CN113694075A - 用于医治疾病的外泌体的用途 - Google Patents
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Abstract
本发明提供基于脂质的纳米颗粒(例如,脂质体或外泌体),所述基于脂质的纳米颗粒具有在所述基于脂质的纳米颗粒表面上的CD47并且包含治疗剂(例如,治疗性蛋白、抗体、抑制性RNA和/或小分子药物)。此外,本发明提供这类基于脂质的纳米颗粒在治疗中的用途。
Description
本申请是题为“用于医治疾病的外泌体的用途”的中国申请号201680033436.8的分案申请。本申请要求2015年6月10日提交的美国临时申请第62/173,838号的优先权权益,所述申请的全部内容以引用的方式并入本文中。
背景技术
1.技术领域
本发明大体上涉及医学和肿瘤学的领域。更具体地说,其涉及外泌体在医治方法中的用途。
2.相关技术的描述
外泌体为具有内体起源的脂质双层的小(40nm到150nm)膜囊泡,其通过全部身体细胞释放(Kowal等人,2014年;EL-Andaloussi等人,2013年;Thery等人,2002年)。外泌体含有蛋白、脂质、mRNA、微RNA(miRNA)和基因组DNA(Valadi等人,2007年;Peinado等人,2012年;Luga等人,2012年;Kahlert等人,2014年)。不同于脂质体和其它合成药物纳米颗粒载剂,外泌体含有可能增强内饮作用和/或与接受体细胞的质膜直接融合的许多跨膜和膜锚定的蛋白,因此增强货物(cargo)递送(Marcus等人,2013年;van den Boorn等人,2013年;Johnsen等人,2014年)。当相比于合成纳米颗粒(如脂质体)时,通过减少从循环中清除(部分经由其缺乏与通过用于噬菌作用的巨噬细胞识别的调理素和凝血和补体因子的相互作用)和将免疫原性反应减到最少(Clayton等人,2003年;van der Meel等人,2014年;Gomes-da-Silva等人,2012年),外泌体天然质膜类磷脂组合物(包括在胞质侧面上的磷脂酰丝氨酸和胆固醇)和膜相关联的蛋白组合物还可提供系统性循环上的优异稳定性。这些特征还将可能在合成纳米颗粒在活体内中使用时将观察到的细胞毒性效应减到最少(Simoes等人,2005年)。最终,与外泌体的生成有关的内体和胞间的囊泡运输机制还可用于通过接受体细胞的外泌体吸收中,这可以增强货物释放(和到RNAi基因沉默机制的结合),从而加强任何治疗剂(例如,基因靶向)的功效。近来的研究评估外泌体作为用于治疗的RNAi载剂的功效,并且指示外泌体的系统性注射使得siRNA能够递送到大脑中,从而引起靶基因的稳健下调(Cooper等人,2014年;Alvarez-Erviti等人,2011年)。此外,人血浆衍生的外泌体据报导还使得RNAi能够递送到接受体细胞(Wahlgren等人,2012年),从而支持其在用于靶细胞中的基因表达修饰的RNAi递送中潜在的治疗性实用性。
在KRAS中的单核苷酸变异(KrasG12D/R/V突变)在多达96%的胰腺肿瘤中发现(Chang等人,2014年),并且Kras突变被认为是早期瘤性事件,其驱动并且维持胰腺恶性转化(Ying等人,2012年;Collin等人,2012年;Collins等人,2012年;Smakman等人,2005年)。Kras表达的RNAi型靶向和使用纳米颗粒的下游信号传递最近据报导减少在肺和结直肠癌模型中的肿瘤负荷(Pecot等人,2014年;Yuan等人,2014年;Xue等人,2014年)。不同于专注于致癌Kras的特异性靶向的努力,这些方法可诱使将需要谨慎的剂量和监测的细胞毒性效应。致癌Kras的特异性靶向在胰腺癌症的异种皮移植模型中已经受限于经由电穿孔(Reiiba等人,2007年)或生物高分子植入物(Zorde Khvalevsky等人,2013年)的递送。需要改善的方法来递送治疗剂或诊断剂。
发明内容
本文提供方法和药物,所述方法和药物使用经工程化的脂质体和外泌体作为递送系统用于医治癌症。
在一个实施例中,提供医药组合物,其包含基于脂质的纳米颗粒和赋形剂,其中基于脂质的纳米颗粒包含在其表面上的CD47并且其中基于脂质的纳米颗粒包含治疗剂。在一些方面中,基于脂质的纳米颗粒为脂质体或外泌体。在某些方面,外泌体与过表达CD47的细胞分离。在一些方面中,外泌体与需要医治的患者分离。在一些方面中,外泌体与成纤维细胞分离。在一些方面中,脂质体为单层状脂质体。在一些方面中,脂质体为多层脂质体。
在各种方面中,治疗剂为治疗性蛋白、抗体(例如,全长抗体、单克隆抗体、scFv、Fab片段、F(ab′)2,双功能抗体、三功能抗体或微型抗体)、抑制性RNA或小分子药物。在一些方面中,治疗性蛋白为例如肿瘤遏制因子、激酶、磷酸酶或转录因子的蛋白,所述蛋白的缺失或失活已知涉及待医治的疾病。在一些方面中,抗体结合细胞内抗原。这类细胞内抗原可为其蛋白,所述蛋白的活性对于细胞增殖和/或存活如癌基因是需要的。在一些情况下,抗体阻止抗原的功能。在一些情况下,抗体破坏蛋白-蛋白相互作用。在一些方面中,抑制性RNA为siRNA、shRNA、miRNA或预miRNA。在各种方面中,抑制性RNA阻止蛋白的表达,所述蛋白的活性对于维持某一疾病病况为必要的,例如癌基因。在其中癌基因为基因的突变形式的情况下,那么抑制性RNA可优先阻止突变癌基因而非野生型蛋白的表达。在一些方面中,小分子药物为显影剂。在一些方面中,小分子药物为化疗剂。
在一些方面中,组合物被配制成用于不经肠投与,例如静脉内、肌内、皮下或腹膜内注射。
在一些方面中,组合物包含抗菌剂。抗菌剂可为苯扎氯铵、苄索氯铵、苄醇、溴硝丙二醇、西曲溴铵、氯化十六烷基吡啶、氯己定、氯丁醇、氯甲酚、氯二甲酚、甲酚、乙醇、丙三醇、氨己嘧啶、咪唑烷脲、苯酚、苯氧基乙醇、苯乙醇、硝酸苯汞、丙二醇或硫柳汞。
在一些方面中,单个基于脂质的纳米颗粒包含多于一种药剂,如治疗剂和诊断剂,多于一种治疗剂,或多于一种诊断剂。
在一个实施例中,提供用于医治有需要的患者的疾病的方法,所述方法包含向患者投与本发明的实施例中的任一个的组合物,从而医治患者的疾病。在一些方面中,疾病为癌症。在一些方面中,患者是人类。在一些方面中,患者先前已患有以手术方式除去的肿瘤。
在一些方面中,治疗剂为靶向癌基因的抑制性RNA。在某些方面,抑制性RNA靶向KrasG12D。在一些方面中,治疗剂为肿瘤遏制蛋白。
在一些方面中,方法进一步包含向患者投与至少第二疗法。在各种方面中,第二疗法包含手术疗法、化疗、放疗、超低温疗法、激素疗法或免疫疗法。
在一个实施例中,提供用于医治有需要的患者的疾病的方法,所述方法包含用治疗剂(例如,单克隆抗体)电穿孔脂质体或外泌体和向患者提供电穿孔的脂质体外泌体,从而医治患者的疾病。在一些方面中,脂质体或外泌体包含在其表面上的CD47。在一些方面中,疾病为癌症。在一些方面中,单克隆抗体特异性地或选择性地结合细胞内抗原。
在一个实施例中,提供用于向有需要的患者投与治疗性蛋白的方法,所述方法包含用编码治疗性蛋白(例如,单克隆抗体或其抗原结合片段)的核酸(例如,DNA或RNA)转染外泌体,在允许在外泌体内的治疗性蛋白表达的条件下培育经转染外泌体,以及向患者提供培育的外泌体,从而向患者投与治疗性蛋白。
在一个实施例中,提供用于向细胞投与治疗性抗体的方法,所述方法包含使细胞与包含抗体的基于脂质的纳米颗粒接触,其中抗体特异性地或选择性地结合细胞内抗原。在一些情况下,细胞包含在患者体内,并且方法包含向患者投与基于脂质的纳米颗粒。
在一个实施例中,提供用于医治患者的癌症的方法,所述方法包含向患者投与治疗有效量的基于脂质的纳米颗粒,其中纳米颗粒包含特异性地或选择性地靶向突变Kras(例如,KrasG12D)的抑制性RNA。在一些方面中,癌症为肺癌、结直肠癌或胰腺癌症。在一些方面中,癌症为胰腺导管腺癌。在一些方面中,基于脂质的纳米颗粒为脂质体或外泌体。在某些方面中,外泌体衍生自患者的自身细胞。在一些方面中,基于脂质的纳米颗粒包含在其表面上的CD47。在一些方面中,抑制性RNA为siRNA或shRNA。在一些方面中,抑制性RNA序列被设计成在靶向区域中含有特异性G到A核苷酸偏差(例如,如在SEQ ID NO:1中发现),以促进KrasG12DmRNA的特异性靶向。在一些方面中,抑制性RNA包含具有根据SEQ ID NO:2的序列的靶向区域。
在一个实施例中,提供组合物,所述组合物包含供用于医治患者的疾病的基于脂质的纳米颗粒和赋形剂。在一些方面中,基于脂质的纳米颗粒包含在其表面上的CD47。在一些方面中,基于脂质的纳米颗粒包含治疗剂。在一些方面中,疾病可为癌症。在一些方面中,治疗剂为靶向癌基因的抑制性RNA。在一些方面中,抑制性RNA靶向KrasG12D。在一些方面中,治疗剂为肿瘤遏制蛋白。在一些方面中,组合物进一步包含至少第二疗法。在一些方面中,第二疗法包含手术疗法、化疗、放疗、超低温疗法、激素疗法或免疫疗法。在一些方面中,患者是人类。
在一些方面中,组合物被配制成用于不经肠投与,例如静脉内、肌内、皮下或腹膜内注射。
在一些方面中,组合物包含抗菌剂。抗菌剂可为苯扎氯铵、苄索氯铵、苄醇、溴硝丙二醇、西曲溴铵、氯化十六烷基吡啶、氯己定、氯丁醇、氯甲酚、氯二甲酚、甲酚、乙醇、丙三醇、氨己嘧啶、咪唑烷脲、苯酚、苯氧基乙醇、苯乙醇、硝酸苯汞、丙二醇或硫柳汞。
在一个实施例中,提供基于脂质的纳米颗粒在制备用于医治疾病的医药中的用途。在一些方面中,基于脂质的纳米颗粒包含在其表面上的CD47。在一些方面中,基于脂质的纳米颗粒包含治疗剂。在一些方面中,疾病为癌症。在一些方面中,治疗剂为靶向癌基因的抑制性RNA。在一些方面中,抑制性RNA靶向KrasG12D。在一些方面中,治疗剂为肿瘤遏制蛋白。
在一些方面中,医药被配制成用于不经肠投与,例如静脉内、肌内、皮下或腹膜内注射。
在一些方面中,医药包含抗菌剂。抗菌剂可为苯扎氯铵、苄索氯铵、苄醇、溴硝丙二醇、西曲溴铵、氯化十六烷基吡啶、氯己定、氯丁醇、氯甲酚、氯二甲酚、甲酚、乙醇、丙三醇、氨己嘧啶、咪唑烷脲、苯酚、苯氧基乙醇、苯乙醇、硝酸苯汞、丙二醇或硫柳汞。
如本文中所使用,关于指定组分的“基本上不含”在本文中用于意指没有指定组分已被有目的地配制成组合物和/或仅作为污染物或以痕量存在。由任何不期望组合物的污染引起的指定组分的总量因此远低于0.05%,优选地低于0.01%。最优选的是其中利用标准分析方法不可检测到指定组分的量的组合物。
如本文说明书中所使用,“一个(种)(a或an)”可以意指一个(种)或多个(种)。如本文一项或多项权利要求中所用,在与单词“包含”结合使用时,单词“一个(种)(a或an)”可以意指一个(种)或多于一个(种)。
尽管本公开支持提及单独替代物和“和/或”的定义,但是除非明确指示提及单独替代物或替代物相互排斥,否则权利要求书中使用的术语“或(or)”用于意指“和/或(and/or)”。如本文中所使用,“另一个(another)”可以意指至少第二个或更多个。
在整个本申请中,术语“约”用于指示一个值包括用于确定所述值的装置、方法的误差的固有变化,或在研究受试者间存在的变化。
本发明的其它目的、特征及优点将通过以下详细描述而变得显而易见。然而应了解,虽然指示了本发明的优选实施例,但是详细描述和具体实例仅为了说明而给出,因为所属领域的技术人员根据此详细描述将显而易见属于本发明精神和范围内的各种改变和修改。
附图说明
以下附图形成本说明书的一部分且为了进一步展现本发明的某些方面而包括在内。通过参考这些附图中的一个或多个以及在本文中呈现的特定实施例的详细描述可更好地理解本发明。
图1A到图1F.通过封装在外泌体中的siRNA/shRNA介导的KrasG12D的靶向诱导癌细胞死亡。(图1A)用绿色核标记染色的Panc-1细胞的共焦显微图的量化以及含有用Alexa647标注的siRNA的内化外泌体(exos)以及脂质体(lipos)的视觉显示。在暴露于含有Alexa荧光剂647标注的siRNA的exos或lipos之前,Panc-1细胞在有或没有蛋白酶K或胰蛋白酶的情况下进行预培育。未配对双尾学生t-检验用于确定在组之间的统计显著性。(图1B到图1C)KRASG12D(图1B)或野生型KRAS(图1C)转录水平在用含有siKrasG12D或shKrasG12D的exos或lipos、含有siScrbl或shScrbl的exos或lipos,或非电穿孔(空货物,对照exos)的exos医治3小时的Panc-1细胞中的实时PCR分析。相对于未经处理的Panc-1细胞(对照)的表达(其任意地设定成1)表示倍数改变。当相比于未经处理的Panc-1细胞转录水平时,未配对双尾学生t-检验用于确定统计显著性。(图1D)来自未经处理的Panc-1(对照物)裂解物的裂解物和来自用针对磷酸化AKT(p-AKT)、磷酸化ERK(p-ERK)和肌动蛋白(内对照物)的siKrasG12D或shKrasG12D exos处理的Panc-1细胞的裂解物的蛋白质印迹法。(图1E)在暴露于所列医治之后Panc-1细胞随着时间推移的相对数量。(图1F)针对在暴露于所列医治的Panc-1细胞中的凋亡标示物TUNEL执行的免疫染色显微图的量化。嘌呤霉素用作阳性对照。(0)指示相对于TUNEL,无细胞检测到阳性。对照物:未经处理的,对照exos:非电穿孔(无siRNA货物)的exos。未配对双尾学生t-检验用于确定在组之间的统计显著性。平均值描绘为+/-SEM。除非另外说明,否则单因素方差分析用于确定统计显著性。***p<0.01,****p<0.001,ns:不显著。
图2A到图2G.用含有si/shKrasG12D货物的外泌体医治引起持续Panc-1原位肿瘤消退。(图2A)生物发光Panc-1原位肿瘤随着时间推移的相对光亮度。PBS:n=7,对照exos:n=6,siKrasG12D lipos:n=3,shKrasG12D lipos:n=3,siKrasG12D exos:n=7,shKrasG12Dexos:n=7。统计测试结果示出为在癌细胞注射后第42天将处理组与PBS对照组比较,除siKrasG12D exos组之外,其与在实验终点处的PBS组比较(癌细胞注射后第28天)。顶部一对线为PBS和对照Exos;中间一对线为lipos;底部一对线为exos。(图2B)生物发光BxPC3原位肿瘤随着时间推移的相对光亮度。PBS:n=3,对照exos:n=3,siKrasG12Dexos:n=3,shKrasG12Dexos:n=3。统计测试结果示出为将在癌细胞注射后第77天时的处理组与PBS对照组比较。(图2C)生物发光Panc-1原位肿瘤随着时间推移的相对光亮度。实验组以PBS:n=7,对照exos:n=6,siKrasG12Dexos:n=7,shKrasG12Dexos:n=7开始,并且逐渐地下降,因为小鼠垂死和安乐死(PBS组和对照exos组)。癌细胞的小病灶见于shKrasG12D exos医治的胰腺中,然而绝大部分胰腺为组织学上不显著的。顶部一对线为PBS和对照Exos;底部一对线为si/shKrasG12Dexos。(图2D)原位Panc-1肿瘤在癌细胞注射后第77天时的生物发光的测量光亮度的比较分析。PBS:n=7,对照exos:n=6,shKrasG12Dexos:n=7。未配对双尾学生t-检验用于确定在组之间的统计显著性。(图2E)在实验组中的胰腺肿瘤中的p-ERK免疫标记(比例尺:50μm)和p-ERK染色百分比的量化。n=6。应注意,对在shKrasG12D exos医治的组中的可测量地更小肿瘤区域执行量化。未配对双尾学生t-检验用于确定在两个组之间的统计显著性。(图2F)在安乐死(PBS:第62到130天,对照exos:第30到132天,shKrasG12Dexos:第200天)时在指示的实验组中的肿瘤负荷(胰腺相对于身体质量的相对质量)。未配对双尾学生t-检验用于确定在组之间的统计显著性。(图2G)在指示的实验组中的小鼠的存活的卡普兰-迈耶(Kaplan-Meier)曲线比较,并且使用对数秩曼特尔-考克斯(Mantel-Cox)测试评估统计差异,PBS:n=7,对照exos:n=6,shKrasG12Dexos:n=7。平均值描绘为+/-SEM。除非另外说明,否则单因素方差分析用于确定统计显著性。*p<0.05,**p<0.01,***p<0.001,****p<0.0001,ns:不显著。
图3A到图3G.封装有KrasG12D siRNA和shRNA的外泌体的注射诱导更慢肿瘤进展,并且增加PKT小鼠的存活。(图3A)Ptf1acre/+;LSL-KrasG12D/+;Tgfbr2flox/flox(PKT)小鼠中的具有实验医治点的肿瘤进展时间表的示意性图示。用含有KrasG12D RNAi的BJ成纤维细胞外泌体的医治在第33天开始,并且随后每隔一天持续,直至小鼠达到实验终点或垂死并且需要安乐死。对照组用相同浓度的非电穿孔BJ外泌体(对照exos)处理。(图3B)在指示的实验组中的小鼠的存活的卡普兰-迈耶曲线比较,并且使用对数秩曼特尔-考克斯测试评估统计差异。在每组中n=5。(图3C)在44天的年龄时在指示的实验组中的肿瘤负荷(胰腺相对于身体质量的相对质量)。在每组中n=3。(图3D)根据来自用含有siKrasG12D的exos或非电穿孔对照exos处理的第44天大PKT小鼠的H&E染色肿瘤的显微图确定的相对百分比的量化,n=3。单因素方差分析用于统计比较。(图3E到图3F)在指示的实验组(外泌体来自PKT衍生的成纤维细胞,在每组n=5;左线为对照Exos;右线为siKrasG12D exos)中小鼠的存活的卡普兰-迈耶曲线比较(图3E),及(图3F)肿瘤负荷,n=5。为了卡普兰-迈耶曲线比较的统计分析,执行对数秩曼特尔-考克斯测试。(图3G)针对来自指示实验组中的44天大PKT胰腺肿瘤的凋亡标示物TUNEL、增殖标示物Ki-67和磷酸化ERK的马森(Masson)三色染色法染色(MTS)和免疫标记的显微图的量化。n=3。数据被表示为平均值±SEM。除非另外说明,否则未配对双尾学生t-检验用于确定统计显著性。**p<0.01,****p<0.0001。
图4A到图4I.使用外泌体的特异KrasG12D靶向。(图4A)RNAi进入外泌体的电穿孔的示意性图示。在图示中的RNAi用Alexa647标注。(图4B)外泌体数量和大小分布-使用NanoSight。(图4C到图D)纯化自BJ成纤维细胞(图4C)和通过免疫金针对CD9染色(图4D)的外泌体的透射电子显微图。(图4E)含有Alexa647-标注的siRNA的BJ成纤维细胞外泌体的蔗糖梯度的RNA印迹。在印迹中描绘Alexa647萤光团的荧光的检测。(图4F)在用siKrasG12D或shKrasG12Dlipos、siScrbl或shScrbl lipos医治3小时的Panc-1细胞中的KRASG12D转录水平的实时PCR分析,其中lipos浓度增加(1×,10×,100×)以及Panc-1细胞处理时间增加(24小时)。相对于未经处理的Panc-1细胞(对照)的表达(其任意地设定成1)表示倍数改变。当相比于未经处理的Panc-1细胞转录水平时,未配对双尾学生t-检验用于确定统计显著性。(图4G)在用如图1B所示的siKrasG12D或shKrasG12D exos医治3小时的Panc-1细胞中的KRASG12D转录水平的实时PCR分析,并且其中exos的浓度增加(~700外泌体/细胞,而非~400外泌体/细胞)。当相比于未经处理的Panc-1细胞转录水平时,未配对双尾学生t-检验用于确定统计显著性。(图4H)在用siKrasG12D或shKrasG12D exos医治3小时的BxPC-3细胞中的野生型KRAS转录水平的实时PCR分析。当相比于未经处理的BxPC3细胞转录水平时,未配对双尾学生t-检验用于确定统计显著性。(图4I)在暴露于所列医治之后BXPC-3细胞随着时间推移的相对数量。未配对双尾学生t-检验在最终时间点使用,*p<0.05,**p<0.01,***p<0.001,****p<0.0001,ns:不显著。
图5A到图5D.含有KrasG12D RNAi的外泌体抑制Panc-1原位肿瘤生长。(图5A)腹膜内注射后24小时从siKrasG12D exos医治的小鼠的血清分离的外泌体的流式细胞测量术分析。使用Alexa647标注的RNAi检测所标记的外泌体,他们在结合到0.4μm珠粒之后含有所述Alexa647标注的RNAi。(图5B)在腹膜内注射含有Alexa荧光剂647标注的RNAi的exos或lipos后12小时的小鼠的血液中的Alexa647+/CD11b+巨噬细胞的百分比的流式细胞测量术分析和量化。(图5C)在针对磷酸化AKT(p-AKT)免疫标记的胰腺肿瘤的显微图中的p-AKT染色区域百分比的量化。n=6。应注意,对在shKrasG12D exos医治的组中的相对地更小肿瘤区域执行量化。(图5D)在指示的实验组中的具有BxPC-3原位肿瘤的小鼠的存活的卡普兰-迈耶曲线比较,PBS:n=3,对照exos:n=3,shKrasG12Dexos:n=3,siKrasG12Dexos:n=3(对数秩(曼特尔-考克斯)测试用于此分析)。数据被表示为平均值±SEM。除非另外指出,否则未配对双尾学生t-检验用于确定统计显著性。*p<0.05,**p<0.01,***p<0.001,****p<0.0001,ns:不显著。
图6A到图6B.Panc-1肿瘤进展。(图6A)在第77天时的生物发光的测量光亮度的比较分析。PBS:n=7,对照exos:n=6,shKrasG12Dexos:n=7。在第77天时的未配对双尾学生t-检验用于确定统计显著性,*p<0.05,**p<0.01,***p<0.001,****p<0.0001,ns:不显著。(FIG.6B)描绘单个肿瘤的蜘蛛网图。PBS:n=7,对照exos:n=6,shKrasG12Dexos:n=7。
图7A到图7D.组织学分析KrasG12D RNAi exos医治的PKT小鼠。(图7A)在实验终点的肿瘤负荷(胰腺相对于身体质量的相对质量)(对照exos:43天的中值存活期,siKrasG12Dexos:60天的中值存活期)。在每组中n=5。(图7B到7C)在指示的实验终点处且用(图7B)BJ成纤维细胞和(图7C)PKT成纤维细胞衍生的siKrasG12D exos或非电穿孔exos(对照exos)处理的PKT小鼠的H&E染色肿瘤的显微图中的组织学表现型的相对百分比的量化。n=5。双因素方差分析用于统计比较。(图7D)来自在指示的实验组中的44天大PKT小鼠的针对磷酸化AKT免疫标记的肿瘤的显微图的量化。数据被表示为平均值±SEM。除非另外说明,否则未配对双尾学生t-检验用于确定统计显著性。**p<0.01,****p<0.0001。
图8A到图8B.循环单核细胞吞噬iLiposomes(即,包含原料药如抑制性RNA的脂质体)比iExosomes(即,包含原料药如抑制性RNA的外泌体)更高效。(图8A)顶部图示出来自总活细胞种群的CD11b阳性细胞的百分比。底部图示出来自总活细胞种群的A647和CD11b双倍地阳性细胞的百分比。(图8B)提供于图8A中的FACS图的量化。
图9A到图9C.对外泌体而非外泌体检测CD47。(图9A)从BJ成纤维细胞中分离的外泌体。顶部图示出仅用二级抗体染色,底部图示出针对CD63或CD47的染色。(图9B)仅用二级抗体或用抗体针对CD63或CD47染色的脂质体(100nm)。(图9C)通过以两种不同方法从三种不同细胞系中分离的外泌体的CD47的表达。
图10.抗CD47抗体通过活体内循环单核细胞刺激外泌体吸收。外泌体用抗CD47抗体处理,所述抗CD47抗体通过活体内循环单核细胞允许外泌体的吸收。
图11.表示存在于胰腺癌细胞的亚群和其相应外泌体中的蛋白的文氏图。从胰腺癌细胞系T3M4的亚群和其相应外泌体提取蛋白。质谱用于鉴别在细胞和相应外泌体中表达的蛋白。针对每个样品鉴别蛋白的列表。当相比于细胞(每对圆形的右侧)时,在细胞和相应外泌体之间的比较鉴别存在于细胞而非存在于外泌体中(每对圆形的左侧)的蛋白、存在于细胞和相应外泌体中(在圆形之间的交叉点)的蛋白和在外泌体中富集的蛋白。细胞表达不出现在外泌体中的蛋白。另外,在与起源细胞相比较时,外泌体含有富集的蛋白。
具体实施方式
不管当前护理标准,针对转移性患者,胰腺导管腺癌(PDAC)具有六个月的中值存活期,其中仅6.7%的患者在五年之后存活(Siegel等人,2014年;Howlader等人,2013年)。因此,PDAC迫切需要有效新疗法。PDAC的基因分析示出,在小GTP酶的RAS家族(KrasGl2/D/R/V)中的突变发生于70%到96%的患者中(Biankin等人,2012年;Hruban等人,1993年;Almoguera等人,1988年;Chang等人,2014年)并且为肿瘤生长和转移的重要驱动基因(Ying等人,2012年;Hingorani等人,2005年;Collins等人,2012a;Collins等人,2012b;Eser等人,2014年)。在小鼠中的基因操纵已经示出,抑制致癌KRAS逆转肿瘤进展(Ying等人,2012年,Collins等人,2012a;Collins等人,2012b;Smakman等人,2005年)。致癌KRAS信号传递及增加的RAS活性已经显现为引发胰腺瘤病的驱动基因(Collins等人,2012a;Eser等人,2014年;Ji等人,2009年);然而,RAS仍然是难处理的目标和治疗挑战(Gysin等人,2011年)。在本文中衍生自正常成纤维细胞的外泌体经工程化以携带RNA干扰(RNAi)净负荷到目标致癌KRASG12D。含有键联TT的siRNA或shRNA的外泌体相对于KrasG12D高效地进入癌细胞并且特异性地抑制致癌Ras,使ERK激活减弱,抑制增殖,并且诱使癌细胞凋亡。当相比于含有si/shRNA的脂质体和具有加扰RNAi构成物的外泌体时,具有KrasG12D靶向货物的全身递送外泌体示出稳健胰腺定位和胰腺癌症的预定原位人胰腺肿瘤以及在基因工程改造的小鼠模型(GEMM)中肿瘤的抑制,以及存活期的改善。用含有si/shRNA的外泌体医治的小鼠的肿瘤显示下游RAS信号介体的显著减少和在正常胰腺组织结构的改善的组织病理学发现。人成纤维细胞衍生的外泌体示出与小鼠成纤维细胞衍生的外泌体在PDAC GEMM上的类似的功效,因此表明,为了允许高效RNAi递送同时将潜在的毒性副作用减到最少,可不需要患者特异性外泌体。这类策略提供抑制致癌基因表达和下游信号传递的具有最小脱靶效应的新颖和高效手段。
CD47(整合素相关联的蛋白)为在大多数组织和细胞上表达的跨膜蛋白。CD47为用于信号调节蛋白α(SIRP-α)的配体,所述信号调节蛋白α在噬菌细胞如巨噬细胞和树突状细胞上表达。活化CD47-SIRP-α引发抑制噬菌作用的信号转导级联。在外泌体注射之前将针对抵抗CD47的单克隆抗体注射到小鼠中,或在注射之前用CD47中和抗体医治外泌体两者都阻断CD47并且准许通过巨噬细胞或单核细胞吞噬外泌体。因此,CD47在外泌体的表面上的表达阻止通过巨噬细胞的噬菌作用。
I.基于脂质的纳米颗粒
在一些实施例中,基于脂质的纳米颗粒为脂质体、外泌体、脂质制剂,或另一种基于脂质的纳米颗粒,如基于脂质的囊泡(例如,DOTAP:胆固醇囊泡)。基于脂质的纳米颗粒可带正电、带负电或中性。
A.脂质体
“脂质体”为包含多种通过生成包封的脂质双层或聚集体形成的单和多层脂质媒剂的通用术语。脂质体可被表征为具有带有双层膜的囊泡结构,通常包含磷脂,和通常包含水性组合物的内部介质。本文所提供的脂质体包括单层脂质体、多层脂质体和多囊脂质体。本文所提供的脂质体可带正电、带负电或不带电。在某些实施例中,脂质体为不带电。
多层脂质体具有通过水性介质分隔开的多种脂质层。在包含磷脂的脂质悬浮于过量水性溶液时,这类脂质体自发地形成。在形成闭合结构之前,脂质组分经受自动重排,并且将水和溶解的溶解物包覆在脂质双层之间。亲油性分子或具有亲油性区域的分子还可溶解在脂质双层中或与脂质双层缔合。
在特定方面中,多肽、核酸或小分子药物可(例如)包封于脂质体的水性内部中、散布在脂质体的脂质双层内、经由与脂质体和多肽/核酸均缔合的键连分子附着到脂质体、包覆在脂质体中、与脂质体络合等。
如本领域的普通技术人员将知道的,根据本发明的实施例使用的脂质体可通过不同方法制得。举例来说,磷脂,例如中性磷脂二油酰基磷脂酰胆碱(DOPC)溶解于叔丁醇中。一种或多种脂质然后与多肽、核酸和/或一种或多种其它组分混合。吐温20添加到脂质混合物,使得吐温20为组合物重量的约5%。过量叔丁醇添加到此混合物,使得叔丁醇的体积为至少95%。混合物经涡动,在干冰/丙酮浴液中冻结,并且冻干过夜。冻干的制剂储存在-20℃下并且可使用至多三个月。在需要时,冻干的脂质体在0.9%盐水中重建。
替代地,脂质体可通过在容器例如玻璃、梨状烧瓶中于溶剂中混合脂质制备。容器应当具有比脂质体的预期悬浮液的体积大十倍的体积。使用旋转式蒸发器,在大约40℃于负压下除去溶剂。根据脂质体的期望容积,溶剂通常在约5分钟到2小时内除去。可在干燥器中在真空下进一步干燥组合物。由于随时间的推移的劣化倾向,干燥的脂质通常在约1周之后舍弃。
通过摇动直至全部脂质膜再悬浮,干燥的脂质可在无菌、无热原质水中在约25mM到50mM磷脂下水合。然后,水性脂质体可分成等分试样,每个置于瓶中,在真空下冻干并且密封。
如上所述制备的干燥脂质或冻干脂质体可在蛋白或肽的溶液中经脱水和重建并且用合适溶剂例如DPBS稀释到适当浓度。然后,混合物在涡流混合器中剧烈振荡。未被包封的附加材料如药剂(包括(但不限于)激素、药物、核酸构建体等)通过在29,000×g下离心除去,并且洗涤脂质体团块。洗涤的脂质体在适当总磷脂浓度例如约50mM到200mM下再悬浮。经包封的附加材料或活性剂的量可根据标准方法确定。在确定包封于脂质体制剂中的补充材料或活性剂的量之后,脂质体可稀释到适当浓度并且储存在4℃下,直至使用。包含脂质体的医药组合物通常将包括无菌、医药学上可接受的载剂或稀释剂,如水或盐水溶液。
可使用于本发明的实施例的附加脂质体包括阳离子脂质体例如如描述于WO02/100435A1、美国专利5,962,016、美国申请2004/0208921、WO03/015757A1、WO04029213A2、美国专利5,030,453和美国专利6,680,068中,全部文献特此以全文引用的方式并入,无需免责声明。
在制备这类脂质体时,可使用本文所述的或如本领域的普通技术人员将已知的任何方案。制备脂质体的附加非限制性实例描述在美国专利4,728,578、4,728,575、4,737,323、4,533,254、4,162,282、4,310,505和4,921,706;国际申请PCT/US85/01161和PCT/US89/05040中,每个以引用的方式并入本文中。
在某些实施例中,基于脂质的纳米颗粒为中性脂质体(例如,DOPC脂质体)。如本文中所使用的“中性脂质体”或“不带电脂质体”定义为具有产生基本上中性净电荷(基本上不带电)的一种或多种脂质组分的脂质体。所谓“基本上中性”或“基本上不带电”,其意指在给定群体(例如,脂质体的群体)内很少(如果存在的话)的脂质组分包括不由另一种组分的相反电荷抵消的电荷(即,少于10%的组分包括未经抵消的电荷,更优选地少于5%并且最优选地少于1%)。在某些实施例中,中性脂质体可包括在生理条件下(即,在约pH值7下)本身中性的大部分脂质和/或磷脂。
本发明的实施例的脂质体和/或基于脂质的纳米颗粒可包含磷脂。在某些实施例中,单个种类磷脂可用于形成脂质体(例如,中性磷脂如DOPC可用于生成中性脂质体)。在其它实施例中,多于一种磷脂可用于形成脂质体。磷脂可来自天然来源或合成来源。磷脂包括例如磷脂酰胆碱、磷脂酰甘油和磷脂酰乙醇胺;因为磷脂酰乙醇胺和磷脂酰基胆碱在生理条件下(即,在约pH值7下)不带电,所以这些化合物可具体地用于生成中性脂质体。在某些实施例中,磷脂DOPC用于产生不带电脂质体。在某些实施例中,可使用不是磷脂的脂质(例如,胆固醇)。
磷脂包括甘油磷脂和某些鞘脂。磷脂包括(但不限于)二油酰基磷脂酰胆碱(″DOPC″)、蛋磷脂酰胆碱(″EPC″)、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″)、二硬脂酰基磷脂酰胆碱(″DSPC″)、1-肉豆蔻酰基-2-软脂酰基磷脂酰胆碱(″MPPC″)、1-软脂酰基-2-肉豆蔻酰基磷脂酰胆碱(″PMPC″)、1-软脂酰基-2-硬脂酰基磷脂酰胆碱(″PSPC″)、1-硬脂酰基-2-软脂酰基磷脂酰胆碱(″SPPC″)、二月桂酰基磷脂酰甘油(″DLPG″)、二肉豆蔻酰基磷脂酰甘油(″DMPG″)、二棕榈酰磷脂酰甘油(″DPPG″)、二硬脂酰基磷脂酰甘油(″DSPG″)、二硬脂酰基鞘磷脂(″DSSP″)、二硬脂酰基磷脂酰乙醇胺(″DSPE″)、二油酰基磷脂酰甘油(″DOPG″)、二肉豆蔻酰基磷脂酸(″DMPA″)、二棕榈酰基磷脂酸(″DPPA″)、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″)、二肉豆蔻酰基磷脂酰丝氨酸(″DMPS″)、二棕榈酰基磷脂酰丝氨酸(″DPPS″)、脑磷脂酰丝氨酸(″BPS″)、脑鞘磷脂(″BSP″)、二棕榈酰基鞘磷脂(″DPSP″)、二肉豆蔻基磷脂酰胆碱(″DMPC″)、1,2-二硬脂酰基-sn-甘油-3-磷酸胆碱(″DAPC″)、1,2-二花生酰基-sn-甘油-3-磷酸胆碱(″DBPC″)、1,2-二(二十碳烯酰基)-sn-甘油-3-磷酸胆碱(″DEPC″)、二油酰基磷脂酰乙醇胺(″DOPE″)、棕榈油酰基磷脂酰胆碱(″POPC″)、棕榈油酰基磷脂酰乙醇胺(″POPE″)、溶血磷脂酰胆碱、溶血磷脂酰乙醇胺和二亚油酰磷脂酰胆碱。
B.外泌体
如本文中所使用的术语“微囊泡”和“外泌体”是指直径(或最大尺寸,其中颗粒不为球形)在约10nm到约5000nm之间,更通常地在30nm和1000nm之间和最通常在约50nm和750nm之间的膜性颗粒,其中外泌体的膜的至少一部分直接地从细胞获得。最常见的,外泌体将具有供体细胞的尺寸的至多5%的尺寸(平均直径)。因此,尤其预期的外泌体包括从细胞脱落的那些。
外泌体可以任何合适样品类型例如体液被检测或从其中分离。如本文中所使用,术语“分离”是指从其天然环境中分开且意指包括至少部分纯化并且可包括实质性纯化。如本文中所使用,术语“样品”是指适于由本发明提供的方法的任何样品。样品可为包括适于检测或分离的外泌体的任何样品。样品的来源包括血液、骨髓、胸膜液、腹膜液、脑脊髓液、尿、唾液、羊膜液、恶性腹水、支气管肺泡灌洗液、滑膜液、母乳、汗液、泪液、关节液和支气管洗液。在一个方面中,样品为血液样品,包括例如,全血或其任何级分或组分。适合与本发明一起使用的血液样品可从任何已知来源提取,所述来源包括血细胞或其组分,如静脉、动脉、末梢、组织、脊髓等。举例来说,样品可使用熟知和常规临床方法(例如,用于抽取和处理全血的程序)获得和处理。在一个方面中,例示性样品可为来自患癌的受试者抽取的外周血液。
外泌体还可从组织样品中分离,所述组织样品如手术样品、活检样品、组织、大便和经培养细胞。在从组织来源中分离外泌体时,可需要均匀化所述组织以便获得单个细胞悬浮液,接着是裂解细胞以释放外泌体。在从组织样品中分离外泌体时,重要的是,选择不导致外泌体破坏的均匀化和裂解程序。在本文中预期的外泌体优选地从在生理学上可接受的溶液例如缓冲盐水、生长介质、各种水性介质等中的体液中分离。
外泌体可从刚采集的样品中或从已经储存冻结或冷藏的样品中分离。在一些实施例中,外泌体可从细胞培养基中分离。虽然不必需,但是如果在与体积排除聚合物一起沉淀之前液体样品澄清以从样品中去除任何碎片,则可获得更高纯度外泌体。澄清的方法包括离心、超速离心、过滤或超过滤。最通常地,外泌体可通过所属领域中众所周知的许多方法来分离。一种优选方法为从体液或细胞培养上清液中差速离心。用于分离外泌体的例示性方法被描述于(Losche等人,2004年;Mesri和Altieri,1998年;Morel等人,2004年)中。替代地,外泌体还可经由如描述于(Combes等人,1997年)中的流式细胞测量术分离。
用于分离外泌体的一种可接受的方案包括超速离心,通常结合蔗糖密度梯度或蔗糖衬垫以使相对低密度外泌体漂浮。由于与其它微囊泡或大分子络合物叠加尺寸分布的可能性,通过顺序不同的离心分离外泌体是复杂的。此外,离心可不足以提供基于囊泡尺寸分开囊泡的手段。然而,在与蔗糖梯度超速离心结合时,顺序离心可提供高富集外泌体。
使用超速离心途径的替代方案,基于尺寸分离外泌体为另一种选项。已经报告使用与超速离心相比较少费时的并且不需要使用特殊设备的超过滤程序成功纯化外泌体。类似地,商业试剂盒是可用的(EXOMIRTM,美国柏尔科学公司(Bioo Scientific),其允许在一个微过滤器上移除细胞、血小板和细胞碎片并且在第二微过滤器上使用正压力驱动液体来捕获大于30nm的囊泡。然而,对于此过程,外泌体不经回收,其RNA内容物直接从勾住第二微过滤器的材料提取,其然后可用于PCR分析。基于HPLC的方案可潜在地允许个体获得极纯外泌体,但是这些过程需要专用设备并且难以按比例放大。显著的问题为,血液和细胞培养基均含有处于与外泌体相同的尺寸范围的大量纳米颗粒(一些不为囊泡)。举例来说,一些miRNA可含在胞外蛋白络合物而非外泌体内;然而,可执行用蛋白酶(例如,蛋白酶K)的医治以消除经由“额外外泌体(extraexosomal)”蛋白的任何可能污染。
在另一个实施例中,癌细胞衍生的外泌体可由常用技术捕获以富集用于外泌体的样品,如涉及免疫特异性相互作用(例如,免疫磁性捕获)的那些。免疫磁性捕获,也被称作免疫磁性细胞分离,通常涉及将针对于在具体细胞类型上发现的蛋白的抗体附着到小顺磁珠粒。在抗体涂布的珠粒与样品如血液混合时,珠粒附着到并且围绕具体细胞。然后,将样品置于强磁场中,使得珠粒结块到一侧。在除去血液之后,所捕获细胞用珠粒保持。此通用方法的许多变型在所属领域中是众所周知的并且适用于分离外泌体。在一个实例中,外泌体可附着于磁珠(例如,醛/硫酸盐珠粒),并且然后将抗体添加到混合物以识别附着到珠粒的外泌体的表面上的表位。已知在癌细胞衍生的外泌体上发现的例示性蛋白包括ATP结合盒亚家族A成员6(ABCA6)、四跨膜蛋白-4(TSPAN4)、SLIT和NTRK类蛋白4(SLITRK4)、推定的原钙粘附蛋白(protocadherin)β-18(PCDHB18)、骨髓细胞表面抗原CD33(CD33)和磷脂酰肌醇蛋白聚糖-1(GPCI)。癌细胞衍生的外泌体可使用例如这些蛋白中的一种或多种的抗体或适体分离。
如本文中所使用,分析包括允许直接或间接视觉显示外泌体的任何方法并且可活体内或离体进行。举例来说,分析可包括(但不限于)离体微观或细胞学检测和视觉显示结合到到固体基质、流式细胞测量术、荧光成像等的外泌体。在例示性方面中,癌细胞衍生的外泌体使用针对于以下中的一个或多个的抗体检测:ATP结合盒亚家族A成员6(ABCA6)、四跨膜蛋白-4(TSPAN4)、SLIT和NTRK类蛋白4(SLITRK4)、推定的原钙粘附蛋白β-18(PCDHB18)、骨髓细胞表面抗原CD33(CD33)、磷脂酰肌醇蛋白聚糖-1(GPC1)、组蛋白H2A型2-A(HIST1H2AA)、组蛋白H2A型1-A(HIST1H1AA)、组蛋白H3.3(H3F3A)、组蛋白H3.1(HIST1H3A)、锌指蛋白37同源物(ZFP37)、层粘连蛋白亚基β-1(LAMB1)、小管间质性肾炎抗原类(TINAGL1)、过氧化物还原酶-4(PRDX4)、胶原蛋白α-2(IV)链(COL4A2)、推定的蛋白C3P1(C3P1)、胞外基质蛋白-1(HMCN1)、推定的rho结合蛋白-2-类蛋白(RHPN2P1)、含锚蛋白重复结构域的蛋白62(ANKRD62)、含三联基元的蛋白42(TRIM42)、连接桥粒斑珠蛋白(JUP)、微管蛋白β-2B链(TUBB2B)、核糖核酸内切酶切丁酶(DICER1)、E3泛素-蛋白接合酶TRIM71(TRIM71)、含剑蛋白p60 ATP酶的亚基A类2(KATNAL2)、蛋白S100-A6(S100A6)、含5′-核苷酸酶结构域的蛋白3(NT5DC3)、缬氨酸-tRNA接合酶(VARS)、Kazrin(KAZN)、ELAV类蛋白4(ELAVL4)、环指蛋白166(RNF166)、含FERM和PDZ结构域的蛋白1(FRMPD1)、78kDa葡萄糖调节蛋白(HSPA5)、运输蛋白粒子复合亚基6A(TRAPPC6A)、角鲨烯单氧酶(SQLE)、肿瘤易感性基因101蛋白(TSG101)、空泡蛋白分选28同源物(VPS28)、前列腺素F2受体负调控剂(PTGFRN)、异丁酰基-CoA脱氢酶、线粒体(ACAD8)、26S蛋白酶调节亚基6B(PSMC4)、延伸因子1-γ(EEF1G)、肌联蛋白(TTN)、酪氨酸-蛋白磷酸酶型13(PTPN13)、丙糖磷酸异构酶(TPI1)或羧基肽酶E(CPE),并且随后结合到固体基质和/或使用微观或细胞学检测视觉化。
应注意,并非在细胞中表达的所有蛋白发现于由所述细胞分泌的外泌体中(参见图11)。举例来说,钙联接蛋白、GM130和LAMP-2为在MCF-7细胞中表达的而非发现于由MCF-7细胞分泌的外泌体中的所有蛋白(Baietti等人,2012年)。作为另一实例,有人研究发现,与健康对照相比,190/190胰腺导管腺癌患者具有更高含量水平的GPC1+外泌体(Melo等人,2015年,其以全文引用的方式并入本文中)。值得注意的是,平均起来,仅2.3%的健康对照具有GPC1+外泌体。
1.用于从细胞培养物中收集外泌体的例示性方案
在第1天时,在T225烧瓶中,将足够细胞(例如,约五百万个细胞)接种在含有10%FBS的培养基中,使得次日细胞将约70%汇合。在第2天时,抽吸在细胞上的培养基,用PBS洗涤细胞两次,并且然后添加25mL至30mL基础培养基(即,无PenStrep或FBS)到所述细胞。将所述细胞培育24小时至48小时。优选48小时培育,但是一些细胞系对无血清培养基更为敏感,并且因此培育时间应当减少到24小时。应注意,FBS含有将使NanoSight结果严重偏移的外泌体。
在第3/4天时,收集培养基并且在室温下在800×.g下离心五分钟,以使死的细胞和大碎片结块。将上清液转移到新圆锥形试管,并且在2000×g下再次离心培养基10分钟以去除其它大碎片和大囊泡。使培养基通过0.2μm过滤器,并且然后使用35毫升/管将其等分试样到超速离心试管(例如,25×89mm贝克曼超澄清)中。如果每管的培养基体积小于35mL,则用PBS填充管的剩余部分以达到35mL。在4℃下,使用SW 32Ti转子(k-因数266.7,RCF最大值133,907),在28,000转/分下超速离心培养基2小时到4小时。小心地抽吸上清液,直至存在大致1-英寸剩余液体。使试管倾斜并且允许剩余培养基缓慢进入抽吸器滴管。如果需要,则外泌体团块可在PBS中再悬浮并且在28,000转/分下超速离心重复1小时到2小时以进一步纯化外泌体的群体。
最终,再悬浮的外泌体在210uL PBS中结块。如果存在用于每个样品的多个超速离心试管,则使用相同210μL PBS以连续再悬浮每个外泌体团块。对于每个样品,采集10μL并且添加990μL H2O以供纳米颗粒追踪分析使用。使用剩余200μL含外泌体悬浮液用于下游过程或立刻在-80℃下存储。
2.用于从血清样品中提取外泌体的例示性方案
首先,使血清样品在冰上解冻。然后,在11mL PBS中稀释250μL的无细胞血清样品;通过0.2μm孔式过滤器过滤。在4℃下,在150,000×g下超速离心稀释的样品,过夜。第二天,小心地弃去上清液并且在11mL PBS中洗涤外泌体团块。在4℃下,在150,000×g下执行第二轮超速离心2小时。最终,小心地弃去上清液并且在100μL PBS中再悬浮外泌体团块用于分析。
C.用于电穿孔外泌体和脂质体的例示性方案
在400μL的电穿孔缓冲液(1.15mM磷酸钾,pH值7.2,25mM氯化钾,21%Optiprep)中,混合1×108个外泌体(通过NanoSight分析测量)或100nm脂质体(例如,购自Encapsula纳米科学公司(Encapsula Nano Sciences))和1μg的siRNA(凯杰公司(Qiagen))或shRNA。使用4mm比色皿电穿孔外泌体或脂质体(参见,例如,Alvarez-Erviti等人,2011年;EL-Andaloussi等人,2012年)。电穿孔之后,用不含蛋白酶的RNA酶处理外泌体或脂质体,接着添加10×浓缩的RNa酶抑制剂。最终,如上所述,在超速离心方法下,用PBS洗涤外泌体或脂质体。
II.疾病的诊断、预后和医治
使用本发明的方法的癌细胞衍生的外泌体的检测、分离和表征可用于评定癌症预后和监测疗效,以便早期检测可引起疾病复发的医治失效。此外,根据本发明的癌细胞衍生的外泌体分析使得能够检测已经完成治疗过程的症状前的患者的早期复发。这可能因为,癌细胞衍生的外泌体的存在可相关联于和/或相关于肿瘤进展和扩散、对治疗的反应不佳、疾病复发,和/或降低在某一时间段上的存活期。因此,癌细胞衍生的外泌体的例举和表征提供方法来相对于基于对治疗的反应而预测初始风险和随后风险的基线特征对患者进行分类。
根据本文公开的方法分离的癌细胞衍生的外泌体可经分析来诊断或预测受试者的癌症。由此,本发明的方法可用于例如评估癌症患者和处于癌症风险中的那些人。在本文所述的诊断或预后的方法中的任一种中,癌症的一种或多种指示物(如基因组突变或癌症特异性外泌体表面标记物)或任何其它病症的一种或多种指示物的存在或不存在可用于生成诊断或预后。
在一个方面中,从患者抽取血液样品,并且癌细胞衍生的外泌体如本文所描述地检测和/或分离。举例来说,外泌体可标记有与ATP结合盒亚家族A成员6(ABCA6)、四跨膜蛋白-4(TSPAN4)、SLIT和NTRK类蛋白4(SLITRK4)、推定的原钙粘附蛋白β-18(PCDHB18)、骨髓细胞表面抗原CD33(CD33)和/或磷脂酰肌醇蛋白聚糖-1(GPC1)结合的一种或多种抗体或适体,并且抗体可具有共价键结荧光标记。接着可执行分析以确定癌细胞衍生的外泌体在样品中的数量和表征,并且根据此测量,可确定存在于初始血液样品中的癌细胞衍生的外泌体的数量。鉴别为癌细胞衍生的外泌体的外泌体可由此通过检测已知选择性地或特异性地发现于癌细胞衍生的外泌体中的第二(或更多)标示物来验证,所述第二(或更多)标示物例如,组蛋白H2A型2-A(HIST1H2AA)、组蛋白H2A型1-A(HIST1H1AA)、组蛋白H3.3(H3F3A)、组蛋白H3.1(HIST1H3A)、锌指蛋白37同源物(ZFP37)、层粘连蛋白亚基β-1(LAMB1)、小管间质性肾炎抗原类(TINAGL1)、过氧化物还原酶-4(PRDX4)、胶原蛋白α-2(IV)链(COL4A2)、推定的蛋白C3P1(C3P1)、胞外基质蛋白-1(HMCN1)、推定的rho结合蛋白-2-类蛋白(RHPN2P1)、含锚蛋白重复结构域的蛋白62(ANKRD62)、含三联基元的蛋白42(TRIM42)、连接桥粒斑珠蛋白(JUP)、微管蛋白β-2B链(TUBB2B)、核糖核酸内切酶切丁酶(DICER1)、E3泛素-蛋白接合酶TRIM71(TRIM71)、含剑蛋白p60 ATP酶的亚基A类2(KATNAL2)、蛋白S100-A6(S100A6)、含5′-核苷酸酶结构域的蛋白3(NT5DC3)、缬氨酸-tRNA接合酶(VARS)、Kazrin(KAZN)、ELAV类蛋白4(ELAVL4)、环指蛋白166(RNF166)、含FERM和PDZ结构域的蛋白1(FRMPD1)、78kDa葡萄糖调节蛋白(HSPA5)、运输蛋白粒子复合亚基6A(TRAPPC6A)、角鲨烯单氧酶(SQLE)、肿瘤易感性基因101蛋白(TSG101)、空泡蛋白分选28同源物(VPS28)、前列腺素F2受体负调控剂(PTGFRN)、异丁酰基-CoA脱氢酶、线粒体(ACAD8)、26S蛋白酶调节亚基6B(PSMC4)、延伸因子1-γ(EEF1G)、肌联蛋白(TTN)、酪氨酸-蛋白磷酸酶型13(PTPN13)、丙糖磷酸异构酶(TPI1)或羧基肽酶E(CPE)。癌细胞衍生的外泌体的数量可通过细胞学或微观技术确定以视觉上定量和表征外泌体。癌细胞衍生的外泌体可通过本领域中已知其它方法(例如,ELISA)检测和量化。
在各种方面中,受试者的癌细胞衍生的外泌体数量的分析和表征可在特定时间过程内以各种间隔进行以评估受试者的进展和病变。举例来说,分析可以规则间隔如一天、两天、三天、一周、二周、一个月、两个月、三个月、六个月或一年执行,以便追踪作为时间的函数的癌细胞衍生的外泌体的含量水平和表征。在现有癌症患者的情况下,这提供疾病的进展的有用指示,并且帮助执业医生基于癌细胞衍生的外泌体的改变的增加、降低或缺乏而作出适当治疗选择。癌细胞衍生的外泌体随着时间推移的任何增加(2倍、5倍、10倍或更高)降低患者的预后并且为患者应当改变治疗的早期指示物。类似地,任何增加(2倍、5倍、10倍或更高)指示患者应当经受进一步测试如成像以进一步评估预后和对治疗的反应。癌细胞衍生的外泌体随着时间推移的任何降低(2倍、5倍、10倍或更高)示出疾病稳定和患者对治疗的反应,且为不改变治疗的指示物。对于处于癌症风险的那些人,检测到的癌细胞衍生的外泌体的数量的突然增加可提供患者已经出现肿瘤的早期预警,因此提供早期诊断。在一个实施例中,癌细胞衍生的外泌体的检测随着癌症的分期而增加。
在本文所提供的方法中的任一种中,还可执行附加分析来表征癌细胞衍生的外泌体以提供附加临床评估。举例来说,除了图像分析和批量数量测量之外,可采用PCR技术,如借助特异于具体癌症标示物的引物的复合扩增以获得信息如癌细胞衍生的外泌体起源的肿瘤的类型、转移性状态和恶性肿瘤的程度。此外,作为评估关于患者的癌症的表征的附加信息的手段,可执行DNA或RNA分析、蛋白质组分析或代谢物组分析。
举例来说,附加分析可提供足以进行确定受试者对具体治疗性方案的反应性的数据,或用于确定候选药剂在医治癌症中的效果。因此,本发明提供通过如本文所描述地检测/分离受试者的癌细胞衍生的外泌体和分析所述癌细胞衍生的外泌体来确定受试者对具体治疗性方案的反应性或确定候选药剂在医治癌症中的效果的方法。举例来说,一旦药物医治投与患者,有可能使用本发明的方法确定药物医治的功效。举例来说,在药物医治之前从患者取得的样品,以及与药物医治同时或之后从患者取得的一个或多个样品,可使用本发明的方法进行处理。通过比较每个处理样品的分析结果,可确定药物医治的功效或患者对药剂的反应性。以此方式,早期鉴别可由失效化合物组成,或早期证实可由有前景的化合物组成。
本发明的某些方面提供用表达或包含治疗剂或诊断剂的外泌体来医治患者。如本文中所使用的“治疗剂”为可用于医治癌症或其它病况的原子、分子或化合物。治疗剂的实例包括(但不限于)药物、化疗剂、治疗性抗体和抗体片段、毒素、放射性同位素、酶类、核酸酶、激素、免疫调节剂、反义寡核苷酸、螯合剂、硼化合物、光敏性药剂和染料。如本文中所使用的“诊断剂”为可用于诊断、检测或观测疾病的原子、分子或化合物。根据本文所述实施例,诊断剂可包括(但不限于)放射性物质(例如,放射性同位素、放射性核素、放射性同位素标记或放射性示踪剂)、染料、造影剂、荧光化合物或分子、生物发光化合物或分子、酶类和增强剂(例如,顺磁离子)。
在一些方面中,治疗性重组蛋白可为具有在患者的细胞中已经丧失的活性的蛋白、具有期望酶活性的蛋白、具有期望抑制性活性的蛋白等。举例来说,蛋白可为转录因子、酶、蛋白质毒素、抗体、单克隆抗体等。单克隆抗体可特异性地或选择性地结合到细胞内抗原。单克隆抗体可抑制细胞内抗原的功能和/或破坏蛋白-蛋白相互作用。本发明的其它方面提供基于癌细胞衍生的外泌体在患者样品中的存在来诊断疾病。
因为外泌体已知包含对于完全mRNA转录和蛋白转译所必要的机制(参见PCT/US2014/068630,其以全文引用的方式并入本文中),所以编码治疗性蛋白的mRNA或DNA核酸可转染到外泌体中。替代地,治疗性蛋白本身可电穿孔到外泌体中或直接地结合到脂质体中。例示性治疗性蛋白包括(但不限于)肿瘤遏制蛋白、肽、突变蛋白的野生型蛋白对应部分、DNA修复蛋白、蛋白水解酶、蛋白质毒素、可抑制细胞内蛋白的活性的蛋白、可活化细胞内蛋白的活性的蛋白或其功能缺失需要重建的任何蛋白。例示性治疗性蛋白的具体实例包括123F2、Abcb4、Abcc1、Abcg2、Actb、Ada、Ahr、Akt、Akt1、Akt2、Akt3、Amhr2、Anxa7、Apc、Ar、Atm、Axin2、B2m、Bard1、Bcl211、Becn1、Bhlha15、Bin1、Blm、Braf、Brca1、Brca2、Brca3、Braf、Brcata、Brinp3、Brip1、Bub1b、Bwscr1a、Cadm3、Casc1、Casp3、Casp7、Casp8、Cav1、Ccam、Ccnd1、Ccr4、Ccs1、Cd28、Cdc25a、Cd95、Cdh1、Cdkn1a、Cdkn1b、Cdkn2a、Cdkn2b、Cdkn2c、Cftr、Chek1、Chek2、Crcs1、Crcs10、Crcs11、Crcs2、Crcs3、Crcs4、Crcs5、Crcs6、Crcs7、Crcs8、Crcs9、Ctnnb1、Cts1、Cyp1a1、Cyp2a6、Cyp2b2、Cyld、Dcc、Dkc1、Dicer1、Dmtf1、Dnmt1、Dpc4、E2f1、Eaf2、Eef1a1、Egfr、Egfr4、Erbb2、Erbb4、Ercc2、Ercc6、Ercc8、Errfi1、Esr1、Etv4、Faslg、Fbxo10、Fcc、Fgfr3、Fntb、Foxm1、Foxn1、Fus1、Fzd6、Fzd7、Fzr1、Gadd45a、Gast、Gnai2、Gpc1、Gpr124、Gpr87、Gprc5a、Gprc5d、Grb2、Gstm1、Gstm5、Gstp1、Gstt1、H19、H2afx、Hck、Lims1、Hdac、Hexa、Hic1、Hin1、Hmmr、Hnpcc8、Hprt、Hras、Htatip2、Il1b、Il10、Il2、Il6、Il8rb Inha、Itgav、Jun、Jak3、Kit、Klf4、Kras、Kras2、Kras2b、Lig1、Lig4、Lkb1、Lmo7、Lncr1、Lncr2、Lncr3、Lncr4、Ltbp4、Luca1、Luca2、Lyz2、Lzts1、Mad111、Mad211、Madr2/Jv18、Mapk14、Mcc、Mcm4、Men1、Men2、Met、Mgat5、Mif、Mlh1、Mlh3、Mmac1、Mmp8、Mnt、Mpo、Msh2、Msh3、Msh6、Msmb、Mthfr、Mts1、Mutyh、Myh11、Nat2、Nbn、Ncoa3、Neil1、Nf1、Nf2、Nfe211、Nhej1、Nkx2-1、Nkx2-9、Nkx3-1、Npr12、Nqo1、Nras、Nudt1、Ogg1、Oxgr1、p16、p19、p21、p27、p27mt、p57、p14ARF、Palb2、Park2、Pggt1b、Pgr、Pi3k、Pik3ca、Piwil2、P16、Pla2g2a、Plg、P1k3、Pms1、Pms2、Pold1、Pole、Ppard、Pparg、Ppfia2、Ppm1j、Prdm2、Prdx1、Prkar1a、Ptch、Pten、Prom1、Psca、Ptch1、Ptf1a、Ptger2、Ptpn13、Ptprj、Rara、Rad51、Rassf1、Rb、Rb1、Rb1cc1、Rb12、Recg14、Ret、Rgs5、Rhoc、Rint1、Robo1、Rpl38、S100a4、SCGB1A1、Skp2、Smad2、Smad3、Smad4、Smarcb1、Smo、Snx25、Spata13、Srpx、Ssic1、Sstr2、Sstr5、Stat3、St5、St7、St14、Stk11、Suds3、Tap1、Tbx21、Terc、Tnf、Tp53、Tp73、Trpm5、Tsc2、Tsc1、Vh1、Wrn、Wt1、Wt2、Xrcc1、Xrcc5、Xrcc6和Zac1。
可期望引入到病变细胞的细胞内空间中的一种具体类型的蛋白为抗体(例如,单克隆抗体)。这类抗体可破坏细胞内蛋白的功能和/或破坏细胞内蛋白-蛋白相互作用。这类单克隆抗体的例示性目标包括(但不限于)与RNAi路径有关的蛋白、端粒酶、控制疾病过程的转录因子、激酶、磷酸酶、对于DNA合成需要的蛋白、对于蛋白转译需要的蛋白。例示性治疗性抗体目标的具体实例包括由以下基因编码的蛋白:Dicer、Ago1、Ago2、Trbp、Ras、raf、wnt、btk、Bcl-2、Akt、Sis、src、Notch、Stathmin、mdm2、ab1、hTERT、c-fos、c-jun、c-myc、erbB、HER2/Neu、HER3、VEGFR、PDGFR、c-kit、c-met、c-ret、flt3、API、AML1、ax1、alk、fins、fps、gip、lck、Stat、Hox、MLM、PRAD-I和trk。除了单克隆抗体之外,此处还预期任何抗原结合片段,如scFv、Fab片段、Fab′、F(ab′)2、Fv、肽体、双功能抗体、三功能抗体或微型抗体。任何这类抗体或抗体片段可糖基化或无糖基化。
因为已知外泌体包含DICER和活性RNA处理RISC络合物(参见PCT公布WO 2014/152622,其以全文引用的方式并入本文中),转染到外泌体中的shRNA可成熟为将siRNA与外泌体本身键结的RISC-络合物。替代地,成熟siRNA本身可转染到外泌体或脂质体中。因此,通过举例的方式,以下为可用于本发明的方法来调节或减弱靶基因表达的可能靶基因的类别:发育基因的野生型或突变形式(例如,粘附分子、细胞周期素激酶抑制剂、Wnt家族成员、Pax家族成员、翼状螺旋家族成员、Hox家族成员、细胞因子/淋巴因子和其受体、生长或分化因子和其受体、神经递质和其受体)、肿瘤遏制基因(例如,APC、CYLD、HIN-1、KRAS2b、p16、p19、p21、p27、p27mt、p53、p57、p73、PTEN、Rb、子宫珠蛋白、Skp2、BRCA-1、BRCA-2、CHK2、CDKN2A、DCC、DPC4、MADR2/JV18、MEN1、MEN2、MTS1、NF1、NF2、VHL、WRN、WT1、CFTR、C-CAM、CTS-1、zac1、ras、MMAC1、FCC、MCC、FUS1、基因26(CACNA2D2)、PL6、Beta*(BLU)、Luca-1(HYAL1)、Luca-2(HYAL2)、123F2(RASSF1)、101F6、基因21(NPRL2),或编码SEM A3多肽的基因)、促凋亡基因(例如,CD95、caspase-3、Bax、Bag-1、CRADD、TSSC3、bax、hid、Bak、MKP-7、PARP、bad、bcl-2、MST1、bbc3、Sax、BIK和BID)、细胞因子(例如,GM-CSF、G-CSF、IL-1α、IL-1β、IL-2、IL-3、IL-4、IL-5、IL-6、IL-7、IL-8、IL-9、IL-10、IL-11、IL-12、IL-13、IL-14、IL-15、IL-16、IL-17、IL-18、IL-19、IL-20、IL-21、IL-22、IL-23、IL-24、IL-25、IL-26、IL-27、IL-28、IL-29、IL-30、IL-31、IL-32、IFN-α、IFN-p、IFN-γ、MIP-1α、MIP-1β、TGF-p、TNF-α、TNF-β、PDGF和mda7)、致癌基因(例如,ABLI、BLC1、BCL6、CBFA1、CBL、CSFIR、ERBA、ERBB、EBRB2、ETS1、ETS1、ETV6、FGR、FOX、FYN、HCR、HRAS、JUN、KRAS、LCK、LYN、MDM2、MLL、MYB、MYC、MYCL1、MYCN、NRAS、PIM1、PML、RET、SRC、TAL1、TCL3和YES),和酶类(例如,ACP去饱和酶和羟化酶、ADP葡萄糖焦磷酸化酶、ATP酶、乙醇脱氢酶、淀粉酶、淀粉葡糖苷酶、过氧化氢酶、纤维素酶、环加氧酶、脱羧酶、糊精酶、酯酶、DNA和RNA聚合酶、半乳糖苷酶、葡聚糖酶、葡萄糖氧化酶、GTP酶、解旋酶、半纤维素酶、整合酶、转化酶、异构酶、激酶、乳糖酶、脂肪酶、脂肪加氧酶、溶菌酶、核酸酶、果胶酯酶、过氧化酶、磷酸酶、磷脂酶、磷酸化酶、聚半乳糖醛酶、蛋白酶和肽酶、普鲁兰酶、重组酶、逆转录酶、拓扑异构酶、木聚糖酶)。在一些情况下,sh/siRNA可被设计成特异性地靶向在癌细胞中表达的基因的突变形式,同时不影响对应野生型形式的表达。实际上,可应用在组合物和本发明的方法中的任何抑制性核酸,如果这类抑制性核酸已经通过任何来源发现为所关注蛋白的经证实的向下调节因子。
在设计RNAi时,存在若干需要考虑的因素,如siRNA的性质,沉默效应的持久性和递送系统的选择。为了产生RNAi效应,引入到生物体中的siRNA通常将含有外显子序列。此外,RNAi过程同源性依赖,所以序列必须小心地选择以便使基因特异性达到最大,同时将在同源而非基因特异序列之间的交叉干扰的可能性减到最少。优选地,siRNA呈现在siRNA的序列和待抑制基因之间的大于80%、85%、90%、95%、98%或甚至100%同一性。与靶基因相同小于约80%的序列基本上较不有效。因此,在siRNA和待抑制基因之间的同源性程度越高,将越不可能影响不相关基因的表达。
除了基于蛋白和基于核酸的治疗剂之外,外泌体可用于递送单独或与任何基于蛋白或基于核酸的治疗性组合的小分子药物。预期供用于本发明的实施例中的例示性小分子药物包括(但不限于)毒素、化疗剂、抑制细胞内蛋白的活性的药剂、活化细胞内蛋白的活性的药剂、用于防止再狭窄的药剂、用于医治肾病的药剂、用于间歇性跛行的药剂、在医治低血压和休克中使用的药剂、血管收缩素转化酶抑制剂、抗心绞痛药剂、抗心律不齐、抗高血压药剂、血管紧张素ii受体拮抗剂、抗血小板药物、b1选择性的b-阻断剂、β封闭剂、用于心脏血管指示的植物产品、钙通道阻断剂、心脏血管/诊断剂、中枢α-2促进剂、冠状血管扩张剂、利尿剂和肾小管抑制剂、中性内肽酶/血管收缩素转化酶抑制剂、外周血管扩张剂、钾通道开放剂、钾盐、抗惊厥剂、止吐药、止恶心药、抗帕金森(anti-parkinson)药剂、抗痉挛药剂、大脑刺激剂、可应用在医治外伤中的药剂、可应用在医治阿尔茨海默(Alzheimer)病或痴呆中的药剂、可应用在医治偏头痛中的药剂、可应用在医治神经退行性疾病中的药剂、可应用在医治卡波西氏(kaposi)肉瘤中的药剂、可应用在医治艾滋病中的药剂、癌症化疗剂、可应用在医治免疫病症中的药剂、可应用在医治精神病症中的药剂、镇痛剂、硬膜外和鞘内麻醉剂、通用、局域、区域性神经肌肉封闭剂镇静剂、麻醉期前的肾上腺/促肾上腺皮质激素、合成代谢类固醇、可应用在医治糖尿病中的药剂、多巴胺促进剂、生长激素和类似物、高血糖药剂、低血糖药剂、口服胰岛素、大容量注射剂(1vps)、脂质改变药剂、代谢研究和先天性代谢缺陷、营养物/氨基酸、营养1vps、减肥剂(减食欲剂)、生长抑素、甲状腺药剂、血管加压素、维生素、皮质类固醇、粘液溶解药剂、肺抗炎剂、肺表面活性剂、解酸剂、抗胆碱激导性剂、止泻药、止吐药、胆石溶解药剂、发炎性肠病药剂、大肠急躁症药剂、肝药剂、金属螯合剂、混杂胃分泌药剂、胰腺炎药剂、胰腺酶类、前列腺素、前列腺素、质子泵抑制剂、硬化性药剂、硫糖铝、抗孕激素、避孕药、口服避孕药、非口服多巴胺促进剂、雌激素、促性腺激素、GNRH促进剂、GHRH拮抗剂、催产药、孕激素、子宫作用药剂、抗贫血药物、抗凝剂、抗纤维蛋白溶解药、抗血小板药剂、抗凝血酶药物、凝结剂、血纤维蛋白溶解剂、血液病、肝素抑制剂、金属螯合剂、前列腺素、维生素K、抗雄激素、氨基糖苷、抗细菌剂、磺酰胺、头胞菌素、克林霉素、皮肤病药、清洁剂、红霉素、驱虫药剂、抗真菌药剂、抗疟疾药、抗分支杆菌的药剂、抗寄生虫剂、抗原虫药剂、抗滴虫剂、抗结核药剂、免疫调节剂、免疫刺激药剂、大环内酯、抗寄生虫剂、皮质类固醇、环加氧酶抑制剂、酶阻断剂用于风湿病的免疫调节剂、金属蛋白酶抑制剂、非类固醇抗炎剂、镇痛剂、退热剂、α肾上腺素促进剂/阻断剂、抗生素、抗病毒剂、β肾上腺素阻断剂、碳酸酐酶抑制剂、皮质类固醇、免疫系统调节剂、肥大细胞抑制剂、非类固醇抗炎剂和前列腺素。
外泌体还可用于递送诊断剂。例示性诊断剂包括(但不限于)磁共振图像增强剂、正电子发射断层扫描产物、放射性诊断剂、放射性治疗剂、无线电不透光造影剂、放射性药物、超声成像药剂和血管造影诊断剂。
如本文中所使用的术语“受试者”是指对其执行本发明方法的任何个体或患者。通常受试者为人类,但是如所属领域的技术人员将了解的,受试者可以是动物。因此,其它动物,包括哺乳动物如啮齿动物(包括小鼠、大鼠、仓鼠和天竺鼠)、猫、犬、兔、耕畜(包括母牛、马、山羊、绵羊、猪等),和灵长类动物(包括猴、黑猩猩、猩猩和大猩猩)包括于受试者的定义内。
“医治”和“医治的”是指向受试者投与或施用治疗剂,或对受试者执行手术或仪器治疗以便获得疾病或健康相关病症的治疗益处。举例来说,医治可包括投与化疗、免疫疗法或放射线疗法,执行手术,或其任何组合。
如本文中所使用的术语“治疗益处”或“治疗上有效”是指相对于此病症的药物医治促进或增强受试者的健康的任何东西。这包括但不限于疾病的标志或症状的频率或严重程度的降低。举例来说,癌症的医治可涉及例如肿瘤侵袭性的降低、癌症生长率的降低,或转移的防止。癌症的医治还可涉及延长患有癌症的受试者的存活期。
如本文中所使用,术语“癌症”可用于描述实体肿瘤、转移性癌症或非转移性癌症。在某些实施例中,癌症可产生在膀胱、血液、骨、骨髓、脑、乳房、结肠、食道、十二指肠、小肠、大肠、结肠、直肠、肛门、牙龈、头部、肾脏、肝、肺、鼻咽、颈、卵巢、胰腺、前列腺、皮肤、胃、睾丸、舌部或子宫中。
癌症可具体为以下组织学类型,但是不限于这些:赘瘤;恶性肿瘤;癌瘤;癌瘤;未分化癌瘤;巨和梭细胞癌;小细胞癌;乳头状癌;鳞状细胞癌;淋巴上皮癌;基底细胞癌;毛母质癌;移行细胞癌;乳头状移行细胞癌;腺癌;恶性胃泌素瘤;胆管癌;肝细胞癌;组合肝细胞癌和胆管癌;小梁腺癌;腺样囊性癌;腺瘤息肉中的腺癌;腺癌,家族性息肉病大肠杆菌;实体癌;恶性类癌瘤;细支气管腺癌;乳头状腺癌;嫌色细胞癌;嗜酸细胞癌;嗜酸性腺癌;嗜碱性血球癌;透明细胞腺癌;晶状细胞癌;滤泡腺癌;乳头状和滤泡腺癌;非包裹性硬化性癌瘤;肾上腺皮层癌瘤;子宫内膜样癌瘤;皮肤附件癌瘤;顶泌腺癌;皮脂腺癌;耵聍腺腺癌;粘液表皮样癌;囊腺癌;乳头状囊腺癌;乳头状浆液性囊腺癌;黏液性囊腺癌;黏液性腺癌;印戒细胞癌;浸润性管癌;髓性癌;小叶癌;炎性癌;乳腺佩吉特氏(paget)疾病;腺泡细胞癌;腺鳞癌;腺癌w/鳞状化生;恶性胸腺瘤;恶性卵巢间质瘤;恶性卵泡膜细胞瘤;恶性粒层细胞瘤;恶性睾丸母细胞瘤;塞尔托利细胞癌;恶性莱迪希细胞肿瘤;恶性脂质细胞肿瘤;恶性副神经节瘤;恶性乳腺外副神经节瘤;嗜铬细胞瘤;筋膜纤维肉瘤;恶性黑色素瘤;无色素性黑色素瘤;浅表扩散性黑色素瘤;在巨大色素痣中的恶性黑色素瘤;上皮样细胞黑色素瘤;恶性蓝痣;肉瘤;纤维肉瘤;恶性纤维组织细胞瘤;黏液肉瘤;脂肪肉瘤;平滑肌肉瘤;横纹肌肉瘤;胚胎横纹肌肉瘤;腺泡状横纹肌肉瘤;基质肉瘤;恶性混合肿瘤;苗勒型(mullerian)混合瘤;肾胚细胞瘤;肝母细胞瘤;癌肉瘤;恶性间叶瘤;恶性布伦纳氏瘤;恶性叶状肿瘤;滑膜肉瘤;恶性间皮瘤;无性细胞瘤;胚胎癌;恶性畸胎瘤;恶性卵巢甲状腺瘤;绒膜癌;恶性中肾瘤;血管内皮瘤;恶性血管内皮瘤;卡波西氏肉瘤;恶性血管外皮瘤;淋巴管肉瘤;骨肉瘤;密质旁骨肉瘤;软骨肉瘤;恶性软骨母细胞瘤;间叶细胞软骨肉瘤;骨巨细胞瘤;尤文氏(ewing)肉瘤;恶性牙源性肿瘤;造釉细胞性牙肉瘤;恶性成釉细胞瘤;造釉纤维肉瘤;恶性松果体瘤;脊索瘤;恶性神经胶瘤;室管膜瘤;星形细胞瘤;原浆性星形细胞瘤;肌原纤维性星形细胞瘤;星形母细胞瘤;神经胶母细胞瘤;少突神经胶质瘤;成少突神经胶质瘤;初期的神经外胚层;小脑肉瘤;节细胞性神经母细胞瘤;神经母细胞瘤;成视网膜细胞瘤;鼻神经性肿瘤;恶性脑膜瘤;神经纤维肉瘤;恶性神经鞘瘤;恶性晶状细胞肿瘤;恶性淋巴瘤;霍奇金氏病;霍奇金氏;副肉芽肿;恶性小淋巴球性淋巴瘤;恶性大细胞、扩散淋巴瘤;恶性滤泡性淋巴瘤;蕈样真菌病;其它指定非霍奇金氏淋巴瘤;恶性组织细胞增多病;多发性骨髓瘤;肥大细胞肉瘤;免疫增殖性小肠疾病;白血病;淋巴白血病;浆细胞白血病;红白血病;淋巴肉瘤细胞白血病;骨髓白血病;嗜碱性白血病;嗜酸性白血病;单核细胞性白血病;肥大细胞白血病;巨核母细胞白血病;髓系肉瘤;和毛细胞白血病。但是,还应认识到,本发明还可用于医治非癌性疾病(例如,真菌感染、细菌感染、病毒感染、神经变性病,和/或基因病症)。
在应用于细胞时的术语“接触”和“暴露”在本文中用于描述过程,通过所述过程,治疗剂递送到靶细胞或置于与靶细胞直接并置。为了实现细胞杀死,例如,一种或多种药剂以杀死细胞或防止其分裂的有效量递送到细胞。
患者的有效反应或患者对医治的“反应性”是指赋予处于疾病或病症风险或患有疾病或病症的患者的临床或治疗益处。这类益处可包括细胞或生物反应、完全反应、部分反应、稳定疾病(不进展或复发),或具有稍后复发的反应。举例来说,有效反应可减小肿瘤尺寸或诊断患有癌症的患者的无进展存活期。
可预测和监测医治结果和/或可经由本文所描述的方法鉴别或选择受益于这类医治的患者。
关于瘤性病症医治,根据瘤性病症的阶段,瘤性病症医治涉及以下疗法中的一个或组合:去除瘤性组织的手术、放疗,和化疗。其它治疗性方案可与投与抗癌剂例如治疗性组合物和化疗剂结合。举例来说,待用这类抗癌剂医治的患者还可接收放疗和/或可经受手术。
对于疾病的医治,适当剂量的治疗性组合物将取决于如上定义的待医治的疾病的类型,疾病的严重程度和病程,患者的临床病史和对药剂的反应,和主治医师的判断。药剂适当地向患者一次或经一系列医治投与。
治疗性和防治性方法和组合物可以可有效地实现期望效应的组合量提供。组织、肿瘤或细胞可与一种或多种组合物或一种或多种包含药剂中的一种或多种的药理学配制物接触,或通过使组织、肿瘤和/或细胞与两种或更多种不同组合物或配制物接触。另外,预期这类组合疗法可与化疗、放射线疗法、手术疗法或免疫疗法结合使用。
以结合方式的投与可包括以相同剂型同步投与两种或更多种药剂,以独立剂型同步投与和分开投与。即,本发明治疗性组合物和另一种治疗剂可以相同剂型调配在一起并且同时投与。替代地,本发明治疗性组合物和另一种治疗剂可同时投与,其中两个药剂均以独立配制物存在。在另一个替代方案中,治疗剂可紧接着另一种治疗剂投与,反之亦然。在分开投与方案中,本发明治疗性组合物和另一种治疗剂可相隔数分钟或相隔数小时或相隔数天投与。
第一抗癌医治(例如,表达重组蛋白或具有从外泌体中分离的重组蛋白的外泌体)可在相对于第二抗癌医治之前、期间、之后或以各种组合投与。投与可以在同时到数分钟到数天到数周的范围内的间隔。在其中第一医治独立于第二医治提供到患者的实施例中,一般将确保每次递送时间之间不停顿显著时间段,使得两种化合物将仍然能够对患者发挥有利地组合效应。在这类情况下,预期可在相互间隔约12小时到24小时或72小时内并且,更具体地说在相互间隔约6小时到12小时内向患者提供第一疗法和第二疗法。在一些情形中,可期望显著延长医治时间段,其中在分别投与之间经过几天(2、3、4、5、6或7)到几周(1、2、3、4、5、6、7或8)。
在某些实施例中,医治过程将持续1天到90天或更长(此这类范围包括介于中间的天数)。预期,一种药剂可在第1天到第90天(此这类范围包括介于中间的天数)中的任一天或其任何组合给予,并且另一种药剂在第1天到第90天(此这类范围包括介于中间的天数)中的任一天或其任何组合给予。在单天(24小时时间段)内,可向患者给予一种或多种药剂的一个或多个投与。此外,在医治过程之后,预期存在一段时间,在所述一段时间时,不投与抗癌医治。根据患者的病症,如其预后、强度、健康等,此时间段可持续1天到7天,和/或1周到5周,和/或1月到12月或更长(此这类范围包括介于中间的天数)。预期医治周期将根据需要重复。
可采用各种组合。对于以下实例,第一抗癌疗法为“A”并且第二抗癌疗法为“B”:
A/B/A B/A/B B/B/A A/A/B A/B/B B/A/A A/B/B/B B/A/B/B B/B/B/A B/B/A/BA/A/B/B A/B/A/B A/B/B/A B/B/A/A B/A/B/A B/A/A/B A/A/A/B B/A/A/A A/B/A/A A/A/B/A
考虑药剂的毒性(如果存在的话),向患者投与本发明的任何化合物或疗法将遵循用于投与这类化合物的通用方案。因此,在一些实施例中,存在监测可归因于组合疗法的毒性的步骤。
1.化疗
根据本发明,可使用各种化疗剂。术语“化疗”是指使用药物医治癌症。“化疗剂”用于意指在医治癌症中投与的化合物或组合物。这些药剂或药物通过其在细胞内的活性模式分类,例如它们是否影响细胞周期及它们在什么阶段影响细胞周期。替代地,药剂可基于其直接交联DNA、插入到DNA中或通过影响核酸合成诱导染色体及有丝分裂畸变的能力来表征。
化疗剂的实例包括烷化剂如噻替派和环磷酰胺;烷基磺酸酯,如白消安、英丙舒凡和哌泊舒凡;氮丙啶,如苯唑多巴、卡波醌、米特多巴和尤利多巴;乙烯亚胺和甲基三聚氰胺,包括六甲蜜胺、三亚乙基蜜胺、三亚乙基磷酰胺、三亚乙基硫代磷酰胺和三羟甲基蜜胺;乙酰精宁(尤其是布拉他辛和布拉他辛酮);喜树碱(包括合成类似物拓朴替康);苔藓虫素;卡利他汀;CC-1065(包括其阿多来新、卡折来新和比折来新合成类似物);念珠藻环肽(具体地念珠藻环肽1和念珠藻环肽8);海兔毒素;倍癌霉素(包括合成类似物,KW-2189和CB1-TM1);艾榴塞洛素;盘克斯塔叮;沙考的汀;海绵毒素;氮芥,如苯丁酸氮芥、萘氮芥、胆磷酰胺、雌氮芥、异环磷酰胺、氮芥、盐酸氧氮芥、美法仑、新氮芥、苯芥胆甾醇、泼尼氮芥、曲磷胺和尿嘧啶芥;亚硝基脲,如卡莫司汀、氯脲菌素、福莫司汀、洛莫司汀、尼莫司汀和雷莫司汀;抗生素,如烯二炔抗生素(例如,卡奇霉素,尤其是卡奇霉素γlI和卡奇霉素QI1);达米辛,包括达米辛A;双膦酸盐,如氯屈膦酸盐;埃斯培拉霉素;以及新抑癌蛋白发色团和相关色蛋白烯二炔抗生素发色团、阿克拉霉素、放射菌素、authrarnycin、氮杂丝氨酸、博来霉素、放线菌素C、卡柔比星、洋红霉素、嗜癌霉素、色霉素、放线菌素D、柔红霉素、地托比星、6-重氮-5-氧代-L-正亮氨酸、阿霉素(包括吗啉基-阿霉素、氰基吗啉基-阿霉素、2-吡咯啉基-阿霉素和脱氧阿霉素)、表柔比星、依索比星、艾达霉素、麻西罗霉素、丝裂霉素如丝裂霉素C、霉酚酸、诺加霉素、橄榄霉素、培洛霉素、泼非霉素、嘌呤霉素、奎那霉素、罗多比星、链黑霉素、链脲霉素、杀结核菌素、乌苯美司、净司他丁和左柔比星;抗代谢物,如甲胺喋呤和5-氟尿嘧啶(5-FU);叶酸类似物,如迪诺特宁、蝶罗呤和三甲曲沙;嘌呤类似物,如氟达拉宾、6-巯基嘌呤、噻咪嘌呤和硫鸟嘌呤;嘧啶类似物,如安西他滨、阿扎胞苷、6-氮尿苷、卡莫氟、阿糖胞苷、双去氧尿苷、去氧氟尿苷、依诺他滨和氟尿苷;雄激素,如二甲睾酮、甲雄烷醇酮丙酸酯、环硫雄醇、美雄烷和睾内酯;抗肾上腺,如米托坦和曲洛司坦;叶酸补充剂,如亚叶酸;醋葡醛内酯;醛磷酰胺糖苷;胺基乙酰丙酸;恩尿嘧啶;安吖啶;倍思塔布;比山群;艾达曲克;得弗伐胺;秋水仙碱;地吖醌;艾福米辛;依利铵乙酸酯;埃坡霉素;依托格鲁;硝酸镓;羟基脲;香菇多糖;罗尼达宁;类美登素,如美登素和安丝菌素;丙脒腙;米托蒽醌;莫哌达醇;硝拉维林;喷司他汀;凡那明;吡柔比星;洛索蒽醌;鬼臼酸;2-乙酰肼;甲基苄肼;PSK多糖复合物;雷佐生;根霉素;西佐糖;螺旋锗;细交链孢菌酮酸;三亚胺醌;2,2′,2″-三氯代三乙胺;单端孢霉烯族毒素(尤其是T-2毒素、疣孢菌素A、杆孢菌素A和蛇形菌素);乌拉坦;长春地辛;达卡巴嗪;甘露氮芥;二溴甘露醇;二溴卫矛醇;哌泊溴烷;甲托辛;阿拉伯糖苷(″Ara-C″);环磷酰胺;类紫杉醇,例如,紫杉醇和多西他赛吉西他滨;6-硫鸟嘌呤;巯基嘌呤;铂配位络合物,如顺铂、奥沙利铂和卡铂;长春碱;铂;依托泊苷(VP-16);异环磷酰胺;米托蒽醌;长春新碱;长春瑞宾;米托蒽醌;替尼泊甙;依达曲沙;道诺霉素;氨基喋呤;希罗达;伊班膦酸盐;伊立替康(例如,CPT-11);拓扑异构酶抑制剂RFS 2000;二氟甲基鸟氨酸(DMFO);类视黄素,如视黄酸;卡培他滨;卡铂、丙卡巴肼、普卡霉素、吉西他滨、诺维本、法呢基-蛋白转移酶抑制剂、反铂和以上中的任一个的医药学上可接受的盐、酸或衍生物。
2.放射线疗法
导致DNA损伤并且已经被广泛使用的其它因素包括通常被称为γ-射线、X-射线和/或直接递送到肿瘤细胞的放射性同位素的因素。还预期其它形式的DNA损伤因素,如微波、质子束辐射(美国专利5,760,395和4,870,287)和紫外线辐射。最可能的是所有这些因素引起对DNA、DNA前驱体、DNA的复制和修复以及染色体的装配和维持的大范围损伤。X-射线的剂量范围在50到200伦琴长时间段(3周到4周)的每日剂量到2000到6000伦琴的单次剂量的范围内。放射性同位素的剂量范围大幅变化,并且取决于同位素的半衰期、发射的辐射的强度和类型,以及瘤性细胞的吸收。
3.免疫疗法
所属领域的技术人员将理解,附加免疫疗法可与本发明的方法组合或结合使用。在癌症医治的情形下,免疫治疗剂通常依赖于使用靶向和破坏癌细胞的免疫效应细胞和分子。利妥昔单抗为这类实例。免疫效应子可以为例如对肿瘤细胞表面上的一些标记物具有特异性的抗体。单独的抗体可以用作疗法的效应子或其可以募集其它细胞以实际实现细胞杀死。抗体还可以结合到药物或毒素(化学治疗、放射性核素、蓖麻毒素A链、霍乱毒素、百日咳毒素等)并且仅用作靶向剂。替代地,效应子可以是携带表面分子的淋巴细胞,其直接或间接与肿瘤细胞目标相互作用。多种效应细胞包括细胞毒性T细胞和NK细胞。
在免疫疗法的一个方面中,肿瘤细胞必须带有一些适合于靶向(即,不呈现于大部分其它细胞上)的标记物。存在许多肿瘤标记物并且这些中的任一个可以适于在本发明的上下中靶向。常见肿瘤标记物包括CD20、癌胚抗原、酪氨酸酶(p97)、gp68、TAG-72、HMFG、唾液酸基路易斯抗原、MucA、MucB、PLAP、层粘连蛋白受体、erb B和p155。免疫疗法的替代方面为将抗癌效应与免疫刺激效应组合。还存在免疫刺激分子,包括:细胞因子如IL-2、IL-4、IL-12、GM-CSF、γ-IFN,趋化因子如MIP-1、MCP-1、IL-8,和生长因子如FLT3配体。
当前所研究的或在使用中的免疫疗法的实例为免疫助剂,例如,牛分枝杆菌(Mycobacterium bovis)、恶性疟原虫(Plasmodium falciparum)、二硝基氯苯和芳香族化合物(美国专利5,801,005和5,739,169;Hui和Hashimoto,1998年;Christodoulides等人,1998年);细胞因子疗法,例如,干扰素α、β、和γ,IL-1、GM-CSF和TNF(Bukowski等人,1998年;Davidson等人,1998年;Hellstrand等人,1998年);基因疗法,例如,TNF、IL-1、IL-2和p53(Qin等人,1998年;Austin-Ward和Villaseca,1998年;美国专利5,830,880和5,846,945);以及单克隆抗体,例如,抗CD20、抗神经节苷脂GM2,和抗p185(Hollander,2013年;Hanibuchi等人,1998年;美国专利5,824,311)。预期可与本文所述的抗体疗法一起采用的一种或多种抗癌疗法。
4.手术
约60%患有癌症的人将经受一些类型的手术,包括预防性、诊断或分期、治愈性和缓解性手术。治愈性手术包括切除术,其中全部或部分癌组织物理地除去、切离和/或破坏,并且可与其它疗法结合使用,如本发明的医治、化疗、放射线疗法、激素疗法、基因疗法、免疫疗法和/或替代疗法。肿瘤切除术指的是物理去除肿瘤的至少一部分。除了肿瘤切除术之外,通过手术的医治包括激光手术、冷冻手术、电手术和显微镜控制的手术(莫氏手术(Mohs′surgery))。
在切离部分或全部癌细胞、组织或肿瘤时,可在体内形成空腔。可以通过向区域灌注、直接注射或局部施用附加抗癌疗法来实现医治。这类医治可以例如每1、2、3、4、5、6或7天、或每1、2、3、4和5周或每1、2、3、4、5、6、7、8、9、10、11或12个月重复。这些医治也可具有变化的剂量。
5.其它药剂
预期其它药剂可与本发明的某些方面组合使用来改善医治的疗效。这些附加药剂包括影响细胞表面受体和GAP结上调的药剂、细胞生长抑制和分化剂、细胞粘附抑制剂、增加过度增殖细胞对凋亡诱导剂的敏感性的药剂或其它生物药剂。通过增加GAP结的数目增加胞间信号传递将提高对相邻过度增殖细胞群体的抗过度增殖作用。在其它实施例中,细胞生长抑制或分化剂可与本发明的某些方面组合使用来改善医治的抗过度增殖功效。细胞粘附抑制剂预期改善本发明的功效。细胞粘附抑制剂的实例是局部粘附激酶(FAK)抑制剂和洛伐他汀(Lovastatin)。进一步预期提高过度增殖细胞对凋亡的敏感性的其它药剂(例如抗体c225)可以与本发明的某些方面组合使用来改善医治功效。
III.医药组合物
预期表达或包含重组蛋白、抑制性RNA和/或小分子药物的外泌体可全身性或局部投与以抑制肿瘤细胞生长并且,最优选地杀死在患有局部晚期或转移性癌症的癌症患者体内的癌细胞。它们可经静脉内、鞘内和/或腹膜内投与。它们可单独或与抗增生药物组合投与。在一个实施例中,它们经投与以减少在手术或其它程序之前在患者体内的癌症负荷。替代地,它们可在手术之后投与以确保任何剩余癌症(例如,手术无法消除的癌症)不存活。
并不意图本发明受治疗制剂的具体性质限制。举例来说,这类组合物可以配制物形式以及生理上可耐受液体、凝胶、固体载剂、稀释剂或赋形剂的形式提供。对于兽医用途而言,这些治疗制剂可投与哺乳动物如家畜并且以类似于其它治疗剂的方式在人类中临床使用。一般而言,疗效所需的剂量将根据用途的类型和投与模式以及个体受试者的具体需要而变化。
在预期临床应用的情况下,可有必要制备包含以适合于意图施用的形式的重组蛋白和/或外泌体的医药组合物。通常,可为不经肠配制物的医药组合物可包含溶解或分散于医药学上可接受的载剂中的有效量的一种或多种重组蛋白和/或外泌体和/或附加剂。短语“医药或药理学上可接受”是指当视需要投与到动物例如人类时,并不产生不利、过敏或其它不良反应的分子实体和组合物。包含如本文所公开的重组蛋白和/或外泌体或附加活性成分的医药组合物的制剂如由《雷明顿药物科学(Remingon′s PharmaceuticalSciences)》,1990年第18版例示,其以全文引用的方式并入本文中用于所有目的。此外,对于动物(例如,人类)投与,应理解,制剂应满足由FDA生物学标准办公室(the FDA Officeof Biological Standards)所要求的无菌、发热性、一般安全性和纯度标准。
另外,根据本发明的某些方面,适合于投与的组合物可在具有或不具有惰性稀释剂情况下提供在医药学上可接受的载剂中。如本文中所使用,“医药学上可接受的载剂”包括任何和所有水性溶剂(例如,水、醇/水溶液、乙醇、盐水溶液、不经肠媒剂如氯化钠、林格氏右旋糖等)、非水性溶剂(例如,脂肪、油、多元醇(例如,丙三醇、丙二醇和液体聚乙二醇等)、植物油和可注入有机酯如油酸乙酯)、脂质、脂质体、分散介质、包衣(例如,卵磷脂)、表面活性剂、抗氧化剂、防腐剂(例如,抗细菌剂或抗真菌剂、抗氧化剂、螯合剂、惰性气体、对羟基苯甲酸酯(例如,对羟基苯甲酸甲酯、对羟基苯甲酸丙酯)、氯丁醇、苯酚、山梨酸、硫柳汞或其组合)、等渗剂(例如,糖和氯化钠)、吸收延迟剂(例如,单硬脂酸酯铝和明胶)、盐、药物、药物稳定剂、凝胶、树脂、填充剂、粘合剂、赋形剂、崩解剂、润滑剂、甜味剂、调味剂、染料、流体和营养补充剂,如这类材料以及它们的组合,如本领域的普通技术人员将知道的。载剂应当是可吸收的并且包括液体、半固体(即,膏体)或固体载剂。另外,如果需要,则组合物可含有少量辅助物质,如润湿剂或乳化剂、稳定剂或pH缓冲剂。在医药组合物中各种组分的pH和准确的浓度根据熟知参数调节。适当的流动性可以例如通过使用包衣如卵磷脂、在分散液的情况下通过维持所需粒径和通过使用表面活性剂来维持。
医药学上可接受的载剂被具体配制成用于向人类投与,虽然在某些实施例中,可期望使用被配制成用于向非人类动物投与的但用于向人类投与将为不可接受的(例如,由于政府法规)医药学上可接受的载剂。除非任何常规载剂与活性成份不相容(例如,不利于接受体或其中含有的组合物的治疗性效果),否则预期在治疗性或医药组合物中使用载剂。根据本发明的某些方面,组合物与载剂以任何便利和实际的方式,即,通过溶液、悬浮液、乳化、掺合物、封装、吸收等组合。这类程序对于本领域的技术人员来说是常规的。
根据载剂是否以固体、液体或气溶胶形式投与和对于投与的途径如注射其是否需要灭菌,本发明的某些实施例可包含不同类型的载剂。组合物可通过吸入(例如,气溶胶吸入)、通过注射、通过输注、通过持续输注、通过直接局部灌注沐浴靶细胞、经由导管、经由灌洗、以脂质组合物(例如,脂质体)形式或通过其它方法或前述内容的任何组合而经静脉内、皮内、经皮、鞘内、动脉内、腹膜内、鼻内、阴道内、直肠内、肌内、皮下、经粘膜、经口、体表、局部投与,这些描述于例如以引用的方式并入本文中的《雷明顿药物科学》,1990年第18版中。
活性化合物可被配制成用于不经肠投与,例如,被配制成用于经由静脉内、肌内、皮下或甚至腹膜内途径注射。由此,实施例包括不经肠配制物。通常,这类组合物可制备为液体溶液或悬浮液;还可制备适用于在注射之前在添加液体时制备溶液或悬浮液的固体形式;并且制剂还可乳化。
根据本发明实施例,不经肠配制物可包括如本文所公开的外泌体以及一种或多种溶质和/或溶剂,一种或多种缓冲剂和/或一种或多种抗菌剂,或其任何组合。在一些方面中,溶剂可包括水、水可混溶的溶剂,例如,乙醇、液体聚乙二醇和/或丙二醇,和/或水不可混溶的溶剂,如不挥发性油,包括例如玉米油、棉籽油、花生油和/或芝麻油。在某些形式中,溶质可包括一种或多种抗菌剂、缓冲液、抗氧化剂、张力剂、低温保护剂和/或冻干保护剂。
根据本公开的抗菌剂可包括在本公开中的其它地方提供的那些以及苄醇、苯酚、汞剂和/或对羟基苯甲酸酯。抗菌剂可包括苯扎氯铵、苄索氯铵、苄醇、溴硝丙二醇、西曲溴铵、氯化十六烷基吡啶、氯己定、氯丁醇、氯甲酚、氯二甲酚、甲酚、乙醇、丙三醇、氨己嘧啶、咪唑烷脲、苯酚、苯氧基乙醇、苯乙醇、硝酸苯汞、丙二醇和/或硫柳汞或其任何组合。在各种方面中,抗菌剂可以确保医药剂需要的本身无菌性必要的浓度存在。举例来说,药剂可以抑菌浓度或抑制真菌浓度存在于制剂中,例如,含于多种剂量容器中的制剂。在各种实施例中,药剂可为防腐剂和/或可在使用时以足够浓度存在以防止微生物(如无意中引入到制剂的微生物)的繁殖,同时例如,用皮下注射针和注射器取出内容物的一部分。在各种方面中,药剂具有最大体积和/或浓度限值(例如,硝酸苯汞和硫柳汞0.01%、苄索氯铵和苯扎氯铵0.01%、苯酚或甲酚0.5%,和氯丁醇0.5%)。在各种例子中,药剂如硝酸苯汞以0.002%的浓度采用。根据实施例还可施用以组合形式的对-羟基苯甲酸甲酯0.18%和对-羟基苯甲酸丙酯0.02%以及苄醇2%。抗菌剂还可包括己基间苯二酚0.5%、苯甲酸苯汞(pheny1mercuric benzoate)0.1%和/或治疗性化合物。
根据本公开的抗氧化剂可包括抗坏血酸和/或其盐,和/或乙二胺四乙酸(EDTA)的钠盐。如本文所描述的张力剂可包括电解质和/或单或二糖。低温保护剂和/或冻干保护剂为保护生物药品免受由于产物在冷冻干燥处理期间的冻结和/或干燥不利的效应的添加剂。低温保护剂和/或冻干保护剂可包括糖(非还原)如蔗糖或海藻糖、氨基酸如甘氨酸或赖氨酸、聚合物如液体聚乙二醇或聚葡萄糖,和多元醇如甘露醇或山梨糖醇,所有是可能的低温或冻干保护剂。本发明实施例还可包括抗真菌剂如对羟基苯甲酸丁酯、对羟基苯甲酸甲酯、对羟基苯甲酸乙酯、对羟基苯甲酸丙酯、苯甲酸、山梨酸钾、苯甲酸钠、丙酸钠和/或山梨酸,或其任何组合。根据本公开可采用的附加溶质和抗菌剂、缓冲液、抗氧化剂、张力剂、低温保护剂和/或冻干保护剂和其特征以及制备本发明不经肠配制物的方法的方面描述于例如《雷明顿药物科学》,2005年第21版,例如,第41章,其以全文引用的方式并入本文中用于所有目的。
适于可注射使用的医药形式包括无菌水溶液或分散液;包括芝麻油、花生油或水性丙二醇的配制物;和用于无菌可注射溶液或分散液的即用型制剂的无菌粉末。在所有情况下,所述形式必须都是无菌的并且流动性必须达到使其可容易注射的程度。其应当在制备和储存条件下稳定并且必须被在免受微生物(如细菌和真菌)的污染活动下保存。
治疗剂可被配制成以游离碱、中性、或盐形式的组合物。医药学上可接受的盐包括酸加成盐,例如那些与蛋白质组合物的游离氨基形成的,或与无机酸(例如盐酸或磷酸)或这类有机酸(如乙酸、草酸、酒石酸、扁桃酸等)形成的盐。与游离羧基形成的盐还可衍生自无机碱,例如氢氧化钠、氢氧化钾、氢氧化铵、氢氧化钙或氢氧化铁;或这类有机碱,如异丙胺、三甲胺、组氨酸或普鲁卡因等。在配制时,溶液将以与剂量配制物相容的方式并且以如治疗有效的这类量投与。配制物易于以多种剂型投与,如配制成用于不经肠投与如可注射溶液、或用于递送到肺部的气溶胶、或配制成用于经消化道投与,如药物释放胶囊等。
在本发明的具体实施例中,组合物与半固体或固体载剂充分地组合或混合。可以任何便利方式如研磨进行混合。还可在混合过程中添加稳定剂以便保护组合物免于损失治疗活性,即,在胃中变性。供用于组合物中的稳定剂的实例包括缓冲剂、氨基酸(如甘氨酸和赖氨酸)、碳水化合物(如右旋糖、甘露糖、半乳糖、果糖、乳糖、蔗糖、麦芽糖、山梨醇、甘露醇等)。
在另外的实施例中,本发明可涉及包含一种或多种脂质和水性溶剂的医药脂质媒剂组合物的用途。如本文中所使用,术语“脂质”将被定义成包括在特征上不溶于水并且可用有机溶剂萃取的宽范围物质中的任一种。此广泛类别的化合物由所属领域的技术人员熟知,并且由于术语“脂质”使用在本文中,所以其不限于任何具体结构。实例包括含有长链脂肪族烃和其衍生物的化合物。脂质可为天然存在或合成的(即,经人类设计或产生)。然而,脂质通常为生物物质。生物脂质在所属领域中是众所周知的,并且包括例如中性脂肪、磷脂、磷酸甘油酯、类固醇、萜类、溶血脂质、鞘醣脂、糖脂、硫脂、带有醚-和酯-连接的脂肪酸的脂质、可聚合脂质以及它们的组合。当然,被本领域的技术人员理解为脂质的除本文特别描述的那些之外的化合物也由组合物和方法涵盖。
本领域的普通技术人员将熟悉可用于将组合物分散在脂质媒剂中的技术的范围。举例来说,治疗剂可分散于含有脂质的溶液中、用脂质溶解、用脂质乳化、与脂质混合、与脂质组合、共价键结到脂质、以悬浮液包含于脂质中、用胶束或脂质体含有或络合,或另外通过本领域普通技术人员已知的以任何手段与脂质或脂质结构缔合。分散可引起或可不引起脂质体的形成。
术语“单位剂量”或“剂量”是指适用于受试者的物理上单个的单位,每个单位含有预定量的经计算的治疗性组合物以产生与其投与(即,适当途径和医治方案)相关联的上文所讨论的期望反应。待投与的量(同时根据医治和单位剂量的数量)取决于期望功效。向患者或受试者投与的本发明的组合物的实际剂量可通过物理和生理因素确定,如受试者的体重、年龄、健康和性别,经医治疾病的类型,疾病渗透的程度,先前或同时发生的治疗性干预,患者的原发症,投与的途径和具体治疗性物质的效价、稳定性和毒性。举例来说,剂量还可包含每次投与约1微克每公斤体重到约1000毫克每公斤体重(此这类范围包括介于中间的剂量)或更多,和其中可导出的任何范围。在由本文中所列的数值可导出的范围的非限制性实例中,可投与的范围为约5微克每公斤体重到约100毫克每公斤体重,约5微克每公斤体重到到约500毫克每公斤体重等。负责投与的医生将在任何情况下确定组合物中一种或多种活性成分的浓度和用于个别受试者的一个或多个适当剂量。
可通过物理和生理因素,如体重、病症的严重程度、经医治疾病的类型、先前或同时治疗性干预、患者的原发症以及投与的途径确定投与到动物患者的组合物的实际剂量。根据投与的剂量和途径,优选剂量和/或有效量的投与次数可根据受试者的反应变化。负责投与的医生将在任何情况下确定组合物中一种或多种活性成分的浓度和用于个别受试者的一个或多个适当剂量。
在某些实施例中,医药组合物可包含例如至少约0.1%的活性化合物。在其它实施例中,活性化合物可包含约2%单位重量到约75%单位重量之间,或例如约25%到约60%之间,和其中可导出的任何范围。理所当然地,在每个治疗上有用的组合物中的一种或多种活性化合物的量可以使得合适剂量将在任何给予单位剂量的化合物中获得的方式制备。制备这类医药配制物的本领域的技术人员将预期因素,如溶解度、生物利用率、生物半衰期、投与的途径、产品保存期限以及其它药理学考虑因素,并且因此,多种剂量和医治方案可为合意的。
在其它非限制性实例中,剂量还可包含每次投与约1微克每公斤体重、约5微克每公斤体重、约10微克每公斤体重、约50微克每公斤体重、约100微克每公斤体重、约200微克每公斤体重、约350微克每公斤体重、约500微克每公斤体重、约1毫克每公斤体重、约5毫克每公斤体重、约10毫克每公斤体重、约50毫克每公斤体重、约100毫克每公斤体重、约200毫克每公斤体重、约350毫克每公斤体重、约500毫克每公斤体重到约1000毫克每公斤体重或更多,和其中可导出的任何范围。在由本文中所列的数值可导出的范围的非限制性实例中,基于以上描述的数值,可投与的范围为约5毫克每公斤体重到约100毫克每公斤体重,约5微克每公斤体重到约500毫克每公斤体重等。
IV.核酸和载体
在本发明的某些方面中,编码治疗性蛋白或含有治疗性蛋白的融合蛋白的核酸序列可被公开。根据使用哪个表达体系,可基于常规方法而选择核酸序列。举例来说,相应基因或其变体可为针对在某一体系中表达优化的密码子。各种载体还可用于表达所关注蛋白。例示性载体包括(但不限于)质粒载体、病毒载体、转座子或基于脂质体的载体。
V.重组蛋白和抑制性RNA
一些实施例涉及重组蛋白和多肽。具体实施例涉及呈现至少一种治疗活性的重组蛋白或多肽。在一些实施例中,重组蛋白或多肽可为治疗性抗体。在一些方面中,治疗性抗体可以是特异性地或选择性结合到细胞内蛋白的抗体。在其它方面中,蛋白或多肽可经修饰以增加血清稳定性。因此,在本申请是指“经修饰蛋白”或“经修饰多肽”的功能或活性时,本领域的普通技术人员将理解此包括例如具有在未经修饰蛋白或多肽内的附加优点的蛋白或多肽。特别预期关于“经修饰蛋白”的实施例可关于“经修饰多肽”实施,且反之亦然。
重组蛋白可具有氨基酸的缺失和/或取代;因此,具有缺失的蛋白、具有取代的蛋白和具有缺失和取代的蛋白为经修饰蛋白。在一些实施例中,这些蛋白还可包括插入或添加的氨基酸,例如融合蛋白或具有连接子的蛋白。“经修饰缺失蛋白”不含原来的蛋白的一种或多种残基,但是可具有原来的蛋白的特异性和/或活性。“经修饰缺失蛋白”还可具有降低的免疫原性或抗原性。经修饰缺失蛋白的实例为具有从至少一个抗原区域(即,在具体生物体如可投与经修饰蛋白的一类生物体中确定为抗原的蛋白的区域)中缺失的氨基酸残基的蛋白。
取代或替代变型通常含有在蛋白内的一个或多个位点处一个氨基酸与另一个氨基酸的交换并且可被设计成调节多肽的一种或多种特性,具体地其效应子功能和/或生物利用率。取代可为或可不为保守的,即,一个氨基酸用类似形状及电荷中的一个替换。保守取代是本领域中众所周知的并且包括例如以下改变:丙氨酸到丝氨酸;精氨酸到赖氨酸;天冬酰胺到谷氨酰胺或组氨酸;天冬氨酸到谷氨酸;半胱氨酸到丝氨酸;谷氨酰胺到天冬酰胺;谷氨酸到天冬氨酸;甘氨酸到脯氨酸;组氨酸到天冬酰胺或谷氨酰胺;异亮氨酸到亮氨酸或缬氨酸;亮氨酸到缬氨酸或异亮氨酸;赖氨酸到精氨酸;甲硫氨酸到亮氨酸或异亮氨酸;苯丙氨酸到酪氨酸、亮氨酸或甲硫氨酸;丝氨酸到苏氨酸;苏氨酸到丝氨酸;色氨酸到酪氨酸;酪氨酸到色氨酸或苯丙氨酸;以及缬氨酸到异亮氨酸或亮氨酸。
除了缺失或取代之外,经修饰蛋白可具有残基的插入,这通常涉及在多肽中至少一个残基的添加。这可包括插入靶向肽或多肽,或仅单一残基。下文论述被称作融合蛋白的末端添加。
术语“生物功能性等效物”在本领域中充分理解并且在本文中详细地进一步限定。因此,包括具有在约70%和约80%之间或在约81%和约90%之间或甚至在约91%和约99%之间的与对照多肽的氨基酸相同或功能上等效的氨基酸的序列,其条件是维持蛋白的生物活性。重组蛋白可在某些方面中在生物学功能上与其原来的对应部分等效。
还将理解,氨基酸和核酸序列可包括附加残基,如附加N-或C-端氨基酸或5′或3′序列,并且仍然基本上如阐述于本文公开的序列中的一个中,只要序列符合上述准则,包括维持其中涉及蛋白表达的生物蛋白活性。末端序列的添加具体地应用到核酸序列,其可例如包括侧接编码区的5′或3′部分中的任一个的各种非编码序列或可包括各种内部序列,即,已知存在于基因内的内含子。
如本文中所使用,蛋白或肽通常是指但不限于大于约200个氨基酸,至多从基因转译的全长序列的蛋白;大于约100个氨基酸的多肽;和/或约3个到约100个氨基酸的肽。为方便起见,术语“蛋白”、“多肽”和“肽”在本文中可互换地使用。
如本文中所使用,“氨基酸残基”是指本领域中已知的任何天然存在的氨基酸,任何氨基酸衍生物或任何氨基酸模拟物。在某些实施例中,蛋白或肽的残基为顺序的,无任何非氨基酸间杂氨基酸残基的序列。在其它实施例中,序列可包含一个或多个非氨基酸部分。在特定实施例中,蛋白或肽的残基的序列可以间杂有一个或多个非氨基酸部分。
因此,术语“蛋白或肽”涵盖包含在天然存在蛋白中发现的20个常见氨基酸中的至少一个或至少一个经修饰或非常见氨基酸的氨基酸序列。
本发明的某些实施例涉及融合蛋白。这些分子可具有在N-或C-端处键联到异源结构域的治疗性蛋白。举例来说,融合体还可采用来自其它物种的前导序列以允许重组表达异源宿主中的蛋白。另一种有用的融合体包括添加蛋白亲和标签如血清白蛋白亲和标签或六个组氨酸残基,或免疫活性结构域如抗体表位(优选可断裂的)以促进融合蛋白的纯化。非限制性亲和标签包括聚组氨酸、甲壳质结合蛋白(CBP)、麦芽糖结合蛋白(MBP)以及谷胱甘肽-S-转移酶(GST)。
在具体实施例中,治疗性蛋白可键联到增加活体内半衰期的肽,如XTEN多肽(Schellenberger等人,2009年)、IgG Fc结构域、白蛋白或白蛋白结合肽。
本领域的技术人员熟知生成融合蛋白的方法。可通过例如从头合成整个融合蛋白或通过附着编码异源结构域的DNA序列,接着表达完整的融合蛋白来制备这类蛋白。
通过将基因与编码在串列连接的多肽之间剪接的肽连接子的桥接DNA片段连接,可促进制备还原父代蛋白的功能性活性的融合蛋白。连接子将具有足够的长度以允许适当的折叠所得融合蛋白。
siNA(例如,siRNA)为本领域中众所周知的。举例来说,siRNA和双链RNA已经描述于美国专利第6,506,559和6,573,099号以及美国专利申请2003/0051263、2003/0055020、2004/0265839、2002/0168707、2003/0159161和2004/0064842中,所有文献以全文引用的方式并入在本文中。
在siNA内,核酸的组分不必自始至终为相同类型或均相(例如,siNA可包含核苷酸和核酸或核苷酸类似物)。通常,siNA形成双链结构;双链结构可由部分或完全互补的两种独立核酸产生。在本发明的某些实施例中,siNA可仅包含单一核酸(多核苷酸)或核酸模拟物并且通过与其自身互补而形成双链结构(例如,形成发夹环路)。siNA的双链结构可包含16、20、25、30、35、40、45、50、60、65、70、75、80、85、90、100、150、200、250、300、350、400、450、500个或更多个连续核碱基,包括其中的所有范围。siNA可包含与互补核酸(其可为相同核酸的另一部分或独立互补核酸)杂交以形成双链结构的17到35个连续核碱基,更优选地18到30个连续核碱基,更优选地19到25个核碱基,更优选地20到23个连续核碱基,或20到22个连续核碱基,或21个连续核碱基。
可用于实践本发明的方法的本发明的药剂包括(但不限于)siRNA。通常,双链RNA(dsRNA)(其可替代地在本文中被称作小干扰RNA(siRNA)的引入诱导强效和特异基因沉默,这被称作RNA干扰或RNAi的现象。RNA干扰已经被称作“共抑制”、“转录后基因沉默”、“有义抑制”和“压制”。RNAi为有吸引力的生物技术工具,因为其提供用于敲除特异基因的活性的手段。
在设计RNAi时,存在若干需要考虑的因素,如siRNA的性质,沉默效应的持久性和递送系统的选择。为了产生RNAi效应,引入到生物体中的siRNA通常将含有外显子序列。此外,RNAi过程同源性依赖,所以序列必须小心地选择以便使基因特异性达到最大,同时将在同源而非基因特异序列之间的交叉干扰的可能性减到最少。优选地,siRNA呈现在siRNA的序列和待抑制基因之间的大于80%、85%、90%、95%、98%或甚至100%同一性。与靶基因相同小于约80%的序列基本上较不有效。因此,在siRNA和待抑制基因之间的同源性程度越高,将越不可能影响不相关基因的表达。
此外,siRNA的大小为重要考虑因素。在一些实施例中,本发明涉及包括至少约19到25个核苷酸并且能够调节基因表达的siRNA分子。在本发明的上下文中,siRNA在长度上优选小于500、200、100、50或25个核苷酸。更优选地,siRNA在长度上为约19个核苷酸到约25个核苷酸。
靶基因通常意指包含编码多肽的区域,或调节复制、转录或转译或对于表达多肽重要的其它过程的多核苷酸区域的多核苷酸,或同时包含编码多肽的区域和可操作地键联到其中调节表达的区域的多核苷酸。可靶向在细胞中表达的任何基因。优选地,靶基因为与对于疾病重要的细胞活性的进展有关或与相关联或作为研究对象而备受关注的基因。
siRNA可从商业来源、天然来源获得,或可使用本领域普通技术人员熟知的许多技术中的任一种合成。举例来说,预先设计的siRNA的一个商业来源为德克萨斯州奥斯汀(Austin,Tex)的另一个为(加利福尼亚州巴伦西亚(Valencia,Calif.))。可应用在本发明的组合物和方法中的抑制性核酸可为任何核酸序列,所述抑制性核酸已经通过任何来源发现为所关注蛋白的经证实的向下调节因子。无需过度实验和使用本发明的公开内容,应理解附加siRNA可被设计和用于实践本发明的方法。
siRNA还可包含一个或多个核苷酸的变化。这类变化可包括将非核苷酸材料添加到如19到25个核苷酸RNA的一个或多个端部或内部(在RNA的一个或多个核苷酸处)。在某些方面中,RNA分子含有3′-羟基。在本发明的RNA分子中的核苷酸还可包含非标准核苷酸,包括非天然存在的核苷酸或脱氧核糖核苷酸。双链寡核苷酸可含有经修饰主链,例如硫代磷酸酯、二硫代磷酸酯或本领域中已知的其它经修饰主链,或可含有非天然核苷间键。siRNA的附加修饰(例如,2′-O-甲基核糖核苷酸、2′-脱氧-2′-氟核糖核苷酸、“通用碱基”核苷酸、5-C-甲基核苷酸、一个或多个硫代磷酸酯核苷酸间键和反向脱氧残基结合)可发现于美国申请公开2004/0019001和美国专利第6,673,611号(所述专利中的每个以全文引用的方式并入)中。总起来说,上述所有这类更改的核酸或RNA被称作经修饰siRNA。
VI.试剂盒和诊断剂
在本发明的各种方面中,设想试剂盒,其含有从体液或组织培养基中纯化外泌体必要的组分。在其它方面中,设想试剂盒,其含有分离外泌体和将其用治疗性核酸、治疗性蛋白或其中编码治疗性蛋白的核酸转染必要的组分。在其它方面中,设想试剂盒,其含有分离外泌体和确定在分离的外泌体内的癌细胞衍生的外泌体特异性标记物的存在必要的组分。
试剂盒可包含含有这类组分中的任一种的一个或多个密封小瓶。在一些实施例中,试剂盒还可包含合适容器装置,其为将不与试剂盒的组分反应的容器,如艾本德试管、测定板、注射器、瓶或试管。容器可由可灭菌材料如塑料或玻璃制得。
试剂盒还可包括说明书页,其概述在本文中阐述的方法的程序步骤,并且将遵循如本文所描述的或所属领域的普通技术人员已知的基本上相同程序。说明书信息可在含有机器可读指令的计算机可读介质中,所述机器可读指令当使用计算机实行时引起以下真实或虚拟程序的显示:从样品纯化外泌体和转染其中的治疗性核酸、表达其中的重组蛋白、电穿孔其中的重组蛋白或鉴别其上或其中的癌细胞衍生的标记物。
VII.实例
包括以下实例以展示本发明的优选实施例。本领域的技术人员应理解,以下实例中所公开的技术表示本发明人发现的在本发明的实践中很好地起作用的技术,并且因此可以被视为构成其实践的优选模式。然而,根据本公开,本领域的技术人员应理解,可以在不脱离本发明的精神和范围的情况下对所公开的具体实施例作出许多改变并且仍获得相似或类似结果。
材料和方法
外泌体的分离和纯化。如先前所描述,外泌体通过差速离心过程来纯化(Alvarez-Erviti等人,2011年;EL-Andaloussi等人,2012年)。从在含有外泌体被消耗的FBS的培养基中培养48小时的细胞采集上清液,且所述上清液随后经受800g 5分钟,和2000g 10分钟的顺序离心步骤。此所得上清液然后使用0.2μm滤膜在培养瓶中过滤,且在超速离心(Beckman)2小时之后,在SW 32Ti转子中在28,000g下回收团块。抽吸上清液并且团块在PBS中再悬浮,并且随后再超速离心2小时。然后,纯化的外泌体被分析并且用于实验程序。
外泌体和脂质体的电穿孔。在400μl的电穿孔缓冲液(1.15mM磷酸钾、pH值7.2,25mM氯化钾,21%OptiprepTM)中,混合1×108个外泌体(通过nanosight分析测量)和1μgsiRNA(凯杰公司)或shRNA。如先前描述,使用4mm比色皿,使用基因脉冲发生器XcellTM电穿孔系统(伯乐公司(BioRad))电穿孔外泌体(Alvarez-Erviti等人,2011年;EL-Andaloussi等人,2012年)。使用脂质体(100nm,购自Encapsula纳米科学公司)执行类似程序。如上所述,在电穿孔之后,用不含蛋白酶的RNA酶A(西格玛阿尔德里奇公司(Sigma Aldrich))医治外泌体,接着添加10×浓缩的RNa酶抑制剂(安必逊公司(Ambion)),并且在超速离心方法下用PBS洗涤。
免疫金标记和电子显微镜。在最佳浓度下的固定标本放置到300目碳/弗姆瓦涂布的网格上并且允许吸收弗姆瓦最少一分钟。对于免疫金染色,网格放置到封闭缓冲液中用于封闭/透化步骤一小时。无需冲洗,网格立刻放置到4℃下的适当稀释度下的初级抗体中过夜(单克隆抗CD9,1∶10,艾博抗公司(Abcam))。作为对照,一些网格不暴露于初级抗体。次日,所有网格用PBS冲洗,然后在室温下漂浮在附着有10nm金颗粒(宾夕法尼亚州哈特菲尔德的AURION公司(AURION,Hatfield,PA))的适当二级抗体的液滴上两小时。用PBS冲洗网格并且置于在0.1M磷酸缓冲液中的2.5%戊二醛中15分钟。在以PBS和蒸馏水冲洗之后,使网格干燥并且使用乙酸铀酰染色用于对比。用TecnaiTM生物双透射电子显微镜(Bio Twintransmission electron microscope)(俄勒冈州希尔斯伯勒的FEI公司(FEI,Hillsboro,OR))查看样品并且用AMT CCD相机(马萨诸塞州丹佛斯(Dancers,MA)的AdvancedMicroscopy Techniques公司)获取图像。
在用外泌体或脂质体处理的细胞中的Alexa荧光剂647的量化。从BJ成纤维细胞中分离的外泌体用Alexa647-标记的siRNA(凯杰公司,SEQ ID NO:1)电穿孔,并且用PBS、蛋白酶K(凯杰公司,在室温下1×,15分钟并且在4℃下用PBS超速离心1小时),或胰蛋白酶(生命技术公司(Life Technologies),在室温下10×,15分钟并且在4℃下用PBS超速离心1小时)处理,用PBS洗涤2小时,并且添加到在玻璃盖玻片上的Panc-1细胞培养基维持3小时。然后,通过用冷PBS洗涤和用4%PFA在室温下培育20分钟来固定细胞。然后,细胞用PBS洗涤,与0.05%Triton X一起培育10分钟,用PBS洗涤并且用绿色核染剂(英杰公司(Invitrogen))染色。然后,通过荧光安装介质,将盖玻片安装到载玻片上。Alexa647的病灶性累积使用蔡司(Zeiss)观测器Z1倒置显微镜视觉化。每视场(400×)计数具有Alexa647标记的细胞的数量并且结果表述为具有阳性标记的细胞在每视场计数的细胞总数中的百分比。
实时PCR分析。根据制造商的说明,用MultiScribe逆转录酶(应用生物系统公司(Applied Biosystems))和遵循用(英杰公司)的总RNA纯化的低聚-d(T)引物来逆转录RNA。使用绿色主混合物(应用生物系统公司)在ABI7300HT序列检测系统仪器上执行实时PCR分析。所关注转录物标准化为18S转录水平。用于KrasG12D的引物如所描述设计(Rachagani等人,2011年)并且Kras野生型引物如所描述设计(Poliseno等人,2010年)。每个测量一式三份地执行。确定阈值循环(片段循环次数,在所述次数下扩增目标的量达到固定阈值),并且使用2-ΔCt化学式测量表达。引物序列在表1中列出。
表1.用于RT-PCR的引物序列
细胞培养。在补充有20%外泌体被消耗的FBS及1%青霉素-链霉素的DMEM中培养人类包皮成纤维(BJ)细胞。在RPMI 10%FBS中培养Panc-1和BxPC-3细胞(从美国典型培养物保藏中心(American Type Culture Collection)[ATCC]获得)。Panc-1和BxPC3细胞(用荧光素酶启动子转染)来自美国德州大学MD安德森癌症中心(UT MDACC)的Dr.ThiruArumugam的好心赠与。通过在未经补充的DMEM和胶原蛋白酶4(400单位/毫升)中切碎分离的肿瘤且培育过夜,Ptf1acre/+;LSL-KRasG12D/+;Tgfbr2flox/flox小鼠(PKT)成纤维细胞从PKT小鼠的胰腺中分离。然后,次日,抽吸培养基,在这之后,细胞培养在补充有20%外泌体被消耗的FBS和1%青霉素-链霉素-安比西林的DMEM中。
RNAi策略。KrasG12D siRNA序列(GUUGGAGCUGAUGGCGUAGTT(SEQ ID NO:1))和KrasG12D shRNA序列(CCGGGTTGGAGCTGATGGCGTAGTTCTCGAGCTACGCCATCAGCTCCAACTTTTTTT(SEQ ID NO:2))同时反映来自野生型Kras基因序列的G到A核苷酸偏差,以便特异性地靶向在KrasG12D突变中的甘氨酸到天冬氨酸的氨基酸取代并且包含TT核苷酸突出物以促进沉默效能。相对于野生型mRNA序列,在此KrasG12DsiRNA中的核苷酸异常的中心位点增强其特异性。这在有义链上的3′端处还标记有Alexa647萤光团以追踪其递送。siRNA从凯杰公司获得(目录号.1027424)。为用作加扰siRNA,所有星形阴性siRNA从凯杰公司获得(目录号.1027287)。靶向GFP的shRNA用作加扰shRNA。
外泌体转染。对于使用外泌体和脂质体的活体外转染,如上所述,将二者电穿孔并且用PBS洗涤,并且如对于每个测定所描述的,在6-孔板中的200,000个细胞用外泌体和脂质体处理所需的时间并且随后用PBS洗涤和用于进一步分析。
生长动力学和凋亡测定。Panc-1和BxPC-3细胞接种在6-孔板(2.5×105)中并且使其生长12小时,在这之后,它们用经si/shRNA电穿孔的外泌体处理。随后,每24小时,通过在使用血细胞计数器的细胞计数之前用胰蛋白酶处理细胞和与锥虫蓝混合来计数活细胞的数量。此过程每隔24小时重复,直至接种后84小时。根据制造商的说明,通过TUNEL的凋亡使用原位细胞死亡试剂盒,TMR red(罗氏公司(Roche))评估。如上所述固定细胞,并且绿色(英杰公司,在PBS中1∶10,000,在室温下历时10分钟)用于对核染色。使用蔡司LSM 510共焦显微镜获取图像,并且图像通过计数每视场(400×)的具有TUNEL阳性的细胞的数量来量化,并且结果表述为具有阳性标记的细胞在每视场计数的细胞总数中的百分比。
蛋白质印迹。为了推断在用外泌体处理24小时之后细胞的蛋白表达,Panc-1细胞收集在RIPA缓冲液中并且蛋白裂解物使用布拉德福(Bradford)量化标准化。40μg的裂解物装载到丙烯酰胺凝胶上用于在变性条件下的蛋白的电泳分离并且通过润湿电泳转移来转移到PVDF膜(ImmobilonP)上。然后,在室温下用在PBS/0.05%吐温-20中的5%脱脂奶粉封闭膜1小时,并且在4℃下用以下初级抗体培育过夜:抗兔p-Erk-p44/p42MAPK(Erk1/2)(Thr202/Tyr 204)(赛信通公司(Cell Signaling),4376,1∶1000)、抗兔p-AKT-抗AKT1(二氧磷基S473)(艾博抗公司,ab81283,1∶5000)、抗兔β-肌动蛋白(赛信通公司,4967,1∶1000)。第二抗体在室温下培育1小时。在抗体培育之后的洗涤在定轨振荡器上用1×PBS0.05%以15分钟间隔进行三次。根据制造商的说明,用来自皮尔斯公司(Pierce)的化学发光反应剂对膜显影并且在膜上捕获化学发光。
RNA印迹。在95℃下,尿素/丙烯酰胺15%凝胶用于装载20μg的蔗糖梯度外泌体RNA以及装载色素的1×RNA历时2分钟,接着是在冰上2分钟。根据制造商的说明书(N2102,纽英伦生物技术公司(New England BioLabs))使用微RNA标记物。使用1×TBE,在4℃下进行电泳3小时。在4℃下,用0.5×TBE,使用沃特曼(Whatman)印迹试纸和带正电尼龙膜(安必逊公司)执行转移2小时。使用紫外线透照器历时20分钟将RNA交联到膜。通过在安必逊公司的杂交溶液(安必逊公司)中在42℃下旋转1小时来预杂交膜。然后,在冰上解冻探针,并且在95℃下培育5分钟之后,每mL的杂交缓冲液添加150ng,在这之后,膜在42℃下保持旋转过夜。进行以下洗涤步骤:2×SSPE/0.5%SDS-两次历时15分钟;0.2×SSPE/0.5%SDS-两次历时30分钟,和2×SSPE-历时5分钟。这些初始洗涤步骤接着更多次洗涤,并且然后根据制造商的说明书(安必逊公司)使用BioDetectTM试剂盒对印迹显影。用四个叠层膜将印迹暴露过夜。使用LI-COR Biosciences公司的奥德赛(Odyssey)红外成像系统直接地检测Alexa647萤光团。
免疫细胞化学。细胞涂覆到盖玻片上且用经KrasG12D siRNA电穿孔的外泌体或脂质体处理3小时。然后,盖玻片用冷1×PBS洗涤并且在室温下用4%多聚甲醛固定细胞20分钟,在室温下用在PBS中的0.5%TritonTM X-100预渗透10分钟,并且用在2%BSA中再悬浮的Sytox绿色染色核。在使用再循环工具维持相同设定下,使用蔡司LSM510立式共焦系统获得图像。含有647-标记的siRNA的聚合外泌体允许可通过共焦显微镜检测的病灶性累积标记的视觉显示。对于数据分析,由从至少两个独立实验绘制的库中选择图像。每视场(×400)计数具有Alexa荧光剂647标记的细胞的数量并且结果表述为具有阳性标记的细胞在每视场计数的细胞总数中的百分比。
小鼠和成像。在21℃到23℃、12小时光-暗循环和40%-60%湿度下,年龄在4周到6周之间的雌性无胸腺nu/nu小鼠(查尔斯河实验室(Charles Rivers))容纳于独立通气笼具中。允许小鼠自由获取辐射饲料和灭菌水。在全身麻醉下,使用27-标准规格注射器将Panc-1或BXPC-3细胞(106,再悬浮在10μl PBS中)注射到胰腺的尾部中。对于荧光素酶表达的检测,在成像之前12分钟到15分钟,将小鼠腹膜内注射100mg/kg荧光素(在PBS中10mg/ml下的200μl),用异氟醚麻醉并且使用IVIS(赛诺金波谱公司(Xenogen Spectrum))成像。对于原位肿瘤分析,Living Image4.4版(卡立泊生命科学公司(Caliper Life Sciences)用于定量所有肿瘤计算。围绕胰腺和肿瘤的圆形关注区域(ROI)被限定并且设定为比较在相同实验组内的所有图像的标准。此外,对于在所有实验组中的所有测量结果,暴露条件(时间、孔径、平台位置、分组)保持相同。然后,在用于所有实验组的相同条件下获得后续肿瘤测量结果(光子/秒/平方厘米/球面度)。定期对小鼠成像并且将小鼠随机分成用于医治的组。每隔一天,以100μl体积的PBS使小鼠腹膜内接受2×108个外泌体或脂质体。用2μg siRNA或shRNA电穿孔外泌体或脂质体并且在注射之前用PBS洗涤。在使用PKT(Ptf1acre/+;LSL-KrasG12D/+;Tgfbr2flox/flox)(等人,2014年)基因工程改造小鼠时,在小鼠存在有PaNIN和PDAC病灶时,在年龄33天时开始外泌体医治。所有动物程序均通过在美国德州大学MD安德森癌症中心的动物管理和使用委员会(Institute for Animal Care and UseCommittee)审查和批准。
巨噬细胞清除作用。具有免疫能力的成体小鼠腹膜内注射含有Alexa647-标记的siRNA的外泌体或脂质体。这些小鼠的血液在注射后12小时采集并且经处理用于流式细胞测量术分析。使用ACK裂解缓冲液(英杰公司)消耗RBC,并且外周细胞用FC封闭剂(1∶1000,BD Pharmingen公司)封闭,用Sytox绿色(1∶200,英杰公司)和CD11b(1∶200,BDPharmingen公司,PerCP/Cye 5.5)抗体染色30分钟,用PBS洗涤,并且使用LSR FortessaTMX-20细胞分析仪分析。在用特异性抗体染色之前用FC封闭剂预培育小鼠细胞悬浮液若干分钟确保任何观察到的染色为由于抗体的抗原结合部分与在细胞表面上的抗原的相互作用。
组织结构、组织病理学和免疫组织化学。组织固定在福尔马林中并且用石蜡包埋处理。切割并且用苏木紫和曙红(H&E)以及马森三色染色法(MTS)(徕卡公司(Leica))染色5μm厚度的组织切片)。对于组织病理学评分,基于胰腺癌症的形态阶段对H&E染色的切片进行评分:正常、胰腺上皮内的腺瘤病(PaNIN)和胰腺导管腺癌(PDAC)。对于每个组织切片,用于三个阶段(正常、PaNIN、PDAC)中的每个的百分比分数由胰腺组织结构方面的专家以盲法方式手动获得,然后,所述分数经平均以得到用于每个群组100的总分数。然后,针对在相应群体中的每个小鼠,获取这些百分比分数的平均值。
为了分析小鼠体内纤维化,针对每个MTS染色的胰腺切片随机选择八个200×视场并且由使用Adobe Photoshop的网格交点分析手动评估纤维化。对于每个图片评估,100个方块的网格重叠在每个图片上,并且每个交点计数为蓝色(纤维化区域)和紫色/红色(非纤维化区域)。然后,获得每个组织切片的百分比分数。在免疫染色之前,组织切片还经受抗原修复(在pH 6和98℃下,在10nM柠檬酸盐缓冲液中15分钟)。在与初级抗体一起培育过夜之前,组织切片在TBS或PBS中与4%CWFS明胶(Aurion公司)一起培育1小时。以下初级抗体用于染色:抗兔p-Erk-p44/p42 MAPK(Erk1/2)(Thr202/Tyr 204)(赛信通公司,4376,1∶400)、抗兔p-AKT-抗AKT1(二氧磷基S473)(艾博抗公司,ab81283,1∶100)、抗兔Ki-67(赛默科技公司(Thermo Scientific),RM-9106-S,1∶400)。对于所有染色,切片与生物素标记的山羊抗兔和抗生蛋白链菌素HRP(Biocare Medical公司)一起培育,每个历时10分钟,并且用苏木紫复染。分析DAB阳性。通过计数每个视场(400×)的阳性染色的细胞核的数量来量化Ki-67染色,而p-Erk和p-AKT染色通过设计仅包括图片的深色染色部分(其然后被认为是用于相应抗体的阳性染色区域)的宏来用ImageJ量化。这在每个组织切片的八个200×图片中执行,并且获得每个组织切片的阳性分数的平均值。根据制造商的说明,使用原位细胞死亡检测试剂盒,TMR Red(罗氏公司(Roche))执行TUNEL测定。通过用绿色染色组织的细胞核(在PBS中1∶10,000,历时10分钟)来在冻结的组织切片上检测Alexa 647。使用蔡司LSM510共焦显微镜获取图像,并且图像通过计数每视场(×400)的具有TUNEL阳性的细胞的数量来量化,并且结果表述为具有阳性标记的细胞在每视场计数的细胞总数中的百分比。
统计分析。在图例中详述所使用的统计分析。使用GraphPad Prism(格拉夫帕德软件公司(GraphPad Software))的单因素方差分析或未配对双尾学生t检验用于建立统计显著性。对于存活期分析,绘制卡普兰-迈耶(Kaplan-Meier)曲线并且使用对数秩曼特尔-考克斯测试评估统计差异。p值<0.05视为在统计学上显著。
实例1-含抑制性RNA的外泌体的抗肿瘤特性
siRNA和shRNA构建体被设计成特异性地靶向KrasG12D。siRNA序列(GUUGGAGCUGAUGGCGUAGTT;SEQ ID NO:1)反映与野生型Kras基因序列的G到A核苷酸偏差(带下划线和粗体的)以便特异性地靶向在发现于细胞系和动物模型中的KrasG12D突变中的甘氨酸到天冬氨酸的氨基酸取代,和TT核苷酸突出物(带下划线的)以促进沉默效能(Rejiba等人,2007年;Ma等人,2004年;Du等人,2005年)。相对于野生型mRNA序列,在这KrasG12D siRNA中的核苷酸异常的中心位点增强KrasG12D siRNA的特异性(Du等人,2005年)。shRNA序列(SEQ ID NO:2)被设计成含有在种子序列中的特异性G到A核苷酸偏差以促进KrasG12D mRNA的特异靶向。用于KrasG12D的siRNA寡核苷酸还标记有Alexa647萤光团以追踪其递送(图4A)。
新电穿孔方法经开发和优化以将shRNA和siRNA构建体插入到外泌体(siKrasG12D/shKrasG12D exos)中,而无需功能上损伤外泌体(图4A到图4C)。为此目的,使用所建立的超速离心方法从人类包皮成纤维细胞(BJ成纤维细胞)中分离外泌体(Kahlert等人,2014年)。外泌体的纯度和均匀性(80nm到150nm直径颗粒)通过NanosightTM测量结果(图4B)、透射电子显微镜(图4C)和CD9免疫金标记(图4D)来证实。蔗糖梯度超速离心和RNA印迹也证实外泌体提取物的纯度以及Alexa荧光剂647在外泌体内的存在(图4E)。还生成含有加扰siRNA和shRNA的外泌体(siScrbl/shScrbl exos)、含有加扰siRNA和shRNA的脂质体(siScrbl/shScrbl)和含有KrasG12D siRNA/shRNA的脂质体(siKrasG12D/shKrasG12D lipos)。致瘤人类胰腺Panc-1(Krasasp12(Reiiba等人,2007年;Sun等人,2001年))细胞与含有Alexa647标记的siRNA的外泌体和脂质体一起培育3小时,并且免疫荧光成像揭示,相较于脂质体处理的细胞,在外泌体处理的细胞中的标记的相当大数量的病灶性累积(图1A)。用蛋白酶K或胰蛋白酶的外泌体的处理减少细胞染色,而脂质体的蛋白酶K或胰蛋白酶处理维持低细胞染色,从而支持外泌体表面蛋白增强标记的siRNA到细胞中的递送(图1A)。与siScrbl/shScrbl exos或未经电穿孔的(对照,无RNAi净负荷)exos相比,siKrasG12D和shKrasG12Dexos处理减少在Panc-1细胞中KrasG12D mRNA含量水平(分别为~70%和~50%的减少)(图1B)。与siScrb1/shScrbl脂质体相比,siKrasG12D和shKrasG12D lipos处理同样减少在Panc-1细胞中的KrasG12D mRNA含量水平(各自为~20%的减少)(图1B)。使用借助特异性地扩增KrasG12D而非野生型Kras的引物的定量实时PCR(qPCR)测量突变KrasG12D转录物的特异性基因敲落(表1),并且siKrasG12D和shKrasG12D exos处理不降低野生型Kras mRNA含量水平,从而支持借助本发明方法的KrasG12D mRNA特异靶向(图1C)。在使用外泌体而非脂质体(图1B)时,突变KrasG12D转录物的基因敲落的效果更好,可以反映与外泌体相比脂质体的减弱的递送(图1A)。增加siKrasG12D和shKrasG12D lipos的浓度或脂质体与Panc-1细胞的培育时间不改善KrasG12DmRNA靶向的效能(图4F),从而支持外泌体相比于脂质体在递送用于有效mRNA靶向的RNAi货物中的优异固有特性。另外的实验优化揭示,与700个外泌体/Panc-1细胞的比率相比,约400个外泌体/Panc-1细胞的比率在抑制KrasG12D转录水平方面是优异的(图4G)。最终,不具有KrasG12D突变(Kraswt,Gly(Sun等人,2001年))的BxPC3胰腺癌细胞用作对照,并且siKrasG12D和shKrasG12D exos处理不抑制在这些细胞中的野生型Kras表达(图4H),从而进一步支持KrasG12D siRNA和shRNA构建体抑制致癌Kras mRNA含量水平的特异性。在用siKrasG12D或shKrasG12D exos处理的Panc-1细胞中的致癌Kras抑制与磷酸化-ERK和磷酸化-AKT蛋白含量水平的减少相关联,从而支持致癌Kras的下游信号传递衰减(图1D)。与具有处理的shScrbl exos或非电穿孔的对照exos的Panc-1细胞相比之下,siKrasG12D或shKrasG12D exos培育的Panc-1细胞的增殖显著减少(图1E)。相比之下,BxPC3细胞的增殖不受siKrasG12D或shKrasG12D exos处理影响(图4I)。最终,siKrasG12D或shKrasG12D exos处理的Panc-1细胞的增殖减少与通过TUNEL测定测量的增强的凋亡相关联,从而证明在用siKrasG12D或shKrasG12D exos处理时这些细胞的增殖减少(图1E)。
活体外实验表明siKrasG12D或shKrasG12D exos特异性地靶向致癌Kras并且经由减弱下游致癌Kras信号传递而诱导凋亡。接下来,探索含有siKrasG12D或shKrasG12D的外泌体使在胰腺肿瘤中的KrasG12D表达沉默的能力。注射后24小时,在胰腺组织中检测到来自在小鼠体内经腹膜内注射的外泌体的Alexa荧光剂647-标记的siRNA的病灶性累积。另外,含有Alexa荧光剂647标记的siRNA的外泌体使用流式细胞测量术在腹膜内注射后24小时的小鼠的血清中检测到(图5A)。这些结果表明,经腹膜内投与在小鼠体内的外泌体进入全身性循环且到达胰腺。在确认接近于胰腺软组织的相当大数量的外泌体之后,1×106个表达荧光素酶的Panc-1人类胰腺(Panc-1-1uc)细胞原位植入在用腹膜内注射外泌体或脂质体处理的裸鼠体内。注射癌细胞10天后,所有小鼠呈现具有通过生物发光成像可检测的且范围在1×105和1×106光子/秒/平方厘米/球面度光亮度之间的肿瘤。将小鼠随机分组并且使其每48小时经受重复的1×106外泌体或脂质体腹膜内注射。值得注意的是,使用的脂质体为100nm大小(接近于外泌体的大小范围)并且以与外泌体同样的浓度和剂量注射。群体的小鼠同样注射有PBS媒剂和未经电穿孔的外泌体。虽然投与PBS或未经电穿孔的外泌体的小鼠的肿瘤以指数速率生长,但是在处理开始后30天,用siKrasG12D或shKrasG12D exos处理的小鼠的肿瘤显著减少到基线生物发光检测含量水平(图2A)。在用siKrasG12D或shKrasG12Dlipos处理的小鼠体内肿瘤生长同样钝化,然而与在使用外泌体时相比,钝化达到小得多的程度(图2A)。另外,检测脂质体相较于外泌体的增加的巨噬细胞清除作用,其中与用含有标记的RNAi的外泌体处理的小鼠相比,含有Alexa荧光剂647标记的RNAi的更多数量巨噬细胞在用含有标记的RNAi的脂质体处理的小鼠的全身性循环中注意到(图5A)。值得注意的是,siKrasG12D或shKrasG12D exos不影响原位BxPC3肿瘤生长(图2B)也不影响整个存活期(图5D),从而支持siKrasG12D或shKrasG12D exos处理对具有KrasG12D突变的癌细胞的特异性抗肿瘤效果。早在癌细胞注射后26天,在天数相配的PBS和siKrasG12D exos处理的小鼠中的组织病理学发现示出在短暂(第16天)siKrasG12Dexos处理之后,胰腺癌症疾病的显著的减少。在癌细胞注射后77天,PBS处理的对照小鼠示出通过生物发光成像测定的大量肿瘤负荷,而shKrasG12D exos处理的小鼠肿瘤负荷减少到几乎不可检测的含量水平(图2C、图6B)。使用shKrasG12D exos进行长期治疗,并且虽然在癌细胞注射130天后,基于垂死准则或过度肿瘤负荷,所有PBS和对照exos处理的Panc-1肿瘤小鼠需要安乐死,但是用shKrasG12D exos处理的所有小鼠在癌细胞注射200天后均健康并且呈现如通过生物发光成像检测的最小肿瘤负荷(图2D、图6B)。用于p-ERK(图2E)和p-AKT(图5C)的肿瘤的免疫标记还揭示,与对照(PBS-处理的)小鼠相比,在用shKrasG12D exos处理的小鼠的肿瘤中的Kras信号传递被抑制。这些数据表示,shKrasG12D的外泌体递送提供肿瘤生长的减少并且维持肿瘤生长的抑制。在这些时间点时的胰腺的组织病理学分析示出,在PBS处理的小鼠中(130天)的所有胰腺涉及晚期肿瘤,相比之下,在shKrasG12Dexos处理的小鼠中(图2D),对于绝大部分的胰腺而言,未涉及小肿瘤病灶。在shKrasG12Dexos之后,肿瘤负荷百分比(基于在实验终点时胰腺质量)(图2F)和存活期(图2G)在携带Panc-1肿瘤的小鼠体内还极大地改善,而所有对照小鼠抵挡不了胰腺肿瘤负荷。在癌细胞植入88天到130天后时,在达到垂死状态时,在PBS组和对照exos处理的组中的小鼠被安乐死,而在shKrasG12D exos处理的组中,几乎所有小鼠身体良好且在癌细胞植入200天后时存活(一个小鼠被发现在第59天时死亡,然而尸检分析揭示在此小鼠体内的最小肿瘤负荷并且尸检分析支持死亡与癌症不相关)。
在具有Panc-1肿瘤的裸鼠中siRNA iExosomes(即,包含原料药如siRNA的外泌体)处理的抗肿瘤特性保证在PDAC的基因工程改造的小鼠模型(GEMM)中的进一步评估。快速进展的Ptf1acre/+;LSL-KRasG12D/+;Tgfbr2flox/flox小鼠(PKT小鼠(等人,2014年))用siKrasG12D exos处理。这些小鼠自发地罹患可靠地重现人类胰腺癌症的临床和组织病理学的胰腺癌(等人,2014年)。模型完全地渗透并且在小鼠中疾病进展高度类似(等人,2014年)。PKT小鼠在年龄约28天时罹患胰腺上皮内腺瘤病(PaNIN)阶段,在约32天时罹患侵入性腺癌并且在年龄45天到55天时死亡。在年龄33天(具有PDAC的小鼠)时开始,每隔48小时,小鼠腹膜内注射未经电穿孔的对照外泌体或siKrasG12D或shKrasG12Dexos(图3A)。在处死后,来自含有标记的siRNA的exos的Alexa647标记的病灶性累积在小鼠的胰腺肿瘤中检测到。siKrasG12D或shKrasG12D exos处理的小鼠示出寿命的显著延长,当相比于对照exos处理的小鼠(其示出43天的平均存活期)时,对于用shKrasG12D exos处理的小鼠平均存活期为50天,而对于用siKrasG12D exos处理的小鼠为60天(图3B)。与在年龄匹配的时间点(图3C)和相应实验终点时的对照exos处理的小鼠相比,增加的存活期与在siKrasG12D exos处理的小鼠体内肿瘤负荷的显著减少相关联(图7A)。除了显著的存活期优点(图3B)之外,siKrasG12D exos处理的小鼠(年龄与对照exos处理的在年龄44天时小鼠匹配)的肿瘤的组织病理学特征揭示正常实质病灶和PaNIN阶段病灶的相对增加,相比之下,在年龄44天时在对照小鼠体内胰腺几乎完全转化到具有侵入性特征的癌组织(图3D)。当与对照小鼠相比较时,siKrasG12D exos处理的小鼠在年龄中值60天(实验终点)时的胰腺仍然证明改善的组织病理学特征(图7B)。具有GEMM的实验最初使用衍生自BJ人类成纤维细胞的外泌体进行。为了解决物质差异对在GEMM中的siRNA exos的效果的潜在影响,同基因型成纤维细胞从PKT小鼠的胰腺中分离并且siKrasG12D exos从这些初级细胞培养物生成。与在使用BJ成纤维细胞衍生的siRNA exos时和当与用对照exos处理的小鼠相比较时一样,在使用小鼠成纤维细胞衍生的siRNA exos时,注意到存活期、肿瘤负荷和组织病理学特征的相同改善(图3E到图3F;图7C)。siKrasG12D exos处理显著减少与PKT小鼠体内胰腺癌症进展相关联的促结缔组织增生反应(减少与PKT肿瘤中的纤维化相关联的胞外基质沉积,增加通过TUNEL染色测定的癌细胞凋亡,减少癌细胞增殖(降低Ki67染色)),并且减少在肿瘤中的磷酸基-ERK和磷酸基-AKT染色(图3G、图7D)。
实例2-CD47通过循环单核细胞防止外泌体的吸收
据发现循环单核细胞吞噬脂质体(100nm;购自Encapsula纳米科学公司)而非外泌体(图8A到图8B)。据发现从BJ成纤维细胞中分离的外泌体包含在其表面上的CD47(图9A和图9C),但是脂质体被确定为缺乏在其表面上的CD47(图9B)。据发现用抗CD47抗体的外泌体的处理通过活体内循环单核细胞而刺激外泌体的吸收(图10)。
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本文中所公开和要求的所有方法均可以在无需过度实验的情况下根据本公开进行和实行。虽然已关于优选实施例描述了本发明的组合物和方法,但是对于本领域的技术人员将显而易见的是,在不脱离本发明的概念、精神和范围的情况下,可将变化应用于本文所述方法和方法的步骤或步骤的顺序。更具体地说,将显而易见的是,在化学上和生理上均相关的某些药剂可取代本文所描述的药剂,同时将实现相同或类似结果。对本领域的技术人员显而易见的是,所有这类类似取代和修改视为在如由所附权利要求书限定的本发明的精神、范围和概念内。
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Hui和Hashimoto,用于在用恶性疟原虫主裂体性孢子表面蛋白1的助剂辅助的免疫期间增强免疫原性的路径(Pathways for Potentiation of Immunogenicity duringAdjuvant-Assisted Immunizations with Plasmodium falciparum Major MerozoiteSurface Protein 1,《感染与免疫(Infec.Immun.)》,66:5329-5336,1998.
Ji等人,Ras活性水平控制胰腺疾病的发展(Ras activity levels control thedevelopment ofpancreatic diseases),《胃肠病学(Gastroenterology)》,137:1072-1082,82e1-6,2009.
Johnsen等人,外泌体作为药物递送媒剂-用于靶向癌症疗法的内因性纳米载剂的综述(A comprehensive overview of exosomes as drug delivery vehicles-endogenous nanocarriers for targeted cancer therapy,《生物化学与生物物理学报(Biochimica et Biophysica Acta),1846:75-87,2014.
Kahlert等人,在患有胰腺癌的患者的血清外泌体中跨越具有突变的KRAS和p53DNA的所有染色体的双链基因组DNA的鉴别(Identification of Double StrandedGenomic DNA Spanning all Chromosomes with Mutated KRAS and p53 DNA in theSerum Exosomes of Patients with Pancreatic Cancer),《生物化学(The Journal ofbiological chemistry)2014.
Kowal等人,外泌体的生物合成和分泌(Biogenesis and secretion ofexosomes),《细胞生物学新见(Current Opinion in Cell Biology)》,29:116-125,2014.
Luga等人,在乳癌细胞迁移中自分泌Wnt-PCP信号传递的外泌体调节基质移动(Exosomes mediate stromal mobilization of autocrine Wnt-PCP signaling inbreast cancer cell migration),《细胞》,151:1542-1556,2012.
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Marcus和Leonard,FedExosomes:真正递送的工程化治疗性生物纳米颗粒(FedExosomes:Engineering Therapeutic Biological Nanoparticles that TrulyDeliver),《医药(Pharmaceuticals)》(巴塞尔)(Basel),6:659-680,2013.
Melo等人,Glypican-1鉴别癌症外泌体并且检测早期胰腺癌(Glypican-1identifies cancer exosomes and detects early pancreatic cancer),《自然》,523∶177-182,2015.
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Pecot等人,使用全身性递送的siRNA的KRAS的治疗性沉默(TherapeuticSilencing of KRAS using Systemically Delivered siRNAs),《分子癌症治疗(Molecular Cancer Therapeutics)》,13:2876-2885,2014.
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Claims (21)
1.一种医药组合物,所述医药组合物包含外泌体和赋形剂,其中所述外泌体包含靶向KrasG12D的抑制性RNA。
2.根据权利要求1所述的组合物,其中所述外泌体包含在其表面上的CD47。
3.根据权利要求1或2所述的组合物,其中所述抑制性RNA为siRNA、shRNA、miRNA或预miRNA。
4.根据权利要求1-3中任一项所述的组合物,其中所述抑制性RNA为siRNA,其包含SEQID NO:1所示的序列(GUUGGAGCUGAUGGCGUAGTT)。
5.根据权利要求1-3中任一项所述的组合物,其中所述抑制性RNA为shRNA,其包含SEQID NO:2所示的序列(CCGGGTTGGAGCTGATGGCGTAGTTCTCGAGCTACGCCATCAGCTCCAACTTTTTTT)。
6.根据权利要求1-5中任一项所述的组合物,其中所述组合物被配制成用于不经肠投与。
7.根据权利要求1-6中任一项所述的组合物,其中所述组合物被配制成用于静脉内、肌内、皮下或腹膜内注射。
8.根据权利要求1-7中任一项所述的组合物,所述组合物进一步包含抗癌剂。
9.根据权利要求8所述的组合物,所述抗癌剂包括化疗剂或免疫治疗剂。
10.包含外泌体和赋形剂的组合物在制备用于治疗患者中疾病的药物中的用途,其中所述外泌体包含靶向KrasG12D的抑制性RNA。
11.根据权利要求10所述的用途,其中所述疾病是癌症。
12.根据权利要求10或11所述的用途,其中所述抑制性RNA为siRNA、shRNA、miRNA或预miRNA。
13.根据权利要求10-12中任一项所述的用途,其中所述抑制性RNA为siRNA,其包含SEQID NO:1所示的序列(GUUGGAGCUGAUGGCGUAGTT)。
14.根据权利要求10-12中任一项所述的用途,其中所述抑制性RNA为shRNA,其包含SEQID NO:2所示的序列(CCGGGTTGGAGCTGATGGCGTAGTTCTCGAGCTACGCCATCAGCTCCAACTTTTTTT)。
15.根据权利要求10-14中任一项所述的用途,其中所述组合物被配制成用于不经肠投与。
16.根据权利要求11-15中任一项所述的用途,其中所述组合物被配制成用于静脉内、肌内、皮下或腹膜内注射。
17.根据权利要求10-16中任一项所述的用途,其中所述组合物与抗癌剂组合物使用来治疗所述疾病。
18.根据权利要求17所述的用途,其中所述抗癌剂包括化疗剂或免疫疗法。
19.根据权利要求10-18中任一项所述的用途,其中所述组合物与至少第二疗法组合使用。
20.根据权利要求19所述的用途,其中所述第二疗法包含手术疗法、化疗、放疗、超低温疗法、激素疗法或免疫疗法。
21.根据权利要求10-20中任一项所述的用途,其中所述患者为人类。
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US20190117570A1 (en) | 2019-04-25 |
AU2016275046A1 (en) | 2018-01-04 |
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AU2016275046B2 (en) | 2022-07-28 |
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KR20180017119A (ko) | 2018-02-20 |
US10959952B2 (en) | 2021-03-30 |
HK1251257A1 (zh) | 2019-01-25 |
CA2988585A1 (en) | 2016-12-15 |
JP2018520125A (ja) | 2018-07-26 |
MA45481A (fr) | 2018-04-18 |
US20180177727A1 (en) | 2018-06-28 |
EA201890006A1 (ru) | 2018-05-31 |
NZ738149A (en) | 2024-02-23 |
CN107980004A (zh) | 2018-05-01 |
WO2016201323A1 (en) | 2016-12-15 |
MX2017015962A (es) | 2018-07-06 |
JP2024023853A (ja) | 2024-02-21 |
BR112017026467A2 (pt) | 2018-09-11 |
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