CN101678121B - 对肿瘤细胞具有杀伤作用的改性羟基聚合物共轭物 - Google Patents
对肿瘤细胞具有杀伤作用的改性羟基聚合物共轭物 Download PDFInfo
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Abstract
本发明涉及改性羟基聚合物共轭物,优选具有肿瘤细胞杀伤活性的胍-葡聚糖共轭物。该改性羟基聚合物共轭物被用作药物,尤其用来制造药物或治疗肿瘤用的肿瘤杀伤组合物。还公开了制造所述羟基聚合物共轭物的方法。
Description
发明的技术领域
本发明涉及改性羟基聚合物共轭物,尤其具有肿瘤杀伤作用的胍-葡聚糖共轭物,和制造所述共轭物的方法及其应用。
发明背景
胍化合物具有很多有意义而重要的生物医药作用并因此具有许多用途。例如,它们被用作游离基清除剂、防止氧化氮形成的氧化氮合酶(NOS)抑制剂。已知它们对细胞具有一定的抗增殖作用。胍类也被用作“抗老化”药物,其中,实现该作用的机理是预防低密度脂蛋白氧化,预防动脉粥样硬化病变,通过抑制深度糖基化最终产物(AGE)的形成而预防糖尿病的组织损伤作用,如心血管损伤作用,如下列科学出版物所述(Yildiz等,Br J Pharmacol,19987月;124(5):905-910;Scaccini等,J Lipid Res,1994年,第35卷,1085-1092;Higashi等,J Biochem,2004,第136卷,第4期,533-539;Szende等,Cancer Cell Int,2001,1:3;Sell等,J Gerontol Soc Am,2001,56:B405-B411;Wang等,World JGastroenterol,2005,7月7日:11,(25)3830-3833;Zhang等,World JGastroenterol,2001,6月7日:3):331-334;JP Beisswenger,Dartmouth Med,http//dartmed.dartmouth.edu/summer 00/html/bench_to_bedside.shtml)。目前,美国以非处方药供应氨基胍并在临床研究中调查其在治疗各种疾病中的作用。胍丁胺靠调节多胺的新陈代谢而对癌细胞增殖的抑制作用已描述在Wang等,Acata Pharmacologica Sinica 2005,5月;26(5):616-622中。
50多年来,葡聚糖一直是用来预防低血容量性休克(原文chock似应为shock-译注),预防栓塞和改进微循环的已有药物。文献中已很好地记载了葡聚糖及其非毒性和高耐受性(AS Segal,1964 In:Modernmedical monographs,Wright编,IS,Green&Stratton,NY,London,pp5-17)。因此常被用作药物学上可应用的羟基聚合物的实例。
发明概述
因此,本发明涉及具有肿瘤细胞杀伤作用的改性羟基聚合物共轭物。该改性羟基聚合物共轭物是被胍化合物取代的羟基聚合物,如葡聚糖,所述胍化合物具有至少一个游离氨基并共价偶联到羟基聚合物部分的活化羟基上。
本发明中的优选胍化合物是胍丁胺或氨基胍,羟基聚合物部分是葡聚糖,所述葡聚糖的分子量为103~106道尔顿,并在被所述胍基化合物取代之前进行活化。
改性羟基聚合物共轭物还包含共价偶联的官能团,包括放射性核素、治疗化合物、抗癌药物、靶向制剂等。
改性羟基聚合物共轭物优选是平均分子量为约70kD±25kD的胍-葡聚糖共轭物,其中葡聚糖中15~60%,优选20~50%的葡萄糖部分被含至少一个游离氨基侧基的胍化合物所取代。所述胍化合物,优选胍丁胺或氨基胍,被共价偶联到所述葡聚糖的活化羟基上。羟基聚合物共轭物还可包含共价偶联的官能团,包括放射性核素、治疗化合物、抗癌药物、靶向制剂等。适用的靶向制剂是,例如,双膦酸盐,如阿仑膦酸钠。
本发明还涉及所述羟基聚合物共轭物作为药物的用途,尤其用于制造治疗肿瘤的药物。这类药物是肿瘤杀伤组合物,它包含改性羟基聚合物共轭物和至少一种药物学上可接受的佐剂。这类药物或肿瘤杀伤组合物可以局部地,在膀胱内,部分地(regiolocal),在腹腔(peritoneal),在肿瘤内,全身性或静脉内给药。这类药物还可包含共价偶联的官能团,包括放射性核素、治疗药物、抗癌药物、靶向制剂等。
本发明还提供制造改性羟基聚合物共轭物的方法。在本方法中,将含至少一个游离氨基的胍化合物与用凝胶过滤法纯化活化羟基聚合物时所得到的洗脱液相混合。羟基聚合物通过氧化反应而被活化,其中将高碘酸盐加进包含所述羟基聚合物的水溶液,然后加入浓硫酸,然后通过加入乙二醇而终止反应。然后,用凝胶过滤法纯化如上所述已被活化的羟基聚合物。
附图简述
图2示意胍-葡聚糖共轭物和蒽环类化合物对尿路上皮癌细胞(RT4,ATCC,Manassas,USA)的毒性作用的对比,其中amgdx=氨基胍-葡聚糖,agmdx=胍丁胺-葡聚糖,百分存活率画在y轴上,培养浓度画在x轴上。尿路上皮癌细胞的存活率是≤1=0。下限值代表100%细胞死亡。
图3示意胍-葡聚糖共轭物和蒽环类化合物对尿路上皮癌细胞(5637,ATCC,Manassas,USA)的毒性作用的对比,其中amgdx=氨基胍-葡聚糖,agmdx=胍丁胺-葡聚糖,百分存活率画在y轴上,培养浓度画在x轴上。尿路上皮癌细胞的存活率是≤1=0。
图4示意胍-葡聚糖共轭物和蒽环类化合物对前列腺癌细胞(PC3,ATCC,Manassas,USA)的毒性作用的对比,其中amgdx=氨基胍-葡聚糖,agmdx=胍丁胺-葡聚糖,前列腺癌细胞的存活率是≤1=0。
图5示意胍-葡聚糖共轭物和蒽环类化合物对乳癌细胞(MDA231,ATCC,Manassas,USA)的毒性作用的对比,其中amgdx=氨基胍-葡聚糖,agmdx=胍丁胺-葡聚糖,乳癌细胞的存活率是≤1=0。
图6示意胍-葡聚糖共轭物和蒽环类化合物对肾细胞癌(A498,ATCC,Manassas,USA)的毒性作用的对比,其中amgdx=氨基胍-葡聚糖,agmdx=胍丁胺-葡聚糖,肾癌细胞的存活率是≤1=0。
发明详述
本发明者已发现,某些具有很低固有毒性的胍化合物,当与非毒性羟基聚合物如葡聚糖共价共轭时,具有高的肿瘤细胞杀伤效力。该肿瘤细胞杀伤效力等于已有的蒽环类抗癌药,如和或在某种浓度下高于已有的抗癌药。似有可能因所述聚合物-胍共轭物构分的无害性质而能预期,这类共轭物,即对于医疗人员的处理和病人在治疗中的副作用而言,都优于传统的化疗抗癌药物。
相信靶向或癌细胞选择性是通过快分割癌细胞所需的加快新陈代谢而实现的,这需要氨基-5-胍基戊酸和结构上相关的胍化合物以及用来形成多胺的其它构分(D Scott Lind,Am Soc Nutr Sci,2004,J Nutr,134:2837-2841;E Wayne,Turk J Med Sci,2003,33,195-205)。所述胍化合物的细胞吸收原则上是通过Na+-独立的碱性氨基酸转运系统y+传递的(Cendan等,Ann Surg Oncol,1995,2:257-265)。
本发明的胍-聚合物-共轭物是作为含羟基聚合物的骨架化合物的化合物,如葡聚糖。羟基聚合物或葡聚糖的分子量为103~106道尔顿。一般,羟基聚合物或葡聚糖被15~60%,优选20~50%的胍侧基所取代,即葡聚糖骨架中20~50%的葡萄糖部分被胍基所取代。
在一个被分析批次中,已证明,葡聚糖聚合物的平均分子量为70kD的100mg氨基胍-葡聚糖-共轭物中,胍侧基约占30mg。换言之,273μmol氨基胍偶联到1.4μmol葡聚糖70上,这意味着约50%葡萄糖部分被胍基所取代。在另一批次中,已发现,葡聚糖聚合物的平均分子量为70kD的100mg氨基胍-葡聚糖-共轭物中,胍侧基约占10mg。换言之,90μmol氨基胍偶联到1.3μmol葡聚糖70上,这意味着约18%葡萄糖部分被胍基所取代。
该药物优选局部给药,例如,膀胱内给药,部分地,例如,腹腔给药,肿瘤内,即直接注射进实体肿瘤中,或全身性即通过静脉内给药。所有这些给药途径都是可能的而且依赖于具体的治疗应用。
羟基聚合物或葡聚糖聚合物用胍的侧基进行取代。胍基是通过胍化合物的游离侧氨基共价偶联到所述葡聚糖聚合物上的。进行取代的方法是通过氧化来活化所述葡聚糖聚合物,由此能与所述游离氨侧基发生反应,形成胍化合物键,然后还原,获得稳定的胺键(Matsunaga等,NuclMed Biol.2005,32,279-285)。
在示例中,氨基胍与羟基聚合物或葡聚糖聚合物形成腙键。腙键可以被进一步还原,生成胍基肼键。适用的胍化合物是胍丁胺和氨基胍。
在所述胍化羟基聚合物共轭物上还可偶联其它官能团。这些官能团包括治疗药物,放射性核素如Tc-99m、I-131、Y-90、Re-188、Sm-153,激素,激素拮抗剂如它莫西芬,肽类如生长激素抑制素,毒素,单克隆抗体或其碎片,自由基清除剂如氨磷汀或蛋白和其它靶向制剂。这类官能团的偶联用直接法或通过在引入官能团之前已偶联到羟基聚合物上的双官能螯合剂来实现。
实施例1
葡聚糖的活化
将药物级葡聚糖PM70(150mg)溶解在6ml水中。加进120mg高碘酸钠,然后加进25μl浓硫酸。搅拌该混合溶液30min。加进75μl乙二醇以终止氧化,并通过再反应15min而破坏过量的高碘酸盐。在PD-10柱上,用0.1M的pH 6.5的乙酸酯作为洗脱液,以凝胶过滤法,以1ml部分,纯化已活化葡聚糖,除去低分子量组分。在每次分离中,获得2ml活化葡聚糖溶液。
共轭化
将1ml由上述步骤所获得的洗脱液与下列混合:
A)110mg硫酸胍丁胺和5mg氰基硼氢化钠,
B)65mg盐酸氨基胍。
在室温下搅拌该溶液过夜并在PD 10柱上用PBS作为洗脱液分离除去低分子量组分。从每次反应获得2ml纯化共轭溶液。
荧光细胞毒性鉴定(图1~6)
荧光细胞毒性鉴定按Larsson和Nygren所述进行(Larson等,Anticancer Res,1989,9:1111-1119).
扼要地,对约10,000个细胞/孔接种(96-孔微滴定板,Falcon.BectonDickinson,Meylan,France)。加入等摩尔浓度(0.1、0.5、1、2和4μM)的蒽环和含氨基胍或胍丁胺基的胍-葡聚糖-共轭物。在对照孔中加入相同量的PBS。培养72h后,离心处理微滴定板(200×g 3min),并轻弹这些板以除去介质。用PBS洗涤这些细胞。将荧光素二乙酸酯(FDA,Sigma,Stockholm,Sweden)溶解在DMSO中并在-20℃保持冷冻,作为贮液(10mg/ml)。用PBS把FDA贮液稀释到浓度为10μg/ml,且在各孔内加进200μl。然后在37℃培育这些板30min。用96-孔扫描荧光计计数发射自活细胞的荧光。把数据输入计算机并计算结果。结果示于图1~5,y轴表示细胞的%存活率,x轴表示试验物质的摩尔浓度。
使用下列肿瘤细胞系(来自ATCC,Manassas,US):RT4、5637(尿路上皮癌)、MDA231(乳癌)、PC3(前列腺癌)、A498(肾细胞癌)。
Claims (12)
1.具有肿瘤细胞杀伤作用的改性羟基聚合物共轭物,其特征在于该改性羟基聚合物共轭物是被胍化合物胍丁胺和氨基胍取代的羟基聚合物葡聚糖,所述胍化合物含至少一个游离氨基并共价偶联到所述羟基聚合物部分的活化羟基上。
2.按照权利要求1的改性羟基聚合物共轭物,其特征在于所述羟基聚合物葡聚糖的分子量为103~106道尔顿。
3.按照权利要求1的改性羟基聚合物共轭物,其特征在于该改性羟基聚合物共轭物还包含至少一个共价偶联的官能团。
4.按照权利要求3的改性羟基聚合物,其特征在于所述官能团是放射性核素。
5.按照权利要求3的改性羟基聚合物,其特征在于所述官能团是治疗化合物。
6.按照权利要求3的改性羟基聚合物,其特征在于所述官能团是抗癌药物。
7.按照权利要求3的改性羟基聚合物,其特征在于所述官能团是另一种靶向制剂。
8.按照权利要求1的改性羟基聚合物共轭物,其特征在于该改性羟基聚合物共轭物是平均分子量为70kD±25kD的胍-葡聚糖共轭物,和其中,葡聚糖中15~60%的葡萄糖部分被含至少一个游离氨基侧基的胍化合物胍丁胺和氨基胍所取代,所述胍化合物共价偶联到所述葡聚糖的活化羟基上。
9.按照权利要求8的改性羟基聚合物共轭物,其特征在于葡聚糖中20~50%的葡萄糖部分被具有至少一个游离氨基侧基的胍化合物胍丁胺和氨基胍所取代,所述胍化合物共价偶联到所述葡聚糖的活化羟基上。
10.具有肿瘤细胞杀伤作用的组合物,其特征在于所述组合物包含被胍化合物胍丁胺和氨基胍取代的羟基聚合物葡聚糖和至少一种药物学上可接受的佐剂,所述胍化合物含至少一个游离氨基并共价偶联到所述葡聚糖部分的活化羟基上。
11.制造按照权利要求1的改性羟基聚合物共轭物的方法,其特征在于将含至少一个游离氨基的胍化合物胍丁胺或氨基胍与包含已用凝胶过滤法纯化的活化葡聚糖的洗脱液进行混合。
12.按照权利要求11的方法,其特征在于活化葡聚糖是通过氧化反应得到的,其中将高碘酸盐加进包含葡聚糖的水溶液,然后加进浓硫酸,以及其中氧化反应靠加入乙二醇而终止,然后用凝胶过滤法进行纯化。
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