CN100562311C - 顺铂胶束的制备以及使用方法 - Google Patents
顺铂胶束的制备以及使用方法 Download PDFInfo
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- CN100562311C CN100562311C CNB008046611A CN00804661A CN100562311C CN 100562311 C CN100562311 C CN 100562311C CN B008046611 A CNB008046611 A CN B008046611A CN 00804661 A CN00804661 A CN 00804661A CN 100562311 C CN100562311 C CN 100562311C
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Abstract
本发明涉及在脂质体中包胶顺铂和其他带正电荷的药物的方法,所述脂质体在其内和外膜层之间具有不同的脂质组成。脂质体在静脉注射于动物及人后到达原位瘤及其转移瘤。经包胶的顺铂在消除各种人实体瘤方面具有高的治疗效力,所述实体瘤包括但不限于乳腺癌和前列腺癌。经包胶的顺铂与包胶的阿霉素或者与其他抗癌药物的组合是有治疗价值的。在消除癌症方面,经包胶的顺铂与多种抗癌基因的组合、经包胶的顺铂与包胶在脂质体中的多种抗癌基因的组合以及经包胶的顺铂与HSV-tk加上经包胶的更昔洛韦的组合,也是具有治疗价值的,所述抗癌基因包括但不限于p53、IL-2、IL-12、制管张素和制癌蛋白。
Description
发明领域
本发明涉及用脂质体包胶的药物及给药系统,特别是脂质体包胶的顺铂。该药物可在静脉内注射后用于杀死各种人恶性肿瘤中的癌细胞。
发明背景
在本申请中,各种出版物、专利以及公开的专利说明书都注有作者及日期,或者用专利号说明。这些出版物的所有著录项目都在本说明书内提供或者在权利要求书之前提供。这些出版物、专利及公开的专利说明书的内容在此并入作为参考,以更详细地描述本发明所涉及领域的现有技术。
顺-二胺二氯合铂(II),cis-[Pt(NH3)2Cl2]2+,简称为顺铂或者cis-DDP,是最广泛使用的抗肿瘤药物之一,用于治疗睾丸癌、卵巢癌以及对抗头和颈部的癌症。超过90%的睾丸癌是用顺铂治疗。最严重的副作用是肾毒性、骨髓毒性和胃肠道刺激作用(Oliver和Mead,1993)。在用160mg/m2顺铂和640mg/m2卡铂治疗的卵巢癌患者中观察到双侧视神经病(Caraceni等人,1997)。口服六甲基蜜胺治疗一组61名对顺铂或卡铂产生耐受性(在治疗结束后6个月内复发)的上皮卵巢癌患者时,表明具有14%的客观反应率(Vergote等人,1992)。
阳离子性胆固醇衍生物已被用于给药治疗剂。例如,它们与磷脂酰乙醇胺混合,然后进行超声处理,形成小的单层囊泡,该囊泡可与NDA复合并介导由内体腔进入细胞溶胶。其中一种脂质体制剂是DC-Chol脂质体,其已被用于对抗黑素瘤的基因治疗临床试验中。人免疫缺损病毒-1反式激活蛋白基因与报道基因在控制HIV-1长端重复单位的情况下共同给药。对顺铂产生耐受性的人肿瘤细胞或者由顺铂治疗失败的患者中分离的人肿瘤细胞对于阳离子性脂质体是高度转染的。这些结果提示出用顺铂和基因疗法来治疗恶性肿瘤的一系列治疗方案(Farhood等人,1994)。
由2-氨基-甲基吡咯烷衍生物作为载体配位体制备的各种铂复合物已在小鼠中测试了它们在皮下和/或腹膜内注射时对结肠26癌和P388白血病的抗肿瘤活性。证明2-氨基甲基吡咯烷在其胺衍生物中是最有效的载体配位体(Morikawa等人,1990)。
通过正交试验确定了用乳液加热稳定法制备顺铂白蛋白微球(Cis-DDP-AMS)(平均大小为148微米)的最佳方法。在相对于顺铂用Cis-DDP-AMS进行肝动脉化学栓塞形成(chemoembolization)后,铂的分布和消除分别延长了3.36倍和1.23倍(Zhang等人,1995)。
对具有更高治疗性质的铂(II)基化合物进行研究,促进设计并合成了一类新的水溶性、连接在尿嘧啶和尿苷上的第三代顺-二胺二氯合铂(II)复合物。但是,所合成的化合物中没有一个对所治疗的三种细胞系显示出任何显著的细胞毒性作用(Kim等人,1998)。
发现最近研制的生物还原剂4-[3-(2-硝基咪唑基)-丙基氨基]-7-氯喹啉盐酸盐(NLCQ-1)可增强化学治疗剂美法伦(L-PAM)、顺铂(cisDDP)和环磷酰胺(CPM)的抗肿瘤作用,但没有同时增强骨髓毒性。该增强作用是严格的程序依赖性的,而且在cisDDP之前45分钟给药NLCQ-1可观察到最佳的作用(1.5-2个log超过可加性的杀死作用(killing beyond additivity))。这些结果支持基于临床研究将NLCQ-1化分为化学致敏剂(Papadopoulou等人,1998)。
在患有非小细胞肺癌(NSCLC)并已用顺铂进行首次治疗的患者中,紫杉醇与顺铂组合作为二线药物,在14名患者中产生了部分反应(40%)(Stathopoulos等人,1999)。
Abra等人(1999年8月31日授权的第5,945,122号美国专利)描述了一种脂质体组合物,其包含包封在大多数为中性的脂质中的非电荷性顺铂。但是,与本专利申请中所公开的用于包封顺铂的非离子脂质DPPG相比,Abra等人的方法使用中性脂质。
因此,虽然现有报道表明脂质体调节顺铂和其他治疗剂的给药是有可能的,但是治疗效力受限于顺铂的低水溶解度和低稳定性。治疗效力还受限于该药物的高毒性。因此,仍需要减少处理含顺铂的药物时所涉及的困难以及降低在治疗使用时顺铂的高毒性。本发明满足该需求并提供相关的优点。
发明公开
在一个方面中,本发明提供将顺铂和其他带正电荷的药物包胶在脂质体中的方法,所述脂质体在其内膜和外膜的双层之间具有不同的脂质组成,而且能够在静脉注射于动物和人后达到原位肿瘤及其转移瘤。在一个方面中,所述方法包括在顺铂与DPPG(二棕榈酰基磷脂酰甘油)或者其他脂质分子之间形成复合物,以便通过水解将顺铂转化为其含水(aqua)形式,该形式是带正电荷的,而且是顺铂的活性形式,具有抗肿瘤活性。在该阶段,可添加膜融合肽和其他具有融合性质的分子,以提高复合物跨过细胞膜的进入性。含水顺铂-DPPG胶束与囊泡形成性脂质如预先制备的脂质体或者脂质混合,然后进行透析并由膜中挤出,高收率地包封并包胶顺铂,由此转化为脂质体。在这些制剂中,可用阿霉素或其他带正电荷的化合物替代顺铂。经包胶的顺铂在消除各种人实体瘤方面具有非常高的治疗效力,包括但不限于乳腺癌和前列腺癌。经包胶的顺铂与经包胶的阿霉素或者与其他抗肿瘤药物组合也是具有治疗价值的。在消除癌症方面,经包胶的顺铂与包胶在脂质体中的多种抗肿瘤基因组合、以及经包胶的顺铂与HSV-tk加上经包胶的更昔洛韦(ganciclovir)的组合,也是具有治疗价值的,所述抗癌基因包括但不限于p53、IL-2、IL-12、制管张素和制癌蛋白。
附图简述
图1描绘了顺铂的包胶。
图2显示了在3-4次注射包胶顺铂后在SCID小鼠中MCF-7肿瘤的缩小。
图3显示了在经或未经顺铂处理的SCID小鼠中肿瘤的组织学。图3A显示了SCID小鼠中发育的未经处理的MCF-7肿瘤,放大40倍。注意肿瘤组织的结构特征的同源性。图3B显示了经顺铂处理的小鼠(4次注射)。细胞是凋亡性的,有许多组细胞进入结构中,而且核染色更大、更暗,这是凋亡细胞的特征。图3C显示了未经处理的动物中的肿瘤,表明侵入到肌肉中,放大20倍。图3D显示经顺铂处理的小鼠。未发现侵入。放大20倍。
图4显示了在用包胶顺铂处理的动物(A)和未经处理的动物(B)之间肿瘤尺寸的宏观(可视)差异。
实施本发明的方式
除非另有说明,本发明的实施将使用免疫学、分子生物学、微生物学、细胞生物学和重组DNA中的常规技术。这些方法描述在以下出版物中。例如参考:分子克隆:实验室指南(MOLECULAR CLONING:A LABORATORY MANUAL),第2版,(1989);分子生物学中流行方案(CURRENT PROTOCOLS IN MOLECULAR BIOLOGY)(F.M.Ausubel等人编辑(1987));酶学中的方法(METHODS INENZYMOLOGY)(Academic Press,Inc.);PCR:实用方法(PCR:APRACTICAL APPROACH)(M.MacPherson等人,IRL Press at OxfordUniversity Press(1991));PCR 2:实用方法(PCR 2:A PRACTICALAPPROACH)(M.J.MacPherson,B.D.Hammes和G.R.Taylors编辑(1995));抗体,实验室指南(ANTIBODIES,A LABORATORYMANUAL)(Harlow和Lane编辑(1988));以及动物细胞培养(ANIMALCEL CULTURE)(R.I.Freshney编辑(1987))。
在说明书及权利要求书中,“一种”、“该”以及“所述”等单数形式,除非另有说明,包括表示复数。例如“一种细胞”包括多个细胞,包括它们的混合物。
术语“包括”或“包含”是指组合物和方法包括所述的组成部分,但不排除其他部分。当用于限定组合物及方法时,“基本上由......组成”表示除对于组合而言显著必须的部分外不包括其他部分。因此,基本上由在此所限定的组分组成组合物不包括由分离及纯制方法产生的痕量杂质以及药物学上可接受的载体如磷酸盐缓冲盐水、防腐剂等。“由......组成”是指不包括其他成分或者给药本发明组合物的实质步骤的其他部分。
术语“多核苷酸”和“核酸分子”可相互交换地使用,并指任何长度的聚合物形式的核苷酸。多核苷酸可包含脱氧核糖核苷酸、核糖核苷酸和/或它们的类似物。核苷酸可具有三维结构,并可具有任何已知或未知的功能。术语“多核苷酸”包括例如单链、双链和三螺旋分子、基因或基因片段、外显子、内显子、mRNA、tRNA、rRNA、核酶、cDNA、重组多核苷酸、分枝多核苷酸、质粒、载体、任何序列的分离DNA、任何序列的分离RNA、核酸探针、和引物。核酸分子还可包括经修饰的核酸分子。
“基因”是指包含至少一个开放阅读框的多核苷酸,其在转录和翻译后能够编码特定的多肽或蛋白。
“组合物”是指活性物质与惰性(例如可检测的物质或标记或药物学上可接受的载体)或活性(如辅剂)的其他化合物或组分的组合。
“药物组合物”是指活性物质与惰性或活性载体的组合,使组合物适合于体外、体内、或活体外诊断或治疗用。
在此所用术语“药物学上可接受的载体”包括任何标准的药物学载体,如磷酸盐缓冲盐水溶液、水、和乳液,如油/水或水/油乳液,以及各种类型的湿润剂。组合物还可包含稳定剂和防腐剂。载体、稳定剂和辅剂的例子可参见Martin,REMINGTON′S PHARM.SCI.,第15版(MackPubl.Co.,Easton(1975))。
“有效量”是指足以实现有益或所希望的结果的量。有效量可在一次或多次给药、一个或多个剂型中给药。
“患者”或“个体”在此可相互交换使用,其是指脊椎、优选哺乳动物,更优选为人。哺乳动物包括但不限于鼠、猿猴、人、农用动物、运动用动物和宠物。
“对照”是在试验中用于对比目的的其他受试者或样品。对照可以是“阳性的”或“阴性的”。例如,如果试验的目的是测定基因的变化表达水平与具体癌症类型之间的相关关系,通常优选使用阳性对照(从携带所述变化并表现该疾病的综合症特征的受试者中选出的受试者或样品)和阴性对照(从缺乏已发生变化的表达以及该疾病的临床综合症的受试者中选出的受试者或样品)。
“基因转运载体”定义为可将插入的多核苷酸携带入宿主细胞中的任何分子。基因转运载体的例子是脂质体,阳离子性脂质体,病毒如杆状病毒、腺病毒、腺相关病毒和逆转录病毒,噬菌体,粘粒,质粒,真菌载体以及本领域中通常使用并用于在各种真核及原核宿主中表达、用于基因治疗以及简单蛋白表达的其他重组载体。
“病毒载体”定义为重组产生的病毒或病毒颗粒,其包含在体内、活体外或体外待转运至宿主细胞中的多核苷酸。病毒载体的例子包括逆转录病毒载体、腺病毒载体、腺相关病毒载体等。如果基因转移是通过逆转录病毒载体介导的,载体构建是指包含逆转录病毒基因组或其部分以及插入的多核苷酸的多核苷酸。在此所用术语“逆转录病毒介导的基因转移”或者“逆转录病毒转导”具有相同的定义,并指其中基因或者核酸序列通过病毒进入细胞以及将其基因组整合在宿主细胞基因组中而被稳定地转移至宿主细胞中的过程。通过其正常感染机理或者修饰为可结合不同宿主细胞表面受体或配体而进入细胞中,由此病毒可进入宿主细胞中。在此所用术语“逆转录病毒载体”是指能够通过病毒或者病毒样进入机理将外源性核酸引入细胞中的病毒颗粒。
逆转录病毒以RNA的形式携带它们的遗传信息,但是一旦病毒感染细胞,RNA则反转录为DNA形式,其整合入被感染细胞的基因组DNA中。经整合的DNA形式称为原病毒。
如果基因转移是通过诸如腺病毒(Ad)或腺相关病毒(AAV)的DNA病毒载体介导的,载体构建是指包含病毒基因组或其部分以及待插入的多核苷酸的多核苷酸。腺病毒(Ad)是一组相对好表征的同源性病毒,包括50种以上的血清类型(参见例如WO 95/27071)。Ad容易生长,而且不需要整合入宿主细胞基因组中。重组Ad衍生的载体,特别是那些降低野生型病毒重组和产生的潜力的载体,也已被构建(参见例如WO 95/00655;WO 95/11984)。野生型AAV具有高的感染性以及整合入宿主细胞基因组中的特异性(Hermonat和Muzyczka(1984)PNAS USA 81:6466-6470;Lebkowski等人(1988)Mol.Cell Biol.8:3988-3996)。
包含启动子以及其中可操作性地连接多核苷酸的克隆位点的载体,在本领域中是众所周知的。此等载体能够在体外或体内转录RNA,而且可由例如Stratagene(La Jolla,CA)或者Promega Biotech(Madison,WI)商购得到。为使表达和/或体外转录最佳化,有可能需要除去、添加或改变克隆中5′和/或3′未翻译部分,以消除额外的、潜在非适当的、可替换的翻译启动密码子或者可在转录或翻译阶段干扰或降低表达的其他序列。或者,共有核糖体结合位点可紧邻启动密码子的5′处插入,以增强表达。
基因转运载体还包括几种非病毒载体,包括DNA/脂质体复合物、以及靶病毒蛋白DNA复合物。也可包含靶向抗体或其片段的脂质体可用于本发明的方法中。为增强向细胞的转运,本发明的核酸或蛋白可与抗体或其结合片段缀合,所述结合片段结合细胞表面抗原,如TCR、CD3或CD4。
多核苷酸可使用本领域已知的方法插入在载体基因组中。例如,在合适的条件下使插入片段和载体DNA与限制酶接触,以在可相互配对并可通过连接酶连接在一起的各分子上产生互补端。或者,合成的核酸连接体可连接在限制性多核苷酸的端部。这些合成的连接体包含相应于载体DNA中的特定限制性位点的核酸序列。另外,可连接包含终端编码子及合适的限制性位点的寡核苷酸,用于插入包含例如以下组中的一些物质或者所有物质的载体:可选择的标记物基因,如用于在哺乳动物细胞中选择稳定或瞬时转染物的新霉素基因;用于高水平转录的由人CMV的立即早期基因中选择的增强子/启动子基因;用于mRNA稳定性的由SV40中选择的转录终端和RNA处理信号;用于复制的SV40多形瘤起点以及用于合适的附加型复制的ColE1;多用途多克隆位点;在插入的多核苷酸中稳定成分3′,以及用于体外转录有意义RNA及反义RNA的T7和SP6 RNA启动子。其他方式在本领域中是已知的而且都可以使用。
“宿主细胞”是指任何可以是或者已经作为载体或者插入外源性多核苷酸、多核苷和/或蛋白的受体的单个细胞或者细胞培养物。其还包括单个细胞的后代,而且所述后代由于天然、偶然或者有意的突变对于原始母细胞而言并不必须是完全相同的(在形态或者基因组或者总DNA互补方面)。细胞可以是原核细胞或者真核细胞,而且包括但不限于细菌细胞、酵母细胞、植物细胞、昆虫细胞、动物细胞、以及哺乳动物细胞,如鼠、猿猴或者人。
在此所用术语“赘生物细胞”、“赘生”、“肿瘤”、“肿瘤细胞”、“癌”、以及“癌细胞”(可相互交换地使用)是指能够相对自动生长的细胞,使它们具有异常生长表型,其特征是显著丧失对细胞增殖作用的控制(即、不可调节的细胞分裂)。赘生细胞可以是恶性或良性的。
“抑制”肿瘤生长表示与对照细胞相比生长状态被降低。肿瘤细胞生长可用本领域已知的任何方法来评估,包括但不限于测量肿瘤大小,使用3H-胸腺嘧啶插入分析测定肿瘤细胞是否增殖,或者计数肿瘤细胞。“抑制”肿瘤细胞生长代表以下状态中的任何一种或者全部:使肿瘤生长减缓、延迟、和停止,以及肿瘤缩小。
本发明的实施方案
胶束、脂质体以及得到它们的方法
本发明所要保护的是用于将顺铂包封在脂质中的方法,其可增加单位体积中的顺铂含量,降低其毒性,能够在静脉注射后靶向原位肿瘤以及它们的转移肿瘤,而且可以使肿瘤缩小,完全治疗携带人肿瘤的SCID小鼠。
顺铂是重金属络合物,其在顺位包含两个氯原子和两个氨基,它们都连接在一个二价过渡金属铂原子上。其是双官能烷基化剂以及抑制DNA合成的DNA嵌入剂。在一个形式中,顺铂是分子量为300.1的黄色粉末,而且在水中的有限溶解度为1mg/ml。其广泛用于治疗癌症患者,特别是那些睾丸癌、淋巴瘤、子宫内膜癌、膀胱癌、卵巢癌、头和颈部鳞状细胞癌、乳腺癌、以及许多其他恶性肿瘤的患者,通常与阿霉素、长春碱、博来霉素、泼尼松、长春新碱、紫杉醇和其他抗肿瘤药物以及放射疗法联合使用。我们在此是要降低患者治疗所需要的总顺铂体积,这是因为增加了脂质包封形式的顺铂的溶解度。
静脉注射时使用的体积通常较大(每个成年患者为约180ml或者约20-120mg/m2),通过24小时输液进行给药。其从血浆中清除分为25-80分钟的快速期以及随后58-73小时的缓慢期。其与血浆蛋白结合,并通过肾排泄(这就是在治疗患者中产生严重肾毒性的原因)。剂量相关的肾毒性可通过剧烈的水合化、甘露醇、呋塞米和其他药物来部分地克服。顺铂产生的其他毒性包括耳毒性、恶心和呕吐、贫血、以及中等骨髓抑制(The Merck Manual of Diagnosis and Therapy)。本发明克服了现有方法和组合物中的局限性。
因此,在一个方面中,本发明提供制备顺铂胶束的方法,其中以1∶1-1∶2.1的比例混合顺铂和磷脂酰甘油脂质衍生物(PGL衍生物),形成顺铂混合物。在另一个实施方案中,顺铂与PGL衍生物的比例为1∶1.2,或1∶1.4,或1∶1.5,或1∶1.6,或1∶1.8,或1∶1.9,或1∶2.0,或1∶2.1。所述混合物然后与有效量的至少20%的有机溶胶混合,所述有机溶胶例如是乙醇溶液,形成顺铂胶束。
在此所用术语“磷脂酰甘油脂质衍生物(PGL衍生物)”是指任何能够形成胶束并具有带净负电荷的头部基团的脂质衍生物。这包括但不限于二棕榈酰基磷脂酰甘油(DPPG)、二肉豆蔻酰基磷脂酰甘油、和二癸酰基磷脂酰甘油。在一个方面中,带有含10-28个碳原子的碳链而且具有不饱和脂族侧链的磷脂酰基衍生物也在本发明的范围内。顺铂与带负电荷的磷脂酰甘油脂质按照不同的摩尔比形成复合物,形成带净正电(1∶1)、中性(1∶2)或者略带负电荷(1∶2.1)的颗粒,将使得在给药后靶向不同的组织。但是,已表明顺铂与带负电荷的PGL复合可增加顺铂的溶解度,降低有效抗肿瘤治疗时所需要的药物体积。另外,顺铂与带负电荷的PGL复合可产生非常高的包胶效率,使得制备过程中的药物损失最小化。这些复合物都是稳定的,不形成沉淀,而且在4℃下储存至少4个月仍保持治疗效力。
在此所用术语“顺铂”包括类似物。其例子包括卡铂、ormaplatin、oxaplatin、2-氨基甲基吡咯烷(1,1-环丁烷二甲酸合)铂、lobaplatin、1-环丁烷-二甲酸合(2-)-(2-甲基-1,4-丁烷二胺-N,N′)铂、zeniplatin、enloplatin、254-S nedaplatin和JM-216(二-乙酸合-胺-二氯-环己基胺-铂(IV))。
还可以理解的是,虽然并没有总是清楚地说明,但可用其他带正电荷的药物替代顺铂,这些药物包括但不限于抗肿瘤药物阿霉素。或者,其他类型的中性药物在用带正电荷的基团衍生化而转化为带正电荷的药物后,也可以使用。将中性或者带负电荷的抗癌药物或者其他类型的药物转化为带正电荷的分子,可通过有机合成领域中已知的许多方法来完成。这些方法例如包括用氨基替换药物中的羟基,或者用三甲基氨基替换,由此在化合物中引入正电荷。在1998年11月17日授予Wang等人的第5,837,868号美国专利中讨论了用氨基替换环羟基。
上述方法不需要按照上述顺序进行所述步骤。例如,该方法可如下实施:使顺铂与有效量的至少20%的有机溶剂溶液混合,形成溶液。该溶液与磷脂酰甘油脂质(PGL)衍生物按照1∶1-1∶2.1的比例范围混合,形成顺铂胶束。如上所述,顺铂与PGL衍生物的比例为1∶1.2,或1∶1.4,或1∶1.5,或1∶1.6,或1∶1.8,或1∶1.9,或1∶2.0,或1∶2.1。
在本发明的方法中,可以使用任何不形成两相体系的有机溶剂或者乙醇溶液,或者在20%醇中混溶的其他有机溶剂(如氯仿)。例如,醇溶液可以是至少30%、35%、40%、45%直至90%溶液中的任何一种,包括它们之间的任何一种。优选的是,对于DPPG,醇溶液为30%乙醇溶液,而对于其他脂质,最佳的百分比可以是不同的。
在一个实施方案中,用带净负电荷的肽替换部分DPPG分子,形成具有融合性质的顺铂复合物,其能够跨越靶细胞膜。融合肽也可共价地连接在PEG的游离端,以更好地暴露。添加少量的阳离子性脂质替换最终顺铂/DPPG复合物中的含水顺铂的正电荷,也可使该复合物具有融合性质,用阳离子性脂质(如DDAB:二甲基双十八烷基溴化铵;DMRIE:N-[1-(2,3-二肉豆蔻基氧基丙基]-N,N-二甲基-N-(2-羟基乙基)溴化铵;DMTAP:1,2-二肉豆蔻酰基-3-三甲基铵丙烷;DOGS:双十八烷基酰胺基甘氨酰基精胺;DOTAP:N-(1-(2,3-二油酰基氧基)丙基)-N,N,N-三甲基氯化铵;DPTAP:1,2-二棕榈酰基-3-三甲基铵丙烷;DSTAP:1,2-二硬脂酰基-3-三甲基铵丙烷)替换的正电荷百分比是较小的,这是因为阳离子性脂质的毒性。一些制剂在胶束中包含一定量的融合性两亲脂质DOPE。
在另一个方面中,顺铂胶束被包胶在囊泡形成性脂质中,例如用于药物转运。
脂质包胶的顺铂在消除各种人实体瘤方面具有高的治疗效力,所述实体瘤包括但不限于乳腺癌、前列腺癌、多形成胶质细胞瘤、非小细胞肺癌、胰腺癌、头和颈部鳞状细胞癌和T细胞淋巴瘤。因此,根据另一个方面,本发明提供使用包胶在脂质体中的顺铂或者其他带正电荷的抗肿瘤药物治疗各种人恶性肿瘤的方法,该脂质体在其内层和外层膜的两个层之间具有不同的组成。脂质体包胶的药物在静脉注射给动物和人后能够达到原位肿瘤及其转移瘤。
经包胶的顺铂与多柔比星的组合或者与其他抗肿瘤药物的组合比单独的顺铂具有更高的治疗效力。经包胶的顺铂与多种抗癌药物组合,例如包胶在类似类型的脂质体中的p53、IL-2、IL-12、制管张素和制癌蛋白,以及经包胶的顺铂与HSV-tk加上经包胶的更昔洛韦组合物,在消除癌症方面也具有更高的治疗效力。
在另一个方面中,本发明提供经包胶的顺铂与以下基因的组合:
(i)在控制CMV、β-肌动蛋白或者其他启动子的情况下的野生型(wt)p53 cDNA表达载体,以及能够维持长期p53基因表达的人复制起点;病毒复制起点,其需要病毒复制起始密码子蛋白如T抗原,用于它们的活化,该起始密码子蛋白对于转移p53基因也是不合适的,因为p53蛋白强烈地与T抗原相互作用。
(ii)PAX5 cDNA表达载体,其是唯一已知的p53基因抑制剂(wt和突变p53基因),与p53基因的内显子1中的短(10个核苷酸)调节区域相互作用。p53基因治疗的主要缺陷是内源性突变形式的p53使wtp53蛋白失活,而内源性突变形式的p53在肿瘤中过度表达,而且能够与p53蛋白四聚化;内源性p53基因被Pax5的表达所抑制,后者是p53基因的强效转录阻抑物。wt p53 cDNA载体缺乏内显子1,并由此缺乏抑制性PAX5结合区域。重要的是抑制内源性突变p53基因表达,并从癌细胞中消除突变p53,以增强凋亡诱导和肿瘤抑制作用。
(iii)单纯疱疹病毒胸腺嘧啶激酶(HSV-tk)基因。单纯疱疹病毒胸腺嘧啶激酶(HSV-tk)自杀基因也包括在p53和Pax5基因的组合中,在用更昔洛韦(GCV)治疗动物模型和人类患者后导致DNA合成的中断;期望增加癌细胞中的链断裂,并增强已知与链断裂物以及损坏的DNA位点结合的p53肿瘤抑制剂功能。在另一个实施方案中,更昔洛韦组合并包胶在脂质体中。
基因治疗是生物医学的一个学纪元,其主要针对在患者的体细胞中引入治疗性基因(综述见Boulikas,1998a;Martin和Boulikas,1998)。两个主要的障碍限制了体细胞基因转移的成功应用:(1)小比例的转导细胞;以及(2)由体内注射起3-7天后治疗性基因的转录信号丢失。
第一个问题源自于(i)不能转运携带基因的载体到达目标细胞表面(绝大多数的脂质体-DNA复合物从血液循环中快速消除);(ii)难以渗透细胞膜;(iii)在被细胞内在化(internalization)后难以由内体释放DNA;以及(iv)不能有效地转运至核酸中。其他人使用了秘密(stealth)脂质体(Martin和Boulikas,1998a),其在循环中持续数天,并浓集于肿瘤中。但是,典型的秘密脂质体不被癌细胞摄入。在此公开的策略是用于增强脂质体的内在化(融合肽)。
第二个问题的起因是由核酸酶降解导致的核中质粒的丢失,不能自动复制,使得它们在细胞增殖期间在后代细胞中被稀释,或者是由于在整合入宿主细胞的染色体后使外源DNA失活。但是,使用能够长期维持质粒的染色体外复制的人序列(参见Teni Boulikas的第5,894,060号美国专利,其题目是“用于捕获人复制起点的克隆方法(Cloning method fortrapping human origins of replication)”)将克服该限制。
在此还要求保护的是使肿瘤消退并降低动物模型和人类中乳腺癌、前列腺癌和其他癌症的肿瘤体积,其是给药经包胶的顺铂(LipoplatinTM)或者经包胶的阿霉素,以及这些药物与基因的组合,所述基因包括但不限于p53、PAX5和HSV-tk/包胶的更昔洛韦、IL-2、IL-12、GM-CSF、制管张素、IL-4、IL-7、IFN-γ、TNF-α、RB、BRCA1、E1A、与包胶的5-氟胞嘧啶联合的胞嘧啶脱氨酶、bcl-2、MDR-1、p21、p16、bax、bcl-xs、E2F、IGF-I VEGF、TGF-β基因等。
因此,本发明还提供向细胞中转运顺铂或其他治疗剂的方法,其中使所述细胞与经包胶的药物或者可用本发明的方法得到的其他中间体相接触。本发明还提供抑制患者中肿瘤生长的方法,其包括向所述患者给药有效量的用本发明的方法得到的包胶药物。这些方法可在体外、活体外或者体内实施。
因此,本发明还提供使用包胶药物和多核苷酸的组合治疗方法。在此所用术语“多核苷酸”包括但不限于编码蛋白质和多肽的基因以及编码核酶及反义的序列。组合基因治疗方法在消除癌症方面要比单独的基因治疗更为有效,这是因为两个机理不同,并可产生协同作用。例如,p53蛋白结合损坏的DNA区域以及DNA的游离端的性质是已知的,而且还触发严重损坏的细胞中凋亡的机理(综述见Boulikas,1998a)。癌细胞中DNA的游离端预期是在被顺铂损坏后产生的,通过转移wt p53的表达增强这些细胞中凋亡通路的诱导(许多肿瘤具有突变的p53,而且有可能不能有效地诱导该通路)。治疗性多核苷酸也可在掺入胶束之前插入在基因转移载体中。
在众多的研究中,野生型p53基因的转移已成功地用于在体内以及细胞培养物中减慢肿瘤细胞的增殖。在最近的临床试验中表明,使用腺病毒/p53载体在肿瘤内注射可有效对抗肺肿瘤(Roth等人,1996),以及对抗动物模型中的前列腺肿瘤(综述见Boulikas,1998a)。但是,肿瘤内注射法不能应用于通常与癌症晚期有关的转移瘤中。全身性给药p53基因以及包胶的顺铂并靶向身体任何区域中的肿瘤,对于癌症治疗都是有效的。我们在此要求保护缓解或者部分克服成功的体细胞基因转移中的四种主要障碍,其中向动物模型中以及待临床测试的患者中的各种人癌使用脂质体转运p53、pax5、HSV-tk、GM-CSF、IL-12、IL-2、IL-4、IL-7、IFN-γ、TNF-α、RB、BRCA1、E1A、胞嘧啶脱氨酶与包胶的5-氟胞嘧啶、bcl-2、MDR-1、p21、p16、bax、bcl-xs、E2F、IGF-I VEGF、TGF-β、制管张素以及其他基因的组合,并组合包胶的顺铂和其他药物。这些包括:(i)在脂质体中浓缩并包胶药物和基因子弹,降低它们的毒性;(ii)用聚乙二醇(PEG)、透明质酸或其他聚合物包敷复合物的表面,靶向实体瘤和转移瘤;(iii)利用阳离子性脂质的融合性质或者小含量,增强癌细胞对药物和质粒的吸收;以及(iv)使用能够维持治疗基因的表型复制或者长期表达治疗性基因以及高水平表达的人复制起点(ORI)维持基因的表达。
在另一个实施方案中,多核苷酸或基因进一步包括能够在几个月而不是几天的时间中维持基因表达的调节性DNA序列。这等于对癌症患者进行更少的治疗以及产生更少的病痛。其也可发挥强的治疗效果,这是因为高水平的抗癌基因表达;在控制弱的调节性DNA时设置的相同基因是无效的。
在使用p53基因给药系统时已设计出几种用于癌症治疗的试验性方法。我们的新方法包括,使用PAX5表达载体抑制内源性突变p53形式,该形式在一半以上的人前列腺恶性肿瘤、特别是那些晚期前列腺癌中过度表达。突变形式的p53主要是在它们的DNA结合域中具有氨基酸取代,但仍能够与wt p53形式四聚合化;p53以四聚物的形式起作用,而且在人癌细胞中存在高水平的内源性突变p53会干扰所给药的wt p53的肿瘤抑制剂作用。
PAX5是同源域蛋白,其在发育期间决定身体结构;PAX5是在哺乳动物发育的早期以及造血干细胞分化期间的成人中表达;p53基因表达在发育的早期被PAX5抑制剂蛋白消除,使细胞在发育胚胎中快速倍增。PAX5在成年的整个阶段中于后期被关闭,使p53被表达,并发挥其肿瘤抑制功能,特别是在造血细胞系中调节凋亡。
在体细胞基因转移中使用了多种给药系统,都各有优缺点。重组腺病毒不能有效复制;重组鼠逆转录病毒随机整合,而且被染色质包围物失活;重组AAV随机整合,而且对于临床应用不能达到高的效价。因为包装限制,它们都有最大3.5-7.5kb的外源蛋白容量。裸DNA在全身给药后快速分解(半衰期为5分钟)。阳离子性脂质体是毒性的,在循环中的存在时间不超过一次心跳,并主要靶向肺、肝和心的内皮。目前,已证明仅有“秘密”脂质体能够浓集在肿瘤部位(还有肝和脾中),而且在血液循环中保留更长的时间(例如1天,而非秘密中性脂质体为数分钟,阳离子性脂质体为几秒)。但是,秘密脂质体不容易被肿瘤细胞吸收,仍存留在细胞外的空间中,在该空间中在溶胞作用后在数天的时间内释放负载的药物(MartinBoulikas,1998)。然而,本发明以下描述的方面用融合肽或者通过在其内侧双层中提供部分阳离子性脂质体组合物或DOPE对秘密脂质体进行了改进,该双层可通过扰乱脂质双层而使它们进入肿瘤细胞膜中。
用秘密脂质体已在动物的实体瘤中浓集并吸收药物和基因子弹,第二步对于我们的药物及基因靶向方法是有效的。在M.D.AndersonCancer Center中进行的人临床试验在患有非小细胞肺癌的患者中使用了野生型p53基因的转移,而且在与顺铂组合时于肿瘤部位处使用局部注射Ad5/CMV/p53重组腺病毒表明在它们的肿瘤中具有p53突变。该临床试验的第一个结果在肿瘤内注射p53后是令人鼓舞的(Roth等人,1996;综述见Boulikas,1998a)。但是,局部注射不适用于通常与恶性肿瘤晚期有关的转移瘤;特别是前列腺癌在骨中产生转移瘤,其机理涉及胰岛素样生长因子I(IGF-I)刺激前列腺肿瘤的增殖,而所述胰岛素样生长因子I特别是由骨细胞分泌的。因此,在此提出的给药系统能够在全身注射后浓集于肿瘤细胞质中,这样就有可能不仅治疗原位肿瘤,而且还可治疗转移瘤。
所建议的顺铂脂质体主要靶向肿瘤,这是因为我们给药系统的性质。在组合治疗方法中的基因将主要靶向分裂细胞,这是因为使用了掺入在复制DNA中的HSV-tk以及更昔洛韦,而且主要是靶向血管化细胞,这是因为秘密脂质体。因此,将不会杀死秘密脂质体也能到达的肝和脾细胞。
在另一个实施方案中,在此描述的经脂质体包胶的药物还包括有效量的融合肽。融合肽是一类螺旋两亲肽,其特征是沿长的螺旋轴具有疏水性梯度。该疏水性梯度使得肽斜插入膜中,由此使脂质芯不稳定,并增强膜融合(Decout等人,1999)。
血凝素(HA)是流感病毒的同源三体表面糖蛋白。在感染中,其在低pH下诱导病毒和内体膜之间的膜融合。各单体组成受体结合HA1域以及膜相互作用HA2域。HA2域的NH2端区域(氨基酸1-127),所谓的“融合肽”,插入目标膜中,并在触发病毒和内体膜之间的融合方面起着关键性的作用。基于区域5-14中8个氨基酸被半胱氨酸取代以及旋转标记电子顺磁共振,其导致肽形成由该膜的水平面倾斜约25度的α-螺旋,其中由磷酸酯基起算具有最大15埃的深度(Macosko等人,1997)。使用由流感病毒血凝素HA-2中得到的融合肽大大增强了细胞对运铁蛋白-聚赖氨酸-DNA复合物的吸收效力;在此情况下,肽连接在聚赖氨酸上,而且复合物是用运铁蛋白受体介导的胞吞作用来转运的(综述见Boulikas,1998a)。该肽具有以下序列:GLFEAIAGFIENGWEGMIDGGGYC(SEQ ID NO:1),而且能够诱导荧光染料calcein由脂质体中的释放,其是用蛋黄磷脂酰胆碱制备的,在酸性pH条件时更高;在0.1-1mM的浓度下,在使用培养基中的CEM-SS淋巴细胞时,该肽还能够将反义寡核苷酸抗HIV效力增加至10倍。该肽在内体略微更酸性的环境中改变构象,使内体膜不稳定并断裂内体膜(综述见Boulikas,1998a)。
在膜中存在带负电荷的脂质对于证明一些肽的融合性而不是其他肽的融合性是重要的;肽的融合作用代表生育素(fertilin)的推测融合域,该生育素是精-卵融合中涉及的精子表面蛋白,该融合作用依赖于带负电荷的脂质的存在。但是,HIV2肽的融合作用却不是(Martin和Boulikas,1997)。
例如,为分析流感病毒血凝素HA的融合肽上的两个域,HA嵌合体设计成HA的胞质尾区和/或跨膜域被Sendai病毒的融合糖蛋白的相应域替换。HA构建成其中胞质尾区被人神经纤维瘤蛋白1型(NF1)(残基1441-1518)或者c-Raf-1(残基51-131)替换。使用痘苗病毒-T7聚合酶瞬时表达体系在CV-1细胞中表达构建物。CV-1细胞与结合的人红细胞(RBC)之间由母或者嵌合HA蛋白介导的膜融合表明,在降低pH后,含水荧光团calcein开始由预先负载的RBC流入表达蛋白的CV-1细胞的胞浆中。这说明膜融合涉及脂质双层的小叶并导致含水融合孔的形成(Schroth-Diez等人,1998)。
显著的发现是HIV的TAT蛋白能够跨过细胞膜(Green和Loewenstein,1988),而且TAT的36个氨基酸域在化学交联至异源蛋白时,产生转导入细胞中的能力。值得一提的是,TAT的11个氨基酸融合肽(YGRKKRRQRRR)(SEQ ID NO:2)是核仁定位信号(见Boulikas,1998b)。
糖蛋白gp41是HIV的另一种蛋白,包含融合肽。衍生于gp41胞外域的近膜区域的线性肽具有用作抗HIV剂的潜力,并通过采用螺旋构象抑制感染性(Judice等人,1997)。HIV-1 gp41的23个氨基酸残基N端肽具有使带负电荷的大单层囊泡不稳定的能力。在缺乏阳离子时,主结构是成孔性α-螺旋,而存在Ca2+时,构象打开为融合性、主要是延伸的β-型结构。HIV(ala)的融合活性(携带R22(A取代)降低70%,而在包括第二个取代(V2(E)时融合性完全消除,表明其不是α-螺旋,而且由HIV-1融合肽采用的延伸结构,所述HIV-1融合肽积极地使包含胆固醇的电中性膜不稳定(Pereira等人,1997)。
朊病毒蛋白(PrP)是一种功能未知的糖蛋白,正常情况下存在于神经元和神经胶质细胞的表面处。其涉及以下疾病如疯牛病以及人中的Creutzfeldt-Jakob病,其中PrP转化为变更形式(称为PrPSc)。根据计算机模型计算,PrP的120-133以及118-135域是与倾斜脂质有关的肽,以倾斜的方式插入在脂质双层中,而且能够与脂质体相互作用,诱导包胶calcein的泄漏(Pillot等人,1997b)。
Alzheimer淀粉样肽的C端片段(氨基酸20-40和29-42)具有与病毒蛋白的融合肽体外诱导脂质体融合有关的性质。这些性质可介导淀粉样肽与细胞膜的直接相互作用,而且是淀粉样肽的细胞毒性的部分原因。鉴于Alzheimer病的病理学与载脂蛋白E(apoE)多态性之间的流行病学及生物化学联系,检查三种普通的apoE同工型与淀粉样肽的C端片段之间的潜在相互作用,表明仅apoE2和apoE3是淀粉样肽融合及聚集性质的强效抑制剂,而apoE4不是。ApoE对淀粉样聚集物形成的保护作用被认为是通过形成稳定的apoE/淀粉样肽复合物来介导的(Pillot等人,1997a;Lins等人,1999)。
当肽锚定在脂质体膜上时,由11个氨基酸残基组成的两亲性、带净负电荷的肽(WAE 11)的融合性质被强烈促进;肽的融合活性似乎不依赖于pH及膜合并,而且目标膜需要正电荷,该正电荷是通过掺入偶联赖氨酸的磷脂酰乙醇胺(PE-K)来提供的。如果偶联肽可通过与PE-K的非特异性静电相互作用导致囊泡聚集,则游离肽不能诱导PE-K囊泡的聚集(Pecheur等人,1997)。
众多研究表明在插入细胞膜或脂质体的脂质双层中后,α-螺旋二级结构的稳定作用是肽的膜融合性质的原因;Zn2+增强肽的融合活性,因为其稳定α-螺旋结构。例如,唾液杀菌肽的HEXXH域位于histatin-5的C端功能域中,是已识别的锌结合基元,为类螺旋构象(Martin等人,1999;Melino等人,1999;Curtain等人,1999)。
融合肽与DNA质粒配制在一起,以产生以肽为基础的基因给药系统。用于将质粒缩合为40-200nm微小颗粒的YKAKnWK肽与GLFEALLELLESLWELLLEA(SEQ ID NO:3)两亲肽(其是pH敏感的溶解剂,有利于从内体中释放质粒)的组合增强包含β-半乳糖苷酶报道基因的表达体系(Duguid等人,1998)。
DOPE(二油酰基磷脂酰乙醇胺)是融合脂质,弹性酶断裂N-甲氧基-琥珀酰基-Ala-Ala-Pro-Val-DOPE,将该衍生物转化为DOPE(总体带正电荷),以将包胶的荧光探针calcein转运入细胞胞浆中(Pak等人,1999)。与β-内啡肽mRNA的区域互补的30个碱基的寡脱氧核酸序列表明,在用小的单层囊泡(50nm)包胶后,该囊泡包含二棕榈酰基-DL-α-磷脂酰-L-丝氨酸,赋予融合性质,在细胞培养物中浓度依赖性地抑制β-内啡肽的产生(Fresta等人,1998)。
本发明中所用的其他融合肽描述在下表1中。
融合肽 | 源蛋白 | 性质 | 参考文献 |
GLFEAIAGFIENGWEGMIDGGGYC | 流感病毒血凝素HA-2 | Bongartz等人,1994 | |
YGRKKRRQRRR | HIV的TAT | Green和Loewenstein,1998 | |
23个残基的融合性N-端肽 | HIV-1跨膜糖蛋白gp41 | 能够以α-螺旋的形式插入中性磷脂双层中 | Curtain等人,1999 |
120-133和118-135域 | 朊病毒蛋白 | 与倾斜的脂质有关的肽;与脂质体相互作用诱导包胶calcein的泄漏 | Pillot等人,1997b |
29-42个残基的片段 | Alzhermer β-淀粉样肽 | 赋予重新组装病毒融合蛋白的倾斜片段的能力 | Lins等人,1999 |
非聚集性淀粉样β-肽(1-40) | Alzhermer β-淀粉样肽 | 诱导调亡性神经元细胞死亡 | Pillot等人,1999 |
LCAT 56-68螺旋片段 | 卵磷脂胆固醇酰基转移酶(LCAT) | 在脂质中形成稳定的β-片 | Peelman等人,1999;Decout等人,1999 |
70个残基的肽(SV-117) | Sendai病毒的融合肽及N-端heptad重复 | 诱导卵磷脂酰胆碱/磷脂酰甘油(PC/PG)大的单层囊泡(LUV)的脂质混合 | Ghosh和Shai,1999 |
融合肽 | 源蛋白 | 性质 | 参考文献 |
MSGTFGGILAGLIGLL | 鸭乙型肝炎病毒(DHBV)的S蛋白的N-端区域 | 插入在脂质双层的疏水芯中并诱导含水内容物从中性及带负电荷的脂质体中泄漏 | Rodriguez-Crespo等人,1999 |
MSPSSLLGLLAGLQVV | 土拨鼠乙型肝炎病毒(WHV)的S蛋白 | 插入在脂质双层的疏水芯中并诱导含水内容物从中性及带负电荷的脂质体中泄漏 | Rodriguez-Crespo等人,1999 |
肽序列B18 | 与膜相关的海胆精蛋白结合蛋白 | 触发脂质囊泡间的融合,对于融合功能需要用于结合锌并富含组氨酸的基元 | Ulrich等人,1999 |
Histatin-5(唾液抗菌肽) | 存在Zn<sup>2+</sup>时聚集并融合带负电荷的小的单层囊泡 | Melino等人,1999 | |
由11个残基组成的两亲性带负电荷的肽(WAV) | 形成插入并锚定于膜上的α-螺旋(37℃有利),该膜几乎平行于脂质酰基链取向;促进大的单层脂质体(LUV)的融合 | Martin等人,1999 | |
聚赖氨酸的聚合物(平均190),部分被组胺酰基残基取代 | 在低于6.0的pH时使咪唑基团质子化,组胺酰基残基变为阳离子性的;使内体膜破碎 | Midoux和Monsigny,1999 | |
GLFEALLELLESLWELLLEA | 两亲肽;pH敏感性的溶解剂,有利于质粒从内体中的释放 | Duguid等人,1998 |
融合肽 | 源蛋白 | 性质 | 参考文献 |
(LKKL)<sub>4</sub> | 两亲性融合蛋白,能够与DMPC的四个分子相互作用 | Gupta和Kothekar,1997 | |
残基53-70(C-端螺旋) | 载脂蛋白(apo)AII | 诱导单层脂质囊泡的融合,并替代HDL和r-HDL中的apo AI | Lambert等人,1998 |
残基90-111 | PH-30α(起精子-卵融合作用的蛋白) | 对酸性磷脂双层具有膜融合活性 | Niidome等人,1997 |
Nef的N-端 | 人免疫缺损类型1(HIV-1)的Nef蛋白 | 在人工膜中具有膜扰乱和融合活性;导致在E.Coli和酵母中杀死细胞 | Macreadie等人,1997 |
蛋白信号肽 | αs2-和β-酪蛋白 | 与二肉豆蔻酰基磷脂酰甘油和-胆碱脂质体相互作用;表现溶解和融合活性 | Creuzenet等人,1997 |
氨基端的序列F1多肽 | 麻疹病毒(MV)的F1多肽 | 可用作CTL表位的载体系统 | Partidos等人,1996 |
在氨基端区域中23个疏水性氨基酸 | 乙型肝炎病毒(HBV)的S蛋白 | 与其他病毒的已知融合肽具有高度的相似性 | Rodriguez-Crespo等人,1994 |
融合肽 | 源蛋白 | 性质 | 参考文献 |
19-27个氨基酸片段 | 牛白血病病毒的糖蛋白gp51 | 具有两亲结构而且在牛白血病病毒诱导的融合过程中起着关键性的作用 | Voneche等人,1992 |
Ac-(Leu-Ala-Arg-Leu)<sub>3</sub>-NHCH<sub>3</sub> | 碱性两亲性肽 | 导致内容物从由蛋黄磷脂酰胆碱和蛋黄磷脂酸(3∶1)组成的小单层囊泡中泄漏 | Suenaga等人,1989;Lee等人,1992 |
两亲性阴离子肽E<sub>5</sub>和E<sub>5</sub>L | 可模拟流感血凝素(HA)的融合活性 | Murata等人,1991 | |
30个氨基酸肽,主要重复单元为Glu-Ala-Leu-Ala(GALA)<sub>7</sub> | 设计用于模拟病毒融合蛋白的融合序列的性质 | 在pH降低至5.0时变为两亲性的;GALA诱导的磷脂酰胆碱小单层囊泡的融合需要肽链长度超过16个氨基酸 | Parente等人,1988 |
Pardaxin | 两亲性多肽,由RedSea Moses soleflatfish Pardachirusmarmoratus的腺体分泌物纯制 | 形成电压控制的阳离子选择性孔;介导由磷脂酰丝氨酸而不是由磷脂酰胆碱组成的脂质体的聚集 | Lelkes和Lazarovici,1988 |
Gramicidin(线性疏水性多肽) | 抗生素,诱导囊泡的聚集和融合 | Massari和Colonna,1986;Tournois等人,1990 | |
聚(Glu-Aib-Leu-Aib)(Aib代表2-氨基异丁酸) | 在形成α-螺旋时为两亲结构;当pH下降时更强烈地导致EYPC脂质体与二棕榈酰基磷脂酰胆碱脂质体的融合 | Kono等人,1993 |
在形成胶束后,与有效量的囊泡形成脂质混合,以形成包含药物的脂质体。本发明有用的脂质包括预先制备的中性脂质体,粉末状的脂质,PEG-DSPE或者氢化的大豆磷脂酰胆碱(HSPC)。囊泡形成脂质的选择应使提供外层的脂质组成的最终复合物具有特定程度的流动性或刚性。这些可包括10-60%的胆固醇,而其他的量包括双极性(bipolar)磷脂,如磷脂酰胆碱(PC)或者磷脂酰乙醇胺(PE),其中碳链长度为14-22,并具有一个或多个双键C=C。本发明中优选使用的脂质是胆固醇(10-60%)、40-90%的氢化大豆磷脂酰胆碱(HSPC)、以及1-7%的衍生化囊泡形成脂质PEG-DSPE。脂质体提供外脂质双层表面,其包敷有亲水性聚合物PEG。PEG链具有1000-5000道尔顿的分子量。其他亲水性聚合物包括透明质酸、聚乙烯吡咯烷酮、DSPE、羟乙基纤维素、和聚天冬酰胺。PEG-DSPC和PEG-HSPC可由Syngena商购得到。
在与囊泡形成脂质混合前,可通过本领域已知的方法除去乙醇或者其他有机溶剂,例如由渗透膜中透析胶束。
诊断和治疗方法
我们要求保护患者如哺乳动物例如小鼠、大鼠、猿猴和人的治疗方法,这些患者患有人癌,包括但不限于乳腺癌、前列腺癌、结肠癌、非小细胞肺癌、胰腺癌、睾丸癌、卵巢癌、子宫颈癌、头和颈部鳞状细胞癌。在一个方面中,本发明还要求保护静脉注射包胶在脂质体中的顺铂,以及经包胶的顺铂与阿霉素、氟脱氧尿嘧啶核苷、博来霉素、长春碱、泼尼松、长春新碱、紫杉醇组合,或者与放射疗法联合使用,或者与包胶的寡核苷酸、具有抗癌性质的核酶以及多种抗肿瘤基因组合,所述基因包括但不限于p53/Pax5/HSV-tk基因。我们的方法由两个主要部分组成:(i)能够靶向癌细胞,(ii)杀死癌细胞的有效性。
因此,本发明还提供向细胞中转运顺铂或者其他治疗剂的方法,包括使细胞与通过本发明的方法得到的包胶药物相接触。本发明还提供抑制患者中肿瘤生长的方法,其包括向所述患者给药有效量的通过本发明的方法得到的包胶药物。根据脂质/胶束制剂的组成,本发明还要求保护通过静脉给药有效量的包胶药物靶向实体瘤和转移瘤的方法,以及通过给药有效量的包胶药物渗透肿瘤细胞膜的方法,其中胶束包含游离的融合肽或者融合肽-脂质缀合物。
上述方法可在体外、活体外或体内实施。
体外实施所述方法涉及除去肿瘤活体组织或者培养包含肿瘤细胞的细胞样品。最终脂质体复合物或者在顺铂包胶期间产生的任何中间产物(如图1A所示的胶束)在适合细胞内掺入药物的条件下与细胞培养物接触。体外方法可用作确定个体患者的最佳药物治疗的筛选方法。抑制细胞生长或者增殖表明细胞或者肿瘤适合用该治疗方法处理。各治疗中有效量的药物随待治疗的肿瘤以及待治疗的患者而变化。本领域普通技术人员可经验性地确定有效量。
当给药于动物时,本发明的方法用于进一步证实药物或者治疗方法对各肿瘤类型的效力。以合适的动物模型为例,多组SCID小鼠或者无毛鼠(Balb/c NCR nu/nu雌性,Simonsen,Gilroy,CA)可皮下接种约105-109个癌细胞或者靶细胞。当肿瘤确立后,给药脂质体。
在此所用术语“给药、转运”是指包括任何最终向肿瘤提供药物/脂质体复合物的方法。其例子包括但不限于局部给药、静脉给药、非胃肠道给药、或者在肿瘤周围皮下注射。测定肿瘤尺寸减小的肿瘤测量是使用venier夹(caplier)在两个方向上一周测量两次来进行。
对于体内给药,药物组合物优选通过非胃肠道途径给药,例如静脉、腹膜内、皮下、鞘内、注射入脊髓中、肌肉内、动脉内、门静脉注射或者肿瘤内。更优选的是,药物组合物以团块注射剂通过静脉或者肿瘤内途径给药。在另一个方法中,药物组合物可通过直接将制剂施用在组织上而与目标组织接触。给药可通过局部“开放”或者“封闭”方法进行。对于“局部”而言,其是指药物制剂直接施用在暴露于环境中的组织上,如皮肤、鼻咽道、外耳道、眼睛、吸入肺中、生殖粘膜等。“开放”法包括切开患者的皮肤,并直接肉眼观察施用药物制剂的下层组织。这通常是通过手术法来实现的,例如接近肺部的胸廓切开术、接近腹部内脏的剖腹术、或者接近目标组织的其他直接手术法。“封闭”法是侵入方法,其中不直接肉眼观察内部目标组织,而是经过皮肤中的小伤口插入仪器。例如,可通过冲洗针向腹膜给药制剂。同样,可在腰部穿刺期间通过输液向脑膜或者脊髓给药药物制剂,然后如脊柱麻醉或者脊髓metrazamide成像那样对患者进行定位。或者,制剂可通过内镜装置给药。
体内给药可在治疗过程中连续或者间断地以一个剂量进行。确定最有效的给药装置和剂量的方法对于本领域技术人员而言是众所周知的,而且可根据治疗所用的组合物、治疗目的、待治疗的靶细胞、以及待治疗的患者而变化。可根据治疗医生所选择的剂量水平和方案进行单次或多次给药。本领域技术人员可经验性地确定给药的合适剂型及方法。
本发明的药物及组合物可用于制备药物或者根据常规方法进行给药用于治疗人和其他动物,例如在药物组合物中的活性成分。
理想的情况是,药物/脂质制剂的给药应在疾病部位产生峰值浓度的活性化合物。这可例如通过静脉注射药物/脂质制剂来实现。所希望的血药浓度可通过连续输液来维持,以在疾病组织中提供治疗量的活性成分。使用可操作性的组合也在本发明的范围内,以使组合治疗所需要的各组分的总剂量低于各单个治疗化合物或者药物单独使用时的总剂量,并由此降低副作用。
虽然可单独给药药物/脂质制剂,但优选以包含至少一种如上所述的活性成分、一种或多种药物学上可接受的载体以及任选其他治疗剂的药物制剂进行给药。各载体在与制剂的其他成分相容而且对或者没有损害性方面必须是“可接受的”。
设计第三代向实体瘤转运抗癌药物和基因的载体是由于在5个方面对现有技术进行了改进的结果:
(1)在无菌稳定的脂质体中包胶抗癌药物成倍地降低了它们的毒性。预期这可结束进行化疗的癌症患者的梦魇。目前使用的大多数抗癌药物具有严重的副作用,如头发脱落、呕吐、体重减轻、导致梗塞,而且对肾、脑、肝和所有其他活组织产生损坏作用。在此所述的抗癌药物隐藏在脂质双层的腔中,对于大多数组织是不可见的,并浓集在目标肿瘤中,而不是在身体的各个组织中。在被实体瘤吸收后,它们对癌细胞发挥具体的细胞毒性作用,不损坏正常细胞。
(2)靶向整个身体中的实体瘤以及它们的转移瘤。超过95%的癌症患者死于与转移瘤有关的并发症,而不是死于原位癌。我们的基因及药物给药系统被设计成在静脉内给药基因和药物子弹后侵入免疫系统中,不仅到达动物和人体中的原位瘤,而且还到达各转移瘤,无论肿瘤的大小。其是基于携带药物和基因的载体具有长的循环时间,并从肿瘤的血管上皮外渗,这是因为在初始形成阶段(生长肿瘤中血管形成)的不完善和泄漏,而且还因为正在生长的实体瘤与正常身体组织之间存在静压差。本发明的脂质体在内脂质层和外脂质层之间具有不同的组成,使得可有效包胶并靶向肿瘤。
(3)癌细胞吸收脂质体子弹。脂质体子弹能够促进与细胞膜的融合。另外研制的类似的“秘密”子弹不能跨越癌细胞的膜屏障。
(4)对于抗癌药物、寡核苷酸和基因达到接近100%的脂质体包胶率,这是主要的进步。其意味着在有效使用药物和基因时仅有最小的损失和成本。这也代表在制备抗癌子弹时具有更简单的步骤。
(5)在此描述的独特技术可鉴别调节性DNA序列,该序列在抗癌子弹中保持基因表达数个月,而不是几天。这意味着癌症患者可进行更少的治疗,仅有更少的痛苦。其还发挥强的治疗作用,这是因为具有更高水平的抗癌基因表达;在控制弱调节性DNA的情况下设置的相同基因是无效的。
以下实施例将用于说明而不是限制本发明。
实施例
制备胶束以及脂质包胶的顺铂
包胶方法包括以下步骤:(A)在至少30%乙醇、0.1M Tris HCl pH7.5中以1∶1-1∶2的摩尔比混合顺铂(粉末或者其他形状)和DPPG(二棕榈酰基磷脂酰甘油)或者其他带负电荷的脂质分子,形成约5mg/ml的最终顺铂浓度。顺铂与DPPG之间的摩尔比变化对于靶向不同的组织也是具有治疗价值的。(B)在50℃下加热。步骤A和B期间,将会产生黄色顺铂粉末沉淀的初始粉末悬浮体转化为凝胶(胶体)形式;在步骤A和B期间顺铂转化为水合形式(水解氯原子,并被结合在铂上的水分子取代),该形式的顺铂带正电荷,而且是顺铂的活性形式,赋予抗癌活性;在30%的乙醇中,水合顺铂同时与带负电荷的脂质复合为胶束。该顺铂-DPPG静电复合物在消除肿瘤方面比游离顺铂具有更好的性质。(C)复合物(或者以下步骤D后的最终制剂)在到达目标后由肿瘤细胞膜中通过的性质通过添加使复合物具有该性质的肽和其他分子而进一步提高。(D)顺铂-DPPG胶束复合物转化为包胶顺铂-DPPG单层的脂质体(图1顶部)或者通过直接添加预制的脂质体转化为其他类型的复合物,然后相对于盐水进行透析,并由膜中挤出,以将它们的直径降低为100-160nm(图1底部)。正是由所添加的脂质体的脂质组成来决定最终顺铂制剂的外表面组成。
步骤(A)的其他实施方案可包胶多柔比星以及其他带正电的抗癌化合物。在中性或者带负电荷的化合物中添加带正电荷的基团,也能使它们类似地包胶在脂质体中。
治疗应用
将释放90天的雌激素丸剂皮下植入在SCID雌性小鼠中。在乳房脂肪垫处向小鼠皮下注射在0.1ml PBS中的7.5ml MCF-7(可从ATCC得到的人乳腺癌)。建立肿瘤后,在尾静脉处向小鼠静脉给药0.1ml的顺铂脂质体。结果见表2-4。
虽然已经详细地参考具体实施方案描述了本发明,但对于本领域技术人员显而易见的是,在不偏离本发明的精神和范围的情况下还可进行各种改变和改进。
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Claims (24)
1、制备顺铂胶束的方法,其包括:
(a)以1∶1-1∶2的摩尔比混合顺铂和磷脂酰甘油脂质衍生物,形成顺铂混合物;以及
(b)使步骤(a)中的混合物与有效量的至少30%的乙醇溶液混合,形成顺铂胶束,其中顺铂为水合形式。
2、制备顺铂胶束的方法,其包括:
(a)使顺铂与有效量的至少30%的乙醇溶液混合,形成顺铂/乙醇溶液;以及
(b)以1∶1-1∶2的摩尔比混合上述溶液和磷脂酰甘油脂质衍生物,形成顺铂胶束,其中顺铂为水合形式。
3、如权利要求1或2所述的方法,其中磷脂酰甘油脂质衍生物选自于以下组中:二棕榈酰基磷脂酰甘油(DPPG)、二肉豆蔻酰基磷脂酰甘油(DMPG)、二癸酰基磷脂酰甘油(DCPG)、二硬脂酰基磷脂酰甘油(DSPG)和二油酰基磷脂酰甘油(DOPG)。
4、如权利要求1或2所述的方法,其中所述摩尔比为1∶1。
5、如权利要求1或2所述的方法,其还包括在步骤(a)的混合物或溶液中混合有效量的游离融合肽、融合肽-脂质缀合物或者融合肽-PEG-氢化大豆磷脂酰胆碱(HSPC)缀合物,所述融合肽是通过在N或C端延长1-6个带负电荷的氨基酸而得以衍生化,从而能够静电性地结合水合铂。
6、如权利要求5所述的方法,其中游离融合肽或者融合肽-脂质缀合物包括二油酰基磷脂酰乙醇胺(DOPE)或者DOPE/阳离子性脂质。
7、如权利要求1或2所述的方法,其进一步包括从顺铂胶束中除去乙醇的步骤。
8、如权利要求7所述的方法,其中由渗透膜中透析胶束,由此除去乙醇。
9、用如权利要求1-8之一所述的方法得到的顺铂胶束。
10、用如权利要求5所述的方法得到的顺铂胶束。
11、包胶顺铂胶束的方法,其包括使有效量的囊泡形成脂质与通过如权利要求1-8之一所述的方法得到的顺铂胶束混合。
12、如权利要求11所述的方法,其中所述囊泡形成脂质选自于预制的中性脂质体,其由胆固醇10-60%,氢化大豆磷脂酰胆碱(HSPC)40-90%和聚乙二醇-氢化大豆磷脂酰胆碱(PEG-HSPC)1-7%组成,或者溶液形式的脂质,粉末状的脂质以及聚乙二醇二硬脂酰基磷脂酰乙醇胺(PEG-DSPE),其中各成分的含量之和为100%。
13、如权利要求11所述的方法,其中所述脂质包含10-60%的胆固醇。
14、用如权利要求11-13之一所述的方法得到的经包胶的顺铂胶束。
15、用于制备顺铂/脂质复合物的方法,该复合物能够在给药于患者时侵入巨噬细胞和免疫系统的细胞中,该方法包括使有效量的如权利要求7或8所述的顺铂胶束与有效量的聚乙二醇二硬脂酰基磷脂酰乙醇胺(PEG-DSPE)、聚乙二醇二硬脂酰基磷脂酰胆碱(PEG-DSPC)或透明质酸-二硬脂酰基磷脂酰乙醇胺混合。
16、用如权利要求15所述的方法得到的经包胶的顺铂胶束。
17、一种组合物,其包括如权利要求14所述的经包胶的顺铂以及经包胶的核酶或者多核苷酸。
18、一种组合物,其包括如权利要求14所述的经包胶的顺铂以及选自于以下组中的药物:阿霉素、氟脱氧尿嘧啶核苷、博来霉素、长春碱、泼尼松、长春新碱和紫杉醇。
19、一种用于体外向细胞给药顺铂的方法,其包括使所述细胞与如权利要求14或16所述的经包胶的顺铂相接触。
20、如权利要求14或16所述的经包胶的顺铂在制备用于抑制人或动物中肿瘤生长的药物中的应用。
21、如权利要求14或16所述的经包胶的顺铂在制备通过静脉给药于人或动物而靶向实体瘤和转移瘤的治疗药物中的应用。
22、如权利要求14或16所述的经包胶的顺铂、以及选自于p53、pax5和HSV-tk基因的基因在制备用于抑制人或动物中肿瘤生长的药物中的应用。
23、如权利要求14或16所述的经包胶的顺铂、选自于p53、pax5和HSV-tk基因的基因、以及有效量的经包胶的更昔洛韦在制备用于抑制人或动物中肿瘤生长的药物中的应用。
24、如权利要求14或16所述的经包胶的顺铂、以及选自于p53、pax5和HSV-tk基因、IL-2、IL-4、IL-7、IL-12、GM-CSF、IFN-γ、TNF-α、RB、BRCA1、E1A、与包胶的5-氟胞嘧啶联合的胞嘧啶脱氨酶、bcl-2、MDR-1、p21、p16、bax、bcl-xs、E2F、IGFI、VEGF、TGF-β的基因在制备用于抑制人或动物中肿瘤生长的药物中的应用。
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1999
- 1999-11-05 US US09/434,345 patent/US6511676B1/en not_active Expired - Lifetime
-
2000
- 2000-10-27 ES ES00972379T patent/ES2261251T3/es not_active Expired - Lifetime
- 2000-10-27 CN CNB008046611A patent/CN100562311C/zh not_active Expired - Fee Related
- 2000-10-27 WO PCT/US2000/029723 patent/WO2001034130A1/en active IP Right Grant
- 2000-10-27 DK DK00972379T patent/DK1156789T3/da active
- 2000-10-27 CA CA002358948A patent/CA2358948C/en not_active Expired - Fee Related
- 2000-10-27 JP JP2001536130A patent/JP2003513911A/ja not_active Withdrawn
- 2000-10-27 AT AT00972379T patent/ATE321541T1/de active
- 2000-10-27 DE DE60027039T patent/DE60027039T2/de not_active Expired - Lifetime
- 2000-10-27 EP EP00972379A patent/EP1156789B9/en not_active Expired - Lifetime
- 2000-10-27 PT PT00972379T patent/PT1156789E/pt unknown
- 2000-10-27 AU AU11048/01A patent/AU777151B2/en not_active Ceased
- 2000-11-03 TW TW089123244A patent/TWI259770B/zh not_active IP Right Cessation
- 2000-11-03 GR GR20000100384A patent/GR1004168B/el not_active IP Right Cessation
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2003
- 2003-01-23 US US10/350,470 patent/US7393478B2/en not_active Expired - Fee Related
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2006
- 2006-06-28 CY CY20061100880T patent/CY1105628T1/el unknown
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2008
- 2008-06-05 US US12/133,634 patent/US20090280164A1/en not_active Abandoned
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2011
- 2011-11-11 JP JP2011247471A patent/JP5711099B2/ja not_active Expired - Fee Related
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ATE321541T1 (de) | 2006-04-15 |
GR20000100384A (el) | 2001-07-31 |
PT1156789E (pt) | 2006-08-31 |
CA2358948A1 (en) | 2001-05-17 |
AU777151B2 (en) | 2004-10-07 |
JP2003513911A (ja) | 2003-04-15 |
JP2012041364A (ja) | 2012-03-01 |
EP1156789B9 (en) | 2006-06-28 |
EP1156789A4 (en) | 2002-08-07 |
US7393478B2 (en) | 2008-07-01 |
GR1004168B (el) | 2003-02-26 |
US6511676B1 (en) | 2003-01-28 |
US20030185879A1 (en) | 2003-10-02 |
ES2261251T3 (es) | 2006-11-16 |
WO2001034130A1 (en) | 2001-05-17 |
CA2358948C (en) | 2010-01-05 |
CN1343118A (zh) | 2002-04-03 |
TWI259770B (en) | 2006-08-11 |
DE60027039T2 (de) | 2007-04-12 |
AU1104801A (en) | 2001-06-06 |
EP1156789A1 (en) | 2001-11-28 |
EP1156789B1 (en) | 2006-03-29 |
US20090280164A1 (en) | 2009-11-12 |
DK1156789T3 (da) | 2006-08-07 |
CY1105628T1 (el) | 2010-12-22 |
JP5711099B2 (ja) | 2015-04-30 |
DE60027039D1 (de) | 2006-05-18 |
WO2001034130A9 (en) | 2001-12-06 |
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