于放射成像和放射性同位素疗法的包含磷酸锶的放射性微粒。
在治疗患有某些类型的癌症或类风湿性关节炎的患者中,已知有将放射性颗粒血管内引入肿瘤部位(放射性栓塞)或局部地引入关节内的滑液中以出于其放射效应将放射性颗粒捕获在特定位点的方法。使用类似的方法对身体部分、器官、肿瘤等成像。
根据本技术,将一定数量的放射性颗粒注入待成像和/或治疗的患者的局部区域。对于成像,γ发射材料通常用于标记提供组织区域、肿瘤或器官成像的载体。这些载体中的一些对某些结合位点或生物化学靶标具有特异性亲和力,从而允许标记载体的靶特异性或位置特异性摄取。
通常使用锝-99m,通常通过单光子发射计算机断层摄影(SPECT)来实现人体内各种组织的放射成像。99m-Tc是用于放射诊断(诸如SPECT)的公知放射性同位素。它发射可检测的低水平140keVγ射线,半衰期为6小时,并在24小时内衰减为Tc-99(93.7%)。它用于脑、心肌、甲状腺、肺、肝、胆囊、肾、骨、血液和肿瘤的成像和功能研究。据报道,它每年用于2000多万例诊断性核医学程序中。正电子发射断层摄影(PET)采用发射正电子的放射性核素,其是一种从其核移动几毫米、与电子碰撞导致湮灭,从而导致产生两个以180°相对方向行进的511KeV光子的β样核颗粒。PET成像系统同时精确地捕获并记录碰撞引起的光子,从而提供卓越的成像灵敏度。PET成像已经成为一种有价值的诊断成像程序,特别是在肿瘤学领域,且据报道,在美国,每年大约有200万次PET扫描。通常用于PET成像的放射性同位素包括半衰期为109.8分钟的氟-18(18F),和半衰期为68分钟的镓-68(68Ga)。
使用微粒或微球的靶向放射疗法也是一种完备的场放射性同位素疗法。放射性核素诸如钇-90和钬-166是微球放射疗法中通常使用的放射性β发射体。聚合物微球(诸如白蛋白、聚乳酸衍生物等)以及玻璃微球两者在用于将药物和放射性药物递送到特定的组织位置的医学领域中是公知的。通常提供预装有单个放射性核素的这些微球,因此缺乏根据患者需要控制剂量或放射性核素的灵活性。此外,当放射性微粒由第三方供应商以批量进行异地制备时,可供使用的放射性核素的选择可在制备和递送所涉及的时间内受到限制。
因此,需要用于递送一种或多种放射性药物的改良的放射性微粒,并且其具有将允许微粒适合于注射到患者中以进行局部成像或疗法的特征。
根据本发明,已经设想出新型多孔微粒载体用于成像和/或治疗某些癌症、携带肿瘤组织、类风湿性关节炎或指示进行核医学成像或治疗的其它疾病。这些载体构成包含具有结合到表面的一种或多种放射性药物的多孔磷酸锶材料的微粒。考虑放射诊断γ和正电子发射剂及放射治疗α和β发射剂。
本发明提供包含结晶磷酸锶和至少一种适用于与其表面结合或吸附的放射成像和/或放射疗法的放射性同位素的放射性微粒。
本发明的放射性微粒通过以下步骤来制备:使含锶硼酸盐玻璃微粒与磷酸盐溶液在合适条件(诸如时间、温度、磷酸盐浓度等)下反应足够的时间以将至少一部分在表面的含锶硼酸盐玻璃转化为结晶磷酸锶,并将适于放射成像和/或放射疗法的至少一种放射性同位素结合到所述微粒的表面。这导致不透射线的多孔颗粒能够装载一种或多种放射性同位素,并因此能够以适用于放射疗法的剂量或根据所选择的同位素递送放射以用于放射诊断。
本发明还提供了制备此类放射性微粒的方法和使用此类微粒进行医学治疗的方法。
因此,本发明还提供了制备磷酸锶放射性微粒的方法,其包括:使含锶的硼酸盐玻璃微粒与磷酸盐溶液接触,以将至少一部分含锶的硼酸盐玻璃转化为磷酸锶;以及将适用于放射成像和/或放射疗法的至少一种放射性同位素结合或吸附到所述微粒。
方便地将放射性同位素与呈溶液、特别是水溶液形式的磷酸锶微粒接触。将放射性同位素方便地呈可溶性盐的形式。优选的是,该盐应至少可溶解至允许放射性同位素与微粒表面结合且以合理的速度进行反应以制备治疗或诊断上有用的微粒的程度。
在其它优选的实施方案中,提供了单独和组合可用的附加特征。
通过这种方法提供的一些优势包括:能够将放射性同位素或不同放射性同位素的组合吸附到多孔微粒上,允许治疗的适应性,定制患者剂量的能力,定制组织成像,减少活化的放射性药物的时间相关降解,并减少对医务人员的暴露。另外的优势包括使用具有较短半衰期的放射性同位素的能力,并避免使用将蒸发某些放射性同位素诸如锝和铼的微粒制造方法。这些微粒还显示出比以前的钙磷灰石颗粒改善的放射不透性,其提供了更清晰的放射照相图像。
磷酸盐溶液转化过程将固体硼酸锶玻璃转化为Bevolite Sr10(PO4)6(OH)2型的多孔磷酸锶材料。
通过制造特定直径的佚名-放射性固体含锶的硼酸盐玻璃微粒,转化得到特定直径的多孔磷酸锶微粒。由于磷酸盐溶液在硼酸盐玻璃上的基本彻底的化学作用,实现了具有高表面积的基本上纯的多孔磷酸锶材料,其中磷酸盐溶液已经与硼酸盐玻璃反应。
含锶的硼酸盐玻璃微粒优选为微球,且优选具有约5至约1000μm的直径。磷酸锶微粒也优选为微球。含锶的硼酸盐玻璃微粒可以完全转化为磷酸锶微粒,或者其可部分地转化以产生覆盖颗粒表面的包含磷酸锶的层和未转化的含锶玻璃核。含磷酸锶的部分优选是多孔的,并且可以是无定形或结晶的,但优选是结晶的。优选地,含磷酸锶表面层至少约0.5um厚,但其可以为至少1、2、3、4、5、7或10um厚,这取决于所需的性质,诸如结合能力、密度等。转化度将取决于反应条件,诸如温度、pH、磷酸盐溶液的浓度、反应时间等,并且本领域技术人员可以容易地确定最佳条件。在一些实施方案中,含锶硼酸盐玻璃微粒可基本上不含钙。
所得到的磷酸锶材料的孔隙率和微粒的可控大小和数量提供了将放射递送到特定位置的优异递送平台。因此,微球的制造过程已经与添加放射性标记或放射性治疗剂的过程相脱离。这通过允许在临床背景中、在递送时间或接近时间决定将一定类型和数量的放射性药物掺入递送媒介物中,为核医学专业人员提供了控制放射诊断和放射治疗方案的能力。
由于磷酸锶组分的多孔性质,微粒具有大大增加的表面积。优选地,磷酸锶微粒的表面积大于约90平方米/克,并且可以高达约200平方米/克或更大。
磷酸锶微粒包含至少一种适用于放射成像和/或放射疗法的放射性同位素。微粒可有利地包含一种、两种、三种或更多种不同的放射性同位素。在一个优选的实施方案中,放射性同位素是或包含治疗性α或β-发射放射性同位素或者诊断性γ-或正电子发射放射性同位素。放射性同位素还可以是或包含治疗性α或β-发射放射性同位素或者诊断性γ或正电子发射放射性同位素的组合。
在一个优选的实施方案中,选择放射性同位素/放射性核素,使得当向患者施用时,微粒发射β放射、γ放射或两者。选择β发射体以递送短程(例如,组织穿透约数毫米或更小)β发射的治疗强度和治疗量,但不发射显著量的不需要的β放射,这可能对围绕癌组织或携带肿瘤的组织的健康组织有负面影响。γ发射体被选择以递送长程(例如,能够进行外部检测)γ放射的诊断强度和诊断量,但不发射显著量的不需要的γ放射。
由于放射性同位素/放射性核素在放射学专业人员递送之前就原位结合或制备,所以可以根据每名患者的需要和诊断,以不受半衰期考虑的限制的方式来选择放射性同位素的类型。通过提供患者特异性给药,患者结果得到改善,且副作用最小化。
在确定放射治疗谱和/或放射诊断谱时,会考虑患者数据,诸如年龄、性别、体重和预先存在的疾患。当确定放射治疗谱和/或放射诊断谱时,还考虑癌症数据,诸如肿瘤大小、肿瘤类型、肿瘤位置、手术干预程度和成功、在被治疗区域内和附近的血管结构以及器官受侵。
形成半衰期大于约两天且小于约30天的放射性同位素的放射性同位素钇-90是一种发射治疗性β放射的特别优选的治疗性放射性同位素。对于诸如SPECT的放射成像技术,放射性同位素锝-99m是特别优选的,且对于PET成像,优选氟-18或镓-68。
放射性同位素优选为放射性药物级的,且选自由以下组成的组:锕-225、锑-127、砷-74、钡-140、铋-2I0、锎-246、钙-46、钙-47、碳-11、碳-14、铯-131、铯-137、铬-51、钴-57、钴-58、钴-60、铜-64、铜-67、镝-165、铒-169、氟-18、镓-67、镓-68、金-198、钬-166、氢-3、铟-111、铟-113m、碘-123、碘-124、碘-125、碘-131(其可以用作诊断或治疗同位素)、铱-192、铁-59、铁-82、氪81m、镧-140、镥-177、钼-99、氮-13、氧-15、钯-103、磷-32、氡-222、镭223、镭-224、铼-186、铼-188、铷-82、钐-153、硒-75、钠-22、钠-24、锶-89、锝-99m、铊-201、氙-127、氙-133、钇-90、锆-89及其组合。
当放射性同位素的组合与微粒一起使用时,放射性同位素的优选组合包括一种或多种β发射体与一种或多种γ发射体的组合。优选组合的实例包括但不限于Y--90/In-111Y-90/Tc-99m、Y-90/Ga-68、Y-90/F-18、Y-90/Cu-64、Cu-67/Cu-64、Y-90/Lu-177、P-32/In-l11、P-32/Tc-99m、P-32/Ga-68、Ho-166/In-111、Ho-166/Tc-99m、Sm-153/ln-111和Sm-153/Tc-99m。
特别优选的放射性同位素包括锝-99m和铟-111(放射诊断γ发射体),镥-177(既是β发射体,也是γ发射体)、钐-153和钇-90(放射治疗β发射体)及氟-18和镓-68(诊断正电子发射体)。Tc-99m已被用于脑、心肌、甲状腺、肺、肝、胆囊、肾、骨、血液和肿瘤的成像和功能研究。铟-111喷曲肽已用于对过表达生长抑素受体的神经内分泌肿瘤成像,并已成为这些肿瘤定位的标准物。这种放射性配体被内化到细胞中并且可以通过发射俄歇电子(Augerelectrons)来诱导受体特异性的细胞毒性。具有γ和β性质的镥-177使得其能够用于成像以及治疗。它具有比Y-90更短的穿透半径,使其成为小肿瘤放射疗法的理想候选物。来昔决南钐-153(化学名钐-153-乙二胺四亚甲基膦酸酯,缩写为钐-153EDTMP,商品名Quadramet)是镧系元素钐的放射性同位素与螯合剂EDTMP的络合物。当癌症扩散到骨骼时,它已被用于治疗癌症疼痛。一旦注射到静脉,它分布在整个身体并定位在癌症侵入骨骼的区域,从而允许β颗粒(电子)破坏附近的癌细胞。它也常用于肺癌、前列腺癌、乳腺癌和骨肉瘤。钇-90已被用于治疗各种癌症,包括淋巴瘤、白血病、卵巢癌、结肠直肠癌、胰腺癌和骨癌,以及通过放射性核素滑膜切除术治疗类风湿性关节炎。
尽管尝试提供详尽的列表,核医学专家们熟知放射性同位素可以使用生成器系统(如Mo-Tc或Sn/In系统)、热中子反应器、回旋加速器或裂变产生。因此,具有列出的那些的功能等效物的任何放射性同位素旨在在适当时内涵盖在本发明的范围内。
在一个优选的实施方案中,放射性同位素选自由以下组成的组:锝-99m、铟-111、镥-177、钐-153、钇-90、镓-68和氟18。
由于微粒在非常简单的反应中结合放射性同位素,所以将放射性同位素结合到磷酸锶微粒的步骤可以刚好在施用给患者时间之前(例如在6、12或24小时内)进行。
本发明还提供了根据本文所述的方法制备的磷酸锶放射性微粒。
磷酸锶微粒达到允许大量放射性同位素结合的孔隙度或表面积。考虑到90平方米/克或更大的表面积值在本发明的范围内。表面积可以达到200平方米/克或更大。
因此,本发明还提供了包含结晶磷酸锶并且具有5至1000um(优选5、10或20至200um)直径的微粒,特别是微球。优选地,此类微球具有90平方米/克或更大的表面积。
重要的是,使用钙磷灰石产生微粒的现有技术提供了仅40平方米/克或更小的低得多的表面积值。此外,这些仅含钙的微粒需要复杂的制造,其包括吸附需要粘合剂的同位素的两步工艺,破坏表面积的加热步骤和化学沉淀。
这些放射性基本上是球状的磷酸锶放射性微粒是通过以下步骤制备的:使预制含锶的硼酸盐玻璃微粒与一定量的磷酸盐溶液在合适的条件下反应足够的时间来将部分或全部将含锶的硼酸盐玻璃微粒转化为无定形或结晶磷酸锶微粒。一旦玻璃被转化并制成多孔材料,然后将携带放射性同位素的放射性药物吸附或结合到基本上纯的磷酸锶微粒上,然后适用于哺乳动物中的放射成像和/或放射疗法。
磷酸盐溶液转化过程将固体硼酸锶玻璃微粒转化成可以是无定形或结晶的多孔磷酸锶材料;无定形磷酸锶随时间推移转化为结晶磷酸锶。玻璃可完全转化,从而形成完全多孔或均匀中空的微粒。玻璃也可以部分转化,从而产生玻璃核心和围绕玻璃核心的外部多孔磷酸锶层,可以将放射性同位素结合或吸附到该玻璃核心。硼酸盐玻璃的转化通过将其暴露于磷酸盐水溶液来进行。许多不同的磷酸盐溶液被考虑在本发明的范围内。一个非限制性实例包括磷酸盐缓冲盐水(PBS)。PBS可以许多不同的方式制备。一些制剂不含钾,而其它制剂含钙或镁。通常,PBS含有以下成分:137mM NaCl、2.7mM KCl、10mM磷酸氢二钠、2mM磷酸二氢钾和pH 7.4。另一个非限制性实例是0.25M K2PO4溶液。非盐水磷酸盐溶液可以使用磷酸一钠(NaH2PO4)、磷酸二钠(Na2HPO4)和水,如所需与调节pH的磷酸或氢氧化钠一起制备。其它浓度和类型的磷酸盐水溶液被涵盖在本发明的范围内。
硼酸锶玻璃的转化在分子水平上导致高表面积多孔材料,其本身是含有磷酸锶化合物的凝聚物。表面的孔提供了达到磷酸锶化合物的途径。当放射性同位素与微粒混合时,用暴露的磷酸锶化合物形成强烈的化学键。不被认为是任何特定的化学反应或理论,据信同位素可结合在去除磷酸根(PO4)基团的取代反应中,或者它可以结合到空隙空间中,或者它可取代锶离子(Sr2+)。
孔隙度可以通过本领域熟知的多种方法来确定,然而优选的方法是氮吸收。这些颗粒优选是不可生物降解的。在2、4或优选6个月后,可生物降解的颗粒不会存在于体内。
通过制造特定直径的非-放射性固体含锶的硼酸盐玻璃微粒,可控制磷酸锶微粒的大小和形状;转化得到特定直径的多孔磷酸锶微粒。因为原料是固体含锶的硼酸盐玻璃微粒,并且其完全(或部分地)转化为多孔磷酸锶微粒,所以形状、大小、直径的物理参数由玻璃微粒制造过程决定。重要的是,转化的锶微粒的大小和尺寸基本上与起始硼酸锶玻璃微粒的大小和尺寸相同。该特征提供了能够控制递送媒介物本身(多孔磷酸锶微粒)的大小和尺寸的显着优势。
如本文所用的"微粒"通常是指相对较小大小但不一定在微米大小范围内的颗粒;该术语用于指代可以小于50nm至1000微米或更大的尺寸的颗粒。"放射性微粒"是指其上吸附有一种或多种放射性同位素的本发明的微粒。微粒优选为具有约20μm及以上的优选直径的圆球体。在其它的优选实施方案中,微粒在约20μm至约200μm、约30-80μm。约20-40μm和约25μm至38μm的范围内。在另一个实施方案中,颗粒的直径为约5至约100微米,优选约10至约50微米。如本文所用,除非另有说明,否则微粒涵盖微球、微胶囊、椭圆体、纤维和微粒。
所得到的磷酸锶材料的孔隙率和微粒的可控大小和数量提供了用于将放射递送到特定位置的优异递送平台。
重要的是,在硼酸盐玻璃微粒中不掺入放射性同位素,因此,微球的制造过程与放射性同位素标记或放射性治疗剂的添加过程相脱离。必须将当前放射微球制造为含放射性同位素作为玻璃或生物聚合物的均匀一体组分的玻璃或生物聚合物颗粒。本发明方法通过允许在临床背景中决定将一定类型和数量的放射性药物掺入递送媒介物中,为医学放射学专业人员提供了控制放射诊断方案和放射治疗方案的能力。
显着增加的表面积和放射性同位素对多孔微粒的电吸引力的组合提供了将多种放射性同位素结合到微粒上。在优选的实施方案中,结合了两种放射性同位素。将第一同位素与多孔微粒结合是通过在预定时间内在合适的溶液中简单混合,然后洗涤和洗脱未结合的同位素来进行的。这提供了放射性同位素与微粒结合的组合物。
通过在具有第二同位素的溶液中简单混合来进行第二同位素与多孔微粒结合。由于微粒具有大的表面积,所以第二同位素不会替代第一同位素,并且核药剂师或其它专业人员可以利用各种放射性同位素对微粒的不同结合能力。因此,三种且甚至四种不同的放射性同位素可以在单个剂量或批次的微粒内结合。
本发明还提供了向有需要的患者施用磷酸锶放射性颗粒的方法,其包括例如通过导管或注射递送包含磷酸锶放射性微粒和生理学上可接受的载体的组合物至患者的组织靶或器官。
在一个优选的实施方案中,该方法是治疗肿瘤、特别是高血管肿瘤的方法。如下进一步描述的此类治疗可以通过递送到血管中,诸如将颗粒进入并固定于脉管系统(放射栓塞)中或通过直接注射到位点中。用于此类处理的本发明的放射性微粒也由本发明提供。
在其它优选的实施方案中,提供了单独和组合可用的附加特征。
在一个优选的方法中,组织靶或器官选自由以下组成的组:脑、心肌、甲状腺、肺、肝、脾、胆囊、肾、骨、血液和头颈、前列腺、乳腺、卵巢和子宫。
本发明还提供了获得患者的组织或器官的放射学图像的方法,其包括向患者的组织靶或器官施用如本文所述的包含磷酸锶放射性微粒的组合物,并通常通过捕获由放射性微粒发射的γ放射获得组织或器官的放射学图像。
因此,本发明也提供了包含本发明的放射性微粒的诊断剂。
在该实施方案中,放射性同位素通常是放射性诊断剂,并且在一个实施方案中优选用于SPECT成像的锝-99m和用于PET成像的氟18或镓68。通常对于这些方法,放射微球将包括直径为约20至约40微米的球。
可以使用任何适合的核成像技术捕获放射学图像。
此外,通过使用显示各种放射性同位素的keV峰的放射剂量计,可以测试活性,并针对具体治疗进行定制。例如,治疗可以在一个非限制性实例中由100单位的同位素#1和50单位的同位素#2组成。
微粒可以以各种方式(诸如经由导管或针)施用给患者,并且可以单独或与血管收缩剂组合或通过任何其它有效使微粒嵌入癌组织或携带肿瘤组织的施用方式递送。为了施用的目的,将微粒优选混悬在药理学上可接受的混悬培养基中。培养基有利地具有足够的密度或粘度,以便在施用程序中防止微粒从混悬液沉淀出。目前优选的用于微粒混悬的液体媒介物包括聚乙烯吡咯烷酮(PVP,诸如由GAF Corp以商品名Plasdone K-30和聚维酮(Povidone)出售的PVP)、造影剂(诸如由Oslo,Norway的Nyegard&Co.以商品名甲泛葡胺(Metrizamide)销售或由E.R.Squibb&Co.以商品名Renografin 76销售的造影剂),及盐水或其混合物。虽然许多造影剂提供比重的调节,但是添加比重调节组分,诸如葡聚糖(例如50%葡聚糖)也是有用的。
本文所述的含锶硼酸盐玻璃微球代表本发明的另一方面。这些微球优选不可生物降解。微球可以由熔融形成所需玻璃组合物的粉末(即,批料)的均匀混合物制备。用于该批次的精确的化学化合物或原料不是关键的,只要它们为正在制备的熔体组合物提供正确比例的必要氧化物即可。例如,为了制造硼酸锶玻璃,然后可将锶、硼酸盐和/或苏打粉末用作一些批料原料。
通常,含锶的硼酸盐玻璃将包含10mol%或更多的氧化锶,但优选15mol%或更多。含锶的硼酸盐玻璃将包含至多25mol%的氧化锶,但更优选20±5mol%的氧化锶。
因此,本发明提供含锶的硼酸盐玻璃微球,其包含10或更多mol%的氧化锶且具有5至1000微米的直径。
通常,含锶的硼酸盐玻璃将包含10mol%或更多的氧化锶,但优选15mol%或更多。优选地,含锶的硼酸盐玻璃将包含至多30mol%的氧化钠。优选地,含锶的硼酸盐玻璃将包含20±5或20±10mol%的氧化钠。玻璃的高达四分之一的氧化钠部分可以被氧化锂或氧化钾(或两者的组合)代替。
通常,含锶的硼酸盐玻璃将包含至少50%的氧化硼,优选地,含锶的硼酸盐玻璃将包含至少60%的氧化硼,优选地,含锶的硼酸盐玻璃将包含至多70%的氧化硼。优选地,含锶的硼酸盐玻璃将包含60±10mol%的氧化硼。
以下给出适用于制备批料的典型组合物,尽管应理解这些组合物不应被认为是限制性的;可以使用具有各种组成的起始玻璃,只要它们含有氧化锶源(来自玻璃)和可来自起始玻璃或者可存在于玻璃进行反应的溶液中的磷酸盐。以下给出的一般组合物假设起始玻璃组合物在作为磷酸盐源的溶液中反应以形成磷酸锶颗粒。
典型的组合物包含:
20±10mol%Na2O,其可含有最多25%的Li2O或K2O或其组合,以摩尔计,
20±5mol%SrO,其最多四分之一可被可替代的不透射线的氧化物(诸如氧化钡、氧化钙锰或氧化钴)取代。
60±10mol%B2O3;和
0-5mol%的其它氧化物。
示例性组合物是20:20:60mol%Na2O:SrO:B2O3。
因此,可以通过将苏打含量改变最多±5或10mol%,或者将氧化硼含量改变±10mol%来改变组合物。也可能取代最多5mol%Li2O或K2O(或两者的组合)为一部分苏打。也可能取代少量的P2O5(据说最多5mol%)为一部分B2O3。可以将少量(至多5)mol%的各种其它氧化物替代为用于各种特定目的(诸如改变熔融温度或转化反应速率,改变放射透明度等)的基础玻璃组合物。如果需要,可将SrO部分(至多5mol%的20)替代为氧化钡、氧化钙、氧化锰或氧化钴(例如CO)或其组合。
除非另外固有地说明,否则本文所有百分比均为mol%。虽然这些材料被描述为含有以摩尔%计的各种氧化物和其它组分,但是本领域技术人员理解,在最终的玻璃或结晶组合物中,化合物被解离,并且特定化合物不是可单独识别的,或者甚至必须单独存在。然而,本领域常规的是将最终组合物指定为含有给定百分比的各种化合物,因此在此进行。因此,从这个角度来看,本文的组合物是在等效的基础上。
每种原料的纯度优选大于99.9%。在粉末干混合或湿混合以获得均匀的混合物之后,可以将混合物置于铂坩埚中以进行熔融。如果在制作的玻璃中至少少量的氧化铝可以耐受,则也可以使用高纯氧化铝坩埚。然后将含有粉末批料的坩埚放置在电炉中,该电炉根据组成加热至1000℃至1600℃。在该温度范围内,批料熔融形成液体,将其搅拌数次以提高其化学均匀性。熔体应保持在1000℃至1600℃下,直到批料中的所有固体材料完全溶解,通常4-10小时就足够了。重要的是,通过不将放射性同位素掺入熔体,不能使放射性同位素汽化,从而避免放射危害。
本发明的另一个优势是使用具有较短半衰期的放射性同位素的能力。例如,Tc-99m(锝-99m)不能制成玻璃的一部分,即当其作为某些均匀的玻璃-放射性同位素组合物的一部分被掺入时,半衰期可能常常太短而不能使用。另外地,能够使用放射性同位素,否则其会被玻璃熔融过程破坏或降解。例如,试图将锝或铑掺入熔体中将蒸发锝或铑。
当完成熔融和搅拌时,将坩埚从炉中取出,并将熔体通过将熔体倾倒在冷的钢板上或清洁的蒸馏水中而将熔体快速猝灭成玻璃。该程序将玻璃破裂成碎片,这有助于并简化将玻璃粉碎成细粉末。然后将粉末定尺寸并球化使用。
为了获得直径在所需微米范围内的球状微粒,使用不同的技术诸如研磨并通过所需尺寸的筛网来加工玻璃,其中玻璃颗粒可以经由使定尺寸的颗粒通过气体/氧气火焰形成球状体,其中它们熔融并通过表面张力形成球形液滴。位于气体/氧气燃烧器上方的振动进料器缓慢地将粉末振动到垂直管中,所述垂直管以5-25gm/h的典型速率将落下的粉末引导到火焰中。火焰被引导到金属容器中,当金属容器从火焰中排出时,其捕获球化颗粒。在它们接触任何固体物体之前,液滴被快速冷却,使得它们的球形保留在固体产物中。
球化后,玻璃球优选基于大小收集和重新筛选。作为非限制性实例,当微粒意在用于治疗肝癌时,回收直径小于30且大于20微米的级分,因为这是用于人类肝脏的理想尺寸。筛选后,用光学显微镜检查-30/+20微粒,然后用弱酸(例如HCl)洗涤、过滤并用试剂级丙酮洗涤数次。然后将洗涤的球体在炉中在空气中加热至500℃至600℃达2-6小时以破坏任何有机材料。
最后一步是在扫描电子显微镜中检查代表性样品球体,以评价球体的大小范围和形状。随着非球形颗粒的浓度,确定尺寸不足的球体的数量。可以通过能量色散x-射线分析来检查球体的组成,以证实组合物是正确的,并且没有化学污染。然后玻璃微粒准备进行磷酸盐转化,与放射性核素结合,并随后施用给患者。
根据本发明,上述处理步骤仅仅是示例性的,并不以任何方式限制本发明。类似地,本发明不限于具有上述尺寸的玻璃微粒;本发明的微粒的尺寸可以根据应用而变化。
本发明的微粒可用于各种临床情况,以及指示内部放射疗法的治疗。这些包括例如肿瘤的治疗和关节炎的治疗。
考虑到良性和癌性肿瘤两者的治疗。肿瘤可以例如通过选择性内部放射疗法(SIRT)治疗,针对不存在(i.a.)高血管肿瘤或具有良好脉管系统的其他肿瘤,包括肝脏(肝肿瘤包括例如肝细胞癌或由其他组织引起的转移性疾病,诸如结肠直肠癌)、脾、脑、肾、头颈、子宫、卵巢和前列腺。微粒可经由脉管系统例如通过导管递送,以提供组织的放射栓塞,或者它们可被直接注射以提供局部贮库。微粒也可用于成像,包括肝/脾扫描-针对肿瘤、囊肿或肝细胞疾病;脑扫描-针对肿瘤、创伤或痴呆;肿瘤扫描,针对肾脏、头颈、子宫/妇科的恶性肿瘤或转移性疾病;以及对这种方法有利的脉管系统的任何扫描或疗法。
由于大多数器官除了肝脏外,只有一个血管饲养,所以可以通过递送到主饲养动脉进行施用,并允许微粒进入并固定于毛细管床中,因为它们太大而不能通过毛细管。肝脏可能需要专门的递送方案。在另一个实施方案中,可以鉴定进食肿瘤的血管,并且使用该动脉以更局部的方式递送微粒。
附图
图1示出了含锶的硼酸盐玻璃微球转化为结晶磷酸锶微球。
图2显示了90Y从氯化90钇的溶液在30分钟的时间段内至本发明的磷酸锶微球中的摄取率。
实施例
实施例1:磷酸锶微球的制备
由如上所述的包含20mol%Na2O、20mol%SrO和60mol%Ba2O3的批料制备含锶的硼酸盐玻璃微球。微球尺寸范围为44至105微米。
使微球与0.25摩尔K2HPO4溶液(pH=12)在85℃下反应1小时、6小时和72小时。冲洗和干燥后,使用Micromeretics Tristar 3000装置通过氮吸收测量表面积。测量多个样品并进行平均。测得的表面积分别为10、93和72m2/gm。
实施例2:用放射性同位素加载磷酸锶微球
将5ug氯化钇(Y-90)在0.5ml 0.05N HCl中的溶液加入至15mg微球并孵育30分钟。在5次重复中,在1、5和30分钟时测定装载到微球体中的钇的量并平均。随着时间推移钇的摄取率在图1中示出。
由于可以在上述方法和产品中进行各种改变,在不偏离本发明的范围的情况下,意图是上述描述中所包含或任何附图中所示的所有内容应被解释为说明性的而不是限制性的。本文引用的任何参考文献以其整体并入本文中,特别当它们涉及教授本领域普通技术水平以及普通了解所要求保护的本发明的主题所必需的任何公开内容。对于本领域普通技术人员将清楚的是,在不脱离本发明的范围的情况下,可以改变上述实施方案或者可以进行非实质性的改变。因此,本发明的范围由以下权利要求书及其合理等同物的范围确定。
Claims (24)
1.一种放射性微粒,其包含:
结晶磷酸锶和至少一种结合或吸附至其表面上的适用于放射成像和/或放射疗法的放射性同位素,其中所述结晶磷酸锶通过如下方法得到:使非放射性的含锶的硼酸盐玻璃微粒与磷酸盐溶液反应,以将至少一部分所述含锶的硼酸盐玻璃转化为结晶磷酸锶。
2.如权利要求1所述的放射性微粒,其具有大于90平方米/克的表面积。
3.如权利要求1所述的放射性微粒,其是微球。
4.如任一项前述权利要求所述的放射性微粒,其具有5μm至1000μm的直径。
5.如权利要求1所述的放射性微粒,其中结合或吸附至所述表面的所述放射性同位素是治疗性α或β-发射放射性同位素。
6.如权利要求1所述的放射性微粒,其中结合或吸附至所述表面的所述放射性同位素是诊断性正电子或γ-发射放射性同位素。
7.如权利要求1所述的放射性微粒,其中结合或吸附至所述表面的所述放射性同位素包括治疗性α或β-发射放射性同位素与诊断性γ或正电子-发射放射性同位素的组合。
8.如权利要求1所述的放射性微粒,其中结合或吸附至所述表面的所述放射性同位素是锝-99m。
9.如权利要求1所述的放射性微粒,其中结合或吸附至所述表面的所述放射性同位素选自由以下组成的组:锝-99m、铟-111、镥-177、钐-153、钇-90、钬-166、镓-68、氟-18及其组合。
10.如权利要求1所述的放射性微粒,其具有结合或吸附至所述表面的至少两种不同的放射性同位素。
11.如权利要求1所述的放射性微粒,其中所述结合的放射性同位素包含至少三种不同的放射性同位素。
12.一种药物组合物,其包含如权利要求1至11中任一项所述的放射性微粒和药学上可接受的载体或稀释剂。
13.一种用于制备放射性微粒的方法,其包括:
(i)使含锶的硼酸盐玻璃微粒与磷酸盐溶液反应,以将至少一部分所述含锶的硼酸盐玻璃转化为结晶磷酸锶,由此形成磷酸锶微粒;和
(ii)将适于放射成像和/或放射疗法的至少一种放射性同位素结合或吸附到所述磷酸锶微粒上。
14.根据权利要求13所述的方法,其中所述放射性同位素通过使所述微粒与所述放射性同位素的溶液接触而结合或吸附到所述磷酸锶微粒的表面。
15.根据权利要求14所述的方法,其中所述结合包括将所述磷酸锶微粒与至少一种放射性同位素混合。
16.根据权利要求15所述的方法,其中所述结合包括在包含所述至少一种放射性同位素的溶液中混合所述磷酸锶微粒。
17.根据权利要求13所述的方法,其中所述含锶的硼酸盐玻璃微粒完全转化为磷酸锶。
18.根据权利要求13所述的方法,其中所述含锶的硼酸盐玻璃微粒完全转化为结晶磷酸锶。
19.根据权利要求13所述的方法,其中所述放射性同位素选自由以下组成的组:锝-99m、镓68、钬-166、氟-18、铟-111、钇-90、镥-177、钐-153及其组合。
20.根据权利要求13所述的方法,其中所述至少一种放射性同位素是选自以下的同位素的组合:Y-90/In-111、Y-90/Tc-99m、Y-90/Ga-68、Y-90/F-18、Y-90/Cu-64、Cu-67/Cu-64、Y-90/Lu-177、P-32/In-111、P-32/Tc-99m、P-32/Ga-68、Ho-166/In-111、Ho-166/Tc-99m、Sm-153/In-111和Sm-153/Tc-99m。
21.一种用于放射治疗的方法中的放射性微粒,其包含作为多孔微粒载体的非放射性结晶磷酸锶和结合或吸附到其表面的至少一种适用于放射疗法的放射性同位素。
22.根据权利要求21所述的放射性微粒,其用于治疗动脉粥样硬化或治疗肿瘤。
23.一种微球,其包含作为多孔微粒载体的非放射性结晶磷酸锶且具有5um至1000um的直径,其通过如下方法得到:使非放射性含锶的硼酸盐玻璃微粒与磷酸盐溶液反应,以将至少一部分所述含锶的硼酸盐玻璃转化为结晶磷酸锶。
24.如权利要求23所述的微球,其具有大于90平方米/克的表面积。
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