CN107043456B - 对氧环己酮与l-苯丙氨酸氮芥共聚物及其应用 - Google Patents
对氧环己酮与l-苯丙氨酸氮芥共聚物及其应用 Download PDFInfo
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Abstract
本发明涉及一种结构式(I)表示的对氧环己酮/L‑苯丙氨酸氮芥共聚物及其在制备治疗肿瘤的药物中的用途。本发明还涉及该共聚物的制备方法,以该共聚物为活性成分的药物组合物,以及本发明共聚物的药物组合物在治疗肿瘤的药物中的用途。
Description
技术领域
本发明涉及一种L-苯丙氨酸体系共聚物,尤其涉及一种对氧环己酮与L-苯丙氨酸氮芥共聚物及其应用。
背景技术
在目前的临床实践中药物缓释载体在肿瘤化疗领域得到了广泛应用,药物缓释载体的使用可以增强药效减弱副作用及缓解患者多次用药的痛苦。目前应用于临床的化疗药物缓释载体多为天然或合成高分子材料包裹的微纳米微球或纤维,纳米尺度微球相较于微米尺度微球比表面积更大,并有可能通过细胞的内吞作用进入细胞内部从而进一步增强药效。然而,目前临床所用载体的负载方式多为物理包裹,这种负载方式存在释放速度不均匀,药物负载效率低等问题。因此,药物释放速率均匀、载药效率高的,可降解共价键结合纳米尺度化疗药物缓释体系更加符合临床化疗的需求。
L-苯丙氨酸氮芥(分子式A),又名L-溶肉瘤素,为烷化剂,是目前仍应用于临床的抗肿瘤药物;主要作用于DNA,适用于治疗多发性骨髓瘤、乳腺癌、卵巢癌。多为口服制剂,其盐酸盐可静脉注射,但该药物毒性较大,以上全身给药方式易造成多种毒副作用。例如,L-苯丙氨酸氮芥在几种造血系统的恶性肿瘤和实体瘤包括卵巢癌的治疗中,容易造成永久性造血干细胞损害,出现急性非淋巴细胞白血病和白血病前期的危险性有所增加,甚至需要干细胞移植支持。(国外医学(内科学分册),1987年09期;VAD、M_2和MP方案治疗多发性骨髓瘤疗效的对比研究,2005年吉林大学硕士学位论文)。
因此,本领域的技术人员致力于开发一种适用于局部注射或局部植入给药的,且药物释放速率均匀、载药效率高的药物缓释体系;通过局部植入缓释体系可保持药物在病灶部位的局部高浓度,从而降低药物的全身性毒副作用。
发明内容
有鉴于现有技术的上述缺陷,本发明所要解决的技术问题是提供一种具有药物释放速率均匀、载药效率高的药物缓释体系。
本发明人意外发现,如果将L-苯丙氨酸氮芥以共价结合的形式结合于聚对氧环己酮分子链上形成一种共聚物进行给药,可以大大降低其毒性,扩展L-苯丙氨酸氮芥的应用范围。
具体地,本发明通过化学方法将L-苯丙氨酸氮芥以共价结合的形式结合于聚对氧环己酮分子链上并通过静电喷雾法制备成纳米颗粒,其目的是使其置于有安全稳定的缓释体系中进行局部给药,降解共价键结合的纳米级L-苯丙氨酸氮芥体系,从而降低L-苯丙氨酸氮芥的毒性。
为实现上述目的,一方面,本发明提供了一种对氧环己酮与L-苯丙氨酸氮芥共聚物PDCM,其结构如分子式(I)所示。
本发明的对氧环己酮与L-苯丙氨酸氮芥共聚物PDCM可通过以下合成路线进行制备。以L-苯丙氨酸氮芥(分子式A)化合物为原料,进行合成制备得到聚(对氧环己酮-co-L-苯丙氨酸氮芥)PDCM。
在本发明的较佳实施方式中,共聚物PDCM的分子量为0.7-0.9kDa,L-苯丙氨酸氮芥的摩尔含量为2%-7%。
发明人发现本发明的分子式(I)共聚物PDCM对肿瘤具有治疗作用。具体地,通过将对氧环己酮与L-苯丙氨酸氮芥共聚物植入体内后,聚合物主链可被逐渐降解,L-苯丙氨酸氮芥可被逐渐释放,从而达到杀死癌细胞的目的。
本发明还提供一种抗肿瘤的药物组合物,包括分子式(I)的共聚物或其可药盐,和可药用辅料或药学上可接受的载体组成。
另一方面,本发明还提供一种包括分子式(I)的共聚物及其药物组合物在制备治疗肿瘤的药物中的用途。
在本发明的具体实施方式中,本发明提供了一种共价键结合化疗药物L-苯丙氨酸氮芥缓释纳米颗粒。优选地,通过静电喷雾方法将式(I)的化合物制备成粒径为100-250nm的纳米颗粒;在给药时其释放效果更好,大大降低了L-苯丙氨酸氮芥的毒性。
在治疗肿瘤时,本发明共聚物或其药物组合物能有效地抑制小鼠的癌细胞的增殖。
上述所述药学上可接受的载体是指药学领域常规的药物载体,例如:稀释剂、赋形剂如水等,填充剂如淀粉、蔗糖等;粘合剂如纤维素衍生物、藻酸盐、明胶和聚乙烯吡咯烷酮;湿润剂如甘油;吸收促进剂如季铵化合物;表面活性剂如十六烷醇;吸附载体如高岭土;润滑剂如滑石粉、硬脂酸钙和镁和乙二醇。另外还可以在组合物中加入其它辅剂如甜味剂等。
本发明化合物可以组合物的形式通过局部注射或局部植入的给药方式施用于需要治疗的患者。用于局部注射时可制备成液体制剂如水悬浮剂或其它液体制剂。用于局部植入时制成常规制剂如片剂、粉剂、粒剂等。
本发明药物组合物的各种剂型可以按照药学领域的常规生产方法制备。例如使活性成分与一种或多种载体组合,然后将其制成所需的剂型。本发明药物组合物优选含有重量比为0.1%-99.5%的活性成分,最优选含有重量比为0.5-95%的活性成分。
本发明化合物的施用量可根据用药途径、患者的年龄、体重、疾病类型和程度等变化,所属领域的技术人员可根据实际情况容易确定给药剂量。
技术效果
以下将结合附图对本发明的构思、具体结构及产生的技术效果作进一步说明,以充分地了解本发明的目的、特征和效果。
附图说明
图1是本发明的一个较佳实施例的PDCM聚合物纳米颗粒SEM,a)PDCM-1纳米颗粒;b)PDCM-2纳米颗粒;c)PDCM-3纳米颗粒;
图2是本发明的一个较佳实施例的不同浓度PDCM-2纳米颗粒对癌细胞增殖的抑制作用。
具体实施方式
下面通过实施例的方式进一步说明本发明,本发明的范围并不因此局限于下述实施例,而是由本发明的说明书和权利要求书限定。
实施例中主要试剂及仪器
对氧环己酮(成都艾科试剂,分析纯),L-苯丙氨酸氮芥(成都艾科试剂,分析纯),三聚光气(成都艾科试剂,分析纯),辛酸亚锡(成都艾科试剂,分析纯),聚(L-丙交酯-co-乙交酯)(PLGA,成都艾科试剂,分析纯)核磁共振仪(德国Bruker,400M)。
实施例1
PDCM聚合物的制备及表征
1)PDCM聚合物的制备
L-苯丙氨酸氮芥4g(13mmol),三聚光气3g(10mmol)置于圆底烧瓶中,用高纯氮气置换瓶中的空气后,加入无水四氢呋喃50mL,回流3小时。旋转蒸发除去反应液中的溶剂,得到黄色油状物,即为L-苯丙氨酸氮芥-N-羧酸酐粗产物。将粗产物用无水四氢呋喃-正己烷重结晶三次。得到纯净的L-苯丙氨酸氮芥-N-羧酸酐。1H NMR(400MHz,DMSO-d6,9.13,s,1H,NHCO;7.01,d,J=8Hz,2H,phenyl H;6.68,d,J=8Hz,2H,phenyl H;4.71,t,J=4Hz,1H,CONHCHCO;3.71,br,8H,NCH2CH2Cl;2.90,d,J=4Hz,2H,CH2-phenyl.),收率57%.
L-苯丙氨酸氮芥-N-羧酸酐2.47g(7.4mmol),对氧环己酮5g(49mmol),置于圆底烧瓶,用高纯氮气置换瓶中的空气后,减压封瓶,95℃反应24h后停止反应,将粗产物以氯仿-乙醚体系溶解-沉淀两次后得到共聚物PDCM。L-苯丙氨酸氮芥-N-羧酸酐收率29%,对氧环己酮收率72%。
2)PDCM聚合物的表征
PDCM聚合的L-苯丙氨酸氮芥含量由核磁共振1HNMR测定;1H NMR(400MHz,CDCl3,7.05,m,2H,phenyl H;6.61,m,2H phenyl H;4.54,t,J=4Hz,1H,CONHCHCO;4.36,t,J=4Hz,2H,OCH2CH 2OCO;4.19,s,2H,COCH2O;4.01,br,8H,NCH2CH2Cl;3.81,t,J=4Hz,2H,OCH 2CH2OCO;3.09,d,J=4Hz,2H,CH2-phenyl.)
L-苯丙氨酸氮芥mol%:7.05ppm积分面积/(7.05ppm积分面积+4.36ppm积分面积)*100%。
聚合物分子量由GPC方法测定(DMF流动相),结果见表1所示。
表1.PDCM系列聚合物
aGPC方法测定重均分子量(Mw)
实施例2
共价键结合化疗药物L-苯丙氨酸氮芥缓释纳米颗粒
将PDCM-1、PDCM-2、PDCM-3分别通过静电喷雾法制备成其相应纳米颗粒。以PDCM-3为例:将PDCM-3溶于六氟异丙醇/甲醇(9∶1,v/v)混合溶剂中制备成浓度为5%w/v的溶液,并将DTBA以2mmol/L的浓度加入溶液中,将溶液置于针尖接8KV高压直流电源的注射器中,注射器置于连续微量注射泵上,注射速率为0.2mL/h,距针尖10cm下方放置75vol.%乙醇水溶液作为负极接收装置,并接-2.5KV高压直流电源。在静电力作用下,聚合物液滴裂解、干燥、收缩即可在接收液中接收到PDCM-3纳米颗粒。所制备得到的PDCM纳米颗粒尺寸为100-200nm之间,如图1所示。
实施例3
PDCM纳米颗粒对癌细胞增殖的抑制作用
将不同浓度的PDCM-2纳米颗粒分别置于U-87(人胶质瘤细胞系)、MCF-7(人乳腺癌细胞系)、SKOV-3(人卵巢癌细胞系)细胞培养基中作为实验组1、2、3;对照组应用正常培养基,具体分组见下表2。将对照组和实验组分别在室温培养相应时间。
表2.PDCM纳米颗粒对癌细胞增殖的测试成分
通过实验组OD值与对照组OD值相比较得到实验组细胞增殖抑制率(如图2所示):
增殖抑制率={1-(实验组OD值/对照组OD值)}×100%
由图2可知,培养第一天,PDCM实验组尚未表现出对癌细胞的抑制作用,甚至会促进癌细胞的增殖,这可能是由于PDCM颗粒部分从培养基沉出并且较好的生物相容性,更有利于癌细胞贴壁生长所致。从培养第三天开始,聚合物纳米颗粒实验组对癌细胞增殖的抑制率已为正值,表明PDCM已开始释放L-苯丙氨酸氮芥抑制癌细胞增殖。到第五至七天,PDCM实验组细胞增殖抑制率可达80%。表明随着时间的延长,L-苯丙氨酸氮芥可被逐渐从PDCM聚合物分子链上释出,从而可有效地抑制了癌细胞的增殖。
以上详细描述了本发明的较佳具体实施例。应当理解,本领域的普通技术无需创造性劳动就可以根据本发明的构思作出诸多修改和变化。因此,凡本技术领域中技术人员依本发明的构思在现有技术的基础上通过逻辑分析、推理或者有限的实验可以得到的技术方案,皆应在由权利要求书所确定的保护范围内。
Claims (4)
1.一种用下列结构式(I)表示的对氧环己酮/L-苯丙氨酸氮芥共聚物:
其中,所述共聚物的分子量为7319g/mol,或7472g/mol,或8399g/mol,L-苯丙氨酸氮芥的摩尔含量为2%-7%。
2.权利要求1所述的式(I)的共聚物在制备治疗肿瘤的药物中的用途。
3.一种抗肿瘤的药物组合物,其特征是包括权利要求1所述的式(I)的共聚物或其可药盐,和可药用辅料或药学上可接受的载体。
4.如权利要求2所述的用途,其中,通过静电纺丝方法将式(I)的共聚物制备成粒径为100-250nm的纳米颗粒。
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