CN114010796A - 糖胺聚糖的化合物、其制备方法及用途 - Google Patents
糖胺聚糖的化合物、其制备方法及用途 Download PDFInfo
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Abstract
本发明涉及将药物与糖胺聚糖，例如透明质酸(HA)缀合的化合物，其中所述药物用于治疗多种疾病，例如炎症、自身免疫疾病、过敏症、感染且优选地，癌症。本发明的缀合化合物可通过用作靶药物递送载体的糖胺聚糖与CD44细胞表面受体的相互作用来增加药物在疾病的特定位点的浓度，然后增强定点递送的(site‑delivered)药物的治疗功效并减少全身性副作用。
Description
本申请为中国专利申请号201480052224.5(发明名称：糖胺聚糖的化合物、其制备方法及用途；申请日：2014年06月27日)的分案
技术领域
本发明涉及由与药物缀合的糖胺聚糖组成的化合物，并且也涉及该化合物的制备方法和用途。
背景技术
细胞外基质(extracellular matrix，ECM)是响应于刺激而调节细胞功能和相互作用的相互作用分子的动态组合。一类细胞外基质大分子，糖胺聚糖，是已知参与大量正常和不正常的生物过程的分子，所述生物过程包括细胞迁移(migration)、分化(differentiation)、增殖(proliferation)、免疫反应(immune response)和细胞骨架的组织(cytoskeletal organization)。
糖胺聚糖(Glycosaminoglycans，GAGs)是包括重复性二糖单元(disaccharideunits)的无支链的聚合物。这些二糖单元总是包含氨基糖(N-乙酰葡糖胺或N-乙酰半乳糖胺)，所述氨基糖在大多数情况下是硫酸化(sulfated)，第二种糖通常是糖醛酸(葡萄糖醛酸或艾杜糖醛酸)。由于GAGs的大部分糖残基上羧基或硫酸根(sulfate)的存在，GAGs是高度带负电荷的，且因此，GAGs是强亲水性的。GAGs往往采取高度延展的构象，并形成空间填充性且耐压缩力的基质。已通过其糖残基、这些残基之间的键的类型以及硫酸根基团的数目和位置区分了四组主要的GAGs。它们包括：(1)透明质酸(hyaluronan，HA)，(2)硫酸软骨素(chondroitin sulphate)及硫酸皮肤素(dermatan sulfate)，(3)硫酸乙酰肝素(heparan sulfate)及肝素(heparin)，以及(4)硫酸角质素(keratan sulfate)。
透明质酸(Hyaluronan，也称为hyaluronic acid、hyaluronate或HA)是GAGs中最简单的。其由非硫酸化的二糖单元，具体地，N-乙酰葡糖胺和葡萄糖醛酸，的规律性重复序列组成。其分子量可从400道尔顿(二糖)至超过数百万道尔顿变化。其可以以不同的量存在于所有组织，例如皮肤、软骨和眼睛中，并且以流体形式存在于大部分成体动物中。其在早期胚胎中尤为丰富。在关节软骨中，透明质酸可形成对于软骨功能非常重要的大的聚集物。此外，细胞运动性和免疫细胞的粘附通过细胞表面受体RHAMM(针对透明质酸介导的运动性的受体)和CD44介导。
HA由单一蛋白酶，透明质酸合成酶(Hyaluronan synthetas,HAS)介导，在细胞表面的内膜处受到生长中的聚合物挤压而直接合成，合成时透明质酸会被挤出细胞外部。相比之下，其他的GAGs在细胞内部高尔基体内被合成并与一些核心蛋白结合，然后通过胞吐作用释放。脊椎动物组织中的体内HA降解通过顺序性地去除糖的透明质酸酶和外切糖苷酶(exoglycosidase)介导。哺乳动物型透明质酸酶同时具有水解和转糖苷酶活性并可降解透明质酸和软骨素。在结缔组织中，透明质酸与水结合的水合作用会在组织之间形成空间，从而产生有利于细胞运动和增殖的环境。透明质酸在与细胞运动性有关的生物学现象中扮演关键作用，所述与细胞运动性有关的生物学现象包括快速发育、再生、修复、胚胎发生、胚胎发育、伤口愈合、血管生成以及肿瘤发生。
CD44(也称作Pgp-1、Hermes-3、HCAM或ECMR III)是具有85kDa至90kDa的分子量的广泛表达的糖蛋白。CD44是糖胺聚糖，透明质酸(HA)的主要细胞表面受体。尽管CD44特异性结合HA，但是某些包含硫酸软骨素的蛋白多糖也可被识别。CD44在多种细胞和生理学功能中发挥作用，包括粘附或迁移至HA，HA降解和肿瘤转移。CD44还已被证明在细胞外基质结合、细胞迁移、淋巴细胞激活、淋巴细胞归巢(lymphocyte homing)和支气管平滑肌细胞的增殖中发挥作用(Gunthert等,1991,A new variant of glycoprotein CD44 confersmetastatic potential to rat carcinoma cells,5；65(1):13-24)。CD44受体在其细胞外结构域的可变区域显示出复杂的选择性剪接模式。CD44似乎是特别重要的HA白细胞(leukocyte)受体，并因此可能在哮喘的发病机制中发挥作用。此外，在对照组小鼠的实验性哮喘中增加的HA水平在抗体治疗的小鼠中明显减少，证实了CD44在HA代谢中的作用(具体地，在高分子量HA分解为促炎性低分子量形式时)。这是特别重要的，因为HA衍生的寡糖可结合并激活Toll受体(Toll-like receptor)。因此，这些结果对于抗CD44的治疗效果具有高度意义。
HA-CD44相互作用可能在发育、炎症、T细胞募集与活化、肺部炎症和肿瘤生长与转移中发挥重要作用。已在许多癌症，包括胃部的癌症中发现了选择性剪接的CD44转录产物的改变的表达(F Reihani-Sabet等,2003,Effects of Inflammation and H.pyloriInfection on Expression of CD44 Variant Exons in Gastric Tissue,Journal ofSciences,14:11-16)。
由于CD44受体的过表达，恶性肿瘤细胞(malignant tumor cells)能够选择性地摄入比正常结缔组织或间质细胞(mesenchymal cell)更多的生物缀合物(bioconjugates)。若干研究显示，HA合成和摄入与癌症进展和转移潜力相关联。某些肿瘤，包括在肺部发现的许多肿瘤，具有过表达CD44细胞表面标志物的情形。已知乳腺癌细胞具有比正常细胞多的HA摄入，需要HA用于高P-糖蛋白表达，而高P-糖蛋白表达是产生多重耐药性(multi-drug resistance)的主要促成因素。此外，浸润性(invasive)乳腺癌细胞过表达HA的主要受体CD44，并依赖于高浓度的CD44内化的HA增殖。因此，带有HA的化疗药物纳米缀合物(nanoconjugates)可有效对抗淋巴转移(Eliaz,R.E.等,2004,Liposome-encapsulated doxorubicin targeted to CD44:a strategy to kill CD44-overexpressing tumor cells,Cancer Res.,61(6):2592-601)。
非类固醇抗炎药物(non-steroidal anti-inflammatory drugs，NSAIDs)以及环氧酶-2(cyclooxygenase-2，COX-2)的选择性抑制剂是通常用于治疗疼痛、炎症及发热的治疗药物组。最近，越来越多的实验暗示了，某些NSAIDs和选择性COX-2抑制剂也可能通过参与遍及肿瘤发生过程的多个生物学事件而具有抗癌活性。例如，流行病学研究已显示，正规使用阿司匹林降低罹患癌症，特别是结肠的癌症风险(Sandler RS.等,2003,A randomizedtrial of aspirin to prevent colorectal adenomas in patients with previouscolorectal cancer,New England J.Med.,348:883-890)。另外，还发现COX-2拮抗剂，例如塞来昔布(Celecoxib)、罗非昔布(Rofecoxib)、尼美舒利(Nimesulide)、美洛昔康(Meloxicam)及依托度酸(Etodolac)等也可能具有抗癌活性(Yamazaki R.等,2002,Selective cyclooxygenase-2 inhibitors show a differential ability to inhibitproliferation and induce apoptosis of colon adenocarcinoma cells.,FEBS Lett.,531(2):278-84)。进一步地，COX-2在许多恶化前、恶性以及转移性人类癌症中长期过表达，且过表达的水平被发现与一些癌症的侵袭性、预后以及存活率有显着相关(DannenbergAJ.等,2003,Targeting cyclooxygenase-2 in human neoplasia:rationale andpromise,Cancer Cell,4(6):431-6)。最大功效通常受COX-1相关毒性的剂量限制；但是，在结肠癌、皮肤癌、肺癌、膀胱癌及乳腺癌的几种动物模型中，COX-2抑制剂已被证实具有肿瘤抑制效果(Alane T.Koki等,2002,Celecoxib:A Specific COX-2 Inhibitor WithAnticancer Properties,Cancer Control,9(2Suppl):28-35)。
WO94/09811描述了CD44在治疗炎症或检测癌症转移中的用途。这些作者表明，在炎性病症中，CD44被上调，且CD44肽能够抑制T细胞活化。但是，没有展示关于CD44抑制转移的数据或内容，并且未对CD44用于抑制肿瘤生长或血管生成的用途做出说明。WO99/45942公开了HA
结合蛋白和肽，包括CD44，抑制癌症及血管生成依赖性疾病的用途。该专利申请使用软骨连接蛋白的38kDa片段，转移抑制素(metastatin)，以及从该片段衍生的HA-结合肽抑制B16小鼠黑色素瘤的肺转移以及Lewis肺癌。在HA-结合肽的情形中，B16黑色素瘤在鸡CAM上的生长，以及内皮细胞在HA上的迁移已被抑制。在上述两份专利申请中，HA-结合肽的使用与其结合透明质酸的能力直接相关。
美国专利第8,192,744号揭示，可溶性重组CD44透明质酸结合域(solublerecombinant CD44 hyaluronic acid binding domain，CD44HABD)抑制鸡和小鼠中的体内血管生成，并从而抑制多种来源的人类肿瘤生长。该发明公开了一种可溶性的，非糖基化的CD44重组蛋白，它基于对血管细胞表面受体的靶向而作为新的一类血管生成抑制剂。
因此，上文提到的现有技术公开了CD44的潜在用途并暗示了，任何作用均可能依赖于HA-CD44相互作用。因此，到目前为止，归属于HA-CD44缀合物的所有实用性直接依赖于它们结合透明质酸的能力。
然而，有些药物仍无法成功与透明质酸缀合并且应进行进一步的试验，藉以确认HA作为活性化合物的定点递送载体的潜在有用性。特别的是，现有技术并未显示细胞表面受体CD44和HA与活性化合物的缀合物的相互作用，可被开发作为一个标的传递物，并用于有效治疗并改善CD44过表达的疾病。
对于多种病理，诸如癌症，事实上仍旧需要具备这样的可用治疗工具，其以更好的安全性特征平衡对肿瘤细胞的细胞毒性作用和对正常细胞的细胞毒性作用。
发明内容
本发明的目的在于提供一种基于HA与活性化合物的缀合的新的化合物，该新的化合物适于在过表达表面细胞受体CD44的疾病中定点递送该活性化合物。
因此，本发明提供了将糖胺聚糖与药物缀合的化合物，其中该药物用于治疗与CD44表达高度相关的癌症疾病。
在第一方面，本发明的目的是由来自糖胺聚糖与活性化合物的缀合物组成的化合物，其中该活性化合物通过官能团与糖胺聚糖、其衍生物或其盐的羧基缀合以形成共价缀合，且其中该活性化合物选自由来那度胺、吉西他滨及COX-2拮抗剂组成的组。
根据本发明的缀合物的糖胺聚糖优选地是透明质酸。
此外，根据本发明的糖胺聚糖缀合物优选地用于治疗癌症疾病。
因此，在第二方面，本发明的另一目的是由来自糖胺聚糖与活性化合物的缀合物组成的化合物用于治疗癌症和制备用于所述治疗性治疗的药物组合物的用途，其中该活性化合物通过官能团与糖胺聚糖、其衍生物或其盐的羧基缀合以形成共价缀合，且其中该活性化合物选自由来那度胺、吉西他滨及COX-2拮抗剂组成的组。
又在一个另外的方面，本发明的目的是，制备由来自糖胺聚糖与活性化合物的缀合物组成的化合物的方法，其中该活性化合物通过官能团与糖胺聚糖、其衍生物或其盐的羧基缀合以形成共价缀合，且其中该活性化合物选自由来那度胺、吉西他滨及COX-2拮抗剂组成的组。
附图说明
为了充分描述本发明，对其实施方案的引述被示出在所附的附图中。此处所附的这些附图形成说明书的一部分。但是，所附的附图不应被认为限制本发明的范围。
图1通过荧光指数示出了正常和受损的结肠组织中的HA的亲和力。
图2示出了以不同的时程作用于HCT15细胞系及HT29细胞系的HA
染料化合物的荧光结果，其中图2A表示6小时的HCT15细胞系；图2B表示12小时的HCT15细胞系；图2C表示6小时的HT29细胞系；图2D表示12小时的HT29细胞系。
图3示出了HA-来那度胺缀合物的结构。
图4A示出了游离的来那度胺、HA以及HA-来那度胺缀合物对HT29细胞系的细胞毒性作用。
图4B示出了游离的来那度胺、HA以及HA-来那度胺缀合物对HCT15细胞系的细胞毒性作用。
图5A示出了真正的尼美舒利(含有NO2基，NiNO2)以及氢化修饰产物(含有NH2基，NiNH2)的结构。
图5B示出了HA-NiNH2缀合物的结构。
图6A示出了NiNO2和NiNH2在HT29或HCT15中的细胞毒性作用。
图6B示出了NiNO2、NiNH2、HA以及HA-NiNH2缀合物在HT29中的细胞毒性作用。
图7A示出了三组中的每一组的小鼠在24天内的总体重。
图7B示出了对照组、NiNO2组以及HA-NiNH2组的肿瘤抑制作用。
图8示出了HA-塞来昔布的合成方法和结构。
图9A示出了HA、塞来昔布、以及HA-塞来昔布缀合物对HT29细胞系的细胞毒性作用。
图9B示出了HA、塞来昔布、以及HA-塞来昔布缀合物对GBM401细胞系的细胞毒性作用。
图10示出了HA-吉西他滨缀合物的合成方法和结构。
图11示出了HA-吉西他滨缀合物对A549细胞系的细胞毒性作用。
图12示出了HA-吉西他滨缀合物对GBM401细胞系的细胞毒性作用。
具体实施方式
本发明的目的、优势和新的特征将从结合所附附图的以下详细描述中变得明显。
普遍来说，经口服或注射至循环系统的药物必须直接到达其靶向治疗区域，且由于药物浓度和特异性在靶向位点并没那么高，因此药物对于靶向疾病和正常器官的作用是非常类似的。因此，在许多情况下，有效量的活性化合物的施用受到活性化合物的安全性特征的削弱和限制。
为了改善治疗功效，将治疗功效与良好的安全性特征组合，一种策略是通过将药物与载体共价结合修饰所述药物以使其对于疾病区域具有更大的靶选择性。如之前预测到的，这在抗肿瘤治疗领域是特别需要的。
在该目的下，发明人设想了探究透明质酸(HA)与其受体CD44之间的相互作用用于靶向递送的活性物质的策略。
在对于HA的长期研究及实验之后，发明人已确立了维持药物在靶位点相对于在正常组织或器官的相对高浓度的策略。
本发明所源于的这些结果被充分描述于实施例中并在下文被简要概括。
事实上，本发明获得了这样的实验结果的支持，该实验结果表明相较于正常组织，具有不同平均分子量的透明质酸在受伤组织中具有较高的粘附指数，且具有低平均分子量的HA比具有高平均分子量的HA表现更好。特别地，如图1所示，比较粘附于受伤结肠组织的三种不同平均分子量的HA之间的区别，受伤结肠组织对350kDa HA的粘附的荧光指数高于其它两种平均分子量的HA(平均分子量为2000kDa＝2MDa和1000kDa＝1MDa)。另外，甚至正常的结肠组织或受伤的结肠组织对1MDa HA的粘附的荧光指数高于2MDaHA。该结果证实了，HA可更特异地粘附在炎症部位，这促使发明人进一步创造了本发明并验证了透明质酸的组织粘附这一独特的特征(被提出由HA与其表面细胞受体CD44的相互作用所造成)是否在该糖胺聚糖与其他化合物缀合时被保持。
因此，发明人进一步将药物与HA缀合以验证HA是否可被用作将药物递送至富含CD44的位点的靶向递送工具。如前所述，当CD44在炎症、感染或癌症的情形期间过表达时，由于配体HA可粘附至受体CD44上，相关药物可容易地在靶向的位点到达并保持且维持相对高的浓度。伴随HA对炎症位点或富含CD44的位点的粘附作用，由于所缀合的药物在所述位点具有相对较高的浓度，该药物应特别地聚集于该位点，并因此相应地减少使用的药物的量，具有更好的安全性特征。
为了证实药物或染料已成功与HA缀合并进一步证实HA粘附作用，本发明的发明人进行了一项实验，该实验包括将染料缀合至HA(HA-染料)和分别处理细胞系和小鼠。图2A和图2B示出了以不同的工作时间对细胞系HCT15(具有较少CD44的结肠直肠腺癌)的实验，而图2C和图2D示出了以不同的工作时间对细胞系HT29(具有丰富的CD44的结肠腺癌)的实验。HT29的结果(图2C和图2D)显示，HA-染料已被成功缀合并粘附于HT29的富含CD44的区域(图2C)，且甚至进入HT29细胞(图2D)。那意味着，本发明的策略是合适和有效的，并还意味着，药物或染料可缀合至HA并且HA保持其与CD44结合的能力。
在小鼠的HT29和HCT15细胞系上进行了游离染料以及HA-染料的粘附条件，持续4周。游离染料被注射到小鼠的尾静脉。结果表明，两种具有不同CD44表达的癌细胞在粘附结果方面无任何差异。HT29的粘附面积的比例为50.15％，而HCT15是49.86％。然而，当HA缀合的染料被注射到小鼠的尾静脉中时，CD44表达较多的癌细胞HT29显示出极大浓度的HA缀合的染料，而CD44表达较少的HCT15显示出非常有限的结果。HT29的粘附面积的比例为74.15％，而HCT15为25.85％。该结果可以表明，当染料与透明质酸缀合时，染料的浓度由于HA粘附至富含CD44的位置而增加。
与CD44高度相关的疾病包括癌症、感染及炎症。在本发明的优选的实施方案中，例如，癌症包括结肠癌、纤维肉瘤、乳腺癌、腺癌及脑恶性胶质细胞瘤。
在本说明书中和权利要求书中，术语“药物”或“活性化合物”或“剂”包含抗癌药物。大部分的抗癌药物可分为烷化剂(alkylating agents)、抗代谢物(anti-metabolites)、蒽环类(anthracyclines)、植物碱类(plant alkaloids)、拓朴异构酶抑制剂(topoisomerase inhibitors)及其他抗癌药物(other anticancer-drugs)。
在优选的实施方案中，抗癌药物的缀合包括，但不限于来那度胺、吉西他滨、塞来昔布及尼美舒利。
尼美舒利是一种广泛使用的选择性COX-2拮抗剂，其相较于其他NSAIDs，具有更好的肠胃安全性。近来，尼美舒利被推测通过诱导p21(一种肿瘤抑制基因)的表达而起抗癌药物的作用，并抑制雷帕霉素相关通路的哺乳动物靶(mTOR)，雷帕霉素相关通路是对于癌细胞的细胞生长、细胞增殖、细胞运动性、细胞存活、蛋白质合成是必不可少的通路(ZhangYJ.等,2011,mTOR signaling is involved in indomethacin and Nimesulidesuppression of colorectal cancer cell growth via a COX-2 independentpathway.Ann Surg Oncol.,18(2):580-8)。
来那度胺，萨力多胺的4-氨基-谷酰基类似物，是通过修饰萨力多胺的化学结构以提高其效力并减少其致畸性和神经性副作用而得到的合成化合物(V.Kotla等,2009,Mechanism of action of Lenalidomide in hematological malignancies,Journal ofHematology and Oncology,2:36)。来那度胺已被证实抗血管生成、抗肿瘤发生以及免疫调节活性，所述活性是由在麻风结节性红斑(ENL)(J.Sheskin,1980,The treatment oflepra reaction in lepromatous leprosy,International Journal of Dermatology,6:318-322)以及自体免疫疾患(E.Atra和E.I.Sato,1993,Treatment of the cutaneouslesions of systemic lupus erythematosus with thalidomide.Clinical andExperimental Rheumatology,11(5):487-93)中的奇特(anecdotes)免疫调节活性实现的。来那度胺已被发现具有抗血管生成特性，并已成为具有对抗各种血液及实体恶性疾病的活性的药物，所述实体恶性疾病例如脊髓发育不良、多发性骨髓瘤、慢性淋巴细胞白血病、原发性全身性类淀粉样变性、非霍奇金淋巴瘤、骨髓纤维化伴骨髓化生(myelofibrosis withmyeloid metaplasia)以及Waldenstrom巨球蛋白血症(Venumadhav Kotla等,2009,Mechanism of action of Lenalidomide in hematological malignancies,Journal ofHematology&Oncology,2:36)。来那度胺在各种恶性病症的治疗潜力的临床证据与药效学作用的程度是一致的，所述药效学作用的程度已在体外和动物模型中在不同的血液恶性疾病中通过多种机制被证实。来那度胺可上调肿瘤抑制基因p21；并由此诱导癌细胞的凋亡(Verhelle D.等,2007,Lenalidomide and CC-4047 inhibit the proliferation ofmalignant B cells while expanding normal CD34+ progenitor cells.Cancer Res.,67(2):746-55)。来那度胺还已被证实在多发性骨髓瘤中极大地减少血管生成因子VEGF和白细胞介素-6(IL-6)的表达；进而减少血管生成，并因此有助于在多发性骨髓瘤中的临床治疗活性(Gupta D.等,2001,Adherence of multiple myeloma cells to bone marrowstromal cells upregulates vascular endothelial growth factor secretion:therapeutic applications.Leukemia,15(12):1950-61)。
本发明的目的是经HA的羧基、羟基或氨基通过或不通过接头或间隔物地将HA与前述药物结合或缀合以在特定的位置和特定的时间实现工作效果。因此，HA作为将药物携带至具有丰富的CD44的特定部位的靶向递送媒介物可产生更好的治疗效果和安全性。
如本文所用的，一般地，术语“接头”或“间隔物”指连接化合物的两个部分的有机部分。接头通常包括直接的键或原子例如氧或硫、例如SS、NH、C(O)、C(O)NH、SO、SO2、SO2NH的单元，或原子链例如取代或未取代的烷基，其中一个或多个亚甲基可被O、S、SO、SO2、NH、NH2或C(O)间隔或终止。本发明的术语“接头”或“间隔物”可以不存在且表示存在于药物与HA之间的可通过化学方法、酶法或可自发分解去除的任何化合物；其还包含对于连接所述药物有用的至少一个其他基团，例如氨基、硫醇基、另外的羧基等。接头或间隔物可以是多肽、肽或脂质。
合适的接头或间隔物是例如，直链的或支链的脂肪族、芳香族或芳脂族(araliphatic)的C2-C20二元羧酸、氨基酸、肽。
当存在时，接头的作用在于构建透明质酸与药物之间的臂(arm)或间隔物。接头在一侧经过酰胺、羧基、羟基或氨基连接接合HA而在另一侧经过任何可能的共价型键接合药物。
当接头或间隔物是二元羧酸时，药物与羧基形成酯键的可以是化合物的羟基。当接头或间隔物是二酰肼时，HA与氨基形成酰胺键的可以是HA的游离羧基。优选的接头或间隔物是对药物的琥珀酸、对HA的己二酰肼。
在优选的实施方案中，本发明提供了由来自糖胺聚糖，优选地透明质酸，和活性化合物的缀合物组成的化合物，其中所述活性化合物通过官能团与糖胺聚糖、其衍生物或其盐的羧基缀合以形成共价缀合，且其中所述活性化合物选自由来那度胺、吉西他滨和COX-2拮抗剂组成的组。
活性化合物来那度胺、吉西他滨或优选的COX-2拮抗剂尼美舒利或塞来昔布可优选地直接通过HA的官能性羧基和活性化合物的-NH2基团结合。
在本发明的优选的实施方案中，HA的一个官能性羧基与活性化合物之间的直接的共价缀合或通过接头的间接共价缀合可以是酰胺键或酯键。
在经过接头间接缀合的情形中，所述接头选自由多肽、肽、脂质、氨基酸或直链或支链的脂肪族、芳香族或芳脂族的C2-C20二元羧酸。
优选的用于缀合的HA具有被包含在10kDa至2000kDa的范围内的平均分子量且所述缀合涉及HA的至少40％的羧基。
根据本发明的糖胺聚糖缀合物优选地用于治疗癌症疾病且优选地在本发明的最优选实施方案中，所述癌症疾病选自肝癌、肝细胞癌、胆管癌、胆管细胞性囊腺癌(cholangiocellular cystadenocarcinoma)、结肠癌、腺癌、淋巴瘤和鳞状细胞癌、乳腺癌、导管癌、小叶癌、肺癌、非小细胞肺癌、小细胞肺癌、卵巢癌、前列腺癌、肾癌、肾细胞癌、尿路上皮细胞癌、多发性骨髓瘤、骨髓增生异常综合征(MDS)、霍奇金淋巴瘤、非霍奇金淋巴瘤、慢性淋巴细胞性白血病或胰腺癌。
因此，本发明提供了HA与来那度胺、HA与吉西他滨、HA与尼美舒利和HA与塞来昔布的抗癌药物缀合物，其中来那度胺、吉西他滨和塞来昔布分别通过在来那度胺的-NH2基团与HA的-COOH基团之间形成酰胺键与HA缀合；此外，对于尼美舒利，-NO2基团被修饰为-NH2基团以使得尼美舒利可通过酰胺键与HA的-COOH基团共价结合以形成HA-NiNH2缀合物。HA-来那度胺缀合物的结构示于图3中。真正的尼美舒利(NiNO2)与氢化产物NiNH2的结构示于图5A中，而HA-NiNH2缀合物的结构示于图5B中。HA-塞来昔布缀合物的结构示于图10中。在一个实施方案中，本发明的结果显示，在富含CD44的细胞系(HT29)中，分别与来那度胺或HA相比，HA-来那度胺缀合物显示出极大的细胞毒性作用(图4A)；然而，在细胞系HCT15中，这种协同效应的趋势却没那么明显(图4B)。本发明的该结果显示，在HA-来那度胺治疗下，含有不太丰富的CD44的HCT15中细胞成活力的趋势高于含有丰富的CD44的HT29，意味着富含CD44的细胞系，HT29对于HA-来那度胺治疗更为敏感；然而，在这两种细胞系中，来那度胺对细胞成活力的影响几乎是相同的。该结果表示，来那度胺不与CD44相互作用，且HA当与来那度胺缀合时相比于相同的药物量下确实可增强来那度胺的治疗功效。
在另一实施方案中，本发明的结果显示，无论是在HT29或HCT15中，真正的尼美舒利(具有硝基官能团，-NO2)的细胞毒性作用通常优于氢化修饰产物(具有氨基官能团，-NH2))的细胞毒性作用，特别是在较高剂量时(图6A)。然而，当NiNH2与HA缀合时，HA-NiNH2的细胞毒性显著超过单独的NiNH2或NiNO2的细胞毒性(图6B)。该结果对于HA与来那度胺缀合的实施方案都是相同的。因此，抗癌药物的细胞毒性作用可通过与HA缀合而得以增强。
此外，在动物试验的实施方案中，本发明的结果显示，HA-NiNH2的肿瘤抑制效果比NiNO2或对照组的肿瘤抑制效果更有效(图7B)。该结果表明，三组中每只小鼠在24天内的平均体重几乎相同(图7A)，显示不存在例如体重损失的明显副作用；然而，当在比较对照组NiNO2或HA-NiNH2时，肿瘤体积显示明显不同，HA-NiNH2组具有比尼美舒利组或对照组更好的肿瘤抑制效果(图7B)。该结果指示，本发明的HA-NiNH2缀合物比单独的NiNO2具有更好的治疗效果。
结果表明，在HT29细胞及GBM8401细胞中，HA-塞来昔布的细胞毒性作用具有比HA和塞来昔布更好的趋势(图9A及9B)。且该结果表明，HA-塞来昔布细胞毒性作用在A549细胞(图11)及GBM8401细胞(图12)中增加的趋势。
综上所述，来那度胺及尼美舒利与HA缀合的抗治疗功效被与单独的来那度胺及尼美舒利比较，且分别显著提高了细胞毒性作用和肿瘤抑制功效。以上提到的结果显示，关于增强包括来那度胺及尼美舒利的癌症药物的治疗效果，本发明做出了巨大贡献。
为了治疗疾病，本发明的制剂或剂型的优选实施方案包括赋形剂以配制用于眼、耳、口、鼻、呼吸道、胃肠道、循环系统施用或局部使用的施用剂型。口服剂型的更优选的实施方案选自由固体剂型、溶液(包括但不限于悬浮液)、片剂(包括但不限于控释片剂)和胶囊(包括但不限于包被肠衣的胶囊)组成的组。胃肠道施用形式的更优选的实施方案选自由固体剂型、灌注液(perfusion)、灌肠剂(enema)、栓剂(suppository)和溶液(包括但不限于悬浮液)组成的组。循环系统或全身施用形式的更优选的实施方案选自由静脉内注射(IV)、肌肉内注射(IM)和皮下注射(SC)组成的组。局部施用形式的更优选的实施方案选自由灌注液、灌肠剂、栓剂、喷雾剂、吸入剂及滴剂组成的组。
本发明的目的之制备由来自糖胺聚糖和活性药物化合物的缀合物组成的化合物的方法包括以下步骤：
准备糖胺聚糖，优选地透明质酸，的水溶液；
准备来那度胺、吉西他滨或COX-2拮抗剂与N-(3-二甲氨基丙基)-N
乙基碳二亚胺盐酸盐和N-羟基琥珀酰亚胺的水溶液；
在室温下混合并搅拌两种溶液至少10小时以获得混合的溶液；和透析所述混合的溶液数天。以下实施例是为了例示本发明的多种实施方案而提供的且不意在以任何方式限制本发明。
具体实施方式
实施例1：透明质酸在结肠组织的粘附(IVIS图像系统-vision 3)
方法：
1.将0.25克高分子量透明质酸钠粉末(HHA；Mw：2MDa；Freda)及0.25克低分子量透明质酸钠粉末(LHA；Mw:0.35MDa；Freda)分别加入50ml PBS缓冲液(磷酸盐缓冲的盐水)中以形成0.5％的溶液，然后搅拌6小时直到粉末完全溶解。将0.25克中分子量透明质酸钠粉末(MHA；Mw:1MDa；Freda)加入50ml PBS缓冲液中，然后搅拌6小时直到粉末完全溶解并以备在下列步骤中使用。
2.荧光HA(HA-f)通过下列步骤制备：(1)将0.39克MES游离酸(2-(N
吗啉代)乙磺酸，Calbiochem)溶解于100ml dd水中。(2)溶液A：将65mg的荧光胺粉末(异构物I，Fluka)溶于9ml 95％乙醇(EtOH)溶液中，然后在黑暗中搅拌10分钟。(3)溶液B：将359mg EDC粉末(N-(3-二甲氨基丙基)-N-乙基碳二亚胺盐酸盐，Sigma)溶于9ml MES缓冲液中，然后搅拌10分钟。(4)溶液C：将216mg NHS粉末(N-羟基琥珀酰亚胺，Sigma)溶于9ml MES缓冲液中，然后搅拌10分钟。(5)将3ml溶液A缓慢地滴入50mL 0.5％的HA溶液中，然后在避光条件下搅拌10分钟。(6)将3ml溶液B和5ml溶液C分别滴入步骤(5)的溶液中，然后在避光条件下搅拌10分钟。(7)将0.02MMES缓冲液缓慢地滴入步骤(6)的溶液中直到体积达到100ml，然后在室温下在避光条件下搅拌24小时。(8)将反应后的产物倒入透析管(MW：12000至14000)中的作为透析液的5L去离子水中，然后在4℃下在黑暗中搅拌5天，每12小时更换透析液，直到透析液没有荧光。(9)将透析后的液体分装到50c.c.塑料离心管中，然后过夜保存在-20℃冰箱，之后在黑暗中在冷冻干燥机中干燥。(10)将干燥的HA-f粉末保存在-20℃冰箱。(11)将50mg HA-f粉末缓慢地加入10ml PBS缓冲液中，然后搅拌6小时，直到粉末完全溶解。
3.将7-8周龄的SD大鼠(Sprague-Dawley大鼠)的结肠组织通过解剖刀切下，然后通过PBS缓冲液冲洗，之后切成3-4cm长，最后浸泡在PBS缓冲液中。
4.通过牙刷纵向刷20次制备受伤的结肠组织，然后浸泡在PBS缓冲液中。
5.将正常与受伤的结肠组织放入12孔板中，然后向每孔中加入1ml 0.5％HA-f溶液，并在室温下振荡2小时。2小时后通过吸头吸除过多的HA-f溶液，然后在PBS缓冲液浸泡10分钟，之后移除PBS缓冲液，重复三次。
6.将干净的结肠组织以衬里组织(lining tissue)朝上放置在12孔板中，然后放置到IVIS(体内成像系统，XENOGEN)的平台(dock)上。默认参数设置为GFP(绿色荧光蛋白)，而激发为465nm，且发射为500nm，然后通过软件记录图像。
7.所有值被计算为观察值的平均数。组织学指数利用学生t检验分析。
结果：荧光指数如图1中所示的定量和排列。正常结肠组织的荧光指数被定义为1。其他结肠组织的测试值通过该定义的值校正。结果表明，相同平均Mw的HA以明显高于正常结肠组织(P<0.01)的荧光指数粘附于受伤的结肠组织。比较粘附于受伤的结肠组织的三种不同平均分子量的HA之间的差别，受伤的结肠组织对350kDa HA的粘附的荧光指数高于其他两种平均分子量的HA(2MDa与1MDa)。进一步地，甚至正常结肠组织或受伤结肠组织对1MDaHA的粘附的荧光指数高于2MDa HA。
实施例2：HA-染料缀合过程与HA-染料体外成像
方法
HA-染料缀合的以下全部过程必须保持在黑暗中。
HA-ADH的合成
1 HA(0.34MDa,50mg)溶解在水中以提供4mg/ml的浓度。
2 5倍过量(114.8mg)的ADH(己二酰阱)加入溶液中。
3 0.1N HCl将反应混合物的pH调整至4.75。
4.接着，加入1当量(25.1mg)固体形式的EDC。通过加入0.1N HCl将反应混合物的pH保持在4.75。
5.反应15分钟后，通过加入0.1N NaOH将反应混合物的pH调整至7.0猝灭反应。
6.将反应混合物转移至预处理的透析管(截留Mw：3500)中，并通过相对于100mMNaCl，然后是4个循环的25％EtOH/水且最后是水来彻底透析。然后通过0.2μm乙酸纤维素膜过滤该溶液，快速冷冻并冻干。
7.ADH的取代度通过1H NMR测量。HA-ADH-FITC的合成：
1.将88mg的HA-ADH(DS＝36％)溶解于35ml水中。
2.将9.5mg FITC溶解于10ml DMSO中。
3.将HA-ADH溶液与FITC溶液混合。
4.室温搅拌48小时后，使用MWCO 12000-14000透析袋用0.3M氯化钠以及纯水交替透析溶液3天。
5.然后冷冻干燥溶液2天。
6.最后，通过UV光谱测定取代度。
HA-染料的体外成像
(1).将1×105HT29细胞和HCT15细胞(人结肠癌，CD44阳性细胞)接种于3.5cm平皿内的显微镜载玻片上。
(2).以指示染料浓度，将1μM的HA-染料(HA：0.34MDa)分别加入细胞中，持续指定的时间。
(3).经孵育后，在PBS中洗涤细胞，然后固定在3.7％甲醛中。
(4).通过共聚焦显微镜进行对HA-染料与细胞之间的相互作用的观察。
结果：荧光视图可显示染料在HCT15(图2A和图2B)及HT29(图2C和图2D)上的粘附位点和量。结果显示，染料已成功与HA缀合，且HA增加HT29上CD44丰富位点的HA-染料浓度，而与HCT15比，HT29具有符合更丰富的CD44的更强的荧光。甚至证明了，HA-染料可以进入细胞(图2D)。在HT29(CD44较多)中，HA-染料在处理6小时后累积并在处理12小时后被内化。在HCT15(CD44较少)中，在6小时或12小时的HA
染料处理后并没有观察到此现象。
实施例3：细胞系和异种移植肿瘤模型
方法
1.细胞培养条件以及传代
(1)细胞培养条件：
HT29：高葡萄糖DMEM、10％FBS、1％丙酮酸钠、1％青霉素、链霉素和新霉素。
HCT15：DMEM/F12、10％FBS、1％丙酮酸钠、1％青霉素、链霉素和新霉素。
(2)传代：
(I)取出并丢弃培养基。
(II)用1×PBS简单冲洗细胞层以去除所有痕量的包含胰蛋白酶抑制剂的血清。
(III)向培养瓶中添加1ml的0.25％胰蛋白酶-EDTA溶液，并在显微镜下观察细胞直至细胞层被分散(通常在5至15分钟内)。然后，加入9mL完全生长培养基并用移液管温和吸出细胞。
(IV)将细胞悬液的适量等分试样加到新的培养皿中(转种率为1:3至1:8)。
(V)在37℃培养箱(5％CO2)中孵育培养物。
2.异种移植肿瘤模型
(1)将HT29及HCT15细胞(2×107细胞/小鼠)分别皮下注射至8周龄雄性裸鼠的右臀和左臀(右后肢和左后肢的上侧)。
(2)当3周至4周后异种移植肿瘤的尺寸为400～500mm3时可开始进行IVIS实验。
3.IVIS实验
(1)通过异氟烷麻醉后，以参数f/stop：8，曝光时间3秒，激发波长633nm或635nm，测量的发射波长668nm取得异种移植裸鼠的图像作为空白。所使用的仪器为XenogenIVIS200。
(2)经尾静分别静脉内注射200μl的12.5μM游离染料或200μl的HA
染料溶液(含有12.5μM染料与0.1mg HA(HA：1.12MDa)的HA-染料)。
(3)在预定时间5分钟、10分钟、30分钟和1小时、2小时后取IVIS图像的照片。观察参数与仪器如步骤1中简单描述的。处死小鼠，然后在注射2h后解剖以分析内脏中的荧光分布。
结果：荧光图像表明，游离染料几乎均匀地分布于HT29(左)以及HCT15(右)。HT29的粘附面积的比例为50.15％，而HCT15为49.86％。然而，HA-染料可尤其更多粘附于HT29的CD44丰富位点，而不是具有比HT29少的CD44的HCT15。HT29的粘附面积的比例为74.15％，而HCT15为25.85％。该结果证明，HA可促进染料累积在CD44丰富的位点。
实施例4：HA-来那度胺缀合物的合成
方法
1.将50mg HA(10K-700KDa)溶解于25ml DD水中。
2.将25.1mg EDC与15.1mg NHS混合于2ml DD水中并于室温下搅拌5分钟。
3.通过加入1.31ml NaOH中和HA溶液。
4.将3.4mg来那度胺溶解在2ml二甲基亚砜(DMSO)溶液中。
5.室温下搅拌混合物(HA、EDC、NHS和来那度胺)12小时。
6.使用透析袋(MWCO：3500)将混合物相对于过量的DD水透析2～3天。
7.通过冷冻干燥器从HA-来那度胺溶液脱水获得HA-来那度胺粉末。
结果：图3显示HA-来那度胺缀合物的结构。
实施例5：来那度胺的体外细胞毒性
方法：
1.将HT29细胞以每孔1×104细胞低密度接种于96孔板中，培养基包含高葡萄糖DMEM、10％FBS、1％丙酮酸钠、1％青霉素、链霉素和新霉素。
2.将HCT15细胞以每孔1×104细胞低密度接种于96孔板中，培养基包含DMEM/F12，10％FBS、1％丙酮酸钠、1％青霉素、链霉素和新霉素。
3.接种后1天(24小时)，将细胞分别培养于包含指定剂量的以下药物的培养液中24小时：来那度胺：400μM、200μM、100μM、50μM、25μM、12.5μM、6.25μM、3.125μM和0μM；HA：4mg/mL、2mg/mL、1mg/mL，0.5mg/mL、0.25mg/mL，0.0625mg/mL、0.3125mg/mL和0mg/mL；HA-来那度胺：400μM、200μM、100μM、50μM、25μM、12.5μM、6.25μM、3.125μM和0μM。
4.使用基于线粒体中的脱氢酶活性将黄色染料3-(4,5-二甲基-2噻唑基)-2,5-二苯基-2H-溴化四氮唑(MTT)裂解为紫色甲瓒晶体的测定评价药物对细胞成活力的影响。
5.药物处理24h后，除去培养基并用培养基清洗细胞层，之后是稀释于培养基中的MTT(0.5mg/mL)，在37℃培养箱(5％CO2)孵育4小时。
6.然后向细胞加入100μL/孔的DMSO，并使用ELISA读板机在570nm下测量细胞匀浆的光学密度。
7.将从处理的细胞获得的平均光学密度除以来自未处理的对照细胞的平均光学密度计算活细胞的分数。
结果：结果表明，在富含CD44的细胞系(HT29)中，与单独的来那度胺或HA相比，HA-来那度胺缀合物具有杀死细胞的作用(图4A)。相似地，这种协同作用的趋势也发现于细胞系HCT15中(图4B)。
实施例6：HA-NiNH2缀合物的合成
NiNO2的氢化
1.将500mg尼美舒利(NiNO2)完全溶解于20ml乙酸乙酯中，然后向该溶液中加入200mg 5％的Pd/C(钯碳)作为催化剂。在持续搅拌下抽除瓶中的空气，并以最多1atm的氢气取代空气，之后搅拌24小时。
2.进行薄层色谱法(TLC硅胶载玻片60F254)以波长254nm鉴定氢化产物的纯度，其中移动相为己烷：乙酸乙酯＝2：1。
3.鉴定产物后，通过过滤去除Pd/C，之后旋转蒸发除去残留溶剂。
4.将氢化产物溶于己烷：乙酸乙酯＝1：1的溶液中以进一步纯化。
5.使用硅胶柱纯化并用洗脱溶液(己烷：乙酸乙酯＝1：1)洗脱。
6.收集有颜色的级分(fraction)并通过UV和NMR分别进行所述结构浓度的测定以确认氢化产物NiNH2的产率。
7.通过冷冻干燥器获得NiNH2粉末。
HA-NiNH2缀合物的合成
1.将50mg HA(10KDa-700KDa)溶解于25ml DD水中。
2.将25.1mg EDC与15.1mg NHS混合于1ml DD水中并于室温下搅拌5分钟。
3.将3.65mg NiNO2溶解于1ml DMSO中，然后用注射器在3分钟内缓慢滴加到HA/EDC/NHS溶液中。
4.将该混合物(HA、EDC、NHS和NiNH2)于黑暗中在室温下搅拌12小时。
5.使用透析袋(MWCO：3500)将混合物相对于过量的DD水透析2～3天。
6.通过冷冻干燥器从HA-NiNH2溶液脱水获得HA-NiNH2粉末。
结果：图5A示出了真正的尼美舒利(NiNO2)和产物NiNH2的结构。图5B示出了HA-NiNH2缀合物的结构。
实施例7：NiNO2的体外细胞毒性
方法：
1.将HT29细胞以每孔1×104细胞低密度接种于96孔板中的包含高葡萄糖DMEM、10％FBS、1％丙酮酸钠、1％青霉素、链霉素和新霉素的培养基中。
2.将HCT15细胞以每孔1×104细胞低密度接种于96孔板中的包含DMEM/F12，10％FBS、1％丙酮酸钠、1％青霉素、链霉素和新霉素的培养基中。
3.接种后1天(24小时)，将细胞培养于包含指定剂量的以下药物的培养液中24小时：NiNO2(代表具有NO2基团的真正的尼美舒利)：200μM、100μM、50μM、25μM、12.5μM、6.25μM、3.125μM和0μM；NiNH2(代表具有NH2基团的尼美舒利)：200μM、100μM、50μM、25μM、12.5μM、6.25μM、3.125μM和0μM；HA：4mg/mL、2mg/mL、1mg/mL、0.5mg/mL、0.25mg/mL、0.0625mg/mL、0.3125mg/mL和0mg/mL；HA-NiNH2：200μM、100μM、50μM、25μM、12.5μM、6.25μM、3.125μM和0μM。
4.使用基于线粒体中的脱氢酶活性将黄色染料3-(4,5-二甲基-2噻唑基)-2,5-二苯基-2H-溴化四氮唑(MTT)裂解为紫色甲瓒晶体的测定评价药物对细胞成活力的影响。
5.药物处理24hr后，除去培养基并用培养基清洗细胞层，之后是稀释于培养基中的MTT(0.5mg/mL)，在37℃培养箱(5％CO2)孵育4小时。
6.然后向细胞加入100μL/孔的DMSO，并使用ELISA读板机在570nm下测量细胞匀浆的光学密度。
7.将从处理的细胞获得的平均光学密度除以来自未处理的对照细胞的平均光学密度计算活细胞的分数。
结果：结果表明，无论在HT29或HCT15中，真正的尼美舒利(具有NO2基团)的细胞毒性作用通常优于修饰产物(具有NH2基团)的细胞毒性作用(图6A)。然而，当NiNO2与HA缀合时，HA-NiNH2的细胞毒性显著超过单独的NiNH2或NiNO2(图6B)。
实施例8：异种移植裸鼠模型中的肿瘤生长抑制
方法：
1.将HT29(2×107细胞/小鼠)皮下注射至8周龄雌性BALB/c无胸腺(nu+/nu+)小鼠右臀部(右腿上侧)。
2.当异种移植肿瘤的尺寸小于100mm3时可开始进行肿瘤生长抑制实验，这被指定为第0天。
3.在实验期间，每3或5天测量肿瘤尺寸和体重。
4.肿瘤体积计算为：1/2(4π/3)(L/2)(W/2)H；其中L是肿瘤的长度，W是肿瘤的宽度，且H是肿瘤的高度。
5.将小鼠分成PBS-对照、NiNO2或HA-NiNH2治疗的不同组。
6.以48或72小时的间隔，经尾静脉分别注射NiNO2(1.5mg/kg)、HA-NiNH2(等同于1.5mg/kg NiNO2)或PBS的剂量对小鼠进行施用。
7.记录每只小鼠的肿瘤大小以及体重变化。
结果：结果表明，每只小鼠的平均体重几乎是相同的(图7A)；然而，当比较对照、NiNO2和HA-NiNH2的每一组时，肿瘤体积显示显著不同，其中HA-NiNH2组相较于NiNO2组和对照组具有更好的肿瘤抑制效果(图7B)。该结果指示，本发明的HA-NiNH2缀合物具有比单独的NiNO2更好的治疗效果。
实施例9：HA-塞来昔布缀合物的合成
方法
1.将100mg HA(10K-700KDa)溶解于25ml DD水中。
2.将0.8当量的四丁基氢氧化铵(TBA-OH)加入到HA溶液中并搅拌16小时。
3.干燥溶液并获得HA-TBA白色固体。
4.将40mg HA-TBA溶解于1ml DD水中，然后将30mg EDC以及18mg NHS粉末加入到该溶液中，并于室温下搅拌5分钟。
5.将4mg塞来昔布溶解于2ml二甲基亚砜(DMSO)溶液中。
6.室温下搅拌该混合物(HA-TBA、EDC、NHS和塞来昔布)72小时。
7.使用透析袋(MWCO：1200～1400)将该混合物相对于DMSO和DD水的比例＝2：1的溶液透析1天，并更换所述溶液3次。
8.使用透析袋(MWCO：1200～1400)将混合物相对于0.3M NaCl透析2天，并每天2次更换该溶液。
9.通过冷冻干燥器从HA-塞来昔布溶液脱水获得HA-塞来昔布粉末。
结果：图8示出了HA-塞来昔布缀合物的合成方法和结构。
实施例10：塞来昔布的体外细胞毒性
方法
1.将HT29细胞以每孔1×104细胞低密度接种于96孔板中的包含高葡萄糖DMEM、10％FBS、1％丙酮酸钠、1％青霉素、链霉素和新霉素的培养基中。
2.将GBM8401细胞以每孔1×104细胞低密度接种于96孔板中的包含DMEM、10％FBS、1％丙酮酸钠、1％青霉素、链霉素和新霉素的培养基中。
3.接种后1天(24小时)，将细胞培养于包含指定剂量的以下药物的培养基中24小时：HA-塞来昔布：100μM、50μM、25μM、12.5μM、6.25μM、3.125μM和0μM。
4.使用基于线粒体中的脱氢酶活性将黄色染料3-(4,5-二甲基-2噻唑基)-2,5-二苯基-2H-溴化四氮唑(MTT)裂解为紫色甲瓒晶体的测定评价药物对细胞成活力的影响。
5.药物处理24hr后，除去培养基并用培养基清洗细胞层，之后是稀释于培养基中的MTT(0.5mg/mL)，在37℃培养箱(5％CO2)孵育4小时。
6.100μL/孔的DMSO，并使用ELISA读板机在570nm下测量细胞匀浆的光学密度。
7.将从处理的细胞获得的平均光学密度除以来自未处理的对照细胞的平均光学密度计算活细胞的分数。
果：结果表明，HA-塞来昔布在HT29细胞以及GBM8401细胞中的细胞毒性作用具有优于HA和塞来昔布的趋势(图9A及图9B)。
实施例11：HA-吉西他滨缀合物的合成
方法：
1.将50mg HA(10KDa-700KDa)溶解于25ml DD水中。
2.将25.1mg EDC与15.1mg NHS混合于2ml DD水中并于室温下搅拌5分钟。
3.通过加入1.44ml NaOH中和HA溶液。
4.将3.9mg吉西他滨溶解在1ml DD水与1ml DMSO溶液中，然后用注射器在3分钟内缓慢滴加到HA/EDC/NHS溶液中。
5.将该混合物(HA、EDC、NHS和吉西他滨)于黑暗中在室温下搅拌12小时。
6.使用透析袋(MWCO：12000～14000)将该混合物相对于过量的DD水透析2-3天。
7.通过冷冻干燥器从HA-吉西他滨溶液脱水获得HA-吉西他滨粉末。
结果：图10示出了HA-吉西他滨缀合物的合成方法以及结构。
实施例12：吉西他滨的体外细胞毒性
方法
1.将A549细胞以每孔1×104细胞低密度接种于96孔板中的包含高葡萄糖DMEM、10％FBS、1％丙酮酸钠、1％青霉素、链霉素和新霉素的培养基中。
2.将GBM8401细胞以每孔1×104细胞低密度接种于96孔板中的包含DMEM、10％FBS、1％丙酮酸钠、1％青霉素、链霉素和新霉素的培养基中。
3.接种后1天(24小时)，将细胞培养于包含指定剂量的以下药物的培养基中48小时：HA-gem：400μM、200μM、100μM、50μM、25μM、12.5μM、6.25μM、3.125μM和0μM；
4.接种后1天(24小时)，将细胞培养于包含指定剂量的以下药物的培养基中24小时：HA-塞来昔布：400μM、200μM、100μM、50μM、25μM、12.5μM、6.25μM、3.125μM和0μM。
5.使用基于线粒体中的脱氢酶活性将黄色染料3-(4,5-二甲基-2噻唑基)-2,5-二苯基-2H-溴化四氮唑(MTT)裂解为紫色甲瓒晶体的测定评价药物对细胞成活力的影响。
6.药物处理24hr后，除去培养基并用培养基清洗细胞层，之后是稀释于培养基中的MTT(0.5mg/mL)，在37℃培养箱(5％CO2)孵育4小时。
7.然后向细胞加入100μL/孔的DMSO，并使用ELISA读板机在570nm下测量细胞匀浆的光学密度。
8.将从处理的细胞获得的平均光学密度除以来自未处理的对照细胞的平均光学密度计算活细胞的分数。
结果：结果表明，HA-吉西他滨的细胞毒性在A549细胞(图11)以及20GBM8401细胞(图12)中增加的趋势。
Claims (12)
1.一种由糖胺聚糖与活性化合物组成的缀合物，其中所述活性化合物通过与所述糖胺聚糖、其衍生物或其盐的羧基形成酰胺键而直接缀合，且其中所述活性化合物选自由来那度胺、吉西他滨、尼美舒利和或塞来昔布组成的组。
2.根据权利要求1所述的缀合物，其中所述糖胺聚糖是透明质酸。
3.根据权利要求2所述的缀合物，其中所述透明质酸的平均分子量为10kDa至2000kDa。
4.根据权利要求1所述的缀合物，其中所述尼美舒利经修饰带有胺基。
5.根据权利要求1至4之一所述的缀合物，用于在治疗癌症中使用。
6.根据权利要求5所述的缀合物，其中所述癌症是肝癌、肝细胞癌、胆管癌、胆管细胞性囊腺癌、结肠癌、腺癌、淋巴瘤和鳞状细胞癌、乳腺癌、导管癌、小叶癌、肺癌、非小细胞肺癌、小细胞肺癌、卵巢癌、前列腺癌、肾癌、肾细胞癌、尿路上皮细胞癌、多发性骨髓瘤、骨髓增生异常综合征(MDS)、霍奇金淋巴瘤、非霍奇金淋巴瘤、慢性淋巴细胞性白血病或胰腺癌。
7.一种由糖胺聚糖与活性化合物组成的缀合物于制备用以治疗癌症的药物组合物的用途，其中所述缀合物系根据权利要求1至4任一者所述。
8.如权利要求7所述的用途，其中所述癌症是肝癌、肝细胞癌、胆管癌、胆管细胞性囊腺癌、结肠癌、腺癌、淋巴瘤和鳞状细胞癌、乳腺癌、导管癌、小叶癌、肺癌、非小细胞肺癌、小细胞肺癌、卵巢癌、前列腺癌、肾癌、肾细胞癌、尿路上皮细胞癌、多发性骨髓瘤、骨髓增生异常综合征(MDS)、霍奇金淋巴瘤、非霍奇金淋巴瘤、慢性淋巴细胞性白血病或胰腺癌。
9.一种药物组合物，包含至少一由糖胺聚糖与活性化合物的缀合物与至少一种赋形剂和/或稀释剂的组合，其中所述缀合物系根据权利要求1至4任一者所述。
10.根据权利要求9所述的药物组合物，其中所述组合物用于治疗癌症。
11.根据权利要求10所述的药物组合物，其中所述癌症是肝癌、肝细胞癌、胆管癌、胆管细胞性囊腺癌、结肠癌、腺癌、淋巴瘤和鳞状细胞癌、乳腺癌、导管癌、小叶癌、肺癌、非小细胞肺癌、小细胞肺癌、卵巢癌、前列腺癌、肾癌、肾细胞癌、尿路上皮细胞癌、多发性骨髓瘤、骨髓增生异常综合征(MDS)、霍奇金淋巴瘤、非霍奇金淋巴瘤、慢性淋巴细胞性白血病或胰腺癌。
12.根据权利要求9所述的药物组合物，其中所述药物组合物适用于经口、经胃肠道或经循环系统投予。
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| BR112021019113A2 (pt) * | 2019-06-03 | 2021-12-14 | Aihol Corp | Conjugados de hialuronano e usos dos mesmos |
| US11458204B2 (en) | 2020-06-02 | 2022-10-04 | Aihol Corporation | Method for improving substitution rate and/or substitution efficiency of hyaluronan-drug conjugates |
| CA3170553A1 (en) * | 2020-06-08 | 2021-12-16 | Hua-Yang Lin | Uses of hyaluronan-nimesulide conjugates in the treatment of acute pulmonary inflammation |
| WO2022266472A1 (en) * | 2021-06-18 | 2022-12-22 | Aihol Corporation | Uses of hyaluronan conjugate |
| CN114377139B (zh) * | 2022-03-11 | 2023-07-04 | 四川省医学科学院·四川省人民医院 | 载体、药物递送系统及其应用 |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5733891A (en) * | 1990-10-18 | 1998-03-31 | Shiseido Co., Ltd. | Compound for medicinal ingredient and hyaluronic acid and process for producing the same |
| EP1082963A1 (en) * | 1998-05-20 | 2001-03-14 | Chugai Seiyaku Kabushiki Kaisha | Remedies for joint diseases bound to hyaluronic acid |
| WO2008134528A1 (en) * | 2007-04-25 | 2008-11-06 | Board Of Regents, The University Of Texas System | Anti-cancer agent-hyaluronic acid conjugate compositions and methods |
| CN101732728A (zh) * | 2010-01-25 | 2010-06-16 | 中国药科大学 | 抗炎药物-多糖偶联物及其药物组合物的制备和应用 |
| WO2011130476A2 (en) * | 2010-04-16 | 2011-10-20 | The Research Foundation Of State University Of New York | Polymer-based therapeutic agents |
Family Cites Families (32)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB8713662D0 (en) * | 1987-06-11 | 1987-07-15 | Skandigen Ab | Hyaluronic acid derivatives |
| JPH0585942A (ja) * | 1991-02-26 | 1993-04-06 | Denki Kagaku Kogyo Kk | インターフエロン−ヒアルロン酸及び／又はその塩の結合体 |
| JPH0673103A (ja) * | 1991-11-27 | 1994-03-15 | Lignyte Co Ltd | ヒアルロン酸高分子複合体及びその製造方法 |
| AU5543594A (en) | 1992-10-30 | 1994-05-24 | Duke University | An adhesion molecule |
| US5616568A (en) * | 1993-11-30 | 1997-04-01 | The Research Foundation Of State University Of New York | Functionalized derivatives of hyaluronic acid |
| WO1999045942A1 (en) | 1998-03-13 | 1999-09-16 | Entremed, Inc. | Metastatin and hyaluronate binding proteins and methods of use |
| ITPD980169A1 (it) * | 1998-07-06 | 2000-01-06 | Fidia Advanced Biopolymers Srl | Ammidi dell'acido ialuronico e dei suoi derivati e processo per la loro preparazione. |
| GB9902412D0 (en) * | 1999-02-03 | 1999-03-24 | Fermentech Med Ltd | Process |
| JP2001081103A (ja) * | 1999-09-13 | 2001-03-27 | Denki Kagaku Kogyo Kk | ヒアルロン酸結合薬剤 |
| JP4266571B2 (ja) * | 2002-05-17 | 2009-05-20 | 生化学工業株式会社 | 脂質結合グリコサミノグリカンの製造法 |
| AU2003265576A1 (en) * | 2002-08-23 | 2004-03-11 | The Mclean Hospital Corporation | Corticosteroid conjugates and uses thereof |
| US8192744B2 (en) | 2002-08-26 | 2012-06-05 | Ibcc Holding As | Drug for treating states related to the inhibition of angiogenesis and/or endothelial cell proliferation |
| AU2003284634A1 (en) * | 2002-11-21 | 2004-06-15 | Chugai Seiyaku Kabushiki Kaisha | Sustained release drug carrier |
| US20060228331A1 (en) * | 2003-10-10 | 2006-10-12 | Novo Nordisk A/S | IL-21 Derivatives and variants |
| WO2005066214A1 (ja) * | 2004-01-07 | 2005-07-21 | Seikagaku Corporation | ヒアルロン酸誘導体及びそれを含む薬剤 |
| EP1724287A4 (en) * | 2004-03-05 | 2010-10-27 | Denki Kagaku Kogyo Kk | HYALURONIC / METHOTREXATE CONNECTION |
| US8143391B2 (en) * | 2004-09-07 | 2012-03-27 | Chugai Seiyaku Kabushiki Kaisha | Process for producing water-soluble hyaluronic acid modification |
| CN103784960A (zh) * | 2005-07-27 | 2014-05-14 | 阿尔卡米亚肿瘤学股份有限公司 | 使用乙酰透明质酸的治疗方案 |
| IE20060049A1 (en) * | 2006-01-25 | 2007-08-08 | Eurand Pharmaceuticals Ltd | A novel drug delivery system: use of hyaluronic acid as a carrier moleclue for different classes of therapeutic active agents |
| WO2009048280A2 (en) * | 2007-10-09 | 2009-04-16 | Postech Academy-Industry Foundation | Long acting hyaluronic acid - peptide conjugate |
| US20090170195A1 (en) * | 2007-12-28 | 2009-07-02 | Kent State University | Curcumin-hyaluronan compounds |
| EP2355853B1 (en) * | 2008-10-10 | 2016-12-07 | Polyactiva Pty Ltd | Biodegradable polymer - bioactive moiety conjugates |
| US8759322B2 (en) * | 2008-11-05 | 2014-06-24 | National University Corporation Tokyo Medical And Dental University | Hyaluronic acid derivative and pharmaceutical composition thereof |
| CA2753388C (en) * | 2009-03-23 | 2016-11-29 | Quark Pharmaceuticals, Inc. | Endo180 antibody to treat cancer and fibrotic disease |
| WO2010140869A2 (en) * | 2009-06-05 | 2010-12-09 | Iljin Copper Foil Co., Ltd. | Complex, multilayer using the same, and device coated with the multilayer |
| US8846110B2 (en) * | 2009-10-13 | 2014-09-30 | Rexahn Pharmaceuticals, Inc. | Polymeric systems for the delivery of anticancer drugs |
| EP2496948B1 (en) * | 2009-11-05 | 2018-01-10 | University of Virginia Patent Foundation | Compositions and methods for detecting plectin-1 as a biomarker for cancer |
| AU2011255647A1 (en) * | 2010-05-18 | 2012-11-15 | Cerulean Pharma Inc. | Compositions and methods for treatment of autoimmune and other diseases |
| DK2682409T3 (en) * | 2011-03-03 | 2017-09-11 | Chugai Pharmaceutical Co Ltd | Hyaluronic acid derivative modified with aminocarboxylic acid |
| EP2545925B1 (en) * | 2011-07-12 | 2018-02-14 | Holy Stone Healthcare Co.,Ltd. | Compositions comprising hyaluronic acid for treating and preventing mucosa related diseases |
| WO2015005458A1 (ja) * | 2013-07-10 | 2015-01-15 | 生化学工業株式会社 | グリコサミノグリカン誘導体及びその製造方法 |
| US9572832B2 (en) * | 2013-08-29 | 2017-02-21 | Holy Stone Healthcare Co., Ltd. | Compound of glycosaminoglycan and its fabrication method as well as application |
-
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Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5733891A (en) * | 1990-10-18 | 1998-03-31 | Shiseido Co., Ltd. | Compound for medicinal ingredient and hyaluronic acid and process for producing the same |
| EP1082963A1 (en) * | 1998-05-20 | 2001-03-14 | Chugai Seiyaku Kabushiki Kaisha | Remedies for joint diseases bound to hyaluronic acid |
| WO2008134528A1 (en) * | 2007-04-25 | 2008-11-06 | Board Of Regents, The University Of Texas System | Anti-cancer agent-hyaluronic acid conjugate compositions and methods |
| CN101732728A (zh) * | 2010-01-25 | 2010-06-16 | 中国药科大学 | 抗炎药物-多糖偶联物及其药物组合物的制备和应用 |
| WO2011130476A2 (en) * | 2010-04-16 | 2011-10-20 | The Research Foundation Of State University Of New York | Polymer-based therapeutic agents |
Non-Patent Citations (2)
| Title |
|---|
| KAVITHA KANKANALA ET AL.: "Nimesulide Based Novel Glycolamide Esters:Their Design, Synthesis, and Pharmacological Evaluation", 《JOURNAL OF CHEMISTRY》, vol. 2013, pages 279 * |
| WM LIU ET AL.: "Inhibition of metastatic potential in colorectal carcinoma in vivo and in vitro using immunomodulatory drugs(IMiDS)", 《BRITISH JOURNAL OF CANCER》, vol. 101, no. 5, pages 120 - 121 * |
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