CN103619802B - 脂质模拟物化合物及其用途 - Google Patents
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- CN103619802B CN103619802B CN201280029374.5A CN201280029374A CN103619802B CN 103619802 B CN103619802 B CN 103619802B CN 201280029374 A CN201280029374 A CN 201280029374A CN 103619802 B CN103619802 B CN 103619802B
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Abstract
本发明公开了式I的脂质模拟物化合物,其中:G代表满足式II的基团:HO-CH2-{CH(OH)-CH2-O}m-CH2-{C(=O)-O-CH2}q-?式II,每个n独立地是1-30的整数;m是1-10的整数;q是0或1。这些化合物可被加入到热敏脂质体的脂质双层中,用于协助防止脂质体内容物在37℃时的泄露,并延缓从循环的清除。
Description
技术领域
本发明属于用于药物或诊断剂的靶向、局部递送的热敏载体的领域。本发明涉及脂质模拟物(lipidomimetic)化合物,且特别涉及适合温度响应性释放包含在其中的材料的载体,例如脂质体,以及涉及借助温度响应性释放载体的药物和/或成像剂的局部递送。
背景技术
许多主要位于某些组织的疾病是由系统施用的药物治疗的。非常熟知的标准癌症疗法的例子是系统化疗,其由于不期望的生物分布和毒性而伴随对于患者显著的副作用。这些药物的治疗窗通常一方面由患病组织中的最低要求治疗浓度限定,另一方面由非靶向器官例如肝、脾中的毒性作用限定。
与标准治疗相比,通过例如来自纳米载体的细胞抑制剂的局部释放的局部治疗有希望具有更加有效的治疗和更大的治疗窗。如果其它治疗选择例如手术过于风险,如对于肝癌这是经常的情况,局部药物递送也是重要的。局部药物递送对于心血管疾病(CVD)的许多适应证还能成为优选的治疗,所述适应症例如冠状动脉中的动脉粥样硬化。
例如磁共振成像(MRI)或超声成像,医疗成像技术不仅能用于治疗规划,还能用于在图像引导下控制局部药物递送。聚焦超声是用于诱导局部药物递送的所选方法,因为它提供多个优点。这个技术是非侵入性的,可聚焦患病组织,并对周围组织仅显示非常有限的副作用。超声可对药物递送提供两种触发。首先,目标组织可以在从体温至100℃的温度范围内以约半摄氏度的精确度被控制的方式被加热。其次,超声波是基于机械力为药物递送提供刺激的强压振荡。
在为例如药物或成像化合物的材料的释放提供载体系统方面,本领域技术人员面临数个挑战。这样,例如需要设计载体系统使其能负载充分量的所述材料。特别是如果待释放的材料包含药物,载体系统应对外界的刺激例如温度或压力的(局部)变化敏感,所述变化允许药物的快速和局部释放。此外,药物递送过程需要被置于完全的控制之下,即,治疗位置的药物释放必须是体内可测量的,药物释放的量和速率应该作为用于确定后续刺激应用的输入参数,从而可以在图像引导反馈环中控制药物递送。
通过借助外部刺激触发药物的释放,可获得脂质体药物疗法功效的显著改善。触发封装分子释放的一个方法是使用温度敏感脂质体。1.这种情况下,药物释放在脂质体膜的融化相转换温度(Tm)以上发生。在Tm,当脂质膜从胶样相变为液相时,脂质膜中发生结构变化。该转变导致膜对溶质和水的渗透性明显增加。在脂质体双层中引入卵磷脂例如溶血磷脂酰胆碱(lyso-PC)、乙酰化MPPC和血小板激活因子(PAF)已对脂质体的性质产生了影响。在1988年,Bratton等证实这些脂质能用于降低基于二棕榈酰磷脂酰胆碱(DPPC)的脂质体的Tm。2.Needham等已设计了由lyso-PC/DPPC/DPPE-PEG2000组成的低温敏感脂质体(LTSLs),其响应轻度超热条件(39-42℃)在仅几秒钟内释放封装阿霉素()。3.在接近Tm的温度下,水性溶质从这些温度敏感系统内部的快速释放归因于短暂孔的形成。这些孔在胶束形成磷脂例如溶血磷脂酰胆碱和PEG化磷脂存在的情况下是热力学稳定的。此外,短暂孔的形成已被归因于脂质双层内通过侧向扩散的溶脂聚集。利用基于溶血磷脂酰胆碱(R=C15H31,图1)的负载阿霉素的LTSLs,并结合外部施加的局部温度增加的临床前试验,清楚地显示了温度诱导药物递送的改善功效。3、4不依赖于肿瘤中的脂质体聚集,在注射阿霉素的温度敏感脂质体制剂之后的头一个小时内,施加高热。该细胞抑制药物在肿瘤的微脉管系统内快速释放,并随后被肿瘤细胞吸收。尽管基于溶血磷脂酰胆碱的负载阿霉素的LTSLs结合基于针的RF消融已成功用于药物递送,脂质体制剂的稳定性在血浆中在37℃下不是最优的,显示1小时内最高达40%的阿霉素释放。
在针对受试者中治疗剂和/或诊断剂的局部递送的热敏载体领域,存在需要提供能够具有较长的循环时间、在正常体温(37℃)较少泄露它们的活性内容物且从系统较慢清除的载体。
解决前述需要的参考文献是LarsH.Lindner等的ClinicalCancerResearch,2004,Volume10,Issue6,pages2168-2178。在此脂质体基于除DPPC(1,2-二棕榈酰-sn-甘油基-3-磷脂酰胆碱)和DSPC(1,2-二硬脂酰-sn-甘油基-3-磷脂酰胆碱)之外的第三成分制备。所述第三成分是DPPGOG(1,2-二棕榈酰-sn-甘油基-3-磷脂酰甘油基甘油)。所获得的三成分脂质体表现出37℃下的较少泄露和从循环的较慢清除。
由Lindner等提供的方案得到结构上更复杂的脂质体,并且局限于磷脂。期望的是提供合成工具以获得热敏脂质体,所述脂质体在避免37℃泄露方面表现至少类似的性能,表现至少同等的缓慢清除,并且还基于较不复杂的脂质体结构。此外,期望的是提供合成工具,以提供展现比由Linder所公开的脂质体还要更慢的清除的热敏脂质体。
发明内容
为了更好地解决上述需要,一方面,本发明提供了式I化合物,
其中,G代表满足式II的基团:
HO-CH2-{CH(OH)-CH2-O}m-CH2-{C(=O)-O-CH2}q-式II
每个n独立地是1-30的整数;
m是1-10的整数;
q是0或1。
另一方面,本发明涉及包含围绕腔的脂质双层壳的热敏载体,其中所述脂质双层包含如上定义的一或多种化合物。
另一方面,本发明是如上定义的式I化合物的用途,作为热敏载体的脂质双层壳的添加物。
另一方面,热敏载体用于治疗剂或诊断剂的局部施用,所述载体包含围绕腔的脂质双层壳,所述壳和/或所述腔包含所述治疗剂或诊断剂,其中所述脂质双层包含如上定义的式I化合物。
在另一方面,本发明涉及任一上述载体用于其中含有的物质的体内释放,分别涉及包括将任一上述载体施用给动物,优选人,以及影响其中含有的物质的体内释放的治疗和成像方法。
附图说明
图1显示在磷脂双层中含有115,3(以下提及)和在水性内腔中含有阿霉素和[Gd(HPDO3A)(H2O)]的热敏脂质体的CryoTEM图像。
图2提供显示阿霉素在含有115,3的TSL的内腔中随时间封装的图表。
图3是在37℃和42℃在50%胎牛血清(FBS)中含有115,3的TSL的图表,显示在升高温度下的阿霉素释放。
图4显示在从25℃到55℃的线性温度升高(升温斜率0.5℃/分钟)期间,在50%胎牛血清中含有115,3的TSL的荧光。
具体实施方式
应理解本发明不限于上文所述的实施方式和配方。还应理解在权利要求中,“包含”不排除其它的成分或步骤。当涉及单数名词,例如a或an(一)、“该/所述”时,使用不定冠词或定冠词的情况下,除非明确指明其它情况,这包括所述名词的复数。
本发明涉及包含磷脂双层壳的载体。特别地,所述壳围绕腔并且是半渗透性的,典型地包含磷脂。所述载体包括微载体,其具有数至数十微米直径等级的粒子尺寸,以及纳米载体,其具有数十至数百纳米等级的粒子尺寸。在本发明上下文中,下文的载体被称之为脂质体。
脂质体通常是含有围绕腔或内腔的双层膜的圆形囊泡。所述双层可由至少一种磷脂构成,可含有或可不含有胆固醇。脂质体可由自然衍生的具有混合脂链(像卵磷脂酰乙醇胺)的磷脂或纯的表面活性剂成分像二油酰磷脂酰乙醇胺(DOPE)组成。如在本发明说明书中所用,术语脂质体包括通常表示为胶束的脂质球体。
典型的半渗透性壳的例子也见于包含磷脂双层的半渗透性膜。磷脂双层对于小的非荷电溶质是渗透性最强的。可基于磷脂双层制备脂质体。
在广义上,本发明基于审慎的领悟,以提供可独立地并入在脂双层中的脂质模拟物化合物,而不是成为脂质体脂双层的组成性部分的另一种磷脂成分。该化合物特别地可混入热敏载体例如热敏脂质体的脂双层中,具有延长载体的循环时间的效果。
脂质模拟物化合物
本发明一方面涉及脂质模拟物化合物本身。这些化合物满足以上式(I)。优选地,化合物选自由下式III、式IV及其组合组成的组。
在此,整数m和n具有上述含义。优选地,m是2-6,更优选2-4以及最优选2或3。优选每个n独立地是8-24,更优选每个n独立地是12-18,以及最优选每个n独立地是13、15或17。
在优选实施方式中,化合物满足下式V,
其中,G具有上述含义,并且r和s每个独立地是1-30的整数,并且(r-s)的差相对比较小,即,低于10,优选0-5,更优选1-3。
本发明化合物可引入到热敏载体的脂质双层。它们通常通过将其混合到制备载体的脂质中而被引入。它们优选以脂质双层的5到50的摩尔百分比存在,优选10-30%。
在热敏脂质体的磷脂双层中引入本发明的脂质模拟物化合物允许在预定义温度下,药物的快速和定量释放。这种温度诱导的转换还可用于在加热时释放所引入的成像探针(例如T1、T2、CESTMRI造影剂)。此外,脂质模拟物的引入可用于调整跨膜水交换率,以最大化体温和高热之间的MR造影增强,这在MR成像引导的药物递送领域是重要的。进一步,脂质模拟物不展示电荷,这将积极地影响脂质体的电动电位,由此电动电位比在Linder等中包含磷酸基团的脂质情况下负电性更少。
所得到的脂质体能够显示如上述基于DPPGOG的脂质体相似长或甚至更长的循环行为。
磷脂
优选的脂质双层(其一般可由脂质构成)基于磷脂。
磷脂已知且通常是指磷脂酰胆碱、磷脂酰乙醇胺、磷脂酰丝氨酸和磷脂酰肌醇。在本发明中,优先使用磷脂酰胆碱。
热敏载体
本发明涉及热敏的载体。这意味着载体的物理或化学状态依赖于其温度。
可使用能包装目标分子、在体温(即37℃)下完整、但在任何其非体温温度下被破坏,能被受试者耐受的任何热敏载体。本发明载体包括但不限于热敏微粒子和纳米粒子、热敏聚合物囊泡、热敏脂质体、热敏纳米囊泡和热敏纳米球体。
热敏纳米囊泡通常具有最高达100nm的直径。在本发明上下文中,大于100nm,典型地达5000nm的囊泡被认为是微囊泡。该术语囊泡描述任何类型的微囊泡或纳米囊泡。囊泡,例如脂质体囊泡,典型地包括可含有任何目标物质的腔。在本发明中,如上概述,这是优选的。
热敏聚合物囊泡包括但不限于任何聚合物囊泡,包括微囊泡和纳米囊泡。
热敏囊泡包括但不限于任何脂质体,包括具有延长的半衰期的那些,例如PEG化的脂质体。
用于本发明的热敏脂质体理想地在约37℃,即人体温度下,保持其结构,但在更高温度下被破坏,优选仅稍微高于人体温度,还优选高于热病的体温。典型地约42℃是对于热引导地药物递送的高度有用的温度。
可使用使热敏药物载体的温度升高由此促进热敏载体破坏的所需要的温度。可以任何生理学可接受的方式施加热,优选通过使用能够诱导高度局部化高热的聚焦能量源。可通过例如微波、超声、磁诱导、红外线能量或光能来提供能量。
本领域已知热敏脂质体。根据本发明的脂质体可由本领域已知的多种技术制备。参见例如美国专利No.4,235,871;公开的PCT申请WO96/14057;NewRRC,Liposomes:Apracticalapproach,IRLPress,Oxford(1990),pages33-104;Lasic,D.D.,Liposomesfromphysicstoapplications,ElsevierSciencePublishers,Amsterdam,1993;Liposomes,MarcelDekker,Inc.,NewYork(1983)。
还可使用本领域任何传统方法,将药物或其它物质截留在本发明的脂质体内。在制备本发明的脂质体组合物中,可使用稳定剂例如抗氧化剂和其它添加剂,只要它们基本上不影响本发明的目的。
药物载体
一方面,本发明涉及适用生物学活性剂例如药物的局部递送的载体。下文中,术语“生物学活性剂”将简称为“药物”,且载体被称为“药物载体”。在本发明上下文中,药物载体指在其中或其上可包含由此能够在受试者体内释放的生物活性剂的任何材料。
药物载体将会被引入待接受MRI的人的体内。这会例如通过注射入血流,或通过其它方法以将载体引入体液。
药物是在疾病或失调的治疗、治愈、预防或诊断中使用的化学物质,或用来以其它方式增强身体或精神健康。本发明所预见的引导递送将主要是有用的治疗剂(即严格意义上的药物,用于疾病或失调的治疗或预防),但也用于出于诊断目的施用的试剂。尽管其它生物活性剂,即非治疗剂或诊断剂的那些,例如功能性食品成分,一般不会进行引导和/或监测递送,但如果需要,可使用本发明进行这些。
本发明的最佳应用在靶向治疗剂(即意用于靶向递送的药物)的情况下实现,因为这种递送在本质上最得益于可由本发明获得的监测。这涉及例如待原位递送的肿瘤治疗中的试剂、心血管疾病(例如冠状动脉中动脉粥样硬化)的治疗和预防中的试剂、或抗血栓试剂(例如用于局部溶解血凝块)或需要穿过血脑屏障的试剂,例如可用于神经病症例如癫痫、阿尔茨海默病、帕金森病或中风的治疗中的神经调质。来自靶向药物递送的引导和监测的益处也可用于靶向诊断剂。类似于靶向治疗剂,在此癌症也是位点特异性递送可具有重要性的领域。
适合在本发明中使用的生物活性剂包括生物学活性剂,包括治疗药物、内源分子和生理学活性剂,包括抗体;营养分子;美容剂;诊断剂;和用于成像的额外造影剂。如本文所用,活性剂包括活性剂的生理学可接受的盐。
本发明药物载体可包含亲水性生活活性剂或疏水性生物活性剂。亲水性生物活性剂可被封装在载体的水性隔室中,而疏水生物活性剂可引入到载体的疏水域,例如在脂质体的脂双层中。核酸、碳水化合物和一般的蛋白和多肽是水溶性的或亲水性的。例如,也可预期小分子、脂质、脂多糖、多核苷酸和反义核苷酸(基因治疗剂)的生物活性剂。因此,可引入的此类生物学活性剂包括非肽、非蛋白药物。在本发明范围内,可引入聚合物性质的药物,也引入相对小分子量的小于1500g/mol、甚至小于500g/mol的药物。
因此,预期在本发明中用作生物活性剂的化合物包括具有治疗或预防效果的任何化合物。它可以是影响或参与组织生长、细胞生长、细胞分化的化合物,能够引起生物反应例如免疫反应的化合物,或能在一或多个生物过程中起任何其他作用的化合物。实例的非限定目录包括抗微生物剂(包括抗细菌剂、抗病毒剂和抗真菌剂)、抗病毒剂、抗肿瘤剂、凝血酶抑制剂、抗血栓形成剂、溶栓剂、纤维蛋白溶解剂、血管痉挛抑制剂、钙通道阻断剂、血管扩张剂、抗高血压药、抗微生物剂、抗生素、表面糖蛋白受体抑制剂、抗血小板药、抗有丝分裂剂、微管抑制剂、抗分泌剂、肌动蛋白抑制剂、重建抑制剂、抗代谢剂、抗增殖剂(包括抗血管生成剂)、抗癌化疗剂、抗炎甾族化合物或非甾族抗炎剂、免疫抑制剂、生长激素拮抗剂、生长因子、多巴胺激动剂、放疗剂、细胞外基质成分、ACE抑制剂、自由基清除剂、螯合剂、抗氧化剂、抗聚合酶剂和光动力治疗剂。
相对小的肽可由氨基酸数目指示(例如二肽、三肽或四肽)。具有相对少数量的酰胺键的肽也可被称为寡肽(最多50个氨基酸),而具有相对多数量的肽(多于50个氨基酸)可被称为多肽或肽。除了作为氨基酸残基的聚合物,某些蛋白可进一步由所谓的四级结构表征,四级结构是不一定由酰胺键化学连接但是由技术人员通常已知的力(例如静电力和范德华力)结合的一些多肽的聚集物(conglomerate)。如本文所用的术语肽、蛋白或其混合物意包括所有上述的可能性。
通常,基于其生物学活性选择蛋白和/或肽。取决于所选聚合物的类型,由本发明方法获得的产品高度适合蛋白和肽的控制释放。在具体实施方式中,所述蛋白或肽是生长因子。
可有利地包含在负载聚合物中的肽或蛋白或包含肽或蛋白的实体的其它实例包括但不限于免疫原性肽或免疫原性蛋白,其包括但不限于以下各项:
毒素,例如白喉毒素和破伤风毒素。
病毒表面抗原或病毒的部分,所述病毒例如腺病毒、EB病毒、甲肝病毒、乙肝病毒、疱疹病毒、HIV-1、HIV-2、HTLV-III、流感病毒、日本脑炎病毒、麻疹病毒、乳头瘤病毒、副粘病毒、脊髓灰质炎病毒、狂犬病病毒、风疹病毒、牛痘(天花)病毒和黄热病毒。
细菌表面抗原或细菌的部分,所述细菌例如百日咳杆菌(Bordetellapertussis)、幽门螺旋杆菌(Helicobacterpylori)、破伤风杆菌(Clostridiumtetani)、白喉棒状杆菌(Corynebacteriumdiphtheria)、大肠杆菌(Escherichiacoli)、流感嗜血杆菌(Haemophilusinfluenza)、克雷伯菌属(Klebsiellaspecies)、嗜肺军团菌(Legionellapneumophila)、牛分枝杆菌(Mycobacteriumbovis)、麻风分枝杆菌(Mycobacteriumleprae)、结核分枝杆菌(Mycrobacteriumtuberculosis)、淋球菌(Neisseriagonorrhoeae)、脑膜炎奈瑟菌(Neisseriameningitidis)、变形杆菌属(Proteusspecies)、绿脓杆菌(Pseudomonasaeruginosa)、沙门氏菌属(Salmonellaspecies)、志贺氏菌属(Shigellaspecies)、金黄色葡萄球菌(Staphylococcusaureus)、化脓性链球菌(Streptococcuspyogenes)、霍乱弧菌(Vibriocholera)和鼠疫杆菌(Yersiniapestis)。引起疾病的寄生虫表面蛋白或寄生虫的部分,所述寄生虫例如间日疟原虫(Plasmodiumvivax)(疟疾)、恶性疟原虫(Plasmodiumfalciparum)(疟疾)、卵形疟原虫(Plasmodiumovale)(疟疾)、三日疟原虫(Plasmodiummalariae)(疟疾)、热带利什曼原虫(Leishmaniatropica)(利什曼病)、杜氏利什曼原虫(Leishmaniadonovani),利什曼病)、巴西利什曼原虫(Leishmaniabranziliensis)(利什曼病)、罗德西亚锥虫(Trypanosomarhodescense)(昏睡病)、冈比亚锥虫病(Trypanosomagambiense)(昏睡病)、克氏锥虫(Trypanosomacruzi)(南美锥虫病)、曼式血吸虫(Schistosomamansoni)(血吸虫病)、埃及血吸虫(Schistosomomahaematobium)(血吸虫病)、日本血吸虫(Schistosomajaponicum)(血吸虫病)、旋毛虫(Trichinellaspiralis)(旋毛虫病)、十二指肠类圆线虫(Stronglyloidesduodenale)(钩虫)、十二指肠钩虫(Ancyclostomaduodenale)(钩虫)、美洲钩虫(Necatoramericanus)(钩虫)、班式丝虫(Wucheriabancrofti)(丝虫病)、马来丝虫(Brugiamalaya)(丝虫病)、罗阿丝虫(Loaloa)(丝虫病)、常现丝虫(Dipetalonemaperstaris)(丝虫病)、麦地那龙线虫(Dracunculamedinensis)(丝虫病)和盘尾丝虫(Onchocercavolvulus)(丝虫病)。
免疫球蛋白例如IgG、IgA、IgM、抗狂犬病免疫球蛋白和抗牛痘病毒免疫球蛋白。
抗毒素,例如肉毒抗毒素、白喉抗毒素、气性坏疽抗毒素、破伤风抗毒素。
引起抗口蹄疫免疫反应的抗原。
激素和生长因子,例如促滤泡激素、催乳素、血管生成素、表皮生长因子、降血钙素、促红细胞生成素、促甲状腺释放激素、胰岛素、生长激素、胰岛素样生长因子1和2、骨骼生长因子、人绒毛膜促性腺激素、黄体化激素、神经生长因子、促肾上腺皮质激素(ACTH)、黄体化激素释放激素(LHRH)、甲状旁腺素(PTH)、促甲状腺激素释放激素(TRH)、加压素、胆囊收缩素和促肾上腺皮质素释放激素;细胞因子,例如干扰素、白细胞介素、集落刺激因子、和肿瘤坏死因子:纤维蛋白溶酶,例如尿激酶、肾纤溶酶原激活物;和凝血因子,例如蛋白质C、因子VIII、因子IX、因子VII和抗凝血酶III。
其它蛋白和肽的实例是白蛋白、心钠素、肾素、过氧化物歧化酶、α1-抗胰蛋白酶、肺表面活性蛋白、杆菌肽素、苯丁抑制素、环孢霉素、δ促睡眠肽(DSIP)、内啡肽、胰高血糖素、短杆菌肽、黑素细胞抑制因子、神经降压素、催产素、生长抑素、壬肽抗压素、血清胸苷因子、胸腺素、DDAVP、皮啡肽、甲硫氨酸-脑啡肽、肽聚糖、满足素、胸腺五肽、纤维蛋白降解产物、des-脑啡肽-α-内啡肽、促性腺激素释放激素、亮丙瑞林、α-MSH和美克法胺。
抗肿瘤剂,例如六甲蜜胺、氟尿嘧啶、安吖啶、羟基脲、天冬酰胺酶、异环磷酰胺、博莱霉素、环己亚硝脲、白消胺、美法仑、苯丁酸氮芥、巯嘌呤、氮芥、甲氨喋呤、顺铂、丝裂霉素、环磷酰胺、甲基苄胼、阿糖胞苷、替尼泊甙、氮烯唑胺、塞替派、放线菌素、硫鸟嘌呤、柔红霉素、苏消安、多柔比星、噻替派、雌莫司汀、长春碱、依托格鲁、长春新碱、足叶乙甙、长春地辛和紫杉醇。
抗微生物剂包含:
抗生素,例如氨苄青霉素、乙氧萘青霉素、羟氨苄青霉素、苯唑青霉素、阿洛西林、青霉素G、羧苄青霉素、青霉素V、双氯青霉素、苯氧乙基青霉素、氟氯青霉素、氧哌嗪青霉素、甲亚胺青霉素、磺苄青霉素、甲氧西林、替卡西林、美洛西林,头孢菌素:头孢克洛、头孢噻吩、头孢羟氨苄、头孢吡硫、头孢孟多、头孢拉定、头孢曲嗪、头孢磺啶、头孢唑啉、头孢他啶、头孢雷特、头孢曲松、头孢西丁、头孢呋辛、头孢乙腈、拉他头孢和头孢氨苄。氨基糖苷类例如丁胺卡那霉素、新霉素、地贝卡星(dibekacyn)、卡那霉素、庆大霉素、奈替米星、托普霉素。大环内酯类例如两性霉素B、新生霉素、杆菌肽、制霉菌素、克林霉素、多粘菌素类、粘菌素、螺旋霉素、红霉素、大观霉素、林可霉素、万古霉素。四环素类例如金霉素、土霉素、地美环素、吡甲四环素、多西环素、四环素和米诺环素。其它抗生素例如氯霉素、利福霉素、利福平和甲砜霉素。
化疗剂,例如磺胺类、磺胺嘧啶、磺胺甲二唑、磺胺二甲氧嗪、磺胺甲噁唑、磺胺二甲嘧啶、磺胺甲氧哒嗪、磺胺二甲异噁唑、磺胺苯吡唑、磺胺林、磺胺二甲异嘧啶、磺胺甲基嘧啶、磺胺异噁唑和具有磺胺甲噁唑或磺胺美曲的三甲氧苄二氨嘧啶。
尿路杀菌剂,例如甲胺、喹诺酮类(诺氟沙星、西诺沙星)、萘啶酸、硝基化合物(呋喃妥因、硝呋妥因醇)和噁喹酸。
用于厌氧感染的药物,例如甲硝唑。
用于结核病的药物,例如氨基水杨酸、异烟肼、环丝氨酸、利福平、乙胺丁醇、硫卡利特、乙硫异烟胺和紫霉素。
用于麻风病的药物,例如缩氨硫脲、利福平、氯苯酚嗪、亚磺氨苯砜钠和二氨基二苯砜(DDS,氨苯砜)。
抗真菌剂例,如两性霉素B、酮康唑、克霉唑、咪康唑、益康唑、纳他霉素、氟胞嘧啶、制霉菌素和灰黄霉素。
抗病毒剂,例如阿普洛韦、碘苷、金刚胺、甲吲噻腙、阿糖胞苷、阿糖腺苷和更昔洛韦。
阿米巴病的化疗,例如氯喹、双碘喹啉、氯碘羟喹、甲硝唑、去氢依米丁、巴龙霉素、二氯尼特、糠酸酯替硝唑和依米丁。
抗疟疾药剂,例如氯喹、乙胺嘧啶、羟氯喹、奎宁、甲氟喹、磺胺多辛/乙胺嘧啶、戊烷脒、苏拉明钠、伯氨喹、甲氧苄啶和氯胍。
抗蠕虫病药剂,例如酒石酸锑钾、尼立达唑、二巯基丁二酸锑钠、羟氨喹、酚乙铵、哌嗪、双氯酚、吡喹酮、乙胺嗪、双羟萘酸噻嘧啶、海蒽酮、扑蛲灵、左旋咪唑、锑波酚、甲苯咪唑、四咪唑、敌百虫、硫苯哒唑和氯硝柳胺。
抗炎剂,例如乙酰水杨酸、甲芬那酸、萘普生、阿扎丙宗(azopropanone)、尼氟灭酸、苄达明、羟基保泰松、双氯芬酸、吡罗昔康、非诺洛芬、吡咯洛、氟比洛芬、水杨酸钠、布洛芬舒林酸、吲哚美辛、噻洛芬酸、酮洛芬和托美汀。
抗痛风剂,例如秋水仙碱和别嘌呤醇。
中枢作用(阿片)镇痛剂,例如阿芬太尼、美沙酮、苯腈米特、吗啡、丁丙诺菲、尼可吗啡、布托菲诺、喷他佐辛、可待因、哌替啶、右旋吗酰胺、哌腈米特、右旋丙氧吩、舒芬太尼和芬太尼。
局部麻醉剂,例如阿替卡因、甲哌卡因、布比卡因、丙胺卡因、依替卡因、普鲁卡因、利多卡因和丁卡因。
用于帕金森病的药物,例如金刚胺、苯海拉明、阿朴吗啡、爱普杷嗪、甲磺酸苄托品、麦角腈、比哌立登、左旋多巴、溴隐亭、麦角乙脲、卡比多巴、美噻吨、氯苯沙明、邻甲苯海明、赛克立明、普环啶、右苄替米特和苯海索。
中枢活性肌肉松弛药,例如巴氯芬、异丙基甲丁双脲、氯美乍酮、氯唑沙宗、环苯扎林、丹曲洛林、安定、非巴氨酯、美芬诺酮(mefenoxalone)、甲苯丙醇、美他沙酮、美索巴莫和托哌松。
皮质类固醇,包含:
矿物皮质类固醇,例如皮质醇、去氧皮质酮和氟氢可的松。
糖皮质类固醇,例如倍氯米松、倍他米松、可的松、地塞米松、氟轻松、氟轻松醋酸酯、氟可龙、氟米龙、氟泼尼龙、氟氢缩松、哈西缩松、氢化可的松、甲羟松、甲强龙、帕拉米松、波尼松龙、强的松和去炎松(丙酮化合物)。
雄激素,包含:
治疗中使用的雄性类固醇(androgenicsteroids),例如达那唑、氟甲睾酮、美睾酮、甲睾酮、睾酮和它们的盐。
治疗中使用的合成代谢类固醇,例如卡鲁睾酮、诺龙及其盐、屈他雄酮、氧雄龙、乙雌烯醇、羟甲烯龙、美雄醇、康力龙、羟甲雄二烯酮和睾内酯。
抗雄激素,例如醋酸环丙孕酮。
治疗中使用的含有雌激素类固醇的雌激素,例如己烯雌酚、雌二醇、雌三醇、乙炔雌二醇、炔雌醇甲醚和炔雌醚。
抗雌激素,例如三对甲氧苯氯乙烯、克罗米酚、乙胺氧三苯醇、萘福昔定和三苯氧胺。
孕激素类,例如烯丙雌烯醇、去氧孕烯、二甲炔酮、去氢孕酮、炔雌烯醇、脱水羟基孕酮、双醋炔诺醇、炔诺醇、羟孕酮、左炔诺孕酮、利奈孕醇、甲羟孕酮、醋酸甲地孕酮、炔诺酮、诺塞甾酮、异炔诺酮、甲基炔诺酮和孕酮。
甲状腺药物,包含:
治疗中使用的甲状腺药物,例如左旋甲状腺素和碘塞罗宁。
治疗中使用的抗甲状腺药物,例如甲亢平、甲巯基咪唑、甲基硫氧嘧啶和丙基硫尿嘧啶。
除了水溶性的生物活性试剂之外,还可以加入其它水溶性的化合物,例如,抗氧化剂、离子、螯合剂、染料、成像化合物。
优选的治疗试剂处在癌症(例如,抗肿瘤)和心血管疾病的领域。
适合纳米粒子或脂质体制剂的亲脂性药物衍生物的制备方法是本领域已知的(参见例如US5,534,499,其描述了治疗剂与磷脂的脂肪酸链的共价连接)。本发明中的药物也可以是前药。
药物可位于载体隔室的内部、外部或内部和外部两者中,例如在脂质体的腔中和/或壳中。药物分布不依赖于药物载体中所包含的任何其它试剂,例如顺磁性化学位移试剂或顺磁性剂。可使用药物组合,并且这些药物的任何一个都可以位于药物载体隔室的内部、外部或内部和外部两者中,例如在脂质体的腔中和/或壳中。
成像剂
在另一方面,本发明涉及适合作为成像剂、优选用于MRI成像剂的载体。为此,载体(在腔中、在壳中、或在其表面上)包含能够诱导造影增强的物质。这些物质包括T1和或T2造影增强剂以及CESTMRI造影增强剂。
几乎所有目前的MRI扫描都基于体相水(bulkwater)分子的成像,体相水分子以非常高的浓度遍布在体内所有组织内。如果不同组织间的对比不足以获得临床信息,则施用MRI造影剂(CA),例如低分子量钆复合物。这些顺磁性复合物降低水分子的质子的纵向弛豫时间(T1)和横向弛豫时间(T2)。锰也作为T1造影剂。载体可包含针对1HMRI或19FMRI或针对两者的造影增强剂。在本发明中,也可结合T1、T2实现一体化概念的19FMRI,且在1HMRI中还优选结合CEST对比。
CESTMRI
在一个优选实施方案中,本发明还涉及CESTMRI造影增强。该方法用于通过使用从选择的、磁预饱和的质子至由MRI确定的体相水分子的化学交换饱和转移(ChemicalExchange-dependentSaturationTransfer)(CEST)来形成图像对比。
如果用于CESTMRI,本发明优选的载体,即具有围绕腔的半渗透性壳的热敏载体,有利于最佳的CEST造影增强。因为,这些载体的优点是可以基于腔中所含的顺磁性化学位移剂进行CEST造影增强,所述顺磁性化学位移剂与也位于腔中的质子库和其它MRI分析物相互作用。
尽管在该优选实施方式中,本发明涉及任何CEST-类型造影增强在热敏药物释放上的应用,但优选利用已可得的更先进的CEST方法。
CEST与顺磁性化学位移试剂结合(顺CEST)是一种方面,其中通过应用射频(RF)辐射,选择性地饱和CEST造影剂的顺磁性位移质子库的磁化。由于质子交换而至体相水分子的该饱和的转移引起CEST造影剂环境中的可激发水质子的量减少。因此,观察到体相水信号强度的降低,这可用于产生MRI图像中的(负)造影增强。
获得高CEST效率的方法基于利用含有顺磁性位移试剂(例如Na[Tm(dotma)(H2O)])的溶液的大量水分子,其中“H4dotma”表示α,α’,α,”α”’-四甲基-1,4,7,10-四乙酸,dotma表示配位体的各自四倍的去质子化的四阴离子形式,以便提供化学地位移的且因此可以通过RF脉冲被选择性地饱和的质子库。如果该系统被封装在载体(例如脂质体)中,则磁饱和可以转移至载体外部没有化学地位移的体相水分子(脂CEST)。磁化转移量和因此造影增强的程度由穿过载体壳(例如磷脂膜)的水的扩散速度以及由载体内的水量所确定。
最佳的水交换率与在载体内部的质子库(pool)和载体外部的体相水之间的化学位移差异直接相关。在脂质体内部的水分子上诱导的顺磁性位移由两个主要贡献构成:起因于水分子和位移试剂(δdip)之间的直接偶极相互作用的化学位移;以及由体磁化率效应(δbms)所造成的化学位移。整体的顺磁性位移是这两个贡献的总和:
δ=δdip+δbms(1)
δbms对于球形粒子是零,但对于各向异性粒子可以是显著的。非球面粒子遇到磁场中的力,这会导致它们与磁场线对齐。在脂质体的情况下,如果它们带有与磷脂膜结合的顺磁分子,该效应将被进一步地提高。
关于使用非球面脂质体的CEST的参考文献是Terreno,E.等人的Angew.Chem.Int.Ed.46,966-968(2007)。
在本发明中,顺磁性位移试剂可以以任何方式被包含在载体中或载体上。优选地,通过在载体的腔中包含试剂和库的两者,使位移试剂与质子库充分相互作用。
一种或多种顺磁性化学位移试剂基本上可以是适合使得包含该顺磁性化学位移试剂的溶液或分散液中的相对大量的水分子成为相对于体相水分子的周围质子,向它们的MR共振频率而化学位移的质子库的任何顺磁性剂。因为脂质体包括根本上允许质子与它们的直接环境进行交换的壳,所以,由选择性的RF脉冲引起的饱和将被转移至加载的热敏药物载体的环境。因此,进行磁共振成像时,热敏药物载体的直接环境相比于其它体相水分子显示了降低的信号强度,并且因此允许由于降低的信号强度而检测造影剂的直接环境。顺磁性化学位移试剂将包含顺磁性化合物的,即,任何具有顺磁性质的任何化合物。优选地,顺磁性化合物包括顺磁金属离子,例如,由螯合配位体所复合的金属离子。顺磁金属离子是本领域的技术人员已知的,不需要在这里阐述。例如,前过渡金属和后过渡金属,明确地包括:铬、锰、铁以及镧系元素,例如钆、铕、镝、钬、铒、铥、镱。
顺磁性化学位移试剂包括将包含能够强烈结合顺磁性金属并允许该金属与水或与其它合适的质子源相互作用的螯合结构。关于合适的螯合结构,参见P.Caravan等的Chem.Rev.,99,2293-2352(1999)。优选地,水至少瞬时地被配位至顺磁试剂的金属。关于顺磁位移机理,参见J.A.Peters等的Prog.Nucl.Magn.Reson.Spectr.,28,283-350(1999)。在一个实施方案中,螯合结构本身也包含可交换的质子,例如:羟基、胺或酰胺质子。
合适地,顺磁性化学位移试剂包含与螯合结构配位的镧系元素离子,例如:大环镧系元素(III)螯合物,其来源于1,4,7,10-四氮杂环十二烷-1,4,7,10-四乙酸(H4dota)、1,4,7,10-四氮杂环十二烷-α,α’,α,”α”’-四甲基-1,4,7,10-四乙酸(H4dotma)以及允许在顺磁试剂中轴向配位的水分子的相关配位体。在这一方面,参见Aime等人的Angew.Chem.Int.Ed.,44,5513-5515(2005)。可以将许多相同的、类似的或不同的螯合单元组合在树枝状的(dendrimeric)或聚合的结构中,提供树枝状的或聚合的化学位移试剂。使用树枝状的或聚合的顺磁性化合物的一般优点是,可以获得高有效浓度的顺磁金属复合物,而没有如使用单核顺磁性化合物时那样多地增加溶液渗透压。这里,参见E.Terreno,A.Barge,L.Beltrami,G.Cravotto,D.D.Castelli,F.Fedeli,B.Jebasingh,S.Aime,ChemicalCommunications,2008,600-602。
优选地,所述顺磁性化学位移试剂是水溶性的。合适的化学位移试剂是本领域的技术人员已知的。CEST造影剂不需要任何特定的化学位移试剂,只要该位移试剂以及该质子库具有足够的相互作用以便生成化学位移质子的库。
优选地,所述顺磁位移试剂是包含金属离子和基于多齿螯合配位体的配位体的金属复合物。更优选地,化学位移试剂与质子库的相互作用以配位的形式被提供。因此,优选金属复合物具有至少一个保留在打开状态的金属的配位位置,以用于至少一个水分子的配位。
合适的水溶性化学位移试剂的实例是[Ln(hpdo3a)(H2O)](1)、[Ln(dota)(H2O)]-(2)、[Ln(dotma)(H2O)]-(3)、[Ln(dotam)(H2O)]3+(4)和[Ln(dtpa)(H2O)]2-(5),包括其衍生物和相关化合物,其中Ln是镧系元素的离子。
优选地,所述顺磁性化学位移试剂是镧系元素的复合物,例如下式1-5中所示:
其中镧系元素是Eu3+、Dy3+、Ho3+、Er3+、Tm3+和Yb3+且优选地是Tm3+或Dy3+。
所述顺磁性化学位移剂通常以从1mM到2000mM、优选地从10mM到1000mM、以及更优选地从50mM到200mM的量包含在试剂中。
上述含金属的化合物可以被溶解、乳化、悬浮或以任何其它形式均匀地或不均匀地分布在腔中,即脂质体的内部隔室中。可选择地,其可以通过至少一个共价键或非共价键或这些的任意组合被链接到脂质体的外部隔室。此外,相同的或至少一个不同的含金属的化合物可以同时出现在任何所述隔室中。
可以设想,如果药物本身包括适当的金属,则顺磁性剂和药物是一个整体且是相同的。
其他造影增强剂
本发明的造影剂可以包括T1、T2或T2 *还原剂。在这方面,参见Aime等的JournaloftheAmericanChemicalSociety,2007,129,2430-2431。此外,可实现T1、T2或T2 *与CEST造影剂的一体化概念。
热敏药物载体的内部和体相水质子之间的化学位移差异还可以通过向热敏药物载体的膜提供另外的顺磁性剂而进一步提高,所述另外的顺磁性剂不必是化学位移试剂。因此,非球面载体在磁场中的取向受到影响,而前述的体磁化率效应被增强。该另外的顺磁性剂优选地是两亲性化合物,其包括镧系元素复合物(在两亲性化合物的极性较大的一侧)并且具有非极性尾部,所述非极性尾部基于疏水性分子的相互作用具有优选地集成在或对齐于热敏药物载体的表面处的脂质双层的趋势。
这些两亲性顺磁性复合物可以例如是:
组合的
19
F和
1
HMR造影增强
根据本发明,可以多种方式实现19F和1HMR的合适组合。
因此,通过利用CEST机制和/或19FMR可以产生双重或多重标记的MR对比。可选择地,多重MR对比可以通过经由位于载体中的含金属化合物对已成像的分析物(典型地是水质子)的纵向弛豫时间(T1),或横向弛豫时间(T2)的改变而产生。任何这些造影增强机理都可以进一步以它们的任意组合使用。
取决于载体的物理状态,使用常规MR设备以顺序或交替方式监测所述双重/多重标记的MRI对比,或使用在双重调节的谱仪系统上的序列组合(例如以1H和19FMR共振频率)同时监测所述双重/多重标记的MRI对比。
在这方面,本发明还涉及同时双核(simultaneousdualnuclei)MR成像在监测和/或引导药物递送中的用途。
热敏脂质体中CEST和19F造影剂的组合提供了通过CEST和19FMRI独立地和同时地监测药物释放过程的机会。两种不同MR信号的同时监测通过相应的双重标记MR技术传递(mediated)。该方式导致了几种可能的益处。因此,装载了药物的粒子的空间分布可以在药物释放之前通过CESTMRI进行估计;1HCEST和19FMR信号与被释放的药物的量成比例,这允许使用反馈回路定量控制体内被递送的药物剂量;在病变部位药物从载体的释放可以通过局部刺激进行诱导,例如在热敏脂质体的情况下使用例如RF或超声进行加热;所述CESTMR造影增强可以随意打开和关闭。
19
FMRI造影剂
MR可检测到的19F不在体内自然产生,即19FMRI因此必需基于使用添加的19F造影剂。
用于19FMRI的造影剂优选具有大量的磁等价的氟基团(敏感性与每分子磁等价的F原子数呈线性比例)。考虑到与CESTMRI的期望组合,所使用的19FMR造影剂优选是水溶性的,特别优选是荷电分子,由此具有尽可能高的水溶性。考虑到在磷脂壳中的应用,优选的19F造影剂不显著地与磷脂结合或联合。考虑到它们在人体或动物体内的释放,19F造影剂优选是低毒性的以及高生物相容性的。
优选的19F造影剂是脂肪烃的荷电的全F类似物(chargedper-Fanalogs)。
将参照以下非限制性实施例和所附非限制性附图解释本发明。
实施例1
(2S)-9,13,17,18-四羟基-5-氧代-4,7,11,15-四氧杂十八烷-1,2-二基二棕榈酸酯115,3的合成。见方案1。
方案1:(2S)-9,13,17,18-四羟基-5-氧代-4,7,11,15-四氧杂十八烷-1,2-二基二棕榈酸酯115,3的合成路线。
通过用酸衍生物107酯化(R)-3-羟基丙烷-1,2-二基二棕榈酸酯(108),然后通过中间体三酯109的酸性去保护来制备三酯115,3。酸性衍生物107是甘油三酯的衍生物,其中通过将丙酮缩甘油(101)添加到2-((烯丙氧基)甲基)环氧乙烷(102)来引入甘油单元的骨架。以这种方式获得的产物103被氧化为环氧化物104,且由苯甲醇将环氧化物环打开以形成105。将余下的羟基保护为10中的四氢吡喃醚以及去除苯甲基后,获得醇106,其通过与溴乙酸反应转化为酸衍生物107。
实施例2
3-(3-(2,3-二羟基丙氧基)-2-羟基丙氧基)丙烷-1,2-二基二硬脂酸酯(217,2)的合成。参见方案2。
方案2:3-(3-(2,3-二羟基丙氧基)-2-羟基丙氧基)丙烷-1,2-二基二硬脂酸酯(217,2)的合成
如方案1中所示制备含有骨架以形成甘油三酯衍生物的产物103。在将羟基保护为四氢吡喃醚以及将烯丙基环氧化之后,获得产物110,其中由硬脂酸铯将环氧化物环打开以形成单酯111。在由硬脂酸将111的剩余羟基酯化,并且用酸去保护之后,获得产物217,2。
实施例3
已将含有脂质模拟物(1n,R)的温度敏感脂质体工程化用于MRI造影剂(例如[Gd(hpdo3a)(H2O)])和药物(例如阿霉素)的触发释放。制备由DPPC:DSPC:115,3=50:20:30(摩尔比)构成的温度敏感脂质体制剂。将脂质溶解在氯仿/甲醇(4:1v/v)的溶液中,并在减压下蒸发溶剂直到形成薄的均匀的脂膜,其被进一步在氮气流中过夜干燥。在60℃下用含有250mM[Gd(HPDO3A)(H2O)]的120mM(NH4)2SO4缓冲液(pH=5.4)进行膜水化。在60℃通过400nm滤器(2次)、200nm滤器(2次)和100nm滤器(5次)挤出悬浮液。挤出之后,通过PD-10柱(GEHealthcare)的凝胶过滤,用pH7.4的HEPES缓冲盐水(HBS)(20mMHEPES、137mMNaCl)替换脂质体外的缓冲液(包含[Gd(HPDO3A)(H2O)])。以20:1的磷脂比DOX重量比例,将HBS中的DOX溶液(5mg/mL)加入到脂质体中,并在37℃孵育。孵育之后,将脂质体通过另一个PD-10柱而去除脂质体外的DOX。分别通过差示扫描量热法(DSC)和动态光散射(DLS)确定脂质体的Tm和流体力学直径(hydrodynamicdiameter)。在脂双层中含有115,3的脂质体表现出111nm的流体力学半径(通过200nmPC滤器挤出之后)和41.9℃的Tm。
Claims (15)
1.一种化合物,满足结构式I
其中:
G代表满足式II的基团:
HO-CH2-{CH(OH)-CH2-O}m-CH2-{C(=O)-O-CH2}q-式II
每个n独立地是1-30的整数;
m是2-10的整数;
q是0或1。
2.根据权利要求1的化合物,选自以下式III、式IV的化合物及其组合,
3.根据权利要求1或2的化合物,其中m是2-6。
4.根据权利要求3的化合物,其中m是2或3。
5.根据权利要求1或2的化合物,其中每个n独立地是12-18。
6.根据权利要求5的化合物,其中每个n独立地是13、15或17。
7.一种化合物,满足式V
其中
G代表满足式II的基团:
HO-CH2-{CH(OH)-CH2-O}m-CH2-{C(=O)-O-CH2}q-式II
m是1-10的整数;
q是0或1,
并且其中r和s每个独立地是1-30的整数,并且(r-s)的差是1-5。
8.根据权利要求7的化合物,其中r和s每个独立地是1-30的整数,并且(r-s)的差是1-3。
9.一种热敏载体,其包含围绕腔的脂质双层壳,其中所述脂质双层包含如权利要求1-8任一项所定义的一或多种化合物。
10.根据权利要求9的热敏载体,其包含选自治疗剂、成像剂及其组合的活性剂。
11.如权利要求1-8任一项所定义的化合物作为热敏载体的脂质双层壳的添加物的用途。
12.根据权利要求9或10的热敏载体在制备用于相应地在治疗和成像方法中于体内释放其中所含的物质的药物递送系统、成像系统或用于成像药物递送的组合系统中的用途,所述方法包括将任一上述载体施用给动物或人,以及影响其中所含物质的体内释放。
13.一种药物递送系统,其包含如权利要求9或10所定义的载体以及至少一种药物物质。
14.一种成像系统,其包含如权利要求9或10所定义的载体以及至少一种MRI对比增强物质。
15.一种用于成像药物递送的组合系统,其包含如权利要求9或10所定义的载体、至少一种药物物质以及至少一种MRI对比增强物质。
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