CN101321542A - Microparticles for microarterial imaging and radiotherapy - Google Patents

Microparticles for microarterial imaging and radiotherapy Download PDF

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CN101321542A
CN101321542A CN 200480016791 CN200480016791A CN101321542A CN 101321542 A CN101321542 A CN 101321542A CN 200480016791 CN200480016791 CN 200480016791 CN 200480016791 A CN200480016791 A CN 200480016791A CN 101321542 A CN101321542 A CN 101321542A
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microparticles
radioactive
radionuclide
core
patient
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CN 200480016791
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Chinese (zh)
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A·S·肯尼迪
A·南
B·R·莱恩
D·A·范厄科
H·甘德哈里
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巴尔的摩马里兰大学
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Publication of CN101321542A publication Critical patent/CN101321542A/en

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Abstract

Microparticles comprising a core, at least one linking carrier on the core, and at least one radioactive therapeutic agent covalently bonded to the linking carrier. The radioactive therapeutic agent may be a radionuclide or a radiopharmaceutical. A method of radiation therapy of a patient by administering to the patient the microparticles. The treatment may be radiation therapy to treat cancer or a tumor. A kit for preparing a microparticle treatment and a method for using the kit to prepare a microparticle treatment dose. The microparticle treatment dose may be made at a location of administration or at a site proximate to the location of administration, such as a local radiopharmacy, laboratory, hospital or physician's office.

Description

用于微动脉成像和放射治疗的微颗粒 Arterioles microparticles for imaging and radiotherapy

相关申请的交叉引用 Cross-Reference to Related Applications

[01]本申请要求2003年6月20日提交的,名为"Instant Microparticles for Microarterial Imaging and Radiotherapy"的美国临时申请60/479,832的优先权,该美国临时申请通过引用方式整体并入本文。 [01] This application claims filed June 20, 2003, the United States called "Instant Microparticles for Microarterial Imaging and Radiotherapy" Provisional Application No. 60 / 479,832, which the United States provisional application is incorporated herein by reference in its entirety. 本申请也要求2004年1月23日提交的, 名为"Microparticles for Microarterial Imaging and Radiotherapy"的美国申请10/762,507的优先权,该美国申请通过引用方式整体并入本文。 This application also claims January 23, 2004, filed, entitled "Microparticles for Microarterial Imaging and Radiotherapy" of US Application No. 10 / 762,507, which is US application is incorporated herein by reference.

发明背景 BACKGROUND OF THE INVENTION

[02]在美国每年有超过IOO,OOO名患者的肝脏患原发性癌症(primary cancer)或转移性癌症(metastatic cancer)。 [02] In the United States each year there are more than IOO, OOO patients suffering from primary liver cancer (primary cancer) or metastatic cancer (metastatic cancer). 大多数患者具有手术不能切除的损害(lesions), 这些损害对化学治疗的反应也很弱。 Most patients with damage (lesions) unresectable, the damage response to chemotherapy is weak. 外部传递的常规放射性治疗能使得肝脏肿瘤退化或被破坏,但是要有选择性地主要对肝脏中的肿瘤细胞进行辐射几乎是不可能的。 Conventional radiation therapy for external delivery enables liver tumor regression or destruction, but must be selectively mainly in the liver tumor cells radiation is almost impossible. 此外,破坏肝脏肿瘤所需要的辐射剂量远远超过紧邻肿瘤的正常肝脏细胞的耐受力。 Further, the destruction of liver tumors require much more than the radiation dose tolerance of normal liver tumor cells immediately adjacent. 因此,尽管辐射作为重要的抗肿瘤治疗方法具有重大潜力,但由这种无选择性的特性所引起的问题没有被克服,因而使得放射治疗没有效果,和/或使得过量的辐射剂量施用于健康组织和细胞上。 Thus, although the method of irradiation as an important anti-cancer therapy has great potential but the problems caused by such non-selective characteristic is not caused overcome, so that no effect of radiation therapy, and / or cause excessive radiation dose administered to healthy organizational and cells. 本发明通过提供定点内部辐射疗法(site-directed internal radiation therapy)来治疗癌细胞、实体肿瘤和类风湿性关节炎,从而克服了这些局限性。 The present invention provides an internal radiation therapy sentinel (site-directed internal radiation therapy) for the treatment of cancer, solid tumors and rheumatoid arthritis, which overcomes these limitations.

肝癌的治疗 Treatment of Liver Cancer

[03]在过去十年中,在测试化学治疗剂肝动脉灌输(hepatic artery infusion)的临床试验中,已经投入大量资源,其中化学治疗剂通常是FUDR或FU。 [03] In the past decade, the test chemotherapeutic agent hepatic artery infusion (hepatic artery infusion) in clinical trials, has invested a lot of resources, which chemotherapeutic agents are generally FUDR or FU. (Kemeny et al., New England Journal of Medicine 1999; 341:2039-2048; Kennedy et al., Proceedingsof the 14th International Congress on Anti-Cancer Treatment 2003: 156; Kennedy et al., Int J Cancer 2002; S13 : 226-227.)。 (Kemeny et al, New England Journal of Medicine 1999; 341:. 2039-2048; Kennedy et al, Proceedingsof the 14th International Congress on Anti-Cancer Treatment 2003: 156; Kennedy et al, Int J Cancer 2002; S13..: 226-227.).

[04]尽管在患有结肠直肠癌肝转移瘤的患者中进行了8个前瞻性的随机试验,对于此种化疗灌输的效率和最佳用法未能取得一致结果。 [04] Despite eight prospective randomized trials in patients with colorectal liver metastases of colorectal cancer, the results failed to reach agreement for such chemotherapy instill efficiency and optimum usage. 对于其他疾病,诸如良性肿瘤、恶性肿瘤、乳腺癌、肺癌和肉瘤,对肝损害进行非手术治疗是主要的手段, 这对于幸存者的短期生命延续可以产生最好的缓解效果。 For other diseases, such as benign and malignant tumors, breast cancer, lung cancer and sarcoma, liver damage non-surgical treatment is the primary means, which can continue to produce the best results for short-term relief of life of survivors. 早已被认识到,对许多实体肿瘤来说化学致敏作用(chemosensitization)是有益的。 Has long been recognized for many solid tumors for chemical sensitization (chemosensitization) is beneficial. 然而,还不清楚如何以最理想的方式传输肝脏辐射,同时考虑正常组织的耐受力。 However, it is unclear how the best way transmission radiation liver, taking into account the tolerance of normal tissue. 短距离治疗为传输杀癌剂量提供了希望。 Treatment for short-distance transport cancer-killing dose to provide hope. 对于扩散性肝癌或很可能发生肝外衰竭时,避免手术切除。 For the diffusion of extrahepatic liver cancer or failure is likely to occur, avoid surgery. 此外,正在探索替代方法,诸如放射性粒源置换(radioactive seed placement),其居先在3D外部束治疗计划(3D external beam treatment planning)取得进展(Kennedy et al., Regulatory Peptides 2002; 108: 32.)。 In addition, alternative methods are being explored, such as a radioactive seed substitutions (radioactive seed placement), in which 3D precedence external beam treatment planning (3D external beam treatment planning) progress (Kennedy et al, Regulatory Peptides 2002; 108:. 32. ).

5 [05]巳经知道其他的局部治疗,诸如射频消融术的侵入性最小,但只是在适用于种子、源植入方法(seed implant approach)的、有限的、灶性的肿瘤(focal tumors) 中才有效。 5 [05] Other known topical treatments has already started, such as radio frequency ablation of minimally invasive surgery, but only applied to the seed, the source implantation method (seed implant approach), limited, multifocal tumor (focal tumors) the only valid. (Murthy et al., J Vase Interv Radiol 2002; 13:S2; Murthy et al" Proceedings of American Association for Cancer Research 2002; 43: 485; Murthy et al., J Vase Interv Radiol 2002; 13:S2; Sarfaraz et al., International Journal of Radiation Biology 10 and Physics 2001; 51:32-33.)。 . (Murthy et al, J Vase Interv Radiol 2002; 13: S2; Murthy et al "Proceedings of American Association for Cancer Research 2002; 43: 485; Murthy et al, J Vase Interv Radiol 2002; 13:. S2; Sarfaraz et al, International Journal of Radiation Biology 10 and Physics 2001; 51:. 32-33)..

[06]尽管最近化学治疗、手术和介入放射学(interventional radiology)取得一定的进展,在肝脏中的实体肿瘤依然保持在实体肿瘤的难治疾病的显著且常见的位置中。 [06] Despite recent chemotherapy, surgery and interventional radiology (interventional radiology) has made some progress in solid tumors in the liver remains a significant and common position intractable diseases solid tumors. 仅对结肠直肠癌中的肝病的保守估计表明,在美国每年至少有77,500个病例。 A conservative estimate is only in colorectal cancer liver disease suggests that there is at least 77,500 cases per year in the United States.

15 (Kemeny et al., New England Journal of Medicine 1999; 341: 2039-2048.)。 15 (. Kemeny et al, New England Journal of Medicine 1999; 341: 2039-2048.). 把胰腺癌、 类癌瘤、胃癌和其他实体肿瘤也考虑进去,患有恶性肝脏肿瘤的患者总数超过150,000位(Fong et al" CA Cancer J Clin 1995; 45: 50-62)。此夕卜,在美国和其他地方的肝细胞癌症(hepatocellular cancer)的发生率日益增加,在1991至1995年间, 美国的速率是每100,000人中2.4个发病(El-Serag et al., N Engl J Med 1999; The total number of patients with pancreatic cancer, carcinoid tumors, gastric cancer, and other solid tumors are also taken into account, malignant liver tumors with over 150,000 (Fong et al "CA Cancer J Clin 1995; 45: 50-62) This evening Bu. in the United States and elsewhere hepatocellular cancer (hepatocellular cancer) incidence increasing between 1991 and 1995, the US rate is 2.4 per 100,000 onset (El-Serag et al, N Engl J Med 1999.;

20 340:745-50)]。 20 340: 745-50)]. 不幸的是,这些患者中的大部分不能进行医疗手术治疗(curative surgicaltlier叩y),需要替代的治疗方法。 Unfortunately, most of these patients can not carry out medical-surgical treatment (curative surgicaltlier knock y), the need for alternative treatments. 尽管辐射治疗为这些患者提供了潜在益处, 通过外部束(externalbeam)输送足够高剂量的辐射,来破坏转移性肝肿瘤或原发性肝肿瘤通常是不现实的,这是因为肝细胞具有相对低的耐辐射能力。 Although radiation therapy offers potential benefits for these patients, a sufficiently high dose of radiation by external beam (externalbeam) conveyed to destroy metastatic liver tumors or primary liver tumors are usually not practical, because the liver cells have a relatively low the radiation resistance. 在Lawrence 进行的开仓'J性工作中,用共肝动脉化学治疗(concurrent hepatic artery chemotherapy) In the Open 'J Lawrence work conducted with a total of hepatic arterial chemotherapy (concurrent hepatic artery chemotherapy)

25 进行的适形三维治疗(conformal three-dimensional treatment)表明,当给予的辐射的剂量范围与输送到非肝脏位点的剂量范围相同时,产生了对肝脏肿瘤持久的控制,而不会致使肝功能丧失。 25 three-dimensional conformal therapy performed (conformal three-dimensional treatment) showed that when administered in a dose range of radiation dose delivered to the range of non-hepatic loci are the same, resulting in long-lasting control of liver tumors, but not cause liver loss of function. (Lawrence et al., Oncology (Huntingt) 1993; 7: 51-7; discussion 57-8,63; Lawrence et al., Front Radiat Ther Oncol 1996; 29: 221-8; Lawrence et al" Int J Radiat Oncol Biol Phys 1991; 20:555-61; McGinn et al" J Clin (Lawrence et al, Oncology (Huntingt) 1993; 7:. 51-7; discussion 57-8,63; Lawrence et al, Front Radiat Ther Oncol 1996; 29:. 221-8; Lawrence et al "Int J Radiat Oncol Biol Phys 1991; 20: 555-61; McGinn et al "J Clin

30 Oncol 1998; 16: 2246-52; McGinn et al., Semin Radiat Oncol 1997; 7: 313-323.)。 30 Oncol 1998; 16: 2246-52; McGinn et al, Semin Radiat Oncol 1997; 7:. 313-323).. 然而,大多数的患者不能接受这种或其他的局部治疗,诸如射频消融术、冷疗法或化学栓塞法。 However, most patients can not accept this or other topical treatments, such as radiofrequency ablation, chemoembolization or cold therapy method. 因此,本领域长期需求这样的技术,其能将辐射治疗剂量特异性地输送到肿瘤,同时不伤害正常、健康的周边组织和细胞。 Therefore, this long-term needs of the art technology, which is capable of specifically radiation therapy dose delivered to the tumor, while sparing normal, healthy cells and surrounding tissue. 特别需要此类发明的一个领域是治疗肝肿瘤。 One area of ​​particular need of such treatment of liver tumors invention.

35 35

[07]栓塞形成是这样的过程,其中将物质注入血管至至少部分充满的水平,或以至塞住血管和/或促进凝块形成,这样,通过血管的血流减少或停止。 [07] embolization is a process in which a blood vessel to be implanted at least partially filled with a substance level, or even plugged vessel and / or promote clot formation, so reducing or stopping blood flow through the vessel. 出于各种医学原因,血管的栓塞作用可能是有用的,包括通过切断血液供给来预防或控制因损伤而引起的流血(例如组织流血、肠胃出血、血管出血和与动脉瘤相关的出血) 或切除疾病组织(例如肿瘤、血管畸形、出血等)。 For various medical reasons, vascular embolization may be useful, including (for example, bleeding tissue bleeding, gastrointestinal bleeding, blood vessels and bleeding associated with an aneurysm) to prevent or control bleeding due to damage caused by cutting off the blood supply or removal of diseased tissue (e.g., tumors, vascular malformations, bleeding, etc.). 栓塞形成也可以用于在手术期间5或刚进行完手术后预防血损失。 Embolization may also be used during surgery or immediately 5 for the prevention of blood loss After surgery. 可以在手术之前对肿瘤进行栓塞作用,从而收縮肿瘤尺寸、帮助看见肿瘤,和防止与手术程序相关的血损失。 Tumor embolization can be prior to surgery, so that shrinkage in tumor size, tumor help seeing, and blood loss associated with surgical procedures can be prevented. [08]无论有无辐射作用,对血管栓塞剂(vascular embolic agents)所作的开拓性努力可以追溯到Prinzmetal (Van Echo et al" Amer Soc Clin Oncol 2001; 260a: 1038.),10 Prinzmetal在1947年的动物研究和人对象中首先通过动脉途径使用玻璃球灌输(glass sphere infusion)。随后不久,Muller在1951年使用静脉注射的、在炭中的放射性金来治疗患有两侧肺癌(bilateral lung cancer)的患者。还有,在20世纪60 年代早期的多位研究者——他们治疗肝脏中的高血管神经内分泌肿瘤(highly vascular neuroendocrine tumor)-报告了约35 的90紀-树脂球进行肝脏动脉15灌输的效率。然而,灌输产生了致命的毒性水平,这与球体在无意中沉积在胃中导致溃疡和出血有关。其他人也描述了因辐射引起的致命的肺部毒性,这是因为放射性球体从肝脏分流(shunt)到肺,肝脏后的相邻的毛细血管床。最近的研究使用玻璃微球体、树脂 [08] with or without radiation, vascular embolic agent (vascular embolic agents) made pioneering efforts can be traced back Prinzmetal (Van Echo et al "Amer Soc Clin Oncol 2001; 260a: 1038.), 10 Prinzmetal in 1947 animal and human research subjects instill (glass sphere infusion) the first to use glass ball by arterial route. shortly thereafter, Muller suffering on both sides to treat lung cancer (bilateral lung cancer using intravenous injection of radioactive carbon in gold in 1951 ) patients as well, a number of researchers in the early 1960s - they treat high blood vessel neuroendocrine tumors (highly vascular neuroendocrine tumor) in the liver - reported a 90 century about 35 - resin ball liver artery 15 instill efficiency. However, instilling its fatal toxicity levels, which inadvertently deposited with the ball in the stomach leads to ulcers and bleeding. other people describe fatal pulmonary toxicity due to radiation-induced, because radioactive ball from the liver shunt (shunt) to the lung, the liver, the adjacent capillary bed. recent studies using glass microspheres, resin 球体和本文中描述的聚合物微球体,表明肠胃道(GI)出血、 胆硬化或肺部毒性的发生率相对小。(Burton et al., 1989; Anderson et al., 1992; Yan et20 al,, 1993; Andrews et al., 1994; Lau et al., 1994; Leung et al., 1994; Kennedy et al" 2001; Kennedy et al., 2002; Coldwell et al., 2001; Wright et al., 2002; Mourtzikos et al" 2002; Hisley et al" 2002;他feli et al., 1999.)。 Microspheres and polymer microspheres described herein, showed gastrointestinal (GI) bleeding, biliary cirrhosis or incidence of pulmonary toxicity is relatively small (Burton et al, 1989;... Anderson et al, 1992; Yan et20 al, , 1993; Andrews et al, 1994;. Lau et al, 1994;. Leung et al, 1994;. Kennedy et al "2001;. Kennedy et al, 2002; Coldwell et al, 2001;.. Wright et al, 2002 ; Mourtzikos et al "2002; Hisley et al" 2002; he feli et al, 1999.).. [09]在20世纪60年代早期,尝试传送附着到树脂或陶瓷微球体上的90Y或32P, 25 在肝脏中使用P辐射。 [09] In the early 1960s, attempts to transmit or 90Y 32P attached to the resin or ceramic microspheres, using 25 P radiation in the liver. (Ariel IM., 1965; Ariel et al., 1967; Simon et al.,1968; CaWaroia et al., 1965; Blanchard et al., 1964; Blanchard et al., 1965; Kim et al., 1962.)。 (Ariel IM, 1965;. Ariel et al, 1967;. Simon et al, 1968;. CaWaroia et al, 1965;. Blanchard et al, 1964;. Blanchard et al, 1965;.. Kim et al, 1962.) . 然而, 由于相比起其他同位素,同位素90Y具有相对高的卩能量,后来的趋势朝使用90Y 发展。 However, as compared to other isotopes, isotope 90Y has a relatively high energy Jie, then the trend toward the use of 90Y development. 钇-90尸Y)是纯(3发射体,其衰变成稳定的锆-90,平均能量为0.94 MeV, 半衰期为2.67天(64.2小时)。在商业反应器中,钇-卯通过对89Y进行中子轰击而30 产生,产生卯Y卩辐射,组织渗透性为2.5mm,最大范围为1.1 cm。 一个GBq (27 mCi)的9QY在组织中传送约50 Gy/Kg的总剂量。放射性微颗粒[10]先前的努力已经将放射性物质局部地传送到患有癌症的患者,作为辐射治疗35 的一种形式。在某些情况下,放射性物质被掺入(包埋)到小颗粒、种子源(seeds)、 金属丝和类似相关的结构中,这些结构物质直接植入癌症位置(肿瘤)。放射性物质也已被配制成微球体,用于注射入目标器官的动脉血液供给中。将放射性颗粒或微球体施于目标器官的血液供给中,称为选择性体内辐射治疗(Selective Internal Radiation Therapy(SIRT))。[11]相对于传统的外部束放射治疗(external beam radiotherapy), SIRT Yttrium-90 corpse Y) of pure (3 emitter that decays to stable zirconium-90, the average energy of 0.94 MeV, a half-life of 2.67 days (64.2 hours) in a commercial reactor, yttrium - 89Y by sockets 30 generates a neutron bombardment, Y d Jie generating radiation, tissue penetration is 2.5mm, a maximum range of 1.1 cm. a total dose GBq (27 mCi) of about 50 Gy 9QY transmitted in the organization / Kg of radioactive micro particles [10] have been previous efforts radioactive substance locally delivered to a patient suffering from cancer, as a form of radiation therapy 35. in some cases, the radioactive substance is incorporated (embedded) into small particles, seeds source (Seeds), wires and similar related structures, the structures of these substances directly into position cancer (tumor). radioactive material has been formulated as microspheres for injection into the arterial blood supply of the target organ. radioactively microspheres or particles applied to the blood supply of the target organ, called selective internal radiation therapy (selective Internal radiation therapy (SIRT)). [11] with respect to conventional external beam radiation therapy (external beam radiotherapy), SIRT 具有许多潜5在的优点。首先,辐射被优先传送到目标器官的癌上。其次,辐射随着放射性核素衰变缓慢而持续地进行传送。第三,通过使用血管活性药物诸如血管扩张素, 比如血管紧张素-2来控制动脉血液供给,相比起健康的正常组织能够增加到达器官癌症部位的放射性微球体的百分比。结果是优先增加了癌症位置的辐射剂量, 同时将正常组织的辐射剂量维持在相当低的水平。(Burton, MA et al.; 1988.)。10[12]在含f乙-90的微球体的最早的临床应用中,钇被掺入(包埋)到聚合物基质中, 聚合物基质配制成微球体。尽管这些微球体密度合适,确保在肝脏中具有良好的分布特征,但放射性试剂钇-90严重地从微球体渗透出来,这导致了其他非目标组织被不适当地辐射,也就是非特异性辐射。15[13]在克服渗透问题的一种尝试中,公开了这样的放射性微球体, Has many potential advantages 5. First, the radiation is preferentially transmitted to the target organ cancer. Second, as the radiation decay of the radionuclide to be slow and sustained delivery. Third, by the use of vasoactive drugs, such as vasodilators factors, angiotensin-2 such as arterial blood supply to the control, from normal healthy tissue can be increased as compared to the percentage of radioactive microspheres reach the organ cancer sites. As a result of preferentially increasing the radiation dose cancer position, while the radiation dose to normal tissues maintained at a relatively low level. (Burton, MA et al .; 1988.). 10 [12] in the first clinical application of b-90 f-containing microspheres, the yttrium was incorporated (embedded) into the polymer matrix, the polymer matrix formulated as microspheres. Although these microspheres suitable density to ensure good distribution characteristics in the liver, but severely radioactive agent yttrium-90 permeation from the microspheres, resulting in other non-target tissue is unduly radiation, i.e., non-specific radiation .15 [13] in an attempt to overcome the problem of permeation, discloses a radioactive microsphere, 包括生物相容性玻璃材料,生物相容性玻璃材料包含有均匀分布(包埋)在玻璃中的p-或Y-辐射放射性同位素诸如钇-90,(国际专利申请WO 86/03124)。此外,这些玻璃微球体需要在使用之前进行中子活化作用。20[14]轻聚合物离子交换微球体(polymeric ion exchange microspheres)的产生已被开发用于解决当注射入体内时,钇透滤的严重问题。当微球体注射入肝脏动脉时, 对于继发性肝癌患者取得了高的目标应答率(objective response rate) (Gray, BN et al. 1992.)。 Biocompatible material comprises a glass, the glass material comprises a biocompatible uniformly distributed (embedded) p- Y- radiation or radioactive isotope yttrium-90, such as a glass, (International Patent Application WO 86/03124). In addition these glass microspheres neutron activation is required prior to use .20 [14] generating light polymeric ion-exchange microspheres (polymeric ion exchange microspheres) have been developed to address when injected into the body, yttrium diafiltered serious problem when the microspheres were injected into the hepatic artery, for patients with secondary liver cancer have made a high objective response rate (objective response rate) (Gray, BN et al. 1992.). 此种聚合物离子交换微球体的缺点是,对稳定的钇-89同位素进行中子25 活化作用后,钇-90放射性核素必须加入到微球体中。 Disadvantage of such a polymer ion exchange microspheres is that after neutron activation of 25 -89 stable isotope of yttrium, yttrium-90 radionuclide must be added to the microspheres. 这就需要专门的设施,对操作人员具有危险性。 This requires specialized facilities, hazardous to the operator. 还有,聚合物离子交换微球体只含有低百分比的钇,这不利地影响了用于给药的剂量水平。 Further, the polymeric ion-exchange microspheres contain only a low percentage of yttrium, which adversely affects the dose levels used for administration. [15]已经对90Y载体进行了改进,其包括基于树脂和陶瓷的材料。 [15] have been improved on the support 90Y, comprising a resin-based material and ceramics. 他fdi和Day 30 报道了对玻璃(硼酸锰铝玻璃,25-32 nm)微球体进行改进,用铼(天然同位素'86Re 和^Re)替换90Y。 He reported fdi and Day 30 of the glass (aluminum manganese borate glass, 25-32 nm) for the microspheres modifications, substitutions 90Y rhenium (natural isotopic '86Re and ^ Re). 这些对中子来说具有大的横截面,更容易产生治疗数量的P-发射体'站Re和哪Re,其分别具有1.1 MeV和2.1 MeV的最大能量,而卯Y的为0.97 MeV。 Which has a large cross-section for neutrons, and more prone to a number of therapeutic P- emitter 'station which Re and Re, which have maximum energy 1.1 MeV and 2.1 MeV, and Y d is 0.97 MeV. 然而,使用它们的效果是,释放的Y-射线为9.5y。 However, the effect of using them is that the release of Y- rays 9.5y. (^Re)和15%(ls8Re)。 (^ Re) and 15% (ls8Re). 已报道,它们被用于患有Novikoff肝癌的斯普拉-道来大鼠,Novikoff肝癌是耐化35 学和放射治疗的肿瘤。 It has been reported, which are suffering from liver Novikoff Sprague - Dawley rats, liver Novikoff tumor is resistant to 35 of the therapy and radiology. 有趣的是,Y-射线的产生使得成像成为可能,然而,相比起卯Y(65小时),,鹏Re非常短的半衰期(17小时),使得186+l88Re对于临床实践不理想的。 Interestingly, that the imaging ray generating Y- possible, however, compared to d Y (65 hours) ,, Re Peng very short half-life (17 hours), such that 186 + l88Re undesirable for clinical practice. [16]临床研究已经报道了使用固体玻璃放射性微球体。 [16] Clinical studies have reported the use of solid glass radioactive microspheres. 例如,Shepherd等用固体玻璃放射性微球体治疗患有原发性肝细胞癌的IO位患者,然而,这些患者中没有一个显示出治疗应答(Shepherd, R et al., 1992.)。 For example, other therapeutic Shepherd solid glass radioactive microspheres IO patients with primary hepatocellular carcinoma, however, these patients do not exhibit a therapeutic response (Shepherd, R et al., 1992.). [17]临床使用的放射性微球体(TheraSphere⑧)(MDS Nordion, Inc., 447 March Road: Ontario, Canada K2K 1X8)由充满90Y的玻璃组成。 [17] Clinical use of radioactive microspheres (TheraSphere⑧) (MDS Nordion, Inc., 447 March Road: Ontario, Canada K2K 1X8) 90Y made of glass filled compositions. 每一球体的直径为25±10 pm, 这样,它们主要在肿瘤末端细动脉中被捕获,肿瘤末端细动脉估计直径为8-10 pm。 Diameter of each sphere is 25 ± 10 pm, so they are captured mainly at the end arterioles tumor, the tumor diameter was estimated terminal arterioles 8-10 pm. 据估计每毫克含有22,000至73,000个微球体。 It is estimated that each contain 22,000 to 73,000 mg of microspheres. 在患者体内,9QY不从玻璃球体渗10 滤出来,这是因为它们被永久捕获在微球体的基质中。 In a patient, 9QY filter 10 does not leak out of the glass spheres, because they are permanently trapped in the matrix of the microspheres. [18]目前可用于微球体治疗的两种产品有重大缺陷。 [18] At present two products can be used for microsphere therapy has a significant drawback. 首先在球体上没有可以使得能够在体内进行成像和对球体位置进行鉴定的源(scmrce)。 First, not on a sphere and may enable imaging source (scmrce) identification of the position of the sphere in vivo. 这也使得开发辐射治疗计划软件(radiation treatment planning software)的努力变得复杂。 It also makes the development of radiation treatment planning software (radiation treatment planning software) complicates efforts. 临床实验和15 这类设备的广泛使用将要求在肝脏内精确的剂量计算和定位,对于任何短距离治疗产品的当前技术来说均是这样的。 15 clinical trials and is widely used such devices will require accurate dose calculations and positioned in the liver, the current technology for any product for brachytherapy are such. 第二,产生^Y球体的工艺是繁杂的,需要从核反应器进行装载(shipment),这会耽误很多时间。 Second, the process of producing the sphere ^ Y is complicated, needs to be loaded (Shipment) from the nuclear reactor, which would delay a lot of time. 还有,就最大剂量而言,产量是有限的。 Also, it is the maximum dose, the production is limited. 因此,需要更有效的生产系统,其将使得更多的患者及时接受治疗。 Therefore, more efficient production system, which will allow more patients to receive timely treatment. 因为放射性活性在制造时是具有固定的活性,对于放射性玻璃球体的治疗应用只20 有4小时的时间(window),而对于树脂球体,是<24小时。 Because radioactivity is fixed during the production activity, for therapeutic use of radioactive glass microspheres 20 have only 4 hours (window), and the resin spheres, is <24 hours. [19]在门诊部(outpatient setting)进行的非手术方法,能够安全地对许多患者进行治疗,同时使用可利用的介入放射学技术和导管。 [19] in the clinic (outpatient setting) for non-surgical methods, it is possible to safely treat many patients, use of the catheter and interventional radiology techniques available. 通过提供能够对肿瘤进行位置特异性治疗的新的治疗用放射性微颗粒,本发明满足了辐射治疗中的长期需要。 By providing a new treatment of tumors can be treated with the specific position of the radioactive microparticles of the present invention satisfies a long-felt need of radiation therapy. 25本发明的微颗粒利用了P-发射同位素的特性,其允许对某一位置诸如肿瘤进行局部照射,并且在附近区域的组织上剂量显著下降,从而不会伤害临近的正常细胞。 25 microparticles invention utilizes the characteristics of the P- emitting isotopes, such as a position that allows for local irradiation of tumors, and a significant decrease in dose vicinity of the tissue, so as not to damage adjacent normal cells. 认识到短程电子(short-range electrons)(诸如那些由(3-发射同位素提供的玩论如何也不能被成像或被确定给予患者后它们的位置,因此,在本发明的需要诊断和/ 或成像功能的某些实施方案中,微颗粒包括导向实体(targetingentity)。30发明概述[20]在本发明的一种实施方案中,提供了微颗粒,其包括核心和直接或间接附着到核心表面的至少一种放射性治疗剂。微颗粒可以通过血管内施用而被引入,可以用于进行成像和/或诊断和/或治疗性介入(therapeutic intervention)。本发明的治35 疗组合物包括放射性微颗粒(粒状材料)在生理学上可接受的液体中的悬浮液,其可以用来注射入人体中。1[21]使用核心和连接载体(linkingcarrier)(诸如,非限制性的例子,聚(甲基丙烯酸甲酯)),其包括生物相容性微球体,微球体的直径在约5至约200微米范围内。 取决于临床需要,该材料可 Recognizing the electronic short (short-range electrons) (such as those provided by the play s (3-emitting isotopes can not be imaged or how to determine their positions after administration to the patient, therefore, to be diagnosed in the present invention and / or imaging in certain embodiments, features, microparticles including a guide entity (targetingentity) .30 SUMMARY oF tHE iNVENTION [20] in one embodiment of the present invention, there is provided a micro-particle comprising a core and directly or indirectly attached to the surface of the core at least one radiotherapeutic agent. microparticles may be introduced via intravascular administration, can be used for imaging and / or diagnostic and / or therapeutic intervention (therapeutic intervention). 35 therapeutic treatment composition of the present invention include radioactive microparticles (granular material) in a physiologically acceptable liquid suspension, which can be used for injection into humans .1 [21] using the core and the connection carrier (linkingcarrier) (such as a non-limiting example, poly (methyl methyl acrylate)), which comprises a biocompatible microspheres, the diameter of the microspheres in the range of about 5 to about 200 microns depending on the clinical need, the material may 附着有a、 P-或Y-发射放射性核素(emitting radionuclide)或它们的任何组合。[22]在某些实施方案中,本发明涉及微颗粒,该微颗粒包括:核心;至少一个位于所述核心上的连接载体,其中所述连接载体包括生物相容性聚合物;以及至少一种共价结合到所述连接载体的放射性治疗剂;其中所述微颗粒的直径在约5至约200微米范围内,并且所述微颗粒是非生物可降解性的。10[23]在本发明的具体实施方案中,放射性治疗剂包括ot-发射放射性核素、P-发射放射性核素、Y-发射放射性核素或其组合,例如包括ot-发射放射性核素和(3-发射放射性核素,和域卩-发射放射性核素和Y-发射放射性核素,和/或a-发射放射性核素和Y-发射放射性核素。15[24]在本发明的某些优选实施方案中,放射性治疗剂包括治疗用放射性核素和成像或诊断用放射性核素。更具体地,治疗用放射性 Attached a, P- or Y- emitting radionuclide (emitting radionuclide), or any combination thereof [22] In certain embodiments, the present invention relates to microparticles, the microparticles comprising: a core; located in at least one of the connection carrier on said core, wherein said connector comprises a biocompatible polymer support; and at least one covalently bound to the radiotherapeutic agents of the connector carrier; wherein the diameter of the microparticles is from about 5 to about 200 the micrometer range, and the non-biodegradable microparticles of .10 [23] in a particular embodiment of the invention, a radioactive therapeutic agent comprises ot- emitting radionuclide, P- emitting radionuclide, Y- emission radionuclide or combinations thereof, including for example ot- emitting radionuclide and (3-emitting radionuclide, and domain Jie - emitting radionuclide and Y- emitting radionuclide, and / or a- emitting radionuclide and Y- emitting radionuclide .15 [24] in certain preferred embodiments of the invention, a radioactive therapeutic agent comprises a radionuclide and a therapeutic or diagnostic radionuclide imaging. more specifically, treatment with radioactive 核素包括卩-发射放射性核素, 成像或诊断用放射性核素包括Y-发射放射性核素。20 [25]考虑被用于本发明微颗粒的治疗用放射性核素的非限制性例子包括但不限于Y-90、 Bi-213、 At-211、 1-123、 1-125、 1-131、 At-211、 Cu-67、 Sc-47、 Ga-67、 Rh冒105、 Pr-142、 Nd-147、 Pm-151、 Sm-153、 Ho-166、 Gd-159、 Tb-161、 Eu-152、 Er-171、 Re-186和Re-188。 Jie radionuclide comprising - emitting radionuclide, radionuclide imaging or diagnostic emitting radionuclides include Y- .20 [25] are considered treatment for microparticles of the present invention Non-limiting examples of radionuclides include, but are is not limited to Y-90, Bi-213, at-211, 1-123, 1-125, 1-131, at-211, Cu-67, Sc-47, Ga-67, Rh run 105, Pr-142, Nd-147, Pm-151, Sm-153, Ho-166, Gd-159, Tb-161, Eu-152, Er-171, Re-186 and Re-188. 考虑用于本发明微颗粒的成像或诊断用放射性核素的非限制性例子包括但不限于Tc-99m、 In-111 、 Ga-67、 Rh-105 、 I陽123 、 Nd-147 、 Pm-151 、 Sm-153 、25 Gd-159、 Tb-161、 Er-171、 Re-186、 Re-188和T1-201 。 Consider for diagnostic imaging or microparticles of the present invention Non-limiting examples of radionuclides include, but are not limited to, Tc-99m, In-111, Ga-67, Rh-105, I Yang 123, Nd-147, Pm- 151, Sm-153, 25 Gd-159, Tb-161, Er-171, Re-186, Re-188, and T1-201. 在优选实施方案中,治疗用放射性核素包括钇-90,成像或诊断用放射性核素包括铟-111或Tc-99m。 In a preferred embodiment, it comprises a therapeutic radionuclide yttrium-90, indium-111 include diagnostic or imaging or radionuclide Tc-99m. [26]在其他实施方案中,放射性治疗剂是放射性核素或放射性药物。 [26] In other embodiments, a radioactive therapeutic agent is a radionuclide or radiopharmaceutical. 用于本发明的放射性核素包括但是不限于一种或多种下述物质:铱、镭、铯、磷、钇、铼、 30 锕、铋、砍、锝、铟、碘、和碳、氮、氟、钠、镁、铝、硅、钾、钒、锰、镓、 铌、碘、铅、Y國90、 Bi-213、 At-211、 1-123、 1-125、 1-131、 At-211、 Cu-67、 Sc-47、 Ga陽67、 Rh-105、 Pr-142、 Nd-147、 Pm-151、 Sm-153、 Ho-166、 Gd-159、 Tb-161、 Eu陽152、 Er-171、 Re-186、 Re-188、 Tc-99m、 In-lll、 Ga-67、 Rh-105、 1-123、 Nd-147、 Pm-151、 Sm-153、 Gd-159、 Tb-161、 Er-17K Re-186、 Re-188和T1-201 。 Radionuclides useful in the present invention include, but are not limited to one or more of the following materials: iridium, radium, cesium, phosphorus, yttrium, rhenium, 30 actinium, bismuth, cut, technetium, indium, iodine, carbon, nitrogen , fluorine, sodium, magnesium, aluminum, silicon, potassium, vanadium, manganese, gallium, niobium, iodine, lead, Y State 90, Bi-213, At-211, 1-123, 1-125, 1-131, At -211, Cu-67, Sc-47, Ga male 67, Rh-105, Pr-142, Nd-147, Pm-151, Sm-153, Ho-166, Gd-159, Tb-161, Eu 152 male , Er-171, Re-186, Re-188, Tc-99m, In-lll, Ga-67, Rh-105, 1-123, Nd-147, Pm-151, Sm-153, Gd-159, Tb -161, Er-17K Re-186, Re-188, and T1-201. 35[27]放射性治疗剂或直接或间接地附着到核心上。 35 [27] or radiotherapeutic agent directly or indirectly attached to the core. 将连接载体间接附着到核心的例子包括通过一个或多个间隔基团或通过螯合剂基团进行附着。 Examples of the carrier are connected indirectly attached to the core includes one or more spacers attached by groups or by chelant groups. 可以考虑的螯合剂基团包括下述的至少一个:环己基二亚乙基三胺五乙酸配体(CHX-DTPA)、 二亚乙基三胺五乙酸(DTPA)、乙二胺四乙酸(EDTA)、 1,4,7,10-四氮杂环十二烷-N,N',N,"N"'四乙酸(DOTA)、四氮杂环十四烷-N,N",N"N"-四乙酸(TETA)、环己基1,2-二胺四乙酸(CDTA)、乙二醇-0,0'-二(-2-氨乙基)-N,N,N',N'-四-乙酸(EGTA)、 5 N,N-二(羟苄基)-乙二胺-N,N'-二乙酸(HBED)、三亚乙基四胺六乙酸(TTHA)、羟乙基二胺三乙酸(HEDTA)、羟基乙叉二膦酸(HEDP)、 二巯基琥珀酸(DMSA)、 二亚乙基三胺四亚甲基瞵酸(DTTP)和l-(p-氨苄基)-DTPA、 1,6-二氨基己烷N,N,N',N'-四乙酸、DPDP和亚乙基-二(氧乙烯腈基)-四乙酸。在优选的实施方案中,螯合剂基团包括DOTA。10[28]将连接载体附着到核心的可选择例子例如包括双功能连接物、碳二亚胺縮合作用或二硫键。[29]本发明的微颗粒包括包含有聚合物的核心。聚合物可以 Chelating groups may be considered include at least one of the following: cyclohexyl diethylenetriamine pentaacetic acid ligand (CHX-DTPA), diethylene triamine pentaacetic acid (DTPA), ethylenediaminetetraacetic acid ( EDTA), 1,4,7,10- tetraaza cyclododecane -N, N ', N, "N"' tetraacetic acid (DOTA), tetraazacyclo tetradecane -N, N ", N "N" - tetraacetic acid (TETA), cyclohexyl 1,2-diamine tetraacetic acid (CDTA), ethylene glycol -0,0'- bis (-2-ethyl) -N, N, N ', N'- four - acetic acid (EGTA), 5 N, N- bis (hydroxybenzyl) - ethylenediamine -N, N'- diacetic acid (HBED), triethylenetetramine hexaacetic acid (TTHA), isethionic diamine triacetic acid (HEDTA), hydroxyethylidene diphosphonic acid (HEDP), dimercaptosuccinic acid (DMSA), diethylene triamine tetra methylene phosphine acid (DTTP) and l- (p- aminobenzyl group ) -DTPA, 1,6- diaminohexane N, N, N ', N'- tetraacetic acid, DPDP, and ethylenebis - bis (oxyethylene nitrile) - tetraacetate in a preferred embodiment, chelating mixture groups include DOTA.10 [28] attached to selectively connect the carrier core examples include, for example, a bifunctional linker, a carbodiimide condensation or disulfide bonds. [29] the microparticles of the present invention comprises a polymerization comprises the core polymer material may 括但不限于聚(甲基15 丙烯酸甲酯)、聚丙烯酸酯、乙烯-醋酸乙烯聚合物、酰基取代的醋酸纤维素、聚氨酯、聚苯乙烯、聚氯乙烯、聚氟乙烯、聚(乙烯咪唑)、氯磺酸酯聚烯烃(chlorosulphonate polyolefm)、聚氧乙烯、它们的混合物、和它们的共聚物、聚膦嗪、聚(乙烯醇)、 聚酰胺、聚碳酸酯、聚亚烷基、聚丙烯酰胺、聚亚烷基二醇、聚环氧烷烃、聚对苯二甲酸亚烷基酯、聚乙烯醚、聚乙烯酯、聚乙烯卤化物(polyvinyl halide)、聚乙20 烯吡咯垸酮、聚乙交酯、聚硅氧烷、它们的共聚物、烷基纤维素(alkylcellulose)、 羟垸基纤维素(hydroxyalkyl cellulose)、纤维素醚、纤维素酯、硝基纤维素或其组合。 在本发明的所有组合物中,核心是非放射性的,直到治疗剂附着到核心上,才具有放射性。在具体的实施方案中,核心包括聚(甲基丙烯酸甲酯)和/或聚苯乙烯。25 [30]在一些实 Including but not limited to, poly (methyl methacrylate 15), polyacrylate, ethylene - vinyl acetate polymer, an acyl substituted cellulose acetate, polyurethane, polystyrene, polyvinyl chloride, polyvinyl fluoride, poly (vinyl imidazole ), chlorosulphonate polyolefins (chlorosulphonate polyolefm), polyoxyethylene, mixtures thereof, and copolymers thereof, polyphosphazines, poly (vinyl alcohol), polyamides, polycarbonates, polyalkylenes, poly acrylamides, polyalkylene glycols, polyalkylene oxides, poly (alkylene terephthalate), polyvinyl ethers, polyvinyl esters, polyvinyl halides (polyvinyl halide), polyvinyl pyrrol-en-20-one embankment, polyglycolides, polysiloxanes, copolymers thereof, alkyl cellulose (alkylcellulose), hydroxypropyl cellulose embankment (hydroxyalkyl cellulose), cellulose ethers, cellulose esters, nitrocellulose, or combinations thereof. in All compositions according to the present invention, the core is non-radioactive until the therapeutic agent is attached to the core, only radioactive. in a specific embodiment, the core comprises poly (methyl methacrylate) and / or polystyrene .25 [30] in some 方案中,至少一个连接载体包括线型聚合物、分支化聚合物和/或树枝状聚合物。在包括树枝状聚合物的具体实施方案中,树枝状大分子在它的核心中包括二硫键,和/或具有外部层,外部层上具有活性基团。在优选的具体实施方案中,活性基团是导向实体(targeting entity)或治疗实体(therapeutic entity)。 Embodiment, the at least one connecting support include linear polymers, branched polymers and / or dendrimers. In a specific embodiment comprises a dendrimer, the dendrimer comprises disulfide bonds in its core and / or an outer layer, having reactive groups on the outer layer. in a preferred embodiment, the active group is a guide entity (targeting entity) or physical treatment (therapeutic entity). 在另一优选的具体实施方案中,活性基团包括胺基团或羧基基团。 In another preferred embodiment, the reactive groups include amine groups or carboxyl groups. 30[31]在其他具体实施方案中,树枝状大分子具有至少一个末端功能基团,该功能基团对于螯合剂是可接触的,所述螯合剂能够与所述至少一个功能基团相互作用。 30 [31] In other embodiments, the dendrimer having at least one terminal functional group, the functional group to the chelating agent is in contact with the chelating agent capable of interacting with said at least one functional group . 该末端功能基团包括酯、醚、硫醇、羰基、羟基、酰胺基、羧基、和/或酰亚胺。 The terminal functional groups include esters, ethers, thiol, carbonyl, hydroxyl, amide group, a carboxyl group and / or imide. 35 [32]在涉及多树枝状大分子的具体实施方案中,这些树枝状大分子是单分散性的。 35 [32] In a specific embodiment involving multiple dendrimers, these dendrimers are monodisperse. [33]作为优点,本发明的微颗粒不会滤出(leach)放射性核素。 [33] As an advantage, the microparticles of the present invention are not filtered out (LEACH) radionuclide. 在某些实施方案中,微颗粒的密度在1至4 gm/cm3范围内,或更优选地,在1至2 gm/cm3范围内。 In certain embodiments, the density of the microparticles in the range of 1 to 4 gm / cm3 range, or more preferably, in the range of 1 to 2 gm / cm3. [34]在另一实施方案中,微颗粒还包括第二治疗剂,其中所述至少一种放射性治疗剂是第一治疗剂,所述第二治疗剂是与第一治疗剂不同的治疗剂。 [34] In another embodiment, the microparticles further comprise a second therapeutic agent, wherein said at least one first therapeutic agent is a radioactive therapeutic agent, said second therapeutic agent is different from the first therapeutic agent therapeutic agent . 在具体实施5 方案中,第二治疗剂包括至少一种下述物质:金属螯合复合物、药物、药物前体、 放射性核素、硼附加物(boron addend)、标记化合物、毒素、细胞因子、淋巴因子、趋化因子、免疫调节剂、辐射敏化剂、门冬酰胺酶、放射性卤素、化学治疗药物和造影剂。 5 In a specific embodiment, the second therapeutic agent comprises at least one of the following materials: a metal chelate complexes, drugs, prodrugs, radionuclides, boron addend (boron addend), the title compound, a toxin, a cytokine , lymphokines, chemokines, immunomodulators, radiosensitizers, asparaginase, radioactive halogen, chemotherapeutic drugs and contrast agents. 10 [35]本发明的另一微颗粒包括核心,和至少两种附着到所述核心的放射性治疗齐ij。 10 [35] The microparticles of the present invention further includes a core, and at least two core attached to the radiotherapeutic Qi ij. [36]在具体的实施方案中,本发明的放射性治疗剂包括a-发射放射性核素、p-发射放射性核素和/或Y-发射放射性核素。 [36] In a particular embodiment, the radiotherapeutic agents of the present invention include a- emitting radionuclide, p-emitting radionuclide and / or Y- emitting radionuclide. 在其他具体实施方案中,放射性治疗剂独立地选自治疗用放射性核素和导向性放射性核素。 In other embodiments, radiotherapeutic agents independently selected therapeutic radionuclides and radionuclide guide. 在优选的具体实施方案中,治15疗用放射性核素包括(3-发射放射性核素,导向性放射性核素包括Y-发射放射性核素。更具体地,卩-发射放射性核素包括钇-90, ?发射放射性核素包括铟-lll或Tc-99m。在某些实施方案中,放射性治疗剂通过共价键各自结合核心。[37]在一种实施方案中,提供了微颗粒,该微颗粒包括核心,至少一种附着到所20 述核心的放射性导向实体,其中所述导向实体包括Y-发射放射性核素,微颗粒的直径在约5至约200微米的范围内,且是非生物可降解的。在进一步的实施方案中,放射性治疗实体进一步包括P-发射放射性核素。在另一进一步的实施方案中, 微颗粒还包括至少一种位于所述核心上的连接载体,其中所述连接载体包括生物相容性聚合物。25[38]在另一种实施方案中,本发明提供了包括微颗粒的颗粒材料,其具有:核心,至少一 In a preferred embodiment, the rule 15 comprises a treatment with a radionuclide (3-emitting radionuclide, radionuclide guide comprising Y- emitting radionuclide More specifically, Jie - emitting radionuclides include yttrium - 90,? -lll emitting radionuclides include indium or Tc-99m. in certain embodiments, radiotherapeutic agents by covalent bonds binding the respective core. [37] in one embodiment, the microparticles provide the microparticles comprising a core, at least one of the radioactivity adhered to the core guide 20 of said entity, wherein said entity comprises a guide Y- emitting radionuclide, the diameter of microparticles in the range of from about 5 to about 200 microns, and abiotic degradable. in a further embodiment, further comprises a radioactive therapeutic entities P- emitting radionuclide. in another further embodiment, the microparticles further comprise at least one of the connection carrier positioned on the core, wherein connecting said carrier comprises a biocompatible polymer .25 [38] in another embodiment, the present invention provides a particulate material comprising microparticles, comprising: a core, at least one of 种位于所述核心上的连接载体,其中所述连接载体包括生物相容性聚合物, 和至少一种共价结合到所述连接载体的放射性治疗剂;其中所述微颗粒的直径在约5至约200微米范围内,且所述微颗粒是非生物可降解的。在具体的实施方案30 中,微颗粒的直径在8-100微米范围内,更具体地,微颗粒直径在25-50微米范围内,最优选地,直径在20-30微米范围内。在所有例子中,颗粒材料的微颗粒足够大,以避免吞噬作用。[39]本发明也提供了使用组合物进行辐射治疗的方法。35[40]利用放射治疗来治疗患者的方法的一种实施方案包括,给予需要放射治疗的患者多个放射性微颗粒,其中所述多个放射性微颗粒中的每一个的直径在约5至约200微米范围内,且是非生物可降解的,放射性微颗粒包括核心、至少一种位于所述核心上的连接载体,其中所述连接载体包括生物相容 The seed is located on the connection carrier core, wherein the connection carrier comprises a biocompatible polymer, and at least one covalently bound to the radiotherapeutic agents of the connector carrier; wherein the diameter of the microparticles is between about 5 to about 200 microns, and the microparticles are non-biodegradable. in a specific embodiment 30, the diameter of the microparticles is in the range of 8-100 microns, more particularly, in the 25-50 micron diameter microparticles within the range, most preferably 20-30 microns in diameter. in all cases, microparticles particulate material is sufficiently large to avoid phagocytosis. [39] the present invention also provides methods of using the compositions for radiation therapy .35 [40] an embodiment of the radiotherapy using the method of treating a patient comprising administering to the patient a plurality of radioactive microparticles need of radiation therapy, wherein the diameter of said plurality of radioactive microparticles of each of from about 5 to the range of about 200 microns, and non-biodegradable, radioactive microparticles comprising a core, at least one connector positioned on said core carrier, wherein said carrier comprises a biocompatible connection 性聚合物、至少一种共价结合到所述连接载体的放射性治疗剂,其中所述多个放射性微颗粒提供给患者辐射治疗。在具体的实施方案中,多个放射性微颗粒被肠胃外给药、静脉内给5 药、通过血管插管进行血管内给药,给药到支持患者肿瘤的动脉血管系统中,和/ 或给药到目标位置诸如肿瘤上或附近。给药方式可以是单剂量形式和/或连续灌输或在一段时间中以多剂量形式给药。在某些实施方案中,利用栓塞作用(embolization),将多个放射性微颗粒固定在给药位置,诸如目标位置,诸如肿瘤或固定在支持肿瘤的动脉血管系统中。 Polymer, covalently attached to at least one radiotherapeutic agents of the connection carrier, wherein said plurality of microparticles of radioactive radiation therapy provided to the patient. In a specific embodiment, the plurality of microparticles are radioactive parenteral medicine, 5 intravenous drug administration intravascular catheter through a blood vessel, artery administered to a patient support system tumors, and / or administration to a target position on or near the tumor. administration may be a single such dosage form and / or continuous infusion or in multi-dose form is administered over a period of time. in certain embodiments, the use of embolization (embolization), a plurality of radioactive microparticles administered at fixed locations, such as target position, such as tumor or tumor immobilized on a support arterial vascular system.

10 10

[41]在本发明的另一实施方案中,提供了对血管进行栓塞作用的方法,包括给予本发明的多个微颗粒。 [41] In another embodiment of the present invention, there is provided a method of embolization of the blood vessel, comprising administering to a plurality of microparticles of the present invention. 在具体的实施方案中,栓塞作用包括将栓塞剂组合物传递到血管,以充满或塞住血管和/或促进凝结形成,这样,经过血管的血流减少、降低或被阻断和/或停止。 In a specific embodiment, the embolization embolic composition comprising transmitting into the vessel, or to fill the vessel plug and / or promote the formation of condensation, so that blood flow through the vessel is reduced, decreased or blocked and / or stop .

15 15

[42]本发明的方法可以用于放射治疗,包括用于治疗癌症患者和/或肿瘤,用于对患者的目标位置诸如肿瘤成像,和/或用于对怀疑患有癌症或肿瘤的对象进行诊断。 [42] The method of the present invention may be used for radiation therapy, including for the treatment of cancer patients and / or tumor, for the target position of the patient such as tumor imaging, and / or a subject suspected of having a cancer or a tumor is diagnosis. 本发明的方法特别适合于患有下述癌症的对象:原发性肝癌或继发性肝癌、类风湿性关节炎、实体肿瘤、肝癌、脑癌、乳腺癌、卵巢癌、肾细胞癌、肝细胞瘤、 20 肉瘤、头或颈癌、或者中枢神经系统肿瘤。 The method of the present invention is particularly suitable subject with a cancer: hepatocellular carcinoma or secondary liver cancer, rheumatoid arthritis, solid tumor, liver cancer, brain cancer, breast cancer, ovarian cancer, renal cell carcinoma, liver cell tumor, sarcoma 20, head or neck cancer, or central nervous system tumors.

[43]对患者体内的目标器官或肿瘤进行成像的一种方法包括,在患者体内的目标位置给予患者多个放射性微颗粒,其中所述多个放射性微颗粒中的每一个的直径在5至约200微米范围内,且是非生物可降解的,放射性微颗粒包括核心、至少 [43] A method for the target organ or patient tumor imaging comprising administering to the patient a plurality of radioactive microparticles at a target location in a patient, wherein said plurality of microparticles of radioactive diameter of each of the 5 to the range of about 200 microns, and non-biodegradable, radioactive microparticles comprising a core, at least

25 —种位于所述核心上的连接载体,其中所述连接载体包括生物相容性聚合物、至少一种共价结合到所述连接载体的放射性治疗剂,其中所述放射性治疗剂包括Y-发射放射性核素;并检测所述多个放射性微颗粒,其中所述检测提供了目标器官或肿瘤的图像。 25 - the connection carrier species located on the core, wherein the connection carrier comprises a biocompatible polymer, at least one covalently bound to the radiotherapeutic agents of the connection carrier, wherein said radiotherapeutic agent comprising Y- emitting radionuclide; and detecting the plurality of radioactive microparticles, wherein the detection target organ or tumor provides an image. 检测可以在辐射期间进行,或可选择性地,在辐射之后进行。 Detection may be performed during the irradiation, or may be selectively performed after the irradiation. 在进一步的实施方案中,该方法还包括检测所述多个放射性微颗粒在患者中的位置。 In a further embodiment, the method further comprising detecting a position of the plurality of radioactive microparticles in a patient.

30可以考虑将多个微颗粒固定在目标位置,目标位置包括目标器官或肿瘤。 30 can be considered a plurality of fixed microparticles at a target position, the target position of the target organ or tumor comprising.

[44]在某些实施方案中,本发明的方法涉及患者体内癌症和/或肿瘤的诊断。 [44] In certain embodiments, the present invention relates to a method of in vivo diagnosis of cancer patients and / or tumor. 此种方法包括将本发明的许多放射性微颗粒施于患者,优选施于目标位置诸如怀疑是肿瘤的位置,或原发性癌症或继发性癌症的位置;检测所述许多放射性微颗粒, 35 和由检测结果确定患者是否患有癌症和/或肿瘤,其中检测到所述肿瘤和/或癌症表明是阳性诊断。 Such a method comprises a number of radioactive microparticles of the present invention is administered to a patient, preferably applied to the target location, such as a suspected location of the tumor, cancer or primary or secondary cancers position; detecting said plurality of radioactive microparticles, 35 and the detection result is determined by the patient suffering from cancer and / or tumors, wherein the tumor is detected and / or cancer indicate a positive diagnosis. 此种诊断方法可考虑用于诊断肝癌、实体肿瘤、脑癌、乳腺癌、 卵巢癌、肾细胞癌、肝细胞瘤、肉瘤、中枢神经系统肿瘤,和/或头和/或颈部癌症。 Such diagnostic methods may be considered for diagnosis of liver cancer, a solid tumor, brain cancer, breast cancer, ovarian cancer, renal cell carcinoma, hepatoma, sarcoma, central nervous system tumors, and / or head and / or neck cancer. [45]在其他实施方案中,提供了用于制备本发明颗粒材料的试剂盒,该试剂盒包括:非放射性核心,至少一种用于将至少一种放射性核素附着到所述颗粒核心的连接载体,和用于制备所述微颗粒治疗剂量(microparticle treatment dose)的指导5 (instructions)或用于获得这样的指导的工具。 [45] In other embodiments, the particulate material provides a kit for the preparation of the present invention, the kit comprising: a non-radioactive core, at least one for the at least one radionuclide attached to the particle core guidance 5 (instructions) connected to the carrier, and used to prepare the therapeutic dose microparticles (microparticle treatment dose) or means for obtaining such guidance. 在具体实施方案中,试剂盒还包括放射性核素,其可以与试剂盒分别提供。 In a specific embodiment, the kit further comprises a radionuclide, which kit may be provided, respectively. 在一个具体实施方案中,试剂盒还包括选自下列的至少一种组分:药学上可接受的惰性载体、配制剂(formulating agent)、 佐剂、活性试剂、水、盐水、转移配体(transfer ligand)、还原剂、冻干助剂、稳定助剂、增溶剂、抑菌剂、缓冲物、X-射线造影剂、超声造影剂和金属药物。 In one particular embodiment, the kit further comprises at least one component selected from the group consisting of: pharmaceutically acceptable inert carrier, the formulation (formulating agent), adjuvants, active agent, water, saline, a transfer ligand ( transfer ligand), a reducing agent, lyophilization aids, stabilization aids, solubilizers, bacteriostatic agents, buffers, X- ray contrast agents, ultrasound contrast agents and metallopharmaceuticals. 在另10 —种具休实施方案中,试剂盒还包括选自下列的至少一种组分:注射器、屏蔽设备和成像设备。 In another 10 - species with Hugh embodiments, the kit further comprises at least one component selected from the group consisting of: syringes, shielding apparatus and the image forming apparatus. 在另一种进一步的具体实施方案中,试剂盒还包括至少两种化学上不同的非放射性核心,或至少两种化学上不同的连接载体。 In another further particular embodiment, the kit further comprises a different non-radioactive core, chemically, or at least two kinds of different connection carrier on at least two chemical.

[46]在另一实施方案中,提供了使用本发明试剂盒的方法。 [46] In another embodiment, a method of using the kit of the present invention. 使用本文描述的试剂15 盒的一种方法是为需要微颗粒治疗的患者制备微颗粒治疗剂量,包括:由所述患者的处方确定所需的微颗粒治疗的类型和剂量,利用所述指导或可获得指导的工具制备所述微颗粒治疗剂量。 Using a method described herein, the agent cartridge 15 is to microparticles need of treatment a patient a therapeutic dose preparing microparticles, comprising: determining a desired prescription of the patient and the type of microparticles dose treatment, or with the guide guidance can be obtained for preparing the microparticles tool therapeutic dose.

[47]使用本发明的试剂盒来为需要微颗粒治疗的患者制备微颗粒治疗剂量的另一 [47] using the kit of the present invention is a further need for the microparticles of treatment the patient a therapeutic dose of microparticles prepared

20 种方法包括:由所述患者的处方确定所需要的微颗粒治疗的类型和剂量,从所述 20 methods comprising: determining microparticles treatment required by the patient's prescription dose and type, from the

试剂盒中的核心中选择非放射性核心的类型,从所述试剂盒中的连接物中选择连接物的类型,选择放射性核素,由所述指导或可获得指导的工具制备所述微颗粒治疗剂量。 Selecting a non-radioactive kit core type core, the type of linker selected from the kit was connected, selected radionuclide, or obtainable by the guide to guide the preparation of the microparticles treatment tool dose.

25 [48]本发明的另一方面涉及栓塞的方法,包括将栓塞剂组合物传递到血管,以充满或塞住血管和/或促进凝结形成,这样通过血管的血流减少或停止。 25 [48] Another aspect of the present invention relates to embolization, the embolic agent comprising a composition delivered to the vessel, or to fill the vessel plug and / or promote condensation is formed, so that blood flow through the vessel is reduced or stopped. 栓塞剂组合物包括本发明的颗粒材料和药学上可接受的载体。 Embolic composition comprises a pharmaceutically particulate material of the present invention and a pharmaceutically acceptable carrier.

附图简述 BRIEF DESCRIPTION

30 [49]图1:微球体结构的典型例子,该微球体结构由通过化学的方式连接到螯合剂 30 [49] Figure 1: A typical example of the structure of the microspheres, the microspheres joined by chemical structure represented by way of the chelating agent

的生物相容性核心构成,螯合剂紧紧结合放射性发射体(emitter)。 Biocompatible core configuration, chelating agents tightly bound radioactivity emitter (emitter). 放射性同位素能够受到树枝状大分子界面的支持,以增加结合的螯合剂的数量。 Radioisotopes can be supported dendrimer interface to increase the number of bound chelator.

[50]图2. PMMA-PAMAM树枝状大分子偶联物的合成。 [50] FIG. 2. Synthesis of PMMA-PAMAM dendrimer conjugate.

35 35

[51]图3. PMMA-DOTA微球体的合成。 [51] FIG. 3. Synthesis of PMMA-DOTA microspheres. [52]图4.微颗粒。 [52] FIG. 4. microparticles.

发明详述I.定义 DETAILED DESCRIPTION I. Definitions

5 [53]为了使下面的描述清楚,提供了下述定义。 5 [53] In order to make the following description clear, the following definitions are provided.

[54]"微颗粒(microparticles)"或"微球体(microspheres)"指支持它表面上的效应物物质的颗粒。 [54] "microparticles (Microparticles)" or "microspheres (Microspheres)" means that it supports the effect of matter on the surface of the particles. 微颗粒是非生物可降解的,并且是生物相容性的。 Non-biodegradable microparticles, and it is biocompatible.

10 [55]"非生物可降解的(non-biodegradable)"指这样的材料,其不会在治疗期间被身体降解到严重的程度。 10 [55] "non-biodegradable (non-biodegradable)" refers to materials that are not degraded in the body serious extent during treatment.

[56]"生物相容性(biocompatible)"是指对身体无毒害,药学上可接受的,非致癌性的,并且不会严重地引发身体组织炎症。 [56] "biocompatible (Biocompatible)" refers to non-toxic to the body, a pharmaceutically acceptable, non-carcinogenic, and does not lead to a serious inflammation of the body tissue.

15 15

[57]如本文中所使用的,"连接载体(linking carrier)"是用于将效应物分子结合到微颗粒的分子。 [57] As used herein, a "connection carrier (linking carrier)" for the binding to effector molecules molecules microparticles. 该连接物能够与效应物和微颗粒基质形成共价键。 The linker is capable of forming a covalent bond with the effector and matrix microparticles.

[58]"效应物(effectoe)"是可以包含螯合剂的分子结构,其在体内发挥有用的生物20 功能。 [58] "effector (effectoe)" is a molecular structure may comprise a chelating agent, which play a useful biological functions in the body 20. 如本文中使用的,术语治疗用效应物(therapeutic effector)用来指任何化合物或分子或同位素,其在目标组织内导致、引发或者启动细胞应答或生理应答。 The term therapeutic effector (therapeutic effector) as used herein refers to any compound or molecule or isotopes, which results in the target tissue, trigger or initiate a cellular response or physiological response.

[59]"螯合剂(chelator)"或"结合单位(bondingunit)"指在试剂上的结合分子诸如金属离子的部分(moiety)或基团,这种结合是通过与一个或多个供电子原子形成25 化学键来实现的。 [59] "chelating agents (chelators)" or "binding unit (bondingunit)" refers to a molecule on the binding agent, such as a portion of the metal ions (the sequestration inactivating moiety) or a group, which is bound by one or more electron donor atoms 25 is formed to achieve a chemical bond.

[60]如本文中所使用的,"身体(body)"优选指人体,但是应该理解身体也可以指非人动物体。 [60] The "body (body)," as used herein preferably refers to the human body, it should be understood that body can also refer to non-human animal body.

30 II.本发明 30 II. The present invention

[61]本发明涉及治疗用放射性组合物及其应用,本发明克服了可在外部放射治疗(extend radiation therapies)中观察到的非特异性辐射的三个主要的局限性:1)使用卩辐射作为治疗剂使正常的周边肝细胞免遭伤害;2)直接传递到肿瘤脉管系统, 放射性微颗粒然后将停留在肿瘤内,使得肿瘤周围的正常细胞和/或组织免遭伤害; 35 和3)使得够能传递数量大大增加的辐射剂量,从而获得将有效地消灭基本上所有实体肿瘤的辐射范围(例如治疗上有效量的辐射)。 [61] The present invention relates to three major limitations therapeutic radioactive composition and its application, the present invention overcomes nonspecific radiation is observed in the external radiation therapy (extend radiation therapies) of: 1) the use of radiation as Jie therapeutic agent to the surrounding normal liver cells from harm; 2) is transmitted directly to the tumor vasculature, and then the radioactive microparticles remain in the tumor, so that the normal cells and / or tissues surrounding the tumor from harm; 35 and 3) such that the number of transfer can be greatly increased radiation dose, thereby obtaining effectively eliminate substantially all of the radiation range of solid tumors (e.g., a therapeutically effective amount of radiation). [62]本发明涉及通过用放射性核素标记生物相容性聚合物而形成的放射性复合物;支持形成微颗粒的聚合物-放射性复合物的微球体/颗粒核心;和用于制备放射性复合物的必要组分的"试剂盒"。 [62] The present invention relates to a radioactive labeled with a radionuclide complex formed by the biocompatible polymer; forming polymer microparticles support - radioactive microsphere composite / particle core; and means for preparing a radioactive compound the essential component of the "kit." 此外,本发明涉及其制备方法,和其在体内辐射诊断剂和/或治疗剂方面的方法和应用。 Further, the present invention relates to a method for their preparation, and methods and uses thereof in vivo diagnostic radiation and / or of a therapeutic agent.

微颗粒 Microparticles

本发明的治疗组合物涉及微颗粒。 The therapeutic composition of the present invention relates to microparticles. 在某些实施方案中,本发明的微颗粒包括核心、至少一个位于所述核心上的连接载体,其中所述连接载体包括生物相容性聚合物、至少一种共价结合到所述连接载体的放射性治疗剂;其中所述微颗粒的10 直径在约5至约200微米范围内,所述微颗粒是非生物可降解的。 In certain embodiments, the microparticles of the present invention comprises a core, at least one of the connection carrier is located on the core, wherein the connection carrier comprises a biocompatible polymer is covalently bound to at least one of the connection carrier radiotherapeutic agents; 10 wherein the diameter of the microparticles range from about 5 to about 200 microns, the microparticles are non-biodegradable.

[63]微球体由非陶瓷、非放射性标记的核心材料构成,其充当聚合物包衣的支持物,聚合物包衣由线形的、分支的或树枝状的生物相容性聚合物构成,合适的结合试剂附着于聚合物包衣。 [63] Microspheres formed of non-ceramic core material, non-radiolabeled, which serves as a support polymer coating, the polymer coating consists of a linear or branched biocompatible polymer of dendritic structure, suitable binding agents attached to the polymer coating. 所述结合试剂可选自大量的化学上稳定的化合物,这些化合物结合放射性或非放射性治疗剂,参见本文中更详细的描述。 The binding reagent may be selected from a large number of compounds chemically stable, these compounds bind radioactive or therapeutic agent, as described in more detail herein.

15 15

[64]在本发明中,在微球体核心的表面上的局部沉积的聚合物(locally deposited polymer),被用作对放射性核素或放射性药物进行固定化并对其进行局部性传送的载体。 [64] In the present invention, the upper surface of the core microsphere polymer deposited partially (locally deposited polymer), it is used as a radiopharmaceutical or radionuclide immobilization carrier and subjected to local transmission.

20 [65]可以使用已经用于局部放射性治疗(local radiotherapy)(近距离放射疗法(brachytherapy))的标准放射性核素,诸如铼、碘、铱、镭、铯、钇或其他元素的放射性核素。 20 [65] may have been used for topical radiotherapy (local radiotherapy) (brachytherapy (brachytherapy)) standard radionuclides, radionuclides such as rhenium, iodine, iridium, radium, cesium, yttrium, or other elements .

[66]合适的治疗剂和诊断剂包括那些物质,其在体内的效率是基于它们保留在血25 管腔隙内或在血管腔隙内被运载的能力来预测的。 [66] Suitable therapeutic and diagnostic agents include those which, based on their efficiency in vivo is retained within the ability of blood or cavities 25 within the vascular compartment to be carried it predicted. 因此,涉及给予本发明组合物的方法可以容易地运用于治疗若干疾病和障碍,包括癌症和/或肿瘤;和/或运用于通过各种成像技术对哺乳动物选定的区域进行成像;和/或对怀疑具有癌症和/或肿瘤,特别是怀疑肝中具有癌症和/或肿瘤的对象进行诊断。 Thus, the method involves administering a composition of the present invention can be readily used in the treatment of several diseases and disorders, including cancer and / or tumors; and / or used for imaging a mammal selected region by a variety of imaging techniques; and / or has a cancer and / or tumor is suspected, in particular suspected of having liver cancer and / or tumor is diagnosed.

30 [67]在具体的实施方案中,通过附着到线形的、分支的或树枝状大分子聚合物包衣上的螯合剂,微颗粒或微球体包括任何或所有的下述物质:磷、钇、铼和/或其他P发射同位素;锕、铋、砹和其他a发射同位素;锝、铟、碘和/或其他Y发射同位素;和碳、氮、氟、钠、镁、铝、硅、钾、钒、锰、镓、铌、碘和/或铅。 30 [67] In a particular embodiment, by attachment to linear, chelators, microparticles or microspheres on a branched or dendrimer polymer coatings include any or all of the following: phosphorus, yttrium, , rhenium and / or other P emitting isotopes; actinium, bismuth, astatine and other a-emitting isotopes; technetium, indium, iodine, and / or other Y-emitting isotope; and a carbon, nitrogen, fluorine, sodium, magnesium, aluminum, silicon, potassium , vanadium, manganese, gallium, niobium, iodine and / or lead.

35 [68]可以对微球体进行选择,以获得大于320小时的更长时间的降解或消亡,而此时,植入的钇-90的5个半衰期己经结束并且大多数的放射性衰变已经发生。 35 [68] The microspheres may be selected in order to obtain the degradation of longer than 320 hours or die, but this time, the half-life was over five implanted yttrium-90 and most of the radioactive decay has occurred . [69]本文中描述的发明利用具有核医疗能力的医院中的技术和设备。 [69] The invention is described herein using a hospital having a capacity in nuclear medicine techniques and equipment. 本发明也涉及"试剂盒",试剂盒包括聚合物球体、连接物和放射性同位素,其可在现场混合或在当地放射药剂室混合。 The present invention also relates to a "kit", a kit comprising polymeric spheres, linker, and radioactive isotopes, or it may be mixed in the mixing chamber radiopharmaceutical local site. 该优点增加了灵活性,使得可以根据预先计划的剂量法来确定剂量以满足单个患者的需要。 The advantage of increased flexibility, so that dosage may be determined according to a pre-planned dose method to meet the needs of the individual patient. 本发明提供了携带Y和(3或a射线源的单个5 或多个跟踪标记。本发明的一个特点在于用现有的微球体解决两种疑难问题,艮卩, 不能成像并随后定位微球体的问题,和产物的有限分布的问题。 The present invention provides a single 5 or more tracking marks Y and carrying (3 or a radiation source. A feature of the present invention is to solve difficult problems with conventional two kinds of microspheres, Gen Jie, and then not be imaged positioned microspheres problem issues, and limited distribution of the product.

[70]本发明提供了微颗粒结构,包括:生物相容性微颗粒核心,可任选的连接载 [70] The present invention provides a micro-particle structure, comprising: a core of a biocompatible microparticles, optionally the carrier is connected

体,和直接偶联到或间接偶联到生物相容性核心的分子效应物。 Body, and coupled directly or indirectly to the effector molecule conjugated to the biocompatible core. 效应物的优选形 Preferably shaped effectors

10式是放射性同位素,其通过螯合剂基团结合到连接载体。 10 is a radioisotope of formula, which is connected to the carrier through binding chelator group. 此外,本发明包括"试剂 Further, the present invention comprises "a reagent

盒"制剂的制备方法,和它们的体内辐射诊断剂和/或治疗剂用途。 Box "method for preparing formulations, and their in vivo radiation diagnostic and / or therapeutic purposes.

[71]在某些实施方案中,生物相容性微球体的直径在10至200微米的范围内。 [71] In certain embodiments, the biocompatible microspheres range in diameter from 10 to 200 microns.

15 [72]在某些实施方案中,生物相容性核心包括非陶瓷的、非放射性标记的材料, 其充当在核心表面上的聚合物包衣的支持物(参见图1),聚合物包衣由线型、分支或树枝状生物相容性聚合物构成,其上附着有合适的结合试剂。 15 [72] In certain embodiments, the core comprises a biocompatible, non-radiolabeled non-ceramic material which serves as the core on the surface of the polymer-coated support (see FIG. 1), polymer coating clothing consists of a linear, branched or dendritic biocompatible polymer, which has a suitable binding reagent is attached. 结合试剂选自各种化学上稳定的化合物,这些化合物结合放射性或非放射性治疗剂。 Compound binding agent is selected from a variety of chemically stable, these compounds bind radioactive or therapeutic agent. 生物相容性聚合物可以己经附着有a、 (3-和/或Y-发射放射性核素,或其任何组合,这取决于临 The biocompatible polymer may have attached a, (3- and / or Y- emitting radionuclide, or any combination thereof, depending on the clinical

20 床需要。 20 needed.

[73]为了克服放射性核素从陶瓷微球体滤漏出来的问题,同时为了维持微球体具有低密度,本发明提供了具有改进的物理性质的微球体。 [73] In order to overcome the problem of radionuclide from ceramic microspheres leak filter, while in order to maintain the microspheres have a low density, the present invention provides microspheres with improved physical properties. 本发明的微颗粒(微球体)可以配制成这样的尺寸、形状和密度,即当它们被施用于待被治疗的目标器25官的动脉供给时,它们具有改良的分布特性。 Microparticles (microspheres) of the present invention may be formulated into such a size, shape and density, i.e., when they are applied to the artery 25 supplied to the official target device to be treated, which have improved distribution characteristics. 此外,相比起现有技术微球体,每一微球体可以传送更高数量的电离辐射。 Further, compared to the prior art microspheres, each microsphere may transmit a higher number of ionizing radiation. 这进而意味着,传递同样的辐射剂量, 需要相对更少数目(更少产品)给予给目标器官。 This in turn means to deliver the same dose of radiation, a relatively smaller number (less products) given to the target organ. 在可选择的实施方案中,微球体在制造后进行标记,从而提高制造工艺水平。 In an alternative embodiment, the microspheres labeled after manufacture, thereby improve the manufacturing process.

30 [74]微球体的化学耐用性是这样的,当被施用时,它们不会将大量的辐射发射放射性同位素(radiation emitting radioisotope)释放到循环系统中。 30 [74] The chemical durability of the microspheres is such that when administered, they will not be a large number of radiation emitting radioisotope (radiation emitting radioisotope) released into the circulatory system.

微颗粒核心 Microparticle core

[75]本发明的扩充材料(augmentation material)包括光滑圆面、基本上球形的颗35 粒状基质材料,优选生物相容性聚合物。 Material Expansion [75] of the present invention (augmentation material) comprises a smooth circular surfaces, substantially spherical particles 35 of a particulate matrix material, preferably a biocompatible polymer. 术语"基本上球形(substantially spherical)" 指这样的事实,本发明颗粒中的一些可以是球体,本发明的大部分颗粒在形状上是像球体的,也就是它们是球形的。 The term "substantially spherical (substantially spherical)" refers to the fact that some of the particles of the present invention may be spheres, most of the particles of the present invention is like a sphere in shape, i.e. they are spherical. 本文中所使用的术语"圆面的(rounded)"或"光滑、圆面的(smooth, rounded)"指这样的实事,即使本发明颗粒不是精确的球形, 它们也不会具有任何锋锐的或有角的边缘(angular edges)。 As used herein, the term "circular surfaces (Rounded)" or "smooth, round surface (smooth, rounded)" refers to a practical, even if the particles of the invention is not exactly spherical, they do not have any Fengrui or the angular edge (angular edges). 颗粒必须是足够大的以避免吞噬作用。 The particles must be sufficiently large to avoid phagocytosis.

5 [76]如本文中所使用的,术语"微颗粒(microparticles)"指数量中位数直径(nutnber median diameter)为大于5微米的颗粒。 5 [76] The term "microparticles (Microparticles)" refers to the number median diameter (nutnber median diameter) of particles greater than 5 microns as used herein. 在特定的实施方案中,微颗粒是数量中位数直径大于约10微米的颗粒。 In certain embodiments, the number of microparticles median diameter greater than about 10 microns. 例如,核心直径可以约10微米至约200微米。 For example, the core diameter may be from about 10 microns to about 200 microns. 也优选地,微颗粒的直径在约20至约80微米范围内。 Also preferably the diameter, microparticles in the range of about 20 to about 80 microns.

10 [77]然而,应该理解,对于注射用,颗粒尺寸的上限将由所使用的特定的注射设备决定。 10 [77] However, it should be understood that, for the injection, the injection device-specific upper limit determined by the particle size used. 也就是说,颗粒必需足够小,以避免当被注射时聚集并阻塞注射器。 That is, sufficiently small particles is necessary to avoid aggregation and clogging of the syringe when being injected. 注射用的典型范围在约10至约150微米内,优选在不超过约35微米的狭小的颗粒尺寸范围内,更优选地在不超过约20至约30微米的范围内,最优选地具有基本上相等的颗粒尺寸。 A typical range for injection is in the range of about 10 to about 150 microns, preferably no more than about 35 microns, a narrow particle size range, more preferably in the range of not more than about 20 to about 30 microns, most preferably having substantially It is equal to the particle size.

15 15

[78]微颗粒直径可以在约10微米至约200微米范围内。 [78] The microparticles may have a diameter from about 10 microns to about 200 microns. 在一种实施方案中,微颗粒的直径在约8至约100微米的范围内。 In one embodiment, the microparticles range in diameter from about 8 to about 100 microns. 在另一实施方案中,微颗粒的直径在约20至约30微米范围内。 In another embodiment, the diameter of the microparticles range from about 20 to about 30 microns in.

20 [79]这些是示范性的,不是限制性的。 20 [79] These are exemplary, not restrictive. 也可以使用总体的尺寸范围在10至150微米范围内的其他狭小的颗粒尺寸范围。 It may also be used other generally narrow size range in the particle size range from 10 to 150 microns. 在讨论这些范围时,应该理解,实践中, 在理想范围之外的少量的颗粒可以存在于本发明的扩充材料样品中。 In discussing these ranges, it should be appreciated that, in practice, a small amount of particles outside the desired range may be present in the expansion material of the present invention in a sample. 然而,在任何给定样品中,大部分的颗粒应该在期望的范围内。 However, within any given sample, the majority of the particles should be within a desired range. 优选地,卯%的颗粒在期望的范围内,最优选地,95-99%的颗粒在期望的范围内。 Preferably, Mao% of the particles within a desired range, and most preferably, 95-99% of the particles within a desired range.

25 25

[80]如本文中所使用的,术语"颗粒尺寸(particle size)"指数量中位数直径,这是用本领域普通技术人员知道的常规颗粒尺寸测量技术进行测量的,例如激光衍射?去、光子关耳关i普(photon correlation spectroscopy)、沉?定il/?荒分级f去(sedimentation field flow fractionation)、转盘式离心法(disk centrifugation)或电敏感区方法30 (electrical sensing zone method)。 [80] The term "particle size (particle size)" as used herein, refers to the number median diameter, which is known to those of ordinary skill in the art of conventional particle size measuring techniques for measuring, for example, a laser diffraction? To , P i ears close off photon (photon correlation spectroscopy), Shen? set il /? f to shortage grade (sedimentation field flow fractionation), rotary centrifugation (disk centrifugation), or electrically sensitive areas method 30 (electrical sensing zone method) . 优选激光衍射法。 Preferably a laser diffraction method. 术语"类女量中位数直径(number median diameter)"作为颗粒直径的函数反映颗粒分布(用数量表示)。 The term "median diameter class Female amount (number median diameter)" is reflected as a function of particle diameter distribution of particles (indicated by number). 本领域经常使用的颗粒尺寸的另一可供选择的表示法是"体积中位数直径(volume median diameter)"。 Another particle size frequently used in the art to choose the representation is "volume median diameter (volume median diameter)". 体积中位数直径是体积加权尺寸分布(volume weighted size distribution) 的中位数直径。 Volume is the volume-weighted median diameter size distribution (volume weighted size distribution) of the median diameter. 体积中位数直径作为颗粒直径的函数反映了体积分布。 The median volume particle diameter as a function of the diameter of the volume distribution is reflected.

35 35

[81]在优选实施方案中,微颗粒的直径根据它所留存在身体的期望区域的大小进行选择。 [81] In a preferred embodiment, the diameter of the microparticles is selected based on its retention in the body size of the desired region. 留存于身体的器官或区域内的微颗粒的用途在血流研究中是常见的(Flaimet al, J Pharmacol. Meth. 11: 1-39,1984; Heymann et al, Prog. Cardiovasc. Dis. 20: 55-79,1977)。 Retained in the organs of the body or the use of microparticles in the bloodstream in the area of ​​study is common (Flaimet al, J Pharmacol Meth 11: 1-39,1984; Heymann et al, Prog Cardiovasc Dis 20....:. 55-79,1977). 例如,选择留存于毛细管中的微颗粒直径通常在15至35微米之间。 For example, select retained in the capillary diameter of the microparticles is typically between 15 and 35 microns. 使用本领域技术人员已知的各种不同的方法,微颗粒可以由不同的聚合物制备而得。 Using various methods known to the skilled person, may be prepared microparticles obtained from a different polymer. 用于制备任何颗粒尺寸范围的微颗粒的众多方法是已知的。 Numerous methods for preparing microparticles of any particle size range is known. 由熔化的材料制5 备微颗粒的合成方法是已知的,包括在乳状液、在喷雾滴(sprayed drop),和在独立的阶段进行聚合作用。 The method of melting synthetic materials prepared microparticles 5 are known, including, spray droplets (sprayed drop), and the polymerization carried out in a separate stage in the emulsion. 对于固体材料或预成型胶,已知方法包括湿磨或干磨、 微粉化、利用空气喷嘴(airjet)或筛进行分级以及类似方法。 For solid materials or preformed plastic, known methods include wet or dry milling, micronization, using an air nozzle (AirJet) or sieve fractionation and the like.

[82]本发明颗粒材料还有一个优选特征是微颗粒的密度在1至4gm/cm3范围内, 10 更优选在1至2 gm/cm3范围内。 [82] There is also a preferred feature of the present invention is the density of the particulate material in the microparticles 1 to 4gm / cm3 range, and more preferably 10 to 1 in the 2 gm / cm3 range.

[83]在本发明中,局部沉积聚合物贮存在微颗粒核心的表面上,用作固定化和局部传递放射性核素或放射性药物的载体。 [83] In the present invention, local deposition on the surface of the polymer microparticles storage core, and used as a fixed or localized delivery radiopharmaceutical radionuclide carrier.

15 [84]在一种实施方案中,微颗粒是水不可膨胀性的(not water swellable)。 15 [84] In one embodiment, the microparticles are non-swelling water (not water swellable).

[85]所述核心的内部优选不含有放射性治疗剂。 The [85] The core preferably contains no internal radiotherapeutic agents. 可选择地,本发明的微颗粒包括y-发射放射性核素,其直接或间接附着到核心。 Alternatively, the microparticles of the present invention comprises a y- emitting radionuclide, which is directly or indirectly attached to the core. 在具体的实施方案中,考虑通过成 In a specific embodiment, to consider the adoption

型到球体中来对,发射放射性核素进行附着作用,例如,在其制备期间进行附着, 20优选附着在表面。 Sphere type to come to, for emitting radionuclides adhesive effect, for example, be adhered to during its preparation, it is preferably attached to the surface 20. 在具体的实施方案中,表面是树脂颗粒表面,将许多树脂颗粒 In a specific embodiment, the surface is a surface of the resin particles, the resin particles are many

与? versus? 发射放射性核素和核心混合在一起,成型,诸如高温和/或高压,通过所述成型作用在核心表面形成树脂-放射性核素层,从而得到放射性微颗粒。 Emitting radionuclide and the core are mixed together, shaped, such as high temperature and / or pressure, is formed by the surface of the core resin molding action - radionuclide layer, whereby radioactive microparticles.

生物相容性微颗粒核心材料 Biocompatible microparticles core material

25 [Sq本发明优选的微颗粒核心是生物相容性的聚合物。 25 [Sq of the present invention is preferably biocompatible microparticle core polymer. 合适的生物相容性聚合物或者可以是缓慢生物可降解的,或可以是非生物可降解的聚合物,或可以是它们的混合物或共聚物,参见本文描述。 Suitable biocompatible polymers can be slow or biodegradable, or may be non-biodegradable polymer, or may be a mixture or copolymer thereof, as described in herein. 适合用于本发明的生物相容性聚合物因此可以是水不溶性的或极小程度水溶性的。 Biocompatible polymer suitable for use in the present invention may thus be water soluble or water insoluble very small extent.

30 [87]如果聚合物和聚合物的任何降解产物对接受者是无毒的,而且对接受者身体无明显的有害或不利的影响诸如在注射位置的免疫应答的话,那么聚合物是生物相容性的。 30 [87] if any of the polymers and polymer degradation products are non-toxic to recipients, and no significant deleterious or untoward effects on the recipient's body, such as an immune response in the injection position, then the polymer is a biocompatible capacitive.

[88]合适的生物相容性的、非生物可降解的聚合物包括选自下述的非生物可降解35的聚合物:聚丙烯酸酯、乙烯-醋酸乙烯和其他酰基取代的醋酸纤维素(acyl substituted cellulose acetates)的聚合物、非可降解性聚氮酯、聚苯乙烯、聚氯乙烯、 聚氟乙烯、聚(乙烯咪唑)、氯磺酸酯聚烯烃、聚氧乙烯,它们的混合物和它们的共 [88] Suitable biocompatible, non-biodegradable polymers include polymers selected from non-biodegradable. 35: polyacrylates, ethylene - vinyl acetate and other acyl substituted cellulose acetates ( acyl substituted cellulose acetates) polymers, non-degradable ester polyethylenimine, polystyrene, polyvinyl chloride, polyvinyl fluoride, poly (vinyl imidazole), chlorosulphonate polyolefins, polyethylene oxide, and mixtures thereof their total

25聚物。 25 polymer.

[89]代表性的合成聚合物包括聚膦嗪、聚(乙烯醇)、聚酰胺、聚碳酸酯、聚亚垸基、 聚丙烯酰胺、聚亚垸基二醇、聚环氧烷烃、聚对苯二甲酸亚烷基酯、聚乙烯醚、 5 聚乙烯酯、聚乙烯卤化物、聚乙烯吡咯垸酮、聚乙交酯、聚硅氧垸、聚氨酯和其共聚物。 [89] Representative synthetic polymers include polyphosphazines, poly (vinyl alcohol), polyamides, polycarbonates, polyalkylene embankment group, polyacrylamides, polyalkylene glycols embankment group, polyalkylene oxide, polyethylene alkylene terephthalate, polyvinyl ether, 5 polyvinyl esters, polyvinyl halides, polyvinylpyrrolidone embankment ketone, polyglycolide, embankment silicone, polyurethane, and copolymers thereof. 合成的修饰的天然聚合物包括垸基纤维素、羟垸基纤维素、纤维素醚、 纤维素酯和硝基纤维素。 Synthesis of modified natural polymers include alkyl with cellulose, hydroxyethyl cellulose embankment, cellulose ethers, cellulose esters, and nitrocellulose. 其他感兴趣的聚合物包括但是不限于:甲基纤维素、乙基纤维素、羟丙基纤维素、羟丙基甲基纤维素、羟丁基甲基纤维素、醋酸纤维素、 丙酸纤维素、醋酸丁酸纤维素、邻苯二甲酸醋酸纤维素、羧甲基纤维素、三乙酸 Other polymers of interest include, but are not limited to: methyl cellulose, ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxybutyl methyl cellulose, cellulose acetate, cellulose propionate, cellulose acetate butyrate, cellulose acetate phthalate, carboxymethyl cellulose, triacetate

10 纤维素、硫酸钠盐纤维素(celMose sulfate sodium salt)、聚(甲基丙烯酸甲酯)、聚(甲基丙烯酸乙酯)、聚(甲基丙烯酸丁酯)、聚(甲基丙烯酸异丁酯)、聚(甲基丙烯酸己酯)、聚(甲基丙烯酸异癸酯)、聚(甲基丙烯酸月桂酯)、聚甲基丙烯酸苯基酯(poly(phenyl methacrylate))、聚(丙烯酸甲酯)、聚(丙烯酸异丙酯)、聚(丙烯酸异丁酯)、 聚(丙烯酸十八烷基酯)、聚乙烯、聚丙烯、聚乙二醇、聚氧乙烯、聚对苯二甲酸乙 10 cellulose, cellulose sulfate sodium salt (celMose sulfate sodium salt), poly (methyl methacrylate), poly (ethyl methacrylate), poly (butyl methacrylate), poly (isobutyl methacrylate ester), poly (hexyl methacrylate), poly (isodecyl methacrylate), poly (lauryl methacrylate), poly phenyl methacrylate (poly (phenyl methacrylate)), poly (methyl acrylate ester), poly (isopropyl acrylate), poly (isobutyl acrylate), poly (octadecyl acrylate), polyethylene, polypropylene, polyethylene glycol, polyoxyethylene, polyethylene terephthalate b

15 二酯、聚醋酸乙烯、聚氯乙烯、聚苯乙烯、聚乙烯吡咯垸酮和聚乙烯基苯酚。 15 diesters, polyvinyl acetate, polyvinyl chloride, polystyrene, polyvinylpyrrolidone and polyvinyl phenol ketone embankment.

[90〗这些聚合物可以从Sigma Chemical Co., St. Louis, Mo., Polysciences, Warrenton, Pa., Aldrich, Milwaukee, Wis., Fluka, Ronkonkoma, NY"禾口BioRad, Richmond, Calif. [90〗 these polymers available from Sigma Chemical Co., St. Louis, Mo., Polysciences, Warrenton, Pa., Aldrich, Milwaukee, Wis., Fluka, Ronkonkoma, NY "Wo mouth BioRad, Richmond, Calif.

获得,可以通过使用标准技术由从这些供应商获得的单体合成而得。 Obtained, it can be obtained using standard techniques synthesized from monomers obtained from these suppliers.

20 20

[91]合适的聚合物组合物优选具有固有的和可控制的生物可降解性,这样,它们 [91] Suitable polymer compositions preferably have intrinsic and controllable biodegradability, so that they

坚持约1周至约6个月;且是无毒的,不含毒性大的单体,和降解成无毒性的组分;是生物相容性的;与待被传递的物质是化学相容的,通过粘附(adherence) 或几何因素(geometric factors),诸如通过在期望的位置被捕获,能够保持在施用25 的位置;能够通过具有最低侵入性的技术(techniques of minimum invasivity)诸如通过插管而被传递。 Adhere about 1 to about 6 months; and non-toxic, non-toxic monomers large, and degrade to non-toxic components; biocompatible; a substance to be delivered is chemically compatible , by adhesion (adherence) or geometric factors (geometric factors), such as by capture in a desired position, it can be held in position 25 of administration; through technique (techniques of minimum invasivity) having a minimally invasive, such as through a cannula It is transferred.

[92]用于本发明的聚合物的可接受的分子量能够被本领域普通技术人员通过考虑各种因素而确定,考虑的因素诸如期望的聚合物降解速度、物理特性诸如机械强30 度、聚合物在溶剂中的溶解速度。 [92] Acceptable molecular weights for polymers of the invention can be those of ordinary skill in the art be determined by considering various factors, such as desired factors into the polymer degradation rate, physical properties such as mechanical strength of 30 degrees, the polymerization dissolution rate was solvent. 通常,可接受的分子量范围在约2,000道尔顿至约2,000,000道尔顿。 Typically, an acceptable range of molecular weight from about 2,000 Daltons to about 2,000,000 Daltons. (聚合物分子量通常用加权平均分子量表示。然而,对于树枝状大分子,当它们具有确定的化学结构时,报道的分子量是绝对的分子量。) (Polymer molecular weight is usually represented by weight average molecular weight. However, for the dendrimers, when they have a chemical structure, the molecular weight is reported in absolute molecular weight.)

[93]在一种实施方案中,生物相容性聚合物核心和所述连接载体的生物相容性聚35 合物包括不同的生物相容性聚合物。 [93] In one embodiment, the biocompatible polymer and a biocompatible connection carrier core polyethylene composition comprises 35 different biocompatible polymer.

连接载体[94]优选的连接载体是生物相容性聚合物(诸如HPMA)、生物相容性组分的大分子聚集体(诸如聚合的树枝状大分子),或多-组分连接载体,其由一个以上的生物相容性组分构成(诸如树枝状大分子包被的聚合物微颗粒)。 Connection carrier [94] is connected to the carrier is preferably a biocompatible polymer (such as HPMA), biocompatible moiety macromolecular aggregates (such as polymeric dendrimer), or - the connection carrier component, which consists of one or more biocompatible components (such as a dendrimer polymer-coated microparticles).

5 [95]连接载体的例子包括但不限于:聚合共聚物、树枝状大分子、聚乙二醇组合、 加帽聚赖氨酸(capped polylysines)、聚羟丁酸、葡聚糖、生物相容性聚合物和共聚物,诸如透明质酸和丙烯酰胺及其衍生物,聚苯乙烯颗粒和其衍生物。 5 [95] Examples of carriers include, but are not connected to: the polymerization copolymer, dendrimer, a combination of polyethylene glycol, polylysine capped (capped polylysines), polyhydroxybutyric acid, dextran, Biofacies capacitive polymers and copolymers, such as hyaluronic acid and derivatives thereof and acrylamide, polystyrene particles and derivatives thereof. 优选的连接载体是树枝状大分子。 The preferred support is connected dendrimer.

10 [96]根据涉及的具体的化学特点,连接载体可以通过各种方法偶联到效应物。 10 [96] The specific chemical characteristics involved, the carrier may be connected to the effector conjugates by various methods. 偶联将是共价的。 The covalent coupling. 适合于将导向实体和治疗用效应物偶联到连接载体的各种方法可以参见Hermanson, "Bioconjugate Techniques", Academic Press: New York, 1996;禾口"Chemistry of Protein Conjugation and Cross-linking", SS Wong, CRC Press, 1993。 And adapted to guide the various entities connected to the coupling method of treating a carrier with effector can be found in Hermanson, "Bioconjugate Techniques", Academic Press: New York, 1996; Wo mouth "Chemistry of Protein Conjugation and Cross-linking", SS Wong, CRC Press, 1993.

具体的偶联方法包括但是不限于:使用双功能连接物、碳二亚胺缩合作用、二硫 Specific coupling methods include, but are not limited to: using a bifunctional linker, carbodiimide condensation, disulfide

15 键形成、和使用特定的结合对(binding pair),其中结合对的其中一个成分在连接载体上,而结合对的另一成分在效应物上。 15 bond formation, and p (binding pair), wherein a binding component which is connected on the carrier, and the other components of the binding pair is used on a specific effector binding. 大量的效应物可以附着到一个微颗粒上。 A large number of effector may be attached to a microparticle.

[97]水溶性聚合物(树枝状大分子,PEG等)可以选作生物相容性连接物,以避免在20 给药时发生免疫应答。 [97] Water soluble polymer (dendrimer, PEG, etc.) may be selected as a biocompatible linker, to avoid the occurrence of an immune response when administered 20.

树枝状大分子连接载体 Dendrimers connection carrier

[98]另一优选的连接载体是树枝状大分子。 [98] Another preferred carrier is connected dendrimer. 树枝状大分子是具有从中心核心出发的、明确的分支的聚合物(例如"星型聚合物(starburst polymers)")。 Dendrimer is a clear departure from the branch polymer center core (such as a "star polymer (starburst polymers)"). 与常规的聚合 And conventional polymerization

25物相比,树枝状大分子趋向于是高度分支的大分子。 25 were compared, dendrimers tend to be highly branched macromolecules. 树枝状大分子描述于美国专利4,507,466、 4,558,120、 4,568,737、 4,587,329、 4,631,337、 4,694,064、 4,737,550 和4,857,599以及大量的其他专利和专利公开中。 Dendrimers described in US Patent 4,507,466, 4,558,120, 4,568,737, 4,587,329, 4,631,337, 4,694,064, 4,737,550 and 4,857,599 and numerous other patents and patent publications. 树枝状大分子的结构、合成和特征论述于下述文献中:Kim and Zimmerman, "Applications of dendrimers in bio-organic chemistry," Current Opinion In Chemical Biology (1998) 2(6):733-42; Tam Structure, synthesis and characteristics of dendrimers are discussed in the following references: Kim and Zimmerman, "Applications of dendrimers in bio-organic chemistry," Current Opinion In Chemical Biology (1998) 2 (6): 733-42; Tam

30 and Spetzler, "Chemoselective approaches to the preparation of peptide dendrimers and branched artificial proteins using unprotected peptides as building blocks," Biomedical Peptides, Proteins & Nucleic Acids (1995) 1 (3): 123-32; Frechet, "Functional polymers and dendrimers: reactivity, molecular architecture, and interfacial energy," Science (1994) 263 (5154》1710-5; Liu and Frechet, "Designing dendrimers for drug delivery," 30 and Spetzler, "Chemoselective approaches to the preparation of peptide dendrimers and branched artificial proteins using unprotected peptides as building blocks," Biomedical Peptides, Proteins & Nucleic Acids (1995) 1 (3): 123-32; Frechet, "Functional polymers and dendrimers: reactivity, molecular architecture, and interfacial energy, "Science (1994) 263 (5154" 1710-5; Liu and Frechet, "Designing dendrimers for drug delivery,"

35 Pharmaceutical Science and Technology Today (1999) 2 (10): 393401; Verprek and Jezek "Peptide and glycopeptide dendrimers. Part 1," Journal of Peptide Science (1999) 5(1): 5-23: Veprek and Jezek, "Peptide and glycopeptide dendrimers. Part II," JournalOf Peptide Science (1999) 5 (5) 203-20; Tomalia et al" "Starburst dendrimers: Molecular-level control of size, shape, surface chemistry, topology, and flexibility from atoms to macroscopic matter" Angewandte Chemie—International Edition in English (1990) 29 (2): 138-175; Bosman et al., "About dendrimers: Structure, physical 5 properties, and applications" Chemical Reviews (1999) 99 (7): 1665-1688; Fischer and Vogtle, "Dendrimers: From design to application—A progress report," Angewandte Chemie-Intemational Edition (1999) 38(7): 885905 ; Roovers and Comanita, "Dendrimers And dendrimer-Polymer Hybrids," Advances In Polymer Science (1999) 142:179-228 ; Smith and Diederich, "Functional dendrimers: Unique Biological 35 Pharmaceutical Science and Technology Today (1999) 2 (10): 393401; Verprek and Jezek "Peptide and glycopeptide dendrimers Part 1,." Journal of Peptide Science (1999) 5 (1): 5-23: Veprek and Jezek, " Peptide and glycopeptide dendrimers Part II, "JournalOf Peptide Science (1999) 5 (5) 203-20; Tomalia et al" "Starburst dendrimers:. Molecular-level control of size, shape, surface chemistry, topology, and flexibility from atoms to macroscopic matter "Angewandte Chemie-International Edition in English (1990) 29 (2):. 138-175; Bosman et al," About dendrimers: Structure, physical 5 properties, and applications "Chemical Reviews (1999) 99 (7): 1665-1688; Fischer and Vogtle, "Dendrimers: From design to application-A progress report," Angewandte Chemie-Intemational Edition (1999) 38 (7): 885905; Roovers and Comanita, "Dendrimers and dendrimer-Polymer Hybrids," Advances In Polymer Science (1999) 142: 179-228; Smith and Diederich, "Functional dendrimers: Unique Biological

10 Mimics," Chemistry—A European Journal (1998) 4(8): 1353-1361;禾卩Matthews et al., "Dendrimers—Branching out from curiosities into new technologies," Progress In Polymer Science (1998) 23(1): 1-56。树枝状大分子的合成通常使用反复的合成循环,这使得可以对树枝状大分子的尺寸、形状、表面化学、弹性和内部拓扑结构进行控制。适合用作连接实体的树枝状大分子的例子描述于Wu et al., 10 Mimics, "Chemistry-A European Journal (1998) 4 (8):. 1353-1361; He Jie Matthews et al," Dendrimers-Branching out from curiosities into new technologies, "Progress In Polymer Science (1998) 23 (1 ): 1-56 synthesis of dendrimer synthesis cycle is generally used repeatedly, which makes it possible to control the size of the dendrimer, the shape, surface chemistry, flexibility and topology suitable for use as an internal branch connected entities. examples of macromolecules like described in Wu et al.,

15 "Metal-Chelate-dendrimer-Antibody Constructs for Use in Radioimmunotherapy and Imaging," Bioorganic and Medicinal Chemistry Letters (1994)4 (3):449-454中。 15 "Metal-Chelate-dendrimer-Antibody Constructs for Use in Radioimmunotherapy and Imaging," Bioorganic and Medicinal Chemistry Letters (1994) 4 (3): 449-454 in.

[99]通过利用各种化学结合技术来结合导向实体和治疗实体,树枝状大分子可方便地被用作连接载体。 [99] bonded via bonding techniques using various chemical and physical treatment of solid guide, dendrimers can be conveniently used as a connection carrier. 例如在美国专利6,020,457中,公开了在它的核心中具有二20 硫(--S--S—)键的树枝状大分子,树枝状大分子可以通过该美国专利中描述的方法构建而得。 For example, in U.S. Patent No. 6,020,457 discloses 20 having two sulfur in its core - dendrimers (--S S-) bonds, dendrimers can be obtained by constructing method described in U.S. Pat. . 树枝状大分子的最终外层可以用活性基团诸如胺基团或羧基基团加帽(封端)。 The final outer layer may be a dendrimer reactive groups such as amine groups or carboxyl groups capped (blocked). 这些活性基团然后或者可以用导向实体或者可以用治疗实体(或在一些情况下用两者的混合物)进行衍生化处理。 These reactive groups can then guide or entity or entities can be treated (or a mixture of both, in some cases) for derivatization.

25 [100]用于本发明目的的树枝状大分子是分支的聚合物,其是三维上高度有序的化合物,其中分支的寡聚/多聚序列通过反复的反应次序形成于核分子(nuclear molecule)的周围,其在某些条件下具有带正电的外表面,这是合适的功能性末端基团所导致的(聚阳离子树枝状大分子)。 Dendrimers 25 [100] for the purposes of the present invention is a branched polymer which is three-dimensionally highly ordered compounds, wherein branched oligomeric / polymeric sequences of molecules formed in the core (nuclear reaction sequence by repeated around the molecule), and an outer surface having a positively charged under certain conditions, which is suitable functional end groups resulting from (polycationic dendrimer). 这类树枝状大分子和它们的制备方法描述于WO 84/02705、美国专利4,507,466、 4,558,120、 4,568,737、 4,587,329、 4,631,337、 Such dendrimers and their preparation are described in WO 84/02705, U.S. Patent No. 4,507,466, 4,558,120, 4,568,737, 4,587,329, 4,631,337,

30 4,694,064、 4,713,975、 4,737,550、 4,871,779、 4,857,599、 EP 0 234 408、 EP 0 247 629、 EP 0 271 180中,以及特别是描述在Tange et al., supra、 WO 95/02397和Tomalia et al" supra中o 30 4,694,064, 4,713,975, 4,737,550, 4,871,779, 4,857,599, EP 0 234 408, EP 0 247 629, EP 0 271 180, and in particular are described in the Tange et al., Supra, WO 95 / 02397 and Tomalia et al "supra in o

[101]适合于本发明的树枝状大分子包括,例如,聚酰胺胺(polyamidoamine) 35 (PAMAM)树枝状大分子,其可以通过逐步加入两种单体:异丁烯酸盐(酯)和乙二胺,围绕着作为核心分子的氨、三-(2-氨基乙基)胺(TAEA)或乙二胺(EDA)合成(Tang et al., supra)。 [101] suitable for the present invention include dendrimers, e.g., polyamidoamines (polyamidoamine) 35 (PAMAM) dendrimers, which by stepwise addition of the two monomers: methacrylic acid (ester) and ethylene amines, ammonia as around the core molecule, tris - (2-aminoethyl) amine (TAEA) or ethylenediamine (EDA) synthesis of (Tang et al, supra.). 此类树枝状大分子的末端基团优选伯胺基团。 Such dendrimer terminal groups are preferably primary amine groups. 优选第5、第6、第7代PAMAM树枝状大分子,特别是第6代PAMAM树枝状大分子,参见Tang et al., supm.。 Preferably the fifth, sixth, seventh generation PAMAM dendrimer, particularly the 6th generation PAMAM dendrimers, see Tang et al., Supm .. 此类PAMAM树枝状大分子的理论分子量、末端胺的数量和流体动力学半径可以参见Tang et al., supra的公开内容。 Such theoretical molecular weight PAMAM dendrimers, the number of terminal amine and the hydrodynamic radius can be found in Tang et al., The disclosure supra. 表1显示了胺功能PAMAM树枝状大分子的特性。 Table 1 shows the characteristics of the amine functional PAMAM dendrimers. 表l. Table l.

<table>table see original document page 29</column></row> <table>[102]可以被使用的树枝状聚合物一般包括任何已知的树枝状结构,包括树枝状大分子、规则树突(dendron)、受控超分支化聚合物(controlled hyperbranched <Table> table see original document page 29 </ column> </ row> <table> [102] A dendrimer may be used generally include any known dendritic structures, including dendrimers, dendritic rules (dendron), controlled hyperbranched polymers (controlled hyperbranched

10 polymer)、树状枝嫁接物(dendrigmfts)和随机超分支化聚合物。 10 polymer), tree branch graft (dendrigmfts) and random hyperbranched polymers. 树枝状聚合物是具有密集分支结构的聚合物,具有大量的活性基团。 Dendrimers are polymers with densely branched structures having a large number of reactive groups. 树枝状聚合物包括若干层或若干代的重复单位,其都含有一个或多个分支点。 Dendrimers comprise several layers or several generations of repeating units which all contain one or more branch points. 树枝状聚合物——包括树枝状大分子和超分支化聚合物——通过具有至少两个活性基团的单体单位的缩合反应制备而得。 Dendrimer - including dendrimers and hyperbranched polymers - prepared obtained by a condensation reaction of at least two monomers having a reactive group units. 可以使用的树枝状大分子包括那些由许多树突构成的树枝状大分子, Dendrimers that may be used include those dendrimers constituted by a number of dendrites,

15 所述许多树突由共同的核心散发(emanate)出来,该核心可以是单个原子或一组原子。 Many of the 15 by a common core for distributing dendrites (Emanate) out, the core may be a single atom or group of atoms. 每个树突通常包括末端表面基团、具有大于或等于两个的分支功能基团(branching functionalities)的内部分支结合点(interior branch junctures )、禾卩共价连接到附近的分支接合点的二价连接物(connectors)。 Each terminal typically includes a dendritic surface groups, branched functional groups having greater than or equal to two (branching functionalities) binding site of the inner branch (interior branch junctures), Wo Jie covalently connected to a branch near the junction of the two divalent linker (connectors).

20 [103]可以被使用的超分支化聚合物代表了一类树枝状聚合物,相比起几乎完全规则结构的树突和树枝状大分子,其含有高水平的非理想的不规则分支。 20 [103] The hyperbranched polymers can be used to represent a class of dendritic polymer, compared to almost completely regular dendritic structure and dendrimers, which contain high levels of non-ideal irregular branching. 具体而言, 超分支化聚合物含有数量相对大的不规则分支区域,其中,不是每个重复单位都含有分支结合点。 Specifically, hyperbranched polymers contain a relatively large number of irregular branching areas in which not every repeat unit contains a branch juncture. 树枝状大分子、树突、随机超分支化聚合物、受控超分支化聚合物和树状枝嫁接物的制备和表征是公知的。 Dendrimers, dendritic, random hyperbranched polymers, controlled preparation and characterization of dendrimers and hyperbranched polymers graft branches are well known. 树枝状大分子和树突,合成它们的 Dendrimers and dendritic synthesis thereof

25 方法的例子描述于美国专利4,410,688、 4,507,466; 4,558,120; 4,568,737; 4,587,329; 4,631,337; 4,694,064; 4,713,975; 4,737,550; 4,871,779和4,857,599。 Examples of the method 25 described in U.S. Patent 4,410,688, 4,507,466; 4,558,120; 4,568,737; 4,587,329; 4,631,337; 4,694,064; 4,713,975; 4,737,550; 4,871,779 and 4,857,599. 超分支化聚合物和制备它们的方法的例子例如描述于美国专利5,418,301中。 Examples of hyperbranched polymers and methods for their preparation are described in U.S. Patent No. 5,418,301, for example, in.

[104]适合用于本发明的树枝状聚合物也包括大分子,通常指级联分子(cascade molecule)、 arborols、树状枝接分子(arborescent grafted molecules)和类似物。 [104] Suitable dendritic polymers used in the present invention also include macromolecules commonly referred to as cascaded molecule (cascade molecule), arborols, grafted dendrimer molecule (arborescent grafted molecules) and the like. 合5 适的树枝状聚合物也包括桥式树枝状聚合物(bridged dendritic polymer),即,或 Suitable dendrimers together 5 also includes a bridge dendrimer (bridged dendritic polymer), i.e., or

者通过表面功能基团连接在一起或者通过将表面功能基团连接在一起的连接分子连接起来的树枝状大分子,和通过物理力结合在一起的树枝状聚合物聚集体。 By dendrimer aggregates are surface functional groups or are joined together by a connecting surface functional groups together are connected together dendrimer molecules, and joined together by physical forces. 也包括球形树枝状聚合物和杆形树枝状聚合物,它们由聚合物核心生长而来。 And also includes a rod-shaped dendrimer spherical dendrimers, are grown from a polymeric core.

10 [105]美国专利5,338,532教导了包括密致星型聚合物(dense star polymers)的聚合物结合物,密致星型聚合物与载体材料相联系,该专利的公开内容通过引用方式引入本文。 10 [105] U.S. Patent No. 5,338,532 teaches polymer comprises a dense star polymer (dense star polymers) combinations, dense star polymer associated with the support material, the disclosure of which is incorporated by reference herein incorporated. (一种类型的密致星型聚合物是Starburst™聚合物(The Dow Chemical Company的商标),其中树枝状大分子是聚酰胺胺(PAMAM))。 (One type of dense star polymer is a Starburst ™ polymers (trademark of The Dow Chemical Company), wherein the dendrimer is a polyamidoamine (PAMAM)). 此类结合物的各种合适的应用论述于美国专利5,338,532中,该专利包括将这些结合物用作生物活性 Various suitable combinations of such applications are discussed in U.S. Patent No. 5,338,532, which patent is used as the biological activity of these combinations

15 试剂的传递载体。 15 agent delivery vehicle. 美国专利5,338,532例举了零价态金属和离子金属或放射性金属的应用,特别举例了Fe、 Rh、 Pd、 Y、 Fn、 Pb、 Gd、 Mn禾BGd。 U.S. Patent No. 5,338,532 include a zero valence state metal or radioactive metal ions and metal applications, in particular for example the Fe, Rh, Pd, Y, Fn, Pb, Gd, Mn Wo BGd.

[106]适合用于本发明的树枝状聚合物也包括大分子,通常指级联分子(例如E. Buhleier et al., Synthesis 155-158 (Feb. 1978); arborols (例如美国专利5,376,690和 [106] Suitable dendritic polymers used in the present invention also include macromolecules commonly referred to as cascaded molecule (e.g. E. Buhleier et al, Synthesis 155-158 (Feb. 1978);. Arborols (e.g. U.S. Patent No. 5,376 , 690 and

20 5,210,309); 树状枝接分子;tectodendrimer (例如Srinivas Uppuluri et al., "Tecto(endrimer) Core-shell Molecules: Macromolecular Tectonics for the Systematic Synthesis of Larger Controlled Structure Molecules" PMSE, Spring Meeting (Mar. 21-25,1999) 55-56)和类似物。 20 5,210,309); grafted dendrimer molecules; tectodendrimer (e.g. Srinivas Uppuluri et al,. "Tecto (endrimer) Core-shell Molecules: Macromolecular Tectonics for the Systematic Synthesis of Larger Controlled Structure Molecules" PMSE, Spring Meeting (Mar. 21- 25,1999) 55-56) and the like. 合适的树枝状聚合物也包括桥式树枝状聚合物,艮P, 或者通过表面功能基团或者通过将表面功能具体连接在一起的连接分子而连接在 Suitable dendritic polymers also include bridged dendritic polymers, Gen P, or are connected by a surface functional groups or through a linker molecule connected to the specific surface functional

25 —起的树枝状大分子,和通过物理力固定在一起的树枝状聚合物聚集体。 25 - from the dendrimer, and held together by physical forces dendrimer aggregates. 也包括球形树枝状聚合物(例如美国专利4,507,466; 4,588,120; 4,568,737; 4,631,337; 4,587,329和4,737, 550,它们的公开内容通过参考引入本文)和杆形树枝状聚合物(例如美国专利4,694,064,它们的公幵内容通过参考引入本文),其从聚合物核心生长而得。 Also includes a spherical dendritic polymers (e.g., U.S. Patent No. 4,507,466; 4,588,120; 4,568,737; 4,631,337; 4,587,329 and 4,737, 550, the disclosures of which are incorporated herein by reference) and rod-shaped dendritic polymers (e.g., U.S. Patent No. 4,694,064, which Jian well incorporated herein by reference), which is derived from the growth of the core polymer. 适用于本发明的其他树枝状聚合物包括所有的基本树枝状结构,其中特 Other suitable dendrimers of the present invention include all the basic dendritic structures, wherein Laid

30 定的螯合基团或部分位于树枝状大分子的中心核心中,和/或位于树突臂的内部结构内,和/或位于树枝状大分子的表面上。 Chelating groups given 30 or the center core portion is located in the dendrimer, and / or within the internal structure of arms of the dendrites, and / or on the surface of the dendrimer. 将会被理解的是,所有上述这些树枝状大分子术语都被包括在术语"树枝状聚合物(dendritic polymer)"中。 It will be appreciated that all of these terms dendron are included in the term "dendritic polymer (dendritic polymer)" in.

[107]用于本发明的实践的树枝状聚合物包括那些具有对称分支单元(symmetrical 35 branch cells)的树枝状聚合物(臂长相等,例如PAMAM树枝状大分子;例如描述于美国专利5,527,524中的那些)和那些具有不对称的支分单元的树枝状聚合物(臂长不相等,例如赖氨酸-分支树枝状大分子,例如描述于美国专利4,410,688中的那些),分支树枝状大分子,级联分子(例如E. Buhleier et al., Synthesis 155-158 (Feb.1978)), arborols(例如美国专利5,376,690禾B 5,210,309)和类似物。 [107] Dendrimers used in the practice of the present invention include those dendrimers (arms of equal length having a symmetrical branching unit (symmetrical 35 branch cells), for example, PAMAM dendrimers; for example described in U.S. Patent No. 5,527,524 those) and those having a branched dendrimer of asymmetric division unit (unequal arm length, e.g. lysine - branched dendrimers, such as those described in U.S. Patent No. 4,410,688), branched dendrimers , cascade molecules (e.g. E. Buhleier et al., Synthesis 155-158 (Feb.1978)), arborols (e.g. U.S. Patent No. 5,376,690 Wo B 5,210,309) and the like.

[108]用于本发明的实践的树枝状聚合物可以是世代上单分散性(generationally 5 monodisperse)的或世代上多分散性的(generationally polydisperse)。 [108] The dendrimers used in the practice of the present invention may be a monodisperse (generationally 5 monodisperse) the generation or generations polydispersity (generationally polydisperse). 在单分散性溶液中的树枝状聚合物基本上是同代的,并因此尺寸和形状一致。 Dendrimers in a monodisperse solution are substantially of the same generation, and thus the size and uniform shape. 在多分散性溶液中的树枝状聚合物包括分布有不同代聚合物。 Dendrimers polydispersity solution include polymers distributed in different generations. 可以用于本发明的实践的树枝状聚合物分子包括由不同的内部和外部组成或功能基团组成的混合物。 Dendrimer molecules may be used in the practice of the present invention include mixtures of different interior and exterior composition or functionality group consisting of. 合适的树枝状聚合物的例子包括聚(醚)树突,树枝状大分子和超分支化聚合物,聚(酯)树突, 10 树枝状大分子和超分支化聚合物,聚(硫醚)树突,树枝状大分子和超分支化聚合物, 聚(氨基酸)树突,树枝状大分子和超分支化聚合物,聚(芳基亚垸基醚(arylalkylene ether))树枝状聚合物和聚丙胺树枝状大分子,树枝状大分子和超分支化聚合物。 Examples of suitable dendritic polymers include poly (ether) dendritic, dendrimers and hyperbranched polymers, poly (ester) dendrites, 10 dendrimers and hyperbranched polymers, poly (thioether ) dendrites, dendrimers and hyperbranched polymers, poly (amino acids) dendrites, dendrimers and hyperbranched polymers, poly (arylalkylene ether embankment (arylalkylene ether)) dendrimer and poly-propylamine dendrimers, dendrimers and hyperbranched polymers. 已经发现,聚(酰胺胺)(PAMAM)树枝状大分子在制备本发明的含金属的复合物中特别有用。 It has been found, poly (amidoamine) (of PAMAM) dendrimers are particularly useful in the preparation of metal-containing composite of the present invention.

15 15

[109]被认为在本发明的实践中最有用的树枝状聚合物是近似单分散性的。 [109] are considered most useful in the practice of the present invention, the dendrimer is approximately monodisperse. 也就是说,优选在单分散性溶液中的树枝状聚合物,在单分散性溶液中所有的树枝状聚合物分子基本上是同一代的,并因此在尺寸和形状上是一致的。 That is, preferably dendrimers in a monodisperse solution, in a monodisperse solution are substantially all of the dendrimer molecule is the same generation, and thus are in the same size and shape. 特别优选树枝状大分子的单分散性溶液。 Particularly preferred dendrimers monodisperse solution.

20 20

[110]优选用于本发明的实践的树枝状聚合物具有末端功能基团,其对于含有螯合 [110] Preferred dendritic polymers used in the practice of the present invention have terminal functional groups, which contain for chelating

剂的化合物是可接触的,其能够与功能基团相互作用。 Agent compound is contacted, which is capable of interacting with functional groups.

[111]术语"功能基团(functional group)"旨在包括这样的基团诸如酯基团、醚基25 团、硫醇基团、羰基基团、羟基基团、酰胺基团、羧基基团和酰亚胺基团以及它们的组合。 [111] The term "functional group (functional group)" is intended to include groups such as ester groups, ether groups 25 groups, thiol groups, carbonyl groups, hydroxyl groups, amide groups, carboxyl groups and imide groups, and combinations thereof. 以胺为末端的聚酰胺胺、聚乙烯亚胺和聚丙烯亚胺树枝状大分子也是已知的,例如来自美国专利5,393,797; 5,393,795; 5,560,929;和5,387,617,所有这些专利都属于Hedstrand等。 Amine-terminated polyamidoamine, polyethyleneimine and polypropyleneimine dendrimers are also known, for example from U.S. Patent No. 5,393,797; 5,393,795; 5,560,929; and 5,387,617, all of which belong to Hedstrand Wait.

30 [112]可以掺入任意的连接树枝状大分子(linkingdendrimers),以增加钇附着位点的多价性。 30 [112] can be incorporated into any connection dendrimer (linkingdendrimers), to increase the polyvalent yttrium attachment site. 微球体表面可以已经含有可以附着钇螯合剂的多个位点。 Microsphere surface may have a plurality of sites containing a chelating agent may be attached yttrium. 然而,因为微球体的表面可以是刚性的,化学修饰是困难的反应。 However, since the surface of the microspheres may be rigid, it is difficult to chemical modification reaction. 因此,可能需要连接物来增加与球体表面之间的距离,以有助于与螯合剂进行反应。 Thus, the linker may be necessary to increase the distance between the surface of a sphere, to facilitate reaction with a chelating agent. 如果在球体表面获得的是螯合剂的次优浓度,则可以附着连接物。 If the surface of the sphere is obtained in the suboptimal concentration of chelating agent, the linker may be attached.

35 35

树枝状大分子的尺寸 Dendrimer size

[113]通常,通过多功能单体的逐步反应或反复反应,获得分支结构,从而制备得到树枝状大分子。 [113] Generally, by stepwise reaction of multifunctional monomers or repeated reaction, a branched structure, thus preparing dendrimers. 例如,在美国专利5,530,092中,以一级二胺(primary diamine) 起始,对丙烯腈反复进行双迈克尔加成反应(double Michael addition),然后进行加氢反应,每一个起始胺获得两个一级胺。 For example, in U.S. Patent No. 5,530,092 in order to a diamine (primary diamine) starting acrylonitrile repeating double Michael addition reaction (double Michael addition), followed by hydrogenation reaction, each of the two obtained starting amine an amine. 这使得一级胺基团的数目加倍。 This enables doubling the number of primary amine groups. 因此, 以二胺起始,在外壳中,第一代树枝状大分子(G1)具有4个一级胺;第二代(G2) 5 具有8个一级胺;第三代(G3)具有16个一级胺;第四代(G4)具有32个一级胺;第五代(G5)具有64个一级胺,以此类推。 Therefore, the starting diamine in the housing, a first-generation dendrimer (G1) with a 4-amine; second generation (G2) 5 primary amines having 8; third generation (G3) having primary amine 16; fourth generation (G4) 32 having a primary amine; fifth generation (G5) having a primary amine 64, and so on. 这些聚胺树枝状大分子可以说对于水解反应中的降解作用是稳定的。 These polyamines can be said for the dendrimer hydrolysis degradation reaction is stable.

[114]可以用于本发明的实践的树枝状聚合物的代数,以及树枝状聚合物的尺寸的10 变化可以相当大。 [114] algebraic dendrimer can be used in the practice of the present invention, and 10 of varying sizes can be quite large dendrimer. 例如,3.5代的聚(酰胺胺)树枝状大分子(3.5 PAMAM)可以用于本发明的实践。 For example, generation 3.5 poly (amidoamine) dendrimers (of PAMAM 3.5) may be used in the practice of the present invention. 然而,更高或更低代数的树枝状聚合物也可以有望用于本发明, 但是具有乙二胺(EDA)核心的、代数在3.5至7.5范围内的PAMAM树枝状大分子是特别有用的。 However, higher or lower algebraic dendrimer used in the present invention may also be expected, but with ethylenediamine (EDA) core, PAMAM dendrimer algebraic within the range of 3.5 to 7.5 is particularly useful.

15偶联到连接载体的方法 15 coupled to a method of connecting a carrier

[115]该方法旨在将效应物共价附着到连接载体。 [115] This method is intended to effector covalently attached to the connection support. 利用连接载体的表面和效应物之间的连接物部分,该共价附着作用可以直接在连接载体表面和效应物之间进行。 Using a linker connecting portion between the support surface and effectors, the covalent attachment may be carried out directly between the carrier surface and connected to the effector. 一些可以使用的连接物描述于美国专利5,527,524; EP 0353450; EP 0570575;和EP 0296522中,这些专利的公开内容通过参考并入本文。 Some linkers may be used are described in U.S. Patent No. 5,527,524; EP 0353450; EP 0570575; and EP 0296522, the disclosures of which are incorporated herein by reference.

20 20

[116] —般地,在连接载体和效应物,以及可任选地,和间隔基团之间形成连接之前,至少其中一个化学官能基团将被激活。 [116] - camel, before forming the connector, wherein the at least one chemical functional group to be activated in the connection between the support and the effects thereof, and optionally, and spacer groups. 本领域普通技术人员将认识到,使用各种标准方法和条件,各种化学官能基团,包括羟基、氨基和羧基可以被激活。 Those of ordinary skill in the art will recognize that a variety of standard methods and conditions used, various chemical functional groups include hydroxy, amino and carboxyl groups can be activated.

25 [117]典型地,使用标准的化学技术,通过它们各自的化学官能基团,试剂共价连接到连接载体上。 25 [117] Typically, using standard chemical techniques through their respective chemical functional groups, the agent is covalently attached to the connection carrier. 可任选地,连接载体或试剂通过一个或多个间隔基团偶联到试齐U。 Optionally, the carrier is connected to the test reagent is coupled together or one or more spacer groups U. 当组合使用时,间隔基团可以是相同或不同的。 When used in combination, spacer groups may be the same or different. 同样地,如果一个以上的连接载体被用于产生试剂-连接载体复合物,树枝状大分子可以是相同或不同的。 Similarly, if more than one connection is used to generate reagent carrier - connected carrier complex, dendrimer may be the same or different.

30 [118]在某些实施方案中,在组装连接载体或连接载体的结合物的一步或多步反应期间,将一个或多个活性基团保护起来。 30 [118] In certain embodiments, one or more steps during assembly of the connector or the connection carrier carrier conjugates, one or more reactive groups protected. 本领域技术人员知道如何保护特定的功能基团,以便它不与选定的一组反应条件进行反应。 Those skilled in the art will know how to protect a particular functional group, so it does not react with a selected set of reaction conditions. 有用的保护基团的例子,例如参见Greene et al., Protective Groups in Organic Synthesis, John Wiley & Sons, New York,簡。 Examples of useful protecting groups, see, e.g., Greene et al., Protective Groups in Organic Synthesis, John Wiley & Sons, New York, Jane.

35 35

[119]通过本领域普通技术人员熟知的许多方法中的任何方法,效应物分子可以附着到连接载体。 [119] by any of numerous methods well known to those of ordinary skill in the effector molecules can be attached to the connection carrier. 通常,效应物或者直接或者通过树枝状大分子或其他连接物(间隔物)结合到微颗粒上。 Typically, either directly or effectors coupled to the microparticle or other dendrimer through a linker (spacer) on.

[120]可选择地,微颗粒和/或间隔物可以进行衍生化,以暴露或附着额外的活性功能基团。 [120] Alternatively, microparticles and / or spacers may be derivatized to expose or attaching additional active functional groups. 衍生化作用可以涉及附着许多连接物分子中的任何连接物分子,诸如5 那些来自Pierce Chemical Company, Rockford 111的连接物分子。 Derivatization may involve any of a number of linker molecules attached to a linker molecule, such as those 5, Rockford linker molecule from Pierce Chemical Company 111's.

[121]具有两个与特定效应物上的基团起反应的功能基团的双功能连接物可以用来形成期望的结合物。 [121] having the two groups on specific effector from a bifunctional linker reactive functional groups may be used to form the desired conjugate.

10 [122]用于将各种化合物附着到蛋白质诸如抗体的许多方法和连接物分子是已知的(例如参见欧洲专利申请188,256;美国专利4,671,958、 4,659,839、 4,414,148、 4,699,784、 4,680,338、 4,569,789和4,589,071;和Borlinghaus et al.(1987)Cancer Res. 47:4071-4075),所述的各种化合物包括放射性核素金属螯合剂,毒素和药物。 Various compounds 10 [122] for attaching to a number of methods, such as protein and a linker molecule an antibody are known (e.g. see European Patent Application 188,256; U.S. Patent No. 4,671,958, 4,659,839, 4,414,148, 4,699,784, 4,680,338, 4,569,789 and 4, 589,071; and Borlinghaus et al (1987) Cancer Res 47: 4071-4075), according to various compounds including radionuclide metal chelates, toxins and drugs...

15 间隔基团(Spacer Groups) 15 spacer group (Spacer Groups)

[123]在连接载体和治疗剂之间可以任意地引入一个或多个间隔基团。 [123] connected between the carrier and the therapeutic agent may be incorporated in any one or more spacer groups. 间隔基团含有至少两个化学官能基团。 Spacer groups contain at least two functional chemical groups. 典型地,间隔基团的一个化学官能基团结合到连接载体的化学官能基团上,而间隔基团的另一个化学官能基团用于结合到治疗剂的化学官能基团上。 Typically, a chemical functional group of the spacer group is chemically bonded to the functional groups connected to the carrier, and the other functional chemical groups spacer groups for binding to the chemically functional groups of the therapeutic agent. 间隔基团的化学官能基团的例子包括羟基、巯基、羰基、羧基、 20 氨基、酮和巯基基团。 Examples of chemical functional groups of the spacer groups include a hydroxyl group, a mercapto group, a carbonyl group, a carboxyl group, an amino group 20, and one mercapto group. 间隔基团也可以联合使用。 Spacer groups may be used in combination. 当联合使用间隔基团时,间隔基团可以是相同的或不同的。 When used in conjunction with a spacer group, the spacer group may be the same or different. 间隔基团是可任选的部分,其可以被引入以增加连接物的长度,这样,它进一步与微球体表面间隔开来,从而产生灵活性,并有助于与放射性核素(即,钇)的螯合剂反应。 Spacer group is optionally portion, which may be introduced to increase the length of the linker, so that it is further spaced apart from the surface of the microsphere, thereby generating flexibility and help with a radionuclide (i.e., yttrium ) the reaction of a chelating agent.

25 [124]无论是直接偶联或通过间隔物偶联,试剂优选通过共价键偶联到连接载体。 25 [124] coupled either directly or through a spacer coupling agent is preferably coupled by a covalent bond to the connection carrier. 共价键可以是非可逆性,部分可逆性的,或完全可逆性的。 Covalent bond may be non-reversible, partially reversible, or completely reversible. 可逆度与试剂-连接载体复合物(agent-linking carrier complex)对体内降解的敏感性(susceptibility)相对应。 With a reagent of reversible - sensitivity (susceptibility) of the connection carrier degradation in vivo complex (agent-linking carrier complex) correspond. 对本领域技术人员显而易见的是,此种可逆基团能够掺入到连接载体-试剂结合物的任何位置。 Apparent to those skilled in the art that such a group can be incorporated into a reversible connection Vector - any agent conjugate position. 引入具有可逆连接的间隔臂(spacer arm)只是示范性的实施 Introducing a spacer arm having a reversible connection (spacer arm) merely exemplary embodiments

30 方案;试剂和树枝状大分子之间的键例如也可以是可逆的。 30 embodiment; the bond between the agent and the dendrimer, for example, may be reversible.

[125]试剂-连接载体复合物对降解的敏感性可以通过研究复合物水解或酶法转化为未结合的药剂而得以确认。 [125] Reagents - connecting carrier complex susceptibility to degradation can be converted to an agent unbound complex by hydrolysis or enzymatic studies and were confirmed. 总之,使用该方法,发现体外和体内活性之间良好的相关性。 In summary, the use of this method, it was found good correlation between in vitro and in vivo activity. 参见Phipps et al J. Pharm. Sciences 78: 365 (1989)。 See also Phipps et al J. Pharm Sciences 78:. 365 (1989). 例如通过分光光度分35析法或通过气-液或高压液相色谱法,可以容易地确定转化率。 E.g. 35 minutes analysis by spectrophotometric methods or by gas - liquid or high pressure liquid chromatography, the conversion rate can be easily determined. 然后,使用标准技术,半衰期和其他动力学参数可以计算出来。 Then, using standard techniques, half-life and other kinetic parameters can be calculated. 参见Lowryetal. MECHANISM AND THEORY IN ORGANIC CHEMISTRY, 2nd Ed" Harper & Row, Publishers, New York(1981)。 See Lowryetal. MECHANISM AND THEORY IN ORGANIC CHEMISTRY, 2nd Ed "Harper & Row, Publishers, New York (1981).

效应物 Effector

[126]连接载体可以连接到用于治疗或鉴定疾病组织的各种效应物上。 [126] connected to the support may be connected to various effector for treating or identifying diseased tissue. 优选地,偶5 联到聚合物共轭物(polymerconjugate)的效应物选自治疗剂或诊断剂。 Preferably, the coupling 5 linked to polymer conjugate (polymerconjugate) effector selected therapeutic or diagnostic agent.

[127]用于本发明的治疗剂的例子包括但是不限于金属螯合复合物、药物、药物前体、放射性核素、硼附加物、标记化合物、毒素和其他效应物分子,诸如细胞因子、淋巴因子、趋化因子、免疫调节剂、辐射敏化剂、门冬酰胺酶、硼附加物和10 放射性卤素。 [127] Examples of therapeutic agents for the present invention include, but are not limited to, metal chelate complexes, drugs, prodrugs, radionuclides, boron addend, labeled compounds, toxins and other effector molecules, such as cytokines, lymphokines, chemokines, immunomodulators, radiosensitizers, asparaginase, 10 boron addend and a radioactive halogen. 优选地,可以结合到聚合物主架上的治疗剂选自治疗用放射性同位素、毒素、药物、药物前体和硼附加物。 Preferably, the therapeutic agent may be incorporated into the polymer main frame of the selected therapeutic radioisotopes, toxins, drugs, drug precursors and boron addend.

[128]用于本发明的药物包括但不限于任何现在批准或还未批准的化学治疗药物, 只要它能够附着到聚合物结合物(polymerconjugate)上就可以。 [128] The medicament used in the present invention include, but are not limited to any chemotherapeutic drug now approved or approved yet, as long as it can be attached to the polymer conjugate (polymerconjugate) can be. 典型的可用的已 Typical already available

15 经批准的药物包括但不限于下述试剂和这些试剂的衍生物:阿那曲唑(anasta)zole)、氮杂胞苷、争光霉素、二甲磺酸丁酯、碳铂、双氯乙亚硝脲、苯丁酸氮芥、顺铂、克拉屈滨、环磷酰胺、阿糖胞苷、达卡巴嗪、放线菌素D、柔红霉素、多烯紫杉醇(docetaxd)、阿霉素、雌二醇氮芥、依托泊苷、氟尿脱氧核苷、阿糖氟腺嘌呤、氟尿嘧啶、氟硝丁酰胺、吉西他滨、羟基脲、盐酸去甲柔红 15 approved drugs include, but are not limited to derivatives of these agents and the following reagents: anastrozole (anasta) zole), azacytidine, bleomycin, busulfan, carboplatin, diclofenac B nitrosourea, chlorambucil, cisplatin, cladribine, cyclophosphamide, cytarabine, dacarbazine, actinomycin D, daunorubicin, docetaxel (docetaxd), doxorubicin Su, estramustine, etoposide, fluorouracil deoxynucleoside, fluoro adenine arabinoside, fluorouracil, flutamide, gemcitabine, hydroxyurea, daunorubicin phenylpropanolamine hydrochloride

20 霉素、异环磷酰胺、伊立替康、氯乙环己亚硝脲、双氯乙基甲胺、甲地孕酮、美法仑、巯基嘌呤、氨甲碟呤、丝裂霉素、氯苯二氯乙烷、米托蒽醌、紫杉醇(paditaxel)、 喷司他丁、甲苄肼、他莫昔芬、替尼泊甙、硫鸟嘌呤、三胺硫磷、羟基喜树缄、 长春碱、长春新碱和长春瑞滨。 20 doxorubicin, ifosfamide, irinotecan, chloroethyl cyclohexyl nitrosourea, mechlorethamine, megestrol, melphalan, mercaptopurine, methotrexate, mitomycin, dichloroethane, chlorobenzene, mitoxantrone, taxol (paditaxel), pentostatin, procarbazine, tamoxifen, teniposide, thioguanine, thiotepa, hydroxy acuminata seal, vinblastine, vincristine, and vinorelbine.

25 [129]此外,聚合物结合物可以包括治疗剂,治疗剂由在硼中子俘获治疗(Boron Neutron Capture Ther叩y) (BNCT)方案中使用的硼附加物组成。 25 [129] In addition, the polymer conjugate may comprise a therapeutic agent, the therapeutic agent in boron neutron capture therapy (Boron Neutron Capture Ther knock y) boron addend (BNCT) scheme used in the composition. BNCT是二进制系统,设计用来将电离辐射传递到肿瘤细胞,这通过肿瘤定位的硼-10原子的中子辐射进行。 BNCT is a binary system designed to be passed to the tumor cells by ionizing radiation, by which the neutron tumor localization radiation of boron-10 atoms. BNCT基于核反应,当稳定的同位素,即同位素富集的B-10(以19.8。/。的自然丰度存在)用热中子照射产生a颗粒和Li-7核子时发生核反应。 BNCT, based on the nuclear reaction of nuclear reaction occurs when a stable isotope, i.e., isotopically enriched B-10 (present in the natural abundance 19.8./.) Of generating a nuclear particle and a Li-7 is irradiated with thermal neutrons. 这些颗粒的径 The diameter of these particles

30 长约一个细胞的直径那么长,从而产生高线性能量转移(linear energy tr咖fer)。 A diameter of about 30 cells so long, resulting in high linear energy transfer (linear energy tr coffee fer). 仅需少数在该核反应中产生的短程1.7 MeV a颗粒就足以靶向细胞核并破坏细胞核。 Only a few short-range produced in the nuclear reaction in the 1.7 MeV a nucleus particles are sufficient to target and destroy cell nucleus. 对癌症成功地进行BNCT,需要将高浓度的硼-10定位在肿瘤位置的方法,与此同时使得非耙向器官基本上无硼。 BNCT of cancers successful, requires a high concentration of boron in the method of locating tumor -10 position, at the same time so that the non harrow organs essentially boron-free. 使用用于BNCT的预先靶向msAb (pre-targeting msAb)来治疗患者肿瘤的组合物和方法描述于美国专利6,228,362 BNCT is used for pre-targeting methods and compositions msAb (pre-targeting msAb) for treating cancer patients is described in U.S. Patent 6,228,362

35 中,并根据本发明可以容易地进行修改,该专利通过参考并入本文。 35, and it can be easily modified according to the present invention, which is incorporated herein by reference. 此外,其他元素也适用于中子俘获反应(neutron capture reactions)。 In addition, other elements are also suitable for neutron capture reaction (neutron capture reactions). 一个例子是铀。 One example is uranium. 大量的铀可以被天然发生的螯合剂诸如铁蛋白结合。 A large amount of a chelating agent may be incorporated, such as uranium ferritin naturally occurring. 此种策略已经描述在现有技术中,例如描述于美国专利6,228,362以及该专利所引用的文献中,并容易地修改用于本发明,因此这些文献通过参考整体并入本文。 Such a strategy has been described in the prior art, such as described in U.S. Patent 6,228,362 and the literature cited in this patent, and easily modified for the present invention, and therefore these documents are incorporated herein by reference in its entirety.

[130]诊断剂是造影剂的本发明实施方案,通过参考基于金属螯合剂的造辯剂5 (metal chelate-based contrast agents)来举例说明。 [130] Embodiment diagnostic agent is a contrast agent of the present invention, by referring to agents based on 5 debate made of metal chelators (metal chelate-based contrast agents) exemplified. 对金属螯合剂的集中描述只是示范性的而不是限制性的。 Description of the concentration of the metal chelating agent is exemplary only and not limiting. 本领域技术人员将认识到,除了金属螯合剂外,许多造影剂可以偶联到本发明的连接载体上(例如颗粒、碘化芳基化合物(iodinated aryl compounds )、石肖基氧等)。 Those skilled in the art will recognize that, in addition to the metal-chelating agent, a contrast agent can be coupled to a number of the connection vector of the invention (e.g. particles, iodinated aryl compounds (iodinated aryl compounds), oxygen Shixiao Ji).

10 [131]在优选实施方案中,治疗用金属离子是通过螯合剂与微颗粒结构相联系的。 10 [131] In preferred embodiments, treatment with the metal ion by a chelating agent linked to the structure of the microparticles.

[132]大量的金属螯合剂是本领域己知的。 [132] The amount of metal chelators are known in the art. 例如参见Pitt et al., "The Design of Cheating Agents for the Treatment of Iron Overload," In, INORGANIC CHEMISTRY IN BIOLOGY AND MEDICINE; Martell, Ed.; American Chemical Society, 15 Washington, DC, 1980, pp.279-312 ; Lindoy, THE CHEMISTRY OF MACROCYCLIC LIGAND COMPLEXES; Cambridge University Press, Cambridge, 1989; Dugas, BIOORGANIC CHEMISTRY; Springer-Verlag, New York, 1989以及包含在其中的参考文献。 See, for example, Pitt et al, "The Design of Cheating Agents for the Treatment of Iron Overload," In, INORGANIC CHEMISTRY IN BIOLOGY AND MEDICINE;. Martell, Ed .; American Chemical Society, 15 Washington, DC, 1980, pp.279- 312; Lindoy, tHE CHEMISTRY oF MACROCYCLIC LIGAND COMPLEXES; Cambridge University Press, Cambridge, 1989; Dugas, BIOORGANIC CHEMISTRY; Springer-Verlag, New York, 1989 and references contained therein.

20 [133]在优选实施方案中,诊断试剂是聚氨基羧酸盐螯合剂(polyaminocarboxylate chelating agent)的金属复合物,聚氨基羧酸盐螯合剂诸如二亚乙基三胺五乙酸(DTPA)。 20 [133] In a preferred embodiment, the diagnostic agent is a polyamino carboxylate chelating agents (polyaminocarboxylate chelating agent) metal complexes, such as polyamino carboxylate chelating agent diethylenetriamine pentaacetic acid (DTPA).

[134]在其他优选实施方案中,治疗实体是化学治疗剂或药物前体或毒素,其中治25 疗实体附着到连接载体的表面。 [134] In other preferred embodiments, the therapeutic entity is a front chemotherapeutic agent or a toxin or drug, wherein the therapeutic treatment entity 25 attached to the surface of the connection carrier. 可选择地,治疗实体被捕获(entrapped)或封装到连接载体内。 Alternatively, the therapeutic entity is captured (entrapped) or encapsulated within the carrier connector.

[135]在特别优选的实施方案中,治疗用放射性核素与螯合剂结合,该螯合剂通过化学的方法附着到微颗粒结构的聚合物表面上。 [135] In a particularly preferred embodiment, the therapeutic radionuclide bound to the chelating agent, the chelating agent is attached to the surface of the polymer microparticles by the method of chemical structure. 在另一特别优选的实施方案中, 30钇-90是治疗用放射性核素,DOTA是螯合剂。 In another particularly preferred embodiment embodiment, Yttrium-90 is 30 therapeutic radionuclides, DOTA chelating agents.

螯合基团(Chelating groups) Chelating groups (Chelating groups)

[136]螯合基团是本领域技术人员熟知的。 [136] chelating groups are well known to the skilled person. Wu et al. (1992) Nucl. Med. Biol., 19(2): 239-244公开了大环螯合剂的合成,用于用min和^Y对蛋白质进行放射性标记。 Wu et al (1992) Nucl Med Biol, 19 (2):.... 239-244 discloses the synthesis of macrocyclic chelating agents for radiolabeling proteins with min and ^ Y.

35 35

[137]用于本发明的实践中的优选水溶性螯合剂包括但不限于:二亚乙基三胺五乙酸(DTPA)、乙二胺四乙酸(EDTA)、 1,4,7,10-四氮杂环十二烷-N,N',N,"N"'四乙酸酯(DOTA)、四氮杂环十四烷-N,N",N"N"-四乙酸(TETA)、环己基1,2-二胺四乙酸(CDTA)、乙二醇-0,0'-二(-2-氨乙基)-N,N,N',N'-四乙酸(EGTA), N,N-二(羟苄基)-乙二胺-N,N'-二乙酸(HBED),三亚乙基四胺六乙酸(TTHA),羟乙二胺三乙酸(HEDTA)、羟亚乙基二瞵酸酯(HEDP)、 二巯基琥珀酸(DMSA)、 二亚乙基三胺四亚5 甲基瞵酸(DTTP)和l-(p-氨苄基)-DTPA、 1,6-二氨基己垸-N,N,N',N'-四乙酸、DPDP、 亚乙基二(氧乙烯腈基)-四乙酸和环己基二亚乙基三胺五乙酸配体(CHX-DTPA)。 [137] Preferably the water-soluble chelating agent used in the practice of this invention include, but are not limited to: diethylenetriamine pentaacetic acid (DTPA), ethylenediaminetetraacetic acid (EDTA), 1,4,7,10- tetraaza cyclododecane -N, N ', N, "N"' tetraacetate (DOTA), tetraazacyclo tetradecane -N, N ", N" N "- tetraacetic acid (of TETA) , cyclohexyl 1,2-diamine tetraacetic acid (of CDTA), ethylene glycol -0,0'- bis (-2-ethyl) -N, N, N ', N'- tetraacetic acid (EGTA), N, N- bis (hydroxybenzyl) - ethylenediamine -N, N'- diacetic acid (HBED), triethylenetetramine hexaacetic acid (TTHA), hydroxyethyl ethylenediamine triacetic acid (HEDTA), ethylene hydroxyethyl two phosphine-yl ester (HEDP), dimercaptosuccinic acid (DMSA), diethylenetriamine tetraacetic acid, ethylene 5-methyl-phosphine (DTTP) and l- (p- aminobenzyl) -DTPA, 1,6- two aminocaproic embankment -N, N, N ', N'- tetraacetic acid, DPDP, ethylene bis (oxyethylene nitrile) - tetraacetic acid and cyclohexyl diethylenetriamine pentaacetic acid ligand (CHX-DTPA) .

[138] —种螯合剂,1,4,7,10-四氮杂环十二烷-N,N,N",N"'-四乙酸(DOTA)特别有意义,这是因为它能够螯合许多诊断上和治疗上重要的金属,诸如放射性核素和放10 射性标记。 [138] - chelating agents, 1,4,7,10-tetraaza cyclododecane -N, N, N ", N" '- tetraacetic acid (DOTA) is particularly interesting because it is capable of chelating together many important diagnostically and therapeutically metals, radionuclides such as 10 and discharge radiolabeled.

[139]在本发明的一些实施方案中,DOTA或其他螯合剂结合物,诸如EDTA或DTPA,例如可以以水溶性盐(钠盐、钾盐、四丁基铵盐、钙盐、铁盐等)的形式制备而得。 [139] In some embodiments of the present invention, DOTA conjugates or other chelators such as EDTA or DTPA, for example, may be water-soluble salts (sodium salt, potassium salt, tetrabutylammonium salt, calcium salts, iron salts ) is obtained in the form of the preparation. 这些盐可以用作肿瘤治疗的治疗剂。 These salts can be used as therapeutic agents for tumor therapy. 第二, DTPA或其他螯合剂也可用作15 诊断剂,当其用放射性核素诸如mIn或99mTc标记时,可以用作放射性示踪剂, 与核成像技术(nuclear imaging techniques) —起用于检测某些肿瘤。 Second, DTPA or other chelating agents are also useful as diagnostic agents 15, such as when it is labeled with 99mTc mIn or radionuclide, it can be used as radioactive tracers, nuclear imaging techniques (nuclear imaging techniques) - for detecting from some tumors.

[140]在一些实施方案中,螯合剂含有1,4,7,10-四氮杂环十二烷-N,N',N",N'"-四乙酸(DOTA),或者螯合剂是1,4,7,10-四氮杂环十二垸-N, N', N", N"'-四乙酸(DOTA) [140] In some embodiments, a chelating agent containing 1,4,7,10-tetraaza cyclododecane -N, N ', N ", N'" - tetraacetic acid (DOTA), or a chelating agent 1,4,7,10-tetraaza cyclododecane embankment -N, N ', N ", N"' - tetraacetic acid (DOTA)

20 的衍生物或是本领域技术人员熟知的螯合剂。 Derivative 20 or well known to the person skilled in the chelating agent. 在其他实施方案中,螯合剂包括可离子化的基团诸如羧基、磷酸盐、膦酸盐、硫酸盐、磺酸盐或亚磺酸盐。 In other embodiments, the chelating agent comprises an ionizable group such as a carboxyl, phosphate, phosphonate, sulfate, sulfonate or sulfinate. 在其它实施方案中,螯合剂包括单个可离子化的基团,所述单个可离子化的基团产生这样的表面,该表面能够结合具有+2或更大,或+3或更大的价态的同位素和金属。 In other embodiments, a chelating agent comprising a single ionizable group, the single ionizable group generating such surface which is capable of binding or more +2, +3 or greater, or state and isotopic metal.

25 [141]可以对本发明的水溶性聚合物或水溶性金属螯合剂的结构进行修改和改变, 依然获得具有类似或其他理想特性的分子,诸如"生物学功能等价物(biologically functional equivalents)"或"功能等价物(functional equivalents)"也包括在本发明中。 25 [141] Modifications and changes to the present invention, the water-soluble polymer or a water-soluble metal chelating agent of the structure, and still obtain a molecule having similar or other desirable characteristics, such "biologically functional equivalents (biologically functional equivalents)" or " functional equivalents thereof (functional equivalents) "are also included in the present invention.

30 [142]医药应用的特性使得潜在的螯合配体(chelating ligand)的化学性质需要满足多种要求。 30 [142] such that the characteristics of medical applications of potential chemical properties of a chelating ligand (chelating ligand) is required to meet various requirements. 它必须是(a)金属离子的强(多齿(multidentate))配位剂;(b)亲水性的,以在水中具有溶解性;(c)无毒的;(d)能够掺入到蛋白质结构中,而不会导致蛋白质变性。 It must be strong (a) metal ion (multidentate (multidentate)) complexing agent; (b) hydrophilic to have a solubility in water; (c) non-toxic; (d) can be incorporated into protein structure, without causing protein denaturation. 实质上对于每一单个放射性核素,技术人员必须设计专门的螯合系统。 For virtually every single radionuclide, the technician must design a special chelating system. 例如,大环双功能螯合剂,特别是DOTA,掺入钇-90和铟-Ill的衍生物 For example, macrocyclic bifunctional chelating agent, in particular DOTA, incorporation of indium and yttrium-90 derivatives of -Ill

35 在生理条件下显示出了优异的动力学稳定性。 35 under physiological conditions exhibits an excellent dynamic stability. 然而,钇-DOTA复合物形成缓慢, 这提出了个技术难题,即这会导致放射性标记产量低,除非小心地控制条件。 However, yttrium -DOTA slow complex formation, which presents technical problems, that this would lead to production of low-level radioactive labeling, unless carefully controlled conditions. [143]制备放射性偶联物(radioconjugates)最成功的螯合剂是复合有机合成的产物。 [143] Preparation of a radioactive conjugate (radioconjugates) chelating agent is the most successful product of a composite of organic synthesis. 合成方法的相当有代表性的例子可以参见Brechbiel, MW; Gansow, 0. A.; Atcher, RW; Schlom, J.; Esteban, J.; Simpson, DE; Colcher, D., Synthesis of 1-(P-isothiocyanatobenzyl) Derivatives of DTPA and EDTA. Antibody Labeling and 5 Tumor Imaging Studies, Inorg. Chem., 1986, 25, 2772-2781 。 Representative examples of considerable synthetic methods can be found in Brechbiel, MW; Gansow, 0. A .; Atcher, RW; Schlom, J .; Esteban, J .; Simpson, DE; Colcher, D., Synthesis of 1- ( P-isothiocyanatobenzyl) Derivatives of DTPA and EDTA. Antibody Labeling and 5 Tumor Imaging Studies, Inorg. Chem., 1986, 25, 2772-2781. 优选用于本发明的其《也螯合剂包括杂环螯合剂这一类螯合剂。 Preferably used in the present invention is its "heteroaromatic chelating agents also include chelating agents of the chelating agent.

[144]如本文中所使用的,术语"杂环(heterocycle)"或"杂环体系(heterocyclic system)"是指稳定的5, 6,或7-元单环或双环或7,8, 9,或10-元双环杂环,其是饱和10 的,部分饱和的或不饱和的(芳香的),其由碳原子和1、 2、 3或4个杂原子组成, 杂原子各自独立地选自N、 NH、 O和S,并包括任何双环基团,其中任何的上述杂环可被稠合到苯环上。 [144] As used herein, the term "heterocyclic ring (heterocycle)", or "heterocyclic ring system (heterocyclic system)" refers to a stable 5, 6, or 7-membered monocyclic or bicyclic or 7, 8, 9 , or 10-membered bicyclic heterocyclic ring which is 10 saturated, partially saturated or unsaturated (aromatic), which consists of carbon atoms and 1, 2, 3 or 4 heteroatoms, the heteroatoms are each independently selected from from N, NH, O and S, and including any bicyclic group in which any of the above heterocycles may be fused to a benzene ring. 氮和硫杂原子可以可任选地进行氧化。 Nitrogen and sulfur heteroatoms may optionally be oxidized.

放射性核素 Radionuclide

15 [145]通过附着到连接载体的螯合剂,本发明的微颗粒可以含有任何或所有的下述元素:磷、钇、铼和其他(3发射同位素;锕、铋、砹和和其他a发射同位素;锝、 15 [145] by the chelator attached to the carrier, the micro-particles of the present invention may contain any or all of the following elements: phosphorus, yttrium, rhenium, and the other (3 emitting isotopes; actinium, bismuth, and other astatine and a transmitter isotopes; technetium,

铟、碘和其他Y发射同位素;和碳、氮、氟、钠、镁、铝、硅、钾、钒、锰、镓、 铌、碘和/或铅。 Indium, iodine and other isotopes emitting Y; and a carbon, nitrogen, fluorine, sodium, magnesium, aluminum, silicon, potassium, vanadium, manganese, gallium, niobium, iodine and / or lead.

20 [146]如本文所使用的,治疗用放射性核素是这样的核素,其经历自发的转化(核衰变),能量转移足以将细胞毒性数量的辐射能施于周围细胞。 20 [146] As used herein, therapeutic radionuclide is a radionuclide, it undergoes spontaneous conversion (nuclear decay), energy transfer sufficient number of cytotoxic radiation applied to the surrounding cells. 与此相比较,用于诊断的放射性核素所发射的辐射能够以最小的细胞损伤水平穿透组织。 Compared with this, a radionuclide used for diagnostic radiation emitted can penetrate tissue with minimal damage to the cellular level. 通过使用合适的闪烁成像物(scintigraphic imager),可以检测此种辐射。 By using a suitable material scintigraphy (scintigraphic imager), this radiation can be detected. 本发明的治疗用放射性核素包括但是不限于Y-90、 Bi-213、 At-211、 1-123、 1-125、 1-131、 At-211、 Therapeutic radionuclides present invention including but not limited to Y-90, Bi-213, At-211, 1-123, 1-125, 1-131, At-211,

25 Cu-67、 Sc-47、 Ga-67、 Rh-105、 Pr-142、 Nd-147、 Pm-151、 Sm-153、 Ho-166、 Gd-159、 Tb-161、 Eu-152、 Er-171、 Re-186禾n Re-188。 25 Cu-67, Sc-47, Ga-67, Rh-105, Pr-142, Nd-147, Pm-151, Sm-153, Ho-166, Gd-159, Tb-161, Eu-152, Er -171, Re-186 Wo n Re-188. 本发明的诊断核素或成像核素包括但不限于Tc-99m、 In-Ill、 Ga-67、 Rh-105、 1-123、 Nd-147、 Pm-151、 Sm-153、 Gd-159、 Tb-161、 Er-171、 Re-186、 Re-188和Tl-201 。 Diagnostic radionuclide or radionuclide imaging of the present invention include, but are not limited to Tc-99m, In-Ill, Ga-67, Rh-105, 1-123, Nd-147, Pm-151, Sm-153, Gd-159, Tb-161, Er-171, Re-186, Re-188 and Tl-201.

30 [147]任何有用的核素都可以在本发明范围内使用。 30 [147] Any useful species can be used within the scope of the present invention. 特别优选的是这样的放射性核素,其具有有用的诊断或治疗特性,分别诸如铟-111或钇-90。 Particularly preferred are radionuclides which have useful diagnostic or therapeutic properties, respectively, such as indium-111 or yttrium-90.

[148]进一步考虑的是,在使用一个以上的放射性核素的实施方案中,这些多个放射性核素可以是不同类型的(a-发射体、P-发射体和/或?发射体),而且可以是不同35 亚类型的a-发射体、卩-发射体和/或Y-发射体。 [148] is further contemplated that, in more than one radionuclide embodiment, a plurality of these radionuclides may be different types of (emitter A-, P- emitter and / or? Emitter), 35 and may be different types of sub-a- emitters, Jie - emitter and / or Y- emitter.

[149]从卯-钇内部源(internal sources)产生的p辐射暴露于肿瘤组织以及正常的肝细胞,这是因为辐射范围超过l cm。 [149] From the d - p yttrium internal radiation source (internal sources) exposed to a tumor tissue and normal liver cells, because the range of radiation than l cm. (X-照射是吸引人的潜在的治疗用同位素, 可以与90-钇联合使用,或替代90-钇,在组织中给出短得多的辐射范围(微米级), 而对于同样短的距离,又具有相对高的辐射活性。本发明也包括将a发射体放射性核素偶联到微球体颗粒,单独与Y-和/或P-放射同位素偶联,或与其他a颗粒一5 起偶联。放射性微颗粒可以通过灌输入肝动脉进行给药,并被捕获在肝肿瘤毛细管床(liver tumor capillary bed)中,从而能传递高强度的杀肿瘤剂量的辐射,而不会暴露于正常的肝组织。可以考虑的是,此种治疗剂可以用于辐射治疗,以治疗肝肿瘤,这些肝肿瘤如果不治疗的话则一律是致命的。 (X- irradiation is an attractive potential therapeutic isotope, yttrium can be used in combination with 90-, 90- yttrium or alternatively, given a much shorter radiation range (in microns) in the tissue, and for the same short distance , but also has a relatively high radiation activity. the present invention also comprises a radionuclide emitter coupled to microsphere particles alone Y- and / P- or radioisotope conjugates, or with a 5 from other particles even a with radioactive microparticles may be administered by infusion hepatic artery, and is trapped in the capillary bed of liver tumors (liver tumor capillary bed), so that the radiation can be transmitted tumoricidal dose of a high strength, but not exposed to normal liver tissue can be considered that such a therapeutic agent can be used in radiation therapy to treat liver cancer, liver cancer if not treated these words is always fatal.

10 [150]放射性金属核素的紧密结合需要放射性金属的螯合剂。 10 [150] needs to closely radiometal chelators of radioactive metal species. 用于对低分子量的螯合剂进行放射性标记的标准放射性标记方法和预防措施也可以用于制备放射性标记的螯合剂聚合物。 Standard radiolabelling method for chelator and prevention of low molecular weight radiolabeled chelators may also be used for the preparation of radiolabeled polymers. 例如,使用放射性金属诸如铟-m和钇-90的方法, 一般需要高纯度的放射性核素供给,去离子水配制的各种缓冲溶液,并且在放射性标记程序期间对所使用的玻璃器皿及塑料器皿用试剂进行酸洗。 For example, using a radioactive metal such as indium and yttrium-90 -m methods generally require the supply of high-purity radionuclides, deionized water, various buffer solutions prepared, and glassware and plastics used during the procedure radiolabeled pickling containers with reagents.

15 15

[151]使用放射性金属诸如铼-188的程序需要化学还原步骤来完成标记,该方法在实施时最好使用耗尽氧的缓冲液(oxygen-depleted buffers)并使用氩气氛来覆盖(overlay)放射性标记反应。 [151] using a radioactive metal such as rhenium-188 procedure requires chemical reduction step completion flag, which is preferably oxygen depletion buffer (oxygen-depleted buffers) and in the practice to use argon cover (overlay) radioactive The labeling reaction. 放射性核素的配位层(coordination sphere)包括结合于该放射性核素的所有配体或基团。 Radionuclide coordination sphere (coordination sphere) includes all the ligands or groups bound to the radionuclide. 对于过渡金属放射性核素Mt,为了能够稳定, 20 它通常具有由大于或等于4并且小于或等于9的整数构成的配位数(供电子原子的数目);也就是说,有4至9个原子结合到金属,可以说是具有完全配位层。 For a transition metal radionuclide Mt, to be able to stabilize, it usually has a greater than 20 or equal to 4 and less than or equal to the coordination number of integers 9 (number of donor atoms); 4-9 That is, there is bonded to the metal atom, it can be said to have a complete coordination sphere. 稳定的放射性核素复合物所需要的确切配位数,由放射性核素的特性、它的氧化状态和供电子原子的类型确定。 The exact number of bits with a stable radionuclide complex is required, its oxidation state and the type of donor atoms is determined by the characteristics of the radionuclide.

25 试剂盒 25 kit

[152]本发明也包括试剂盒。 [152] The present invention also includes kits. "试剂盒"包括各种组分,这被称之为制剂,它们在一个或多个管形瓶中,其由在临床或药房环境中的最终实施使用者来使用,以合成诊断用放射性药物。 "Kit" includes the various components, which is called the formulation, in which one or more vials which are used by in clinical or pharmacy setting the final embodiment the user, to synthesize diagnostic radiopharmaceuticals .

30 [153]当放射性效应物或其他效应物用作诊断剂和/或治疗剂时,如果期望使用者可以使用随时可用的(ready-for-use)组合物,这常常是不可能的。 30 [153] When a radioactive effector or other effects are used as diagnostic and / or therapeutic agent, if desired the user may use ready (ready-for-use) composition, it is often not possible. 这是因为放射性标记的化合物的货架期短和/或所使用的放射性核素的半衰期短。 This is because of the short shelf life of the radiolabeled compound and / or radionuclide used short half-life. 在此种情况下, 使用者可以在临床医院、医生事务室或实验室中进行放射性核素的标记反应。 The user can mark the reaction of the radionuclide in the clinical hospital, doctors affairs office or the lab in this case. 为了达到这个目的或其他目的,各种反应组分则可以以所谓的"试剂盒"的形式提供给 To achieve this and other purposes, various reaction ingredients may be provided in the form of a so-called "kit" in

35 使用者。 35 users. 优选设计这样的试剂盒,这些试剂盒可以使实施期望的反应所需要的操作尽可能的简单,从而使得使用者可以通过使用他所拥有的设施,从试剂盒制备得到期望的组合物。 Such a kit preferably designed, these kits make a desired operation of the reactor required embodiment as simple as possible, so that the user can use the facilities he has to obtain the desired composition is prepared from kits. 因此,本发明也涉及用于制备本发明的组合物的试剂盒。 Accordingly, the present invention also relates to a kit for preparing the compositions of the present invention. [154]本发明的此种试剂盒优选包括本发明的微颗粒。 [154] Preferably the present invention such a kit comprises microparticles of the present invention. 可以提供微颗粒结构,如果需要,加入药学上可接受的惰性载体和/或配制剂和/或佐剂。 Microparticles structure may be provided, if desired, the addition of a pharmaceutically acceptable inert carrier and / or formulation and / or adjuvant. 此外,试剂盒可任选地包括盐或合适的放射性核素的螯合剂(或其他化学试剂)的溶液,以及说明书, 5 说明书与处方一起用于对试剂盒中的组分进行施用和/或反应。 In addition, the kit may optionally include salts or suitable radionuclide chelator (or other chemicals) was added, and instructions, instructions 5, together with the prescription for the kit component for administration and / or reaction.

[155]试剂盒提供了用于合成和使用诊断性放射性药物所有必需的组分,除了那些对于最终实施使用者常见的组分,诸如注射用的水或盐水、放射性核素的溶液、 [155] A kit is provided for the final embodiment that the user common components, such as water for injection or saline solution for the synthesis of radionuclide used and all components necessary for diagnostic radiopharmaceuticals, in addition,

在合成放射性药物期间用于加热试剂盒的设备,如果需要的话,将放射性药物投10 药给患者所必需的设备,诸如注射器和屏蔽设备(shielding equipment)和成像设备。 During the synthesis of a radiopharmaceutical kit for the heating apparatus, if desired, be administered radiopharmaceutical drug 10 to a patient the necessary equipment, such as syringes and shielding apparatus (shielding equipment) and the image forming apparatus.

[156]试剂盒可以含有转移配体(transfer ligand)、还原剂、冻干助剂、稳定助剂、 增溶剂和抑菌剂以及活性微颗粒和结合的效应物。 [156] The kits may contain a transfer ligand (transfer ligand), a reducing agent, a lyophilization aid, stabilizing aid, solubilizing agents and bacteriostats and microparticles and the active effector binding.

15 15

[157]"转移配体"是这样的配体,其与金属离子形成中间复合物,该中间复合物足够稳定以防止不想要的副反应,但也足够不稳定以转化为金属药物(metallopharmaceutical)。 [157] "transfer ligand" is a ligand which is an intermediate form complexes with metal ions, the intermediate complex is stable enough to prevent unwanted side reactions but labile enough to be converted to a metal medicament (metallopharmaceutical) . 中间复合物的形成在动力学上是有利的,而金属药物的形成在热动力学上是有利的。 Forming an intermediate complex is kinetically advantageous to form the metal medicament is advantageous thermodynamically. 用于制备金属药物以及用于诊断试剂盒——其用于20 制备诊断用放射性药物——的转移配体包括但不限于葡萄糖酸盐、葡庚糖酸盐、 甘露醇、葡萄糖二酸盐、N,N,N',N'-乙二胺四乙酸、焦磷酸盐和亚甲基二膦酸盐。 And means for producing a metal medicament diagnostic kit - 20 for the preparation of diagnostic radiopharmaceuticals - transfer ligand include, but are not limited to gluconate, glucoheptonate, mannitol, glucarate salt, N, N, N ', N'- ethylenediaminetetraacetic acid, pyrophosphate and methylene diphosphonate. 总之,转移配体由氧或氮供电子原子组成。 In short, a transfer ligand oxygen or nitrogen donor atoms.

[158]"还原剂(reducing agent)"是这样的化合物,其与放射性核素——其通常是25作为相对无活性、高氧化态的化合物被获得——反应,通过将电子转移到放射性 [158] "Reducing agent (reducing agent)" is a compound which with a radionuclide - generally as 25 is relatively inactive, high oxidation state compound is obtained - the reaction, the electron transfer by radioactive

核素上来将降低它的氧化状态,从而使它更具活性。 Species up to reduce its oxidized state, so that it is more active. 用于放射性药物制备以及诊 For the preparation of radiopharmaceuticals and diagnosis

断试剂盒——其用于制备放射性药物——的还原剂包括但不限于二氯化锡(stannous chloride)、 二氟化锡(stannous fluoride)、甲脒亚磺酸、抗坏血酸、半 A kit off - for the preparation of radiopharmaceuticals - reducing agents include, but are not limited to stannous chloride (stannous chloride), tin difluoride (stannous fluoride), formamidine sulfinic acid, ascorbic acid, half

胱氨酸、磷化氢和一价铜盐或铁盐。 Cystine, phosphine, and a monovalent copper salt or an iron salt. 其他还原剂描述于Brodack et. al.; PCT申请30 94/22496中,它们通过参考并入本文。 Other reducing agents are described in Brodack et. Al .; PCT Application 30 94/22496, and they are incorporated herein by reference.

[159]"冻干助剂(lyophilizationaid)"是具有对冻干作用有利的物理特性诸如玻璃化温度的组分,冻干助剂被加入到制剂中,以改善用于冻干的制剂的所有组分的物理特性。 [159] "lyophilization aid (lyophilizationaid)" is an advantageous effect on the physical properties of the freeze-dried glass transition temperature of a component, such as a lyophilization aid is added to the formulation to improve the formulation for lyophilization of all physical properties of the constituents.

35 35

[160]用于制备诊断试剂盒——其用于制备放射性药物——的冻干助剂包括但不限于甘露醇、乳糖、山梨醇、葡聚糖、聚蔗糖(Ficoll)和聚乙烯吡咯垸酮(PVP)。 [160] for preparing a diagnostic kit - for the preparation of a radiopharmaceutical - lyophilization aids include, but are not limited to, mannitol, lactose, sorbitol, dextran, Ficoll (Ficoll) embankment and polyvinylpyrrolidine ketone (PVP). [161]"稳定助剂(stabilizationaid)"是这样的一种组分,其被加入到放射性药物或诊断试剂盒中,以便稳定放射性药物,或者在它必须被使用之前延长试剂盒的使用寿命。 [161] "stabilization aid (stabilizationaid)" is a component which is added to the radiopharmaceutical or a diagnostic kit in order to stabilize the radiopharmaceutical, or prolong the kit before it must be used in life. 稳定助剂可以是抗氧化剂、还原剂或自由基清除剂(radical scavenger), 5 并可以通过优先与降解其他组分或放射性药物的物质反应来提高稳定性。 Stabilization aids can be antioxidants, reducing agents or radical scavenger (radical scavenger), 5 and can preferentially degrade other components or the radiopharmaceutical substance by reaction with improved stability.

[162]用于放射性药物的制备以及在诊断试剂盒^其用于制备放射性药物—— 中有用的稳定助剂包括但不限于抗坏血酸、半胱氨酸、硫代甘油(monothioglycerol)、亚硫酸氢钠、焦亚硫酸钠、龙胆酸和肌醇。 [162] for the preparation of radiopharmaceuticals and in diagnostic kits for the preparation of a radiopharmaceutical ^ - useful in stabilizing aids include, but are not limited to ascorbic acid, cysteine, thioglycerol (monothioglycerol), bisulphite sodium metabisulfite, gentisic acid, and inositol.

10 10

[163]"增溶剂(solubilization aid)"是这样的组分,其提高一种或多种其他组分在制剂所需的介质中的溶解性。 [163] "solubilizer (solubilization aid)" is a component, which improves the solubility of one or more other components in the formulation media desired.

[164]用于放射性药物的制备以及用于诊断试剂盒——其用于制备放射性药物15 ——的增溶剂包括但不限于乙醇、丙三醇、聚乙二醇、丙二醇、聚氧乙烯脱水山梨糖醇单油酸酯、脱水山梨糖醇单油酸酯、聚山梨醇酯、聚(氧乙烯)聚(氧丙烯)聚(氧 [164] and for the preparation of radiopharmaceuticals for diagnostic kits - for the preparation of a radiopharmaceutical 15-- solubilizers include, but are not limited to, ethanol, glycerin, polyethylene glycol, propylene glycol, polyoxyethylenesorbitan sorbitan monooleate, sorbitan monooleate, polysorbates, poly (oxyethylene) poly (oxypropylene) poly (oxy

乙烯)嵌段共聚物(Pluronics)和卵磷脂。 Ethylene) block copolymers (Pluronics) and lecithin. 优选的增溶剂是聚乙二醇和Pluronics。 Preferred solubilizers are polyethylene glycol and Pluronics.

[165]用于放射性药物制备以及用于诊断试剂盒——其用于制备所述放射性药物20 ——的缓冲液包括但不限于磷酸盐、柠檬酸盐、磺基水杨酸盐和醋酸盐。 [165] and for the preparation of radiopharmaceuticals for diagnostic kits - for the preparation of the radiopharmaceutical 20-- buffers include but are not limited to phosphate, citrate, sulfosalicylate, and acetate salt. 更完整的列举可以参见United States Pharmacopeia。 A more complete enumeration can be found in United States Pharmacopeia.

[166]用于放射性药物制备以及用于诊断试剂盒——其用于制备放射性药物—— 的抑菌剂包括但不限于苄醇、苯扎氯铵、三氯叔丁醇、和羟基苯甲酸甲酯、羟基25 苯甲酸丙酯或羟基苯甲酸丁酯。 [166] and for the preparation of radiopharmaceuticals for diagnostic kits - for the preparation of radiopharmaceuticals - bacteriostatic agents include but are not limited to benzyl alcohol, benzalkonium chloride, chlorobutanol, hydroxybenzoate, and methyl ester, 25-hydroxy propyl or butylparaben.

[167]诊断用试剂盒中的组分也可以具有一种以上的功能。 [167] The diagnostic kit of components may also have more than one function. 还原剂也可以充当稳定助剂,缓冲液可以充当转移配体,冻干助剂也可以充当转移、辅助或共-配体(co-ligand),诸如此类。 The reducing agent can also serve as a stabilization aid, a buffer can act as a transfer ligand, a lyophilization aid can also serve as a transfer, ancillary or co - ligand (co-ligand), and the like.

30 30

[168]治疗用放射性药物、X-射线造影剂药物、超声造影剂药物和用作磁共振成像造影剂的金属药物以制剂的最终形式提供给终端使用者,所述制剂通常以冻干固体或以水溶液的形式包含在一个小瓶中。 [168] therapeutic radiopharmaceuticals, X- ray contrast agent pharmaceuticals, ultrasound contrast agent pharmaceuticals and as magnetic resonance imaging contrast agent provided in final form metal pharmaceutical formulation to the end user, usually in the formulation or lyophilized solid an aqueous solution contained in a vial. 最终使用者用水或盐水重构冻干物质, 取出患者剂量,或仅仅是从提供的水溶液制剂中取出患者剂量(patientdose)。 End user lyophilized material reconstituted with water or saline, remove the patient dose or simply remove the patient dose (patientdose) from an aqueous solution formulation provided.

35 35

[169]通过在水溶液中,在0至10(TC的温度中,混合放射性核素的盐、本发明的化合物和还原剂,容易制得本发明的锝和铼放射性药物。锝和铼放射性核素优选是高锝酸盐或高铼酸盐的形式,并且是药学上可接受的阳离子。高锝酸盐形式优选高锝酸钠,诸如来自商业的Tc-99m生产商的高锝酸钠。用于制备本发明放射性药物的高锝酸盐的数量可以在0.1 mCi至1 Ci范围内,更优选在1至200 mCi的范围内。 [169] by an aqueous solution, at 0 to 10 (in the temperature TC, the mixed salt of a radionuclide, the reducing agent and the compound of the present invention, the present invention is easy to prepare the technetium and rhenium radiopharmaceuticals. Technetium and rhenium radionuclides pigment is preferably in the form of pertechnetate or perrhenate and a pharmaceutically acceptable cation. in the form of pertechnetate is preferably sodium pertechnetate such as Tc-99m sodium from the manufacturer's commercial pertechnetate. number of pertechnetate for the preparation of radiopharmaceuticals of the present invention may be in the range of 0.1 mCi to 1 Ci, more preferably in the range of 1 to 200 mCi.

5 5

[170]用于制备本发明的锝和铼放射性药物的本发明化合物的数量可以在0.01吗至10mg范围内,更优选地在0.5吗至200吗范围内。 Amount of a compound of the present invention [170] for preparing the technetium and rhenium radiopharmaceuticals of the invention may be in the range of 0.01 it into the 10mg, more preferably in the range of 0.5 to 200 do it. 使用的量取决于其他反应物的数量和待被制备的本发明放射性药物的特性。 The amount depends on the nature and amount of the other reactants of the present invention is the radiopharmaceutical to be prepared.

10 [171]通过在水溶液中,在0至10(TC的温度中,混合放射性核素的盐和本发明的试剂,很容易制备本发明的铟、铜、镓、银、钯、铑、金、铂、铋、钇和镧系元素的放射性药物。这些放射性核素通常是作为在无机酸诸如盐酸、硝酸或硫酸中的稀释水溶液的形式获得。将放射性核素与一至约一千个当量的溶解于水溶液中的本发明试剂混合起来。缓冲液通常用于将反应混合物的pH维持在3至IO之间。 10 [171] by an aqueous solution, 0 to 10 (the temperature TC, the salt mixture of radionuclides and reagents of the present invention are readily prepared according to the present invention, indium, copper, gallium, silver, palladium, rhodium, gold radiopharmaceutical platinum, bismuth, yttrium and lanthanides. these radionuclides are usually in the form of inorganic acids such as dilute aqueous hydrochloric acid, nitric acid or sulfuric acid is obtained. radionuclides with one to about one thousand equivalents of It was dissolved in an aqueous solution of the mixed reagent of the present invention. the buffer used is typically pH of the reaction mixture is maintained between 3 to the IO.

15 15

[172]制备的总时间会变化,这取决于金属离子的特性、反应物的特性和数量,和制备方法。 Total Time [172] Preparation will vary depending upon the nature and quantity, method of preparation and characteristics of the metal ion reactants. 制备可以是完全的,在1分钟内产生>80%的放射性药物产物,或需要更多的时间。 Preparation can be complete in 1 minute to produce> 80% of the radiopharmaceutical product, or require more time. 如果需要或想要得到更高纯度的金属药物,产物可以用本领域技术人员熟知的许多技术中的任何技术进行纯化,诸如液相层析、固相萃取、溶剂萃20 取、透析或超滤。 If you need or want to get higher purity metal medicament, the product may be performed by any number of techniques techniques well known to those skilled in purification, such as liquid chromatography, solid phase extraction, solvent extraction 20 to take, dialysis or ultrafiltration .

[173]当试剂盒成分用作药学上被施用的组分时(例如作为注射液体),它们应该是无菌的。 [173] When the components of the kit components are administered as a pharmaceutically acceptable (e.g., as an injection liquid), they should be sterile. 当成分以千的状态提供时,使用者优选使用无菌的生理盐水溶液作为溶齐IJ。 When the ingredient is provided in a state of a thousand, the user sterile physiological saline solution is preferably used as the solvent together IJ. 如果需要,成分可以用合适的稳定剂用常规的方法稳定,合适的稳定剂诸如25 抗坏血酸、龙胆酸或这些酸的盐,或它们可以包括其他辅助试剂,例如填充物诸如葡萄糖、乳糖、甘露醇和类似物。 If desired, the composition may be suitable stabilizing agents stabilized by conventional means, suitable stabilizing agents such as 25-ascorbic acid, gentisic acid or salts of these acids, or they may comprise other auxiliary agents, for example, fillers such as glucose, lactose, mannitol alcohols and the like.

[174]供应给使用者的试剂盒也可以包括上面定义的组分,以及使用说明书,然而上面定义放射性核素的盐或螯合剂的溶液具有有限的货架期,它们可以独立地提30 供给使用者处理。 [174] supplied to the user of the kit may also comprise components, and instructions for use as defined above, but the salt as defined above, or a radionuclide chelator solution has a limited shelf life, they may independently provide supply 30 using by treatment.

[175]试剂盒可以可任选地,额外地包括组合物使用说明和/或处方,它们用于指导试剂盒的组分之间的反应,以形成期望的产物。 [175] The kit may optionally additionally comprise instructions for use compositions and / or prescription, they are used to guide the reaction between the components of the kit to form the desired product. 当存在时,尽管指导材料通常是手写的或打印的材料,但它们不限于此。 When present, While the instructional materials are typically hand-written or printed materials, but they are not limited thereto. 能够保存此种指导和将它们传输到终35 端使用者的任何工具都在本发明的考虑之内。 Such guidance can be stored and transfer them to an end user of any tool end 35 are within the contemplation of the present invention. 此种工具包括但不限于电子储存介质(例如磁盘、磁带、盒式磁盘、芯片)、光学介质(例如CDROM)和类似物。 Such tools include, but are not limited to electronic storage media (e.g. disks, tapes, cartridges, chips), optical media (e.g. CDROM), and the like. 此类介质可以包括因特网地址,该因特网提供此种指导材料。 Such media may include the Internet address of the Internet to provide such guidance material. 药物组合物 The pharmaceutical composition of

[176]可以使用流质载体传递微颗粒,流质载体可以是能够将微颗粒传递到期望的组织位置的任何生物相容性材料,诸如生物相容性悬浮液、溶液或其他形式的流5体。 [176] a carrier liquid can pass microparticles, liquid carrier may be capable of microparticles delivered to the desired tissue location of any biocompatible material, such as biocompatible suspensions, solutions or other forms of flow body 5.

[177]本发明的药物组合物特别适用于肠胃外给药,诸如静脉内给药。 The pharmaceutical composition of [177] of the present invention are particularly suitable for parenteral administration, such as intravenous administration. 用于施用的组合物通常将包括溶解于药学上可接受载体优选含水载体中的微颗粒溶液。 For administration compositions will generally include pharmaceutically microparticles dissolving solution is preferably an aqueous carrier in a pharmaceutically acceptable carrier. 可以使用各种含水载体,诸如缓冲盐水和类似物。 Variety of aqueous carriers may be used, such as buffered saline and the like. 这些溶液是无菌的,通常没有不需10 要的物质。 These solutions are sterile and generally does not need to be of material 10. 这些组合物可以用常规的公知的灭菌技术灭菌。 These compositions may be sterilized by conventional sterilization techniques known. 如果需要接近生理条件,组合物可以含有药学上可以接受的辅助物质,诸如pH调节剂和缓冲试剂、毒性调节剂和类似物,例如醋酸钠、氯化钠、氯化钾、氯化钙、乳酸钠和类似物。 If required to approximate physiological conditions, the compositions may contain pharmaceutically acceptable auxiliary substances, such as pH adjusting and buffering agents, toxicity adjusting agents and the like, for example, sodium acetate, sodium chloride, potassium chloride, calcium chloride, sodium lactate and the like.

[178]本发明的组合物也可以包括其他组分,诸如药学上可接受的赋形剂、佐剂、 15 和/或载体。 [178] The compositions of the present invention may also include other components such as excipients, adjuvants, 15 and / or pharmaceutically acceptable carrier. 例如,本发明的组合物可以用赋形剂配制。 For example, compositions of the invention may be formulated with an excipient. 此类赋形剂的例子包括水、 盐水、林格氏溶液、右旋糖溶液、甘露醇、Hank's溶液、和其他含水生理平衡盐溶液(aqueous physiologically balanced salt solutions)。 Examples of such excipients include water, saline, Ringer's solution, dextrose solution, mannitol, Hank's solution, and other aqueous physiologically balanced salt solution (aqueous physiologically balanced salt solutions). 贝武形剂也可以含有少量的添加剂,诸如增加等渗性和化学稳定性的物质。 Wu shaped shell agents may also contain minor amounts of additives such as substances that enhance isotonicity and chemical stability. 含有活性组分的含水组合物的制备是本领域已知的。 Aqueous solution containing the active ingredient compositions are known in the art. 通常,此类组合物制备成可注射形式的,是液体溶液或悬浮液; 20 也可以制备成适合于在注射之前制成溶液或悬浮液的、固体形式的组合物。 Typically, such compositions are prepared as injectables, in the form of, liquid solutions or suspensions; 20 can also be prepared in suitable form a solution or suspension prior to injection, in the form of a solid composition.

[179]"药学上可接受的(pharmaceutically acceptable)"是指那些化合物、材料、组合物和/或剂量形式,其在可靠的医学判断范围内,适用于与人和动物体的组织相接触,而不会引起过多的毒性、刺激、过敏反应、或其他问题或并发症,具有合25 理的效益/风险比均衡。 [179] "acceptable (pharmaceutically acceptable) acceptable" refers to those compounds, materials, compositions and / or dosage forms which are, within the scope of sound medical judgment, suitable for contact with the human and animal body tissue, without causing excessive toxicity, irritation, allergic response, or other problem or complication, together with a 25 reasonable benefit / risk ratio balanced.

[180]诊断用放射性药物通过静脉内注射给药,诊断用放射性药物通常是在盐水溶液中,剂量为l至100mCi,或优选5至50mCi。 [180] Diagnostic radiopharmaceuticals administered by intravenous injection, the diagnostic radiopharmaceuticals are usually in saline solution, at a dose of l to 100 mCi, preferably 5 or to 50mCi. 使用已知的方法进行成像。 Imaging using known methods.

30 [181]治疗用放射性药物通过静脉内注射给药,通常是在盐水溶液中,剂量为每70kg人体重0.1至700 mCi,或优选0.5至10 mCi/kg体重的剂量。 30 [181] therapeutic radiopharmaceuticals administered by intravenous injection, usually in saline solution, the dosage per body weight of 70kg person 0.1 to 700 mCi, or preferably 0.5 to 10 mCi / kg of body weight.

[182]对于在含水溶液中的肠胃外给药,例如,如果必要,溶液应该进行适当的缓冲作用,液体稀释剂首先用足够的盐水或葡萄糖进行等渗化处理。 [182] For parenteral administration in an aqueous solution containing, for example, if necessary, the solution should be suitably buffered effect, the liquid diluent first rendered isotonic with sufficient saline treatment or glucose. 依据正被治疗35 的对象的状况,有必要在剂量上作一些变化。 According to the condition being treated objects 35, it is necessary to make some changes in dose. 在任何情况下,负责给药的人员将为每一个体确定合适的剂量。 In any case, the person responsible for administration will determine the appropriate dose for each individual. 还有,对于人类给药,制剂应该满足FDA Office of Biologies standards所要求的无菌、无热和通用的安全和纯度标准。 Also, for human administration, preparations should meet sterility FDA Office of Biologies standards required, no heat, and general safety and purity standards. [183]无菌可注射溶液通过下述方法制备而得,将活性化合物以所需的数量掺入到合适的溶剂中,如果需要,活性化合物可以与上面列举的其他组分中的若干种一起掺入,然后再进行过滤灭菌。 [183] ​​Sterile injectable solutions can be prepared by the following method to give the desired amount of active compound is incorporated into a suitable solvent, if necessary, together with several other components of the active compounds can be exemplified in the above incorporation, and then filter sterilized. 通常,通过将各种灭过菌的活性组分掺入到无菌5载体中制备得到分散体,无菌载体含有基本的分散体介质和上述所需要的其他组分。 Typically, by incorporating the various sterilized active ingredient into a sterile carrier prepared 5 dispersions, sterile vehicle which contains the basic dispersion medium and the required other ingredients described above.

[184]制备肠胃外给药的组合物的实际方法对本领域技术人员是已知的或显而易见的,并更为i羊细地描述在公开文献中诸如Remington's Phamaceutical Science,15th 10 ed., Mack Publishing Company, Eastern, Pa.( 1980)中。 [184] Actual methods for preparing a composition for parenteral administration are known to the skilled person or readily apparent, and more finely i sheep described Remington's Phamaceutical Science, 15th 10 ed, such as disclosed in the literature., Mack Publishing Company, Eastern, Pa (1980) in.

[185]对于注射,本发明的试剂可以在水溶液中配制,优选在生理上可相容的缓冲液中诸如Hanks's溶液、林格氏溶液或生理盐水缓冲液中配制。 [185] For injection, the agents of the invention may be formulated in aqueous solutions, preferably in physiologically buffer compatible formulated such as Hanks's solution, Ringer's solution, or physiological saline buffer.

15 [186]依据患者所需要的以及能够忍受的剂量和频率,可以单次或多次给予组合物。 15 [186] according to patient dosage and frequency required and tolerable, it can be a single or multiple administration of the compositions. 在任何情况下,组合物应该提供足够数量的本发明微颗粒以有效地治疗患者。 In any event, the composition should provide a sufficient number of micro-particles of the invention to effectively treat the patient. 治疗上有效数量的治疗剂可以是足以带来有利效果的任何数量或剂量,这部分地取决于癌症的状况、类型和位置,患者的大小和状况,以及本领域技术人员知道的其他因素。 A therapeutically effective amount of the therapeutic agent can be any amount or dose sufficient to bring beneficial effects, depending in part on the status of cancer, type and location, size and condition of the patient, and other factors known to a person skilled in the art. 剂量可以作为单剂量给予,或多剂量给予,例如,在若干周的吋间 Doses may be administered as a single dose, or multiple doses, e.g., several weeks between inch

20 里分次给药。 20 miles administered several times.

患者选择和评价 Patient selection and evaluation

[187]在本发明的某些实施方案中,本发明的微颗粒用于辐射治疗。 [187] In certain embodiments of the invention, the microparticles of the present invention is used for radiation therapy. 可以想象到的是,本领域普通技术人员知道这样的方法,通过该方法筛选和/或确定患者,以用 It is envisioned that those of ordinary skill in the art know that such a method, by which the screening and / or determining the patient to use

25辐射治疗方法进行治疗,更具体地,用本发明的放射性微颗粒进行治疗。 25 The method of radiation therapy for treatment, more specifically for treatment with radioactive microparticles according to the present invention. 在非限制性例子中,需要进行辐射治疗的患者包括已经接受过标准的一线和二线治疗(standard first and second line therapies)并失败的患者。 Patients in the non-limiting example, the need for radiation treatment include those already received standard first and second line treatment (standard first and second line therapies) and patients who have failed. 合适的医学学科诸如医学肿瘤学、辐射肿瘤学和介入放射学(interventional radiology)的专家可以在接触治疗方案之前,评测患者。 Appropriate medical disciplines such as medical oncology, radiation oncology specialists and interventional radiology (interventional radiology) can be contacted prior to treatment programs, evaluation of the patient. 患者的选择基于满足某些参数,诸如年龄,非血液性恶 Patient choice based on meeting certain parameters, such as age, non-blood evil

30 疾的确认诊断(confirmed diagnosis of a non-hematologic malignancy),可领!l到的不可切除的疾病,诸如肝肿瘤。 30 confirm the diagnosis of disease (confirmed diagnosis of a non-hematologic malignancy), can lead! L to unresectable disease, such as liver cancer. 理想地,患者能够提供告知后同意书(informed consent), ECOG行为分值(ECOG Performance Status)小于或等于2。 Ideally, the patient can provide informed consent (informed consent), ECOG behavior score (ECOG Performance Status) is less than or equal to 2. 在某些实施方案中, 需要放射治疗的患者具有足够的骨髓(粒细胞>1500〜1,血小板>60,000&1);充足的肝功能(胆红素52.0mg/dl, SGOT/SGPT,或碱性磷酸酶<正常水平上限的5倍)和足 In certain embodiments, a patient in need of radiation therapy have sufficient bone marrow (granulocyte> 1500~1, platelets> 60,000 & 1); adequate liver function (bilirubin 52.0mg / dl, SGOT / SGPT, alkaline or phosphatase <5 times the upper limit of normal) and foot

35 够的肺功能(FEV^1L)。 35 enough lung function (FEV ^ 1L). 如本领域技术所知道的,患者不禁忌血管造影术和选择性内脏导管插入术(selective visceral catheterization),或>10%的肺分流或任何流到肠胃道的流量(anyflowtotheGItract)。 As is known in the art techniques, not contraindicated in patients with selective visceral angiography and catheterization (selective visceral catheterization), or> 10% or any pulmonary shunt flow (anyflowtotheGItract) flow to the gastrointestinal tract. 某些不能进行本发明放射治疗的患者是怀孕妇女,患有肝血、流(hepatofugal blood flow)、全门静&]c血栓(complete portal vein thrombosis)的患者,或之前以估计吸收剂量〉30Gy,接受过来自任何源的肺部照射的患者,或在4周的治疗时间内需要进行系统的化学治疗的患者也不适合这种治疗。 Some patients can not radiation therapy of the present invention is a pregnant woman suffering from liver blood flow (hepatofugal blood flow), the whole door & static] c thrombotic patients (complete portal vein thrombosis) or prior to estimate the absorbed dose> 30Gy , patients received a patient lung radiation from any source or within 4 weeks of treatment time required for the system is not suitable for such chemotherapeutic treatment.

[188]在作出关于微球体辐射治疗的最终决定之前,由治疗小组进行全面的病史和身体检测(治疗小组即辐射肿瘤工作者、医学肿瘤工作者和介入放射工作者组成的联合研究小组)。 [188] before making a final decision on the microsphere radiation therapy, a comprehensive history and physical detected by a treatment team (ie, radiation oncology treatment team worker, medical oncology and interventional radiology workers, workers formed a joint research group). 适当的血液工作(blood work)包括肝功能测试、电解液(electrolytes)、全血液计数(complete blood count),用差异性的,PT、 PTT、 INR、 10 脂肪酶,和合适的肿瘤标记来研究其恶性程度(CEA、 AFP、 CA19-9、嗜铬粒蛋白A、 CA27-29、 5-HIAA等)。 Appropriate blood work (blood work) including liver function tests, electrolyte (Electrolytes), full blood count (complete blood count), with the difference, PT, PTT, INR, 10 lipases, and a suitable tumor markers to study degree of malignancy (CEA, AFP, CA19-9, chromogranin A, CA27-29, 5-HIAA, etc.). 所有这些实验室参数可以在灌输后一段时间内间隔地反复进行以监控毒性,优选在灌输后每周进行一次,进行8周,然后再两周一次和/或随后每月一次。 All of these parameters may be spaced in the laboratory within a period of time after infusion repeated to monitor toxic, preferably once a week, 8 weeks after the infusion, then biweekly and / or monthly subsequently.

15 [189]在涉及对诊断有肝癌的患者进行放射治疗的实施方案中,无论什么肿瘤类型,都通过胸、腹和骨盆CT扫描对患者进行评价,努力检测其它的肝转移(hepatic metastasis)。 15 [189] In embodiments directed to the diagnosis of hepatocellular carcinoma in patients with radiation therapy, regardless of what type of tumor, through the chest, abdomen, and pelvic CT scans of the patients were evaluated, tries to detect other liver (hepatic metastasis). 肝细胞癌症患者通常也用肝造影剂(contrast of the liver)进行MRI , 以更好地确定肿瘤位置,大小和数量。 Hepatocellular carcinoma patients often also liver contrast agents for MRI (contrast of the liver), to better identify tumor location, size and number. 为了进一步协助肿瘤负荷和对治疗的应答, 带有神经内分泌肿瘤的患者接受In"11 Octreoscan (OctreoScanTM Kit, Indium In-111 To further assist the tumor burden and response to treatment in patients with neuroendocrine tumors accept In "11 Octreoscan (OctreoScanTM Kit, Indium In-111

20 Pentetreotide, Mallinckrodt Medical Inc., St. Louis, MO, USA)。 20 Pentetreotide, Mallinckrodt Medical Inc., St. Louis, MO, USA). 所有其他非肝癌患者接受FDG-PET扫描,这是治疗前和治疗后的常规检査。 All other non-liver cancer patients who received FDG-PET scan, which is a routine examination before treatment and after treatment. 基于肝脏的三维重构,针对预先计划的剂量,在辐射肿瘤科(Radiation Oncology d印artment)迸行肝的无造影剂CT扫描。 Based on three-dimensional reconstruction of the liver, for pre-planned dose, radiation oncology (Radiation Oncology d printing artment) into line liver CT scan without contrast agent. 然后将体积数据用于计算微颗粒对于单个患者的确切活性。 Volume data is then used to calculate the exact active microparticles for the individual patient. 用MAA-SPECT扫描估算微球体分布,基于微球体分布计算剂量分布,剂量分布的计 Scanning the estimated distribution of microspheres with MAA-SPECT, the distribution of microsphere-based calculation of the dose distribution, dose distribution meter

25 算通过记录这些计划CT扫描(planning CT scans)得到辅助。 25 count assisted by recording these plans CT scan (planning CT scans).

[190]利用股动脉导管方法(femoral catheter approach),对腹部、主动脉和肝血管绘图。 [190] The method of using a femoral artery catheter (femoral catheter approach), abdominal aorta and liver vascular drawing. 治疗小组检査最合适的传递途径,并确定由右和/或左肝动脉供给的肝容量(hepatic volumes),这有助于进行治疗前计划和剂量计算。 Check the most appropriate treatment group transfer pathway and determined by the right and / or left hepatic artery liver supply capacity (hepatic volumes), which facilitates pre-treatment planning and dose calculations. 通常,血管造影在治30 疗前至少一周时实施;有时,在实际传送微球体治疗之前最多3周时实施。 Typically, during angiography performed before treatment 30 treatment at least one week; sometimes embodiment up to 3 weeks before the time of the actual transmission microspheres treatment. 如果在血管造影期间确定胃十二指肠动脉很有可能发生微球体逃逸到肠胃道,那么就进行线圈栓塞术(coil embolization)。 If during the gastroduodenal artery angiography determined likely to occur microspheres escape to the gastrointestinal tract, then the process of embolization coil (coil embolization). 在两种情况下,肿瘤在隔膜附近具有寄生动脉(parasitizedarteries),其被栓塞住以使得微球体沿着隔膜的沉积被最小化。 In both cases, the tumor has a parasitic artery (parasitizedarteries) in the vicinity of the diaphragm, which is live so that the plug is minimized along the microspheres deposited diaphragm.

35 分流评价(Shunt Evaluation) Evaluation of shunt 35 (Shunt Evaluation)

[191]通过对4.5-6.0-mCi"mTc-标记的大颗粒白蛋白(macro aggregated albumin) (MAA)进行平面和SPECT成像,对所有患者测试由肝动脉系统到肺或肠胃静脉系统的隐分流(occult shunt)。 MAA颗粒的尺寸近似于微球体的尺寸,但是MAA颗粒容易通过y照相机进行成像和定量。每一99mTc-maa灌输通常含有3.6-6.5百万个微颗粒,>85%的微颗粒在20 nm禾b 40 之间(Package insert of Pulmolite®-CIS-US, Inc, 10 DeAngelo Drive, Bedford, Massachusetts, USA)。对所有5 患者进行平面和SPECT成像,以更好地确定是否存在分流现象。该方案提出的给肺的累计总剂量的上限为30 Gy或16.5 mCi。在某些情况下,如果在肺中,灌输的Tc99m MAA活性在筛选研究(screening study)中检查到10%的绝对分流值, 或者如果在肠胃道中检测到解剖性分流(anatomic shunting),那么患者被剥夺掉辐射治疗的资格,以防止肺毒性。因为分流系数估计(shunt f [191] by large particles albumin 4.5-6.0-mCi "mTc- labeled (macro aggregated albumin) (MAA) planar and SPECT imaging, all patients tested by the hepatic arterial system to the venous system or parenteral pulmonary shunt Implicit (occult shunt). MAA particle size approximately equal to the size of the microspheres, but y MAA particles are easily performed by the imaging camera and quantified. each infusion 99mTc-maa generally contain 3.6-6.5 million microparticles,> 85% of the microstructures particles. planar and SPECT imaging for patients in all 5 Wo between 20 nm b 40 (Package insert of Pulmolite®-CIS-US, Inc, 10 DeAngelo Drive, Bedford, Massachusetts, USA), to better determine whether there shunt phenomenon. the upper limit of the cumulative total dose of the proposed solution to the lungs of 30 Gy or 16.5 mCi. in some cases, if the lungs instilled Tc99m MAA activity screening study (screening study) checks to 10% the absolute value of the shunt, or if it detects anatomical shunt (anatomic shunting) in the gastrointestinal tract, the patient is deprived of qualified radiation therapy to prevent lung toxicity. because shunt coefficient estimate (shunt f raction estimate)深受 raction estimate) by

10所使用的估计程序的影响,我们选择几何平均分析方法对自由肝脏感兴趣区(liberal hepatic region of interest) (ROI)进行分析。 Affects an estimated 10 to use the program, we chose an average geometric analysis method of liver freedom regions of interest (liberal hepatic region of interest) (ROI) analysis. 通过增加图像强度以包括进来自那个器官的大多数散射,获得自由肝脏ROI。 Most of the scattering intensity by increasing to include into the image from that organ, freedom liver ROI. 针对背景(background),修正所有ROI计数,背景获自紧接着肝脏下面的腹部区域并避开尿道。 For background (background), to fix all ROI counts, background obtained from the abdominal area immediately below the liver and avoid the urethra. 在较前和较后的全身平面图像中(whole body planar images),围绕着肝脏和肺绘制感兴趣区,使 In the image plane of the body and more than before the (whole body planar images), liver and lung drawn around the region of interest, so that

15用下述公式计算分流值: 15 calculates the value of the shunt by the following equation:

分流系数二ROI肺计数/ (ROI肺计数+1101肝计数) Two tap coefficients lung ROI counts / (ROI lung liver counts count +1101)

[192]进行SPECT成像以更好的确定是否存在肠胃分流,并提供三维数据与治疗前和治疗后的PET扫描建立相互关系。 [192] SPECT imaging performed to determine whether there is a better parenteral shunt, and provides three-dimensional data to establish correlation with PET scan before treatment and after treatment.

20 20

[193]在灌输微球体的24小时内,所有患者回到核医学室,获取平面和torso SPECT 图像,这些图像由微球体本身通过释放韧致辐射(力辐射而产生。该质量保证试验(quality assurance test)证明,辐射剂量仅仅沉积在肝脏中(也就是在目标位置上), 并可以与预处理99mTc-MAA扫描上见到的活性分布相比较。 [193] microspheres within 24 hours of infusion, all patients returned to nuclear medicine chamber, and torso SPECT image acquisition plane, the images generated by the microspheres themselves by releasing the bremsstrahlung (radiation force. This quality assurance test (quality assurance test) demonstrated that radiation dose deposited only (i.e. at the target position), and can be compared with the activity profile seen in the scanning pretreated 99mTc-MAA in the liver.

25 25

放射治疗计划 Radiation treatment planning

[194]在典型的患者评估中,患者在辐射肿瘤科(Radiation Oncology department) 接受CT治疗计划,使用AcQ-sim v.4,0软件(Picker International, Inc., 595 Miner Rd. HighlandHts., OH 44143),从由辐射肿瘤学家描绘的肝脏轮廓重构肝脏体积(liver [194] In a typical patient assessment, patients in radiation oncology (Radiation Oncology department) to accept the CT treatment planning, using AcQ-sim v.4,0 software (Picker International, Inc., 595 Miner Rd. HighlandHts., OH 44143), liver volume reconstructed from the drawing by the radiation oncologist contour liver (liver

30 volumes)(整体肝脏,右叶和左叶)。 30 volumes) (the whole liver, right lobe and a left lobe). 在没有IV造影剂或口服造影剂(oral contrast) 的情况下,使用3mm厚的薄片进行CT扫描,肝脏成像期间患者屏住呼吸。 IV contrast medium in the absence of a contrast agent or oral (oral contrast) in the case of using a 3mm thick sheet CT scan, a patient holding their breath during imaging the liver. 基于150 Gy的标称目标剂量(nominal target dose)和由AcQ-sim数据测得的患者的肝质量,计算每一个患者所需要的活性,假定在整体肝脏体积中微颗粒均匀分布(Package Insert, TheraSphere®, MDS Nordion, Inc., 447 March Road, Ontario, Canada Based on the nominal target dose (nominal target dose) and liver mass sensed by the data obtained AcQ-sim patient activity was calculated for each patient is required to 150 Gy, it is assumed that the entire volume of the liver uniformly distributed microparticles (Package Insert, TheraSphere®, MDS Nordion, Inc., 447 March Road, Ontario, Canada

35 K2K1X8): 35 K2K1X8):

爿=D (G少)(紐)/50 其中A为活性,D是标称目标剂量,M是肝质量。 Valves = D (G low) (New Zealand) / 50 where A is an active, D is the nominal target dose, M is the mass of the liver. 对于肝质量为2 Kg的典型患者,所需要的活性是6GBq。 For the typical patient the liver mass of 2 Kg of the desired activity is 6GBq. 将肺剂量维持在30Gy以下以防止放射性肺炎,从而将患者选择限制在分流系数^10%的患者。 The lung dose was maintained at 30Gy or less in order to prevent radiation pneumonitis limit the selection of the patient so that 10% of patients ^ tap coefficients. 使用玻璃或陶瓷微球体,微球体必须从供应商定购,并安排患者进行治疗,这样可以由校准时间获得合适的衰变。 Glass or ceramic microspheres, the microspheres must be ordered from the supplier, and to arrange the patient treated, which can be obtained by a suitable calibration time decay. 此种微球体包封入1.2cm厚的有机玻璃柱状体中的密封管形瓶中,进行发送。 Such microspheres are encapsulated into 1.2cm thick plexiglass columnar body in a sealed vial, is transmitted.

[195]当收到制造商的传送时,使用辐射测量仪(radiation survey meter),在30cm 的固定距离,测量来自有机玻璃柱状体外的韧致辐射,核实微球体的活性。 [195] Upon receipt of the transmission manufacturer, a radiation meter (radiation survey meter), at a fixed distance of 30cm, measured from plexiglass cylindrical tough radiation induced in vitro to verify the activity of the microspheres. 该测量充当灌输程序之前的一致性检测(consistency check)以及基线值。 This acts as a consistency check before measurement infusion procedure (consistency check) as well as baseline values. 灌输之后, 将微球体小瓶和传送导管和线放入同样厚度的大的有机玻璃容器中,并在同样的 After infusion, the vials and microsphere delivery catheter line and into a large plexiglass container of the same thickness and the same

10 距离进行测量。 10 distance measurements. 灌输前后测量得到的值给出了微颗粒百分比,和正被传送到患者的标称剂量。 Measured before and after infusion gives the percentage of microparticles, and being transmitted to the patient nominal dose.

[196]筛选程序特别是MAA扫描的一个安全特征是,防止高剂量水平的辐射进入/或出现在肠胃道或肺中。 [196] In particular a screening program MAA scan security feature is to prevent high levels of radiation dose to enter / or present in the gastrointestinal tract or lungs. 因为分流不容易在血管造影、CT或MRI中看见,MAA Because the shunt is not readily visible in angiography, CT or MRI in, MAA

】5 扫描被用来评估分流程度。 5] scans were used to assess the extent of the shunt. 然而,有关MAA的潜在的原理是,由于它的尺寸的缘故,它将刺激玻璃微球体的沉积。 However, the underlying principles relating MAA is, due to its size, it will stimulate the deposited glass microspheres. 然而,因为玻璃颗粒的比重远远大于盐水或MAA 颗粒,该提法在本领域没得到一致认同。 However, since the specific gravity of the glass particles is far greater than the MAA salt particles or the formulation did not get consensus in the art. 事实上,当MAA显示出小于15。 In fact, when less than 15 exhibit MAA. /。 /. 的分流系数时,在前期临床试验中使用这些玻璃球体的患者中没有出现严重的肺部毒性。 The shunt coefficient is used in pre-clinical trials in patients with these glass spheres does not appear severe lung toxicity. 还有,MAA的目的——筛选分流——容易实现,但是白蛋白颗粒的形状和重量都20 不是很像玻璃微球体。 Still another object of MAA - Filter bypass - easy to implement, but the shape and weight of the albumin particles 20 are not like glass microspheres.

[197]剂量测定法目前不能用灌输这类方法被实施;但是,报道了灌输的球体的总活性。 [197] Dosimetry infusion by such methods have not been implemented; however, reported that infusion of the total active sphere. 在过去为开发剂量测定模型所作的有限的努力[20,45-47]已包括了病理学取样和核医学图像,但不包括现代辐射治疗方法。 Limited efforts [20,45-47] done in the past for the development of dosimetry models have included a sample pathology and nuclear medicine images, but does not include modern radiation treatment. 申请人第一次提供了微球体治疗25 的剂量-体积矩形分布函数图和3D等剂量体积(3D isodose volumes)。 Applicants for the first time provides a therapeutic dose of microspheres 25 - the volume of a rectangular distribution function and 3D isodose volume (3D isodose volumes). [30]这些体积基于MAA数据。 [30] These MAA based on volume data.

微颗粒的使用和给药方法 Use of microparticles and methods of administration

[198]本方法提供了控制传递到某位置的总剂量而同时控制对身体其他区域的暴30 露的三种方法。 [198] The present method provides three methods to control the total dose delivered to a position control while the other critical regions of the body 30 exposed. 首先,同位素的总数量可以变化。 First, the total number of isotopes can vary. 第二,选择同位素的半衰期, 这提供了应用剂量的上限。 Second, choose the half-life of the isotope, which provides an upper bound dose of application. 第三,可以控制在局部传送贮存区(local delivery depot) 中的放射性同位素的寿命。 Third, the transfer may be controlled locally in the storage area (local delivery depot) of the life of the radioisotope.

[199]本发明的一个方面涉及栓塞的方法,包括将栓塞剂组合物传送到血管,以充35 满或阻塞血管和/或促进凝块形成,这样,通过血管的血流减少或停止。 [199] One aspect of the invention relates to a method of embolization, the embolic agent comprising composition to a blood vessel to block blood vessels or over 35 charge and / or facilitate clot formation, so reducing or stopping blood flow through the vessel.

[200]本发明也涉及与成像放射性同位素效应物混合的治疗用放射性同位素效应物,其中治疗用放射性核素和成像或诊断用放射性核素贮存在相同的微颗粒载体上。 [200] The present invention also relates to the treatment of mixed with a radioisotope imaging using radioisotopes effector effector, wherein the therapeutic or diagnostic radionuclide, and imaging with radionuclide stored on the same carrier microparticles.

[201]还有,本发明涉及定向微颗粒结构(targeted microparticle constructs),其中, 5 钇-90和铟-111或锝同位素可以在同一微颗粒结构中混合。 [201] Further, the present invention relates to microparticles oriented structure (targeted microparticle constructs), wherein 5 yttrium-90 or indium-111 and technetium isotope microparticles may be mixed in the same structure.

[202]本发明也提供了对人或其他哺乳动物患者进行辐射治疗的方法,其包括向患者施用辐射发射放射性核素。 [202] The present invention also provides a method of human or other mammalian patient for radiation therapy, comprising administering to a patient in a radiation emitting radionuclide. 优选地,卩-辐射发射放射性核素是钇-90。 Preferably, Jie - radiation emitting radionuclide yttrium-90.

10 [203]在优选的实施方案中,本发明的治疗包括治疗癌症或肿瘤,特别是患者的原发性肝癌或继发性肝癌。 10 [203] In a preferred embodiment, the present invention includes a therapeutic treatment of cancers or tumors, particularly in patients with hepatocellular carcinoma or secondary liver cancer.

[204]微颗粒治疗给药在门诊血管造影术室(outpatient angiography suite)中进行, 其中有辐射医师来检査离开治疗室(treatment suite)的人员,并监控任何可能的污15染。 [204] Microparticles administered in the outpatient treatment angiography chamber (outpatient angiography suite) performed in which the radiation leaving the physician inspectors treatment room (treatment suite), and to monitor any possible pollution 15 dye. 在治疗之前,血管造影术室的地面覆盖大大的帘子,以防止任何潜在的污染。 Prior to treatment, the ground cover angiography chamber greatly curtain to prevent any potential contamination. 收集所有的污染物质(例如帘子、手套、鞋套等),并作为辐射废物处理掉。 Collect all the contaminants (e.g. curtains, gloves, shoes, etc.), and as the radioactive waste disposal.

[205]介入放射学工作者通过患者的股动脉将插管经皮放入合适的肝动脉。 [205] interventional radiologist through the patient's femoral artery cannula percutaneously into the right hepatic artery. 医师、 辐射肿瘤学工作者和介入放射学工作者独立地确认患者的鉴定是正确、将传送的 MD, radiation oncology and interventional radiologists workers independently confirm patient identification is correct, the transfer of

20剂量、待被灌输的叶或整个肝脏、和待被灌输的微球体的活性。 20 doses, to be infused leaves or whole liver, and are taught to be active microspheres. 实施灌输的辐射肿瘤学工作者与介入放射学工作者一起检查插管位置。 Instill implementation of radiation oncology workers check tube position with the interventional radiologist. 设置微颗粒的灌输流速(通常l-2cc/秒),以避免球体倒流回胃动脉供给(gastric artery supply)中。 Infusion flow rate is set microparticles (generally l-2cc / s), to prevent flow back into the ball supplying gastric artery (gastric artery supply) in. 将微球体小瓶连接到给药装置,将微球体从小瓶送到患者插管。 The microsphere vial was connected to the drug delivery device, the microspheres from the vial to the patient cannula. 辐射肿瘤学工作者进行每一次灌输时,连续灌输10至20 cc。 Oncology radiation workers in each infusion, continuous infusion 10 to 20 cc. 将辐射暴露计(radiation exposure meter)放在 The radiation exposure count (radiation exposure meter) on

25 靠近源瓶(source vial)的地方,以评估管形瓶内剩余的活性。 Bottle 25 closer to the source (source vial) where, in order to assess the remaining active tubular bottle. 医师使用定向GM 计数器(directional GM counter)在灌输期间监控通过整个系统的暴露情况。 GM physician using directional counter (directional GM counter) monitored by the exposure system during the entire infusion. 当已经获得最大活性转移时,他也告诉辐射肿瘤学工作者。 When the transfer has been obtained maximum activity, he also told workers in radiation oncology. 高于总剂量的95%的灌输是期望的。 95% higher than the total dose of indoctrination is desired. 所使用的管形瓶和连接插管被置于有机玻璃罐中,然后测量残留的活性。 Vial used and are placed in plexiglass cannula connected to the tank, and then measuring the residual activity. 当接受到源时,传送到患者的实际活性便由来自有机玻璃罐的暴露量与来自 When the source is received, the actual activity of the patient will be transferred to and from the exposure from plexiglass tank

30微球体管形瓶的暴露量的比率来确定(对同样的距离进行标准化并对衰变进行修正)。 Exposure ratio of 30 microspheres is determined vial (for the same distance and normalized decay corrected).

[206]微球体灌输装置已允许对微球体进行安全的传送。 [206] microspheres infusion devices have the microspheres allows secure transmission. 然而由于系统的复杂性, 有潜在的缺陷,这使得在将盐水灌输入微球体室,清除线路、废瓶中的空气,和35 将微球体灌输入患者之间可能产生误时(miss-timing)。 However, due to the complexity of the system, there are potential pitfalls, such that when the ball nuanced saline infusion chamber, purge line, the waste air of the bottle, and filling the microspheres 35 between the input lead wrong patient (miss-timing) . 如果一部分的剂量流入废瓶中,再也没有办法取回。 If a portion of the dose flow into the waste bottle, no way to get it back. 如果发生这种情况,患者可能需要灌输额外的微球体。 If this happens, patients may need additional infusion of microspheres. 提供这种治疗产品的公司正在开发将解决这个问题的替代灌输装置。 Provide such therapeutic products companies are developing alternatives to solve the problem of the infusion device. [207]接受介入放射术的所有患者在自己的房间里,从麻醉中恢复过来。 [207] All patients received interventional radiology surgery in his room, to recover from anesthesia. 在距患者肝脏一定距离的地方测量暴露率,获得测量值来确定患者需要避免与别人接触(< 3 英尺)的天数。 Exposure ratio measured from the liver of a patient where a certain distance, the measured values ​​is obtained to determine the number of days a patient required to avoid contact with others (<3 feet). 在某些实施方案中,例如对于成人在灌输后3天进行测量,对于儿5 童和孕妇在灌输后14天进行测量。 In certain embodiments, for example, for an adult measured at 3 days after infusion, for children 5 children and pregnant women were measured at 14 days post infusion. 大多数的患者能够在缝合处的近旁找到股动脉位点,并因此可能要在灌输完成后约2小时进行排放(discharge)。 Most of the patients were able to find a site in the femoral artery near the suture, and therefore may have to be discharged (discharge) approximately two hours after the infusion is completed.

[208]当微球体或其他小颗粒投药给目标器官的动脉血液供给时,具有可导致在目标器官内产生最佳均匀分布的尺寸、形状和密度是有利的。 [208] When microspheres or other small particles are administered to the arterial blood supply of the target organ, has lead to the best within the target organ size uniform distribution, shape and density are advantageous. 如果微球体或小颗粒 If the microspheres or small particles

10 分布不均匀,并且是作为绝对动脉血流量的函数,那么它们会以过多的数量积聚在某些区域,并引起焦点区域(focal areas)的过量辐射。 10 unevenly distributed, and as a function of the absolute arterial blood flow, then they may accumulate in excessive amount in certain areas, and cause the focus area (focal areas) excessive radiation. 已经显示,当投药到肝脏的动脉循环时,直径约25-50微米的微球体具有最好的分布特征(Meade, V. et al; Distribution of different sized microspheres in experimental hepatic tumours. Europ. J. Cancer & Clin. Oncol. 1987,23 : 23-41)。 It has been shown, when administered into the arterial circulation of the liver, about 25 to 50 microns in diameter microspheres have the best distribution characteristics (Meade, V. et al;.. Distribution of different sized microspheres in experimental hepatic tumours Europ J. Cancer & Clin Oncol 1987,23:.. 23-41).

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[209]如果微球体或小颗粒不含有足够的电离辐射,那么将需要过量的微球体或小颗粒来将所必需的辐射剂量传送给目标器官。 [209] If the microspheres or small particles do not contain sufficient ionizing radiation, then an excess of the microspheres or small particles to the radiation dose delivered to the target organ necessary. 已经显示,如果将大量的微球体投药入肝脏的动脉供应中,那么它们积聚在通往肿瘤的小动脉(small arteries)中并阻塞小动脉,而不是均匀地分布在肿瘤的毛细管和毛细血管前微动脉中。 Have shown that if a large number of arteries supplying the microsphere administration into the liver, then they accumulate in the arteries leading to the tumor (small arteries) and blocked arteries, rather than evenly distributed in front of the tumor capillaries and capillaries arterioles. 因此, 20 使用最小数量的微球体是有利的,最小数量的微球体将均匀分布在肿瘤循环的血管网络中。 Thus, using the minimum number of 20 microspheres are advantageous, the minimum number of microspheres evenly distributed in the vascular network of the tumor circulation.

[210]类似地,如果微球体或小颗粒太浓或太重,那么它们将不会在目标器官中均匀分布,并将以过大的浓度积聚在肝脏的一部分中,而那一部分不含有癌。 [210] Similarly, if the microspheres or small particles too heavy or too thick, they will not be uniformly distributed in the target organ, and the accumulation of an excessive concentration in a portion of the liver, and that does not contain a portion of cancer . 已经25 显示,当注射入肝脏动脉供给中时,固态沉重的微球体在肝脏软组织内的分布较差。 25 has been displayed, when injected into the arterial supply of the liver, poor distribution of the solid heavy microspheres soft tissue in the liver. 这转而减少了到达目标器官中的癌上的有效辐射量,从而降低了放射性微球体杀死肿瘤细胞的能力。 This in turn reduces the effective amount of radiation reaching the cancer in the target organ, thereby reducing the ability of the radioactive microspheres to kill the tumor cells. 相反,微球体在肝脏内分布良好。 In contrast, microspheres of good distribution in the liver. (Burton, MA et al.; Selective International Radiation Therapy; Distribution of radiation in the liver. Europ.丄Cancer Clin. Oncol. 1989, 25: 1487-1491)。 (Burton, MA et al .; Selective International Radiation Therapy; Distribution of radiation in the liver Europ Shang Cancer Clin Oncol 1989, 25:.. 1487-1491..).

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[211]对于成功用于癌症治疗的放射性微球体,从微球体发射出的辐射应该是高能量的和短程的。 [211] For radioactive microspheres for the successful treatment of cancer, the radiation emitted from the microspheres should be of high energy and short range. 这确保从微球体发射出的能量将沉积到紧临微球体周围的组织, 而不沉积入非目标组织中。 This ensures that the energy emitted from the microspheres will be deposited into the tissue surrounding the microspheres close to, but not deposited into non-target tissue. 有许多可以掺入到微球体用于SIRT的放射性核素。 Many can be incorporated into the microspheres used in SIRT radionuclides. 尽管其他同位素诸如碘也可以使用,但特别适合用于这种形式的治疗的是不稳定的35 同位素钇(Y-90)和磷(P-32)。 Although other isotopes such as iodine can also be used, but particularly suitable for this form of treatment is unstable isotope of yttrium 35 (Y-90) and phosphorus (P-32). 钇-90是钇-89的不稳定的同位素,其可以通过将稳定的钇-89放置在中子束中制备而得。 Yttrium-90 is the unstable isotope of yttrium-89, which can be stabilized by yttrium -89 placing the prepared neutron beam obtained. 产生的钇-90发生衰变,半衰期是64小时,同时发射出高能的纯的P辐射。 Produced yttrium-90 to decay, the half-life is 64 hours, while emitting a high energy pure P radiation. [212]因此,本发明的微颗粒被施用用于治疗、诊断和/或成像目的,它们相对于纯钇具有低密度,尺寸在约20至约80微米范围内,且是稳定的,因此当投药给 [212] Thus, the microparticles of the invention are administered for therapeutic, diagnostic and / or imaging purposes, they have a low density relative to pure yttria, size in the range from about 20 to about 80 microns, and are stable, so as administration to

人或其他哺乳动物患者身体时,没有放射性物质从微颗粒渗滤出来。 When human or other mammal patient's body, there is no infiltration of radioactive material from the microparticles.

[213]本发明微颗粒的化学耐用性比起先前公开的微颗粒有所提高,这是因为当被施用时,本发明微颗粒不会释放大量的辐射发射放射性同位素到循环系统中。 [213] The chemical durability of the microparticles of the present invention compared to previously disclosed microparticles improved, because when it is administered, the microparticles of the present invention do not release large amounts of radiation emitting radioisotope into the circulatory system.

[214]为了将可控剂量的不溶性物质传送到活体中,物质以装在小瓶里的、可测数10 量的形式提供,并提供了系统,用于将掺入放射性同位素的不溶性物质的整个内容物由小瓶冲洗入体中。 [214] In order to transmit a controllable amount of insoluble matter into a living body, substance contained in a small bottle, can be measured to provide the amount of the form of the number 10, and a system for incorporating a radioactive isotope throughout the insoluble matter the vial contents were rinsed into the body.

[215]依据所选择的小瓶中的放射性活度一一这是通过放射性活度的初始测量和同位素的天然半衰期来确定的,通过给予一个小瓶中的全部内容物,可以传送精15确剂量的放射性活度。 [215] based on the selected vial radioactivity-this is achieved by measuring initial radioactivity of the isotope and natural to determine the half-life, by administering the entire contents of a vial, may be transmitted correct dose of 15 fine radioactivity.

[216]通过将放射性复合物通过血管途径直接施于损害部位,放射性复合物可以用作体内辐射治疗,治疗肝癌、类风湿性关节炎或实体肿瘤,诸如肝癌、脑癌、乳腺癌、卵巢癌或类似疾病。 [216] by a radioactive compound applied directly to the lesion site through the vascular pathway, the radioactive compound may be used as in vivo radiation therapy, treatment of liver cancer, rheumatoid arthritis or solid tumors, such as liver, brain, breast, ovary or similar diseases.

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[217]本发明包含体内照射肝癌的材料和方法。 [217] The present invention comprises a method of irradiating material and liver cancer in vivo.

[218]可选择性地,本发明的放射治疗的方法可以应用于血管插管可到达的任何肿瘤。 [218] selectively, radiation therapy method of the present invention may be applied to any tumor vessel cannulation reachable. 该技术可特别应用于高度血管化的肿瘤,或具有单个支配动脉血管供给(single 25 dominant arterial vascular supply)的肿瘤。 This technique is particularly applicable to highly vascularized tumor, or a tumor having a single dominant arterial supply (single 25 dominant arterial vascular supply) of. 具体地,本发明的方法涉及对肾细胞癌、 肝癌、肉瘤、头颈癌和中枢神经系统肿瘤进行治疗、成像和/或诊断。 In particular, the present invention relates to a method of renal cell carcinoma, hepatoma, sarcoma, head and neck cancer, and central nervous system tumors for treatment, imaging and / or diagnosis. 在具体的实施方案中,通过注射入支持肿瘤的动脉,将含有钇-90的许多放射性微颗粒施用给患者。 In a specific embodiment, the tumor by injection into the artery to support the many radioactive microparticles containing yttrium-90 is administered to a patient. 当微颗粒固定在沉积位置时,在沉积区域的局部肿瘤体积(local tumor volume)被辐射。 When deposition of microparticles fixed in a position, in local tumor volume of the deposition area (local tumor volume) is radiated.

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[219]在某些实施方案中,施用治疗用放射性微颗粒给患者,以诊断具有癌症和/ [219] In certain embodiments, the treatment is administered to a patient with radioactive microparticles to diagnosed with cancer and /

或肿瘤的患者。 Or the patient's tumor. 对怀疑具有肿瘤的患者进行癌症诊断的一种方法包括:在所述患 A method for a patient suspected of having a tumor cancer diagnosis comprising: the patient

者的目标位置,给予患者许多放射性微颗粒,其中所述许多放射性微颗粒中的每 Target position's, many radioactive microparticles administered to a patient, wherein said plurality of microparticles each radioactive

一个的直径在约5至约200微米范围内,且是非生物可降解的,并包括核心、至35少一种位于所述核心上的连接载体,其中所述连接载体包括生物相容性聚合物, 和至少一种共价结合到所述连接载体的放射性治疗剂,其中所述放射性治疗剂包括Y-发射放射性核素;检测所述许多放射性微颗粒;和从所述检测结果确定患者是否具有肿瘤,其中检测到所述肿瘤便诊断出患有癌症的所述患者。 A diameter in the range of about 5 to about 200 microns, and non-biodegradable, and comprises a core, 35 to support at least one connector positioned on said core, wherein said connector comprises a biocompatible polymer support and at least one covalently bound to the radiotherapeutic agents of the connection carrier, wherein said radiotherapeutic agent comprising Y- emitting radionuclide; said plurality of detecting radioactive microparticles; and determining from the detection result whether the patient tumor, wherein the tumor is detected will be diagnosed with cancer of the patient. 成像检测 An imaging detector

[220]在本发明的一种实施方案的实施中,在给予诊断剂后,可以进行成像。 [220] In one embodiment of the embodiment of the present invention, after administration of the diagnostic agent, imaging can be performed. 通过5将光传递到各种结构上然后进行收集,直接或间接观察这些结构,可以检测体腔内的肿瘤。 5 by the light transmitted to the various structures then collected, direct or indirect observation of these structures, a body cavity can be detected tumor. 只要非电离辐射可以传送到这些结构,并从这些结构重新捕获到,便可以观察到在任何身体位置的损害。 As long as non-ionizing radiation can be delivered to these structures, and to re-capture from these structures, it can be observed damage in any body position. 例如,高分辨率、非侵入性的成像技术—— 正电子成像术(PET)可以与本发明的抗体一起用于观察人类疾病。 For example, high-resolution, non-invasive imaging techniques - positron emission tomography (PET) may be used in human disease was observed with the antibodies of the present invention. 在PET中,在正电子湮没衰变(positron annihilation decay)期间产生的511 keVy光子被检测。 In PET, positron annihilation decay photons generated during 511 keVy (positron annihilation decay) is detected. PET 10 的类似的预靶向策略(pre-targeting strategies)——使用氟-18和镓-68——已分别描述于美国专利6,187,284和美国系列号09/644,706中。 Similar pre-targeting strategies PET 10 (pre-targeting strategies) - -68-- using fluorine-18 and gallium have been separately described in U.S. Patent 6,187,284 and U.S. Serial No. 09 / 644,706. 描述于这些申请中的方法可以容易地进行修改以用于本发明,因此它们通过参考整体并入本文。 The method described in these applications can be easily modified for use in the present invention, they are incorporated herein by reference in its entirety.

[221]考虑使用具有多种放射性核素的颗粒,其中一种或多种放射性核素被附着到15 核心和/或连接载体上。 [221] Consider the use of radionuclides having a plurality of particles, wherein the one or more radionuclide is attached to the core 15 and / or the connection carrier.

[222]本发明的一个独立的实施方案是在单个微颗粒上使用多种放射性核素。 [222] A separate embodiment of the present invention is the use of radionuclides in a plurality of single microparticles. 诸如核心,至少两种放射性治疗剂被附着到所述核心上。 Such core, at least two radioactive therapeutic agent is attached to the core. 所述至少两种放射性治疗剂可以独立地选自治疗用放射性核素和成像或诊断用放射性核素。 The at least two radioactive therapeutic agents may be independently selected from a therapeutic or diagnostic radionuclide imaging and radionuclide. 该至少两种放射20 性治疗剂可以独立地选自a-发射放射性核素、P-发射放射性核素和/或Y-发射放射性核素。 The at least two radiation therapeutic agent 20 may be independently selected from emitting radionuclide a-, P- emitting radionuclide and / or Y- emitting radionuclide.

[223]在一个实施方案中,至少两种放射性治疗剂是P-发射放射性核素和Y-发射放射性核素的组合。 [223] In one embodiment, the at least two radioactive therapeutic agent is a combination of P- and Y- emitting radionuclide emitting radionuclide. 例如,(3-发射放射性核素——其是治疗用放射性核素,和,发射25放射性核素——其是成像或诊断用放射性核素。诸如钇-90作为治疗用放射性核素,铟-111和/或Tc-99m作为成像或诊断用放射性核素。 For example, (3-emitting radionuclides - which is a therapeutic radionuclide, and, emitting radionuclide 25 - which is an imaging or diagnostic radionuclides, such as yttrium-90 as therapeutic radionuclides, indium. -111 and / or Tc-99m as a radionuclide for imaging or diagnosis.

[224]在一种实施方案中,核心是非陶瓷和非放射性标记的。 [224] In one embodiment, a non-ceramic core and non-radiolabeled. 核心可以是聚合物, 诸如聚丙烯酸、乙烯-醋酸乙烯聚合物、酰基取代的醋酸纤维素、聚氨酯、聚苯乙30 烯、聚氯乙烯、聚氟乙烯、聚(乙烯咪唑)、氯磺酸酯聚烯烃、聚氧乙烯、其混合物、 和其共聚物、聚膦嗪、聚(乙烯醇)、聚酰胺、聚碳酸酯、聚亚垸基、聚丙烯酰胺、 聚亚烷基二醇、聚环氧烷烃、聚对苯二甲酸亚烷基酯、聚乙烯醚、聚乙烯酯、聚乙烯卤化物、聚乙烯吡咯烷酮、聚乙交酯、聚硅氧垸和其共聚物、垸基纤维素、 羟垸基纤维素、纤维素醚、纤维素酯和/或硝基纤维素。 The core may be a polymer, such as polyacrylic acid, ethylene - vinyl acetate polymer, an acyl substituted cellulose acetate, polyurethane, polystyrene 30, polyvinyl chloride, polyvinyl fluoride, poly (vinyl imidazole), chlorosulphonate polyolefins, polyethylene oxide, mixtures thereof, and copolymers thereof, polyphosphazines, poly (vinyl alcohol), polyamides, polycarbonates, polyalkylene embankment group, polyacrylamides, polyalkylene glycols, polyethylene oxygen alkanes, poly (alkylene terephthalate), polyvinyl ethers, polyvinyl esters, polyvinyl halides, polyvinylpyrrolidone, polyglycolides, silicone embankment and copolymers thereof, alkyl with cellulose, hydroxypropyl embankment cellulose, cellulose ethers, cellulose esters and / or nitrocellulose.

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[225]所述至少两种放射性治疗剂可以通过共价键,各自附着到所述核心。 [225] The at least two radioactive therapeutic agent can be by covalent bonds, are each attached to the core. [226]在一种实施方案中,颗粒不会渗滤出放射性核素。 [226] In one embodiment, the particles do not leach radionuclides.

[227]具有多种放射性核素的颗粒可以用于这些方法,包括放射治疗和成像和/或诊断。 Granules [227] having a variety of radionuclides may be used in these methods, including imaging and radiation therapy and / or diagnosis. 具有两种或三种同位素复合物的微颗粒的应用使得能够进行实时和治疗后5诊断成像。 Application of microparticles having two or three isotopes composite enables real-time diagnostic imaging and 5 after treatment.

[228]可以测定Y-放射,以确定微颗粒在患者中的位置。 [228] Y- radiation can be determined, to determine the position of the microparticles in the patient.

实施例 Example

10 [229]下述实施例用来示范性说明本发明的优选实施方案。 10 [229] The following examples are intended to illustrate preferred exemplary embodiments of the present invention. 根据本发明的公开内容,所有公开的组合物和方法可以被制备和执行,无需额外的实验。 According to the disclosure of the present invention, all the disclosed compositions and methods can be made and executed without undue experimentation.

[230]尽管本发明的组合物和方法依据优选实施方案进行描述,对本领域技术人员显而易见的是,可以对本文中描述的组合物和/或方法进行变化,而不会脱离本发15 明的概念、精神和范围。 [230] While the compositions and methods of the present invention will be described in terms of preferred embodiments, the skilled person will be apparent that changes may be made to the compositions and / or methods described herein without departing from the present 15 out of concept, spirit and scope.

[231]更具体地,显而易见的是,某些在化学上和生理上相关的试剂可以取代本文中描述的试剂,同时能取得同样或类似的结果。 [231] More specifically, it is apparent, in certain related chemically and physiologically reagent may be substituted for the agents described herein, can be achieved while the same or similar results.

20 [232]对本领域技术人员显而易见的所有此种类似的替代和修饰都认为是在本发明的精神、范围和概念之内。 20 [232] The apparent to those skilled all such similar substitutes and modifications are deemed to be within the spirit, scope and concept of the present invention.

[233]实施例l:具有功能化表面的PMMA微颗粒的制备 [233] Example l: Preparation of PMMA microparticles having a functionalized surface

25 [234]PMMA是疏水性聚合物,但是它的表面在化学上是惰性的,不含有适合用于直接偶联生物活性物质的功能基团。 25 [234] PMMA is a hydrophobic polymer, but its surface is chemically inert, does not contain a functional group suitable for direct coupling of biologically active substances. PMMA也对有机试剂和溶剂具有低耐受性。 PMMA also has a low resistance to organic solvents and reagents. 对PMMA微颗粒珠进行功能化作用的一种方法是对PMMA表面的甲基酯基团进行水解作用(Holmberg and Hyden, 1985)。 A method for PMMA beads microparticles functionalization of the methyl ester groups is carried PMMA surface hydrolysis (Holmberg and Hyden, 1985). 这使得可以附着载体分子,如树枝状大分子,其含有氨基官能基团。 This allows the carrier molecule may be attached, such as dendrimers containing amino functional groups. 因为树枝状大分子在它的表面具有多个功能基团,所 Because dendrimer having a plurality of functional groups on its surface, the

30 得到的修饰过的微颗粒表面将提供具有高浓度的活性位点的表面,从而可以进一步附着螯合剂用于进行标记。 Modified microparticles obtained surface 30 provides a surface active sites with a high concentration can be further attached to a chelating agent for labeling. 材料包括PMMA微颗粒,25p直径,PAMAM-NH2 聚(酰胺胺)树枝状大分子(Sigma)、 p-N02-Bz-DOTA、 p-NH2-Bz-DOTA (Macracyclic, TX,USA)、 l-乙基-3-(3-二甲基氨基丙基)碳二亚胺EDAC(Fluka)。 PMMA material comprising microparticles, 25p diameter, PAMAM-NH2 poly (amidoamine) dendrimers (Sigma), p-N02-Bz-DOTA, p-NH2-Bz-DOTA (Macracyclic, TX, USA), l- ethyl-3- (3-dimethylaminopropyl) carbodiimide EDAC (Fluka). PMMA酯基团的 PMMA ester groups

水解:向冷却到0'C的甲醇:水(l: l)中的PMMA微颗粒悬浮液中,在搅拌下逐35 滴加入过量的10(N)NaOH。 Hydrolysis: To a cooled to 0'C methanol: water (l: l) PMMA microparticles in suspension, under stirring by dropwise addition of excess 35 10 (N) NaOH. 反应混合物在0。 The reaction mixture at 0. C搅拌1.5小时,在40。 C stirred for 1.5 hours at 40. C搅拌16小吋。 C was stirred for 16 inches. 微颗粒用Ol(N)HCl和甲醇:水(l: l)洗涤,离心,倒空液体,重新悬浮于PBS (7.4) 中,获得PMMA-COOH。 Microparticles with Ol (N) HCl and methanol: water (l: l), centrifuged, emptying the liquid and resuspended in PBS (7.4), obtained PMMA-COOH. [235]实施例2: PMMA-COOH球体的活化和偶联到PAMAM树枝状大分子 [235] Example 2: PMMA-COOH sphere activation and coupling to dendrimers PAMAM

[236]如上制备的PMMA-COOH微颗粒(IO mg)在10 ml PBS中洗涤2次。 [236] PMMA-COOH microparticles (IO mg) prepared as above was washed twice in 10 ml PBS in. 将沉淀5 物(pellet)重新悬浮在10 ml的PBS中,并加入100 mg的EDAC,混合。 The precipitate was 5 (a pellet) is resuspended in 10 ml of PBS and 100 mg of EDAC were added, and mixed. 反应混合物在室温搅拌15-30分钟,然后加入处于5ml PBS中的树枝状大分子(PAMAM-NH2)(10X)。 The reaction mixture was stirred at room temperature for 15-30 minutes and then added in dendrimer (PAMAM-NH2) (10X) 5ml PBS in. 使反应在室温中继续进行30分钟至1小时。 The reaction was continued at room temperature for 30 minutes to 1 hour. 微颗粒(PMMA-PAMAM-NH2)用PBS洗涤2次,并重新悬浮于PBS中。 Microparticles (PMMA-PAMAM-NH2) were washed twice with PBS, and and resuspended in PBS.

10 [237] l-乙基-3-(3-二甲基氨基丙基)碳二亚胺(EDAC)的反应/水解速度随低pH而增力口。 10 [237] l- ethyl-3- (3-dimethylaminopropyl) carbodiimide (EDAC) in the reaction / hydrolysis rate with low pH and booster port. 反应的最佳缓冲范围是pH4.5-7.5。 The optimum range of the reaction buffer is pH4.5-7.5. 在单一步骤中,进行EDAC介导的COOH 基团活化和与NH2-官能基团的偶联,对于偶联更大的分子来说常常是困难的,然而对于更小的分子像半抗原和类固醇是有效的。 In a single step, the activated coupling group and a COOH group NH2- functional groups EDAC-mediated coupling to larger molecules, it is often difficult, however, for smaller molecules like haptens and steroids It's effective. EDAC与羧基反应,得到中间产物o-acylisourea。 EDAC is reacted with a carboxyl group, to give intermediate o-acylisourea. 该中间产物与胺反应,形成肽结合的偶联物。 The intermediate reaction product with an amine, to form a peptide conjugate bound. 然而,该中间产物 However, this intermediate

15 在水溶液中发生水解,因此,稳定性通常是必需的,这可以通过加入N-羟基琥珀酰亚胺来实现。 15 hydrolysis in aqueous solution, therefore, stability is often required, which can be achieved by adding N- hydroxysuccinimide. 为了减少树枝状大分子之间偶联,PAMAM的浓度应该大大过量(也请参见Holmberg K, Hyden H. Methods of immobilization of proteins to polymethacrylate. Preparative Biochemistry, 15 (5): 309-319 (1985》。 In order to reduce the coupling between dendrimers PAMAM concentration should be large excess (also see Holmberg K, Hyden H. Methods of immobilization of proteins to polymethacrylate Preparative Biochemistry, 15 (5):. 309-319 (1985 ".

20 [238]实施例3 : DOTA螯合剂附着到树枝状大分子以便传送钇 20 [238] Example 3: DOTA chelating agent is attached to the dendrimer for delivery yttrium

[239]向PMMA-PAMAM-NH2微颗粒的PBS悬浮液中,搅拌着逐滴加入p-N02-Bz-DOTA的PBS溶液。 [239] PBS to a suspension of PMMA-PAMAM-NH2 micro particles, was added dropwise with stirring p-N02-Bz-DOTA in PBS. 在室温中,反应混合物搅拌16小时。 At room temperature, the reaction mixture was stirred for 16 hours. 过夜搅拌之后,珠子用PBS洗涤2次,并重新悬浮于缓冲液中。 After stirring overnight, the beads were washed twice with PBS, and and resuspended in buffer. 可替代地,使用同样的方法, 25 与p-NH2-Bz-DOTA(Macrocyclic, TX, USA)反应,也能将DOTA直接偶联到PMMA-COOH微颗粒。 Alternatively, using the same method, reaction of 25 with p-NH2-Bz-DOTA (Macrocyclic, TX, USA), it can also be directly conjugated to DOTA PMMA-COOH microparticles.

[240]实施例4:微颗粒螯合剂浓度的测定 4 [240] Example: Determination of microparticle concentration of chelating agent

30 [241]在变化量的钇-89存在的条件下,使用恒定量的钇-90(100pCi),测定螯合剂的浓度,总钇浓度在20-1000 ^M范围内,其中,钇90-lpm。 30 [241] Under the condition change amount of yttrium present -89, using a constant amount of yttrium -90 (100pCi), determining the concentration of the chelating agent, the total concentration of yttrium in the M range 20-1000 ^, wherein yttrium 90- lpm. 简单地说,钇-90 (20 mCi,在100 pl的50 mMHCl中)或在50 mM的HC1中的氯化钇-89,用50 的50 mM HCl和350^L的50mM拧檬酸钠稀释。 Briefly, (, 20 mCi in 50 mMHCl 100 pl's), diluted with ^ yttrium chloride, yttrium-90 or -89 in HC1 50 mM in a 50 mM HCl 50 and 350 L of 50mM sodium citric . 在典型的测定中,钇-89溶液(100-200 ^Ci, 4^1),钇-89溶液(5 pL),含有10mM柠檬酸钠pH 7.4的lOOmM组氨酸缓冲 In a typical assay, a solution of yttrium -89 (100-200 ^ Ci, 4 ^ 1), yttrium -89 solution (5 pL), containing 10mM histidine pH lOOmM sodium citrate buffer 7.4

35 液(25 pL),水(16 pi);在50mM组氨酸缓冲液中的2mg/mL的微颗粒(50pl),该50mM 组氨酸缓冲液含有5mM pH7.4的柠檬酸钠。 35 solution (25 pL), water (16 pi); in 50mM histidine buffer 2mg / mL microparticles (50pl), the histidine buffer containing 50mM sodium citrate in 5mM pH7.4. 结合到颗粒上的钇用上面描述的方法测定,由结合的钇的百分比对钇浓度作图,由该图外推确定螯合剂浓度。 Binding assay described above to use a method of yttrium on the particles, a percentage of yttrium is yttrium binding plotted against the concentration by determining the concentration of chelating agent to push the outer FIG. 可选择性地,通过加入变化数量的钇-89到微颗粒,然后加入钇-卯,来测定螯合剂浓度。 Optionally, by addition of varying amounts of yttrium microparticles to -89, followed by addition of yttrium - d, the chelating agent concentration determined.

[242]这些滴定实验过加入"冷(cold)"钇-89到微颗粒,然后加入钇-90同位素, 测量结合到微颗粒的钇-90的量来实施。 [242] These experiments titration addition of "cold (Cold)" microparticles to -89 yttrium, yttrium-90 isotope is then added, to measure the amount of yttrium-90 bound microparticles be implemented. 随着钇-89数量增加,钇-90的结合减少, As the number of yttrium -89, combined with yttrium-90 is reduced,

5 这是因为微颗粒上的结合位点饱和,导致钇-90的结合被抑制的缘故。 5 This is because the binding sites on the microparticles saturation, resulting in binding sake of yttrium-90 is suppressed. 在钇-90不再有结合的时候,钇-89浓度等于螯合位点的浓度。 Yttrium-90 is no longer at the time of binding, a concentration equal to the concentration of yttrium -89 chelation site. 可选择性地,滴定是这样的进行的,将微量的钇-90加入到钇-89,将该含有过量钇-89的混合物加入到微颗粒。 Selectively, titration is carried out, a trace amount of yttrium-90, yttrium is added to -89, the mixture contains an excess of yttrium-89 is added to the microparticles. 存在于溶液中的、测量得到的DOTA螯合剂的浓度与计算得到的浓度相符。 Present in the solution, the concentration of the chelating agent DOTA and calculation of the measured concentration obtained match. 对于含有1和5摩尔百分比的DOTA螯合剂的微颗粒,计算得到的浓度0.11和0.55 mM For microparticles containing the chelating agent DOTA 1 and 5 mole percent of 0.11 and a calculated concentration 0.55 mM

10 与测量得到的浓度0.5和0.1 mM的DOTA螯合剂很相符。 10 is consistent with the measured concentrations of 0.5 and 0.1 mM of the chelating agent DOTA.

[243]实施例5: Y-卯结合到微颗粒 [243] Example 5: Y- bound to microparticles d

[244]通过螯合到DOTA螯合剂,将天然发生的钇-89以及同位素钇-90和铟-111 15 附着到微颗粒。 [244] by a DOTA chelator chelated to, naturally occurring -89 yttrium and yttrium-90 isotope and indium -11115 attached to microparticles. 标记效率大于98%,钇-90的标记容量为每mg颗粒约10 mCi。 Labeling efficiency greater than 98%, yttrium-90 labeled capacity per mg of particles of about 10 mCi. 在醋酸盐、MES和HEPES缓冲液中,检测pH对钇-90结合效率的影响,结果,在pH5-7内,结合是不受pH影响的。 In acetate, MES and HEPES buffer, pH detection of yttrium-90 Binding efficiency, result in the pH 5-7, binding is not affected by pH. 微颗粒也可以用铟-111标记,铟-Ul是常用于体内成像研究的Y-放射同位素。 Microparticles may be labeled with indium-111, indium -Ul is commonly used for in vivo imaging studies Y- radioisotope. 在每mg微颗粒50-500 ^Ci的载量水平,测量标记效率。 50-500 mg per microparticles Ci ^ loading level measured labeling efficiency. 因为金属结合容量高的缘故,微颗粒也同时结合钇-90和铟-111。 Since high-capacity metal binding reason, the microparticles also bind indium-111 and yttrium-90. 按照每mg 20 微颗粒每种同位素为0.1或1 mCi,进行后续的装载实验(sequential loading experiments),测量所得到的两种同位素的结合百分比。 Mg 20 microparticles each according to each of the isotopes of 0.1 or 1 mCi, subsequent loading experiments (sequential loading experiments), the percentage of binding two isotopes measurements obtained.

[245]实施例6:由标记Y-90的微颗粒的稳定性——组氨酸攻击研究(Histidine challenge studies ) [245] Example 6: Stability of Labeled microparticles of Y-90 - histidine challenge studies (Histidine challenge studies)

25 25

[246]在50 mM HC1中的氯化钇-90或氯化铟-111(10-20 mCi)用50 mM柠檬酸(pH 4)稀释,得到50 mCi/mL的溶液。 [246] chloride of yttrium-90 or indium-111 chloride in 50 mM HC1 in (10-20 mCi) was diluted with 50 mM citric acid (pH 4), 50 mCi / mL was obtained. 向50 mM的组氨酸缓冲液中的90 微颗粒溶液,加入含有100-200 ^Ci的10 同位素溶液,所述组氨酸缓冲液含有pH7的5 mM柠檬酸盐。 90 microparticles to a solution of 50 mM histidine buffer, added to the solution containing 100-200 Ci ^ 10 isotope, and the histidine buffer solution containing 5 mM of citrate pH7. 将溶液在室温温育30分钟,然后加入到100K MWCO旋转滤筒(spin 30 filter cartridge) (Nanosep),旋转滤筒被置于台式高速离心机(table top centrifoge) 中。 The solution was incubated for 30 minutes at room temperature, then added to a 100K MWCO filter cartridge rotation (spin 30 filter cartridge) (Nanosep), rotation of the filter cartridge is placed in a high-speed desktop centrifuge (table top centrifoge) in. 在3000 rpm旋转90-120分钟之后,使用Capintec CRC-15R剂量校准器(dose calibrator)对同位素进行量化。 After the 3000 rpm rotational 90-120 minutes using a Capintec CRC-15R dose calibrator (dose calibrator) isotopic quantized. 将筒的含有微颗粒-同位素复合物的过滤部分移走, 对剩下的未结合的同位素进行量化。 The cartridge containing microparticles - isotopes composite filter portion is removed, the remaining unbound isotope quantify. 这些值被用来计算结合的金属的百分比,或每mg微颗粒结合的同位素的数量。 The percentage of metal used to calculate these values ​​are combined, or the quantity bound per mg of microparticles isotopes.

35 35

[247]实施例7:微颗粒-同位素结合物的体外稳定性[248]为了评价结合物在血清中的稳定性,将含有5摩尔百分比的螯合剂的微颗粒90Y复合物在37。 [247] Example 7: Microparticles - stability in vitro [248] isotope conjugates To evaluate the stability thereof in conjunction with serum, containing 5 mole percent of the chelating agent in the composite microparticles 90Y 37. C温育在兔血清中。 C incubated in rabbit serum. 将溶液在室温温育30分钟,然后加入到100K MWCO旋转滤筒(Nanosep),旋转滤筒被置于台式高速离心机中。 The solution was incubated at room temperature for 30 minutes and then added to a rotary filter cartridge 100K MWCO (a Nanosep), high-speed rotation of the filter cartridge is placed in a desktop centrifuge. 在3000 rpm旋转90-120分钟后,使用CapintecCRC-15R剂量校准器对同位素进行量化。 After 90-120 minutes the rotation 3000 rpm, using a dose calibrator CapintecCRC-15R isotopic quantized. 移走含5 有微颗粒-同位素复合物的筒过滤部分,对剩下的未结合的同位素进行量化。 Removing particulate containing 5 micro - cylindrical filter composite isotope portion, the remaining unbound isotope quantify. 这些值被用来计算结合的金属的百分比,或每mg微颗粒结合的同位素的数量。 The percentage of metal used to calculate these values ​​are combined, or the quantity bound per mg of microparticles isotopes.

[249]实施例8:对DOTA螯合剂进行特异性Y-90标记 [249] Example 8: DOTA chelating agents specific for Y-90 labeled

10 [250]在DOTA-脂的浓度为0.56-560 的情况下,用弱螯合剂柠檬酸盐和强螯合剂二乙胺三胺五乙酸(DTPA)温育微颗粒90Y复合物,证明了在囊泡(vesicles)上的DOTA的特异性标记。 10 [250] DOTA- lipid concentration is 0.56-560 case, the weak and strong chelator chelating citrate diethylamine triamine pentaacetic acid (DTPA) was incubated 90Y composite microparticles, vesicles proved DOTA-specific markers on the (vesicles). 金属复合物在500mM拧檬酸盐存在的条件下是稳定的, 在lmM DTPA存在的条件下,对微颗粒90Y复合物温育30分钟后,约90%的钇保留下来。 Metal complexes are stable in the presence of 500mM citric acid, in the presence of lmM DTPA, after incubation of the composite fine particles 90Y 30 minutes, about 90% of yttrium retained.

15 15

[251]本发明提供了现场制备试剂的实施方法,这样,它可以被优化以满足患者剂量要求(patient dose requirements)和医疗设施和人员安排。 [251] embodiment of the present invention provides a method of reagent preparation site, so that it can be optimized to meet the requirements of the patient dose (patient dose requirements) and medical facilities and personnel arrangements. 此外,本发明具有下述优点:i)提供了使用Y、 P和a放射性核素来进行放射性检测和/或治疗的手段, Y、 P和(x放射性核素在同一颗粒上单独使用或联合使用;ii)提供了准确测量生物20 分布和被施用的组织剂量的手段;不需要该产品预先在使用场所外的核反应器中产生,从而最大程度地适用于世界各地的私人、大学或公共管理(managed-care) 医疗中心。 Further, the present invention has the following advantages: i) providing a use Y, P, and performs a radionuclide radioactive detection means and / or treated, Y, P, and (x radionuclide used alone or in combination on the same particles use; ii) provide a means to accurately measure tissue dose of 20 distribution creatures and are administered; do not need the product generated in advance in the use of nuclear reactor outside of grounds, to the greatest extent applicable to the world of private, university or public administration (managed-care) medical Center.

[252]本发明的微颗粒特别吸引人的优点是,它们提供了血流分布(blood flow 25 distribution)的动脉内检测,以及可以用于对任何目标器官(其需要辐射治疗以破 [252] a particularly attractive micro-particles of the present invention has the advantage that they offer a distribution of blood flow (blood flow 25 distribution) detected intra-arterial, and can be used for any target organ (which require radiation therapy to break

坏、杀死、抑制异常细胞和/或促进异常细胞死亡)或血管内的可接近肿瘤(intravascularly accessible tumor)进行辐射治疗。 Bad, kill, suppress abnormal cells and / or promote abnormal cell death) or accessible tumors (intravascularly accessible tumor) intravascular radiation treatment. 用a或卩发射放射性核素对血管 Emitting radionuclide or a pair of vessels with Jie

可接触的器官或肿瘤进行的治疗,允许通过将本发明的多个微颗粒施给需要辐射 Treating an organ or tumor can be contacted, and allows a plurality of microparticles of the present invention is administered to a required radiation

治疗的患者来完成辐射治疗。 Patients treated with radiation therapy to complete. 在选择性的实施方案中,微颗粒还包括诊断或成像30放射性核素。 In alternative embodiments, the microparticles further comprise diagnostic or imaging radionuclide 30.

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[266] 14. Blanchard RJ, LaFave JW, Kim YS. Treatment of Patients with Advanced Cancer Using Y-90 microspheres. Cancer 1965; 18: 375. . [266] 14. Blanchard RJ, LaFave JW, Kim YS Treatment of Patients with Advanced Cancer Using Y-90 microspheres Cancer 1965; 18:. 375.

[267] 15, Kim YS, LaFave JW, MacLean LD. The Use of Radiating Microspheres in the Treatment of Experimental and Human Malignancy. Surgery 1962; 52: 220. [267] 15, Kim YS, LaFave JW, MacLean LD The Use of Radiating Microspheres in the Treatment of Experimental and Human Malignancy Surgery 1962; 52:.. 220.

[268] 16. Blanchard RJW. Treatment of Liver tumours with yttrium-90 microspheres. 10 The Canadian Journal of Surgery 1983; 26: 442-443. [268] 16. Blanchard RJW Treatment of Liver tumours with yttrium-90 microspheres 10 The Canadian Journal of Surgery 1983; 26:.. 442-443.

[269] 17, Mantravadi RV, Spigos DG, Tan WS, Felix EL. Intraarterial yttrium 90 in the treatment of hepatic malignancy. Radiology 1982; 142: 783-6. . [269] 17, Mantravadi RV, Spigos DG, Tan WS, Felix EL Intraarterial yttrium 90 in the treatment of hepatic malignancy Radiology 1982; 142:. 783-6.

15 [270] 18' Ariel IM, Padula G Treatment ofasymptomatic metastatic cancer to the liver from primary colon and rectal cancer by the intraarterial administration of chemotherapy and radioactive isotopes. J Surg Oncol 1982; 20: 151-6. 15 [270] 18 'Ariel IM, Padula G Treatment ofasymptomatic metastatic cancer to the liver from primary colon and rectal cancer by the intraarterial administration of chemotherapy and radioactive isotopes J Surg Oncol 1982; 20:. 151-6.

[271] 19. Grady ED. Internal radiation therapy of hepatic cancer, Dis Colon Rectum 20 1979;22:371-5. . [271] 19. Grady ED Internal radiation therapy of hepatic cancer, Dis Colon Rectum 20 1979; 22: 371-5.

[272] 20. Blanchard RJ, Morrow IM, Sutherland JB. Treatment of liver tumors with yttrium-90 microspheres alone. Can Assoc Radiol J 1989; 40:206-10. .. [272] 20. Blanchard RJ, Morrow IM, Sutherland JB Treatment of liver tumors with yttrium-90 microspheres alone Can Assoc Radiol J 1989; 40: 206-10.

25 [273] 21. Burton MA, Gray BN, Jones C, Coletti A. Intraoperative dosimetry of 90Y in liver tissue. Int JRadAppl Inst謹B 1989; 16: 495-8. . 25 [273] 21. Burton MA, Gray BN, Jones C, Coletti A. Intraoperative dosimetry of 90Y in liver tissue Int JRadAppl Inst wish B 1989; 16: 495-8.

[274] 22. Anderson JH, Goldberg JA, Bessent RG, et al. Glass yttrium-90 microspheres for patients with colorectal liver metastases, Radiother Oncol 1992; 25: 137-9. . [274] 22. Anderson JH, Goldberg JA, Bessent RG, et al Glass yttrium-90 microspheres for patients with colorectal liver metastases, Radiother Oncol 1992; 25: 137-9.

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35 [276] 24. Yan ZP, Lin G, Zhao HY, Dong YH. An experimental study and clinical pilot trials on yttrium-90 glass microspheres through the hepatic artery for treatment of primary liver cancer. Cancer 1993; 72: 3210-5. . 35 [276] 24. Yan ZP, Lin G, Zhao HY, Dong YH An experimental study and clinical pilot trials on yttrium-90 glass microspheres through the hepatic artery for treatment of primary liver cancer Cancer 1993; 72:. 3210-5 .

[277] 25. Andrews JC, Walker SC, Ackermann RJ, Cotton LA, Ensminger WD, Shapiro 40 B. Hepatic radioembolization with yttrium-90 containing glass microspheres : preliminary results and clinical follow-up [see comments]. J Nucl Med 1994; 35:1637-44. [277] 25. Andrews JC, Walker SC, Ackermann RJ, Cotton LA, Ensminger WD, Shapiro 40 B. Hepatic radioembolization with yttrium-90 containing glass microspheres:. Preliminary results and clinical follow-up [see comments] J Nucl Med 1994 ; 35: 1637-44.

[278] 26. Lau WY, Leung WT, Ho SK, et al. Treatment of inoperable hepatocellular carcinoma with intrahepatic arterial yttrium-90 microspheres: a phase I and II study, Br 5 J Cancer 1994; 70: 994-9. [278] 26. Lau WY, Leung WT, Ho SK, et al Treatment of inoperable hepatocellular carcinoma with intrahepatic arterial yttrium-90 microspheres:. A phase I and II study, Br 5 J Cancer 1994; 70: 994-9.

[279] 27. Leung TW, Lau WY, Ho SK, et al. Radiation pneumonitis after selective internal radiation treatment with intraarterial 90yttrium-microspheres for inoperable hepatic tumors. Int J Radiat 0,1 Biol Phys 1995; 33: 919-24. .. [279] 27. Leung TW, Lau WY, Ho SK, et al Radiation pneumonitis after selective internal radiation treatment with intraarterial 90yttrium-microspheres for inoperable hepatic tumors Int J Radiat 0,1 Biol Phys 1995; 33: 919-24.

10 10

[280] 28. Leung WT, LauWY, Ho SK, et al. Measuring hmg shunting in hepatocellular carcinoma with intrahepatic-arterial teclmetium-99m macroaggregated albumin. J Nucl Med 1994; 35: 70-3. . [280] 28. Leung WT, LauWY, Ho SK, et al Measuring hmg shunting in hepatocellular carcinoma with intrahepatic-arterial teclmetium-99m macroaggregated albumin J Nucl Med 1994; 35:. 70-3.

15 [281] 29. Kennedy AS, Murthy R, Sarfaraz M, et al. Outpatient Hepatic Artery Brachytherapy for Primary and Secondary Hepatic Malignancies. Radiology 2001; 221P:468. .. 15 [281] 29. Kennedy AS, Murthy R, Sarfaraz M, et al Outpatient Hepatic Artery Brachytherapy for Primary and Secondary Hepatic Malignancies Radiology 2001; 221P: 468.

[282] 30. Kennedy AS, Murthy R, Van Echo DA. Preliminary Results of Outpatient 20 Hepatic Artery Brachytherapy for Colorectal Hepatic Metastases. European Journal of Cancer 2001 ;37: 289. . [282] 30. Kennedy AS, Murthy R, Van Echo DA Preliminary Results of Outpatient 20 Hepatic Artery Brachytherapy for Colorectal Hepatic Metastases European Journal of Cancer 2001; 37:. 289.

[283] 31. Kennedy AS, Murthy R, Kwok Y, al. e. Hepatic Artery Brachytherapy for Unresectable Hepatocellular Carcinoma: An Outpatient Treatment Approach. 25 Proceedings of the 12th International Congress on Anti-Cancer Treatment 2002; 1: 198-199, ... [283] 31. Kennedy AS, Murthy R, Kwok Y, al e Hepatic Artery Brachytherapy for Unresectable Hepatocellular Carcinoma: An Outpatient Treatment Approach 25 Proceedings of the 12th International Congress on Anti-Cancer Treatment 2002; 1: 198-199 ,

[284] 32. Kennedy AS, Salem R, Comparison of two 90Yttrium microsphere agents for hepatic artery brachytherapy. Proceedings of the 14th International Congress on 30 Anti-Cancer Treatment 2003: 156. [284] 32. Kennedy AS, Salem R, Comparison of two 90Yttrium microsphere agents for hepatic artery brachytherapy Proceedings of the 14th International Congress on 30 Anti-Cancer Treatment 2003:. 156.

[285] 33. Kennedy AS, Van Echo DA, Murthy R, al. e. Colorectal (CRQ liver metastases and Hepatocellular carcinoma (HCC) treated with outpatient hepatic artery brachytherapy, TheraSphere: Imaging response and toxicity. Int J Cancer 2002; S 13 : 35 226-227. ... [285] 33. Kennedy AS, Van Echo DA, Murthy R, al e Colorectal (CRQ liver metastases and Hepatocellular carcinoma (HCC) treated with outpatient hepatic artery brachytherapy, TheraSphere: Imaging response and toxicity Int J Cancer 2002; S 13:35 226-227.

[286] 34. Kennedy AS, Van Echo DA, Murthy R, al. e. Hepatic artery brachytherapy for neuroendocrine carcinoma. Regulatory Peptides 2002; 108: 32. ... [286] 34. Kennedy AS, Van Echo DA, Murthy R, al e Hepatic artery brachytherapy for neuroendocrine carcinoma Regulatory Peptides 2002; 108: 32.

40 [287] 35. Murthy R, Kennedy AS, Coldwell D, al, e. Technical aspects of TheraSphere (TS) infusion. J Vase Interv Radiol 2002; 13:S2.[288] 36. Murthy R, Kennedy AS, Tucker Q al. e. Outpatient trans arterial hepatic'low dose rate' (TAH-LDR) brachytherapy for unresectable hepatocellular carcinoma. Proceedings of American Association for Cancer Research 2002; 43: 485. .. 40 [287] 35. Murthy R, Kennedy AS, Coldwell D, al, e Technical aspects of TheraSphere (TS) infusion J Vase Interv Radiol 2002; 13: S2 [288] 36. Murthy R, Kennedy AS, Tucker. .. Q al e Outpatient trans arterial hepatic'low dose rate '(TAH-LDR) brachytherapy for unresectable hepatocellular carcinoma Proceedings of American Association for Cancer Research 2002; 43:. 485.

[289] 37. Murthy R, Line BR, Kennedy AS, al. e. Clinical utility of Brehmstralung scan (BRM-Scan) after TheraSphere (TS). J Vase Interv Radiol 2002; 13:S2. ... [289] 37. Murthy R, Line BR, Kennedy AS, al e Clinical utility of Brehmstralung scan (BRM-Scan) after TheraSphere (TS) J Vase Interv Radiol 2002; 13: S2.

[290] 38. Sarfaraz M, Kennedy AS, Cao ZJ, Li A, Yu C. Radiation Dose Distribution in 10 Patients Treated with Y-90 Microspheres for Non-Resectable Hepatic Tumors. International Journal of Radiation Biology and Physics 2001; 51: 32-33. [290] 38. Sarfaraz M, Kennedy AS, Cao ZJ, Li A, Yu C. Radiation Dose Distribution in 10 Patients Treated with Y-90 Microspheres for Non-Resectable Hepatic Tumors International Journal of Radiation Biology and Physics 2001; 51.: 32-33.

[291] 39. Van Echo DA, Kennedy AS, Coldwell D. TheraSphere (TS) at 143 Gy median dose for mixed hepatic cancers; feasibility and toxicities. Amer Soc Clin Oncol 2001 ; 15 260a: 1038. [291] 39. Van Echo DA, Kennedy AS, Coldwell D. TheraSphere (TS) at 143 Gy median dose for mixed hepatic cancers; feasibility and toxicities Amer Soc Clin Oncol 2001; 15 260a:. 1038.

[292] 40. Coldwell D, Kennedy AS, Van Echo DA, al. e. Feasibility of trea加ent of hepatic tumors utilizing embolization with yttrium-90 glass microspheres. J Vase Interv Radiol 2001; 12: S113. .. [292] 40. Coldwell D, Kennedy AS, Van Echo DA, al e Feasibility of trea added ent of hepatic tumors utilizing embolization with yttrium-90 glass microspheres J Vase Interv Radiol 2001; 12:. S113.

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[293] 41. Wright AA, Jenkins JJ, Lodge MA, Murthy R, Kennedy AS, Line BR. Predictive factors in 90Y microsphere therapy for shunt fraction. J Nuclear Medicine 2002; 43: 103P. .. [293] 41. Wright AA, Jenkins JJ, Lodge MA, Murthy R, Kennedy AS, Line BR Predictive factors in 90Y microsphere therapy for shunt fraction J Nuclear Medicine 2002; 43: 103P.

25 [294] 42. Mourtzikos K, Lodge MA, Maragh M, et al. Measurement of Hepatopulmonary shunt fraction prior to 90Y microsphere treatment of hepatic malignancy. J Nuclear Medicine 2002; 43: 317P. .. 25 [294] 42. Mourtzikos K, Lodge MA, Maragh M, et al Measurement of Hepatopulmonary shunt fraction prior to 90Y microsphere treatment of hepatic malignancy J Nuclear Medicine 2002; 43: 317P.

[295] 43. Hisley C, Lodge MA, Kennedy AS,Mourtzikos K, Line BR. Estimation of 30 90Y TheraSphere Treatment Effectiveness by Statistical Segmentation of Hepatic Tissue Volumes. J Nuclear Medicine 2002; 43: 103R .. [295] 43. Hisley C, Lodge MA, Kennedy AS, Mourtzikos K, Line BR Estimation of 30 90Y TheraSphere Treatment Effectiveness by Statistical Segmentation of Hepatic Tissue Volumes J Nuclear Medicine 2002; 43: 103R

[296] 44.Hafeli UO, Casillas S, Dietz DW, et al. Hepatic tumor radioembolization in a rat model using radioactive rhenium (186RE/188RE) glass microspheres. Int J Radiat 35 Oncol Biol Phys 1999; 44: 189-199. .. [296] 44.Hafeli UO, Casillas S, Dietz DW, et al Hepatic tumor radioembolization in a rat model using radioactive rhenium (186RE / 188RE) glass microspheres Int J Radiat 35 Oncol Biol Phys 1999; 44: 189-199.

Claims (90)

1.一种微颗粒,包括: 核心; 位于所述核心上的至少一种连接载体,其中所述连接载体包括生物相容性聚合物,和共价结合于所述连接载体的至少一种放射性治疗剂; 其中所述微颗粒的直径在约5至约200微米范围内,所述微颗粒是非生物可降解的。 A microparticle, comprising: a core; a core of the at least one connection carrier, wherein said carrier comprises at least one connecting radioactivity bound to the carrier is connected to a biocompatible polymer, and covalent a therapeutic agent; wherein the diameter of said microparticles is in the range of about 5 to about 200 microns, the microparticles are non-biodegradable.
2. 如权利要求1所述的颗粒,其中所述至少一种放射性治疗剂是(x-发射放射性核素、 P-发射放射性核素或Y-发射放射性核素。 2. A particle according to claim 1, wherein the at least one therapeutic agent is a radioactive (x- emitting radionuclide, P- or Y- emitting radionuclides emitting radionuclide.
3. 如权利要求l所述的颗粒,其中所述至少一种放射性治疗剂包括a-发射放射性核素和卩-发射放射性核素。 L of the particles as claimed in claim 3, wherein said therapeutic agent comprises at least one radiation emitting radionuclide and a- Jie - emitting radionuclide.
4. 如权利要求I所述的颗粒,其中所述至少一种放射性治疗剂包括卩-发射放射性核素和Y-发射放射性核素。 4. The particle of claim I, wherein the at least one therapeutic agent comprises radioactive Jie - emitting radionuclide and Y- emitting radionuclide.
5. 如权利要求1所述的颗粒,其中所述至少一种放射性治疗剂包括a-发射放射性核素和Y-发射放射性核素。 5. The particle according to claim 1, wherein said therapeutic agent comprises at least one radiation emitting radionuclide and Y- a- emitting radionuclide.
6. 如权利要求1所述的颗粒,其中所述至少一种放射性治疗剂包括治疗用放射性核素和成像或诊断用放射性核素。 6. The particle according to claim 1, wherein the at least one therapeutic agent comprises radioactive therapeutic or diagnostic radionuclide imaging and radionuclide.
7. 如权利要求6所述的颗粒,其中所述治疗用放射性核素是卩-发射放射性核素,所述成像或[会断用放射性核素是Y-发射放射性核素。 7. Particles according to claim 6, wherein the therapeutic radionuclide is Jie - emitting radionuclide, the imaging or [off with a radionuclide may be Y- emitting radionuclide.
8. 如权利要求6所述的颗粒,其中所述治疗用放射性核素选自Y-90、Bi-213、At-211、 1-123、 1-125、 1-131、 At-211、 Cu-67、 Sc-47、 Ga-67、 Rh-105、 Pr-142、 Nd-147、 Pm-151、 Sm-153、 Ho-166、 Gd-159、 Tb-161、 Eu-152、 Er-171、 Re-186和Re-亂 8. Particles according to claim 6, wherein the therapeutic radionuclide is selected from Y-90, Bi-213, At-211, 1-123, 1-125, 1-131, At-211, Cu -67, Sc-47, Ga-67, Rh-105, Pr-142, Nd-147, Pm-151, Sm-153, Ho-166, Gd-159, Tb-161, Eu-152, Er-171 , Re-186, and Re- chaos
9. 如权利要求6所述的颗粒,其中所述成像或诊断用放射性核素选自Tc-99m、In-lll、 Ga-67、 Rh-105、 1-123、 Nd-147、 Pm-151、 Sm-153、 Gd-159、 Tb-161、 Er-171、 Re-186、 Re-188禾HTl- 201。 9. Particles according to claim 6 Pm-151, wherein said diagnostic imaging or radionuclide selected from Tc-99m, In-lll, Ga-67, Rh-105, 1-123, Nd-147, , Sm-153, Gd-159, Tb-161, Er-171, Re-186, Re-188 Wo HTl- 201.
10. 如权利要求6所述的颗粒,其中所述治疗用放射性核素包括钇-90,所述成像或诊断用放射性核素包括铟-111或Tc-99m。 10. Particles according to claim 6, wherein said therapeutic radionuclides include yttrium-90, or said diagnostic imaging comprises indium-111 or Tc-99m radionuclide.
11. 如权利要求l所述的颗粒,其中所述放射性治疗剂是放射性核素或放射性药物。 11. The particles of claim l, wherein said radiotherapeutic agent is a radionuclide or radiopharmaceutical.
12. 如权利要求ll所述的颗粒,其中所述放射性核素选自铱、镭、铯、磷、钇、铼、 锕、铋、砹、锝、铟、碘,和碳、氮、氟、钠、镁、铝、硅、钾、钒、锰、镓、铌、 碘、铅、Y-90、 Bi-213、 At-2U、 1-123、 1-125、 1-131、 At-2H、 Cu-67、 Sc-47、 Ga-67、 Rh-105、 Pr-142、 Nd陽147、 Pm-151、 Sm-153、 Ho掘、Gd-159、 Tb-161、 Eu-152、 Er-171、 Re-186、 Re-188、 Tc-99m、 In-lll、 Ga-67、 Rh-105、 1-123、 Nd-147、 Pm-151、 Sm-153、 Gd-159、 Tb-161、 Er-171、 Re-186、 Re-188和T1-201 。 12. The particle of Claim ll, wherein the radionuclide is selected from iridium, radium, cesium, phosphorus, yttrium, rhenium, actinium, bismuth, astatine, technetium, indium, iodine, carbon, nitrogen, fluorine, sodium, magnesium, aluminum, silicon, potassium, vanadium, manganese, gallium, niobium, iodine, lead, Y-90, Bi-213, At-2U, 1-123, 1-125, 1-131, At-2H, Cu-67, Sc-47, Ga-67, Rh-105, Pr-142, Nd male 147, Pm-151, Sm-153, Ho dig, Gd-159, Tb-161, Eu-152, Er-171 , Re-186, Re-188, Tc-99m, In-lll, Ga-67, Rh-105, 1-123, Nd-147, Pm-151, Sm-153, Gd-159, Tb-161, Er -171, Re-186, Re-188, and T1-201.
13. 如权利要求1所述的颗粒,其中所述放射性治疗剂是钇-卯。 13. The particle according to claim 1, wherein said radiotherapeutic agent is yttrium - d.
14. 如权利要求l所述的颗粒,其中所述放射性治疗剂通过一个或多个间隔基团或螯合剂基团被共价结合到所述连接载体。 14. The particles of claim l, wherein said radiotherapeutic agent is covalently bonded via one or more spacer groups or chelating groups into the connection carrier.
15. 如权利要求l所述的颗粒,其中所述放射性治疗剂通过螯合剂基团被共价结合到所述连接载体。 15. The particles of claim l, wherein said radiotherapeutic agent is covalently bound to the chelator radical by connection carrier.
16. 如权利要求15所述的颗粒,其中所述螯合剂基团是选自下述物质中的至少一种: 环己基二亚乙基三胺五乙酸配体(CHX-DTPA)、 二亚乙基三胺五乙酸(DTPA)、乙二胺四乙酸(EDTA)、 1,4,7,10-四氮杂环十二垸-N,N',N,"N"'四乙酸(DOTA)、四氮杂环十四垸-N,N",N〃N"-四乙酸(TETA)、环己基1,2-二胺四乙酸(CDTA)、乙二醇-0,0'-二(-2-氨乙基)-N,N,N',N'-四-乙酸(EGTA)、 N,N-二(羟苄基)-乙二胺-N,N'-二乙酸(HBED)、三亚乙基四胺六乙斷TTHA)、羟乙基二胺三乙酸(HEDTA)、羟基乙叉二膦酸(HEDP)、 二巯基琥珀酸(DMSA)、 二亚乙基三胺四亚甲基瞵酸(DTTP)和l-(p—氨苄基)-DTPA、 1,6-二氨基己垸N,N,N',N'-四乙酸、DPDP和亚乙基二(氧乙烯腈基)-四乙酸。 16. The particle according to claim 15, wherein the chelating agent is at least one group selected from the following substances: cyclohexyl diethylenetriamine pentaacetic acid ligand (CHX-DTPA), diethylenetriamine diethylenetriaminepentaacetic acid (DTPA), ethylenediaminetetraacetic acid (EDTA), 1,4,7,10- tetraaza cyclododecane embankment -N, N ', N, "N"' tetraacetic acid (DOTA ), tetraazacyclo fourteen embankment -N, N ", N〃N '- tetraacetic acid (of TETA), cyclohexyl 1,2-diamine tetraacetic acid (of CDTA), ethylene glycol two -0,0'- (-2-ethyl) -N, N, N ', N'- four - acetic acid (EGTA), N, N- bis (hydroxybenzyl) - ethylenediamine -N, N'- diacetic acid (HBED by ), triethylenetetraamine hexaacetates off TTHA), hydroxyethyl-diamine triacetic acid (HEDTA), hydroxyethylidene diphosphonic acid (of HEDP), dimercaptosuccinic acid (DMSA), diethylene triamine tetramethylene methyl phosphine acid (DTTP) and l- (p- aminobenzyl) -DTPA, 1,6- diamino-hexyl embankment N, N, N ', N'- tetraacetic acid, DPDP, and ethylenebis (oxyethylene-carbonitrile yl) - tetraacetic acid.
17. 如权利要求15所述的颗粒,其中所述放射性治疗剂是P-发射放射性核素,所述螯合剂基团是DOTA。 17. The particle according to claim 15, wherein said radiotherapeutic agent is a P- emitting radionuclide, said chelating group is DOTA.
18. 如权利要求17所述的颗粒,其中所述(3-发射放射性核素包括钇-90。 18. The particle according to claim 17, wherein the (3-emitting radionuclides include yttrium-90.
19. 如权利要求1所述的颗粒,其中所述共价键包括双功能连接物、碳二亚胺縮合作用,或二硫键。 19. The particle according to claim 1, wherein said covalent bond comprises a bifunctional linker, carbodiimide condensation, or disulfide bonds.
20. 如权利要求l所述的颗粒,其中所述核心包括选自下述的聚合物:聚(甲基丙烯酸甲酯)、聚丙烯酸酯、乙烯-醋酸乙烯聚合物、酰基取代的醋酸纤维素、聚氨酯、聚苯乙烯、聚氯乙烯、聚氟乙烯、聚(乙烯咪唑)、氯磺酸酯聚烯烃、聚氧乙烯、它们的混合物、和它们的共聚物、聚膦嗪、聚(乙烯醇)、聚酰胺、聚碳酸酯、聚亚垸基、聚丙烯酰胺、聚亚垸基二醇、聚环氧烷烃、聚对苯二甲酸亚烷基酯、聚乙烯醚、聚乙烯酯、 聚乙烯卤化物、聚乙烯吡咯垸酮、聚乙交酯、聚硅氧烷、它们的共聚物、烷基纤维素、 羟烷基纤维素、纤维素醚、纤维素酯、和硝基纤维素。 20. The particles of claim l, wherein said core comprises a polymer selected from: poly (methyl methacrylate), polyacrylate, ethylene - vinyl acetate polymer, an acyl substituted cellulose acetate , polyurethanes, polystyrenes, polyvinyl chloride, polyvinyl fluoride, poly (vinyl imidazole), chlorosulphonate polyolefins, polyethylene oxide, mixtures thereof, and copolymers thereof, polyphosphazines, poly (vinyl alcohol ), polyamides, polycarbonates, polyalkylene embankment group, polyacrylamide, polyalkylene glycol embankment, polyalkylene oxides, poly (alkylene terephthalate), polyvinyl ethers, polyvinyl esters, polyvinyl halides, polyvinylpyrrolidone embankment ketone, polyglycolides, polysiloxanes, copolymers thereof, alkyl cellulose, hydroxyalkyl celluloses, cellulose ethers, cellulose esters, and nitrocellulose.
21. 如权利要求l所述的颗粒,其中所述至少一种连接载体是选自线形的聚合物、分支的聚合物和树枝状聚合物。 21. The particles of claim l, wherein said carrier is connected to the at least one polymer selected from a linear, branched polymers and dendrimers.
22. 如权利要求1所述的颗粒,其中所述至少一种连接载体包括树枝状大分子。 22. The particle according to claim 1, wherein said carrier comprises at least one connection dendrimers.
23. 如权利要求22所述的颗粒,其中所述树枝状大分子在它的核心中包括二硫键。 23. The particle according to claim 22, wherein said dendrimer comprises disulfide bonds in its core.
24. 如权利要求22所述的颗粒,其中所述树枝状大分子具有由活性基团加帽的最终外部层。 24. The particle according to claim 22, wherein said final outer layer dendrimer having a reactive group was added by the cap.
25. 如权利要求24所述的颗粒,其中所述活性基团包括胺基团或羧基基团。 25. A particle according to claim 24, wherein said reactive groups include amine groups or carboxyl groups.
26. 如权利要求24所述的颗粒,其中所述活性基团用选自所述放射性治疗剂、导向实体和治疗实体的至少一种实体衍生化处理。 26. A particle according to claim 24, wherein said reactive group selected from the radiotherapeutic agents, therapeutic entities, and entities guide at least one entity derivatization.
27. 如权利要求22所述的颗粒,其中所述树枝状大分子具有至少一个末端功能基团, 该末端功能基团对于螯合剂是可接触的,所述螯合剂能够与至少一个功能基团相互作用。 27. The particle according to claim 22, wherein said dendrimer having at least one terminal functional group, the functional terminal group to the chelating agent is contacted with the chelating agent can be at least one functional group interaction.
28. 如权利要求27所述的颗粒,其中所述至少一种功能基团是选自下述的至少一种,功能基团:酯、醚、硫醇、羰基、羟基、酰胺基、羧基和酰亚胺。 28. The particle according to claim 27, wherein said at least one functional group is selected from at least one functional group: ester, ether, thiol, carbonyl, hydroxyl, amide group, carboxyl group, and imide.
29. 如权利要求22所述的颗粒,其包括多个树枝状大分子,其中所述树枝状大分子是单分散性的。 29. The particle according to claim 22, comprising a plurality of dendrimer, wherein the dendrimer is monodisperse.
30.如权利要求1所述的颗粒,其中所述连接载体是线型聚合物。 30. A particle according to claim 1, wherein said carrier is connected to a linear polymer.
31. 如权利要求l所述的颗粒,其中所述颗粒的密度在l至4gm/cn^范围内。 31. The particles of claim l, wherein the density of said particles l to 4gm / cn ^ the range.
32. 如权利要求l所述的颗粒,其中所述颗粒的密度在1至2gm/cr^范围内。 32. The particles of claim l as claimed in claim 1 to 2gm / cr ^ wherein the density range of said particles.
33. 如权利要求1所述的颗粒,其中所述颗粒进一步包括第二治疗剂,其中所述至少一种放射性治疗剂是第一治疗剂,所述第二治疗剂是不同于第一治疗剂的治疗剂。 33. The particle according to claim 1, wherein said particle further comprises a second therapeutic agent, wherein said at least one first therapeutic agent is a radioactive therapeutic agent, said second therapeutic agent is different from the first therapeutic agent the therapeutic agent.
34. 如权利要求33所述的颗粒,其中所述第二治疗剂是选自下述的至少一种物质-金属螯合复合物、药物、药物前体、放射性核素、硼附加物、标记化合物、毒素、细胞因子、淋巴因子、趋化因子、免疫调节剂、辐射敏化剂、门冬酰胺酶、放射性卤素、 化学治疗药物和造影剂。 34. The particle according to claim 33, wherein said second therapeutic agent is at least one substance selected from - metal chelate complexes, drugs, prodrugs, radionuclides, boron addend, mark compounds, toxins, cytokines, lymphokines, chemokines, immunomodulators, radiosensitizers, asparaginase, radioactive halogen, chemotherapeutic drugs and contrast agents.
35. —种微颗粒,其包括: 核心;和附着到所述核心的至少两种放射性治疗剂。 35. - kind of microparticles, comprising: a core; and attached to the at least two core radiotherapeutic agents.
36. 如权利要求35所述的颗粒,其中所述至少两种放射性治疗剂独立地选自a-发射放射性核素、(3-发射放射性核素和,发射放射性核素。 36. A particle according to claim 35, wherein said at least two radioactive therapeutic agents independently selected from a- emitting radionuclide, (3-emitting radionuclide and, emitting radionuclide.
37. 如权利要求35所述的颗粒,其中所述至少两种放射性治疗剂独立地选自治疗用放射性核素和导向放射性核素。 37. A particle according to claim 35, wherein said at least two radioactive therapeutic agents independently selected from therapeutic radionuclides and radionuclide guide.
38. 如权利要求37所述的颗粒,其中所述治疗用放射性核素包括(3-发射放射性核素, 所述导向放射性核素包括,发射放射性核素。 38. A particle according to claim 37, wherein said therapeutic radionuclides include (3-emitting radionuclide, said guide comprising a radionuclide, emitting radionuclide.
39. 如权利要求35所述的颗粒,其中所述至少两种放射性治疗剂中的至少一种包括^ 发射放射性核素,并且所述至少两种放射性治疗剂中的至少一种包括Y-发射放射性核素。 39. The particle according to claim 35, wherein said at least two radioactive therapeutic agent includes at least one ^ emitting radionuclide and the at least two radioactive therapeutic agent comprising at least one emission Y- radionuclides.
40. 如权利要求39所述的颗粒,其中所述P-发射放射性核素包括钇-90,所述? 40. The particle according to claim 39, wherein said P- emitting radionuclides include yttrium-90, the? 发射放射性核素包括铟-111或Tc-99m。 Emitting radionuclides include indium-111 or Tc-99m.
41. 如权利要求35所述的颗粒,其中所述核心是非放射性的。 41. A particle as claimed in claim 35 wherein said non-radioactive core requirements.
42. 如权利要求35所述的颗粒,其中所述核心包括选自下列的聚合物:聚(甲基丙烯酸甲酯)、聚丙烯酸酯、乙烯-醋酸乙烯聚合物、酰基取代的醋酸纤维素、聚氨酯、聚苯乙烯、聚氯乙烯、聚氟乙烯、聚(乙烯咪唑)、氯磺酸酯聚烯烃、聚氧乙烯、它们的混合物、和它们的共聚物、聚膦嗪、聚(乙烯醇)、聚酰胺、聚碳酸酯、聚亚烷基、聚丙烯酰胺、聚亚烷基二醇、聚环氧垸烃、聚对苯二甲酸亚烷基酯、聚乙烯醚、聚乙烯酯、聚乙烯卤化物、聚乙烯吡咯垸酮、聚乙交酯、聚硅氧烷、它们的共聚物、烷基纤维素、羟烷基纤维素、纤维素醚、纤维素酯、和硝基纤维素。 42. The particle according to claim 35, wherein said core comprises a polymer selected from the group consisting of: poly (methyl methacrylate), polyacrylate, ethylene - vinyl acetate polymer, an acyl substituted cellulose acetate, polyurethanes, polystyrenes, polyvinyl chloride, polyvinyl fluoride, poly (vinyl imidazole), chlorosulphonate polyolefins, polyethylene oxide, mixtures thereof, and copolymers thereof, polyphosphazines, poly (vinyl alcohol) , polyamides, polycarbonates, polyalkylenes, polyacrylamides, polyalkylene glycols, polyethylene oxide embankment hydrocarbons, poly (alkylene terephthalate), polyvinyl ethers, polyvinyl esters, polyvinyl halides, polyvinylpyrrolidone embankment ketone, polyglycolides, polysiloxanes, copolymers thereof, alkyl cellulose, hydroxyalkyl celluloses, cellulose ethers, cellulose esters, and nitrocellulose.
43. 如权利要求35所述的颗粒,其中所述核心包括聚(甲基丙烯酸甲酯)或聚苯乙烯。 43. The particle according to claim 35, wherein said core comprises poly (methyl methacrylate) or polystyrene.
44. 如权利要求35所述的颗粒,其中所述至少两种放射性治疗剂通过共价键各自附着到所述核心。 44. The particle according to claim 35, wherein the at least two radiotherapeutic agents are each attached by a covalent bond to the core.
45. —种微颗粒,包括: 核心;附着到所述核心的至少一种放射性导向实体,其中所述导向实体包括Y-发射放射性核素;其中所述微颗粒的直径在约5至约200微米范围内,并且是非生物可降解的。 45. - kind of microparticles, comprising: a core; core attached to the guide at least one radioactive entity, wherein said entity comprises a guide emitting radionuclide Y-; wherein the diameter of the microparticles is from about 5 to about 200 the micrometer range, and is non-biodegradable.
46. 如权利要求45所述的颗粒,所述颗粒进一步包括至少一种放射性治疗实体,所述治疗实体由(3-发射放射性核素构成。 46. ​​The particle of claim 45, wherein said particles further comprise at least one entity radiotherapy, the therapeutic entity from (3-emitting radionuclide configuration.
47. 如权利要求45所述的颗粒,所述颗粒进一步包括位于所述核心上的至少一种连接载体,其中所述连接载体包括生物相容性聚合物。 47. The particle of claim 45, wherein the particle further comprises at least one connector positioned on said core carrier, wherein said carrier comprises a biocompatible polymer connection.
48. —种颗粒材料,包含微颗粒,其具有: 核心;位于所述核心上的至少一种连接载体,其中所述连接载体包括生物相容性聚合物;和共价结合到所述连接载体的至少一种放射性治疗剂;其中所述微颗粒的直径在约5至约200微米范围内,并且所述微颗粒是非生物可降解的。 48. - kind of particulate material comprising microparticles, comprising: a core; a core on at least one of the connection carrier, wherein said carrier comprises a biocompatible polymer connector; covalently bonded to the connection carrier at least one radioactive therapeutic agent; wherein the diameter of said microparticles is in the range of about 5 to about 200 microns, and the microparticles are non-biodegradable.
49. 如权利要求48所述的颗粒材料,其中所述微颗粒的直径在8-100微米范围内。 49. The particulate material according to claim 48, wherein the diameter of said microparticles is in the range 8-100 microns.
50. 如权利要求48所述的颗粒材料,其中所述微颗粒的直径在25-50微米范围内。 50. The particulate material according to claim 48, wherein the diameter of said microparticles is in the range 25-50 microns.
51. 如权利要求48所述的颗粒材料,其中所述微颗粒的直径在20-30微米范围内。 51. The particulate material according to claim 48, wherein the diameter of said microparticles is in the range 20-30 microns.
52. 如权利要求48所述的颗粒材料,其中所述微颗粒足够大,从而避免了吞噬作用。 52. The particulate material according to claim 48, wherein said microparticles is sufficiently large to avoid phagocytosis.
53. 利用辐射疗法来治疗患者的方法,包括:给予需要辐射治疗的患者多个放射性微颗粒,其中所述多个放射性微颗粒中的每一放射性微颗粒的直径在约5至约200微米的范围内,且是非生物可降解的;并且所述微颗粒包括核心、位于所述核心上的至少一种连接载体,其中所述连接载体包括生物相容性聚合物,和共价结合到所述连接载体的至少一种放射性治疗剂, 其中所述多个放射性微颗粒提供给所述患者辐射治疗。 53. The use of radiotherapy to treat a patient, comprising: administering to a patient in need of radiation plurality of radioactive microparticles, wherein the diameter of each of the plurality of radioactive microparticles radioactive microparticles is from about 5 to about 200 microns the range, and non-biodegradable; and the microparticles comprise a core, at least one connector positioned on the carrier core, wherein said connector comprises a biocompatible polymer support, covalently bound to the a radioactive therapeutic agent is at least connected to a carrier, wherein said plurality of radioactive microparticles of the radiation therapy provided to the patient.
54. 如权利要求53所述的方法,其中所述给予包括肠胃外给予。 54. A method according to claim 53, wherein said administering comprises parenteral administration.
55. 如权利要求53所述的方法,其中所述给予包括静脉内注射。 55. The method according to claim 53, wherein said administering comprises intravenous injection.
56. 如权利要求53所述的方法,其中所述给予包括在目标位置或目标位置附近进行血管内注射。 56. The method according to claim 53, wherein said administering comprises intravascular injection near the target position or the target position.
57. 如权利要求56所述的方法,其中所述目标位置是肿瘤。 57. The method according to claim 56, wherein said target location is a tumor.
58. 如权利要求53所述的方法,其中所述放射性微颗粒被固定在给药位置。 58. The method according to claim 53, wherein said radioactive microparticles are administered at fixed positions.
59. 如权利要求53所述的方法,其中所述给予包括对支持患者肿瘤的动脉血管系统进行血管内注射。 59. The method according to claim 53, wherein said support comprises administering to the patient's tumor artery intravascular injection system.
60. 如权利要求53所述的方法,其中所述患者是原发性肝癌或继发性肝癌患者。 60. The method according to claim 53, wherein said patient is a primary or secondary liver cancer patients with liver cancer.
61. 如权利要求53所述的方法,其中所述患者患有肝癌、类风湿性关节炎、实体癌症、肝脏癌症、脑癌、乳腺癌或卵巢癌。 61. The method according to claim 53, wherein the patient is suffering from liver cancer, rheumatoid arthritis, solid cancers, liver cancer, brain cancer, breast cancer or ovarian cancer.
62. 如权利要求53所述的方法,其中所述患者患有肾细胞癌、肝细胞癌、肉瘤、头或颈部癌症或中枢神经系统肿瘤。 62. The method according to claim 53, wherein the patient is suffering from renal cell carcinoma, hepatocellular carcinoma, sarcoma, head or neck cancer or a central nervous system tumors.
63. 如^i利要求53所述的方法,其中所述至少一种放射性治疗剂包括a-发射放射性核素、卩-发射放射性核素或Y-发射放射性核素中的至少一种。 63. The method of claim 53 ^ i claims, wherein said therapeutic agent comprises at least one radiation emitting radionuclide a-, Jie - at least one transmitter emitting radionuclide or radionuclides in the Y-.
64. 如权利要求53所述的方法,其中所述至少一种放射性治疗剂包括a-发射放射性核素和卩-发射放射性核素。 64. The method according to claim 53, wherein said therapeutic agent comprises at least one radiation emitting radionuclide and a- Jie - emitting radionuclide.
65. 如权利要求53所述的方法,其中所述至少一种放射性治疗剂包括p-发射放射性核素和Y-发射放射性核素。 65. The method according to claim 53, wherein said therapeutic agent comprises at least one radiation emitting radionuclide and p- Y- emitting radionuclide.
66. 如权利要求65所述的方法,进一步包括检测所述的Y-发射放射性核素,以确定所述多个放射性微颗粒在患者中的位置。 66. The method according to claim 65, further comprising detecting the Y- emitting radionuclides to determine a location of the plurality of radioactive microparticles in a patient.
67. 对患者的目标器官或肿瘤进行成像的方法,包括:在患者的目标位置给予患者多个放射性微颗粒,其中所述多个放射性微颗粒中的每一放射性微颗粒的直径在约5至约200微米范围内,且是非生物可降解的;并且所述微颗粒包括核心、位于所述核心上的至少一种连接载体,其中所述连接载体包括生物相容性聚合物,和共价结合到所述连接载体的至少一种放射性治疗剂,其中所述放射性治疗剂包括Y-发射放射性核素;检测所述多个放射性微颗粒,其中所述检测提供了所述目标器官或肿瘤的图像。 67. The method of target organ or tumor imaging a patient, comprising: administering to the patient a plurality of radioactive microparticles at a target location of a patient, wherein the diameter of each of the plurality of radioactive microparticles radioactive microparticles is from about 5 to the range of about 200 microns, and non-biodegradable; and the microparticles comprise a core, at least one connector positioned on the carrier core, wherein said connector comprises a biocompatible polymer support, and covalently bound to said at least one connection carrier radiotherapeutic agents, wherein said radiotherapeutic agent comprising Y- emitting radionuclide; said plurality of detecting radioactive microparticles, wherein said providing a detection of the target organ or tumor image .
68. 如权利要求67所述的方法,其中所述检测在辐射的寿命期间进行。 68. The method according to claim 67, wherein said detecting is performed during the life of the radiation.
69. 如权利要求67所述的方法,其中所述检测在辐射之后进行。 69. The method according to claim 67, wherein said detection is performed after irradiation.
70. 如权利要求67所述的方法,其中所述至少一种放射性治疗剂包括a-发射放射性核素、p放射放射性核素或Y-发射放射性核素中的至少一种。 70. A method according to claim 67, wherein said at least one radiotherapeutic agent comprising at least one radionuclide emitting a-, P radionuclide or radiation emitting radionuclide in the Y-.
71. 如权利要求67所述的方法,其中所述至少一种放射性治疗剂包括a-发射放射性核素和(3-发射放射性核素。 71. A method according to claim 67, wherein said therapeutic agent comprises at least one radiation emitting radionuclide and a- (3-emitting radionuclide.
72. 如权利要求67所述的方法,其中所述至少一种放射性治疗剂包括P-发射放射性核素和Y-发射放射性核素。 72. A method according to claim 67, wherein said therapeutic agent comprises at least one radiation emitting radionuclide and P- Y- emitting radionuclide.
73. 如权利要求67所述的方法,进一步包括确定所述多个放射性微颗粒在患者中的位置。 73. The method according to claim 67, further comprising determining a position of the plurality of radioactive microparticles in a patient.
74. 如权利要求67所述的方法,其中所述多个微颗粒被固定在目标位置。 74. A method according to claim 67, wherein said plurality of microparticles are fixed to the target position.
75. 如权利要求74所述的方法,其中所述目标位置是肿瘤。 75. A method according to claim 74, wherein said target location is a tumor.
76. 如权利要求67所述的方法,其中所述多个微颗粒中的每一个的直径在约15至约35微米的范围内。 76. A method according to claim 67, wherein the range of diameters of the plurality of microparticles each from about 15 to about 35 microns.
77. 在怀疑具有肿瘤的患者中诊断癌症的方法,包括: 在所述患者的目标位置,给予患者多个放射性微颗粒,其中所述多个放射性微颗粒中的每一放射性微颗粒的直径在约5至约200微米范围内,且是非生物可降解的; 并且所述微颗粒包括核心、位于所述核心上的至少一种连接载体,其中所述连接载体包括生物相容性聚合物,和共价结合到所述连接载体的至少一种放射性治疗剂,其中所述放射性治疗剂包括Y-发射放射性核素;检测所述多个放射性微颗粒;和由所述检测来确定所述患者是否具有肿瘤,其中对所述肿瘤所作的检测珍断出所述患者患有癌症。 77. A method of diagnosing cancer in a patient suspected of having a tumor, comprising: a target location in the patient, administering to the patient a plurality of radioactive microparticles, wherein a diameter of said plurality of microparticles each radioactive radioactive microparticles in about 5 to about 200 microns, and non-biodegradable; and the microparticles comprise a core, said core positioned on at least one connection carrier, wherein said carrier comprises a biocompatible polymer is connected, and covalently bound to at least one of the connection carrier radiotherapeutic agent, wherein said therapeutic agent comprises radioactive Y- emitting radionuclide; said plurality of detecting radioactive microparticles; detection by said determining whether the patient having a tumor, wherein the tumor is made that the detected off Jane patient suffering from cancer.
78. 如权利要求77所述的方法,其中所述癌症是肝癌、实体癌症、脑癌、乳腺癌或卵巢癌。 78. The method according to claim 77, wherein said cancer is liver cancer, solid cancers, brain cancer, breast cancer or ovarian cancer.
79. 如权利要求77所述的方法,其中所述肿瘤是肾细胞癌、肝细胞癌、肉瘤或中枢神经系统肿瘤。 79. The method of claim 77 hepatocellular carcinoma, sarcoma, or central nervous system tumors, wherein the tumor is renal cell carcinoma.
80. 如权利要求77所述的方法,其中所述至少一种放射性治疗剂包括oi-发射放射性核素、e-发射放射性核素或Y-发射放射性核素中的至少一种。 80. The method according to claim 77, wherein said therapeutic agent comprises at least one radiation emitting radionuclide oi-, E- or transmitting at least one radionuclide emitting radionuclide in the Y-.
81. 如权利要求77所述的方法,其中所述至少一种放射性治疗剂包括oc-发射放射性核素和卩-发射放射性核素。 81. The method according to claim 77, wherein said therapeutic agent comprises at least one radiation emitting radionuclide and oc- Jie - emitting radionuclide.
82. 如权利要求77所述的方法,其中所述至少一种放射性治疗剂包括卩-发射放射性核素和Y-发射放射性核素。 82. The method according to claim 77, wherein the at least one therapeutic agent comprises radioactive Jie - emitting radionuclide and Y- emitting radionuclide.
83. 用于制备权利要求48所述的颗粒材料的试剂盒,其中所述试剂盒包括: 非放射性核心;至少一种连接载体,其用于将至少一种放射性核素附着到所述颗粒核心;和用于制备所述微颗粒治疗剂量的指导或用于获得所述指导的工具。 83. for the preparation of particulate material as claimed in claim 48, said kit, wherein said kit comprises: a non-radioactive core; connected to at least one carrier for at least one radionuclide attached to the core particles ; and means for preparing microparticles of the therapeutic dose for obtaining the instructions or guidance tool.
84. 如权利要求83所述的试剂盒,其中所述试剂盒进一步包括放射性核素。 84. The kit according to claim 83, wherein said kit further comprises a radionuclide.
85. 如权利要求83所述的试剂盒,其中放射性核素与所述试剂盒分开提供。 85. The kit according to claim 83, wherein the radionuclide is provided separately from the kit.
86. 如权利要求83所述的试剂盒,进一步包括选自下述物质的至少一种组分:药学上可接受的惰性载体、配制剂、佐剂、活性试剂、水、盐水、转移配体、还原剂、冻干助剂、稳定助剂、增溶剂、抑菌剂、缓冲物、X-射线造影剂、超声造影剂和金属药物。 86. The kit according to claim 83, further comprising at least one component selected from the group of: a pharmaceutically acceptable inert carrier, formulations, adjuvants, active agent, water, saline, a transfer ligand reducing agent, lyophilization aids, stabilization aids, solubilizers, bacteriostatic agents, buffers, X- ray contrast agents, ultrasound contrast agents and metallopharmaceuticals.
87. 如权利要求83所述的试剂盒,进一步包括选自下述的至少一种组分:注射器、 屏蔽设备和成像设备。 87. The kit according to claim 83, further comprising at least one component selected from: a syringe shield device and the image forming apparatus.
88. 如权利要求83所述的试剂盒,进一步包括至少两种化学上不同的非放射性核心或至少两种化学上不同的连接载体。 88. The kit according to claim 83, further comprising at least two chemically different non-radioactive chemically core or at least two kinds of different connection carrier.
89. 应用权利要求83所述的试剂盒来为需要微颗粒治疗的患者制备微颗粒治疗剂量的方法,包括:由开给患者的处方,确定所需微颗粒治疗的类型和剂量,和由所述的指导或获得所述指导的工具,制备出所述的微颗粒治疗剂量。 89. The kit of claim 83 application claims is a method of preparing microparticles of a therapeutic dose a patient in need of treatment microparticles, comprising: a prescription prescribed for a patient, and the dosage required to determine the type of treatment microparticles, and the by the obtaining the guidance or guidance of said tool, the microparticles prepared according to the therapeutic dose.
90.应用权利要求89所述的试剂盒来为需要微颗粒治疗的患者制备微颗粒治疗剂量的方法,包括.-由开给患者的处方,确定所需微颗粒治疗的类型和剂量; 从包含于所述试剂盒的核心中,选择非放射性核心的类型; 从包含于所述试剂盒的连接物中,选择连接物的类型; 选择放射性核素,和由所述的指导或获得所述指导的工具,制备出所述的微颗粒治疗剂量。 The kit according to claim 89 90. The use of a method of preparing microparticles of a therapeutic dose microparticles patient in need of treatment, including the opening .- prescription to a patient, and the dosage required to determine the type of microparticle treated; from the group consisting the core in the kit, select the type of non-radioactive core; the linker included in the kit, select the type of linker; selected radionuclides, and is obtained by the guidance or the guidance tool, the microparticles prepared according to the therapeutic dose.
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