CN1194764C - 镭-223在制备用于治疗影响骨的疾病的药物中的用途 - Google Patents
镭-223在制备用于治疗影响骨的疾病的药物中的用途 Download PDFInfo
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- CN1194764C CN1194764C CNB998161020A CN99816102A CN1194764C CN 1194764 C CN1194764 C CN 1194764C CN B998161020 A CNB998161020 A CN B998161020A CN 99816102 A CN99816102 A CN 99816102A CN 1194764 C CN1194764 C CN 1194764C
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Abstract
本发明描述了用于治疗钙化肿瘤,骨肿瘤,治疗骨骼、骨骼表面和软组织的镭223的制备方法、制备的溶液以及用途。
Description
本发明涉及制备和使用“钙类似物”碱土放射性核素镭-223用于对准钙化组织例如骨以及包含223Ra的生理学上可接受的溶液。
生物医学上使用放射性核素用于缓解疼痛和/或治疗癌症,包括骨表面的预防性治疗以减慢/灭活未被发现的转移,以前是基于β-放射体和转换电子放射体。
相当百分比的癌症病人受骨骼转移的影响。多至85%患有晚期肺癌、前列腺癌和乳腺癌的病人发展成骨的转移(Garret,1993;Nielsen等人,1991)。已确立的治疗例如激素治疗、化学疗法和外部放射疗法常常引起暂时的反应,但是最终大多数骨癌病人经历复发(Kanis,1995)。因此强烈需要新的治疗方法以减轻疼痛和减慢肿瘤的发展。对准骨的放射性同位素已经包括在用于治疗骨癌的临床试验中(De Klerk等人,1992,Fossa等人,1992,Lee等人,1996,Silberstein,1996)。这些放射性药物基于β-粒子放射体(Atkins,1998),近来也基于转换电子放射体(Atkins等人,1995)。迄今为止经美国食品和药物管理局批准的这些化合物中有锶-89(MetastronTM)和153Sm EDTMP(LexidronamTM)。锶-89化合物仅仅能够以足以缓解疼痛的量用药,不能用于肿瘤治疗,因为在能够达到有效的抗肿瘤治疗剂量程度之前将会发生显著的骨髓中毒性(Silberman,1996)。
最近,一个发明人写作一本书(Larsen等人,1999),其中通过放射剂量测定法表明α-放射体作为亲骨物质比β放射体更有利。即当放射源位于骨表面时,较短射程的a-放射体引起较少骨髓辐射。在该研究中将两个α-放射二膦酸酯骨探查剂与两个具有相似的化学结构和骨亲合力的β-放射化合物相比较。剂量测定法的计算表明,在小鼠中,α-放射体与β-放射体相比骨表面与骨髓剂量比大约高3倍。这表明α-放射骨探查剂也许比放射β粒子-和/或放射电子化合物更具有优点,因为辐射剂量能够更强地浓缩至骨表面上。因为短半衰期(t1/2=7.2h)以及由于其生产限于全世界仅仅少数地方,砹-211目前在大规模的市场中尚不能得到。
除砹-211之外只有少数放射a-粒子的放射性同位素目前被考虑可用于生物医学应用中(Feinendegen等人,1997)。铅-212/铋-212体系以前已经用于制备骨探查剂。与乙二胺-四(亚甲基膦酸)(EDTMP)或1,4,7,10-四氮杂环十二烷-1,4,7,10-四(亚甲基膦酸)(DOTMP)配合的铋-212显示了显著的骨亲合力。但是由于铋-212的短半衰期(t1/2=60.6min),在放射性药物的摄入阶段中正常组织的辐射将相当多(Hassfjell等人,1994,1997)。与另一个考虑作为生物医学用途的α-放射铋同位素铋-213(t1/2=46min)相比这将更显著。已经尝试使用β-放射体铅-212(t1/2=10.6h)作为212Bi的体内发生器。然而,观察到影响高肾积聚的a-放射体的显著易位(Hassfjell等人,1997)。其他可能用于生物医学应用的α-放射放射性同位素是镭同位素224和226。如同其他的11簇碱土金属一样,阳离子状态的镭是天然的骨探查剂。
以前已经研究过镭同位素224和226,部分是因为它们的骨亲合力(Loyd等人,1982,1991;Muggenburg等人,1996,Tiller,1971;Raabe等人,1993;Rundo,1978)。由于其长半衰期(1600年)以及其稀有气体氡-222子体(t1/2=3.8天),镭-226不被考虑可用于靶的放射性核素治疗。由于其化学性质,氡在体内条件下对于化学键合是惰性的。当它产生自母核衰变时,因此能够迅速地在体内易位(Rundo,1978)。吸入的氡主要溶于体液以及脂肪中并且主要通过呼气从体内除去(Rundo,1978)。在使用骨样品的实验中,Lloyd和Bruenger(1991)报导了在将镭-226给药于狗之后,89.5-94.25%的氡-222从骨中选出。与镭-226相反,镭-224具有似乎很适合生物医学应用的半衰期(t1/2=3.64天)。224Ra在医学上被使用多年以治疗强直性脊柱炎(Delikan,1978)。令人遗憾的是,也有显著部份的镭-224的子体同位素从骨中逸出,大概主要由于氡-220(t1/2为55.6s)子体(Lloyd等人,1982;Miiller等人,1971;Rundo,1978)。
因此从早先的研究中知道当将镭同位素224Ra和226Ra结合到骨中时,它们的氡子体发生显著的易位,这至少能够部分地解释这两个镭同位素的已知的致癌效果。这可能是为什么在临床上α-放射体没有被评估作为治疗骨癌的骨探查放射性药物的一个原因。
本发明的目的在于提供可用作药剂的骨探查放射性核素,表明来自其蜕变的放射性衰变产物在其结合到骨中之后没有显著地易位(至少在给药3天之后有效)。
本发明人显著和有点料想不到的发现,根据骨中定位的223Ra,发生了极少的氡子体(以及来自衰变链的其他的放射性核素)的易位。因此,223Ra系列可以用来照射骨表面,而没有任何显著的放射性核素的易位(包括扩散至骨髓)。此外镭-223,更应该适合作为骨探查的放射性药物,因为其半衰期(11.4天)大约是224Ra的三倍,这使在发生衰变之前更深地结合到骨表面的基质中。同样,也许更重要的是,氡子体氡-219具有短的半衰期(3.9秒),在氡阶段或作为氡阶段结果其应该减少易位。在223Ra和子体核素衰变过程中放射的四个α-粒子中的三个直接地在223Ra蜕变后立即放射出(Seelman-Eggebert等人,1981),即作为在223Ra后面初期的三种蜕变,3.9秒219Rnα衰变是具有最长的半衰期的一个(表1)。223Ra链中的最后的α-放射体,211Bi(t1/2=2.15分钟)跟随β-放射体铅-211的衰变(t1/2=36.1分钟),因此也许显示一些易位。然而,如果前体铅-211被截留在骨基质之内,223Ra系列中的最后的α-粒子也可能传送到骨表面区域。另外α-粒子具有高线性能量传递(高-LET)辐射,也就是说对于哺乳动物细胞具有极端地细胞毒性(Hall,1994;Ritter等人,1977)。定位在靶组织中的放射α-粒子的辐射源能够将辐射传送至较小靶区,因此与β-放射体相比降低了正常组织的辐射。
本发明涉及制备和使用“钙类似物”碱土放射性核素镭-223用于对准钙化组织例如骨以及包含223Ra的生理学上可接受的溶液。
本发明提供了镭-223盐在制备用来治疗影响骨、骨表面以及软组织的非恶性和恶性疾病的药物中的用途。
在本专利申请中,本发明人已经发明了223Ra的一种新用途,即作为α-放射的放射性药物用于对准钙化的组织,例如骨表面和骨瘤损伤。依据放射性核素的性质以及存在于本专利申请中实验的实施例表明,镭-223能够适合作为骨探查放射性药物。例如,本发明可以通过传送集中的剂量至病人的骨表面用作预防性的癌症治疗,该病人很有可能在骨表面具有未被发现的微小转移瘤。其潜在性用途的的另一个例子将是按照类似于以前描述的用于缓和骨疼痛的放射β粒子和放射电子的放射性药物的方式治疗疼痛的骨部位。
定位在骨表面之上和/或钙化肿瘤中的镭-223能够与其子体核素一起传送强的和高度局部剂量的α-粒子,其与目前使用的放射β粒子和/或放射电子的放射性药物相比具有较少骨髓剂量。骨骼的疾病例如原发性或转移性的骨癌可以用223Ra放射性药物治疗。
本发明包括使用核素作为阳离子种类和/或与螯合剂或对钙化组织具有亲合力的另一种形式的载体分子结合。这也包括,但是不局限于镭-223与能够随后连接至对钙化组织具有亲合力分子的螯合剂的结合。本目的在于使用放射性同位素在骨表面上和/或钙化肿瘤中产生级联的α-粒子用于缓和由不同的疾病所引起的疼痛和/或用于预防可能最小的骨骼疾病,和/或也用于确定的骨癌的治疗。能够使用放射性同位素的疾病包括,但是不局限于前列腺癌、乳腺癌、肾癌和肺癌的骨骼的转移以及原发性骨癌和多发性骨髓瘤。
制备镭-223溶液用于对准钙化组织或用于骨表面照射。下列例子显示223Ra在骨中具有高的和选择性的吸收,其中极少的子体核素再定位。这表明骨表面能够消毒以灭活用显镜可见的沉积的癌细胞以及钙化的癌的损伤能够用该同位素照射用于缓和或者治疗。该化合物不同于具有骨亲合力的其他常用放射性药物,因为主要的剂量组分来自α-粒子,其与经常使用的β和电子放射体相比具有更窄的范围。因此传送至红骨髓的剂量能够用这种新化合物显著地降低,即骨髓中毒性可能被降低。镭-223不同于以前使用的医用放射性核素镭-224如下:(1)223Ra具有显著长的半衰期,较好地影响骨与软组织比率,因为在发生衰变之前显著大量的这种同位素部份将从该软组织中被除去。(2)当进行骨合成之时较长的半衰期也使放射性核素深深地结合至骨表面,由于化学的扩散和核的反冲可能提高了否则会易位的子体同位素的保留。(3)与来自224Ra的220Rn相比来自223Ra的较短的半衰期的219Rn,确保了来自223Ra系列的子体核素较少的易位。
223Ra盐或其衍生物将通过全部有效的给药途经例如口服、皮下、静脉内、动脉内或经皮给药需要的哺乳动物例如人。该活性化合物优选通过注射或输液给药。
通过使用片剂、胶囊剂、粉剂或液体形式例如悬浮液、溶液、糖浆或乳剂进行口服。当制成片剂时使用传统的赋形剂(expicients)、润滑剂和粘合剂。当以液体的方式给药时使用传统的液体载体。当以注射或或输液溶液的方式给药时,载体优选为等渗盐水,其中含有或不含有以稳定镭阳离子预防镭盐或不溶的络合物沉淀的试剂。
能够使用本发明的有效成分用于受疾病侵害的骨和软组织的非恶性和恶性疾病的预防、缓和和治疗。恶性疾病选自前列腺癌、乳腺癌、肾癌和膀胱癌(urinary cancer)、原发性骨癌、肺癌和多发性骨髓瘤,非恶性疾病选自影响关节和骨骼的自身免疫疾病例如类风湿性关节炎、schleroderma和脊椎关节病。
根据本发明用于体内给药的生理学上可接受的制剂,除了药理学上可接受的载体和助剂之外,包括溶解的镭-223盐,其中含有或者不含有单个阳离子或几个阳离子的结合,作为稳定碱土金属阳离子类似物载体,含有或者不含有一种试剂以预防沉淀和/或胶体的产生。作为稳定碱土金属阳离子的阳离子可选自镁、钙和锶。此外,预防沉淀和/或胶体产生的试剂为羧酸或羧酸的组合,例如草酸、草酰乙酸、酒石酸、琥珀酸、苹果酸和丙二酸。制剂中化合物的浓度通常小于个体LD50剂量,例如小于20%的LD50剂量,因此对于不同的组分会有变化。以单剂量或多剂量方式给哺乳动物例如人用药时,223Ra的活性取决于给药的类型和途径以及基本病情或疾病,在约50KBq-10MBq之间变化。
此外根据本发明镭-223用于生产药学活性制剂以缓和以及治疗影响骨、骨表面以及软组织的非恶性和恶性疾病。该制剂以缓和或治疗地有效量给药于需要其的哺乳动物例如人或动物如狗。
根据本发明镭-223可被用于结合治疗,其中223Ra制剂与下列种类的治疗结合;包括二膦酸酯的化学疗法、手术、外部光束照射、放出骨探查的放射性药物的低LET辐射以及激素治疗。
此外本发明涉及试剂盒,包括根据本发明方法生产的223Ra、作为稳定碱土金属阳离子类似物载体相应的阳离子以及预防沉淀和/或胶体产生的试剂,药学上可接受的载体以及适合的给药设备。
在下文中通过实施例详细描述本发明,其决不是用来限制如附上权利要求所述的本发明的范围。
表1给出了镭-223及其子体核素的物理特性(Ekstrom等人,1989)。223Ra及其子体的衰变引起四个α-粒子的发射。这种级联的α-粒子能够传送大辐射剂量至有限的体积中。因此与大多数α-放射体相比,镭-223也具有极度的细胞毒性(Howell等人,1997)。
如下显示了镭-223及其子体衰变系列(括号中表示半衰期和衰变方式):
223Ra(11.4d.,α)219Rn(3.9s.,α)215Po(1.8ms.,α)Pb(36,1min.,B-)211Bi(2.15min.,α)207T1(4,8min.,B-)207Pb(稳定的)
表1 223Ra和子体的放射*。
核素 | 223Ra | 219Rn | 215Po | 211Pb | 211Bi | 207T1 |
α-能量 | 5.64MeV | 6.75MeV | 7.39MeV | 6.55MeV | ||
β-能量(最大) | 0.47MeV | 0.47MeV | ||||
能量分数 | 0.207 | 0.248 | 0.271 | ≤0.017 | 0.24 | ≤0.017 |
*数据来自Seelmann-Eggebert等人,1981和Ekstrφm等人,1989
#相对整个衰变链的总的发射能量。
与223Ra和子体整个衰变有关的发射辐射的结合能:~27.5MeV
以α-粒子的形式放射的能量部份:>96%
以β-粒子的形式放射的能量部份:<3%
在衰变过程中也放射一些γ辐射(总计<0,3MeV)并且可用于使用γ波谱学决定样品中同位素的数量和质量。例如镭-223在154.19keV有一特征γ峰(5.59%丰度),氡-219在401.78keV有一峰(6,6%)以及铋-211有一351.0keV峰(12.8%)(Ekstrom等人,1989)。这些可用于决定子体同位素是否在体内发生重分布。223Ra也有一269.41keV峰,丰度为13.6%,但是这很难区别于219Rn的丰度为9.9%的271.23keV峰。
现已经描述了镭-223的制备方法(Atcher等人,1989;Howell等人,1997)。镭是天然放射族中的一员,来源于U(t1/2=7×108y)经231Th(t1/2=25.6y.)以及顺序231Th->231Pa(t1/2=3.3×104y.)->227Ac(t1/2=21.7y.)->227Th(t1/2=18.7d.)->223Ra(11.4d.)。Atcher等人(1989)使用阳离子交换体系(Bio-rad AG 50)从227Ac生成223Ra。Howell等人(1997)使用226Ra(n,r)227Ra核反应生成223Ra。227Ra(t1/2=42min)快速地变成227Ac(t1/2=21.77年),其可以通过不同的方法从226Ra靶物中分离。Howell等人(1997)用化学方法从靶溶液中分离227Ac。然后227Ac与其子体产物一起转移到保留227Th的阴离子交换柱中,同时洗脱该核素的母体和子体。十天后能够从离子交换柱中洗脱出223Ra。如果通过利用发生器原理制备临床批量,应用基于有机主链的离子交换柱也许是亚最佳的,因为辐射分解可以防止基于这类材料镭发生器的长期综合利用(Atcher等人,1989)。
最近已经开发新型材料,并且现在市场上能买到,其可用于锕系元素放射性核素的分离(f-元素对碱土元素的选择性)。这些是基于共价键合活性基团或掺杂活性基团的硅石微粒。可以使用该材料制备柱子使得在能够保留其他元素的条件下洗脱出一些元素。也可能使用活性基团用于采用有机和水相的湿/湿法提取体系中的分离。
实施例
在下面的实施例1中制备了223Ra。本发明制备用于生物医学应用的223Ra的新方法包括无机基质柱和液/液体系。含有在无机基质上的甲烷双膦酸衍生物的发生器柱或所述方法也可以包括液/液提取操作步骤,其中一个或多个P,P′二酯化的亚甲基双膦酸衍生物用作相转移剂。
在该方法中发生器柱含有在硅石基质上的P,P′二辛基甲烷双膦酸以及液/液提取操作是使用P,P′二辛基亚甲基双膦酸或P,P′二(2-乙基己基)甲烷双膦酸或其结合作为相转移剂。关于发生器柱的操作通过使用在中和之后能够得到生理学上相容的它们盐的溶液的无机酸、优选硝酸或氢氯酸进行。所述的无机酸的浓度在0.01-8M范围之内,更优选在0.1-2M之间,最优选在0.5-1M之间。使用含有无机酸、优选硝酸或盐酸的水相进行液/液提取步骤,酸浓度在0.01-8M范围之内,更优选在0.1-2M之间,最优选在0.8-1.5M之间。
实施例1
通过使用f-元素选择提取的色谱树脂从27年以前制备的231Pa源(样品由挪威奥斯陆大学,化学系,放射化学组提供)中分离227Ac和227Th。提纯的227Ac和277Th随后吸附在另一种f-元素选择提取的色谱树脂之上并且用作223Ra的母牛。后者材料已经被吴等人(1997)用于建造基于225Ac的213Bi发生器。
方法:用1M HCl将在5M H2SO4和1M HF水溶液中的231Pa放射源(含有子体)的样品稀释10倍。将该溶液装载在内径3毫米和长度70毫米并含有用1M HCl预平衡过的TRU-树脂(EiChroM工业,Darien,IL,美国)的柱子上。231Pa保留在柱子上,而227Ac、227Th和223Ra则部分通过装入操作洗脱以及部分通过用另外的10毫升1M HCl洗涤柱子来洗脱。在这以后通过使用Wu等人描述的装柱技术的改进法来制备223Ra发生器(1997)。制备并且用1M HCI事先处理3×50毫米硅石锕系元素树脂柱子(EiChroM,Darien,IL,美国),该柱子由直径在20-50μm范围内硅石微粒上的P,P′二辛基甲烷双膦酸(DIPEX,EiChroMEiChroM工业,Darien,IL,美国)组成。然后从该柱子中除去大约一半的树脂然后与来自TRU-树脂柱的洗脱液混合。
其后将含有227Ac、227Th和223Ra的洗脱液装载在3毫米内径和50毫米长的柱子中,该柱子含有30-50μm硅石(EiCroM工业,Darien IL,美国)上的锕系元素-树脂(Ac-树脂)。简要地说,根据Wu等人的方法制备该柱子。(1997)。在用1M HCl事先处理柱子之后,一半的物质被除去然后与来自在前步骤的洗脱液混合。
在室温下缓和搅拌4小时之后,将含有放射性核素的浆液装载在该柱子中。最后,用5毫升1M HCl洗涤该柱子。该柱子中保留了227Ac和227Th,而223Ra可以用几毫升HCl或者HNO3洗脱,其母体和祖母体放射性核素没有任何显著的漏出。如果希望的话,可以加入随后的纯化步骤,即通过第二AC-树脂柱简单地洗脱223Ra洗脱液以除去任何微量的母体和祖母体核素。
含有223Ra的HCl溶液可以在缓冲器中稀释、无菌过滤然后照这样使用。另外,纯化的223Ra可以在使用之前被浓缩,即通过将HCl溶液装载在2毫米内径和25毫米长的含有树脂例如AG 50W-X4-16(Bio-Rad,Richmond,CA,美国)的柱子中。其后223Ra可以通过少量体积的6M HNO3几乎被定量地洗脱。其后HNO3可以被蒸发,残余物可以再溶解在溶液中,随后被无菌过滤。
使用与来自EG&G Ortec(Oak Ridge,TN,美国)用于γ液谱学的放大器和偏压器相结合的锗-检测器和/或者与用于α波谱学的EG&G Ortec相结合的Canberra(型号7404 0 1 A)进行放射性数量和质量的测量。
结果:在TRU树脂柱中,231Pa被定量地保留,即与子体放射性相比该漏出小于检测极限的0.5%。90%以上的227Ac和227Th收集在来自TRU树脂的洗脱液中。对于AC-树脂,多次的实验显示在柱子(也称为母牛或发生器)中在最初几毫升的汽提溶液中每100kBq 227Th一般产生60-85kBq 223Ra。与223Ra相比227Ac和227Th的漏出经测定小于(受到检测能力的限制)4×10-3%。应该注意,所述的分离方法也可以和由226Ra经226Ra(n,γ)227Ra->227Ac生成的227Ac一起使用。
结论:描述了一组方法用于制备确保可用于生物学应用的高产率和高纯度的223Ra。其区别在于由227Ac常规制备临床上相关的放射性级的223Ra更容易。该方法使用基于硅石基质的发生器柱子进行(Wu等人,1997),而先前存在的方法包括更多含有有机基质的对辐射分解敏感的离子交换树脂(Atcher等人,1989)。
实施例2
研究了如实施例1中所述方法制备的镭-223的生物分布。
方法:用含9kBq 223Ra的150ul等渗盐水给体重为19-21克的幼少的雄性Balb/C小鼠注射。每组5只动物,在注射后的6小时和3天将各组动物处死并解剖。测量样品的重量,使用(A)与Scaler计时器ST7(NE技术有限公司,Reading,英国)相结合的well型NaI闪烁晶体(Harshaw Chemie BV,De Meern,Holland)数字装置,(B)Beckman LS 6500(Beckman仪器公司Fullerton,CA,美国)计数样品。使用与来自EG & G Ortec(Oak Ridge,TN,美国)放大器和偏压器相结合的锗-检测器(Canberra,Meriden,CT,美国)研究在血、肝、肾和标准样品中母体/子体处于平衡时放射性核素的相对丰度。
结果:该生物分布数据列于表2中。数据显示与软组织相比223Ra在骨中被有选择地浓缩。而注射后的6小时和3天之间所有软组织值减少,骨值随时间而增加。自6小时到3天起股骨与血的比例从129增加到691。脾中含有的软组织中具有测量的最高的保留值,但是在注射后6小时和3天之间股骨与脾的比例也随时间从6.4增加到23.7。
表2 镭-223在Balb/C小鼠中的生物分布,表示为每克的注射剂量%
组织 | 6小时 | 3天 |
股骨 | 25.86±1.99 | 34.55±7.87 |
血 | 0.20±0.23 | 0.05±0.10 |
肾 | 4.04±0.33 | 0.38±0.08 |
肝 | 0.89±0.18 | 0.22±0.32 |
肺 | 0.59±0.56 | 0.06±0.07 |
肌肉 | 0.72±0.39 | 0.30±0.16 |
心脏 | 0.10±0.10 | 0.06±0.07 |
脑 | 0.04±0.01 | 0.12±0.12 |
脾 | 4.06±1.4 | 1.46±0.54 |
小肠 | 0.79±0.26 | 0.04±0.03 |
大肠 | 2.30±0.60 | 0.13±0.02 |
根据γ波谱学,在骨和大部分的软组织中观察不到由211Bi丰度确定的镭-223及其子体相对分布的显著差异。在6小时点脾中211Bi∶223Ra的比例与标准溶液相比平均为54%。另一方面,在肝脏和肾中样品中的211Bi∶223Ra比例平均分别为标准的256和207%。这表明在软组织中发生了一些易位。与该核素的骨放射性相比软组织中211Bi放射性一般也非常低。软组织中的211Bi也许已经从存在于软组织中的223Ra产生。
结论:由223Ra和子体得到极好的骨与正常组织放射性比例,这表明用该放射性核素系列对准钙化组织的显著的潜能。
实施例3
为了检验骨样品中的镭-223和铋-211之间是否会出现放射性同位素保留的差异,研究了骨对含有处于平衡的223Ra和子体放射性核查的标准溶液的γ波谱数据。
方法:在该动物死亡和解剖之后直接地在小鼠股骨的样品上用锗检测器(Canberra,Meriden,CT,美国)进行γ波谱分析。研究了处于平衡的223Ra和子体放射性核素的标准溶液的样品。使用在351.0keV(211Bi)和154.2keV(223Ra)处明显的γ峰。定位指数(LI)被定义如下:
LI=(BBi/SBi)/(BRa/SRa)
例如,BBi-211Bi在骨中的计数率;SRa-223Ra的标准计数率
使用Student t-测试数据柱子将来自6小时组和3天组的五个样品的γ波谱分别与来自标准溶液的五个和三个样品进行比较。
结果:在6小时点的LI值平均为0.85(P=0.059),在3天点的LI值平均为0.97(P=0.749)。然而,相对于数据组P=0.05的水平差异不显著。
结论:即使对于代表223Ra、211Pb-蜕变系列中第四个蜕变的放射性核素来说,骨中的保留值与223Ra相似。
实施例4
为了研究在223Ra被吸收在骨中之后子体同位素有潜力的释放,由于核的反冲或者扩散过程,检验注射后6小时被杀死的五个动物和3天被杀死的五个动物的股骨。
方法:为了照射使红骨髓(spongious)区域,将骨纵向劈开,其后切成小于3毫克的小碎片。其后使用离心法用Dulbeccos PBS(Sigma-Aldrich CO.LTD.,Irvine,英国)洗涤样品。除去上层清液,与闪烁液混合(外加Insta-Gel11,Packard BioScience BV,Groningen,荷兰),然后在闪烁计数器(Beckman仪器公司,Fullerton,CA,美国)上计数。一天之后重复计算样品。在校正两次测量之间223Ra衰变之后计数的差异被用作表示子体核素从骨基质中的释放。
结果:6小时之后被杀死的动物显示了从骨中一些放射性的释放。与骨中的总放射性相比在洗涤过程中平均1.8%溶于PBS。当12小时之后再次测定洗涤液时,放射性仅仅平均为骨样品的0.2%。这表明发生了一些子体同位素的易位但是程度非常小(大概小于子体同位素的2%)。与洗涤之后洗涤液中的基底相比3天之后被杀死的动物没有显示显著的数目。这表明如果发生易位,则低于检测极限,估计小于总骨放射性的1%。
结论:根据从精细粉碎的骨样品中可提取的放射性部分,表明子体核素从骨基质中的释放(易位)对于镭-223系列来说较低。
实施例5
已经研究了具有类似于病人中经常观察到的实验的转移类型的动物模型(Engebraaten和Fodstad,1999)。这些模型中的一个是由心内注射到裸露的大鼠中MT-1细胞组成,特征在于在动物中一致地形成了后腿麻痹。用化学治疗剂顺氯氨铂或阿德利亚霉素治疗(接种肿瘤细胞七天之后)没有提高存活率。解剖并且用显微镜检验患肿瘤动物的脊柱显示大量替换正常骨髓并且腐蚀脊柱骨的部分的肿瘤细胞。
在上述研究的模型中骨骼的累及使得其适合于证明本发明223Ra针对骨骼转移治疗的潜力。
方法:在MT-1/裸露的大鼠模型中研究了镭-223的治疗潜力,其中通过如所述的那样注射到左心室给动物接种1×106MT-1人的乳腺癌细胞(Engebraaten和Fodstad,1999)。这些动物通常发展成由脊柱中肿瘤的生长所引起的麻痹。在七天后通过接受不含有或含有10kBq本发明镭-223的200ul载体溶液的静脉注射处理4和5个动物的组。
结果:仅仅用载体溶液处理的四个动物的组在接种肿瘤细胞之后患有受脊柱中肿瘤生长影响的麻痹并且在20-25天之间处死(指22,25天)。在接受含有223Ra载体溶液的五个动物的组中,一个动物在26天之后麻痹,一个在40天之后麻痹,一个在64天之后麻痹,而剩余的两个动物在接种肿瘤细胞之后的90天整个实验跟踪时期中存活,没有显示麻痹的迹象。
结论:223Ra证明在患有骨胳转移的动物中具有显著的抗肿瘤效果。
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Claims (5)
1.镭-223盐在制备用来治疗影响骨、骨表面以及软组织的非恶性和恶性疾病的药物中的用途。
2.根据权利要求1的用途,其中所述药物用来与选自下列的治疗有效方法结合使用:化学疗法、手术、外部光束照射、放出探查骨骼的放射性药物的低线性能量传递辐射和激素治疗。
3.根据权利要求1或2的用途,其中所述药物包含骨靶向的溶解的镭-223盐,并且为用于治疗或缓解影响骨的非恶性疾病的药物。
4.根据权利要求1或2的用途,其中所述药物包含骨靶向的溶解的镭-223盐,并且为用于治疗或缓解影响骨的恶性疾病的药物。
5.根据权利要求4的用途,其中恶性疾病选自转移性前列腺癌、转移性乳腺癌、转移性肾和膀胱癌、原发性骨癌、转移性肺癌和多发性骨髓瘤。
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NO310544B1 (no) * | 1999-01-04 | 2001-07-23 | Algeta As | Opparbeidelse og anvendelse av radium-223 til fremstilling av preparat samt kit til behandling av kalsifisert vev for palliasjon, benkreft-terapi og/eller overflatebehandling av ben |
NO314537B1 (no) * | 1999-12-06 | 2003-04-07 | Anticancer Therapeutic Inv Sa | Reseptorbindende konjugater |
NO313180B1 (no) * | 2000-07-04 | 2002-08-26 | Anticancer Therapeutic Inv Sa | Bensökende alfapartikkel emitterende radiofarmasöytika |
AUPQ923100A0 (en) * | 2000-08-07 | 2000-08-31 | Peplin Research Pty Ltd | Treatment of prostate cancer |
EP1469860A4 (en) * | 2002-01-24 | 2005-09-07 | Yissum Res Dev Co | ANTICANCER COMBINATION AND USE THEREOF |
GB0213261D0 (en) * | 2002-06-10 | 2002-07-17 | Anticancer Therapeutic Inv Sa | Method |
GB0308731D0 (en) * | 2003-04-15 | 2003-05-21 | Anticancer Therapeutic Inv Sa | Method of radiotherapy |
EP1644049B1 (en) * | 2003-04-30 | 2007-09-26 | Ramot at Tel Aviv University Ltd. | Method and device for radiotherapy |
AU2005215234B2 (en) * | 2004-02-20 | 2009-02-19 | Algeta As | Alpha-emitting Hydroxyapatite particles |
DE102004022200B4 (de) * | 2004-05-05 | 2006-07-20 | Actinium Pharmaceuticals, Inc. | Radium-Target sowie Verfahren zu seiner Herstellung |
US7914766B1 (en) * | 2004-06-03 | 2011-03-29 | Ut-Battelle Llc | Inorganic resins for clinical use of 213Bi generators |
GB0423565D0 (en) * | 2004-10-22 | 2004-11-24 | Algeta As | Formulation |
HUE041388T2 (hu) * | 2005-07-26 | 2021-12-28 | Alpha Tau Medical Ltd | Radioaktív felületi forrás és eljárás elõállítására |
US8709380B1 (en) * | 2006-02-07 | 2014-04-29 | Sirius Medicine, Llc | Targeting agents for enhancing radiation therapy |
DE102006008023B4 (de) * | 2006-02-21 | 2008-05-29 | Actinium Pharmaceuticals, Inc. | Verfahren zum Reinigen von 225Ac aus bestrahlten 226Ra-Targets |
EP2796575B8 (en) * | 2006-09-08 | 2020-04-01 | Actinium Pharmaceuticals, Inc. | Method for the purification of radium from different sources |
EP2116539A1 (en) | 2008-04-25 | 2009-11-11 | Laboratorios Del. Dr. Esteve, S.A. | 1-aryl-3-aminoalkoxy-pyrazoles as sigma ligands enhancing analgesic effects of opioids and attenuating the dependency thereof |
EP2353598A1 (en) | 2010-02-04 | 2011-08-10 | Laboratorios Del. Dr. Esteve, S.A. | Sigma ligands for use in the prevention and/or treatment of postoperative pain |
EP2353591A1 (en) | 2010-02-04 | 2011-08-10 | Laboratorios Del. Dr. Esteve, S.A. | Sigma ligands for potentiating the analgesic effect of opioids and opiates in post-operative pain and attenuating the dependency thereof |
GB201002508D0 (en) | 2010-02-12 | 2010-03-31 | Algeta As | Product |
GB201007354D0 (en) * | 2010-04-30 | 2010-06-16 | Algeta Asa | Method |
GB201007353D0 (en) * | 2010-04-30 | 2010-06-16 | Algeta Asa | Method |
EP2388005A1 (en) | 2010-05-21 | 2011-11-23 | Laboratorios Del. Dr. Esteve, S.A. | Sigma ligands for the prevention and/or treatment of emesis induced by chemotherapy or radiotherapy |
EP2415471A1 (en) | 2010-08-03 | 2012-02-08 | Laboratorios Del. Dr. Esteve, S.A. | Use of sigma ligands in opioid-induced hyperalgesia |
EP2524694A1 (en) | 2011-05-19 | 2012-11-21 | Laboratorios Del. Dr. Esteve, S.A. | Use of sigma ligands in diabetes type-2 associated pain |
CA2895356A1 (en) | 2012-12-19 | 2014-06-26 | Bayer Pharma Aktiengesellschaft | Combination comprising radium-223 for the treatment of cancer |
GB201314718D0 (en) * | 2013-08-16 | 2013-10-02 | Algeta As | Quantification method |
WO2015082378A1 (en) | 2013-12-03 | 2015-06-11 | Bayer Pharma Aktiengesellschaft | Combination of pi3k-inhibitors |
JP6499657B2 (ja) | 2013-12-03 | 2019-04-10 | バイエル ファーマ アクチエンゲゼルシャフト | Pi3k阻害剤の組み合わせ |
AU2014364647A1 (en) | 2013-12-17 | 2016-06-23 | Laboratorios Del Dr. Esteve, S.A. | Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs) and Sigma receptor ligands combinations |
WO2016083739A1 (fr) | 2014-11-26 | 2016-06-02 | Rhodia Operations | Composition de lanthane et d'actinium-227 |
GB201600153D0 (en) * | 2016-01-05 | 2016-02-17 | Bayer As | Isotope preparation method |
GB201600154D0 (en) * | 2016-01-05 | 2016-02-17 | Bayer As | Isotope preparation method |
CZ307369B6 (cs) * | 2016-12-22 | 2018-07-04 | České vysoké učení technické v Praze | Kombinace pro radionuklidovou terapii pro použití jako léčivo |
AR110995A1 (es) | 2017-02-24 | 2019-05-22 | Bayer Ag | Combinación de inhibidores de quinasa atr con sal de radio-223 |
KR102560243B1 (ko) | 2017-05-11 | 2023-07-27 | 알파 타우 메디컬 리미티드 | 근접치료 디바이스용 폴리머 코팅 |
AU2019247818B2 (en) | 2018-04-02 | 2021-10-14 | Alpha Tau Medical Ltd. | Controlled release of radionuclides |
EP3563875A1 (en) * | 2018-05-04 | 2019-11-06 | Ceské vysoké ucení technické v Praze | Radium for radionuclide therapy, in combination with calcium metabolism affecting treatment |
FR3086186B1 (fr) * | 2018-09-26 | 2022-01-28 | Orano Med | Procede de production de plomb-212 a partir d'une solution aqueuse comprenant du thorium-228 et ses descendants |
FR3088769B1 (fr) * | 2018-11-15 | 2020-12-25 | Orano Med | Procede de preparation d'au moins un generateur a haute teneur en radium-228 |
WO2020180756A1 (en) * | 2019-03-01 | 2020-09-10 | Washington University | Compositions and methods for radiotherapy using chelated radiotherapeutic agents and non-target tissue blockade |
RU2752845C1 (ru) * | 2020-05-13 | 2021-08-11 | Акционерное Общество "Наука И Инновации" | Способ получения высокочистого радия-223 |
WO2022130195A1 (en) * | 2020-12-16 | 2022-06-23 | Alpha Tau Medical Ltd. | Diffusing alpha-emitters radiation therapy with enhanced beta treatment |
CN113066598B (zh) * | 2021-03-25 | 2023-08-08 | 中国科学院近代物理研究所 | 一种从高能质子束辐照232Th靶引起的散裂反应中分离纯化223Ra的方法 |
US11964168B2 (en) | 2021-06-10 | 2024-04-23 | Alpha Tau Medical Ltd. | Diffusing alpha-emitter radiation therapy for prostate cancer |
WO2023159229A1 (en) | 2022-02-21 | 2023-08-24 | Bayer Healthcare Llc | System, method and device for delivery of a therapeutic or diagnostic agent |
WO2023159230A1 (en) | 2022-02-21 | 2023-08-24 | Bayer Healthcare Llc | System, method and device for delivery of a therapeutic or diagnostic agent |
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CH668489A5 (de) * | 1982-01-22 | 1988-12-30 | Vnii Mineralnogo Syrya | Radiometrisches verfahren zur bestimmung der konzentration natuerlicher radiumisotope und einrichtung zur durchfuehrung des verfahrens. |
US5362473A (en) * | 1988-10-14 | 1994-11-08 | Mallinckrodt Medical, Inc. | Radiolabelled particulate composition |
US4970062A (en) * | 1989-05-30 | 1990-11-13 | The United States Of America As Represented By The United States Department Of Energy | Colloid labelled with radionuclide and method |
JPH07501332A (ja) * | 1991-11-14 | 1995-02-09 | バッテル・メモリアル・インスティチュート | 癌を診断および治療する方法 |
IL109666A0 (en) * | 1993-05-17 | 1994-08-26 | Immunomedics Inc | A targeting composition containing a biotin- or avidinprotein conjugate and methods for the use thereof |
US5809394A (en) * | 1996-12-13 | 1998-09-15 | Battelle Memorial Institute | Methods of separating short half-life radionuclides from a mixture of radionuclides |
US6117413A (en) * | 1997-11-12 | 2000-09-12 | Battelle Memorial Institute | Radionuclide-binding compound, a radionuclide delivery system, a method of making a radium complexing compound, a method of extracting a radionuclide, and a method of delivering a radionuclide |
NO310544B1 (no) * | 1999-01-04 | 2001-07-23 | Algeta As | Opparbeidelse og anvendelse av radium-223 til fremstilling av preparat samt kit til behandling av kalsifisert vev for palliasjon, benkreft-terapi og/eller overflatebehandling av ben |
NO314537B1 (no) * | 1999-12-06 | 2003-04-07 | Anticancer Therapeutic Inv Sa | Reseptorbindende konjugater |
NO312708B1 (no) * | 2000-02-21 | 2002-06-24 | Anticancer Therapeutic Inv Sa | Radioaktive liposomer til terapi |
NO313180B1 (no) * | 2000-07-04 | 2002-08-26 | Anticancer Therapeutic Inv Sa | Bensökende alfapartikkel emitterende radiofarmasöytika |
GB0213261D0 (en) * | 2002-06-10 | 2002-07-17 | Anticancer Therapeutic Inv Sa | Method |
US20060228297A1 (en) * | 2003-04-15 | 2006-10-12 | Roy Larsen | Thorium-227 for use in radiotherapy of soft tissue disease |
GB0308731D0 (en) * | 2003-04-15 | 2003-05-21 | Anticancer Therapeutic Inv Sa | Method of radiotherapy |
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