CN101208057B - 结缔组织的弹性蛋白稳定化 - Google Patents
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- CN101208057B CN101208057B CN200680022770XA CN200680022770A CN101208057B CN 101208057 B CN101208057 B CN 101208057B CN 200680022770X A CN200680022770X A CN 200680022770XA CN 200680022770 A CN200680022770 A CN 200680022770A CN 101208057 B CN101208057 B CN 101208057B
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Abstract
提供用于治疗归因于组织构造破坏的结缔组织衰弱的方法,尤其是归因于弹性蛋白降解的结缔组织衰弱。治疗剂使用酚类化合物的某些独特性质以开发用于降低弹性蛋白降解的方案,例如发生在血管结构中动脉瘤的形成期间。根据本发明,能够将弹性蛋白体内稳定化,并且能够将结缔组织的破坏例如导致生命危险的血管结构中动脉瘤一起缓和或停止。依照多种递送方法能够将所述治疗剂短期或长期地递送或施用,所述方法包括:包含血管周或血管内补片的持续释放方法、微球载体的使用、水凝胶或渗透泵。
Description
相关申请
本发明要求在2005年4月25目提交的美国临时申请序列号60/674,631(U.S.Provisional Application Serial No.60/674,631)的优先权。
联邦政府资助的研发
依照National Institutes of Health Grant No.HL-61652,美国政府对本发明持有权利。
发明背景
血管结构降解最普遍的结果之一是动脉瘤。根据定义,术语“动脉瘤”简单来说是血管壁上异常的扩张或气胀(ballooning)。由于存在能够导致大量出血、中风或出血性休克的破裂或剥离(dissection)的可能性,这种情况可以是破坏性的,并且在估计80%的情况下能够致死。动脉瘤能够由一大类变性疾病(degenerative disease)和病理学中的任一种引起,包括动脉粥样硬化症(atherosclerotic disease)、动脉成分缺陷(defects in arterial components)、遗传易感性(genetic susceptibilities)和高血压,除此之外,动脉瘤能够在数年间无症状地(silently)发展。动脉瘤的特点包括血管结构蛋白例如弹性蛋白的酶促降解、炎性浸润(inflammatory infiltrate)、钙化(calcification)和最终血管构造的全面破坏。例如,图1图解了健康主动脉(aorta)和动脉瘤主动脉之间弹性蛋白含量的区别。从图中能够看出,损坏结构的弹性蛋白含量与健康结构的弹性蛋白含量相比少70%。
目前对于已诊断动脉瘤的治疗方法限于侵入性外科手术技术。在最初诊断出小动脉瘤之后,最常用的医学方法是追踪动脉瘤的发育,在达到预定大小(例如,大约直径5cm)之后,实施外科手术治疗。目前外科手术治疗限于血管内支架移植修复(endovascular stent graft repair)或者用血管移植物(vascular graft)取代患病血管。尽管这些外科手术治疗能够拯救生命并且改善动脉瘤患者的生活质量,但是因为可能的术后并发症(例如,神经性损伤(neurological injuries)、出血或中风)以及装置相关的并发症(device-relatedcomplication)(例如,血栓形成(thrombosis)、渗漏或衰竭),外科手术本身对患者存在危险。此外,依赖于动脉瘤的位置,侵入性外科手术方法的危险可能超过该方法可能带来的助益,例如在动脉瘤深入脑内的情况下,患者几乎没有能够选择的治疗方式。此外,外科手术治疗不一定能提供永久的解决方案,因为如果动脉瘤在校正手术之后有所发展,血管移植物可能松动并移开。
动脉瘤不是以结构蛋白酶促降解为特点的唯一病症。结构性蛋白质降解在其中起重要作用的其它病症包括马方综合征(Marfan syndrome)、瓣膜上主动脉狭窄(supravalvular aortic stenosis)和慢性阻塞性肺病(chronic obstructivepulmonary disease;COPD)。对于受到病痛折磨的人而言,从最轻的方面说,这些病症导致生活质量的降低,并且通常导致早产儿死亡(premature death)。
酚类化合物(phenolic compounds)是一组种类丰富的材料,其已经被公认用在多种应用之中。例如,它们天然存在于许多植物中,并且经常是人饮食的成分。已对酚类化合物作为自由基清除剂(scavenger)和中和剂的效率进行了深入的研究,例如在局部皮肤施用(topical skin application)和食品增补剂(foodsupplements)中。同样认为酚类化合物预防存在于特定炎症中细胞膜交联,并且认为由于酚类化合物对自由基和其它氧化性种类的调节(modulation)而影响特定基因的表达(参见,例如,U.S.Patent Application No.6,437,004 toPerricone)。
本领域需要的是用于使受到变性疾病如动脉瘤影响的器官和组织稳定的治疗规程和组合物。具体而言,使用酚类化合物的治疗规程能够提供安全、低侵入性途径用于稳定结构性构造从而缓和这些病症的增长和/或发展。
发明概述
在一个实施方式中,本发明涉及用于使包含弹性蛋白的结缔组织稳定的方法。例如,所述方法可包括将酚类化合物直接施用于结缔组织。在所公开的方法中使用的酚类化合物包含疏水核心和至少一个结合至该疏水核心的酚基。
在一个优选的实施方式中,所述规程靶向的结缔组织可以是血管的成分。例如,可将所述方法用于治疗动脉,并且在一个具体的实施方式中,可将所述方法用于治疗主动脉。
本发明的方法可包括在合适的药物递送运载体(drug delivery vehicle)中提供酚类化合物,所述药物递送运载体例如,持续释放药物递送运载体(sustainedrelease drug delivery vehicle)。在一个实施方式中,可将药物递送运载体,例如微囊化、水凝胶、可植入装置如支架、补片(patch)、血管移植物等,定位于邻近结缔组织处从而直接将酚类化合物递送至该组织。
在另一个实施方式中,可以使用其它递送方法和装置。例如,可将包含酚类化合物和肠胃外可用载体(parenterally acceptable carrier)的组合物直接注射到结缔组织中。而在另一个实施方式中,可通过静脉内递送(intravenousdelivery)将所公开的化合物递送至血管壁的结缔组织。
本文描述的方法和组合物在一个实施方式中可有益地用于体内治疗或预防性治疗中,并且在一个具体的实施方式中,可用于动脉瘤血管的治疗。
本发明还涉及能够用于所述方法的组合物。例如,本发明的组合物可包含在大约0.0001w/v%-大约10w/v%的酚类化合物和肠胃外可用载体。通常而言,所述组合物可具有在大约4-大约9的pH,例如大约5.5-大约7。
在一个优选实施方式中,所述酚类化合物可以是鞣质(tannin)或鞣质衍生物。例如,所述酚类化合物可以是五没食子酰葡糖(pentagalloylglucose)。
附图简述
对本领域普通技术人员而言,对本发明完整的并且可实施的公开内容,包括其最佳方式,将在本说明书的以下部分进行更具体的阐述,包括对附图的涉及,其中:
图1是动物模型中健康主动脉和动脉瘤主动脉在弹性蛋白含量上的差别的图示;
图2说明鞣酸的化学结构,其中将五没食子酰葡糖用圈突出显示;
图3示意性说明本发明一些实施方式的酚类化合物示例性递送方法,包括血管周递送(图3A)和血管内递送(图3B);
图4A-4D显示实施例部分所述染色的主动脉组织切片,说明在弹性蛋白酶存在下结缔组织弹性蛋白的稳定化;
图5A说明如实施例部分所述用于检测猪主动脉切片开角(opening angle)的方法;
图5B图示说明猪主动脉切片开角的测定结果;
图5C包含猪主动脉切片的照片,其显示处理的组织样品和对照组织样品的回缩评估(recoil evaluation);
图6A-6E显示如实施例部分所述处理的组织样品的活/死试验(live/deadassay)结果的数码照片;
图7显示鞣酸结合至纯主动脉弹性蛋白的动力学的图示;
图8图示说明大鼠主动脉(未处理)损伤之后直径的增加,并且说明对于如本文所述使用酚类化合物处理的主动脉而言动脉瘤的显著减少;
图9说明图8的对照主动脉和处理的主动脉直径的百分比增加(percentageincrease);
图10A图示说明图8的对照主动脉和处理的主动脉的弹性蛋白含量;
图10B和10C说明Verhoeff van Giesson染色之后的对照主动脉和处理的主动脉;和
图11比较了处理后立即从处理组织提取酚类化合物后的结果(本文所述的原位)和从处理之后体内28天从处理组织提取酚类化合物后的结果。
发明详述
现在具体涉及本发明的实施方式,其一个或多个实施例将在下文中阐明。各实施例均以说明本发明而非限制本发明的方式提供。实际上对于本领域技术人员显而易见的是,可在不背离本发明范围和精神的前提下对本发明进行各种修饰和改变。例如,作为一个实施方式的一部分来说明或描述的特征,可以用在另一个实施方式中以得到其它实施方式。
本发明主要涉及能够有益地用于使结缔组织稳定的方法和酚类化合物。具体而言,在此公开的方法和化合物能够使结缔组织的弹性蛋白成分稳定,并且由此防止结缔组织结构性构造的降解。例如,能够将本发明公开的方法用于防止包含靶向结缔组织的器官(例如血管)的结构性破坏。在一个具体实施方式中,本文公开的材料和方法能够用在慢性结缔组织变性疾病的治疗中。例如,本发明能够涉及体内治疗方法和组合物。能够使由所述方法靶向的结缔组织稳定,以使其对蛋白质降解较不易感,所述蛋白质降解可因多种机制和/或病症中的任一种而发生,包括例如与动脉瘤、动脉粥样硬化症、遗传易感性、钝力伤(blunt force injury)、马方综合征等有关的那些机制和/或病症。
结缔组织是其上支撑其它类型组织(即,上皮、肌肉和神经组织)的框架。结缔组织通常包含彼此不直接附着(attach)并且保持于胞外基质(extracellularmatrix)内的单独细胞。胞外基质依次包含基质(ground substance)(例如,骨骼的矿质、血液的血浆等),和包含胶原纤维和弹性蛋白纤维的纤维性成分。结缔组织能够呈现迥然不同的各种构造,从血液到致密结缔组织,前者中缺乏纤维性成分并且基质是液体,后者包含相对高比例的胞外纤维(例如,胶原)并且可几乎不含其它结缔组织成分。存在许多结缔组织的特化类型,一个实例是弹性组织,其中弹性纤维是该组织的主要成分,而通常存在于其它类型结缔组织中的要素例如胶原和蛋白聚糖的量可以是最低限量。
本文公开的化合物和方法涉及结缔组织弹性蛋白成分的稳定化,并且在一个具体的实施方式中,涉及血管结构的弹性蛋白成分的稳定化。应该理解的是,尽管本发明在一个具体实施方式中涉及使对形成动脉瘤易感的血管稳定,但在其它实施方式中,本发明能够治疗其它器官、其它疾病和/或其它病症。具体而言,本发明公开的治疗剂和治疗规程能够应用于包含弹性蛋白成分的任何动物或人结缔组织。
弹性蛋白是结缔组织中负责组织的弹性和回缩的蛋白成分。此外,弹性蛋白在结缔组织中十分丰富。实际上,弹性蛋白是主动脉壁中存在的最丰富的胞外基质蛋白。弹性蛋白多肽链天然地交联在一起以形成橡胶样弹性纤维。与胶原不同,弹性蛋白分子在纤维受到拉伸时能够解开(uncoil)成为更延伸的构型,并且一旦拉力放松就将自发回缩。结缔组织病理学中的弹性蛋白降解通常由酶引起,所述酶包括能够通过血管细胞以及通过浸润的炎性细胞分泌的基质金属蛋白酶(MMP)和弹性蛋白酶。尽管导致弹性蛋白降解的多种酶的方法和方案的许多方面仍然未知,通常认为大多数酶在远离交联的位点攻击并结合蛋白质。
根据本发明,能够通过用酚类化合物稳定该组织的弹性蛋白成分来防止或减缓结缔组织的降解。具体而言,认为许多天然和合成的酚类化合物中的任一种能够结合弹性蛋白并且由此保护弹性蛋白免于降解,例如归因于弹性蛋白降解酶作用的降解。因此,在一个实施方式中,本发明涉及的方法和化合物能够抑制酶催化的弹性蛋白降解,尤其是弹性蛋白酶和/或MMP催化的弹性蛋白降解。
本发明包含的酚类化合物包括任何包含至少一个结合至疏水核心的酚基的化合物。尽管不希望受到任何具体理论的限制,认为酚类化合物和弹性蛋白之间的相互作用包括涉及所述分子的羟基以及疏水核心的多个方面。具体而言,认为酚类化合物能够通过空间方法(steric means)和键形成来稳定弹性蛋白,并且由此保护蛋白质上对酶介导的(例如,弹性蛋白酶或MMP介导的)切割易感的位点。具体而言,认为酚类化合物的羟基能够多价地结合弹性蛋白,例如通过与氨基酸残基形成氢键,所述氨基酸残基例如极性氨基酸残基,包括甲硫氨酸、甘氨酸和脯氨酸,由此多个蛋白质能够与单一分子相互作用于产生包括多个弹性蛋白分子的三维交联结构。此外,在一些实施方式中,本发明的酚类化合物能够包含一个或多个双键,由此该酚类化合物能够与弹性蛋白共价结合,在酚类化合物和结缔组织弹性蛋白之间形成更强和更持久的保护性结合。此外,认为弹性蛋白的大疏水区包含对弹性蛋白酶介导的切割易感的位点,还认为弹性蛋白的大疏水区包含酚类化合物疏水核心和蛋白质之间的结合位点。因此,认为酚类化合物和蛋白质分子之间的结合通过将蛋白质与疏水核心结合来保护酶靶向的蛋白质上的特异性结合位点,并且还能够通过发展大的三维交联结构从空间上阻碍蛋白质的降解。
本发明包含的酚类化合物所包括的材料包含疏水核心和从该分子疏水部分延伸的一个或多个酚基。例如,本发明的示例性酚类化合物可包括但不限于,黄酮类化合物及其衍生物(例如,花色素苷(anthocyanins)、栎精(quercetin))、黄木脂素类(flavolignans)、酚根茎(phenolic rhizomes)、包括(+)-儿茶素((+)-catechin)和(-)-表儿茶素((-)-epicatechin)的黄烷-3-醇(flavan-3-ols)、其它鞣质及其衍生物(例如鞣酸、五没食子酰葡糖、nobotanin、表没食子儿茶精没食子酸(盐)(epigallocatechin gallate)和没食子鞣质(gallotannins))、鞣花酸(ellagicacid)、原花青素(procyanidins)等。
本发明的酚类化合物包括合成的和天然的酚类化合物。例如,天然的酚类化合物可包括来自基于天然植物来源的提取物中存在的那些天然酚类化合物,所述提取物例如橄榄油(例如,羟基酪醇(3,4-二羟基苯基乙醇))和橄榄苦苷(oleuropein)的提取物、可含有表儿茶素和类似化合物的可可豆(cocoa bean)的提取物、包括茶(C.senensis)和C.assaimic的茶属(Camellia)的提取物、甘草(licorice)、柳珊瑚(sea whip)、芦荟(aloe vera)、甘菊(chamomile)等的提取物。
在一个优选实施方式中,本发明的酚类化合物可以是鞣质及其衍生物。鞣质可存在于许多植物种类中。例如,茶(Camellia sinensis)具有天然的高鞣质含量。绿茶叶是鞣质的主要植物来源,因为它们不仅含有鞣酸基团和没食子酸基团,还包含原花色素(proanthocyanidin)、原飞燕草素(prodelphinidin)。鞣质同样存在于葡萄酒(wine)中,尤其是红葡萄酒,以及葡萄皮和种子中。石榴(pomegranate)也含有多种鞣质,尤其是可水解的鞣质。
鞣酸是普遍的天然得到的鞣质,其结构示于图2。鞣酸作为交联剂在许多性质上类似于通常用于制备和形成异种移植物(xenograft)或同种异体移植物(allograft)组织植入物中的许多固定剂,例如戊二醛固定剂。此外,鞣酸能够与其它结缔组织成分以及弹性蛋白相互作用,并且因此除了弹性蛋白成分之外,在本发明公开的方法中鞣酸能够使靶向的结缔组织的其它成分稳定。例如,鞣酸能够交联糖胺聚糖多糖以及其它结缔组织成分。
在一个实施方式中,本发明涉及将所公开的剂用于在体内使结缔组织稳定。因此,在这些实施方式中,在包含所公开的化合物的治疗制备物中,所述剂的生物相容性和细胞毒性可能是重要的。同时,怀疑含鞣酸的制备物引起肝脏毒性(hepatoxicity)。这种毒性目前主要归因于制备物的低纯度和在所述组合物中包含毒性没食子酸残基。因此,在一个实施方式中,本发明涉及包含高纯度鞣酸、几乎不含或不含游离没食子酸残基的组合物。例如,在一个实施方式中,本发明的组合物可在制备物中包含少于大约5%游离没食子酸残基。在一个实施方式中,本发明的组合物可在组合物中包含大约1%-大约5%的游离没食子酸残基。
在一个本发明的优选实施方式中,所公开的组合物包含有效量的五没食子酰葡糖(pentagalloylglucose)(PGG)。PGG是鞣酸分子在图2中圈出的部分,包括鞣酸的疏水核心以及多个酚羟基,但不具有外部的没食子酸残基和与鞣酸结合的可水解酯键。因此,在本发明的一个实施方式中,通过使用无没食子酸残基的化合物(例如PGG)作为选择的剂,能够阻止在长期应用过程期间游离没食子酸残基释放的可能性。
通常而言,本文所述的酚类化合物能够作为生物相容性组合物提供。例如,本文公开的组合物可包含一种或多种浓度能大范围变化的酚类化合物,优选的浓度通常依赖于具体的应用、酚类化合物靶向的递送位点和将用于递送过程的模式。例如,在一个实施方式中,本发明的组合物可包含一种或多种浓度在大约0.0001%至大约10%的酚类化合物。(除非另有说明,本文报导的所有浓度均为重量/体积百分比。)然而应该注意的是,尽管这些示例性浓度在一些实施方式中有效,但本发明包含的组合物包含更宽范围的酚类化合物浓度。例如,除了如上所述的递送模式之外,使用的实际浓度可以受到方法靶向的器官、靶向区域的大小、期望的温育时间和优选的pH的影响。在本发明的一个实施方式中,所公开的组合物可包含浓度范围从大约0.1%至大约1%的酚类化合物。
在一个实施方式中,可使用本领域普通技术人员已知的配制方法将酚类化合物以可药用的配制物提供。通常这些配制物可通过标准途径施用。例如,在一个实施方式中,可将所述配制物直接施用于结缔组织,例如通过曝露结缔组织并且对其直接施用,或通过直接将所述配制物注射到靶向的结缔组织。然而,在其它实施方式中,可将所述配制物间接施用于靶向的组织。
在全身性递送规程(systemic delivery protocol)中,可将配制物在静脉内递送。例如,可使用渗透微泵(osmotic mini-pump)通过直达感兴趣位点的套管来提供高浓度治疗剂的受控递送,例如直接递送至靶向的血管。本领域技术人员公知并在下文讨论的原位可聚合水凝胶(in situ polymerizable hydrogel)是递送运载体的另一个实例,其能够用在递送规程中,例如以直接到达靶向套管的静脉内递送的方式。一旦通过任何本领域接受的合适方法递送至靶向的血管,所述酚类化合物能够穿过血管壁并使血管的结缔组织稳定化。例如,当从血管内腔递送至结缔组织时,本文公开的酚类化合物穿过血管壁的内皮以接触结缔组织的弹性蛋白并使结构性构造稳定化。
除了酚类化合物之外,本发明的组合物还能够包含额外的剂。这些剂可以是活性剂,其向组织提供除了由酚类化合物提供的稳定化之外的直接助益;或可以是支持剂(supporting agent),其改进递送、相容性或组合物中其它剂的反应性。例如,在一个实施方式中,组合物可包含戊二醛。在靶向结缔组织时,戊二醛能够在蛋白质中的游离胺之间形成共价交联以进一步稳定组织。如有必要,组合物可包含没食子酸清除剂,例如抗坏血酸或谷胱甘肽,从而阻止游离没食子酸残基的释放。
能够将所述酚类化合物与许多可能的降脂药物(lipid-lowering medication)中的任一种组合,从而防止通常与动脉瘤形成一起存在的钙化脂质沉积(calcified lipid deposits)或动脉硬化斑(arteriosclerosis plaques)的发展。
本发明的酚类组合物可包含一种或多种本领域公知的缓冲剂。例如,配制包含一种或多种酚类化合物并且pH为大约4.0至大约9.0的组合物可同时将生物相容性缓冲剂包含在内,所述缓冲剂例如蒸馏水、盐水、磷酸盐缓冲液、硼酸盐缓冲液、HEPES、PIPES和MOPSO。在一个实施方式中,可将本发明的组合物配制成pH为大约5.5-大约7.4。
用于肠胃外递送例如通过注射的组合物,可包含可药用的无菌水溶液或非水溶液、分散体、悬液或乳剂,以及使用之前即复原成无菌可注射溶液或分散体的无菌粉末。合适的水和非水的载体、稀释剂、溶剂或运载体的实例包括水、乙醇、多元醇(例如,甘油、丙二醇、聚乙二醇等)、羧甲基纤维素和它们合适的混合物、植物油(例如,橄榄油)和可注射有机酯例如油酸乙酯。此外,所述组合物可包含能够增强酚类化合物有效性的小量辅助物质例如润湿剂或乳化剂、pH缓冲剂等。例如,可通过使用包覆材料如卵磷脂(lecithin),在分散系的情况下通过保持所需粒度和通过使用表面活性剂来保持合适的流动性。这些组合物还可包含佐剂例如防腐剂、润湿剂、乳化剂和分散剂。
可通过包含各种抗细菌剂和抗真菌剂例如对羟基苯甲酸酯类(paraben)、氯丁醇(chlorobutanol)、苯酚、山梨酸等,来确保对微生物作用的防止。还可能理想地包含等渗剂例如糖、氯化钠等。
在一个实施方式中,所述组合物可在其中包含可药用盐成分,例如,源自无机酸或有机酸的盐。可药用盐是本领域内熟知的。例如,S.M.Berge等在通过引用并入本文的J.Pharmaceutical Sciences(1977)66:1et seq.中详细描述了可药用盐。可药用盐包括与无机酸(例如盐酸或磷酸)形成的酸加成盐(acidaddition salts),或与例如乙酸、酒石酸、扁桃酸等有机酸形成的酸加成盐。与游离羧基形成的盐也可源自无机碱例如氢氧化钠、氢氧化钾、氢氧化铵、氢氧化钙或氢氧化铁,和有机碱例如异丙胺、三甲胺、2-乙氨基乙醇、组氨酸、普鲁卡因等。所述盐可在本发明化合物的最终分离和纯化期间原位制备,或独立地通过将游离碱官能(free base function)与合适的有机酸反应制备。代表性的酸加成盐包括但不限于乙酸盐、己二酸盐、藻酸盐、柠檬酸盐、天冬氨酸盐、苯甲酸盐、苯磺酸盐、硫酸氢盐、丁酸盐、樟脑酸盐、樟脑磺酸盐(camphorsulgfonate)、二葡糖酸盐(digluconate)、甘油磷酸盐、半硫酸盐(hemisulfate)、庚酸盐(heptonoate)、己酸盐、延胡索酸盐、氢氯化物、氢溴化盐(hydrobromide)、氢碘化物(hydroiodide)、2-羟基甲磺酸盐(2-hydroxymethanesulfonate)(羟乙磺酸盐)、乳酸盐、马来酸盐、甲磺酸盐、烟酸盐(nicotinate)、2-萘磺酸盐、草酸盐、扑酸盐(pamoate)、果胶酸盐、过硫酸盐、3-苯丙酸盐(3-phenylpropionate)、苦味酸盐、新戊酸盐(pivalate)、丙酸盐、琥珀酸盐、酒石酸盐、硫氰酸盐、磷酸盐、谷氨酸盐、碳酸氢盐、对甲苯磺酸盐(p-toluenesulfonate)和十一烷酸盐(undecanoate)。此外,使用如下的剂能够将碱性含氮基团季铵化:低级卤代烷(lower alkyl halides)例如甲基、乙基、丙基和丁基氯化物、溴化物和碘化物;二烷基硫酸酯例如二甲基、二乙及、二丁基和二戊基硫酸酯;长链卤化物例如癸基、月桂基、肉豆蔻基和硬脂基氯化物、溴化物和碘化物;芳烷基卤化物例如苯甲基和苯乙基溴化物等。由此获得水溶性或油溶性或可分散的产物。可用于形成可药用酸加成盐的酸的实例包括无机酸例如氢氯酸、氢溴酸、硫酸和磷酸,和有机酸例如草酸、马来酸、琥珀酸和柠檬酸。
在一个实施方式中,本发明能够包括使用本领域公知的经时释放(timedrelease)或持续释放递送系统。例如,在期望将剂长期递送至具体的器官或血管位置的情况下,这些系统可以是理想的。根据这种具体实施方式,持续释放基质可包含由通常是聚合物的材料制造的基质,其能够通过酶促水解或酸/碱水解或通过溶解来降解。一旦将基质定位于靶组织上或邻近靶组织处,例如插入到体内,例如在下文进一步描述的补片或支架的形式,这样的基质能够根据酶和体液来发挥作用。持续释放基质可选自生物相容性材料例如脂质体、聚交酯(聚乳酸)、聚乙交酯(乙醇酸的聚合物)、聚交酯共乙交酯(polylactideco-glycolide)(乳酸和乙醇酸的共聚物)、聚酐、聚原酸酯(poly(ortho)esters)、多蛋白、透明质酸、胶原、硫酸软骨素、羧酸、脂肪酸、磷脂、多糖、核酸、聚氨基酸、氨基酸例如苯丙氨酸、酪氨酸、异亮氨酸、多核苷酸、聚乙烯基丙烯、聚乙烯吡咯烷酮和硅树脂(silicone)。可能的生物可降解聚合物和它们的用途在例如Brem et al.(1991,J.Neurosurg.74:441-6)中有详细描述,该文献以其完整形式通过参考并入本文。
将有效量本发明的剂通过静脉内或皮下注射施用时,所述组合物可通常为无致热原、肠胃外可用的水溶液形式。这些肠胃外可用溶液的制备考虑到pH、等渗性、稳定性等,在本领域的技术之内。用于静脉内、皮肤或皮下注射优选的药用组合物除了本发明的酚类化合物之外还可包含等渗运载体例如Sodium Chloride Injection、Ringer′s Injection、Dextrose Injection、Dextrose andSodium Chloride Injection、Lactated Ringer′s Injection或本领域已知的其它运载体。本发明的治疗组合物还可包含稳定剂、防腐剂、抗氧化剂或本领域技术人员已知的其它添加剂。
本发明公开的治疗剂的剂量可依赖于治疗的疾病状态或具体病症,和其它临床因素例如人或动物的重量和情况,以及施用所述化合物的途径。本发明公开的治疗剂可在一天数次到单次治疗规程之间施用。任选地,治疗剂可根据公开的方法短期地、在一次介入期间或长期地递送,例如使用定时或持续释放体系的多次施用或任选地单次施用。应该理解的是,本发明同时具有用于人用和兽用的应用。本发明的方法考虑到同时或在一段延长的时间中给予的单次以及多次施用。此外,本发明公开的治疗剂可与其它形式的治疗一起施用,例如外科血管内支架移植修复或血管结构过度损伤区域的置换术。
在一个实施方式中,包含一种或多种酚类化合物的组合物能够靶向特异性位点,例如靶向已诊断的体内动脉瘤,使用最低限度侵入性方法从生物相容性可植入装置提供治疗剂的局部长期递送。例如,图3图示说明可能的血管周(图3A)和血管内(图3B)递送途径,可将其中任一用于本发明公开的治疗剂的局部靶向递送,例如递送至已诊断的动脉瘤。
适合用于本发明的血管周递送技术是本领域技术人员公知的,并且因此无需在本文中详细解释。例如,示例性的已知血管周药物递送技术包括由Chen,et al.(美国专利申请公开号2005/0079202)和Nathan(美国专利申请公开号2003/0228364)描述的技术,其均通过引用并入本文。这些示例性的血管周递送系统包括能够注射至或直接置于(例如通过外科手术)具体位置的聚合物递送运载体,从而提供胶囊化的或在一段时间之内以其它方式装载于其中的酚类化合物的受控释放。
本发明的酚类化合物可通过包囊作用、包覆、浸渍(infusion)或本领域已知的任何其它装载机制装载至药物递送运载体中。
通过包含能够延迟吸收的剂如单硬脂酸铝(aluminum monostearate)和明胶,可得到可注射药用形式的延长吸收。例如,可注射贮存形式能够通过形成微囊基质制备,所述基质包含装载至由生物可降解聚合物例如聚交酯-聚乙交酯、聚(原酸酯)和聚(酐)形成的基质中的酚类化合物。依赖于治疗剂相对于聚合物的比例和所用具体聚合物的性质,能够控制药物释放速率。也能够通过将治疗剂包埋在与身体组织相容的脂质体或微乳状液中来制备长效可注射配制物(depot injectable formulation)。可将所述可注射配制物灭菌,例如,通过经保留细菌的过滤器(bacterial-retaining filter)或通过以无菌固体组合物的形式并入灭菌剂,所述无菌固体组合物能够于使用前溶解或分散在无菌水或其它无菌可注射介质中。
许多血管内药物递送方法同样是本领域已知的。例如,DiCarlo,et al.(美国专利号6,929,626,通过引用并入本文)描述了腔内可确定位置的管状装置(intraluminally placeable tubular device),其能够置于血管腔内并且用药物包覆或以其它方式与药物(例如本文所述的酚类化合物)一起装载。管状构件包含以界定相对的内外织物表面的模式相互连接的纱线。至少一个所述织物表面是体液接触腔表面(body fluid-contacting luminal surface)或体腔接触外表面(bodylumen-contacting exterior surface)。
Wu,et al.(美国专利号6,979,347,通过引用并入本文)描述用于将治疗物质例如本发明的酚类化合物递送至血管腔的设备和相关方法。具体而言,能够使用在其上形成了凹槽(groove)或沟槽(trench)的可植入假体例如支架。在支架支柱(stent strut)的特定区域上形成凹槽以增加支架的灵活性。凹槽还提供用于携带植入后从装置中递送的酚类化合物的位置。例如,能够使用常规喷雾或修饰的浸渍技术(modified dip technique)将酚类化合物或其组合物直接贮存在凹槽中。
在另一个实施方式中,能够通过使用水凝胶递送运载体将本发明公开的剂靶向至结缔组织。本文定义的水凝胶包含能够高度水合并且保持结构稳定性的聚合物基质。合适的水凝胶基质可包含非交联和交联水凝胶。此外,本发明的交联水凝胶递送运载体能够任选地包含可水解部分,由此所述基质在含水环境中应用(例如体内)时能够降解。例如,递送运载体能够包含交联水凝胶并且能够在体内降解,所述交联水凝胶包含可水解交联剂,例如聚乳酸。
本发明的水凝胶递送运载体可包含天然聚合物例如糖胺聚糖、多糖、蛋白质等,以及如本领域公知的合成聚合物。能够用于形成本发明水凝胶的亲水聚合材料的非限制性列表可包括葡聚糖,透明质酸,壳多糖,肝素,胶原,弹性蛋白,角蛋白,白蛋白,乳酸、乙醇酸的聚合物和共聚物,羧甲基纤维素,聚丙烯酸酯,聚甲基丙烯酸酯,环氧化物,硅树脂,多元醇例如聚丙二醇、聚乙烯醇和聚乙二醇和它们的衍生物,藻酸盐例如藻酸钠或交联藻酸胶(crosslinked alginate gum),聚己内酯(polycaprolactone),聚酐,果胶,明胶,交联蛋白肽和多糖等。
本发明的水凝胶能够根据本领域公知的任何方法形成。例如,在接触多种成分时或结合具体环境条件(例如温度或pH)的存在进行接触时,所述水凝胶能够自组装。或者,能够遵循成分的组合根据任何已知方法诱导组装。例如,多功能单体、寡聚物或大分子单体的分步或链式聚合能够通过光聚合、温度依赖性聚合和/或化学活化聚合来诱导。任选地,水凝胶能够在引发剂(initiator)存在下聚合。例如,在一个实施方式中,水凝胶能够在合适的引发剂存在下进行光聚合,例如可从Ciba Specialty Chemicals获得的Irgacure或Darocur光引发剂。在另一个实施方式中,可存在阳离子引发剂。例如,可使用多价元素阳离子例如Ca2+、Mg2+、Al3+、La3+或Mn2+。在另一个实施方式中,可使用聚阳离子多肽例如聚赖氨酸或聚精氨酸作为引发剂。
还可对水凝胶递送运载体的成分进行设计从而提供自组装递送运载体。例如,可将水凝胶前体施用于受试者,并且在施用前体之后水凝胶基质能够在生理条件下自组装。例如,所述水凝胶前体可包含自组装生物聚合物例如胶原、层粘连蛋白(laminin)、前弹性蛋白肽等。任选地,自组装水凝胶前体可包含能够根据结构域自身排列的合成聚合物,如本领域所公知的。例如,可将亲水、相对电中性的合成多肽例如聚甘氨酸或聚赖氨酸进行修饰以发挥这种能力。通过使用羧基活化交联剂例如水溶性碳二亚胺能够将多肽交联。这些交联剂能够用于将自组装蛋白质或其它自组装大分子附着于多肽。此方法的一个实例包括形成胶原或层粘连蛋白与聚赖氨酸的碳二亚胺键。能够以相似方式连接其它羟基化实体。例如,在一个实施方式中,如本领域已知的,使用环氧活化方法能够将聚乙烯醇与多肽连接,或通过其侧链上可聚合的甲基丙烯酸酯基团能够将聚乙烯醇交联。
在另一个实施方式中,能够通过使用经衍生以包含偏好反应基团(favorably reactive group)的前体来产生自组装水凝胶。例如,使用以特殊反应部分衍生的第一前体和以第二部分衍生或包含第二部分的第二前体,能够组装此类水凝胶,所述第二部分能够与第一前体上的第一部分优先反应。同样,使用这些反应对(reactive pair)能够产生其它这样的水凝胶,所述反应对中反应形成键的两个部分各自与相同或不同类型的聚合物结合。例如,所述反应对可以是抗体-抗原对或抗生物素蛋白-生物素(例如抗生蛋白链菌素-生物素)。
在其它实施方式中,水凝胶递送运载体无需是自组装基质。例如,在其它实施方式中,可在水凝胶组装之后,根据合适的施用方法(例如,经皮地)将用于体内的水凝胶基质施用于患者。在本发明的其它实施方式中,所公开的体系能够用于活体外(ex vivo)的应用中,例如在组织工程应用中,并且本发明的载体基质同样无需是自组装基质。
本发明的递送运载体可包括一种或多种递送运载体的组合。例如,可将水凝胶递送运载体与补片(patch)、支架(stent)、带孔气囊(perforated balloon)、血管移植物或任何其它合适的装置组合,用于将所公开的剂递送至结缔组织。
本发明的递送运载体同样可包括血管移植物。例如,能够将同种异体移植物、异种移植物或自体移植物与如本文所述的酚类化合物在植入前结合。例如,可用如本文所述的酚类化合物或包含酚类化合物的组合物包覆血管移植物。在另一个实施方式中,可将血管移植物与依次装载了酚类化合物的如上所述的水凝胶递送运载体或非水凝胶聚合物递送运载体相结合。在植入期间,可结合靶向的结缔组织来定位血管移植物,并且因此用于将酚类化合物递送至组织。
现将涉及以下提出的本发明的例示性实施方式。通过说明本发明而非限制本发明的方式提供了各实施例。实际上,对于本领域技术人员而言显而易见的是,可在不背离本发明的范围或精神的前提下对本发明进行各种修饰和改变。
实施例
全部实施例中所用的材料如下获得:鞣酸、戊二醛(50%溶液),和其它高纯度化学药品获得自Sigma-Aldrich(St.Louis,MO)。二乙醚获得自AcrosOrganics(Morris Plains,NJ)。乙酸乙酯获得自EM Science(Gibbstown,NJ)。高纯度猪胰弹性蛋白酶(135U/mg)从Elastin Products Company,Inc.(Owensville,MO)购买。DME培养基(Dulbecco’s modified eagle media;DMEM)和胎牛血清(fetal bovine serum;FBS)获得自Cellgro(Herndon,VA)。用于细胞培养的青霉素-链霉素获得自Invitrogen(Carlsban,CA)。CellTiter 96AQueous One SolutionReagent(用于MTS)来自Promega(Madison,WI)。LIVE/DEADViability/Cytoxicity Kit获得自Molecular Probes(Eugene,OR)。
猪升主动脉(动脉瓣上的段(supravalvular segment),长度大约3cm)新鲜收集自USDA批准的屠宰场并且置于冰上运输。将脂肪和外部组织从主动脉清除,将主动脉在冷生理盐水中彻底漂洗,并且切割成适合于各实施例的各种形状。
实施例1
将新鲜猪主动脉切割成大约4mm×4mm的正方形,并且用pH 5.5的50mM HEPES(Na2HPO4)缓冲盐水中的0.3%鞣酸(TA)(1.76mM)在室温处理4天。将对照样品在pH 5.5的mM Hepes缓冲盐水中处理。随后将样品在100mLddH2O中于室温漂洗三次(每次1小时),并且冻干以记录干重。将对照和TA处理的样品(大约15-25mg干重)与1.0mL纯弹性蛋白酶(20单位/ml,在100mM Tris、1mM CaCl2、0.02%NaN3、pH 7.8缓冲液中)一起在37℃、650rpm定轨摇动温育48小时。随后将样品离心(10000rpm,10分钟,4℃),并且保留上清以评估酶活性。再次将组织样品在100mL ddH2O中于室温漂洗三次(每次1小时),冻干以记录弹性蛋白酶作用之后的干重,并且计算消化的组织的百分比。通过测量质量损失(弹性蛋白酶接触之前和之后的干重)并且通过制备用弹性蛋白特异性染料(Voerhoff van Gieson染料)染色的组织学切片来评估弹性蛋白的降解。
评估时,发现对照样品损失了几乎80%的质量(平均值,79.74%,n=6),而TA预处理的样品损失仅4-5%的质量(平均值4.33%,n=6)。组织学显示在对照样品中弹性蛋白酶将弹性蛋白纤维完全消化,而在TA预处理的样品中,弹性蛋白纤维保留完整,可参见说明组织学研究结果的图4A-4D。图4A-4D显示用Voerhoff van Gieson染料染色的主动脉组织切片,其将弹性蛋白纤维显示为深色带状物(dark ribbons)。具体而言,图4A和4B分别显示所述过程之前和之后的新鲜对照主动脉,而图4C和4D分别图解所述过程之前和之后的TA预处理的样品。可见,与TA预处理的主动脉中完整保留的弹性蛋白(图4D)相比,在对照主动脉中弹性蛋白酶将弹性蛋白完全消化(图4B)。图中箭头指示的位置(locale)包含保留的弹性蛋白(图4A、4C和4D)和消化的弹性蛋白(图4B)。
实施例2
将新鲜猪主动脉横穿直径切割成高度大约1cm的连续的环,如图5A中所示,并且用戊二醛处理(Glut处理)。对于这种处理,首先将主动脉环样品用pH 7.4的50mM Hepes缓冲盐水中的0.6%戊二醛固定,在室温过夜,接着用相同缓冲液中0.2%的戊二醛在室温处理7天。
随后将部分Glut处理的环用0.3%五没食子酰葡糖(PGG)处理。PGG首先如Hagerman,et al.(Hagerman A.E.,Zhao Y,and Johanson J.,“Methods fordetermination of condensed and hydrolyzable tannins,”Shahadi,F.,Ed.,Antinutrients and Phytochemicals in Foods,Washington,D.C.,AmericanChemical Society,p.209-222(1997))所述从TA制备。具体而言,使用甲醇和乙酸(盐)缓冲液的溶液对TA进行甲醇分解。甲醇分解之后,通过旋转蒸发去除甲醇并且用ddH2O代替。进行一系列涉及二乙醚和乙酸乙酯的分离提取,以及稀释的甲醇和ddH2O的漂洗以纯化PGG。将所得沉淀物离心并且冻干以形成固体。PGG的纯度通过MALDI质谱和NMR确认。随后将部分Glut处理的组织用相同缓冲液中的PGG处理4天(Glut/PGG处理,在图5中标记为PGG)。
将另外的Glut处理的样品根据相同的流程用TA处理(Glut/TA处理,在图5标记为TA),并且将对照样品仅用缓冲液处理(在图5标记为“新鲜”)。
随后使用开角测量法(opening angle measurement)测试样品回缩的能力。具体而言,将每个环置于一培养皿的水中(足以完全覆盖该组织),主动脉的横截面朝上,使样品能够自由移动。随后将环径向切割一次,使其松开15分钟,再进行数码照相。将这些数码照片输入AdobePhotoshop7.0,并且对于每个样品,在切割边缘的末端和径向切割位置对面的腔壁中点之间连线,如图5C的Glut样品照片中所示。使用这些线计算主动脉环的开角。结果示于图5B和下表1,包括平均值的标准误差(standard error of the mean;SEM)值。
为了评估机械性质,将主动脉切割成长大约40mm、两端宽大约10mm并且中间宽大约5mm的哑铃形,哑铃形的长轴与主动脉圆周方向平行。使用标准应力/应变分析在Synergie 100测试设备(MTS Systems Corporation,Eden Prairie,MN)上测试样品的拉伸性能(tensile property),在0.2mm/秒的恒定单轴速度(constant uniaxial velocity)下操作,使用10-Newton测压元件(loadcell)测定样品的弹性模量(elastic modulus)。将弹性模量计算为应力-应变曲线在0和5%应变之间的斜率。结果示于下表1。
表1
预处理 | 平均开角(度) | SEM(n=5) | 平均弹性模量(kPa) | SEM(n=4) |
对照 | 177.50 | 11.0 | 0.16 | 0.01 |
Glut | 35.9 | 3.3 | 1.28 | 0.04 |
Glut/TA | 11.8 | 0.7 | 4.85 | 0.30 |
Glut/PGG | 5.9 | 0.7 | 4.61 | 0.40 |
可见,Glut/TA和Glut/PGG处理的环呈现小得多的开角,说明鞣酸与弹性蛋白成分相互作用并且使得回缩不能充分地发生。类似地,计算的弹性模量在用鞣酸和PGG处理之后有所增加。这些结果说明鞣质强有力地结合至组织的弹性成分,由此将组织变硬并且强化。
实施例3
如上所述将新鲜猪主动脉用Glut、Glut/TA或Glut/PGG处理。彻底漂洗(3次,每次1小时,100mL ddH2O)之后,将样品在pH7.4的PBS/叠氮化物缓冲液中于37℃、120rpm定轨摇动14天,用于提取可溶的、细胞毒性化合物(50mL/6个组织样品,各4mm×4mm)。
将大鼠皮肤成纤维细胞接种在24孔平板(50,000细胞/孔)上补充以10%FBS和1%青霉素-链霉素的1mL DMEM中。将细胞保持在37℃具有10%CO2的润湿培养箱中。24小时之后,去除培养基并且用在新鲜培养基中稀释10倍的PBS/叠氮化物溶液之一替代。作为对照,将样品保持在单独的缓冲液中(阴性对照),并且同样保持在70%乙醇溶液中(阳性对照)。实际上,对于每个孔将100μL“测试溶液”添加至900μL培养基中(除了乙醇的情况,其中不添加培养基)。将细胞与这些溶液一起温育2小时,随后用1mL PBS漂洗。使用定性LIVE/DEAD染色荧光染料评估细胞的生存力。此外,使用定量测量MTS以测量细胞酶的活性。具体而言,将试剂在培养基中稀释5倍,随后施用于细胞持续90分钟。将部分所得溶液(100μL/孔)转移至96孔平板并且读取490nm的吸光度。将包含培养基和MTS试剂而无细胞的孔作为样品的空白。
引入LIVE/DEAD的细胞显微照片在曝露45分钟后进行。结果示于图6A-6E,其中活细胞显示为黑暗背景上的亮点,而死细胞显示为较深的灰点。参考该图可以看出,曝露于来自Glut处理组织(图6B)和Glut/PGG处理组织(图6A)的提取物的细胞在曝露2小时后保持存活。此外,显示在此时限中小浓度叠氮化物几乎没有或没有细胞毒性方面的影响,正如PBS/叠氮化物组中存在活细胞所说明的(图6D)。然而,引入至来自Glut/TA处理主动脉的提取物的细胞经历了显著的细胞死亡(大约40%,图6C)。同期望的一样,EtOH阴性对照基本上未留下活细胞(图6E)。
来自MTS试验的定量结果在下表2中给出。这些结果说明酚类鞣质(phenolic tannin)通常不是细胞毒性的,而PGG与TA相比似乎细胞毒性较弱。
表2
预处理 | 生存力(live/dead试验) | 生存力(MTS试验) | SEM(n=3) |
Glut | 100% | 1.04 | |
Glut/PGG | 100% | 0.94 | 0.03 |
Glut/TA | 60% | 0.53 | 0.06 |
EtOH | 0% | 0.03 | 0.02 |
PBS/叠氮化物 | 100% | 1.04 | 0.00 |
实施例4
在屠宰场新鲜收集猪升主动脉并且置于冰上运输至实验室。清除脂肪和粘附组织之后,将主动脉切割成2×4mm的条(strip)并且在冷盐水中彻底漂洗。通过一系列提取将主动脉弹性蛋白纯化。具体而言,将主动脉条在100mM氢氧化钠中悬浮(100mL中60条)并且在pH 8.0的50mM Tris缓冲液、10mM氯化钙中与胶原酶(0.5单位/mg湿组织)一起于37℃温育14小时。将所述胶原酶制备物用弹性蛋白纤维预吸附(pre-adsorb)以去除残留的弹性组织解离活性(elastolytic activity)。最终消化步骤将残留的胶原完全去除,留下纯主动脉弹性蛋白。
将纯主动脉弹性蛋白条置于2mL小离心管(microfuge tube)中,并且在pH5.5的50mM磷酸氢二钠、0.9%氯化钠缓冲液中制备的1.5mL 8mg%TA溶液中悬浮。由纯主动脉弹性蛋白组成的第二组悬浮在包含相同缓冲液中的8mg%TA和16mg%Glut的溶液中。作为对照,将TA溶液和TA和Glut的混合物温育,其中无弹性蛋白样品。将样品在室温温育并且在限定的时间间隔(0、20、40、60、120、360分钟和24小时)将样品回收并且分析溶液中的TA含量。具体而言,将样品与钨酸盐/磷钼酸盐(tungstate/phosphomolybdate)试剂混合,接着添加饱和碳酸钠溶液和ddH2O。室温10分钟之后,在微量培养板分光光度计中测量760nm的OD。用在0-8mg%范围的TA并用与Glut(16mg%)混合的TA(0-8mg%)构建标准曲线。Glut对TA显色反应的干扰是最小限度的(所有数据点均不存在统计学差异)。最后,将弹性蛋白带(strop)在ddH2O中漂洗并且冻干。由溶液中初始TA浓度和与弹性蛋白带温育之后溶液中TA浓度之间的差异来计算结合至纯主动脉弹性蛋白的TA量,并且表示为由1mg干弹性蛋白结合的TA的微克数。对所有样品均进行三次试验。
结果图示于图7。参考该图可见,未与弹性蛋白一起温育的对照溶液中的TA水平在整个研究中保持恒定,说明该溶液是稳定的。然而,在与弹性蛋白温育1小时之后,溶液中TA的量降低了大约50%,在6小时后降低至初始TA的10%,并且在24小时降低至初始TA的3.5%以下,这清楚地说明TA与弹性蛋白的结合。动力学显示在最初6小时内的快速结合,稳定(level off)在大约3mg TA/mg干弹性蛋白。发现来自TA和Glut混合物的TA结合比率高于只含TA的情况,说明Glut可能促进或加速TA对弹性蛋白的结合。
实施例5
对所公开的剂的体内用途进行检查。使用的动脉瘤模型以高浓度氯化钙(CaCl2)溶液的血管周施用为基础,是一种最初用于在兔颈动脉中诱导动脉瘤的方法(参见,Gertz SD,Kurgan A,Eisenberg D.J Clin Invest1988;81(3):649-656.),并且近来已将其用于啮齿动物的腹主动脉(参见,例如,Freestone T.,et al.,Arterioscler Thromb Vasc Biol 1995;15(8):1145-1151.Freestone T.,et al.,Arterioscler Thromb Vasc Biol 1997;17(1):10-17.Tambiah J.,et al.Br J Surg 2001;88(7):935-940.)。这种模型导致动脉组织的局部适度损伤(localized mild insult)。在大部分研究中,在损伤后的3至6周之后观察到主动脉直径的显著增加(说明动脉瘤形成)。对于本实施例,对大鼠主动脉进行基于CaCl2的化学损伤。
将成年雄性Sprague-Dawley大鼠全身麻醉(2%至3%异氟烷(isoflurane)),使得能够沿腹部进行中线切开以曝露肾下的腹主动脉。一旦曝露,使用预浸的8叠无菌绵纱布条(1.5cm×0.5cm)以0.03%PGG的盐水溶液将腹主动脉处理15分钟。随后将该区域用盐水简单漂洗,使化学损伤诱导得以发生(0.5MCaCl2,用纱布递送15分钟)。作为对照,用生理盐水处理大鼠主动脉15分钟,漂洗,随后施以氯化钙。用CaCl2处理之后,将纱布去除并且用皮下缝合将腹腔关闭,接着进行外科包扎(surgical staples)。28天之后将大鼠麻醉,同时再次将腹主动脉曝露。使用数码照相(在第0天PGG施用之前,以及28天之后)测量每只大鼠在28天的时间后直径的百分比增加。收集主动脉组织用于分析。
图8图示说明主动脉节段(n=12/组)直径的绝对变化。可见,在对照主动脉中,主动脉节段的直径增加为大约530μm。相反在PGG处理节段中,增加为大约100μm,并且发现该差异是统计学显著的。插入照相显示损伤前对照主动脉、损伤后28天对照主动脉和损伤后28天PGG处理的主动脉的实例。图9图示说明根据节段直径百分比改变的结果一对照大于40%,而PGG处理的主动脉小于10%。
在表面检查主动脉节段之后,通过弹性蛋白含量的锁链素(desmosine)分析来分析所述节段。根据分析规程,较高的锁链素含量意味着较低的弹性蛋白降解。结果示于图10。参考该图可见,对照包含大约750pmol锁链素/mg蛋白质,而PTT处理的主动脉包含大约1350pmol锁链素/mg蛋白质。图10B和10C分别显示在将弹性蛋白染成黑色的Verhoeff van Giesson染色后的对照主动脉和处理主动脉。可见对照主动脉具有非常少的弹性蛋白,而处理的主动脉保留了弹性蛋白(通过图中弹性纤维柒成黑色来显示)。
还对血管进行分析以测定鞣质与组织的长期结合。从处理后立即外植的主动脉提取鞣质(在图11上标记为PGG原位),并且将其测量水平与从PGG处理之后28天外植的主动脉中得到的鞣质水平(在图11上标记为PGG体内)相比。可见,尽管鞣质水平随着时间存在稍许降低,从大约1.8μg PGG/mg干组织变为大约1.3μgPGG/mg干组织,更大百分比的鞣质保持体内对组织结合更长的时间。
应该理解的是,不应将出于说明目的给出的前述实施例理解为对本发明范围的限制。尽管在上文中仅详细描述了本发明的少数示例性实施方式,但本领域技术人员而言应该容易理解的是,在本质上不背离本发明的新教导和优势的前提下,可对所述示例性实施方式进行多种修饰。因此,所有这些修饰应包括在如下权利要求书及其所有等同物中所定义的本发明范围之内。此外,应该认识到的是,可得到不实现一些实施方式的全部优势的许多实施方式,而不应因为具体优势的缺失而必然地认为这种实施方式在本发明的范围之外。
Claims (43)
1.液体组合物在制备用于体内使结缔组织稳定的药物中的用途,其中有效量的所述组合物直接施用于结缔组织,其中所述结缔组织包含弹性蛋白,并且其中所述组合物几乎不含有或不含有游离的没食子酸残基,具有4-9的pH,并包含化合物,该化合物具有疏水核心和多个结合至该疏水核心的酚基。
2.权利要求1的用途,其中所述结缔组织是血管的成分。
3.权利要求1的用途,进一步包含将所述组合物在药物递送运载体中提供。
4.权利要求3的用途,其中所述药物递送运载体包含持续释放药物递送运载体、水凝胶、血管周药物递送运载体、血管内药物递送运载体、可植入装置、支架或它们的组合。
5.权利要求3的用途,进一步包含将所述药物递送运载体定位至邻近结缔组织处。
6.权利要求1的用途,其中将所述组合物注射到结缔组织中。
7.权利要求1的用途,其中所述用途预防处理用途。
8.权利要求1的用途,其中所述化合物是黄酮类化合物或黄酮类化合物衍生物、黄酮木脂素(flavolignan)或黄酮木脂素衍生物、酚根茎或酚根茎衍生物、包括(+)-儿茶素和(-)-表儿茶素的黄烷-3-醇、鞣质或鞣质衍生物、鞣花酸或鞣花酸衍生物、或原花青素或原花青素衍生物。
9.权利要求1的用途,其中所述化合物是花色素苷、栎精、诺伯鞣质(nobotanin)、表没食子儿茶精没食子酸或没食子鞣质。
10.权利要求1的用途,其中所述化合物是橄榄油、可含有表儿茶素和类似化合物的可可豆、茶属、甘草、柳珊瑚、芦荟或甘菊的提取物。
11.权利要求1的用途,其中所述组合物抑制由一种或多种弹性蛋白酶介导的弹性蛋白降解。
12.权利要求1的用途,其中所述组合物抑制由一种或多种基质金属蛋白酶介导的弹性蛋白降解。
13.权利要求2的用途,其中所述血管是动脉瘤的。
14.权利要求1的用途,其中所述化合物是五没食子酰葡糖。
15.权利要求1的用途,其中所述组合物进一步包含戊二醛。
16.权利要求1的用途,其中所述组合物进一步包含没食子酸清除剂、降脂药物、抗细菌剂或抗真菌剂。
17.权利要求1的用途,其中所述组合物具有大约5.5-大约7.4的pH。
18.液体组合物在制备用于使活受试者中结缔组织稳定的药物中的用途,其中有效量的组合物直接施用于结缔组织以使该组织稳定,其中所述组合物具有大约4-大约9的pH,所述结缔组织包含弹性蛋白,并且所述组合物包含戊二醛和在结缔组织中与弹性蛋白相互作用以使该结缔组织稳定的化合物。
19.权利要求18的用途,其中所述结缔组织是血管的成分。
20.权利要求19的用途,其中所述血管是动脉瘤的。
21.权利要求18的用途,进一步包含将所述组合物在药物递送运载体中提供。
22.权利要求21的用途,其中所述药物递送运载体包含持续释放药物递送运载体、水凝胶、血管周药物递送运载体、血管内药物递送运载体、可植入装置、支架或它们的组合。
23.权利要求21的用途,进一步包含将所述药物递送运载体定位至邻近结缔组织处。
24.权利要求18的用途,其中将所述组合物注射到结缔组织中。
25.权利要求18的用途,其中所述化合物是黄酮类化合物或黄酮类化合物衍生物、黄酮木脂素或黄酮木脂素衍生物、酚根茎或酚根茎衍生物、包括(+)-儿茶素和(-)-表儿茶素的黄烷-3-醇、鞣质或鞣质衍生物、鞣花酸或鞣花酸衍生物、或原花青素或原花青素衍生物。
26.权利要求18的用途,其中所述化合物是花色素苷、栎精、诺伯鞣质、表没食子儿茶精没食子酸或没食子鞣质。
27.权利要求18的用途,其中所述化合物是橄榄油、可含有表儿茶素和类似化合物的可可豆、茶属、甘草、柳珊瑚、芦荟或甘菊的提取物。
28.权利要求18的用途,其中所述化合物是五没食子酰葡糖。
29.权利要求18的用途,其中所述组合物抑制由一种或多种弹性蛋白酶介导的弹性蛋白降解。
30.权利要求18的用途,其中所述组合物抑制由一种或多种基质金属蛋白酶介导的弹性蛋白降解。
31.权利要求18的用途,其中所述组合物进一步包含没食子酸清除剂、降脂药物、抗细菌剂或抗真菌剂。
32.权利要求18的用途,其中所述组合物具有大约5.5-大约7.4的pH。
33.用于体内使结缔组织的结构构造稳定的液体组合物,其包含:
大约0.0001w/v%-大约10w/v%的化合物,该化合物包含疏水核心和多个结合至该疏水核心的酚基;和
肠胃外可用载体;
其中所述组合物具有大约4-大约9的pH并且几乎不含有或不含有游离没食子酸残基。
34.权利要求33的组合物,其中将所述组合物装载于药物递送运载体中。
35.权利要求34的组合物,其中所述药物递送运载体包含持续释放药物递送运载体、可植入装置、水凝胶、血管周药物递送运载体、血管内药物递送运载体、支架或它们的组合。
36.权利要求33的组合物,其中所述化合物是黄酮类化合物或黄酮类化合物衍生物、黄酮木脂素或黄酮木脂素衍生物、酚根茎或酚根茎衍生物、包括(+)-儿茶素和(-)-表儿茶素的黄烷-3-醇、鞣质或鞣质衍生物、鞣花酸或鞣花酸衍生物、或原花青素或原花青素衍生物。
37.权利要求33的组合物,其中所述化合物是花色素苷、栎精、诺伯鞣质、表没食子儿茶精没食子酸或没食子鞣质。
38.权利要求33的组合物,其中所述化合物是橄榄油、可含有表儿茶素和类似化合物的可可豆、茶属、甘草、柳珊瑚、芦荟或甘菊的提取物。
39.权利要求33的组合物,其中所述化合物是鞣质或其衍生物。
40.权利要求33的组合物,其中所述化合物是五没食子酰葡糖。
41.权利要求33的组合物,其中所述组合物具有大约5.5-大约7.4的pH。
42.权利要求33的组合物,其中所述组合物进一步包含戊二醛。
43.权利要求33的组合物,其中所述组合物进一步包含没食子酸清除剂、降脂药物、抗细菌剂或抗真菌剂。
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CN102225028A (zh) | 2011-10-26 |
EP1874223A4 (en) | 2009-05-13 |
US20120114732A1 (en) | 2012-05-10 |
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JP5282956B2 (ja) | 2013-09-04 |
WO2006115733A3 (en) | 2006-12-14 |
US7713543B2 (en) | 2010-05-11 |
US20070281026A1 (en) | 2007-12-06 |
CN102225028B (zh) | 2016-02-24 |
US20060240066A1 (en) | 2006-10-26 |
JP2008542195A (ja) | 2008-11-27 |
US20100185272A1 (en) | 2010-07-22 |
US8100961B2 (en) | 2012-01-24 |
EP1874223B1 (en) | 2013-08-07 |
EP2460525B1 (en) | 2016-07-13 |
EP2460525B8 (en) | 2016-09-14 |
US8435553B2 (en) | 2013-05-07 |
US7252834B2 (en) | 2007-08-07 |
CN101208057A (zh) | 2008-06-25 |
EP2460525A1 (en) | 2012-06-06 |
EP1874223A2 (en) | 2008-01-09 |
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