CN102202694A - 包含抗-聚合物抗体的靶向构建体和结合它们的脂质体或微泡 - Google Patents
包含抗-聚合物抗体的靶向构建体和结合它们的脂质体或微泡 Download PDFInfo
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- CN102202694A CN102202694A CN2009801421310A CN200980142131A CN102202694A CN 102202694 A CN102202694 A CN 102202694A CN 2009801421310 A CN2009801421310 A CN 2009801421310A CN 200980142131 A CN200980142131 A CN 200980142131A CN 102202694 A CN102202694 A CN 102202694A
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Abstract
药用试剂盒,其包含:(i)含有靶向配体和抗-聚合物抗体的靶向构建体和(ii)含有聚合物的脂质体或充气微泡,其能结合或联合所述构建体。也公开了制备和施用所述集合体的方法,以及包含所述靶向构建体和所述脂质体或充气微泡的集合体。
Description
技术领域
本发明涉及一种集合体(assembly),该集合体包含:(i)靶向构建体,其包含靶向配体和抗-聚合物抗体,和(ii)含有聚合物的脂质体或充气微泡,其能结合或联合所述集合体。本发明另外涉及制备和施用所述集合体的方法,以及包含所述靶向构建体和所述脂质体或充气微泡的药用试剂盒。
背景技术
采用能增强使用不同成像技术可得到图像的试剂(称作“造影剂”或“图像增强剂”)的诊断性成像已经成为诊断领域中被广泛采用的实践。
近年来造影剂的快速发展已经产生了许多不同的制剂,它们可用于人或动物体的器官和组织的反差增强的成像。
对超声反差成像特别有用的一类造影剂包括分散在水性介质中的纳米和/或微米尺寸的气泡的悬浮液。特别感兴趣的是,其中气泡被稳定化的那些制剂,所述稳定化例如通过使用乳化剂、油、增稠剂或糖类,或通过使气体或其前体陷入或包封在多种系统中。这些稳定化的气泡在本领域通常用不同的术语来表示,例如,“微泡”、“微球”、“微气泡”、“微囊”或“微气球”。在本发明的说明书和权利要求书中,使用术语“微泡”来表示上述稳定化的气泡中的任一种。
其它造影剂包括碘化产物(诸如碘帕醇或碘美普尔),它们广泛地用于X-射线反差分析中,尤其是计算机体层成像(CT)X-射线,而含有顺磁离子的化合物(诸如或Bracco Imaging)被广泛地用于MRI分析中。可以有利地将有活性的(X-射线或MRI)成像剂掺入脂质体结构中(参见例如参考文献1或参考文献2)。
充气微泡可以在它们的制剂中包括聚合物,尤其是亲水聚合物(例如聚乙二醇,PEG),已经发现所述聚合物可以用于例如,降低免疫原性、提高生物相容性、减少受体介导的网状内皮系统(RES)的摄取和/或增加造影剂的血清半衰期。出于类似的原因,诸如PEG等聚合物也已经被包含在用作造影剂或治疗剂的载体的脂质体制剂中。
最近,已经用合适的靶向特异性的组分修饰充气微泡,所述组分能使微泡选择性地结合到目标器官或组织上。
例如,可以给微泡或脂质体结合(例如通过包含在它们的边界外膜(envelope)内)特异性的组分,所述组分能结合到患者体内的确定的靶物或区域(称作“靶向配体”),从而选择性地增强所述靶物或区域的成像。
靶向配体的实例包括,例如,肽、蛋白或抗体,其能结合特定器官或组织,例如,生成血管的炎性的或形成血栓的组织。
例如,通过使靶向配体结合到合适的分子上(所述分子用于形成微泡的或脂质体的外膜),可以修饰微泡或脂质体的结构。靶向部分可以直接或通过合适的间隔物连接到形成外膜的分子上。该方法学因而通常会使形成微泡或脂质体外膜的组分修饰成为必需,以允许其结合希望的靶向部分。
申请人现在已经发现了一种新方法,其中借助于能特异性地识别包含在脂质体或微泡中的聚合物组分的抗体,使靶向配体结合所述含有聚合物的脂质体或充气微泡。
发明内容
本发明的一个方面涉及药用试剂盒,其包含:
a)第一组合物,其包含脂质体或充气微泡或其前体,它们具有包含多个聚合物分子的稳定化外膜;和
b)第二组合物,其包含靶向构建体,所述构建体包含靶向配体和能选择性地结合所述聚合物的抗体。
根据一个优选的实施方案,所述聚合物是亲水聚合物。优选地,所述聚合物含有重复氧乙烯单元(oxyethylene units),且更优选地,它以甲氧基终止。根据一个特别优选的实施方案,所述聚合物是聚乙二醇。优选地,所述抗体因而结合亲水聚合物,更优选地,它结合含有重复氧乙烯单元的聚合物,且甚至更优选地,它结合含有重复氧乙烯单元并以甲氧基终止的聚合物。根据一个特别优选的实施方案,所述抗体结合聚乙二醇。
根据另一个优选的实施方案,所述聚合物的摩尔量是相对于所述稳定化外膜的组分的总量的至少0.05%,优选地是至少0.2%,且甚至更优选地是至少1%。
根据一个特别优选的实施方案,所述聚合物共价结合到两亲化合物上,优选磷脂。
根据另一个优选的实施方案,所述微泡具有稳定化外膜,所述外膜包含两亲物质,优选磷脂;优选地所述两亲物质占所述稳定化外膜的总组分的摩尔数超过50%,且更优选地超过80%,且甚至更优选地超过90%。
根据另一个方面,本发明涉及脂质体或充气微泡或其前体,其包含:a)多个聚合物分子;b)与所述聚合物结合的抗体;和c)与所述抗体结合的靶向配体。
优选的抗体和聚合物如上面所定义。
本发明的另一个方面涉及将脂质体或充气微泡施用至患者的身体部分的方法,所述方法包括下述步骤:
a)施用第一组合物,其包含靶向构建体,所述构建体包含:(i)能选择性地结合所述身体部分中的分子或组织的靶向配体,和(ii)能选择性地结合聚合物分子的抗体;
b)施用第二组合物,其包含所述脂质体或所述充气微泡,它们具有包含多个所述聚合物分子的稳定化外膜。
根据一个优选的实施方案,在足以允许靶向构建体到达选择的身体部分的时间后,施用所述脂质体或充气微泡。
附图说明
图1-3解释了根据本发明的靶向构建体的实施例。
图4解释了本发明的靶向构建体以及造影剂/治疗剂的应用实施例。
具体实施方式
定义
表述“结合”,特别当表示靶向配体与能选择性地结合亲水聚合物的抗体的结合时,在它的含义中包括能在参与结合的组分之间建立相对稳定的相互作用的任意共价的或非共价的结合。
表述“非共价的结合”包括不参与共价键的2个或更多个分子之间的分子间相互作用,例如,离子或静电相互作用、偶极-偶极相互作用、氢键合、亲水的或疏水的相互作用、范德华力及其组合。非共价的结合另外包括亲和结合对的部分之间的相互作用,例如,抗生物素蛋白或链霉抗生物素蛋白和生物素之间的相互作用;蛋白A或G结合和免疫球蛋白的Fc-区之间的相互作用;寡核苷酸和互补序列之间的相互作用,例如聚脱氧腺苷酸(polydesoxyadenylic acid)和聚脱氧胸苷酸(polydesoxythimidylic acid),或聚脱氧鸟苷酸和聚脱氧胞苷酸;Ni-NTA(次氮基三乙酸,镍盐)和聚组氨酸-标签化的配体。
表述“造影剂”在它的含义中包括可以与下述方法联合使用的任意化合物、构建体、组合物或制剂,所述方法用于成像患者的目标区域,和/或辅助诊断患者中疾病的存在与否,且通常能增强诊断性成像技术的成像。诊断技术的实例包括超声成像、磁共振成像、X-射线成像(尤其是计算机体层摄影术)、光学成像、核成像或分子成像。合适的造影剂的实例包括,例如,充气微泡(例如用于超声成像)、碘化的化合物、碘化的脂质体;磁性纳米颗粒;顺磁离子螯合的复合物;荧光染料;包含超极化的原子或放射性药剂的化合物。
术语“治疗剂”在它的含义中包括可以用于任意治疗用途(例如用于治疗患者的疾病的方法中)的任意物质、组合物、制剂或药物递送系统,以及在体外和/或在体内能产生或负责产生生物学或生理学效应的任意物质。治疗剂因而包括能用于治疗(包括预防、减轻、疼痛减轻或治愈)患者的任意病理学状况(包括疾病、痛苦、病灶(disease lesion)或损伤)的任意化合物或物质,诸如药物、药剂、生物活性剂、细胞毒性剂、化疗剂、放射疗法剂、蛋白、天然的或合成的肽(包括寡肽和多肽)、维生素、甾类和遗传物质(包括核苷、核苷酸、寡核苷酸、多核苷酸和质粒)。在它们中,药物或药剂是优选的。
治疗剂的实例包括抗溃疡剂诸如奥美拉唑、法莫替丁或雷尼替丁;抗高血压剂诸如氨氯地平、缬沙坦或氯沙坦;β阻滞剂诸如阿替洛尔或普萘洛尔;钙通道阻滞剂诸如尼群地平或维拉帕米;血管紧张素转换酶抑制剂诸如依那普利或雷米普利;血管紧张素II抑制剂诸如氯沙坦钾;钾通道活化剂、诸如尼可地尔;利尿剂和抗利尿剂诸如氢氯噻嗪或氨苯蝶啶;抗心绞痛药诸如硝酸异山梨酯或地尔硫卓;促凝药诸如缀合的甲萘醌或蝮蛇血凝酶;抗凝血药、抗血栓药或抗血小板药诸如组织纤溶酶原活化剂或肝素;抗心律不齐药诸如丙吡胺或胺碘酮;血管扩张剂诸如洋地黄毒苷、地高辛或洋地黄苷;青霉素诸如哌拉西林或阿莫西林(任选地与克拉维酸相组合);β-内酰胺类诸如亚胺培南或美罗培南;喹诺酮类或荧光喹诺酮类诸如萘啶酸、左氧氟沙星或莫西沙星;头孢菌素类诸如头孢地尼或头孢克洛;磺胺类药诸如磺胺甲基异唑(sulphametoxazole);氨基糖苷类诸如阿奇霉素或庆大霉素;多粘菌素类诸如多粘菌素-b;四环素类诸如多西环素;大环内酯类诸如红霉素或克林霉素;唑烷酮类诸如利奈唑胺;抗病毒剂诸如阿扎那韦、齐多夫定、依法韦仑、替诺福韦、阿巴卡韦、替诺福韦、洛匹那韦、阿昔洛韦、伐昔洛韦、奥塞米韦(ozeltamivir);抗疟药诸如青蒿琥酯或甲氟喹;抗结核药诸如异烟肼;链霉素或吡嗪酰胺;抗蠕虫药和抗感染药诸如哌嗪、双羟萘酸噻嘧啶或甲苯达唑(membendazole);抗麻风药诸如抗原生动物药;抗阿米巴药诸如甲硝唑;抗真菌药诸如卡泊芬净、伏立康唑、氟康唑;抗过敏药诸如莫米松、非索非那定、特非那定或西替利嗪;骨骼肌松弛药诸如替扎尼定或巴氯芬;非甾体抗炎药诸如塞来考昔、美洛昔康或布洛芬;抗肿瘤药诸如氮芥化合物(例如环磷酰胺)、氮丙啶(例如thioepa)、N-硝基脲衍生物(例如洛莫司汀)、铂化合物(例如奥沙利铂)、丙卡巴肼、达卡巴嗪甲氨蝶呤、多柔比星、丝裂霉素、安丝菌素、胞嘧啶阿糖核苷、长春新碱、盐酸柔红霉素、盐酸多柔比星、表柔比星、米托蒽醌、博来霉素、氨鲁米特、醋酸亮丙瑞林、戈舍瑞林、比卡鲁胺、柠檬酸他莫昔芬、曲洛司坦、门冬酰胺酶(L-门冬酰胺酶)、依托泊苷、干扰素α-2a、干扰素α-2b、替尼泊苷(VM-26)、硫酸长春碱(VLB)、硫酸长春新碱、紫杉醇、多西他赛、喜树碱、伊立替康、甲氨蝶呤、多柔比星、阿拉伯糖基、羟基脲;叶酸拮抗剂诸如氨基蝶呤、甲氨蝶呤、培美曲塞;核苷类似物拮抗剂诸如吉西他滨、卡培他滨、巯嘌呤、硫鸟嘌呤、氟尿嘧啶或阿糖胞苷;酪氨酸激酶抑制剂诸如伊马替尼、索拉非尼、抗体诸如利妥昔单抗、西妥昔单抗、厄洛替尼、曲妥单抗或贝伐单抗;芳香酶抑制剂诸如阿那曲唑或来曲唑;麻醉品、阿片剂或镇静药诸如柠檬酸芬太尼、盐酸氟西泮、戊巴比妥、替马西泮或三唑仑;局部的或全身的麻醉药诸如七氟烷、普鲁卡因、丁卡因或氟哌利多;神经肌肉阻滞剂诸如阿曲库铵甲磺酸酯;激素系统的治疗剂诸如生长激素、黑素细胞刺激激素、雌二醇、丙酸倍氯米松、倍他米松、醋酸可的松、地塞米松;针对肢端肥大症的药物诸如生长抑素;针对阿尔茨海默病的药物诸如美金刚、多奈哌齐、利斯的明;针对贫血的药物诸如促红细胞生成素;针对注意力缺陷伴多动障碍的药物诸如哌甲酯和阿托西汀;针对良性前列腺增生的药物诸如坦洛新、非那雄胺、阿夫唑嗪;针对出血的药物诸如凝血因子VII、因子VIII;针对糖尿病的药物诸如胰岛素或格列美脲;针对丙型肝炎的药物诸如聚乙二醇化的干扰素α2a、聚乙二醇化的干扰素α-2b、针对不育的药物诸如促卵泡素α和促卵泡素β;针对多发性硬化的药物诸如格拉默、干扰素β-1a或干扰素β-1b;针对骨质疏松症的药物诸如阿屈膦酸盐;针对呼吸道合胞病毒的药物诸如帕利珠单抗;针对类风湿性关节炎的药物诸如英夫利昔单抗、依那西普或阿达木单抗;针对精神分裂症的药物诸如利培酮或奥氮平;或针对移植排斥的药物诸如他克莫司、麦考酚酯或环孢素。
术语“充气微泡”包括含有被稳定化物质的外膜或层(包括膜形式层)包围的微米或纳米尺寸(例如0.1-10μm,通常1-8μm)的气泡的任意结构。该术语特别地包括本领域已知的充气的脂质体、微气泡、微球、微气球或微囊。稳定化物质可以是本领域通常已知的任意物质,包括,例如,表面活性剂、脂质(lipids)、鞘脂、寡脂、糖脂、磷脂、蛋白、多肽、碳水化合物和合成的或天然的聚合物质。优选的充气微泡是其中形成外膜的不同组分之间的相互作用属于非共价类型的那些,通常包括偶极-偶极相互作用、氢键合、亲水的或疏水的相互作用、范德华力及其组合,尤其是疏水相互作用。典型地,充气微泡用于CEUS(反差增强超声)成像中。另外,这些微泡也可以用于治疗性处理中,例如本文解释的超声介导的药物递送。
术语“微气泡”包括水性悬浮液,在悬浮液中,气泡被非常薄的外膜(薄膜)(在本领域有时称作“挥发性的”外膜)限制在气/液界面上,所述外膜包括安置在气-液界面处的稳定两亲物质。可以如下制备微泡悬浮液:通过使其合适的前体诸如粉末状的两亲物质(例如冻干的预制脂质体或冻干的或喷雾干燥的磷脂溶液)接触空气或其它气体,然后再与水性载体接触,同时进行搅拌,产生微泡悬浮液,其然后可以施用,优选在悬浮液制成之后尽快施用。气体微泡的水性悬浮液、前体及其制备的实施例公开在例如参考文献3、参考文献4、参考文献5、参考文献6和参考文献7中,它们通过引用整体并入本文。
术语“微气球”或“微囊”包括这样的悬浮液:在该悬浮液内,气泡被脂质(lipid)或天然或合成聚合物固体物质外膜所包围。微气球及其制备的实施例公开在例如参考文献8和参考文献9中。
术语“脂质体”在它的含义中包括两亲化合物的基本上球形的聚集体,所述两亲化合物包括脂质化合物,通常是分子的一个或多个同心双层的形式,在所述双层之间存在非共价相互作用。
术语“其前体”包括这样的任意组合物,其在与水性载体重配(reconstitution)后,能生成希望的分子集合体的悬浮液。具体地,当提及充气微泡的前体时,该表述包括这样的任意组合物,其在有气体存在下与水性载体重配后,能生成如上定义的充气微泡的悬浮液。所述前体组合物通常包含干粉形式(例如冻干的或喷雾干燥的)的任一种上面引用的稳定化物质,其在有气体存在下摇动其水性悬浮液后,能形成充气微泡。类似地,脂质体的前体包括干粉形式的合适的(两亲的)物质,其在与水性载体重配后,能形成脂质体悬浮液。
短语“外膜形成部分”包括能参与脂质体或充气微泡的稳定化外膜的形成的任意部分。所述部分优选地是两亲物质,优选地包含磷脂。
表述“MRI造影剂”是指这样的造影剂,其包含对磁共振做出响应的化合物、组合物或制剂,诸如顺磁金属离子或磁体颗粒,以及包含所述化合物的超分子构建体,例如,脂质体或胶束。
表述“X-射线造影剂”或“CT-造影剂”是指能增强计算机体层成像分析的X-射线成像的那些造影剂,包括,例如,碘化的化合物,尤其是非离子(诸如碘帕醇或碘美普尔,购自Bracco Imaging)、硫酸钡或金纳米颗粒。
表述“光学成像剂”是指能在不同的光学成像技术中增强成像的化合物或制剂,所述光学成像技术包括扩散性光学体层摄影术(DOT)、光学投影体层摄影术(OPT)、近红外荧光成像(NIR)或生物发光成像(BLI)。用于光学成像的造影剂包括有机荧光团(例如荧光蛋白)和无机荧光半导体纳米晶体或量子点(参见例如参考文献10)。
表述“核成像剂”是指能在核成像中增强成像的化合物或制剂,所述核成像包括正电子发射断层摄影术(PET)和单光子发射断层摄影术(SPECT)。第一种成像技术使用发射正电子的同位素诸如11C、13N、15O、18F、68Ca、94mTc(参见例如参考文献11)。第二种成像技术使用发射γ的同位素诸如133Xe、99mTc、123I、201Tl、111In和67Ca。使用纳米颗粒作为载体系统诸如脂质体,可以配制所有这些试剂(参见例如参考文献12和参考文献13)。
术语“聚合物”是指包含重复结构单元(单体)的大分子,例如通过共价化学键连接的5至多达100万或更多的单体。聚合物可以是合成的、半合成的或天然存在的,且包含同聚物(即包含相同的重复单元)或共聚物(即包含至少2种不同的单体)。共聚物可以是周期共聚物(例如其中单体A和B排列成重复序列,诸如A-B-A-B-B-A-A-A-A-B-B-B)或具有单体A和B的随机序列的随机的(或统计的)共聚物。嵌段共聚物通常包含2个或更多个同聚物亚基,它们通过共价键或连接段彼此相连。具有2个或3个不同的段的嵌段共聚物分别称作二嵌段共聚物(AAAAA-BBBBB)和三嵌段共聚物(AAAAA-BBBBB-AAAAA)。聚合物可以是线性的(具有单个主链)或分支的(具有一个或多个连接到主链上的侧链)。含有重复单元的聚合物链通常被鉴别为“聚合物主链”,而安置在该链的各个末端处的单元则通常被鉴别为“末端基团”。
表述“亲水聚合物”包括对水具有亲和力的聚合物,通常在它们的主链中含有极性基团,例如,-O-、-NH-、-SH-、-CO-或它们的任意组合。亲水聚合物的实例包括聚(C2-C3)烷基-氧化物(例如PEG或PPG)、多糖(例如葡聚糖)、聚氨基酸、半合成肽和聚核苷酸。
抗-聚合物抗体
在下面的说明书中,术语“抗-聚合物抗体”意图在它的含义中包含能识别并选择性地结合作为抗原的聚合物或其一部分的任意抗体,特别当所述聚合物被包含在本文所述的脂质体或充气微泡的外膜中时。
本文使用的术语抗体包括多克隆抗体、单克隆抗体、天然抗体片段、重组抗体片段和多特异性抗体。该术语另外包含设计用于与抗体竞争特异性结合的蛋白的抗原结合片段,诸如亲和体(affibodies)。
通过本领域已知的任意方法(例如免疫野生型或转基因动物、从人患者血清分离、和筛选抗原结合片段文库),可以生产抗-聚合物抗体。这里提及的抗体可以来自任意物种和任意类别,包括,哺乳动物IgG、M、A和E。它们可以遵循来源物种的天然抗体序列或其氨基酸变体,包括所谓的“人源化的”或PRIMATIZEDTM抗体。
在本领域中通常将抗体鉴别为免疫球蛋白(Ig),即免疫系统响应于病原体侵入而生产的多聚体糖蛋白家族。它们由抗原结合部分(Fab)和效应子功能(Fc)组成。例如,小鼠IgG是2个相同重链(H)和2个相同轻链(L)的Y-形异四聚体。每个轻链通过疏水相互作用和经常的共价二硫键连接到重链上,而重链之间的二硫键的数目在抗体亚类中存在差异。每个重链和轻链还具有规则间隔的链内二硫键,其参与称作“免疫球蛋白结构域”的球形折叠的稳定化。每条链的氨基端结构域称作“可变的”(VH和VL,相对于“恒定”结构域CH1、CH2、CH3和CL),因为它在抗体的序列之间存在广泛差异,该差异是结合特异性的基础。但是,差异性不是均匀地分布在抗体的可变结构域中。它集中在3个称作互补性决定区(CDR)的区段中,而最保守的可变结构域部分称作框架区(FR)。
表述“多克隆抗体”通常包括针对相同抗原的不同决定簇(表位)的不同抗体。多克隆抗体的制备是本领域技术人员众所周知的,且描述在许多参考书中,例如,参考文献14。
表述“单克隆抗体”是指从基本上同源的抗体群体得到的抗体,即除了可能存在的微量的可能的天然存在的突变以外,构成该群体的单个抗体是相同的。单克隆抗体是高度特异性的,针对单个抗原决定簇。单克隆抗体经常被鉴别为“完整”单克隆抗体,其中术语“完整”表示该抗体包含所有它的天然存在的部分(抗原结合部分和效应部分),且处于它的天然形式(例如单体二价(IgG)、二聚体四价(IgA)和五聚体十价(IgM)),无论它已经通过下述哪种方法生产:杂交瘤方法(参见例如参考文献15)、重组DNA技术(参见例如参考文献16)、直接克隆不同的氨基酸链(参见例如参考文献17)、使B-细胞永生化(参见例如参考文献18)或筛选抗体文库(参见例如参考文献19)。
表述“天然抗体片段”是指包含抗体的一部分的那些化合物,优选抗原结合区,其保留选择性地结合它的抗原的一些能力。术语“天然的”指示,通过完整抗体的酶或化学裂解来得到它们。天然抗体片段的实例包括Fab、Fab’和F(ab’)2。
术语“Fab”表示含有抗体分子的单价抗原结合片段的片段。Fab片段可以如下生产:用木瓜蛋白酶消化完整抗体,以产生一个完整的轻链和一个重链的一部分。
术语“Fab′”(或“Fab已接触抗原”)表示可以如下得到的抗体分子片段:用胃蛋白酶处理完整抗体,随后还原,以产生完整的轻链和重链的一部分。每个抗体分子得到2个Fab′片段。Fab′片段与Fab片段的差别在于,在重链CH1结构域的羧基端添加了几个残基,包括一个或多个来自抗体铰链区的半胱氨酸。
术语“(Fab′)2”表示可以如下得到的抗体片段:用胃蛋白酶处理完整抗体,没有随后的还原。(Fab′)2是通过2个二硫键保持在一起的2个Fab′片段的二聚体。
制备抗体片段的方法是本领域众所周知的。这些方法描述在例如参考文献14中。
“重组抗体片段”在体外直接合成为小抗体部分。工程化的抗体片段的实例包括Fab、Fab’和F(ab’)2、Fv、scFv、Fd、VH、VL、CDR肽、微体(minibodies)、多体(multibodies)、VhH和V-NAR。
可变片段“Fv”由紧密的、非共价连接的一个重链和一个轻链可变结构域的二聚体(VH-VL二聚体)组成。它是含有完整抗原识别和结合位点的最小抗体片段。在该结构中,每个可变结构域的3个CDR相互作用,界定在VH-VL二聚体表面上的抗原结合位点。或者,所述可变链可以通过分子间二硫键相连,或通过诸如戊二醛等化学试剂交联。
“scFv”是单链可变片段,且是含有通过合适的多肽连接物彼此相连的轻链可变区(VL)和重链可变区(VH)的遗传工程化的分子,诸如遗传地融合的单链分子。在结构域之间的多肽连接物使scFv能形成希望的用于抗原结合的结构(参见例如参考文献20)。
“Fd”是包含2个氨基端结构域(VH和CH1)的免疫球蛋白重链部分。它可以通过体外表达系统与轻链一起生产,以便产生重组Fab,如在例如参考文献21中所公开的。
6个CDR(每个可变区3个)共同地赋予抗体抗原结合特异性。但是,即使单个可变结构域(或仅包含3个对抗原特异性的CDR的一半Fv)具有识别和结合抗原的能力,尽管亲和力低于整个结合位点。由于暴露的疏水残基,它们单独地表现出非常低的溶解度。但是,它们可以组合形成Fv。
表述“CDR肽”包括编码单个互补性决定区的最小识别单元。通过构建编码目标抗体的CDR的基因,可以得到CDR肽。这样的基因如下制备,例如,通过使用聚合酶链式反应来从抗体生产细胞的RNA合成可变区。或者,通过筛选噬菌体展示或核糖体展示文库,可以得到CDR肽(参见例如参考文献22)。
术语“微体”是指完整抗体的微小形式,其在单链中编码完整抗体的基本元件。它包含与铰链区和CH3结构域融合的天然抗体的VL和VH结构域。它们由用微体基因转化的宿主细胞表达(参见例如参考文献23或参考文献24)。
术语“多体”是指具有几个源自抗体的抗原结合位点的多价构建体,例如双抗体、二-scFV、三链抗体、四抗体(tetrabody)。例如,“双抗体”是具有2个抗原结合位点的小抗体片段,该片段包含在相同多肽链(VH-VL)中连接到轻链可变结构域(VL)上的重链可变结构域(VH)。通过使用太短而不允许在相同链上的2个结构域之间配对的连接物,迫使所述结构域与另一链的互补结构域配对,并建立2个抗原结合位点。双抗体更详细地描述在例如参考文献25或参考文献26中。二-scFv具有与双抗体接近的总结构,但是它由仅一个包含4个可变结构域的多肽组成(参见例如参考文献25)。
术语“VhH”和“V-NAR”分别是指骆驼状和鲨鱼Ig的单个高亲和力V-样结构域(参见例如参考文献27)。不同于啮齿动物或灵长类动物VH结构域(它们是可溶片段),而骆马(IIama)VhH结构域似乎是仅微小免疫原性的。
重组抗体片段的综述可以参见例如参考文献27,而生产这些重组抗体片段的方法描述在例如参考文献28或参考文献29中。
抗-聚合物抗体实际上可以针对任意类型的聚合物抗原产生。例如,已经针对许多天然的、合成的和半-合成的聚合物产生了多克隆和单克隆抗体,例如,抗-血凝素、抗-HIV gp120、抗-磷蛋白、抗-DNA、抗-半乳聚糖、抗-葡聚糖、抗-聚赖氨酸、抗-聚精氨酸、抗-聚丙烯酰胺、抗-聚乙烯吡咯烷酮和抗-聚乙二醇抗体,如在例如参考文献30中所述。
优选的抗体是识别并特异性地结合亲水聚合物的那些,所述亲水聚合物包括,例如,在它们的主链中包含氧乙烯重复单元的聚合物或共聚物,诸如聚乙二醇(PEG,在本领域也鉴别为“聚环氧乙烷”-PEO或“聚氧乙烯”-POE)及其衍生物,含有氧丙烯重复单元的聚合物或共聚物,诸如聚丙二醇(PPG,在本领域也鉴别为“聚环氧丙烷(polypropylene oxide)”-PPO或“聚氧丙烯”-POP)及其衍生物,多糖(例如葡聚糖)、聚氨基酸(例如聚赖氨酸)、多核苷酸或寡核苷酸或半合成肽。更优选的抗体是能识别并特异性地结合在它们的主链中包含重复氧乙烯重复单元的聚合物或共聚物的那些,诸如PEG或环氧乙烷和环氧丙烷的共聚物(例如PEG和PPG的嵌段共聚物)。特别优选的是识别并结合包含重复氧乙烯重复单元(例如PEG)且以甲氧基终止(例如mPEG,即甲氧基-终止的PEG)的聚合物的那些抗体。
例如,能特异性地结合mPEG的抗体是特别有利的,因为它们可以用于特异性地结合含有所述mPEG的超分子集合体,其可以包含在还含有未甲氧基化的PEG聚合物的制剂中(例如,没有末端甲氧基的PEG经常在充气微泡或脂质体的冻干前体的制备中用作冷冻保护剂物质)。
抗-PEG抗体是本领域众所周知的,且描述在例如参考文献31或参考文献32中,它们二者通过引用并入本文。对结合PEG-主链(即对聚合物主链中的重复氧乙烯单元序列)特异性的商业抗-PEG抗体可作为AGP3和E11(Institute of Biomedical Sciences,Academia Sinica,Taipei,Taiwan)得到,而对结合以甲氧基终止的PEG聚合物特异性的抗体可作为抗体PEG-B-47(Epitomics Inc.USA)得到。
靶向配体
为了实现含有聚合物的脂质体或充气微泡与希望的身体区域或组织的有效结合,使抗-聚合物抗体与能结合所述特定身体区域或组织的合适组分相结合。所述组分因而包含能结合所述特定身体区域或组织的对应靶物(例如在特定身体区域或组织中表达的受体)的靶向部分。本文使用的术语“靶向配体”包括具有或能够促进在体内对组织和/或受体的靶向活动的任何化合物、部分或残基。靶向配体可结合的靶物包括组织诸如心肌组织(包括心肌的细胞和心肌细胞(cardiomyocyte)、膜组织(包括内皮和上皮)、层、结缔组织(包括间质组织)或肿瘤;血块;和受体,诸如肽激素、神经递质、抗原、补体片段、免疫球蛋白的细胞表面受体,以及类固醇激素的胞质受体。因为它们的平均尺寸,脂质体和充气微泡具有保留在血管内隔室中的一般趋势;因而优选地,靶向位点的位置最优选地是在腔内。因此,分子靶物优选地与血管内皮衬里的内皮细胞相结合。这些靶物可以是在内皮细胞的表面处或整合进内皮细胞膜内。
合适的靶向配体的实例包括,例如,蛋白,包括抗体、抗体片段、受体分子、受体结合分子、糖蛋白和凝集素;肽,包括寡肽和多肽;假肽;糖类,包括单糖和多糖;维生素;甾类、类固醇类似物、激素、辅因子、生物活性剂,包括取代的小分子和遗传物质,包括核苷、核苷酸和多核苷酸及其模仿物诸如肽核酸。
合适的靶物和靶向配体的实例公开在例如参考文献33中,它通过引用并入本文。
本发明的靶向微泡的合适的特异性靶物的实例是,例如,纤维蛋白和活化的血小板上的GPIIbIIIa受体。纤维蛋白和血小板通常存在于“血栓”即凝块中,所述凝块可以形成在血流中,并造成血管阻塞。另外,纤维蛋白也可能与不同的肿瘤过程有关。优选的对纤维蛋白靶向特异性的结合肽公开在例如参考文献34中,其通过引用并入本文。其它优选的对纤维蛋白靶向特异性的结合肽也公开在参考文献35和参考文献36中,它们也通过引用并入本文。
重要的靶物的其它实例包括脆弱血小板中的受体和肿瘤特异性的受体,诸如激酶插入结构域受体(KDR)和VEGF(血管内皮生长因子)/KDR复合物。适用于靶向KDR或VEGF/KDR复合物的结合肽的实例公开在例如参考文献37、参考文献38、参考文献39和参考文献40中,它们都通过引用并入本文。肿瘤特异性的配体的其它实例是,例如,转铁蛋白、叶酸、精氨酸-甘氨酸-门冬氨酸序列(RGD)、NRG序列(用于靶向在新形成的血管上表达的氨肽酶)或GA3肽序列(靶向参与肿瘤血管发生的Tie2受体)、促吞噬肽-样序列(靶向在参考文献41中所述的NRP-1受体)。
根据本发明的一个实施方案,所述靶向配体是抗体,其中术语抗体包括上面定义的多克隆抗体、单克隆抗体、天然抗体片段、重组抗体片段和多特异性抗体,以及它们的抗原结合片段(例如亲和体)。在下表中列举了合适的抗体和它们各自的潜在靶物(当可得到时)的实例。
抗-聚合物抗体与靶向配体的结合
用于本发明中的有用的靶向构建体可以通过下面的通式来表示:
(TL)n Z(APA)m
其中
TL表示上面定义的靶向配体,其任选地用能与连接物Z反应或形成连接物Z的部分官能化;
APA表示上面定义的抗-聚合物抗体,其任选地用能与连接物Z反应或形成连接物Z的部分官能化;
Z表示双或多功能连接物,其选自:共价键;连接部分;螯合部分;结合蛋白(例如抗生物素蛋白或链霉抗生物素蛋白);或超分子载体,诸如胶束(micelle)、脂质体或纳米颗粒;且
n和m是在1至100,000之间独立地变化的整数。
例如,当Z是共价键(即双功能连接物)时,TL和APA被适当地修饰,以彼此反应(从而形成连接物Z作为共价键),且m和n都是1。
当Z是链霉抗生物素蛋白(四功能连接物)时,TL和APA被适当地修饰,以与连接物相互作用(具体地,将生物素部分引入TL和APA的各个结构),m可以是1、2或3,且n可以是3、2或1(m+n的总和为4)。
当Z是诸如胶束或脂质体等多功能连接物时,TL和APA被修饰,以与连接物相互作用(例如它们可以连接到胶束或脂质体的分子上),且n和m可以在1至100,000之间变化,取决于连接物的组成和它的尺寸。
根据不同的操作和方法学,可以使抗-聚合物抗体与靶向配体相结合,以提供希望的靶向构建体。
在第一个实施方案中,所述抗-聚合物抗体共价结合到靶向配体上。在该情况下,APA和TL优选地作为重组融合蛋白(诸如双抗体或双特异性的二-scFv)产生。通过融合2个杂交瘤(杂种杂交瘤),或通过经由二硫键连接2个还原的抗体片段,也可以生产双特异性的抗体。或者,可以如下生产双特异性的抗体:通过使用异双功能的或同双功能的连接物、多价功能化的聚合物诸如4-臂PEG-马来酰亚胺(CreativePegWorks,USA)来化学偶联2种不同的抗体,或通过引入定向的偶联基团,诸如可在“生物缀合物工具试剂盒试剂”(Pierce,Switzerland)中得到的那些。例如,APA可以通过将肼部分引入它的结构中来修饰,例如通过使该组分与琥珀酰亚胺基4-肼基烟酸盐丙酮腙反应。单独地,修饰TL(例如靶向抗体或其片段),以将醛基引入它的结构中,例如通过使它与琥珀酰亚胺基4-甲酰基苯甲酸盐反应。然后使这样修饰的化合物以等摩尔比在室温反应数小时,以形成共价结合的双特异性的缀合物。如果需要,可以通过凝胶过滤色谱法,将异源二聚体与未反应的化合物和/或多聚体分离。当然,通过将肼基团引入靶向配体(例如靶向抗体或其片段)中,和通过将醛基引入抗-聚合物抗体的结构中,可以类似地实现上述操作。类似地,作为双抗体的替代,可以适当地修饰双功能的APA和TL,以生成四抗体,其中2个APA连接到2个TL上。
在一个优选的实施方案中,使抗-聚合物抗体与靶向配体非共价地结合(例如以超分子集合体的形式,诸如胶束、纳米颗粒或脂质体)。
例如,抗体和靶向配体可以以图1所示的胶束形式非共价地结合。为此,使两亲化合物101(例如磷脂)共价结合抗-聚合物抗体102,而使另一种(或相同的)两亲化合物结合希望的靶向配体103。然后在水性载体中混合含有各自的额外组分的2种两亲化合物,以得到胶束集合体形式的靶向构建体。
或者,抗体和靶向配体可以以图2所示的脂质体形式非共价地结合。例如,类似于上述操作,可以使APA和TL(分别指示为202和203)共价地结合各自的两亲化合物201,然后将其包含在脂质体的外膜204(例如由相同的和/或不同的两亲化合物形成)中。有利地,胶束结构、尤其是脂质体的使用,允许增加含有聚合物的脂质体或微泡的结合位点的量,特别是在目标区域中的靶向位点的量相对较少的那些情况下。
或者,所述非共价结合可以基于图3所示的生物学特异性亲和相互作用(例如链霉抗生物素蛋白-生物素结合)。例如,通过将生物素部分301引入它的结构中,可以修饰靶向配体303(例如通过在含有反应生物素的溶液存在下,温育靶向抗体的磷酸盐缓冲悬浮液)。类似地,也可以以类似的方式修饰抗-聚合物抗体302,以得到生物素化的抗-聚合物抗体。然后使2种生物素化的抗体的混合物与含有链霉抗生物素蛋白304(能结合4个生物素部分)的悬浮液反应,以得到希望的双特异性的构建体,如图3的示意图所示。如果需要,包含靶向配体和APA的构建体也可以有利地包含治疗剂。例如,所述治疗剂可以包含在脂质体组合物内。
在一个替代实施方案中,也可能制备不同的(即2种或更多种)靶向构建体的混合物,所述靶向构建体包含与抗-聚合物抗体结合的不同靶向配体。
例如,这可以通过简单地混合2种或更多种如上所述制备的不同的靶向构建体制品(在抗体和靶向配体之间存在共价的或非共价的结合)来得到。或者,可以如下得到混合物:通过使用2种或更多种靶向配体(与抗-聚合物抗体相混合)用于制备超分子载体(例如胶束、脂质体),或通过使用2种或更多种不同的生物素化的靶向配体(与生物素化的抗-聚合物抗体相混合)用于制备生物素-链霉抗生物素蛋白靶向构建体(根据上述方法)。
充气微泡
根据本发明的充气微泡可以是本领域已知的任意微泡,包括充气的微气泡、微囊和微气球。
优选的微泡是充气的微气泡,即通常用一种或多种两亲组分稳定化的微泡。适用于形成微气泡的稳定化外膜的两亲组分包括,例如,磷脂;溶血磷脂质;脂肪酸,诸如棕榈酸、硬脂酸、花生四烯酸或油酸;携带聚合物的脂质,例如壳多糖、透明质酸、聚乙烯吡咯烷酮或聚乙二醇(PEG)(也称作“聚乙二醇化的脂质”);携带磺化单-、二-、寡-或多糖的脂质;胆固醇、胆固醇硫酸酯或胆固醇半琥珀酸酯;维生素E半琥珀酸酯;具有醚或酯连接的脂肪酸的脂质;聚合脂质;联乙酰磷酸酯;联十六烷基磷酸酯;神经酰胺;聚氧乙烯脂肪酸酯(例如聚氧乙烯脂肪酸硬酯酸酯)、聚氧乙烯脂肪醇、聚氧乙烯脂肪醇醚、聚氧乙基化失水山梨醇脂肪酸酯、甘油聚乙二醇蓖麻油酸酯、乙氧基化大豆甾醇、乙氧基化蓖麻油或环氧乙烷(EO)和环氧丙烷(PO)的嵌段共聚物;甾醇脂族酸酯,包括胆固醇丁酸酯、胆固醇异丁酸酯、胆固醇棕榈酸酯、胆固醇硬脂酸酯、羊毛甾醇乙酸酯、麦角甾醇棕榈酸酯或植物甾醇正丁酸酯;糖酸的甾醇酯,包括胆固醇葡糖苷酸、羊毛甾醇葡糖苷酸、7-脱氢胆固醇葡糖苷酸、麦角甾醇葡糖苷酸、胆固醇葡糖酸酯、羊毛甾醇葡糖酸酯或麦角甾醇葡糖酸酯;糖酸和醇的酯,包括月桂基葡糖苷酸(glucoronide)、硬脂酰葡糖苷酸、肉豆蔻酰葡糖苷酸、月桂基葡糖酸酯、肉豆蔻酰葡糖酸酯或硬脂酰葡糖酸酯;糖与脂族酸的酯,包括蔗糖月桂酸酯、果糖月桂酸酯、蔗糖棕榈酸酯、蔗糖硬脂酸酯、葡糖醛酸、葡糖酸或多糖醛酸;皂角苷,包括萨尔萨皂草配基、菝葜配基、常春配基、齐墩果酸或毛地黄毒苷配基;甘油或甘油酯,包括甘油三棕榈酸酯、甘油二硬脂酸酯、甘油三硬脂酸酯、甘油二肉豆蔻酸酯、甘油三肉豆蔻酸酯、甘油二月桂酸酯、甘油三月桂酸酯、甘油二棕榈酸酯;长链醇,包括正-癸醇、月桂醇、肉豆蔻醇、十六醇或正-十八醇;6-(5-胆甾-3β-基氧)-1-硫代-β-D-吡喃半乳糖苷;双半乳糖二甘油酯;6-(5-胆甾-3β-基氧)己基-6-氨基-6-脱氧-1-硫代-β-D-吡喃半乳糖苷;6-(5-胆甾-3β-基氧)己基-6-氨基-6-脱氧-1-硫代-β-D-吡喃甘露糖苷;12-(((7’-二乙基氨香豆素-3-基)羰基)甲氨基)十八酸;N-[12-(((7’-二乙基氨香豆素-3-基)羰基)甲氨基)十八酰基]-2-氨基棕榈酸;N-琥珀酰-二油酰基磷脂酰乙醇胺;1,2-二油酰基-sn-甘油;1,2-二棕榈酰基-sn-3-琥珀酰甘油;1,3-二棕榈酰基-2-琥珀酰甘油;1-十六烷基-2-棕榈酰基甘油磷乙醇胺或棕榈酰基高半胱氨酸;包括至少一个(C10-C20)、优选(C14-C18)烷基链的烷基胺或烷基铵盐,例如,N-硬脂酰胺、N,N’-二硬脂酰胺、N-十六烷基胺、N,N’-二(十六烷基)胺、N-硬脂酰氯化铵、N,N’-二硬脂酰氯化铵、N-十六烷基氯化铵、N,N’-二(十六烷基)氯化铵、二甲基双十八烷基溴化铵(DDAB)、十六烷基三甲基溴化铵(CTAB);包括一个或优选包括两个(C10-C20)、优选(C14-C18)酰基链(此链通过(C3-C6)亚烷基桥连接到N原子上)的三价或四价铵盐,例如1,2-二硬脂酰基-3-三甲基铵-丙烷(DSTAP)、1,2-二棕榈酰基-3-三甲基铵-丙烷(DPTAP)、1,2-二油酰基-3-三甲基铵-丙烷(DOTAP)、1,2-二硬脂酰基-3-二甲基铵-丙烷(DSDAP);以及这些物质的混合或组合。
根据一个优选实施方案,至少一个形成微气泡外膜的化合物是磷脂,并且任选地与任何其它上述物质相混合。根据本发明的描述,术语磷脂意在包含任何两亲磷脂化合物,其分子能够在最终的微泡悬浮液中的气-液边界界面处形成稳定物质膜(一般是单分子层的形式)。据此,这些物质在本领域内也称作“成膜磷脂”。
两亲磷脂化合物一般含有至少一个磷酸基和至少一个、优选两个亲脂长链烃基。
合适磷脂的实例包括甘油和一个或优选两个(等同或不同)脂肪酸残基的酯以及甘油和磷酸的酯,其中磷酸残基又与亲水基团结合,例如胆碱(磷脂酰胆碱-PC)、丝氨酸(磷脂酰丝氨酸-PS)、甘油(磷脂酰甘油-PG)、乙醇胺(磷脂酰乙醇胺-PE)、肌醇(磷脂酰肌醇)。磷脂与脂肪酸的仅仅一个残基的酯在本领域内通常称作磷脂的“溶血”形式或“溶血磷脂质”。存在于磷脂中的脂肪酸残基通常是长链脂族酸,一般含有12-24个、优选14-22个碳原子;脂族链可含有一个或多个不饱和基团,或者优选地完全饱和基团。包括在磷脂中的合适脂肪酸的实例有,例如月桂酸、肉豆蔻酸、棕榈酸、硬脂酸、花生酸、山萮酸、油酸、亚油酸和亚麻酸。优选地,采用例如肉豆蔻酸、棕榈酸、硬脂酸和花生酸之类的饱和脂肪酸。
磷脂的进一步实例是磷脂酸,即甘油-磷酸和脂肪酸的二酯;鞘脂例如鞘磷脂,即甘油二酯与脂肪酸的残基被神经酰胺链取代的那些磷脂酰胆碱类似物;心磷脂,即1,3-二磷脂酰甘油与脂肪酸的酯;糖脂(glycolipids)例如神经节苷脂GM1(或GM2)或脑苷脂;糖脂(glucolipids);硫苷脂和糖鞘脂。
本文使用的术语磷脂包括能够单独使用或作为混合物使用的天然存在的、半合成或合成制备产物。
天然存在的磷脂实例有,天然磷脂酰胆碱(磷脂酰胆碱(PC)衍生物)例如一般为大豆或蛋黄卵磷脂。
半合成磷脂的实例有,天然存在的卵磷脂的部分或完全氢化衍生物。优选的磷脂是磷脂酰胆碱、乙基磷脂酰胆碱、磷脂酰甘油、磷脂酸、磷脂酰乙醇胺、磷脂酰丝氨酸、磷脂酰肌醇或鞘磷脂的脂肪酸二酯。
优选磷脂的实例如有二月桂酰基-磷脂酰胆碱(DLPC)、二肉豆蔻酰基-磷脂酰胆碱(DMPC)、二棕榈酰基-磷脂酰胆碱(DPPC)、二花生四烯酰基-磷脂酰胆碱(DAPC)、二硬脂酰基-磷脂酰胆碱(DSPC)、二油酰基-磷脂酰胆碱(DOPC)、1,2二硬脂酰基-sn-甘油-3-乙基胆碱磷酸(乙基-DSPC)、双十五酰-磷脂酰胆碱(DPDPC)、1-肉豆蔻酰-2-棕榈酰-磷脂酰胆碱(MPPC)、1-棕榈酰-2-肉豆蔻酰-磷脂酰胆碱(PMPC)、1-棕榈酰-2-硬脂酰-磷脂酰胆碱(PSPC)、1-硬脂酰-2-棕榈酰-磷脂酰胆碱(SPPC)、1-棕榈酰-2-油基磷脂酰胆碱(POPC)、1-油基-2-棕榈酰-磷脂酰胆碱(OPPC)、二月桂酰-磷脂酰胆碱(DLPG)及其碱金属盐、二花生四烯酰基磷脂酰甘油(DAPG)及其碱金属盐、二肉豆蔻酰基磷脂酰甘油(DMPG)及其碱金属盐、二棕榈酰基磷脂酰甘油(DPPG)及其碱金属盐、二硬脂酰基磷脂酰甘油(DSPG)及其碱金属盐、二油酰基-磷脂酰甘油(DOPG)及其碱金属盐、二肉豆蔻酰基磷脂酸(DMPA)及其碱金属盐、二棕榈酰基磷脂酸(DPPA)及其碱金属盐、二硬脂酰基磷脂酸(DSPA)、二花生四烯酰基磷脂酸(DAPA)及其碱金属盐、二肉豆蔻酰基磷脂酰乙醇胺(DMPE)、二棕榈酰基磷脂酰乙醇胺(DPPE)、二硬脂酰基磷脂酰乙醇胺(DSPE)、二油基磷脂乙醇胺(DOPE)、二花生四烯酰基磷脂酰乙醇胺(DAPE)、二亚油酰基磷脂酰乙醇胺(DLPE)、二肉豆蔻酰基磷脂酰丝氨酸(DMPS)、二花生四烯酰基磷脂酰丝氨酸(DAPS)、二棕榈酰基磷脂酰丝氨酸(DPPS)、二硬脂酰基磷脂酰丝氨酸(DSPS)、二油酰基磷脂酰丝氨酸(DOPS)、二棕榈酰基鞘磷脂(DPSP)和二硬脂酰基鞘磷脂(DSSP)、二月桂酰基-磷脂酰肌醇(DLPI)、二花生四烯酰基磷脂酰肌醇(DAPI)、二肉豆蔻酰基磷脂酰肌醇(DMPI)、二棕榈酰基磷脂酰肌醇(DPPI)、二硬脂酰基磷脂酰肌醇(DSPI)、二油酰基-磷脂酰肌醇(DOPI)。
特别优选的磷脂是DAPC、DSPC、DPPC、DMPA、DPPA、DSPA、DMPG、DPPG、DSPG、DMPS、DPPS、DSPS和乙基-DSPC。最优选的是DPPG、DPPS和DSPC。
也可以采用磷脂混合物,例如DPPE、DPPC、DSPC和/或DAPC与DSPS、DPPS、DSPA、DPPA、DSPG、DPPG、乙基-DSPC和/或乙基-DPPC的混合物。
在优选的实施方案中,磷脂是微泡的稳定外膜的主要组分,占形成充气微泡外膜的组分总量的至少50%(w/w)。在一些优选实施方案中,基本上外膜整体(即至少90%)是由磷脂形成。
磷脂可便利地以与上述列出的任何两亲化合物混合的形式来使用。由此,例如,脂质(例如胆固醇、麦角固醇、植物甾醇、谷甾醇、羊毛固醇、生育酚、没食子酸丙酯或棕榈酸抗坏血酸酯)、脂肪酸(例如肉豆蔻酸、棕榈酸、硬脂酸、花生酸及其衍生物)或丁羟甲苯和/或其它非磷脂化合物,可任选地加入到一种或多种上述磷脂中,所占的比例为0-50%(按重量计)、优选高达25%。特别优选的是棕榈酸。
为了与抗-聚合物抗体适当地相互作用,微泡的稳定化外膜则应当包含聚合物,优选亲水聚合物。合适的亲水聚合物的实例包括,例如,在它们的主链中包含氧乙烯重复单元的聚合物或共聚物(诸如PEG)及其衍生物、含有氧丙烯重复单元的聚合物或共聚物(诸如PPG)及其衍生物、多糖(例如葡聚糖)、聚氨基酸(例如聚赖氨酸)、多核苷酸或寡核苷酸或半合成肽。在这些聚合物中,合成的或半合成的聚合物是优选的,特别优选的是在它们的主链中包含重复氧乙烯单元的聚合物或共聚物诸如PEG,或环氧乙烷和环氧丙烷的共聚物(例如PEG和PPG的嵌段共聚物)。根据一个优选的实施方案,包含重复氧乙烯单元的聚合物以甲氧基终止,即:
-(O-CH2-CH2)n-O-CH3
其中自由边界指示聚合物与微泡外膜(或其组分)的结合,且n是指示聚合物的重复氧乙烯单元的数目的整数,其可以在约10至约2,000、优选约20至约200、更优选约40至约160内变化。特别优选的聚合物是甲氧基-终止的PEG(mPEG)。
聚合物的分子量可以在约500至约100,000道尔顿、优选约1,000至约10,000道尔顿内变化。特别优选的是分子量为约2,000至8,000道尔顿,更优选约5,000道尔顿的mPEG。
所述聚合物通常共价结合到与微气泡的稳定化外膜的组分相容的化合物上,优选在其中至少包含疏水部分的化合物(从而与形成外膜的其它稳定化化合物发生疏水相互作用),优选两亲化合物例如磷脂。优选的含有亲水聚合物的磷脂的实例是用PEG修饰的磷脂酰乙醇胺(PE)(简称“PE-PEG”)即其中亲水的乙醇胺部分连接到可变分子量的PEG分子上的磷脂酰乙醇胺,诸如DPPE-PEG(或DSPE-、DMPE-、DOPE-、DAPE或DLPE-PEG),即具有与其相连的PEG聚合物的DPPE(或DSPE、DMPE、DOPE、DAPE或DLPE)。例如,DPPE-PEG5000是指具有与其相连的平均分子量为约5,000的PEG聚合物的DPPE。或者,所述聚合物可以结合到其它两亲的脂质组分上,例如,糖基磷脂酰肌醇(GPI)、二酰基甘油、二烷基氧丙基、神经酰胺或胆固醇,以形成对应的聚乙二醇化的脂质衍生物。其它可能的包含亲水聚合物的组分包括非离子型表面活性剂,诸如聚氧乙烯二(咪唑基羰基)、聚氧乙烯脂肪醚(诸如商业的)、泊洛沙姆(即聚环氧乙烷与聚环氧丙烷的嵌段共聚物,诸如商业的或)、聚山梨酯(即与脂肪酸反应的聚乙二醇化的山梨聚糖的衍生物,诸如商业的)、聚乙二醇硬脂酸酯或聚氧乙烯硬脂酸酯(诸如商业的Myrj)。
申请人观察到,为了实现充气微泡与含有抗-聚合物抗体的靶向构建体的有效结合,微泡的稳定化外膜中的聚合化合物的摩尔量应当优选地是相对于形成所述外膜的组分的总摩尔量的至少0.05%,更优选至少0.2%、且甚至更优选至少1%。所述多个聚合物分子在微泡表面上的存在,允许微泡与不同的APA的多价结合,从而由于更高的亲合力而提高结合。
另一方面,申请人已经观察到,过量的聚合化合物并非必然相应地增加微泡的结合效能。因此,聚合化合物的摩尔量通常低于约15%、优选地低于约12%、且更优选地低于约10%。在某些优选的实施方案中,特别当不希望脂质体或充气微泡在血管系统中广泛(时间)循环时,优选地,聚合化合物的摩尔量不高于4%,更优选地不高于2%。
根据本发明的组合物的微气泡可以根据本领域内任何公知的方法来生产。典型地,制造方法包括制备含有如上所述的两亲物质(包括携带聚合物的两亲物质)的干粉物质,优选地通过冻干(冷冻干燥)包括所述物质的水性或有机悬浮液。
例如,如参考文献3所述,首先通过任何脂质体形成方法,可将成膜两亲化合物转化成层状形式。为此,可对包含成膜脂质和任选的其它添加剂(例如增粘剂、非成膜表面活性剂、电解质等)的水溶液进行高速机械匀化,或者在声频或超声频率下进行声处理,然后冻干,以形成可自由流动的粉末,然后在气体存在下贮存粉末。在冻干之前,可进行任选的洗涤步骤。
根据一个替换实施方案(例如在参考文献6中描述),可以将成膜化合物及亲水稳定剂(例如聚乙二醇、聚乙烯吡咯烷酮、聚乙烯醇、乙醇酸、苹果酸或麦芽醇)溶解在有机溶剂(例如叔丁醇、2-甲基-2-丁醇或C2Cl4F2)中,然后将该溶液冻干,形成干粉。
优选地,如在例如参考文献7中所公开的,可以在搅拌下将磷脂(选自以上提到的那些,包括携带聚合物的磷脂)和冻干保护剂(例如前面列出的那些,尤其是碳水化合物、糖醇、聚二醇、聚氧化亚烷基二醇及其混合物)分散在具有水不混溶的有机溶剂(例如支链或直链烷烃、烯烃、环烷烃、芳香烃、烷基醚、酮、卤化烃、全氟化烃或其混合物)的水乳液中。所述乳液可以如下得到:通过在有至少一种磷脂存在下,对水性介质和溶剂进行本领域已知的任意适当的乳液生成技术,例如,声处理、摇动、高压匀化、微观混合、膜乳化、高速搅拌或高剪切混合。例如,可以采用转子-定子式匀浆器,诸如PT3000。根据乳液的组分、乳液的体积、有机溶剂的相对体积、装有乳液的容器的直径、和乳液中溶剂的微滴的希望的最终直径,可以选择转子-定子式匀浆器的搅拌速度。或者,可以使用微观混合技术来乳化混合物,例如通过第一个入口将有机溶剂引入混合器中(例如以0.05-5mL/min的流速),并将水相从第二个入口引入(例如以2-100mL/min的流速)。根据乳液技术,可以在乳化步骤中逐渐引入有机溶剂,或在开始乳化步骤之前一次引入。或者,可以在乳化步骤中将水性介质逐渐加入水不混溶的溶剂中,或在开始乳化步骤之前一次加入。优选地,将磷脂分散在水性介质中,然后使该水性介质与有机溶剂混合。或者,可以将磷脂分散在有机溶剂中,或可以在乳化步骤之前或过程中将它单独加入水性-有机混合物中。然后根据常规技术,冻干如此获得的含有被磷脂物质(和任选的其它两亲成膜化合物和/或添加剂)包围和稳定化的溶剂微滴的微乳液,从而获得冻干物质,将其贮存(例如在合适气体存在下,在瓶中),并可与水性载体重配,从而最终获得充气的微泡悬浮液,其中微泡的尺度和尺寸分布基本上与微滴悬浮液的尺度和尺寸分布相当。
制备充气微泡的其它工艺包括如下制备气体微泡分散体:在所需气体存在下,对包含磷脂(以及任选的其它两亲成膜化合物和/或添加剂)的水性介质施加受控的高搅拌能量(例如借助于转子定子混合器),并将所获得的分散体冻干,从而产生干燥的重配产品。此方法的一个实例在例如参考文献42中给出,该文献通过引用并入本文。
也可以使用喷雾干燥技术(例如在参考文献43中所公开的)来得到干粉,其在接触生理水性载体后可重配,以得到充气的微气泡。
用以上任一技术获得的干燥或冻干产品通常是粉末或饼的形式,并可以在与希望的气体接触下作为微泡前体贮存(例如在瓶内)。在轻轻搅拌悬浮液后,所述产品在生理上可接受的水性液体载体(通常是可注射的)内可容易地重配,以形成充气的微气泡。合适的生理上可接受的液体载体是无菌水、水性溶液例如盐水(它可以有益地是平衡的,从而最终的注射产品不是低渗的),或一种或多种张力调节物(例如盐或糖、糖醇、二醇或其它非离子多元醇物质(例如葡萄糖、蔗糖、山梨醇、甘露醇、甘油、聚乙二醇、丙二醇等)的溶液。
根据一个替代实施方案,本发明的充气微泡可以是微囊。优选的微囊实例是具有包含聚合物(优选可生物降解的聚合物)或可生物降解的水不溶性的脂质(诸如棕榈精(tripalmitine))(其任选地与可生物降解的聚合物相混合)的稳定化外膜的那些。合适的微囊及其制备的实例公开在例如参考文献8和参考文献9中,它们通过引用整体并入本文。也可以采用具有蛋白性外膜(即由天然蛋白(白蛋白、血红蛋白)制成)的微囊,诸如在参考文献44或参考文献45(通过引用并入本文)中描述的那些。也在该情况下,易于被APA识别的聚合物(例如PEG或mPEG)优选地以与前述相同的摩尔量结合到与形成微囊的各个外膜的组分相容的化合物上,例如聚合物(例如聚甲基丙烯酸酯、聚苯乙烯或聚(L-丙交酯)),如上所述的两亲脂质或蛋白(例如白蛋白或乳清蛋白)。可以使用任意生物相容的气体、气体前体或其混合物来填充上述微泡(在下文中也鉴别为“形成微泡的气体”)。
气体可以包括,例如,空气;氮气;氧气;二氧化碳;氢气;氧化亚氮;稀有气体或惰性气体例如氦、氩、氙或氪;放射性气体例如Xe133或Kr81;超极化惰性气体例如超极化氦、超极化氙或超极化氖;低分子量烃(例如含有高达7个碳原子),例如:烷烃(例如甲烷、乙烷、丙烷、丁烷、异丁烷、戊烷或异戊烷)、环烷烃(例如环丁烷或环戊烷)、烯烃(例如丙烯、丁烯或异丁烯)或炔烃(例如乙炔);醚;酮;酯;卤化气体,优选氟化气体,例如卤化、氟化或全氟化低分子量烃(例如含有高达7个碳原子);或任意这些前述物质的混合物。当使用卤化烃时,优选所述化合物中的至少一些、更优选所有卤素原子是氟原子。
氟化气体是优选的,尤其是全氟化气体,特别是在超声成像领域中。氟化气体包括含有至少一个氟原子的物质,例如氟化烃(含有一个或多个碳原子和氟的有机化合物);六氟化硫;氟化、优选全氟化酮例如全氟化丙酮;和氟化、优选全氟化醚例如全氟化乙醚。优选化合物是全氟化气体,例如SF6或全氟化碳(全氟化烃),即所有氢原子都被氟原子取代的烃,已知是为了形成特别稳定的微泡悬浮液,如参考文献4中公开的。
术语全氟碳包括饱和的、不饱和的以及环化全氟碳。生物相容的生理上可接受的全氟碳的实例是:全氟烷烃,例如全氟甲烷、全氟乙烷、全氟丙烷、全氟丁烷(例如全氟-正-丁烷,任选地是与其它异构体例如全氟-异丁烷的混合物形式)、全氟戊烷、全氟己烷或全氟庚烷;全氟烯烃,例如全氟丙烯、全氟丁烯(全氟丁-2烯)或者全氟丁二烯;全氟炔烃(例如全氟丁-2-炔);以及全氟环烷烃(例如全氟环丁烷、全氟甲基环丁烷、全氟二甲基环丁烷、全氟三甲基环丁烷、全氟环戊烷、全氟甲基环戊烷、全氟二甲基环戊烷、全氟环己烷、全氟甲基环己烷和全氟环庚烷)。优选的饱和全氟碳包括,例如,CF4、C2F6、C3F8、C4F8、C4F10、C5F12和C6F14。
还有益的是,采用任何比例的任意上述气体的混合物。例如,混合物可包括常规气体(例如氮气、空气或二氧化碳)和形成稳定微泡悬浮液的气体(例如六氟化硫或如上所述的全氟碳)。合适气体混合物的实例可以参见例如参考文献46,它通过引用并入本文。以下组合是特别优选的:气体(A)和(B)的混合物,其中气体(B)是氟化气体,其选自前面列出的那些,包括它们的混合物,(A)选自空气、氧气、氮气、二氧化碳或它们的混合物。气体(B)的量为混合物总量的约0.5%至约95%v/v,优选约5%至80%。
特别优选的气体是SF6、C3F8、C4F10或它们的混合物,其任选地与空气、氧气、氮气、二氧化碳或它们的混合物相混合。
在某些情况下,期望包括气态物质的前体(即能够在体内转化成气体的物质)。优选地,气体的前体及其衍生的气体是生理上可接受的。气体的前体可以是pH激活的、光激活的、温度激活的等。例如,某些全氟碳可用作温度激活的气体前体。这些全氟碳(例如全氟戊烷和全氟己烷)具有室温(或者试剂制备或贮存温度)以上但体温以下的液态/气态转变温度;由此,它们发生液相/气相转变,并在人体内转变成气体。
为了用于MRI,微泡优选包含超极化稀有气体例如超极化氖、超极化氦、超极化氙或它们的混合物,任选地是与空气、二氧化碳、氧气、氮气、氦气、氙气或如上所述的任何卤化烃的混合物形式。
为了用于闪烁扫描术,微泡优选包含放射性气体例如Xe133或Kr81或它们的混合物、任选地是与空气、二氧化碳、氧气、氮气、氦气、氪或如上所述的任何卤化烃的混合物形式。
除了它们作为诊断剂的用途以外,充气微泡也可以用于递送治疗剂,如例如在参考文献47、参考文献48或参考文献49中所述,它们都通过引用并入本文。典型地,与希望的治疗剂一起(与其混合或与其结合)施用充气微泡,一旦微泡和治疗剂到达患者中希望的目标区域,施加能破坏充气微泡的受控声功率,将在所述区域造成治疗剂的释放(由超声介导)。
脂质体
脂质体可以有利地用作任一种前述造影剂(尤其是MRI或X-射线造影剂)或上述治疗剂的的载体。
用于制备脂质体的优选物质是磷脂,诸如前面列出的那些,其任选地与其它两亲化合物(诸如前面列出的那些)相混合。用于本发明的脂质体另外含有亲水聚合物,诸如前面列出的那些,特别优选的是PEG或mPEG,所述聚合物如下有利地插入脂质体结构中:通过使所述聚合物共价结合包含在稳定化外膜中的化合物,尤其是磷脂。亲水聚合物的优选摩尔量如前关于充气微泡的制剂所述。
为了制备脂质体悬浮液,可以使用本领域已知的常规技术。所述制备技术通常包括,将形成脂质体的化合物(例如磷脂)溶解在有机溶剂中,在真空下蒸发有机溶剂,得到形成脂质体的化合物的膜,最后水合所述膜。典型地,当形成脂质体的化合物是磷脂时,在超过磷脂转变温度以上的温度进行水合。优选地,随后如下在希望的尺寸校准如此得到的脂质体:通过使囊泡尺寸分布缩窄到适当限度内,例如通过方便地分级的过滤膜挤出。为了将希望的造影剂或治疗剂(“活性化合物”)包囊在脂质体的内部,例如作为所述活性化合物的水性溶液或悬浮液,一种优选的方法包括使用所述活性化合物的溶液或悬浮液来在脂质转变温度或以上水合脂质,随后洗涤(例如通过透析)得到的脂质体,以去除多余的未包囊的溶液或悬浮液。或者,首先在未负载的水性载体中水合脂质,然后如下将活性化合物导入脂质体内部:通过跨膜渗透装载,通过在活性化合物的浓溶液存在下温育得到的脂质体(参见例如参考文献50,其通过引用并入本文),随后洗涤脂质体。
根据常规技术,实现希望的脂质体的尺寸减小,包括声处理、挤压或微流化最初的脂质体悬浮液。因此,可以将如上所述得到的水合的脂质体暴露于超声辐射,以适当减小脂质体尺度。或者,可以使水合的脂质体挤过具有递减孔径(例如2.0、1.0、0.8、0.6、0.4和0.2μm)的多重膜(例如聚碳酸酯膜),以将脂质体尺寸减小至最终希望的尺度。作为另一个替代方案,可以在微流化仪(例如购自Microfluidics Corporation)中在高压下均质化大囊泡,以逐渐减小脂质体尺寸至希望的尺寸,这取决于脂质体在微流化仪中再循环的量。
优选地,在尺寸减小后,约80%的囊泡是选自0.2至1.0μm的任意标称值±10%。但是,容许在前述限度内的任何其它更宽或更窄的分布。在尺寸减小处理后,优选地检查悬浮液,以确保脂质体悬浮液中的脂质的浓度是足够的,任选地调节该浓度,以符合希望的用途。如果脂质浓度超过希望的限度,通过用更大体积的载体液体进行稀释,可以实现调节;另一方面,通过常见的方式,可以增加浓度,例如通过在具有适当孔隙率的膜上的微滤或超滤,所述膜保留囊泡,但是可透过载体液体。优选地如下插入易于被APA识别的聚合物:通过使它结合与形成脂质体外膜的组分相容的化合物,优选两亲的脂质化合物(例如磷脂),如上面所解释的。
脂质体和它们的制备方法的综述也可以参见参考书,诸如参考文献51。
可以如下将希望的造影剂(优选MRI响应剂)或治疗剂插入到脂质体结构中:通过将所述化合物包封在脂质体内部,或通过使它结合脂质体的膜(磷脂双层)或脂质体的表面。例如,可以将磁性纳米颗粒或治疗剂悬浮于脂质体的液体内部。或者,可以使螯合的顺磁离子结合与形成脂质体外膜的组分相容的化合物,优选两亲的脂质化合物(例如磷脂),如上面所解释的。根据一个优选的实施方案(例如在参考文献52中所公开的,其通过引用并入本文),可以使包含MRI造影剂的胶束结合(例如通过静电相互作用)脂质体的表面。有利地,脂质体的应用允许治疗剂和/或诊断剂在其结构中的相对较高的负载。
优选的顺磁金属离子具有原子序数21-29、42、44或57-83,包括过渡金属或镧系元素系列的离子,其具有至少1个、且更优选5个或更多个未成对电子和至少1.7玻尔磁子的磁矩。优选的顺磁金属包括、但不限于:铬(III)、锰(II)、锰(III)、铁(II)、铁(III)、钴(II)、镍(II)、铜(II)、镨(III)、钕(III)、钐(III)、钆(III)、铽(III)、镝(III)、钬(III)、铒(III)、铕(III)和镱(III)。优选的顺磁离子是钆。所述顺磁离子优选地与螯合部分或螯合剂螯合。本领域已知的合适的螯合剂包括具有下述基团的酸:亚甲基膦酸基团、亚甲基糖胺酸(carbohydroxamine acid)基团、羧基亚乙基基团或羧基亚甲基基团,例如,二亚乙基三胺五乙酸(DTPA)、1,4,7,10-四氮杂环十二烷-1,4,7,10-四乙酸(DOTA)、1,4,7,-三羧甲基1,4,7,10-四氮杂环十二烷三乙酸(DO3A),诸如1,4,7,10-四氮杂环-十二烷-1-(2-羟丙基)-4,7,10-三乙酸(HP-DO3A)、乙二胺四乙酸(EDTA)和1,4,8,11-四氮杂环十四烷-1,4,8,11-四乙酸(TETA)。任一种这样的螯合的顺磁离子可以结合到上述的合适的两亲脂质(例如磷脂酰乙醇胺)上,并根据已知的技术,将得到的构建体与脂质体外膜的其它组分相混合。
可以掺入脂质体中的其它造影剂的实例包括,例如,碘化的化合物,诸如碘美普尔或碘帕醇(可从Bracco Imaging商业得到);包含超极化的原子的化合物,诸如13C、15N、19F、23Na、31P或35.5Cl,包括例如[13C]脲(参见例如参考文献54)或二-1,1-羟甲基-1-13C-环丙烷-D8(参见例如参考文献55);放射性药剂,诸如锝(99mTc)、镓(67Ga或68Ga)、铟(111In)或铊(201Tl)的复合物;或上面定义的光学成像剂或核成像剂。
脂质体/微泡和靶向构建体
可以以许多不同的方式,并在造影/治疗方法的许多不同的步骤中,使靶向构建体结合脂质体或充气微泡。
根据一个实施方案,可以在上述任何制备方法的任何合适的阶段,使靶向构建体与形成超分子集合体的组分相混合。例如,在参考文献7所公开的方法的情况下,可以使靶向构建体与最初混合物的组分相混合,进行乳化和冻干步骤。或者,可以单独制备含有构建体的悬浮液,随后加入到已经形成的乳液(含有其它成膜组分)中,优选地在加热下进行。或者,可以使靶向构建体与超分子集合体的悬浮液相混合(例如作为悬浮液),得到的含有与集合体结合的靶向构建体的混合物可以原样用于施用,或可以经历进一步的冻干步骤,然后进行最后的重配和使用。
根据优选的实施方案,在施用造影剂(例如充气微泡)之前,将靶向构建体单独施用给患者。在预定的时间段之后(例如以允许靶向构建体在希望的目标区域有效积累),然后施用造影剂。造影剂因而将结合在患者体内的靶向构建体,特别是在目标区域,其中构建体的靶向配体将结合对应的靶位点。
药用试剂盒、施用和成像
包含根据本发明的脂质体或充气微泡和靶向构建体的药用试剂盒可以以不同形式呈现,取决于脂质体或微泡与靶向构建体的结合方式。
根据一个优选的实施方案,所述药用试剂盒含有至少2种组分,第一种是脂质体或充气微泡(或其前体),第二种是靶向构建体。任选地,在试剂盒中可以包括一种或多种其它不同的靶向构建体(例如具有相同的抗-聚合物抗体,但是不同的靶向配体)。典型地,每种组分包含在各自的单独的容器中。或者,可以将不同靶向构建体的混合物包含在单个容器中。
优选地,第一个容器包含干粉形式的充气微泡前体,其接触形成微泡的气体。
第二组分可以以干燥固体形式或作为在生理上可接受的水性载体中的悬浮液存在于容器中。
上述试剂盒可以任选地含有生理上可接受的水性载体(在分开的容器中,或在双室容器中),用于在注射之前重配干燥组分。
组分的重配取决于选择的施用方法学。例如,如果分开施用靶向构建体和造影剂/治疗剂,两种组分相应地分别用各自的载体重配。或者,如果预知提前用靶向构建体装配脂质体或充气微泡(对于它们的同时施用),两种组合物可以先后用相同载体重配。
或者,当冻干的组合物含有已经与靶向构建体混合的微泡前体时,试剂盒可以包含两个容器,第一个容器含有与选择的形成微泡的气体(如前面讨论的那些)相接触的冻干组合物,第二个容器含有生理上可接受的水性载体。
本发明的集合体可以用于多种体内和体外反差成像方法中,具体包括超声成像。反差成像包括身体部分或组织的任何反差增强的成像,以及任何其它诊断技术或方法,例如,定量诊断技术(包括例如血压、血流量和/或血液流注评估)。
典型地,给患者施用有效量的集合体(例如通过注射),作为单独的组分,或作为已经形成的集合体,并对要成像或治疗的身体部分或组织(“目标区域”)进行希望的成像方法学。术语患者包括接受集合体施用的任意受试者(人或动物),无论为了诊断/治疗目的,还是为了实验目的(包括,例如,造影剂在实验动物中的应用,例如跟踪实验治疗处理)。
根据图4所示的一个优选的实施方案,首先给患者施用有效量的靶向构建体(浓度为例如从约1nmol/kg至500nmol/kg、优选5nmol/kg至50nmol/kg,更优选10nmol/kg至30nmol/kg,取决于例如构建体的类型和/或靶向配体的类型),通常通过注射其悬浮液。然后使组合物在患者的血管系统中循环足够的时间,以使靶向构建体401到达目标区域404(即假定表达或含有构建体的靶向配体403的各个靶物或受体405的区域),并通过各个靶向配体403与它们结合,如图4a所示。为了澄清,已经在图4中指出双特异性的靶向构建体401,其仅包含一个靶向配体403和一个抗-聚合物抗体402,但是应当理解,该图示包括任一种前述的靶向构建体。然后,将含有亲水聚合物407的希望的造影剂/治疗剂406(例如在该情况下的充气微泡)的悬浮液注射进患者,用合适的成像技术对目标区域成像,和/或对目标区域进行希望的治疗性处理(例如超声介导的治疗剂释放)。实践人员基于普通的医疗实践,根据例如患者(例如类型、年龄、体重)、靶向构建体的类型和性质(例如它在血液中的半衰期和/或它在靶组织/区域中的积累)、成像方法的类型和/或治疗以及目标区域的位置,可以容易地确定施用靶向构建体和施用造影剂之间的时间间隔。例如,在使用充气微泡的超声成像的情况下,2次施用之间的时间间隔可以是,例如,约5分钟至约48小时,通常约30分钟至约24小时。微泡406的存在因而增强目标区域的成像,所述微泡406通过在其外膜中包含的聚合物407的末端部分408结合到固定化在目标区域404上的靶向构建体401的一种或多种抗-聚合物抗体402上,如图4b所示。
多种成像技术可以用于超声用途中,例如包括基础的和谐波B-模式成像,脉冲或倒相成像和基础的和谐波多普勒成像;如果可以使用希望的三维成像技术。此外,也预见到能够破碎充气微泡的诊断技术(例如借助于在高音压的超声波),例如在评估血液灌注的方法中。
根据本发明的微泡通常以约0.01至约5.0μl气体/kg患者的浓度施用,取决于例如它们各自的组成、要成像的组织或器官和/或选择的成像技术。该一般浓度范围当然可以随具体成像用途而异,例如当可以在非常低的剂量观察到信号时,诸如在彩色多普勒或功率脉冲倒转中。可能的其它诊断性成像用途包括闪烁显像、光成像、和X-射线成像,包括X-射线相衬成像。
下面的非限制性实施例意在更好地解释本发明。实施例1-9、11和14-21是实际实施例,而实施例10、12、13和22-30是预测实施例。
实施例
在随后的实施例中,采用下面的缩写和物质:
实施例1
生物素化的抗-小鼠P-选择蛋白抗体的制备
将1mg Chromalink生物素354S(目录号B-1001-110,Solulink,USA)溶于在室温的DMF(100μL)中,得到12.3mM溶液。将该溶液(10mol当量)加入到大鼠抗小鼠P-选择蛋白抗体(克隆RB40.34,目录号553741,BD Biosciences,USA)的溶液中,后一种溶液通过将1mg/ml抗体溶于磷酸盐缓冲盐水(pH 7.4)中来制备。将反应混合物在室温温育2小时,然后使用Zeba旋转柱通过凝胶过滤进行纯化,在PBS中平衡(2min 1,000g,Pierce,USA)。按照生产商的推荐,通过光谱测定法测量测得,得到的生物素化的抗体含有2.0生物素残基/抗体分子。
实施例2
生物素化的抗-mPEG抗体的制备
通过用兔抗-mPEG抗体(克隆PEG-B-47,目录号2061-1,来自Epitomics,USA)替换抗-小鼠P-选择蛋白抗体,重复实施例1。得到的生物素化的抗体含有1.9生物素残基/抗体分子。
实施例3(对比)
生物素化的大鼠同种型抗体(对照)的制备
通过用大鼠同种型对照抗体(亲和纯化的大鼠IgG1同种型对照,eBioscience,目录号14-4301)替换抗-小鼠P-选择蛋白抗体,重复实施例1。得到的生物素化的抗体含有1.9生物素残基/抗体分子。
实施例4
双特异性的靶向的链霉抗生物素蛋白(抗小鼠P-选择蛋白抗体和抗mPEG抗体)的制备
将10μg根据实施例1制备的生物素-抗小鼠P-选择蛋白抗体和10μg根据实施例2制备的生物素-抗mPEG抗体溶于800μL磷酸盐缓冲盐水(pH 7.4)中。然后,在搅拌下,将该抗体混合物加入到28.3μL通过将链霉抗生物素蛋白(IBA,目录号2-0203-100)溶解在蒸馏水中制备的链霉抗生物素蛋白溶液(1mg/mL)中。在25℃混合该溶液30分钟。
实施例5(对比)
双特异性的对照链霉抗生物素蛋白(对照)的制备
通过用根据实施例3制备的生物素大鼠同种型对照抗体替换生物素-抗小鼠P-选择蛋白抗体,重复实施例4。
实施例6
含有mPEG的充气微泡的制备
将27mg DSPC和2.2mg棕榈酸溶解在60℃的3.9g环辛烷中。将得到的溶液冷却至室温,并分散在含有5.5g PEG4000(Fluka)和19mg DPPE-mPEG5000的50mL蒸馏水中,所述分散使用高速匀浆器(Polytron T3000)在8000rpm处理1分钟来实现。在搅拌下在80℃加热得到的乳液1小时,然后冷却至室温。在含有10% PEG4000的蒸馏水中稀释得到的乳液5倍,然后装入DIN8R瓶中(每瓶0.75mL)。将瓶在-50℃冷冻2小时(Christ Epsilon冻干机),然后在-20℃和0.5mBar冻干12小时,最后的干燥步骤是在30℃和0.2mBar 6小时。
然后使冻干产品暴露于含有35%全氟-正丁烷和65%氮气的气氛,密封瓶。
通过轻轻手摇,用2ml盐水溶液(0.9% NaCl)重配瓶(冻干饼+气体),最终得到标题的含有mPEG的充气微泡。
实施例7
体外2-步结合双特异性的链霉抗生物素蛋白(抗小鼠P-选择蛋白抗体和抗-mPEG抗体)和含有mPEG的充气微泡
a.用小鼠Fc-P-选择蛋白包被的玻璃盖玻片的制备
简而言之,将小鼠Fc P-选择蛋白的干粉(50μg,R&D System,目录号737-PS-050)溶于在玻璃瓶中的100μL pf PBS pH 7.4,然后转入12.4mLPBS,得到4μg/mL的小鼠Fc P-选择蛋白溶液。将小鼠Fc P-选择蛋白溶液(400μL 4μg/mL)放置在40mm玻璃盖玻片上,并在4℃温育过夜。然后,抛弃多余的小鼠Fc P-选择蛋白溶液,并替换为封闭溶液(500μL含有1%(w/v)BSA的PBS)在室温2小时。用洗液(3mL含有0.05%吐温的PBS)洗涤盖玻片,然后在-20℃保存。在使用前,使小鼠Fc P-选择蛋白包被的盖玻片在室温平衡。
b.结合实验
用400μL根据实施例4制备的双特异性的链霉抗生物素蛋白悬浮液温育如上所述制备的玻璃盖玻片30分钟。然后,在流式室(FCS2,Bioptech,USA)中计数盖玻片。使根据实施例6制备的含有mPEG的充气微泡穿过流式室,在50%在PBS中的人血浆(v∶v,Biomeda收集在柠檬酸盐中,目录号ES1020P,Stehelin & Cie AG)存在下,以1.0mL/min的流速(剪切率为114s-1),评估它们在盖玻片的包被层上的粘附10min。如下定量分析微泡积累:使用图像处理程序Analysis FIVE(SIS,Germany),以2min间隔,在共10min输注内,计数在观察区域中粘附的微泡的数目。10min后,随机取出5幅图像,取平均值,然后除以10,得到的数值代表每分钟的微泡积累速率(RMA/min)。每个观察区域是183x137μm,这在镜台测微计的辅助下测量。在小室的中央和出口之间进行成像。测得4.5RMA/min的平均值,指示微泡与双特异性的靶向的链霉抗生物素蛋白的抗mPEG抗体的良好结合,所述链霉抗生物素蛋白又通过抗小鼠P-选择蛋白抗体结合在包被的盖玻片的表面上。
实施例8(对比)
体外2-步结合双特异性的链霉抗生物素蛋白(同种型对照抗体和抗-mPEG抗体)和含有mPEG的气体微泡
通过用400μL根据对比实施例5制备的未结合的双特异性的链霉抗生物素蛋白温育用小鼠Fc P-选择蛋白包被的玻璃盖玻片30分钟,重复实施例7。测得0.02RMA/min的平均值,指示微泡基本上没有结合到盖玻片表面上。
实施例9
硫醇化的CD62P抗体的制备
使纯化的抗P-选择蛋白抗体克隆RB40.34的溶液与在80μL 50mM磷酸盐缓冲液150mM NaCl pH 7.4中的20μL 10mM磺基-LC-SPDP溶液((磺基琥珀酰亚胺基6-[3’-(2-吡啶基二硫)丙酰氨基]-己酸盐),Pierce,#21650)在室温反应40min。使溶液在1000g的2mL旋转柱(Zeba旋转柱,Pierce,#89889)中旋转,所述旋转柱在磷酸盐缓冲液5mM pH7.4中平衡过。然后用1mM TCEP、50mM Tris HCl/5mM EDTA pH 6.8在室温还原官能化的抗体10min。然后在1000g的2mL旋转柱中旋转还原的抗体,得到硫醇化的抗体的悬浮液。
实施例10
硫醇化的抗-PEG抗体的制备
通过用抗-mPEG兔单克隆抗体(来自Epitomics #2061-1)替换抗-小鼠单克隆抗体,重复实施例9,得到抗-mPEG抗体的溶液。
实施例11
马来酰亚胺-官能化的胶束的制备
将2mg(0.69μmoles)DSPE-PEG2000-马来酰亚胺溶于在40℃的乙醇中。在N2下在40℃去除溶剂,得到脂质膜。在真空下(0.2mBar)在25℃干燥该脂质膜过夜。在60℃的0.5mL磷酸盐缓冲液(50mMpH=6.5)中水合干燥的膜,得到DSPE-PEG2000-马来酰亚胺胶束的澄清悬浮液。
实施例12
双特异性的靶向的胶束的制备
混合325μL根据实施例9制备的硫醇化的抗P-选择蛋白抗体克隆RB40.34的悬浮液和325μL根据实施例10制备的硫醇化的抗-mPEG抗体的悬浮液,并加入到250μL根据实施例11制备的胶束悬浮液中。将混合物在25℃混合3小时。然后,将半胱氨酸(0.69μmol)加入该溶液,以封闭剩余的马来酰亚胺基团。不经进一步纯化地使用得到的双特异性的靶向的胶束。
实施例13
共价缀合的双特异性的抗体的制备
在修饰缓冲液(100mM磷酸盐,150mM氯化钠,pH 7.2-BupHTMPBS,Pierce,Switzerland)中,将兔单克隆IgG抗-mPEG(克隆PEG-B-47,Epitomix,USA)和抗P-选择蛋白抗体克隆RB40.34稀释至1.5mg/mL(即10μM)。
在DMSO中,将琥珀酰亚胺基4-肼基烟酸盐丙酮腙(SANH,Pierce,Switzerland)稀释至2.9mg/mL(10mM)。在DMSO中,将琥珀酰亚胺基4-甲酰基苯甲酸盐(SFB,Pierce,Switzerland)稀释至2.47mg/mL(即10mM)。
使一种抗体(100μg)与稀释的SANH在室温反应1小时,得到5倍摩尔过量的修饰试剂。使相同量的其它抗体与稀释的SFB在室温反应1小时,得到5-20倍摩尔过量的修饰试剂。针对缀合缓冲液(100mMMES,150mM NaCl pH 4.7-BupHTM MES,Pierce,Switzerland)透析两种抗体,然后混合到一起,并在室温温育2小时。
通过在S300柱上的尺寸排阻色谱法,分离异源二聚体缀合物。
实施例14
双特异性的靶向的脂质体的制备
将30.2mg胆固醇、73.2mg DSPC、23.0mg DPPG.Na和3.6mgDIO溶于在65℃的20mL氯仿中,随后加入31μL 3H胆甾醇基十六烷基醚。蒸发溶剂,并在真空下干燥组分混合物2小时。将残余物重新悬浮于蒸馏水中,至10mg/mL的浓度,得到脂质体悬浮液。随后在1μm、0.6μm和0.4μm的过滤器上挤出悬浮液,以减小脂质体的尺寸。针对磷酸盐缓冲的葡萄糖溶液透析脂质体悬浮液。然后,将10.5mg DSPE-PEG2000-马来酰亚胺溶于0.5mL磷酸盐缓冲的葡萄糖溶液中。将该溶液加入到脂质体悬浮液中。将悬浮液在65℃维持1小时,以允许马来酰亚胺衍生物插入脂质体结构中。然后,根据在实施例9中所述的方法,处理472μL 10mg/mL的链霉抗生物素蛋白溶液,以得到对应的硫醇化的链霉抗生物素蛋白。将硫醇化的链霉抗生物素蛋白加入脂质体悬浮液中,并在室温反应2.5小时。通过离心(30min,30000g)纯化脂质体悬浮液,然后重新悬浮于Tris缓冲的葡萄糖溶液中。
随后,在1090μL PBS中混合65.5pmol大鼠IgG1抗-小鼠CD62P(如实施例1所述制备)和65.5pmol兔抗-PEG抗体(如实施例2所述制备)。然后将该混合物加入到19μL上面制备的脂质体悬浮液中,得到希望的双特异性的脂质体。
实施例15
对比的(非抗-PEG结合的)靶向的脂质体的制备
如实施例14所述制备脂质体悬浮液,差别在于,已经用生物素化的兔非特异性的IgG替换兔抗-PEG抗体。
实施例16
对比的(非抗-P-选择蛋白特异性的)靶向的脂质体的制备
如实施例14所述制备脂质体悬浮液,差别在于,用大鼠非特异性的IgG1替换抗P-选择蛋白抗体克隆RB40.34。
实施例17
体外2-步结合双特异性的脂质体(抗P-选择蛋白抗体和抗-mPEG抗体)和含有mPEG的充气的微泡
根据在实施例7中所述的方法学,用小鼠-Fc-P-选择蛋白包被盘。将包被的盘放在24-孔板的孔中。
然后,在Thermanox盘上面温育根据实施例14制备的脂质体悬浮液4小时(每个孔500μL)。
然后用PBS(每个孔、每次洗涤1mL)洗涤盘(5次),以去除未结合的脂质体。
然后,将600μl根据实施例6制备的微气泡悬浮液加入每个孔中。1小时后,用PBS洗涤盘2次,并通过光学显微镜检查(Leica DC300S DMR,具有Q-Win图像分析软件)进行分析,以测定微气泡有效覆盖的平均百分比。
测得60.8%的平均表面覆盖度。
通过分别用实施例15和16的对比制品替代实施例14的脂质体制品,重复该操作。观察到的平均表面覆盖度分别是0.8%和1.3%。
实施例18
含有mPEG的脂质体的制备
将30.2mg胆固醇、73.2mg DSPC、23.0mg DPPG.Na和3.6mgDIO溶于在65℃的20mL氯仿中,随后加入31μL放射性标志物3H胆甾醇基十六烷基醚。蒸发溶剂,并在真空下干燥组分混合物2小时。将残余物重新悬浮于蒸馏水中,至10mg/mL的浓度,得到脂质体悬浮液。随后在1μm、0.6μm和0.4μm的过滤器上挤出悬浮液。针对磷酸盐缓冲的葡萄糖溶液透析脂质体悬浮液。然后,将10.5mgDSPE-mPEG2000溶于0.5mL磷酸盐缓冲的葡萄糖溶液中。将该溶液加入到脂质体悬浮液中。将悬浮液在65℃维持1小时,以允许马来酰亚胺衍生物插入脂质体结构中。通过离心(30min,30000g)纯化脂质体悬浮液,然后重新悬浮于Tris缓冲的葡萄糖溶液中。
实施例19
体外2-步结合双特异性的链霉抗生物素蛋白(抗小鼠P-选择蛋白抗体和抗-mPEG抗体)和含有mPEG的脂质体(19a)
根据在实施例7中所述的方法学,用小鼠-Fc-P-选择蛋白包被盘。将包被的盘放在24-孔板的孔中。然后,在Thermanox盘上面温育根据实施例4制备的双特异性的链霉抗生物素蛋白溶液1小时(每个孔400μL)。
然后用PBS(每个孔、每次洗涤1mL)洗涤盘(3次),以去除未结合的双特异性的链霉抗生物素蛋白。
然后,将400μL根据实施例18制备的脂质体悬浮液加入每个孔中。4小时后,用PBS洗涤盘4次,并使用液体闪烁分析仪(2200CA-Tri-Carb,Packard)通过放射性计数(以dpm表示:崩解度/分钟)进行分析,以测定结合的脂质体的量。
使用根据实施例5(19b)制备的双特异性的链霉抗生物素蛋白溶液,重复类似的实验。
使用根据实施例4制备的双特异性的链霉抗生物素蛋白溶液,但是用生物素大鼠同种型对照抗体替代生物素-抗mPEG抗体,重复第三个实验(19c)。
结果如下表所示,表明对比实验基本上不会提供脂质体与盘的结合。
实施例 | 双特异性的链霉抗生物素蛋白 | dpm |
19a | 抗P-选择蛋白/抗-mPEG | 227 |
19b | 对照/抗-mPEG | 34 |
19c | 抗P-选择蛋白/对照 | 22 |
实施例20
碘美普尔-负载的聚乙二醇化的脂质体的制备
将70.3mg DSPC、22.1mg DPPG.Na和29.1mg胆固醇溶于20mL氯仿中。在圆底烧瓶中将该溶液加热至60℃,在减压下蒸发氯仿,并在真空干燥箱中在最大真空下彻底去除残余溶剂3小时。然后,用含有775 mg碘美普尔/mL的碘美普尔溶液(Bracco Imaging)重新水合脂质,以形成碘美普尔-负载的脂质体。然后通过选定的孔径的过滤器挤出脂质体悬浮液,其缩小至0.2μm。然后在5%葡萄糖溶液中,透析得到的校正过的脂质体。将DSPE-PEG2000溶液溶于pH7.4的20mM吐温中,将1ml该溶液加入10mL脂质体悬浮液。摇动该混合物,并在65℃温育1小时。得到碘美普尔-负载的聚乙二醇化的脂质体,并准备用于进一步用作X-射线造影剂。
实施例21
双特异性的靶向的链霉抗生物素蛋白(小鼠抗人纤维蛋白抗体和抗mPEG抗体)的制备
通过用生物素-小鼠抗人纤维蛋白抗体替换抗P-选择蛋白抗体克隆RB40.34,重复实施例1。将10μg纤维蛋白抗体和10μg生物素-抗mPEG抗体(根据实施例2制备)溶于800μL磷酸盐缓冲盐水pH 7.4中。然后,在搅拌下,将该抗体混合物加入28.3μL链霉抗生物素蛋白溶液(1mg/mL)中,后者通过将链霉抗生物素蛋白(IBA,目录号2-0203-100)溶解在蒸馏水中制备,并将所述溶液在25℃温和30分钟。
实施例22
碘美普尔负载的脂质体的体内靶向施用
将人血块插入大鼠的左颈动脉中。然后,将根据实施例21制备的双特异性的构建体静脉内注射给大鼠。2小时后,以0.5mg/kg的碘美普尔剂量,将根据实施例21制备的含有碘美普尔的脂质体静脉内注射给大鼠。然后,借助于大鼠中的计算机体层摄影术,对反差增强的血栓成像。与注射碘美普尔溶液后得到的图像相比,血栓的反差增强。
实施例23
使用特异性地结合PEG链的主链的抗-PEG构建体的体外结合
a.双特异性的链霉抗生物素蛋白构建体(抗小鼠P-选择蛋白抗体和抗PEG抗体E11)的制备
通过用生物素化的抗-PEG抗体E11(参见参考文献30)替换生物素化的抗mPEG抗体,重复实施例4。
b.用共聚物PEG-聚赖氨酸包被的微气泡的制备
将DPPS(10mg)与5%丙二醇-甘油水溶液(2mL)相混合。将该分散体加热至65℃ 5分钟,然后冷却至室温。将1.5mL分散体转移进2mL瓶,并用C4F10冲洗,并摇动60秒。在水中洗涤得到的微气泡,然后用含有5mg/mLPEG-聚赖氨酸(甲氧基-聚(乙二醇)-嵌段-聚(L-赖氨酸)盐酸盐(Alamanda Polymers,Inc.)的溶液温育。通过ζ电位测量,证实PEG-聚赖氨酸对微气泡表面的包被。
c.在流式室中在P-选择蛋白包被的盖玻片上的体外结合
除了分别用在上面步骤a和b中制备的PEG-聚赖氨酸包被的微气泡和双特异性的链霉抗生物素蛋白抗体(抗小鼠P-选择蛋白和抗-PEG E11)替换微气泡和双特异性的链霉抗生物素蛋白抗体(抗小鼠P-选择蛋白和抗-mPEG B47)以外,重复实施例7。得到PEG-聚赖氨酸包被的微气泡在P-选择蛋白包被的表面上的良好结合。
实施例24
使用抗-PEG靶向构建体和含有PEG的微气泡的超声介导的基因递送
a.双特异性的靶向构建体的制备
通过用通过噬菌体展示筛选选出的生物素-肽序列(IPLVVPLGGSC-生物素)替换生物素化的IgG抗-P-选择蛋白,重复实施例4,所述序列特异性地结合在LNCaP细胞上过表达的hepsin受体(参见参考文献56)。
b.体外基因递送实验
使用在参考文献49中所述的基因递送方法。简而言之,在225cm2组织培养瓶中,在添加了10%v/v热灭活的胎牛血清(FCS)和1%v/v抗生素的含有Glutamax-I的Mac Coy氏5A培养基(Life Technologie,Switzerland)中,在37℃在5% CO2气氛下,培养LNCaP前列腺肿瘤细胞。用浓度为10μg/mL的质粒(GFP)和30的微气泡/mL细胞比,进行基因递送实验。将试管固定在旋转暴露系统上,并浸入37℃水浴中。传感器和试管之间的距离是7.6cm。使用2.25MHz传感器(空气回声),使试管受声波作用10秒。
首先用根据上面步骤(a)制备的靶向构建体(10μg/mL)温育细胞。1小时后,用培养基洗涤细胞,用含有mPEG的微气泡(参见实施例6)再次温育,并暴露于超声声波作用。然后使用FACS Calibur(Becton Dickinson AG,Switzerland)分析细胞,以测定GFP-阳性细胞的百分比和阳性转染的细胞的平均荧光强度。观察到良好的转染率和荧光强度。
实施例25
组合抗-mPEG靶向构建体和含有mPEG的微气泡的超声成像
a.抗-PEG靶向构建体的制备
通过用生物素-肽序列替换生物素化的IgG抗-P-选择蛋白,重复实施例4,所述序列特异性地结合在肿瘤的血管生成脉管的内皮细胞上过表达的KDR受体(参见例如参考文献39)。
b.体内超声成像研究
将1x106 MATBIII肿瘤细胞注射进麻醉的雌性Fisher 344大鼠的乳房脂肪垫中。将大鼠分成2组,以测试反差增强的成像:(i)仅含有mPEG的气体微泡,和(ii)靶向构建体+含有mPEG的气体微泡。在肿瘤诱导(肿瘤尺寸:0.5~1cm)后第5-7天,使用配有运行在7MHz的探头的超声扫描仪和CPS反差成像模式,进行反差增强的超声成像。
对于大鼠组(i),将0.4mL含有mPEG的气体囊泡(实施例6)注射进大鼠,并在注射含有mPEG的气体囊泡后10分钟,进行超声成像。
对于大鼠组(ii),首先将双特异性的靶向构建体(含有抗-mPEGB-47和生物素化的肽KDR)注射进携带MATBIII肿瘤的大鼠的尾巴。在注射靶向构建体后6h,将0.4mL含有mPEG的气体囊泡(实施例6)注射进大鼠,并在注射含有mPEG的气体囊泡后10分钟,进行超声成像。
结果表明,在大鼠组(ii)中观察到的反差效应(LPO:用视频强度表示的晚期浑浊化)强很多。
实施例26
评估癌症对使用抗-PEG靶向构建体和双诊断成像(光学和超声)的治疗的应答
a.双特异性的靶向构建体(抗PEG B-47和肽HVGGSSV)的制备
使用Cy7-标记的链霉抗生物素蛋白、生物素化的抗-mPEGB-47(实施例2)和生物素化的肽序列HVGGSSV(1∶1∶2),制备抗-PEG靶向构建体。通过噬菌体展示(基于T7噬菌体的随机肽文库)选出该肽,并表现出对通过放射疗法治疗的肿瘤的特异性结合(参见参考文献57)。
b.用于区分应答和无应答肿瘤的体内成像
将1x106 BxpC3(人胰腺癌细胞,ATCC)接种进裸鼠的右和左后肢,并在肿瘤尺寸达到0.5cm直径时进行治疗。治疗包括,使用酪氨酸激酶抑制剂(索拉非尼30mg/kg)和辐照γ(在小鼠的一肢处仅3Gy)。
使用2种成像技术(反差光学和超声)来评估肿瘤对放射疗法的应答。对于光学成像,使用IVIS成像系统(Xenogen),得到NIR(近红外荧光)图像。对于超声反差成像,使用Siemens Sequoia超声扫描仪(15L8探头处于CPS模式)和聚乙二醇化的气体微泡(实施例6)。
在注射聚乙二醇化的气体微泡之前2小时,将靶向构建体(生物素化的抗-mPEG和生物素化的肽序列HVGGSSV和Cy7-链霉抗生物素蛋白)注射进小鼠。进行光学成像和反差超声成像(在治疗性处理后24小时)。
结果表明,在1天治疗(24小时)后,辐照肢的NIR和超声图像的强反差影像都增强,而未辐照处理的肢显示出可忽略的反差效应。这些结果表明,抗-PEG靶向构建体可以用于癌症治疗的随诊(follow-up)。
使用抗-PEG靶向构建体和被PEG聚合物包被的量子点,也可以进行光学成像。
实施例27
a.双特异性的抗体(抗小鼠VEGFR2和抗mPEG)的制备
通过用抗-VEGFR2(CD101,参见参考文献56)替换IgG抗-P-选择蛋白,重复实施例13。
b.体内施用
将U-87 MG肿瘤细胞注射进裸鼠的右大脑半球,以建立颅内肿瘤。当肿瘤生长至几毫米大小时,以20μg/小鼠的剂量,将双特异性的抗体(抗小鼠抗VEGFR2和抗mPEG)注射给小鼠。在抗体施用后6小时,以3mg/kg的剂量,将施用给小鼠,所述是负载多柔比星的长循环的含有mPEG的脂质体的商业制品(Alza Corporation)。预见到,与用相同剂量的单独的治疗的小鼠的存活相比,用双特异性的抗体和治疗的携带肿瘤的小鼠的存活延长。
实施例28
使用抗-PEG靶向构建体和含有PEG的微气泡的超声介导的基因递送
a.双特异性的靶向构建体的制备
通过用通过噬菌体展示筛选选出的生物素-肽序列(IPLVVPLGGSC-生物素)替换生物素化的IgG抗-P-选择蛋白,重复实施例4,所述序列特异性地结合在LNCaP细胞上过表达的hepsin受体(参见参考文献57)。
b.体外基因递送实验
使用在参考文献49中所述的基因递送方法。简而言之,在225cm2组织培养瓶中,在添加了10%v/v热灭活的胎牛血清(FCS)和1%v/v抗生素的含有Glutamax-I的Mac Coy氏5A培养基(Life Technologie,Switzerland)中,在37℃在5% CO2气氛下,培养LNCaP前列腺肿瘤细胞。用浓度为10μg/mL的质粒(GFP)和30的微气泡/mL细胞比,进行基因递送实验。将试管固定在旋转暴露系统上,并浸入37℃水浴中。传感器和试管之间的距离是7.6cm。使用2.25MHz传感器(空气回声),使试管受声波作用10秒。
首先用根据上面步骤(a)制备的靶向构建体(10μg/mL)温育细胞。1小时后,用培养基洗涤细胞,用含有mPEG的微气泡(参见实施例6)再次温育,并暴露于超声声波作用。然后使用FACS Calibur(Becton Dickinson AG,Switzerland)分析细胞,以测定GFP-阳性细胞的百分比和阳性转染的细胞的平均荧光强度。观察到良好的转染率和荧光强度。
实施例29
组合抗-mPEG靶向构建体和含有mPEG的微气泡的超声成像
a.抗-PEG靶向构建体的制备
通过用生物素-肽序列替换生物素化的IgG抗-P-选择蛋白,重复实施例4,所述序列特异性地结合在肿瘤的血管生成脉管的内皮细胞上过表达的KDR受体(参见例如参考文献39)。
b.体内超声成像研究
将1x106 MATBIII肿瘤细胞注射进麻醉的雌性Fisher 344大鼠的乳房脂肪垫中。将大鼠分成2组,以测试反差增强的成像:(i)仅含有mPEG的气体微泡,和(ii)靶向构建体+含有mPEG的气体微泡。在肿瘤诱导(肿瘤尺寸:0.5~1cm)后第5-7天,使用配有运行在7MHz的探头的超声扫描仪和CPS反差成像模式,进行反差增强的超声成像。
对于大鼠组(i),将0.4mL含有mPEG的气体囊泡(实施例6)注射进大鼠,并在注射含有mPEG的气体囊泡后10分钟,进行超声成像。
对于大鼠组(ii),首先将双特异性的靶向构建体(含有抗-mPEGB-47和生物素化的肽KDR)注射进携带MATBIII肿瘤的大鼠的尾巴。在注射靶向构建体后6h,将0.4mL含有mPEG的气体囊泡(实施例6)注射进大鼠,并在注射含有mPEG的气体囊泡后10分钟,进行超声成像。
结果表明,在大鼠组(ii)中观察到的反差效应(LPO:用视频强度表示的晚期浑浊化)强很多。
实施例30
评估癌症对使用抗-PEG靶向构建体和双诊断成像(光学和超声)的治疗的应答
a.双特异性的靶向构建体(抗PEG B-47和肽HVGGSSV)的制备
使用Cy7-标记的链霉抗生物素蛋白、生物素化的抗-mPEGB-47(实施例2)和生物素化的肽序列HVGGSSV(1∶1∶2),制备抗-PEG靶向构建体。通过噬菌体展示(基于T7噬菌体的随机肽文库)选出该肽,并表现出对通过放射疗法治疗的肿瘤的特异性结合(参见参考文献58)。
b.用于区分应答和无应答肿瘤的体内成像
将1x106 BxpC3(人胰腺癌细胞,ATCC)接种进裸鼠的右和左后肢,并在肿瘤尺寸达到0.5cm直径时进行治疗。治疗包括,使用酪氨酸激酶抑制剂(索拉非尼30mg/kg)和辐照γ(在小鼠的一肢处仅3Gy)。
使用2种成像技术(反差光学和超声)来评估肿瘤对放射疗法的应答。对于光学成像,使用IVIS成像系统(Xenogen),得到NIR(近红外荧光)图像。对于超声反差成像,使用Siemens Sequoia超声扫描仪(15L8探头处于CPS模式)和聚乙二醇化的气体微泡(实施例6)。
在注射聚乙二醇化的气体微泡之前2小时,将靶向构建体(生物素化的抗-mPEG和生物素化的肽序列HVGGSSV和Cy7-链霉抗生物素蛋白)注射进小鼠。进行光学成像和反差超声成像(在治疗性处理后24小时)。
结果表明,在1天治疗(24小时)后,辐照肢的NIR和超声图像的强反差影像都增强,而未辐照处理的肢显示出可忽略的反差效应。这些结果表明,抗-PEG靶向构建体可以用于癌症治疗的随诊。
使用抗-PEG靶向构建体和被PEG聚合物包被的量子点,也可以进行光学成像。
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Claims (15)
1.药用试剂盒,其包含:
a)第一组合物,其包含脂质体或充气微泡或其前体,它们具有包含多个聚合物分子的稳定化外膜;和
b)第二组合物,其包含靶向构建体,所述构建体包含靶向配体和能选择性地结合所述聚合物的抗体。
2.根据权利要求1的药用试剂盒,其中所述聚合物是亲水聚合物。
3.根据权利要求1的药用试剂盒,其中所述聚合物包含重复氧乙烯单元。
4.根据权利要求3的药用试剂盒,其中所述聚合物以甲氧基终止。
5.根据权利要求3的药用试剂盒,其中所述聚合物是聚乙二醇。
6.根据权利要求3的药用试剂盒,其中所述抗体选择性地结合所述重复氧乙烯单元的序列。
7.根据权利要求4的药用试剂盒,其中所述抗体选择性地结合以甲氧基终止的重复氧乙烯单元的序列。
8.根据前述权利要求中任一项的药用试剂盒,其中所述聚合物的摩尔量是相对于所述稳定化外膜的组分的总量的至少0.05%。
9.根据权利要求8的药用试剂盒,其中所述摩尔量是至少0.2%。
10.根据权利要求8的药用试剂盒,其中所述摩尔量是至少1%。
11.根据前述权利要求中任一项的药用试剂盒,其中所述充气微泡包含超过50%的按摩尔计的磷脂。
12.根据前述权利要求中任一项的药用试剂盒,其中所述脂质体包含治疗剂或造影剂。
13.根据前述权利要求中任一项的药用试剂盒,其中所述靶向配体非共价地结合所述抗体,以形成所述靶向构建体。
14.根据权利要求13的药用试剂盒,其中所述靶向构建体是胶束或脂质体的形式。
15.脂质体或充气微泡或其前体,其包含:a)亲水聚合物;b)与所述亲水聚合物结合的抗体;和c)与所述抗体结合的靶向配体。
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CA (1) | CA2748995C (zh) |
WO (1) | WO2010040772A2 (zh) |
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CN106459211A (zh) * | 2014-03-03 | 2017-02-22 | 中央研究院 | 双功能抗体及其用途 |
CN109310634A (zh) * | 2016-04-19 | 2019-02-05 | 南洋理工大学 | 用于治疗前段眼部疾病的持续输送他克莫司的纳米脂质体 |
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Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN106459211A (zh) * | 2014-03-03 | 2017-02-22 | 中央研究院 | 双功能抗体及其用途 |
CN106459211B (zh) * | 2014-03-03 | 2020-03-10 | 中央研究院 | 双功能抗体及其用途 |
CN111499753A (zh) * | 2014-03-03 | 2020-08-07 | 中央研究院 | 双功能抗体及其用途 |
CN111499753B (zh) * | 2014-03-03 | 2022-10-21 | 高雄医学大学 | 双功能抗体及其用途 |
CN109310634A (zh) * | 2016-04-19 | 2019-02-05 | 南洋理工大学 | 用于治疗前段眼部疾病的持续输送他克莫司的纳米脂质体 |
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CA2748995C (en) | 2018-01-16 |
JP2012505179A (ja) | 2012-03-01 |
AU2009301141A1 (en) | 2010-04-15 |
US20110200530A1 (en) | 2011-08-18 |
EP2346532B1 (en) | 2020-10-07 |
CA2748995A1 (en) | 2010-04-15 |
US9192685B2 (en) | 2015-11-24 |
AU2009301141B2 (en) | 2015-08-27 |
EP2346532A2 (en) | 2011-07-27 |
JP5491511B2 (ja) | 2014-05-14 |
WO2010040772A2 (en) | 2010-04-15 |
CN102202694B (zh) | 2014-03-12 |
WO2010040772A3 (en) | 2010-07-22 |
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