CN102186902B - 产生一氧化氮的生物可降解聚合物和相关生物医学装置 - Google Patents

产生一氧化氮的生物可降解聚合物和相关生物医学装置 Download PDF

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CN102186902B
CN102186902B CN200980142162.6A CN200980142162A CN102186902B CN 102186902 B CN102186902 B CN 102186902B CN 200980142162 A CN200980142162 A CN 200980142162A CN 102186902 B CN102186902 B CN 102186902B
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G·阿米尔
M·基比
赵海超
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Abstract

本文公开了包含释放一氧化氮的N2O2 -(NONO酯)官能团的产生一氧化氮的生物可降解聚合物。所述聚合物可应用于治疗各种疾病如血栓形成和再狭窄的各种医学装置。

Description

产生一氧化氮的生物可降解聚合物和相关生物医学装置
本申请要求2008年9月19日提交的专利申请序列号61/192,654的优先权，其通过引用全文纳入本文。
发明领域
本发明涉及某些具有释放一氧化氮的N2O2 -官能团的自发产生一氧化氮的基于柠檬酸的生物可降解聚合物。具体而言，本发明涉及用于预防血栓形成和再狭窄的二醇二氮烯鎓化脂族生物可降解弹性体。
发明背景
诸多现代医疗方案需要合成医学装置保持在个体经历的治疗中。尽管现在采用大量聚合材料制备各种接触血液的可植入的体外医学装置，但这类材料的血栓形成性质可在患者中引起严重的并发症，最终导致功能衰竭。因此，临床上几乎始终需要全身抗凝血方案降低血栓形成的风险，特别是在血管移植物的情况中。此外，动脉粥样硬化在所有发达国家中普遍存在，在美国是造成死亡和残疾的主要原因。心血管疾病造成的死亡为每天2400例，或每年871，517例，超过其后五个主要死亡原因的总和。目前采用气囊血管成形术和建立支架、搭桥移植术或动脉内膜切除术治疗严重的冠状动脉粥样硬化或外周动脉疾病。
然而，由于级联事件引起新内膜增生的发生，最终导致沿动脉壁排列的平滑肌细胞发生侵袭性生长并侵占内腔，引起血管的再狭窄或闭塞，因此这些方案的持久性有限。作为该问题的普遍性的证据，目前7900万美国人具有心血管疾病，估计该数量会由于老龄化人口的增长而显著增加。此外，估计美国每年花费4320亿美元用于心血管疾病，其中一大部分为重复介入治疗的费用(Rosamond W.等，Circulation，2007，115：e69-e171)。
预防血栓形成和新内膜增生的一种有前途的治疗策略集中在一氧化氮(NO)的使用上，该分子通常产生于负责保护血管壁的内皮细胞。NO是半衰期非常短的可扩散的小分子，其通过三种不同的NO合酶(NOS)中的一种由L-精氨酸产生。NO作为强效血管舒张剂、血管细胞增殖和迁移抑制剂、血小板聚集抑制剂、白细胞趋化性抑制剂和内皮细胞生长刺激物发挥重要的作用(Ahanchi S.等，Journal of Vascular Surgery，2007，45：A64-73)。因此，对自发分解而释放NO的化合物在脉管系统中的应用进行了广泛研究。
金属络合物、亚硝基硫醇、亚硝胺和二醇二氮烯鎓均为已开发的作为有效NO供体的分子结构的例子(Wang P.等，Chem Rev，2002，102：1091-1134)。特别地，是二醇二氮烯鎓NO供体对医学应用特别具有吸引力，因为其在生理条件(即37℃、pH 7.4)下自发解离，每摩尔NO供体产生两摩尔NO(Hrabie J.等，Chem Rev，2002，102：1135-1154)。采用可长时间局部释放或产生NO的合成聚合材料可提供显著降低接触血液的多种类型生物医学植入物表面血栓形成风险的最终方法，以及防止新内膜增生的发生。
迄今为止，二醇二氮烯鎓化聚合物如聚氨酯(Jun H.等，Biomacromolecules，2005，6：838-844)、聚氮杂环丙烷(Davies K.等，J MedChem，1996，39：1148-1156)、聚甲基丙烯酸酯(Parzuchowski P.等，J AmChem Soc，2002，124：12182-12191)、聚氯乙烯(Saavedra J.等，J Org Chem，1999，64：5124-5131)、二氨基交联聚二甲氧基硅烷(Smith D.等，Biomaterials，2002，23：1485-1494)、树枝状大分子(Stasko N.等，J Am Chem Soc，2006，128：8265-8271)是研究最多的NO供体试剂种类。然而，还未制备出产生NO的二醇二氮烯鎓化脂族生物可降解弹性体。
发明概述
基于上述内容，本发明的一个目的是提供一种用于预防血栓形成和再狭窄的包含释放一氧化氮的N2O2 -(NONO酯)官能团的释放一氧化氮的生物可降解聚合物。本领域技术人员应理解，本发明的一个或多个方面可满足某些目的，而一个或多个其他方面可满足某些其他目的。各目的在其所有方面可能无法等同应用于本发明的每个方面。同样地，可在本发明任一方面的替代形式中观察到以下目的。
因此，本发明的一个目的是提供一种制备含氨基的基于柠檬酸的弹性体的方法，其包括对柠檬酸、脂族二醇和含氨基的单体进行缩聚。
本发明的另一个目的是提供一种控制含氨基的基于柠檬酸的生物可降解弹性体的机械性质和NO释放的方法，其在一定量的含仲胺单元的存在下进行。
本发明的另一个目的是提供一种制备涂布ePTFE移植物的方法，其包括向所述移植物涂布NO释放性弹性体、交联和用NO进行处理。
本发明还有一个目的是提供一种包含NO释放性弹性体的生物医学装置。
附图简要说明
图1和图2为显示用来制备NONO酯PPOC和NONO酯PDC的方法的示意图。
图3总结了具有各种氨基二醇组成的PDC和具有各种脯氨酸含量的PPOC的机械性质。
图4显示PDC和PPOC的拉伸应变曲线。
图5显示PDC的降解性质。
图6为在(a)PPOC 20上和(b)PDC 10上培养24小时(x 200)以及在(c)PPOC 20和(d)PDC 10上培养1周的HAEC的显微照片。
图7为(a)ePTFE移植物对照的内表面，(b)涂布ePTFE移植物的内表面，(c)ePTFE移植物对照的横截面和(d)涂布ePTFE移植物的横截面的SEM图像。
图8是膜和PDC10涂布ePTFE的NO释放。
某些实施方式的详述
如若干非限制性实施方式所述，本发明涉及包含释放一氧化氮的N2O2 -官能团的产生一氧化氮的生物可降解聚合物。一氧化氮(NO)是众所周知的血小板粘着抑制剂，显著有利于健康内皮的抗血栓形成性质。一氧化氮还是新内膜增生的强效抑制剂，新内膜增生是通常在例如气囊血管成形术和建立支架、搭桥移植术和动脉内膜切除术等血管介入治疗之后引起动脉再狭窄的过程。本发明的聚合物在其表面局部释放或产生NO，因此显示显著增强的抗血栓形成性，并可减少由血管壁的装置损伤引起的新内膜增生。本发明的NO释放性生物可降解聚合物可提供机械动态环境内的稳定性和结构完整性，而不刺激寄宿组织并显示与软组织类似的机械性质。
更具体而言，本发明涉及具有式I的生物可降解弹性体聚合物：
Figure BPA00001349776800041
其中R是氢或聚合物，各个A独立选自含NONO酯的胺二醇单元或脂族二醇单元，n是大于1的整数，限制条件是含NONO酯的胺二醇单元和脂族二醇单元各存在至少一个。在具体实施方式中，各个A独立选自-O-(CH2)8-O-或-(CH2)2-N[(N+＝N-O-)O-]-(CH2)2-N+H2-(CH2)2-O-。本发明还涉及柠檬酸-脂族二醇预聚物的特定胺可交联弹性体。在一个具体实施方式中，所述柠檬酸-脂族二醇预聚物的胺交联物是脯氨酸，优选反-4-羟基-L-脯氨酸。
在涉及某些实施方式时，本发明的聚合物可以是基于柠檬酸的生物可降解弹性体聚酯，其具有可调节的机械性质以及体外和体内生物相容性。这样的聚合物可用各种胺单元和各种脂族二醇制备，所述胺单元可以是单羟基和二醇类等，所述脂族二醇例如是2004年9月20日提交的U.S.S.N.10/945,354中公开的脂族二醇，所述专利通过引用全文纳入本文。无论是哪种情况，可通过将NH官能团引入聚合物网状结构来实现NO的产生。NO释放性弹性体可铸塑成型，或通过其它成型方式形成整体装置，如可植入装置(例如药物储器)或留置装置(例如，导管或体外管道组肾透析)。弹性体聚合物还可用作另一基材如聚合物基材(例如发泡聚四氟乙烯)或金属植入物表面上的涂层。本发明的弹性体还可用作包裹血管的生物膜。
就某些非限制性实施方式而言，本发明可涉及自发释放NO的基于柠檬酸的生物可降解弹性体的制备。可通过合成柠檬酸和脂族二醇的预聚物，之后在后交联和NO气体反应期间加入可交联胺单元来获得所述弹性体(图1)。也可通过将柠檬酸、脂族二醇和氨基二醇进行缩聚，之后进行交联和NO处理来制备所述弹性体(图2)。
图3总结了所述弹性体的密度和机械性质，而图4显示具有不同组成的所述弹性体的典型拉伸应变曲线。如图3所示，所述弹性体的机械性质可通过调整脯氨酸和胺二醇的含量进行良好控制。特别地，尽管伸长略有减少，所有含仲胺弹性体的强度均大于基于柠檬酸/1，8-辛二醇的弹性体(POC)。PDC的拉伸强度高达10.71MPa，杨氏模量的范围在合成条件下为5.91-32.64MPa，而所述拉伸强度和杨氏模量相对POC增大约4倍到超过60倍。
弹性体PDC的降解特征见图5所示。具有各种氨基二醇含量的弹性体显示类似的降解速率。所述弹性体的质量损失在置于37℃PBS中的开始两周后为4-6％，4周后为7-12％，6周后为18-22％。
在1天和1周后观察到所述弹性体上的HAEC细胞粘着和增殖。图6(a)和(b)的显微照片显示两种细胞在弹性体PPOC20和PDC10上均发生附着并显示正常表型。1周后，所述细胞汇合(图6(c)和(d))。
图7显示用PDC10涂布之前和之后的ePTFE微结构，表明原纤维的微结构和涂布ePTFE的节点网状结构在沉积的POC层内得到保持。
图8显示NONO酯弹性体和涂布ePTFE的NO释放性质。PPOC10持续释放NO 7天。就PPOC 20和PPOC 30而言，约90％的NO在开始2天释放。PDC 5和PDC 15显示类似的释放趋势。
ePTFE移植物为多孔状，对气体或有机溶剂具有透过性。此外，可通过在制造过程中改变拉伸量来调整ePTFE的孔径。液体预聚物溶液也可透过ePTFE并在后交联后获得聚合物改性ePTFE。如图8中可见，涂布移植物中NONO酯PDC10涂布ePTFE的NO释放为约20重量(wt)％。大多数NO在开始3天从所述移植物释放。
本发明的实施例
材料：从西格玛-奥德里奇公司(Sigma-Aldrich)(美国密苏里州圣路易斯(St.Louis，MO，USA))购得1，8-辛二醇(98％)、N，N’-二(2-羟乙基)-乙二胺、反-4-羟基-L-脯氨酸和柠檬酸(99.5％)，直接使用。ePTFE移植物从WLG联合有限公司(W.L.Gore & Associates，Inc.)(美国亚利桑那州弗拉格斯塔夫麻雀大道3300E，86004(3300E.Sparrow Ave，Flagstaff，Arizona，86004，USA))购得。
以下非限制性实施例和数据显示涉及本发明组合物和/或方法的各个方面和特征，包括本文所述基于柠檬酸的生物可降解弹性体聚酯的制备和应用。相关实施例、方案和方法见共待批申请2004年9月20日提交的U.S.S.N.10/945,354和2007年2月8日提交的11/704,039所述，两个共待批申请通过引用纳入本文。
实施例1
含脯氨酸的聚(1，8-辛二醇柠檬酸酯)(PPOC)的制备。采用柠檬酸∶1，8-辛二醇∶反-4-羟基-L-脯氨酸摩尔比分别等于100∶100∶10(PPOC10)、100∶100∶20(PPOC20)、100∶100∶30(PPOC30)的单体制备羟基脯氨酸交联弹性体膜。作为例子，将0.1摩尔1，8-辛二醇和0.1摩尔柠檬酸加入到100ml圆底烧瓶中，使其接触恒定氮气流。所述混合物在160-165℃剧烈搅拌下发生熔融。熔融之后，所述混合物在130℃聚合30分钟以产生预聚物，然后加入0.02摩尔反-4-羟基-L-脯氨酸。使所述体系再聚合30分钟以产生含脯氨酸的预聚物。将具有各种脯氨酸含量的预聚物在80℃交联4天，得到交联弹性体。
实施例2
氨基二醇官能化聚(二醇柠檬酸酯)(PDC)的制备。采用柠檬酸∶1，8-辛二醇∶N，N’-二(2-羟乙基)-乙二胺摩尔比分别等于100∶95∶5(PDC5)、100∶90∶10(PDC10)、100∶85∶15(PDC15)的单体制备交联弹性体膜。作为例子，将0.09摩尔1，8-辛二醇和0.1摩尔柠檬酸加入到100ml圆底烧瓶中，使其接触恒定氮气流。所述混合物在160-165℃剧烈搅拌下发生熔融。熔融之后，向混合物中加入0.01摩尔N，N’-二(2-羟乙基)-乙二胺，将所述复合物在130℃氮气气氛中聚合40分钟以产生PDC10预聚物。然后将所述预聚物铸塑到玻璃板中，在80℃后聚合4天以形成交联弹性体PDC10。
实施例3
弹性体的表征。根据阿基米德定律，通过具有密度测定工具套件(瑞士格里芬斯公司(Greifensee，Switzerland))的MT(Mettler Toledo)天平测定弹性体密度。将无水乙醇用作辅助液体。根据ASTM D412a，在配有SOON负载传感器的Instron 5544机械测试仪(马萨诸塞州卡顿的昂斯朗公司(Instron Canton，MA))上进行拉伸机械测试。以500mm/mm的速率牵引所述样品(26-4-1.0mm，长度-宽度-厚度)。将数值转换为应力-应变，从初始斜率计算杨氏模量。测定4-6个样品，取平均值。
实施例4
体外降解。将圆盘形样品(直径6mm，厚度约1mm)置于包含10ml磷酸盐缓冲盐水(pH 7.4)的管中，在37℃温育。温育后，用水洗涤样品并冻干1周。如公式(1)所示，通过将初始质量(Wo)与在给定时间点测定的质量(Wt)进行比较计算质量损失。对降解测试进行5个单独实验。结果以平均值表示。
质量损失(％)＝[(Wo-Wt)/Wo]×100公式(1)
实施例5
体外细胞培养。用EBM-2培养基(马里兰州维克斯威尔克隆尼克公司(Clonetics，Waikersville，MD))培养人主动脉内皮细胞(HAEC)(马里兰州维克斯威尔克隆尼克公司)。将细胞培养物保持在37℃用5％CO2平衡的水套培养箱中。将PDC膜切为小片(1-2cm2)，置于细胞培养皿(直径6cm)中。所有聚合物样品通过在70％乙醇中温育30mm，之后在紫外线中再暴露30分钟来灭菌。将密度为1.0x106个细胞/ml的HAEC分别加入到组织培养皿的弹性体膜中。细胞移种约30分钟后，向培养皿加入5ml培养基。在细胞移种1天和7天后用配有光度计CooISNAP HQ(马里兰州西维尔斯普林公司(Silver Spring，MD))的倒置光学显微镜(尼康(Nikon)Eclipse，TE2000-U)观察并记录附着细胞的形态学(图6)。
实施例6
PDC涂布ePTFE的制备。用10％PDC10乙醇溶液涂布标准壁非拉伸ePTFE移植物(Gore-Tex，内径6mm，亚利桑那州弗拉格斯塔夫WLG联合有限公司(W.L.Gore & Associates，Flagstaff，AZ))的内腔。封闭6cm长ePTFE的一端，通过另一端将15ml 10％PDC10乙醇溶液注射到ePTFE中，使聚合物溶液透过移植物的内层。将PDC溶液去除之后，将移植物留置于室温24h以使乙醇蒸发。随后在80℃进行3天后聚合反应，得到PDC涂布ePTFE。
实施例7
NONO酯PDC或涂布ePTFE的制备及其NO释放。用NO气体的乙腈溶液在室温对PDC膜和PDC涂布ePTFE移植物处理48小时。然后将经处理的膜在室温真空干燥48小时。将所述膜和涂布ePTFE在37℃PBS中温育1-7天。采用定量分析NO初级降解产物亚硝酸盐的格里斯(Griess)鉴定测定所述膜的NO释放。
结果
本发明提供基于柠檬酸的NO释放性生物可降解弹性体，例如脯氨酸交联聚(1，8-辛二醇柠檬酸酯)(PPOC)和含胺二醇的聚(二醇柠檬酸酯)(PDC)。所述弹性体的机械性质可取决于仲胺含量，根据体外细胞培养，所述弹性体显示良好的生物相容性。NO从所述聚合物膜和涂布ePTFE成功释放。所述弹性体具有与市售合成血管移植物类似的机械性质，可用于多种心血管应用中，包括但不限于在涂层、血管移植物和管道中的应用。

Claims (8)

1.一种生物相容性弹性体聚合物，其是柠檬酸脂族二醇预聚物的胺交联的弹性体；其中用于胺交联的胺交联物是反-4-羟基-L-脯氨酸，其中制备柠檬酸脂族二醇预聚物的胺交联的弹性体的方法包括：
a)合成柠檬酸和脂族二醇的预聚物；
b)将所述预聚物与反-4-羟基-L-脯氨酸进行后聚合；和
c)使来自后聚合的后聚物与NO气体反应。
2.如权利要求1所述的聚合物，其特征在于，所述脂族二醇是1,8-辛二醇。
3.一种制备柠檬酸脂族二醇预聚物的胺可交联弹性体的方法，包括：
a)合成柠檬酸和脂族二醇的预聚物；
b)将所述预聚物与可交联胺单元进行后聚合；和
c)使来自后聚合的后聚物与NO气体反应；
其中所述可交联胺单元是反-4-羟基-L-脯氨酸。
4.如权利要求3所述的方法，其特征在于，所述脂族二醇是1,8-辛二醇。
5.一种生物医学装置，其特征在于，所述装置的至少一个表面上沉积有包含NO释放性弹性体的涂层，所述弹性体是柠檬酸脂族二醇预聚物的胺交联的弹性体；其中用于胺交联的胺交联物是反-4-羟基-L-脯氨酸；
其中制备柠檬酸脂族二醇预聚物的胺交联的弹性体的方法包括：
a)合成柠檬酸和脂族二醇的预聚物；
b)将所述预聚物与反-4-羟基-L-脯氨酸进行后聚合；和
c)使来自后聚合的后聚物与NO气体反应。
6.如权利要求5所述的生物医学装置，其特征在于，所述脂族二醇是1,8-辛二醇。
7.如权利要求5所述的生物医学装置，其特征在于，所述装置是可植入装置。
8.如权利要求6所述的生物医学装置，其特征在于，所述装置是可植入装置。
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