CN105611914B - 局部递送治疗剂的化学构造物 - Google Patents
局部递送治疗剂的化学构造物 Download PDFInfo
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- CN105611914B CN105611914B CN201480035539.9A CN201480035539A CN105611914B CN 105611914 B CN105611914 B CN 105611914B CN 201480035539 A CN201480035539 A CN 201480035539A CN 105611914 B CN105611914 B CN 105611914B
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Abstract
本发明提供一种用于选择性递送治疗剂或诊断剂至患者体内靶器官或组织的方法,所述方法通过植入与第一结合剂连接的生物相容固体支持体,和向患者施用连接于所述治疗剂或诊断剂的第二结合剂,使得所述治疗剂或诊断剂在所述靶器官或组织积累。
Description
相关申请的交叉引用
本申请要求2013年6月19日提交的、申请号为61/836,800的美国申请的优先权,其通过引用全文纳入本文。
关于联邦政府资助研发下作出的发明的权利声明
不适用
背景
在美国,骨科医生为600,000名愈合延迟的骨折患者以及100,000名变成骨不连的患者不断探求改进疗法。感染骨不连仍然是一个挑战,常常需要分阶段治疗方案。第一步是除去受感染的硬件,手术清创和放置预装洗脱剂的固体支持体(例如,抗生素小珠)。第二步包括全身性静脉内递送抗生素。最后,患者经历第二次外科手术以便可能除去固体支持体、永久的手术稳定作用以及手术期间治疗制剂的局部递送(例如重组人骨形态发生蛋白2)和骨移植。
目前的疗法面临着多重挑战,并且是侵入性的。它们涉及反复的手术方式,并且受限于移植后无法更改疗法(例如,如果培养物出现耐药机体)。抗生素的全身给药是需要高血液浓度以便在骨折环境中实现治疗水平的后续问题。需要密切监测这些高血清水平的副作用,以避免严重的并发症。该问题将受益于改进的药物递送方法。
就治疗剂的递送而言,这绝非是外科医生面临的唯一问题。其他的问题包括在外科手术时治疗剂的全身静脉内递送(例如用于癌症的化疗剂或静脉止痛药物)、局部递送(例如脊柱融合术后重组人骨形态发生蛋白2的递送)、以及直接注射到关节(例如,注射皮质骨醇类至膝盖用于骨关节炎治疗)。这些问题将受益于改进的治疗剂递送,也就是抗生素、消炎止痛药物、骨愈合调节剂和化疗剂的改进递送。所需要的是一种靶向递送治疗剂或诊断剂的方法,从而将制剂在所需部位浓缩,如此降低给予病人的治疗剂或诊断剂的总剂量。令人意外地,本发明满足了这种和其他的需要。
本发明简要描述
在一些实施例中,本发明提供了一种方法,用于选择性地递送有效量的治疗剂或诊断剂至患者体内靶器官或组织的第一位置,包括在患者体内靶器官或组织的第一位置植入生物相容的固体支撑体的步骤,其中所述固体支撑体与第一结合剂连接,并且与患者体内靶器官或组织的其他位置相比,其中所述靶器官或组织的第一位置不能被化学或生物靶向剂选择性地定向。所述方法还包括给予患者连接到第二结合剂的治疗剂或诊断剂的步骤,使得第一和第二结合剂在接触后彼此结合,从而选择性地递送有效量的治疗剂或诊断剂至患者体内靶器官或组织的第一位置。
在一些实施例中,本发明提供了一种方法,用于治疗患者疾病或病症,包括给予患者连接于第一结合剂的治疗剂,使得当所述第一结合剂在疾病或病症部位接触所述第二结合剂时,所述第一结合剂和第二结合剂彼此结合,在疾病或病症部位上形成治疗有效量的治疗剂,其中给予患者的治疗剂剂量少于没有第二结合剂存在下给予患者的治疗剂有效量。
在一些实施例中,本发明提供了一种组合物,包括生物相容的固体支持体和连接于该生物相容的固体支持体的至少一种环辛烯固体支持体。
在一些实施例中,本发明提供了一种组合物,包括治疗剂或诊断剂、1,2,4,5-四嗪、和接头,以便共价连接治疗剂或诊断剂与1,2,4,5-四嗪。
附图简述
图1显示了四嗪连接的治疗剂的制备。
图2显示了环辛烯-接头组分9的制备。
图3显示了0.1mM的1在DMF中的吸收光谱(550nm的顶线)。加入0.5当量的9导致540nm的吸收谱带逐渐减少。加入1.5当量的9后,不再观察到减少(550nm的两条底线),从而表明产物9含有不超过33%的顺式环辛烯异构体。
图4显示了用反式环辛烯(TCO)对藻酸盐水凝胶的修饰。
图5显示了起始原料四嗪5的RP-HPLC色谱曲线。
图6显示了64Cu-四嗪5反应混合物的原始放射性-ITLC曲线。
图7显示了64Cu-四嗪5反应混合物的原始放射性-RP-HPLC曲线。
图8显示了RP-HPLC纯化后,64Cu-四嗪5的放射性-RP-HPLC曲线。
图9显示了111In-四嗪5反应混合物的原始ITLC曲线。
图10显示了111In-四嗪5反应混合物的原始放射性-HPLC曲线。
图11显示了111In-四嗪5在HPLC纯化后的放射性-HPLC曲线。
图12显示了尺寸排阻HPLC图谱,表明TCO-凝胶对放射性的摄取。
图13显示了海藻酸-PEG-TCO与四嗪-PEG-DOTA-金属的偶联。
图14显示了体外研究中,用圆盘表明实验组摄取放射性的增长。
图15显示了注射四嗪之后,24小时的64Cu-四嗪5的生物分布(biodistribution)。
图16显示了注射四嗪之后,在1小时时间点的111In-四嗪5的生物分布。
图17显示了接受64Cu-四嗪5(0.09–0.21mCi)的小鼠的CT图像。
图18显示了接受64Cu-四嗪5(0.09–0.21mCi)的小鼠的CT图像。
图19显示了通过ROI和活性测定(注射量的绝对值)对64Cu-四嗪5注射的图像数据作分析。
图20显示了通过ROI和活性测定(注射量的绝对值)对64Cu-四嗪5注射的图像数据作分析。
详细描述
I概述
本发明提供了一种方法以及组合物,用于选择性地靶向器官或组织的多个部分,所述部分不能从化学上或生物学上与同一个器官或组织的其他非靶向部分区分开来。所述方法包括在患者体内移植植入一报道物,连接至生物相容的固体支持体的结合剂。所述植入患者体内的结合剂为一对彼此有很高反应速率的结合剂的一半。所述报道物植入器官或组织的特定部位,该部位不能从化学上或生物上与同一器官或组织的其他非靶向部位区分开来。然后将共价连接到治疗剂或诊断剂的第二结合剂(探针)给予患者。当所述报道物和探针的两种结合剂相接触,迅速反应并形成共价键,从而将所述治疗剂或诊断剂共价连接于所述器官或组织的靶向部位。因此,可将治疗有效量的所述诊断剂或治疗剂选择性递送至患者的器官或组织的靶向部位。
II定义
“选择性递送”指的是将治疗剂或诊断剂递送至需要治疗的器官或组织的一部分,而不递送至无需治疗的该器官或组织的其他部分。
“治疗剂”指的是能够治疗和/或改善病症或疾病的制剂。代表性的治疗剂包括,但不限于:紫杉醇、阿霉素、依托泊苷、伊立替康、7-乙基-10-羟基喜树碱、环孢菌素A、鬼臼毒素、卡莫司汀、两性霉素、伊沙匹隆、帕土匹龙(埃博霉素类)、万古霉素、雷帕霉素和铂类药物。本发明的治疗剂还包括前体药物。
“诊断剂”指的是帮助诊断病症或疾病的制剂。代表性的诊断剂包括成像剂如顺磁剂、光学探针、和放射性核素。顺磁剂成像剂在外部作用场下具有磁性。顺磁剂的例子包括,但不限于含纳米颗粒的铁粒子。光学探针是可以在一种波长辐射下激发并且在第二种不同波长的辐射下检测到的荧光物质。本发明中可用的光学探针包括但不限于:Cy5.5、Alexa680、Cy5、DiD(1,1'-双十八烷基-3,3,3',3'-四甲基吲哚二碳花青高氯酸盐)以及DiR(1,1'-双十八烷基-3,3,3',3'-四甲基吲哚三碳菁碘化物)。其他光学探针包括量子点。放射性核素是经过放射性衰变的元素。本发明中可用的放射性核素包括但不限于:3H、11C、13N、18F、19F、60Co、64Cu、67Cu、68Ga、82Rb、90Sr、90Y、99Tc、99mTc、111In、123I、124I、125I、129I、131I、137Cs、177Lu、186Re、188Re、211At、Rn、Ra、Th、U、Pu和241Am。
“靶向器官或组织”指的是为递送治疗剂或诊断剂而靶向的器官或组织。代表性的靶向器官和组织包括那些可被化学或生物靶向剂定向,以及那些不能由化学或生物靶向剂定向的器官和组织。代表性的器官或组织包括骨。
“植入”指的是手术植入病人体内。
“生物相容的固体支持体”指的是可植入患者体内的,支撑所述结合剂之一,也在结合剂偶联之后支撑治疗剂或诊断剂的固相支持材料。固相支持物与患者身体相容。代表性的生物相容的固体支持体包括但不限于,水凝胶如多糖水凝胶、藻酸盐、纤维素、脱乙酰壳多糖、透明质酸、硫酸软骨素、以及其他。
“接触”或“接触的”指的是使得至少两种不同物质接触,从而它们可以反应的过程。但是应当理解,所得到的反应产物可以直接由所添加的试剂之间的反应制得,或者由来自一种或多种添加的试剂在反应混合物中产生的中间体制得。
“接头”、“连接的”、“连接”指的是将本发明化合物连接于靶向特定类型细胞(例如肿瘤细胞、其他类型的病变细胞或正常细胞类型)的生物材料的化学部分。所述连接可以通过形成共价或离子键来实现。所述连接可以是在所连接的两个部分之间的直接连接或,例如通过接头的间接连接。本发明可用的接头长度可达30个碳原子。优选地,接头长度为5-15个碳原子。用于将所述接头连接于本发明化合物和生物分子的键的类型包括但不限于:酰胺、胺、酯、氨基甲酸酯、脲、硫醚、硫代氨基甲酸酯、硫代碳酸酯和硫脲。本领域技术人员应当理解,其它类型的键在本发明中是可用的。
“结合剂”指的是在生物环境中可以与另一结合剂形成共价键的任意基团。这通常被称为生物偶联或生物正交化学。代表性的结合剂包括但不限于,胺类和活化酯、胺类和异氰酸酯、胺类和异硫氰酸酯、用于形成二硫化物的硫醇、用于烯胺形成的醛类和胺类、用于通过施陶丁格连接反应形成酰胺的叠氮化物、用于通过点击化学反应(Click-chemistry)形成三唑的叠氮化物和炔烃、反式环辛烯(TCO)、和四嗪以及其他。用于本发明的所述结合剂与相应的结合剂有高反应活性,因此反应迅速。
“治疗”、“治疗的”、“治疗方法”指的是损伤、病理特性、病情或病症(例如疼痛)的治疗或改善中任何成功的迹象,包括任何客观的或主观的参数,如病症的减轻、缓解、衰减或造成病症、损伤、病理或病情更能被患者所容忍;降低病症或病情的频率或持续时间;或者;在一些情况下,防止病症或病情的发作。病症的治疗或改善可基于任何客观的或主观的参数,包括例如:体检结果。
“施用”指的是口服给药、栓剂给药、局部接触、胃肠外给药、静脉内给药、腹膜内给药、肌内给药、病灶内给药、鼻内或皮下给药、鞘内给药、或向主体植入缓释装置,如,迷你渗透泵。
“患者”指的是需要治疗的动物,例如哺乳动物,包括但不限于灵长类(例如人)、牛、绵羊、山羊、马、狗、猫、兔、大鼠、小鼠等等。在特定实施例中,所述患者为人。
“治疗有效量或剂量”或“治疗足够量或剂量”或“有效或足够量或剂量”指的是对施用对象产生治疗效果的剂量。准确的剂量取决于治疗目的,可由本领域技术人员使用已知技术确定(参照,例如,Lieberman,《药物剂型》(Pharmaceutical Dosage Forms)(卷1-3,1992);Lloyd,《药物配制的技艺、科学和技术》(The Art,Science and Technology ofPharmaceutical Compounding)(1999);Pickar,《剂量计算》(Dosage Calculations)(1999);和Remington:《药学科学和实践》(The Science and Practice of Pharmacy),第20版,2003,Gennaro编.,Lippincott,Williams&Wilkins))。在致敏细胞中,治疗有效剂量常可低于非致敏细胞的常规治疗有效剂量。
III治疗剂的选择性递送方法
本发明提供一种方法,用于将治疗剂选择性地递送至患者体内靶器官或细胞的位置。在一些实施例中,本发明提供了一种方法,用于将有效量的治疗剂或诊断剂选择性地递送至患者体内靶器官或组织的第一位置,包括在患者体内靶器官或组织的第一位置植入生物相容的固体支持体,其中该固体支持体连接于第一结合剂,并且与患者体内靶器官或组织的其他位置相比,所述靶器官或组织的第一位置不能被化学或生物靶向剂选择性地靶向。所述方法还包括对患者施用连接于第二结合剂的治疗剂或诊断剂的步骤,使得第一和第二结合剂在接触后彼此结合,从而将有效量的治疗剂或诊断剂选择性递送至患者体内靶器官或组织的第一位置。
任何适当的生物相容的固体支持体可在本发明的方法中使用。例如,所述生物相容的固体支持体可以是水凝胶、交联的聚合物基质、金属、陶瓷、塑料等等。本发明中可用的水凝胶包括但不限于:多糖水凝胶、藻酸盐、纤维素、透明质酸、脱乙酰壳多糖、甲壳素、壳多糖、透明质酸、硫酸软骨素,肝素等。其它糖基生物材料是本领域已知的,例如那些如2014年聚合物先进技术448-460页所述(Polymer Advanced Technology 2014,25,448-460)。用作生物相容支持体的聚合物可以包括但不限于聚磷腈、聚酐、聚缩醛、聚(原酸酯)、聚磷酸酯、聚己内酯、聚氨酯、聚交酯、聚碳酸酯、聚酰胺、和聚醚、以及其共混物/复合物/共聚物。代表性的聚醚包括但不限于,聚(乙二醇)(PEG)、聚(丙二醇)(PPG)、三嵌段普朗尼克([PEG]n-[PPG]m-[PEG]n)、PEG二丙烯酸酯(PEGDA)和PEG二甲基丙烯酸(PEGDMA)。所述生物相容的固体支持体还可以包括蛋白质和其它聚(氨基酸)例如胶原、明胶、弹性蛋白和弹性蛋白样多肽、白蛋白、纤维蛋白、聚(γ-谷氨酸)、聚(L-赖氨酸)、聚(L-谷氨酸)、和聚(天冬氨酸)。
在一些实施例中,所述固体支持体可以为水凝胶。在一些实施例中,所述固体支持体可以为藻酸盐。在一些实施例中,所述固体支持体可以为壳多糖。在一些实施例中,所述固体支持体可以为透明质酸。在一些实施例中,所述固体支持体可以为甲壳素。
任何适当的结合剂可以在本发明的方法中使用。代表性的结合剂可见于《生物偶联技术》(Bioconjugate Techniques).Greg T.Hermanson,1996和ACS Chemical Biology2014,9,592-605。例如,本发明方法可用的结合剂包括但不限于,环辛烯、四嗪、叠氮化物、炔烃、胺类、活化酯、异氰酸酯、异硫氰酸酯、硫醇、醛、酰胺以及其他。在一些实施例中,第一和第二结合剂各自独立地为:环辛烯、四嗪、叠氮化物或炔烃。在一些实施例中,第一和第二结合剂各自独立地为:反式环辛烯或1,2,4,5-四嗪,从而使得结合剂之一为反式环辛烯,而另一种为1,2,4,5-四嗪。
采用本发明的方法可以靶向任意适当的器官或组织。代表性的器官或组织包括但不限于,骨骼、软骨、韧带、肌腱、肠、肌肉、神经系统包括脑、脊髓、心脏、和神经以及其他神经系统。例如,当所述器官为心脏时,本发明方法可用于心脏修复。在一些实施例中,所述靶器官或组织为骨骼。
本发明方法可采用任何治疗剂或诊断剂。代表性的治疗剂包括但不限于,抗生素类例如万古霉素、紫杉醇、阿霉素、依托泊苷、伊立替康、7-乙基-10-羟基喜树碱、环孢菌素A、鬼臼毒素、卡莫司汀、两性霉素、伊沙匹隆、帕土匹龙(埃博霉素类)、雷帕霉素和铂类药物。其他治疗剂包括脱氧土霉素和其他MMP抑制剂。在一些实施例中,所述治疗剂可以为万古霉素。
代表性的诊断剂包括成像剂如顺磁剂、光学探针、和放射性核素。顺磁剂成像剂在外部作用场下具有磁性。顺磁剂的例子包括但不限于包括纳米颗粒的铁粒子。光学探针是可以在一种波长辐射下激发并且在第二种不同波长的辐射下检测到的荧光物质。本发明中可用的光学探针包括但不限于:Cy5.5、Alexa 680、Cy5、DiD(1,1'-双十八烷基-3,3,3',3'-四甲基吲哚二碳花青高氯酸盐)以及DiR(1,1'-双十八烷基-3,3,3',3'-四甲基吲哚三碳菁碘化物)。其他光学探针包括量子点。放射性核素是经过放射性衰变的元素。本发明中可用的放射性核素包括但不限于:3H、11C、13N、18F、19F、60Co、64Cu、67Cu、68Ga、82Rb、90Sr、90Y、99Tc、99mTc、111In、123I、124I、125I、129I、131I、137Cs、177Lu、186Re、188Re、211At、Rn、Ra、Th、U、Pu和241Am。所述诊断剂也可以包括螯合剂,例如1,4,8,11-大环-1,4,7,10-四氮杂十二烷-1,4,8,11-乙酸(TETA),4,11-双(羧甲基)-1,4,8,11-四氮杂双环[6.6.2]十六烷(CB-TE2A),二乙烯三胺五乙酸(DTPA)和1,4,7,10-四氮杂环十二烷-1,4,7,10-四羧酸(DOTA)。其他螯合剂在本发明方法中可用。
本发明所述方法将所述治疗剂或诊断剂集中在靶器官或组织。在一些实施例中,在靶器官或组织第一位置的治疗剂或诊断剂的浓度高于患者体内其他部位的浓度。
所述第一结合剂可以采用本领域技术人员已知的任何适当方法连接到生物相容的固体支持体。例如,所述第一结合剂可以通过共价键或离子键连接到生物相容的固体支持体上。或者,所述第一结合剂可以插入到生物相容的固体支持体的基质中,其中所述第二结合剂可以结合到存在于生物相容的固体支持体表面的所述第一结合剂或生物相容的固体支持体的内部部分。
在一些实施例中,所述第一结合剂可以共价连接到生物相容的固体支持体。所述第一结合剂可以直接共价连接到生物相容的固体支持体或通过使用接头间接连接。本发明可以使用任何适当的接头将结合剂连接到生物相容的固体支持体或治疗剂或诊断剂。代表性的接头可含有约10到100个连接原子,可以包括乙烯-氧基团、胺、酯、酰胺和酮官能团。本发明方法中可用的其他接头可含有约10到约50个连接原子,或从约25到约50个连接原子。代表性的接头包括但不限于以下所示的:
所述生物相容的固体支持体和治疗剂或诊断剂可用适当的接头以任何适当的报道基团或探针结合剂来修饰,例如那些如下所示的:
当使用本发明的报道基团和探针结合剂时,生物相容的固体支持体可以通过本领域技术人员已知的任何方法进行修饰。例如,共价修饰可以酯化任何存在的羧酸,将醇转换为醚或酯,或将酸或胺转化为酰胺,如下所示:
其中R1、R2、R3、R4和R5可以为任意适当的接头和结合基团。生物相容的固体支持体的其他修饰可以包括羟基或氨基的羧甲基修饰。
所述的生物相容的固体支持体可以用本领域技术人员已知的任何方法植入。
所述治疗剂或诊断剂可以足以治疗患者正在经受的疾病或病症的任何适当量施用。此类施用的剂量、频率和时间选择很大一部分取决于所选择的治疗剂、治疗病症的本质、患者主体的情况例如年龄、体重和其它病症或疾病的存在、施用的配方以及主治医师的自由裁量。通常来说,治疗剂或诊断剂的给药剂量范围为每天约2mg到约2000mg,虽然根据以上条件、目标疾病、患者以及给药途径,剂量必然会发生变化。本发明的治疗剂或诊断剂可以根据需要频繁施用,包括每小时、每天、每周或每月。在本发明的药理学方法中,所用的治疗剂或诊断剂以每天约0.0001mg/kg的初始剂量到约1000mg/kg的剂量施用。从约0.01mg/kg至约500mg/kg,或约0.1mg/kg至约200mg/kg,或约1mg/kg至约100mg/kg或约10mg/kg至约50mg/kg的每日剂量范围都可以使用。然而,所述剂量可以根据患者的需求、所治疗病症的严重程度、和所采用的化合物来改变。例如,所述剂量可以凭经验确定考虑诊断特定患者的疾病类型和阶段。在本发明的上下文中,施用于患者的剂量随时间应足以在患者体内产生有益的治疗反应,但是一般低于治疗未植入生物相容的固体支持体所需的剂量,该支持体将治疗剂或诊断剂浓缩在需要治疗的器官或组织上。剂量的大小还由任意不良副作用的存在、性质和程度决定,该副作用伴随着在特定病人体内施用特定化合物而产生。决定特定情况下适当的用量是在执业医师的技能范围内。通常地,治疗开始时剂量较小,小于化合物的最佳剂量。此后,渐渐地加大剂量直至达到最佳效果。为方便起见,如果需要的话,总的每日剂量可以按需在一天按份给药。由主治医师决定,可按每日、或隔日施用剂量。也可在更长时期(周、月或年)内在定期的或连续的基础上给药。
IV治疗方法
本发明提供采用上述方法治疗患者的疾病或病症的方法。在一些实施例中,本发明提供了一种治疗患者疾病或病症的方法,包括对患者施用连接于第一结合剂的治疗剂,以致当第一结合剂在疾病或病症部位接触第二结合剂,第一和第二结合剂彼此结合,从而在疾病或病症部位形成药学上有效量的治疗剂,其中对患者施用的治疗剂剂量低于缺少第二结合剂时对患者施用的药学上有效量。
任何疾病或病症都可以用本发明的方法进行治疗。代表性的疾病或病症包括但不限于:癌症、自身免疫性疾病、遗传性疾病、感染、炎症、神经性障碍,和代谢障碍、及其组合。在一些实施例中,所述疾病或病症可以是感染或炎症、及其组合。在一些实施例中,所述疾病或病症可以是骨髓炎。
所述疾病或病症可以用任何适当的治疗剂进行治疗,例如上述那些。在一些实施例中,所述治疗剂可以是万古霉素。
V.组合物
本发明还提供了用于植入患者体内的报道基团组合物,以及用于对患者施用并结合报道基团组合物的探针组合物。在一些实施例中,本发明提供了一种组合物,包括生物相容的固体支持体和至少一种连接于生物相容的固体支持体的环辛烯。
如上所述,生物相容的固体支持体可以为任一适当的固体支持体。在一些实施例中,所述固体支持体可以为水凝胶。在一些实施例中,所述固体支持体可以为藻酸盐。
本发明的报道基团组合物可任选地包括接头。在一些实施例中,本发明提供了一种组合物,所述组合物包括生物相容的固体支持体、至少一种环辛烯和将各环辛烯共价连接至生物相容的固体支持体的接头。所述接头可以为如上所述的任一适当的接头。在一些实施例中,所述接头可具有以下结构:
在一些实施例中,报道基团组合物可具有如下式所示结构:
本发明还提供对患者施用的探针组合物。所述探针组合物可具有与报道基团组合物的结合剂互补的结合剂,因此当所述探针组合物与报道基团组合物接触时,两种结合剂发生反应形成共价键。在一些实施例中,本发明提供了一种组合物,所述组合物包括治疗剂或诊断剂、1,2,4,5-四嗪、和将治疗剂或诊断剂共价连接至1,2,4,5-四嗪的接头。
本发明在探针组合物中可用的任意适当的治疗剂或诊断剂如上所述。代表性的治疗剂包括万古霉素。代表性的诊断剂包括DOTA-64Cu或DOTA-111In。在一些实施例中,所述组合物可具有结构:
本发明的化合物可通过各种本领域技术人员已知的方法来制备。例如,代表性的探针组合物可如图1所示制备,其中,化合物1(即一种修饰的四嗪)可以按以前所述方法合成(Fox,J.M.;Hassink,M.,Blackman,M.;Li,Z.;Conti,P.S.PCT/US2011/044814;WO 2012/012612)。1与受保护的接头2在酰胺形成条件下反应产生中间体3。保护基团脱保护形成4后,治疗剂或诊断剂可连接至4,从而形成探针化合物5。
报道基团组合物同样地制备。例如,如图2所示,在标准的胺形成条件下,如前所述合成的化合物6可连接至受保护的接头生成8,然后脱保护生成9。然后如图4所示,通过9与生物相容的固体支持体(如藻酸盐)反应形成报道基团组合物。
制备本发明化合物的方法可包括任何适当的保护基或保护基策略。保护基指的是这样一种化合物,其使得某官能团不与特定的一组反应条件反应,但之后在后续合成步骤中可移除,以便使得该官能团恢复至原来的状态。这些保护基团是本领域技术人员所公知的,包括《有机合成中的保护基团》(Protective Groups in Organic Synthesis),第4版,T.W.Greene和P.G.M.Wuts,John Wiley&Sons,纽约,2006中公开的化合物,其通过引用全文纳入本文。
VI.制剂
本发明的组合物可以制成各种各样的口服剂、胃肠外以及局部剂型。口服制剂包括适于患者摄入的片剂、丸剂、粉末、锭剂、胶囊、液体、锭剂、扁囊剂、凝胶剂、糖浆、浆液、悬浮液等。本发明的组合物也可以通过注射进行给药,即静脉内、肌内、皮内、皮下、十二指肠内、或腹膜内。此外,本文描述的组合物可通过吸入给药,例如,鼻内给药。另外,本发明的组合物可以经皮给药。本发明的组合物还可以通过眼内、阴道内、直肠内途径给药,包括栓剂、吹入剂、粉剂和气雾剂制剂(例如,类固醇吸入剂,参见Rohatagi,J.Clin.Pharmacol.35:1187-1193,1995;Tjwa,Ann.Allergy Asthma Immunol.75:107-111,1995)。因此,本发明还提供药物组合物,包括药学上可接受的载体或赋形剂以及本发明的化合物。
就从本发明化合物制备药物组合物而言,药学上可接受的载体可以是固体或液体。固体形式制剂包括粉剂、片剂、丸剂、胶囊剂、扁囊剂、栓剂和分散颗粒剂。所述固体载体可以是一种或多种物质,其也可作为稀释剂、调味剂、粘合剂、防腐剂、片剂崩解剂或包封材料。制剂及给药方面的技术细节在科技和专利文献中有很好的描述,参见,例如最新版的《雷明顿药物科学》(Remington's Pharmaceutical Science),Maack Publishing Co,伊斯顿宾夕法尼亚州("Remington's")。
在粉剂中,所述载体是极细微固体,其与极细微活性组分混合。在片剂中,活性组分与具有所需结合性能的载体以一定比例混合,并压制成所需的形状和尺寸。粉剂和片剂优选含有5%或10%至70%的本发明化合物。
适当的固体赋形剂包括但不限于:碳酸镁、硬脂酸镁、滑石、果胶、糊精、淀粉、黄蓍胶、低熔点蜡、可可脂、碳水化合物;糖类包括但不限于:乳糖、蔗糖、甘露醇或山梨糖醇、玉米淀粉、小麦、水稻、马铃薯或其他植物淀粉;纤维素如甲基纤维素、羟丙基甲基纤维素、或羧甲基纤维素钠;和树胶,包括阿拉伯和黄蓍胶;以及蛋白,包括但不限于:明胶和胶原蛋白。如果需要,可加入崩解剂或增溶剂,如交联聚乙烯吡咯烷酮、琼脂、海藻酸、或其盐如藻酸钠。
给糖衣丸芯提供合适的包衣,例如浓缩糖溶液,其也可包含阿拉伯树胶、滑石、聚乙烯吡咯烷酮、卡波姆凝胶、聚乙二醇和/或二氧化钛、漆溶液和适当的有机溶剂或溶剂混合物。可向片剂或糖衣丸包衣中加入染料或色素用于产品识别或表征活性化合物的量(即,剂量)。本发明的药物制剂也可以口服使用,例如,由明胶制成的插接式胶囊,以及由明胶和如甘油或山梨醇包衣制成的密封软胶囊。插接式胶囊可包含本发明化合物,并与填料或粘合剂,如乳糖或淀粉,润滑剂,如滑石或硬脂酸镁,以及任选的稳定剂相混合。在软胶囊中,本发明的化合物可以溶解或悬浮在适当的液体中,例如脂肪油、液体石蜡、或液体聚乙二醇,含或不含稳定剂。
为了制备栓剂,首先将低熔点蜡(如脂肪酸甘油酯或可可脂的混合物)熔化,并将本发明化合物通过搅拌均匀分散在其中。然后将熔化的均相混合物倒入适宜大小的模具中,使其冷却并由此固化。
液体形式制剂包括溶液、悬浮液和乳液,例如,水或水/丙二醇溶液。对于胃肠外注射,液体制剂可以在聚乙二醇水溶液中配制溶液。
适合于口服的水溶液可通过在水中溶解本发明的化合物并根据需要加入适当的着色剂、调味剂、稳定剂和增稠剂来制备。适于口服使用的水性混悬剂可以利用以下材料通过在水中分散极细微活性成分制得:粘性材料,例如天然或合成的树胶、树脂、甲基纤维素、羧甲基纤维素钠、羟丙基甲基纤维素、海藻酸钠、聚乙烯吡咯烷酮、黄蓍树胶和阿拉伯树胶,以及分散或润湿剂,例如天然存在的磷脂(例如,卵磷脂)、环氧乙烷与脂肪酸(例如,聚氧乙烯硬脂酸酯)的缩合物,环氧乙烷与长链脂肪醇的缩合物(例如十七乙烯氧十六醇(heptadecaethylene oxycetanol)),环氧乙烷与衍生自脂肪酸和己糖醇的偏酯的缩合物(如,聚氧乙烯山梨糖醇单油酸酯),或者环氧乙烷与来自脂肪酸和己糖醇酐的偏酯(例如,聚氧乙烯山梨糖醇酐单油酸酯)的缩合物。所述水性悬液也可以包含一种或多种防腐剂,例如乙基或正丙基对羟基苯甲酸,一种或多种着色剂,一种或多种调味剂和一种或多种甜味剂,例如蔗糖、阿斯巴甜或糖精。可调节制剂的摩尔渗透压浓度。
还包括固体形式制剂,在使用之前不久可被转化成液体制剂形式以便口服给药。这样的液体形式包括溶液、悬浮液和乳液。这些制剂可以含有除了活性成分之外的着色剂、调味剂、稳定剂、缓冲剂、人工和天然甜味剂、分散剂、增稠剂、增溶剂,等等。
在另一实施例中,本发明的组合物可以配制用于胃肠外给药,如静脉内(IV)给药或施用到体腔内或器官内腔。用于给药的制剂通常包含本发明组分溶解于药学上可接受的载体中的溶液。可接受的载体和可以使用的溶剂为水和林格氏溶液,一种等渗氯化钠溶液。此外,无菌的不挥发油可常规地用作溶剂或悬浮介质。为此,可以使用任何温和的固定油,包括合成的单甘油酯或二甘油酯。此外,脂肪酸(如油酸)同样地可用于制备注射剂。这些溶液是无菌的,并且通常没有不合需要的物质。这些制剂可以通过常规的、众所周知的灭菌技术进行灭菌。该制剂可含有所需的药学上可接受的辅助物质以接近生理条件,如pH调节剂和缓冲剂、毒性调节剂,例如乙酸钠、氯化钠、氯化钾、氯化钙、乳酸钠等等。这些制剂中的本发明组分浓度范围可以极为不同,主要基于流体体积、粘度、体重等等进行选择,与所选的特定给药方式和病人需求相一致。对于静脉内给药,所述制剂可以是无菌注射制剂,如无菌注射水性或油性悬浮液。这种悬浮液可以根据已知技术使用适当的分散或润湿剂和悬浮剂来配制。无菌可注射制剂还可以是在无毒非肠道稀释剂或溶剂中的无菌注射溶液或悬浮液,例如1,3-丁二醇溶液。
在另一实施例中,本发明的组合物的制剂可通过使用与细胞膜融合或被内吞的脂质体来递送,即,通过采用附着于脂质体的配体或直接附着于寡核苷酸,结合细胞表面膜蛋白受体从而产生内吞作用。通过使用脂质体,特别是脂质体表面携带靶细胞的特异性配体,或者以其他方式优先指向特定器官时,可以在体内将本发明组合物集中递送至靶细胞。(参见:例如Al-Muhammed,J.Microencapsul.13:293-306,1996;Chonn,Curr.Opin.Biotechnol.6:698-708,1995;Ostro,Am.J.Hosp.Pharm.46:1576-1587,1989)
VII.给药
本发明的组合物可通过任何适当的方式,包括口服、非肠道和局部给药的方法来递送。通过局部途径的经皮给药方法,可以配制成敷药棒、溶液、悬浮液、乳液、凝胶、霜剂,软膏剂、糊剂、胶冻剂、涂料、粉末和气雾剂。
所述药物制剂优选为单位剂型。以这种形式,所述制剂又细分为含有适量的本发明化合物的单位剂量。所述单位剂型可以是包装制剂、含有离散量的制剂(如包装的片剂)、胶囊和小瓶或安瓿中的粉剂。此外,单位剂量形式可以是胶囊、片剂、扁囊剂或锭剂本身,或者可以是任何这些包装形式的适宜数目。
本发明所述化合物可以任何适当的量存在,根据不同的因素,包括但不限于对象的体重及年龄、疾病状态等。本发明化合物的适当剂量范围包括从约0.1mg到约10000mg,或约1mg至约1000mg,或约10mg至约750mg,或约25mg至约500mg,或约50mg至约250mg。本发明化合物的适当剂量包括约1mg、5、10、20、30、40、50、60、70、80、90、100、200、300、400、500、600、700、800、900或1000mg。
本发明的化合物可以任何适当的频率、间隔和持续时间给药。例如,为了提供更佳的剂量水平,本发明的化合物给药可每小时一次,或每小时两次、三次或多次、每天一次、或每天两次、三次或多次,或每2、3、4、5、6、7天一次。若本发明化合物给药每天超过一次,代表性的间隔包括5、10、15、20、30、45和60分钟,也包括1、2、4、6、8、10、12、16、20和24小时。本发明化合物也可在1小时、1至6小时、1至12小时、1至24小时、6至12小时、12至24小时、每一天、1至7天、每一周、1至4周、每一月、1至12个月、一年或更多给予一次、两次或三次或过多次,或者甚至无定期地进行给药。
本发明的化合物可以与另一种活性剂共同施用。共同施用包括彼此在0.5、1、2、4、6、8、10、12、16、20或24小时内施用本发明化合物和活性剂。共同施用还包括同时地、大致同时地(例如,彼此在约1、5、10、15、20或30分钟)或以任何顺序连续地施用本发明化合物和活性剂。此外,本发明的化合物和活性剂可以各自每天一次、或两次、或三次或更多次给药,以提供每天较佳的剂量水平。
在一些实施例中,共同施药可以通过共制剂完成,即,制备包含本发明化合物和活性剂的一种单独的药物组合物。在其他实施例中,本发明的化合物和活性剂可以分开配制。
本发明化合物和活性剂可在本发明组合物中以任何适当的重量比存在,例如从约1:100至约100:1(w/w),或约1:50至约50:1,或约1:25至约25:1,或约1:10至约10:1,或约1:5至约5:1(w/w)。本发明的化合物和另一种活性剂可以任何适当的重量比存在,例如约1:100(w/w)、1:50、1:25、1:10、1:5、1:4、1:3、1:2、1:1、2:1、3:1、4:1、5:1、10:1、25:1、50:1或100:1(w/w)。本发明化合物和活性剂的其他剂量以及剂量比在本发明组合物和方法中也是适宜的。
VIII.实施例
除非另有说明,所有试剂和NMR溶剂均购自西格玛奥德里奇公司-Sigma-Aldrich(圣路易斯,密苏里州)。化合物2来自虹膜生物技术(Iris Biotech)(马克特雷德维茨,德国),而化合物8购自Polypure(奥斯陆,挪威)。DOTA-NHS酯来自Macrocyclics(达拉斯,德克萨斯州)。硅胶购自Silicycle(魁北克,加拿大),预制TLC平板(20x 20cm;1000m厚度)购自Analtech(纽瓦克,德国)。超纯海藻盐购自ProNova生物医学(挪威)。[111In]氯化铟溶液购自珀金埃尔默公司-PerkinElmer(沃尔瑟姆,美国)。[64Cu]稀释HCl中的氯化铜购自华盛顿大学(圣路易斯,密苏里州)或通过64Ni(p,n)64Cu核反应,使用11MeV西门子RDS 111回旋加速器,通过离子交换色谱提纯(Biorad AG 1-X8)来内部自产。杜氏磷酸盐缓冲液(DPBS)购自英杰公司(Invitrogen Corporation)(卡尔斯巴德,加州)。
NMR实验在CDCl3或[D6]DMSO中进行,使用Varian400MHz的VNMRS仪器。在波士顿大学化工仪表中心(Boston University Chemical Instrumentation Center)使用安捷伦离子捕集器LC/MSD SL以正离子模式或负离子模式获得高分辨率ESI质谱数据。在有机合成阶段,装备有Waters XBridge C18柱(19x250mm)的安捷伦1100系列系统施加含0.1%TFA的用于高效液相色谱纯化的一个梯度的水和乙腈。
在放射化学中以及体内分析和提纯中,反相高效液相色谱用Beckman-Colter系统金128(布雷亚,加州)色谱系统检测,该系统配备有Jupiter Proteo C-12柱(250×4.6mm,4μm,菲罗门,托伦斯,加州)和单波长或二极管阵列UV检测器(设置为220&254nm),串联连接到Bioscan FlowCount光电倍增管(PMT)(Bioscan,华盛顿,哥伦比亚特区)。使用32Karat程序包(Beckman-Colter)分析数据。除非另作说明,流动相由溶剂A:0.05%三氟乙酸(水中)和溶剂B:100%乙腈组成,流速为1.5mL/min,注射之后2min出现线性梯度,随后在超过30min时间内,从9%的溶剂B增至81%。
在使用藻酸盐凝胶的体外试验期间,在带有Waters 2487双吸光度检测器(220&320nm)和Bioscan流计数辐射探测器的Waters Breeze柱层分析仪上进行分子筛高效液相色谱(高效液相色谱)。在等度0.1M磷酸钠中,pH6.8下,以1.0mL/min洗脱菲罗门BioSepSEC-S3000柱(7.8x 300mm)。
64Cu和111In标记的收率通过薄层放射性扫描仪radio-TLC确定,使用快速薄层层析法-SG带(珀尔生命科学,安拉伯,密歇根州),用200mM EDTA 0.9%氯化钠水溶液洗脱,并且使用Bioscan 200成像扫描仪进行。在这些条件下,游离的放射性核素以Rf=0.9移动,并且附属于四嗪6的放射性核素保持在原点。
PET/CT数据使用Inveon临床影像仪(西门子医疗保健公司)。
动物处理:所有动物依照加利福尼亚大学,戴维斯分校,动物使用和照料委员会(Animal Use and Care Committee)通过的准则进行。
统计分析:群体变异描述为平均值±1标准偏差。采用双尾未配对t测试比较单个组。P<0.05的组认为是显著不同的。所有的统计计算采用Microsoft Excel12.8.9版本。
实施例1 四嗪修饰诊断剂(5)
叔丁基(37,41-二氧-41-((6-(6-(吡啶-2-基)-1,2,4,5-四嗪-3-基)吡啶-3-基)氨基)-3,6,9,12,15,18,21,24,27,30,33-十一氧杂(undecaoxa)-36-氮杂四十一烷基)氨基甲酸酯(3)
将2(0.39g,0.61mmol)溶解在DMF(15mL)中。向2在DMF的搅拌溶液中加入1(0.20g,0.55mmol)、苯并三唑-1-基氧基三(二甲基(Demethyl)氨基)磷鎓六氟磷酸盐(BOP)(0.25g,0.55mmol)和三乙胺(0.55g,5.5mmol)。反应混合物在室温,氮气气氛下搅拌18h。低真空下除去溶剂,题述产品通过重力硅胶柱,使用CH2Cl2(0-10%)中的甲醇梯度进行提纯,收率=0.40g(74%)。NMR光谱与之前发表的内容相符(Rossin,R.;Verkerk,P.R.;van den Bosch,S.M.;Vulders,R.C.M.;Verel,I.;Lub,J.;Robillard,M.S.Angew.Chem.Int.Ed.2010,49,3375.Mooney,1999)。
N1-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-氨基乙氧基)乙氧基)乙氧基)乙氧基)乙氧基)乙氧基)乙氧基)乙氧基)乙氧基)乙氧基)乙氧基)乙基)-N5-(6-(6-(吡啶-2-基)-1,2,4,5-四嗪-3-基)吡啶-3-基)戊二酰胺(4).
将化合物3溶解在CH2Cl2:TFA(10mL)的5:1混合物中,在室温下搅拌2小时。溶液从粉红色转变为深红色。除去溶剂,将产品与MeOH(2x20mL)共沸。粗产品不经进一步提纯留待下一步处理。1H NMR(CDCl3)δ10.36(s,1H),9.37(s,1H),9.26(bs,1H),9.01(s,1H),8.91(d,J=7.8Hz,1H),8.81(d,J=8.6Hz,1H),8.61(d,J=8.1Hz,1H),8.39(t,8.0Hz,1H),7.95(t,J=5.0Hz,1H),7.50(s,1H),6.94(bs,3H),3.72-3.08(m,35H),2.51(t,J=4.6Hz,2H),2.36(t,J=6.0Hz,2H),1.99(t,J=6.7Hz,2H),1.26(t,J=7.3Hz,7H).
13C NMR(CDCl3)δ175.27,173.06,161.32,161.17,159.42(q,J=39.5Hz,TFA),147.52,145.94,142.85,140.89,139.13,138.48,130.81,128.95,126.65,125.97,115.2(q,J=287.5Hz,TFA),70.13,70.09,70.05,69.98,69.92,69.88,69.77,69.72,69.66,69.55,69.49,69.38,69.35,69.26,68.82,66.52,46.59,39.61,35.63,34.67,29.59,21.21,8.38.
HRMS:C41H66N9O13[M+H2O]计算值.892.4702(不同于数据中所列值),实验值892.4739。
2,2',2”-(10-(2,40,44-三氧-44-((6-(6-(吡啶-2-基)-1,2,4,5-四嗪-3-基)吡啶-3-基)氨基)-6,9,12,15,18,21,24,27,30,33,36-十一氧杂-3,39-二氮杂四十四烷基)-1,4,7,10-四氮杂环十二烷-1,4,7-取代基)三醋酸(5).
将DOTA-NHS酯(100mg,0.131mmol)加入4(129mg,0.131mmol)和三乙胺(179L,1.31mmol)在DMF(5mL)中的溶液中。反应混合物在室温下搅拌4小时。减压条件下除去溶剂。粗产物溶解于水中,含0.1%TFA(2mL),通过0.45μm聚偏氟乙烯膜(PVDF)过滤。使用H2O(0.1%TFA)和CH3CN(0.1%TFA)的梯度,通过制备型HPLC提纯题述产物。产率78mg(47%)。NMR光谱与之前发表的内容相符(Rossin,R.;Verkerk,P.R.;van den Bosch,S.M.;Vulders,R.C.M.;Verel,I.;Lub,J.;Robillard,M.S.Angew.Chem.Int.Ed.2010,49,3375.Mooney,1999)。
HRMS:C57H91N13O20计算值.1278.6503,实验值1278.6580。
实施例2 TCO偶联物的制备
4-(((S,E)-环辛-4-烯基氧基)甲基)-(N-(9H-芴-9-基)氨基甲酸甲酯)-N-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-氨基乙氧基)乙氧基)乙氧基)乙氧基)乙氧基)乙氧基)-乙氧基)乙氧基)乙氧基)乙氧基)乙氧基)乙基)苯甲酰胺(8).
在100mL圆底烧瓶中,在CH2Cl2(10mL)中溶解化合物7(0.15g,0.58mmol)。加入7(0.50g,0.58mmol)的CH2Cl2(10mL)溶液,随后加入三乙胺(0.3mL,2.3mmol)。反应混合物在氮气气氛中室温下搅拌18h。随后除去溶剂,使用1:20MeOH:CH2Cl2溶液作为洗脱液,通过重力硅胶柱将题述产物提纯。收率=0.19g(33%)。
1H NMR(CDCl3)δ7.75(t,J=7.9Hz,2H),7.68(d,J=7.4Hz,2H),7.54(d,J=7.3Hz,2H),7.34(d,J=7.8Hz,2H),7.30(d,J=7.7Hz,2H),7.23(t,J=7.4Hz,2H),5.65-5.39(m,2H),4.43(dd,J1=14.4Hz,J2=5.2Hz,2H),4.32(d,J=6.8Hz,2H),4.14(t,J=6.9Hz,1H),3.59-3.34(m,48H),2.33-1.21(m,10H).
13C NMR(CDCl3)δ167.33,156.25,143.90,142.96,141.18,135.78,133.26,131.20,127.54,127.04,126.93,126.64,125.01,119.83,74.14,70.40,70.25,69.81,66.43,50.56,47.25,40.08,39.68,34.47,32.81,29.78,27.56.
4-(((S,Z)-环辛-4-烯基氧基)甲基)-N-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-氨基乙氧基)乙氧基)乙氧基)乙氧基)乙氧基)乙氧基)乙氧基)乙氧基)乙氧基)乙氧基)乙氧基)乙烷)苯甲酰胺(9).
向8(193mg,0.19mmol)的CH2Cl2(10mL)溶液中逐滴地加入哌啶(2.5mL)。所得溶液在室温下搅拌4h。除去溶剂,使用1:10MeOH:CH2Cl2溶液作为洗脱液,通过重力硅胶柱将题述产物提纯。收率=86mg(57%)。
1H NMR(CDCl3)7.73(t,J=7.9Hz,2H),7.36-7.28(m,2H),6.96(bd,J=7.5Hz,1H),5.65-5.40(m,2H),5.30-5.26(m,1H),4.54-4.33(m,3H),3.60-3.36(m,48H),3.06-2.99(m,1H),2.40-1.44(m,10H).
HRMS:C40H70N2O13计算值.787.4878,实验值787.4938。
实施例3 使用9进行藻酸盐化学修饰
所有研究中都采用MVG藻酸盐,一种高含G的藻酸盐(由制造商指定的40:60的M:G比例)。采用以前所述的碳化二亚胺化学方法,用反式环辛烯9修饰高M-和高G-含量的藻酸盐中的羧酸。所有反应均在25mL 0.1M的2-(N-吗啉基)乙磺酸(MES)缓冲液中进行,该缓冲液含0.3M NaCl,pH为6.5,含250mg藻酸盐,浓度为1%(w/v)。向藻酸盐中加入12.1mg(0.063mmol)的1-乙基-3-(3-二甲基氨丙基)碳化二亚胺(EDC)以激活沿聚合物链的羧酸,EDC与藻酸盐的糖醛酸单体的摩尔比为1:20。将6.9mg(0.032)的N-羟基硫代丁二酰亚胺(硫代-NHS)作为共反应剂加入,其与EDC的摩尔比为1:2。将胺9(10mg,0.013mmol)加入到1mLMES缓冲液的反应中,并且允许藻酸盐反应20h。修饰后的藻酸盐用广泛透析(MWCO 3500)提纯超过5天。然后将藻酸盐从透析管中除去,并用0.22μm的密理博(Millipore)无菌过滤器过滤至25mL锥形瓶中。然后,将其置于冰箱冷藏1小时,然后-20℃冷冻2小时,最后-80℃冷冻过夜以冻结藻酸盐。然后将样品放置在冻干器中直至完全干燥(5-10天),之后在-80℃下储存直至需要时。
准备使用时,用含0.25%(w/v)PBS的ddH2O稀释钙交联的藻酸盐水凝胶到2.5%(v/v)藻酸盐溶液。制备浓度为0.21g CaSO4/ml ddH2O的无菌过饱和硫酸钙溶液。每10ml的2.0%藻酸盐溶液加入约0.4ml的悬浮液。
对于体内应用,上述的藻酸盐凝胶溶液和过饱和硫酸钙溶液通过双阴连接器(double female connector)在注射器中迅速混合,并且迅速注射入动物体内。
对于体外实验,上述的藻酸盐凝胶溶液和过饱和硫酸钙溶液通过双阴连接器在注射器中迅速混合。然后将2%藻酸盐胶凝溶液浇筑在2mm间隔的平行玻璃板之间,以制备凝胶薄膜。使用打孔机(McMaster-Carr,芝加哥,伊利诺州)从膜上冲下水凝胶圆片。
完全相同的方法用于离子键合基团,除了反式环辛烯9不与EDC和硫代-NHS一起添加,而在稍后步骤与过饱和硫酸钙溶液添加。对于对照组,整个过程在任何一步都不添加反式环辛烯9。
实施例4.体外实验
四嗪铜放射性标记。0.1M乙酸铵缓冲液(pH 7,50-100μL)稀释64Cu-氯化物(5-10μL在0.5M HCl中)。DOTA-偶联四嗪(5)溶解在0.1M乙酸铵中,pH为7.0。5的等分试样与适当量的[64Cu]铜氯化物混合,并且在室温下轻微搅拌温育10min。通过放射性TLC监测放射性核素的完全掺入。HPLC提纯和轻微加热蒸发溶剂之后,64Cu-四嗪5的放射化学纯度由放射性-HPLC监测。
对于动物实验,64Cu-四嗪溶液用无菌盐水稀释。用于体内实验的64Cu-四嗪5溶液的比活度典型地为3.3MCi/g。
实施例5.四嗪铟放射性标记
111铟-氯化物(5-10μL在0.5M HCl)用0.1M乙酸铵缓冲液稀释(pH 7,50-100μL)。DOTA偶联的四嗪(5)(1.28mg/mL)溶解在0.1M乙酸铵中,pH为7.0。5的等分试样与适当量的[111In]铟氯化物混合,并且在37℃下轻微搅拌温育10min。通过放射性TLC监测放射性核素的完全掺入。HPLC提纯和轻微加热蒸发溶剂之后,111In-四嗪5的放射化学纯度由放射性-HPLC监测。
对于动物实验,111In-四嗪溶液用无菌盐水稀释。用于体内实验的111In-四嗪5溶液的比活度典型地为18Ci/g。
实施例6.体外反应
尺寸排阻HPLC。使用放射性标记的四嗪5作为代用指标定量测定化合物9对藻酸盐骨架的掺入情况。简言之,将2%的藻酸盐凝胶溶液与已知量的测定了比活性的四嗪放射性核素混合。通过尺寸排阻HPLC测定凝胶中放射活性的掺入量,凭借尺寸排阻HPLC较大的化合物(藻酸盐凝胶)比较小的化合物更早洗脱。
圆盘.藻酸盐-TCO的反应性在PBS和小鼠血清中进行检测。通常地,大约重25μg的预制圆盘放置于测试试管中。作为对照组,使用TCO未作处理的藻酸盐圆盘。所述圆盘加入到含已知量的标记有放射性核素(64Cu-四嗪5或111In-四嗪5)的化合物10的盐水或血清溶液中。使用Wallac 1470Wizard gamma计数器(珀金埃尔默公司-PerkinElmer,Inc)测量放射性。然后洗涤圆盘,用250μL盐水涡流三次,再次检测放射性。
实施例7.体内研究
生物分布实验。进行了两组生物分布研究。第一组采用64Cu-四嗪5,在所有扫描完成之后26小时进行。第二组生物分布研究采用111In-四嗪5,在皮下注射藻酸盐凝胶之后3小时进行,随后静脉内注射四嗪5。
通过颈脱位法处死小鼠。取得感兴趣的器官和体液,如尿液、血液、胆囊、肝脏、心脏、肾脏、胰腺、脾、肺、胃、小肠、大肠、膀胱、皮肤、肌肉、骨骼、尾、脑以及实验组(凝胶,TCO凝胶,STCO+凝胶),所有的都经去离子水洗涤以除去过量的血液,并称重。使用Wallac1470Wizard gamma计数器(珀金埃尔默公司)测定放射性。放射性吸收以每克注射剂量的百分比(%ID/g)表示。所有值修正为同位素衰变值。
实施例8.成像实验
小鼠在皮下部位(右肩或左肩)接受藻酸盐实验组(对照,TCO-凝胶,STCO+凝胶)之一的注射。大约两小时后,小鼠接受64Cu-四嗪5的尾静脉注射(0.09–0.21mCi)。在四嗪5注射一小时后,用1%-2%的异氟烷麻醉小鼠,并通过PET扫描30分钟,然后采集CT图像。收集15或30分钟的静态图像,用Inveon研究工作站软件(西门子医疗保健公司,孟菲斯,田纳西州)配准。在初始注射藻酸盐之后的第6、14和26小时时重复该过程。重建PET图像。使用Inveon研究工作站分析小动物PET图像。使用CT分析指南从PET图像中选择感兴趣的区域,并且,用Inveon研究工作站软件测量与这些区域相关的活性。
为了清楚理解,尽管前述发明已在一定程度上通过举例说明和实施例的方式详细描述,本领域技术人员应理解,在所附权利要求的范围内可实施某些变化和修改。此外,本文提供每篇参考文献通过整体引用的方式纳入本文,如同每篇参考文献单独纳入参考。本申请和本文所引用的存在冲突时,以本申请为准。
Claims (19)
1.一种与第一结合剂连接的可植入的生物相容的固体支持体的用途,用于生产用于选择性递送有效量的治疗剂或诊断剂至患者体内靶器官或组织的药物,其中:
(a)所述可植入的生物相容的固体支持体选自下组:多糖水凝胶、藻酸盐、纤维素、透明质酸、脱乙酰壳多糖、壳多糖、硫酸软骨素、肝素、交联的聚合物基质、金属、陶瓷和塑料;和
(b)在靶器官或组织中植入与第一结合剂连接的可植入的生物相容的固体支持体且施用连接在第二结合剂的治疗剂或诊断剂,使得第一和第二结合剂发生生物正交反应,其中,所述第一结合剂和第二结合剂各自独立地选自下组:反式环辛烯和四嗪;所述生物正交反应是反式环辛烯和四嗪之间的反应,从而有选择性地递送有效量的所述治疗剂或诊断剂至患者体内靶器官或组织。
2.如权利要求1所述的用途,其中所述可植入的生物相容的固体支持体包含水凝胶。
3.如权利要求1所述的用途,其中所述可植入的生物相容的固体支持体包含藻酸盐。
4.如权利要求1所述的用途,其中所述第一和第二结合剂各自独立地选自下组:反式环辛烯和四嗪。
5.如权利要求1所述的用途,其中所述第一和第二结合剂各自独立地选自下组:反式环辛烯和1,2,4,5-四嗪,从而使得结合剂之一为反式环辛烯,并且另一种为1,2,4,5-四嗪。
6.如权利要求1所述的用途,其中所述靶器官或组织为骨。
7.如权利要求1所述的用途,其中所述靶器官或组织的治疗剂或诊断剂浓度高于患者体内其他部位的浓度。
8.如权利要求1所述的用途,其中所述治疗剂为万古霉素。
9.连接在第一结合剂的治疗剂的用途,用于生产用于治疗患者疾病或病症的药物,其中,当所述第一结合剂接触连接在植入疾病或病症部位的可植入的生物相容的固体支持体的第二结合剂时,所述第一结合剂和第二结合剂彼此结合且发生生物正交反应,其中,所述生物正交反应是反式环辛烯和四嗪之间的反应,从而在疾病或病症部位形成给患者施用的来自更低总剂量的治疗有效量的治疗剂,其低于没有第二结合剂时在疾病或病症部位对患者施用的治疗有效量的治疗剂;且其中所述可植入的生物相容的固体支持体选自下组:多糖水凝胶、藻酸盐、纤维素、透明质酸、脱乙酰壳多糖、壳多糖、硫酸软骨素、肝素、交联的聚合物基质、金属、陶瓷和塑料。
10.如权利要求9所述的用途,所述疾病或病症为骨髓炎。
11.如权利要求9所述的用途,其中所述治疗剂为万古霉素。
12.一种组合物,包括可植入的生物相容的固体支持体和至少一种连接到所述生物相容的固体支持体上的结合剂;所述可植入的生物相容的固体支持体选自下组:多糖水凝胶、藻酸盐、纤维素、透明质酸、脱乙酰壳多糖、壳多糖、硫酸软骨素、肝素、交联的聚合物基质、金属、陶瓷和塑料;
其中,所述至少一种结合剂可与相应的结合剂进行生物正交反应,且所述生物正交反应是反式环辛烯和四嗪之间的反应。
13.如权利要求12所述的组合物,其中所述组合物进一步包括接头来共价连接各结合剂至生物相容的固体支持体。
14.如权利要求12所述的组合物,其中所述可植入的生物相容的固体支持体包含水凝胶。
15.如权利要求12所述的组合物,其中所述可植入的生物相容的固体支持体包含藻酸盐。
17.如权利要求12所述的组合物,其中所述可植入的生物相容的固体支持体包含透明质酸。
18.连接在第一结合剂的治疗剂或诊断剂的用途,用于生产用于选择性递送治疗剂或诊断剂至患者体内靶器官或组织的药物,其中,当所述第一结合剂接触连接在植入疾病或病症部位的可植入的生物相容的固体支持体的第二结合剂时,所述第一结合剂和第二结合剂彼此结合且发生生物正交反应,其中,所述生物正交反应是反式环辛烯和四嗪之间的反应,从而在患者中向靶器官或组织选择性递送治疗剂或诊断剂;其中所述可植入的生物相容的固体支持体选自下组:多糖水凝胶、藻酸盐、纤维素、透明质酸、脱乙酰壳多糖、壳多糖、硫酸软骨素、肝素、交联的聚合物基质、金属、陶瓷和塑料。
19.权利要求1、9或18所述的用途,其中所述可植入的生物相容的固体支持体包含透明质酸。
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CN105611914A (zh) | 2016-05-25 |
WO2014205126A1 (en) | 2014-12-24 |
EP3010486A4 (en) | 2017-01-04 |
JP2016522261A (ja) | 2016-07-28 |
JP6622192B2 (ja) | 2019-12-18 |
US10130711B2 (en) | 2018-11-20 |
US20190111140A1 (en) | 2019-04-18 |
US10953098B2 (en) | 2021-03-23 |
JP2019089794A (ja) | 2019-06-13 |
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