CN113559279A - 使用超小纳米粒子通过铁死亡诱导营养素剥夺癌细胞的细胞死亡的治疗方法 - Google Patents
使用超小纳米粒子通过铁死亡诱导营养素剥夺癌细胞的细胞死亡的治疗方法 Download PDFInfo
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Abstract
本申请涉及使用超小纳米粒子通过铁死亡诱导营养素剥夺癌细胞的细胞死亡的治疗方法。本文描述通过纳米粒子摄入通过铁死亡诱导细胞死亡的方法。另外,本发明描述在治疗过程中高浓度超小纳米粒子的多次投与与营养素耗尽环境组合,由此调节细胞代谢路径以通过铁死亡机制诱导细胞死亡。铁死亡涉及铁、活性氧类和细胞死亡执行的同步模式。
Description
本申请是申请日为2016年5月26日,申请号为201680035303.4,发明名称为“使用超小纳米粒子通过铁死亡诱导营养素剥夺癌细胞的细胞死亡的治疗方法”的申请的分案申请。
相关申请案的交叉参考
本申请案主张于2015年5月29日提出申请的美国申请案第62/168,636号和于2016年1月20日提出申请的美国申请案第62/280,960号的权益,所述申请案的揭示内容的全文均以引用方式并入本文中。
政府支持
本发明是在由国立卫生研究院(National Institutes of Health(NIH)/国家癌症研究所)授予的批准号1U54 CA199081-01、R01GM111350和1R01CA161280-01A1的政府支持下完成。
技术领域
本发明大体上涉及纳米粒子(例如超小纳米粒子)于调节分子水平相互作用(例如细胞/亚细胞功能,例如细胞死亡)的用途。在具体实施例中,本发明涉及使用超小纳米粒子(例如,C或C’点)通过铁死亡选择性诱导营养素剥夺癌细胞的细胞死亡的治疗方法。
背景技术
高度整合的癌症靶向纳米药剂的设计和研发有希望增强疾病特异性靶向且改良对细胞内药理学靶的可及性。然而,业内对驱动生物系统中的纳米药剂命运的分子水平相互作用(例如,细胞/亚细胞功能调节)的详细理解仍不清楚。例如,胞吞作用与细胞内输送、生理和/或代谢路径之间的复杂相互影响和靶向纳米粒子操纵这些复杂系统的方式可对稳态调控至关重要。另外,此相互影响可因粒子探针的性质、周围生物条件和疾病本身的性质而变化。另外,特定细胞内隔室内的粒子摄取和积累可改变功能、代谢和/或能量稳态。例如,已显示,经历胞吞作用和细胞内输送的多个基于粒子的探针诱导自体吞噬且抑制溶酶体功能。然而,这些作用随时间调节细胞存活的方式尚不清楚。
发现先前经PET放射性标记和整合素靶向肽环-(Arg-Gly-Asp-Tyr)(cRGDY)表面调整的经FDA批准的超小(例如,具有不大于20nm、例如不大于15nm、例如不大于10nm的直径)荧光有机二氧化硅粒子(C点)是人类中的工作分子癌症成像剂。例如,显示在小和较大动物和人类个体黑色素瘤模型中C点优先在表达αvβ3整合素的原发性和/或转移性病灶中积累,且展示较大肾清除率。关于C点的细节描述于美国专利第8298677 B2号“基于二氧化硅的荧光纳米粒子(Fluorescent silica-based nanoparticles)”、美国公开案第2013/0039848 A1号“基于二氧化硅的荧光纳米粒子”和美国公开案第US 2014/0248210 A1号“基于二氧化硅的多模式纳米粒子(Multimodal silica-based nanoparticles)”,所述专利的内容的全文均以引用方式并入本文中。另外,发现另外经14聚体肽类似物α-黑色素细胞刺激激素(α-MSH)表面修饰的直径可控低至亚10nm范围的超小聚(乙二醇)涂布的(聚乙二醇化)近红外(NIR)荧光二氧化硅纳米粒子(称为C’点)靶向在恶性黑色素瘤细胞上表达的黑皮质素-1受体(MC1-R)。然而,业内仍未知这些粒子可调节细胞功能和细胞内输送的方式。
因此,业内需要确定基于浓度和时间的工艺的变化如何影响基于粒子的探针的内化后命运以改良应用特异性纳米药剂(例如,C和C’点)平台的设计。
发明内容
本文描述通过纳米粒子摄入通过铁死亡诱导细胞死亡的方法。另外,本发明描述在治疗过程中高浓度超小(例如,具有不大于20nm、例如不大于15nm、例如不大于10nm的直径)纳米粒子的多次投与与营养素耗尽环境组合,由此调节细胞代谢路径以通过铁死亡机制诱导细胞死亡。铁死亡涉及铁、活性氧类和细胞死亡执行的同步模式。
发现即使在药物不存在下,在特定营养素剥夺环境中用α-MSH-PEG-C’点处理细胞仍可诱导癌细胞的铁死亡(或不含α-MSH的PEG-C’点,例如与α-MSH-PEG-C’点相比需要较长时间段)。总之,本文所述的结果指示,在氨基酸不存在下培养且经α-MSH-PEG-C'点处理的细胞通过铁死亡经历细胞死亡。观察到在此背景下铁死亡以波形方式自细胞至细胞扩散。不受限于理论,此表明死亡诱导信号的细胞至细胞通信。
在一个方面中,本发明涉及治疗个体的方法,所述方法包含:投与纳米粒子以在肿瘤组织中以足够高的浓度积累来诱导铁死亡(例如,涉及铁依赖性坏死或活性氧类依赖性坏死的铁细胞死亡)。
在某些实施例中,纳米粒子包含超小纳米粒子(例如C点,例如C’点)。
在某些实施例中,高浓度大于1μM,例如大于15μM,例如大于60μM。在某些实施例中,高浓度是肿瘤组织中在0.18μM至1.8μM范围内的局部浓度(例如,其中高浓度是肿瘤组织中至少0.18μM、至少0.3μM、至少0.4μM、至少0.5μM或至少0.6μM的局部浓度;例如,其中纳米粒子是基于二氧化硅的,例如其中纳米粒子是C点或C’点)。
在某些实施例中,肿瘤组织经充分氨基酸(或在代谢上)剥夺。
在某些实施例中,肿瘤组织对铁死亡的诱导敏感。
在另一方面中,本发明涉及组合治疗个体的方法,所述方法包含:投与药物以转运至肿瘤组织(和/或在其中积累);和投与纳米粒子以在肿瘤组织中以足够高的浓度积累(以诱导铁死亡)。
在某些实施例中,药物包含化学治疗剂(例如,TAS-102)。
在某些实施例中,纳米粒子包含超小纳米粒子(例如C点,例如C’点)。
在某些实施例中,高浓度大于1μM,例如大于15μM,例如大于60μM。在某些实施例中,高浓度是肿瘤组织中在0.18μM至1.8μM范围内的局部浓度(例如,其中高浓度是肿瘤组织中至少0.18μM、至少0.3μM、至少0.4μM、至少0.5μM或至少0.6μM的局部浓度;例如,其中纳米粒子是基于二氧化硅的,例如其中纳米粒子是C点或C’点)。
在某些实施例中,肿瘤组织经充分氨基酸(或在代谢上)剥夺。在某些实施例中,肿瘤组织对铁死亡的诱导敏感。
在某些实施例中,投与药物和投与纳米粒子是通过投与包含药物和纳米粒子二者的组合物来实现。
在某些实施例中,组合物包含纳米粒子药物偶联物。
在另一方面中,本发明涉及组合治疗个体的方法,所述方法包含:剥夺肿瘤组织(例如,前列腺癌组织)的激素;和投与纳米粒子以在肿瘤组织中足够高地积累来诱导铁死亡。
在某些实施例中,通过阉割(例如,化学阉割)剥夺肿瘤组织的激素。
在某些实施例中,纳米粒子包含超小纳米粒子(例如C点,例如C’点)。
在某些实施例中,高浓度大于1μM,例如大于15μM,例如大于60μM。在某些实施例中,高浓度是肿瘤组织中在0.18μM至1.8μM范围内的局部浓度(例如,其中高浓度是肿瘤组织中至少0.18μM、至少0.3μM、至少0.4μM、至少0.5μM或至少0.6μM的局部浓度;例如,其中纳米粒子是基于二氧化硅的,例如其中纳米粒子是C点或C’点)。
在某些实施例中,肿瘤组织经充分氨基酸(或在代谢上)剥夺。
在某些实施例中,肿瘤组织对铁死亡的诱导敏感。
在某些实施例中,肿瘤组织选自由以下组成的群组:肾肿瘤、前列腺肿瘤、黑色素瘤、胰脏肿瘤、肺肿瘤、纤维肉瘤、乳房肿瘤、脑肿瘤、卵巢肿瘤和结肠肿瘤组织。在某些实施例中,肿瘤胰脏组织包含BxPC3细胞。在某些实施例中,肿瘤肺组织包含H1650细胞。
在某些实施例中,纳米粒子具有不大于15nm的平均直径。在某些实施例中,纳米粒子具有不大于10nm的平均直径。在某些实施例中,纳米粒子具有约5nm到约7nm(例如,约6nm)的平均直径。
在某些实施例中,纳米粒子包含1到20个靶向部分,其中靶向部分结合至肿瘤细胞上的受体(例如,其中纳米粒子具有不大于15nm、例如不大于10nm、例如约5nm到约7nm、例如约6nm的平均直径)。在某些实施例中,1到20个靶向部分包含α-黑色素细胞刺激激素(αMSH)。在某些实施例中,纳米粒子包含靶向部分(例如,αMSH)。
在某些实施例中,在治疗过程中多次投与纳米粒子。
在某些实施例中,所述方法进一步包含在治疗过程中每3天或4天投与纳米粒子。
在某些实施例中,经投与纳米粒子附接有药物(例如,化学治疗剂)。在某些实施例中,药物是通过连接体部分附接(例如,共价或非共价附接)。
在某些实施例中,药物递送与经投与纳米粒子的天然免疫调节性质组合(例如,其中纳米粒子包含α-MSH-PEG-C’点,例如其中α-MSH结合至纳米粒子的表面)(例如,其中纳米粒子包含有机聚合物涂层(例如,聚乙二醇(PEG)))以增加C点在癌症治疗和/或组织修复过程(例如,伤口愈合)中的治疗潜能。
在另一方面中,本发明涉及包含纳米粒子(例如,超小纳米粒子,例如C点,例如C’点)的组合物用于治疗个体的方法中,其中治疗包含将组合物递送至个体的肿瘤组织以在肿瘤组织中以足够高的浓度(例如,大于1μM,例如大于15μM,例如大于60μM)积累(例如,其中高浓度是肿瘤组织中在0.18μM至1.8μM范围内的局部浓度)(例如,其中高浓度是肿瘤组织中至少0.18μM、至少0.3μM、至少0.4μM、至少0.5μM或至少0.6μM的局部浓度;例如,其中纳米粒子是基于二氧化硅的,例如其中纳米粒子是C点或C’点)(例如,其经充分氨基酸(或在代谢上)剥夺或以其它方式对铁死亡的诱导敏感)以诱导铁死亡。
在另一方面中,本发明涉及包含纳米粒子(例如,超小纳米粒子,例如C点,例如C’点)的组合物,其在肿瘤组织中以足够高的浓度(例如,大于1μM,例如大于15μM,例如大于60μM)积累(例如,其中高浓度是肿瘤组织中在0.18μM至1.8μM范围内的局部浓度)(例如,其中高浓度是肿瘤组织中至少0.18μM、至少0.3μM、至少0.4μM、至少0.5μM或至少0.6μM的局部浓度;例如,其中纳米粒子是基于二氧化硅的,例如其中纳米粒子是C点或C’点)(例如,其经充分氨基酸(或在代谢上)剥夺或以其它方式对铁死亡的诱导敏感)以诱导铁死亡,其用于疗法中。
在另一方面中,本发明涉及包含药物(例如,化学治疗剂,例如TAS 102)的第一组合物和包含纳米粒子(例如,超小纳米粒子,例如C点,例如C’点)的第二组合物用于治疗个体的方法中,其中治疗包含递送第一组合物以转运至个体的肿瘤组织(和/或在其中积累);和将第二组合物递送至个体的肿瘤组织以在肿瘤组织中以足够高的浓度(例如,大于1μM,例如大于15μM,例如大于60μM)积累(例如,其中高浓度是肿瘤组织中在0.18μM至1.8μM范围内的局部浓度)(例如,其中高浓度是肿瘤组织中至少0.18μM、至少0.3μM、至少0.4μM、至少0.5μM或至少0.6μM的局部浓度;例如,其中纳米粒子是基于二氧化硅的,例如其中纳米粒子是C点或C’点)(例如,其经充分氨基酸(或在代谢上)剥夺或以其它方式对铁死亡的诱导敏感)以诱导铁死亡。
在另一方面中,本发明涉及包含药物(例如,任一化学治疗剂,例如TAS 102)的第一组合物以转运至个体的肿瘤组织(和/或在其中积累);和包含纳米粒子(例如,超小纳米粒子,例如C点,例如C’点)的第二组合物以在肿瘤组织中以足够高的浓度(例如,大于1μM,例如大于15μM,例如大于60μM)积累(例如,其中高浓度是肿瘤组织中在0.18μM至1.8μM范围内的局部浓度)(例如,其中高浓度是肿瘤组织中至少0.18μM、至少0.3μM、至少0.4μM、至少0.5μM或至少0.6μM的局部浓度;例如,其中纳米粒子是基于二氧化硅的,例如其中纳米粒子是C点或C’点)(例如,其经充分氨基酸(或在代谢上)剥夺或以其它方式对铁死亡的诱导敏感)以诱导铁死亡,其用于疗法中。
在另一方面中,本发明涉及包含纳米粒子(例如,超小纳米粒子,例如C点,例如C’点)的组合物用于治疗个体的方法中,其中治疗包含剥夺个体肿瘤组织(例如,前列腺组织)的激素(例如,通过阉割(例如,化学阉割));和将组合物递送至个体的肿瘤组织以在肿瘤组织中以足够高的浓度(例如,大于1μM,例如大于15μM,例如大于60μM)积累(例如,其中高浓度是肿瘤组织中在0.18μM至1.8μM范围内的局部浓度)(例如,其中高浓度是肿瘤组织中至少0.18μM、至少0.3μM、至少0.4μM、至少0.5μM或至少0.6μM的局部浓度;例如,其中纳米粒子是基于二氧化硅的,例如其中纳米粒子是C点或C’点)(例如,其经充分氨基酸(或在代谢上)剥夺或以其它方式对铁死亡的诱导敏感)以诱导铁死亡。
涉及本发明一个方面(例如,方法)的实施例的要素可应用于涉及本发明其它方面(例如,系统)的实施例中,且反之亦然。
定义
为更容易地理解本发明,首先在下文中定义某些术语。在本说明书通篇中陈述以下术语和其它术语的额外定义。
在本申请案中,除非另有说明,否则使用“或”意指“和/或”。如本申请案中所用的术语“包含(comprise)”和所述术语的变化形式(例如“包含(comprising)”和“包含(comprises)”)不打算排除其它添加剂、组分、整数或步骤。如本申请案中所用的术语“约”和“大约”是以等效物使用。本申请案中所用具或不具约/大约的任何数值打算涵盖所属领域技术人员所了解的任何正常波动。在某些实施例中,除非上下文另有说明或其它含义较明显,否则术语“大约”或“约”是指在任一方向上(大于或小于)在所述参考值的25%、20%、19%、18%、17%、16%、15%、14%、13%、12%、11%、10%、9%、8%、7%、6%、5%、4%、3%、2%、1%或更小内的值范围(所述数值将超过可能值的100%的情形除外)。
“投与”:术语“投与”是指将物质引入个体中。一般来说,可使用任一投与途径,包括例如非经肠(例如,静脉内)、经口、局部、皮下、腹膜、动脉内、吸入、阴道、直肠、鼻、引入脑脊髓液中或滴入身体隔室中。在某些实施例中,投与是经口。另外或或者,在某些实施例中,投与是非经肠。在某些实施例中,投与是静脉内。
“生物相容性”:如本文所用术语“生物相容性”打算描述不会在体内引发显著有害反应的材料。在某些实施例中,如果材料对细胞无毒性,那么其具有“生物相容性”。在某些实施例中,如果材料在体内添加到细胞引起小于或等于20%细胞死亡和/或其体内投与不会诱导炎症或其它所述不利作用,则其具有“生物相容性”。在某些实施例中,材料是生物可降解的。
“生物可降解”:如本文所用“生物可降解”材料是在引入细胞中时,通过细胞机构(例如,酶降解)或通过水解成细胞可再利用或处置且对细胞无显著毒性作用的组分分解的那些。在某些实施例中,通过分解生物可降解材料产生的组分不会诱导体内炎症和/或其它不利作用。在某些实施例中,生物可降解材料被酶分解。或者或另外,在某些实施例中,生物可降解材料通过水解分解。在某些实施例中,生物可降解聚合材料分解成其组分聚合物。在某些实施例中,生物可降解材料(包括例如生物可降解聚合材料)的分解包括水解酯键。在某些实施例中,材料(包括例如生物可降解聚合材料)的分解包括裂解氨基甲酸乙酯键联。
“癌症”:如本文所用术语“癌症”是指恶性赘瘤或肿瘤(斯特德曼医学辞典(Stedman’s Medical Dictionary),第25版;亨斯利(Hensly)编辑;威廉姆斯与威尔金斯(Williams&Wilkins):费城,1990)。实例性癌症包括(但不限于)听神经瘤;腺癌;肾上腺癌;肛门癌;血管肉瘤(例如,淋巴管肉瘤、淋巴管内皮肉瘤、血液肉瘤);阑尾癌;良性单克隆免疫球蛋白病变;胆管癌(例如,胆管上皮癌);膀胱癌;乳癌(例如,乳房腺癌、乳房乳头状癌、乳腺癌、乳房髓样癌);脑癌(例如,脑脊髓膜瘤、神经胶质母细胞瘤、神经胶质瘤(例如,星形细胞瘤、少突神经胶质瘤)、髓母细胞瘤);支气管癌;类癌肿瘤;宫颈癌(例如,宫颈腺癌);绒毛膜癌;脊索瘤;颅咽管瘤;结缔组织癌;上皮癌;室管膜瘤;内皮肉瘤(例如,卡波西氏肉瘤(Kaposi’s sarcoma)、多发性特发性出血性肉瘤);子宫内膜癌(例如,子宫癌、子宫肉瘤);食道癌(例如,食道腺癌、巴瑞特氏腺癌(Barrett’s adenocarcinoma));尤文氏肉瘤(Ewing’s sarcoma);眼癌(例如,眼内黑色素瘤、视网膜母细胞瘤);家族性嗜伊红细胞增多症;胆囊癌;胃癌(例如,胃腺癌);胃肠基质肿瘤(GIST);胚细胞癌;头颈癌(例如,头颈鳞状细胞癌、口癌(例如,口鳞状细胞癌)、喉癌(例如,喉头癌、咽癌、鼻咽癌、口咽癌));血液癌(例如白血病,例如急性淋巴细胞性白血病(ALL)(例如,B细胞ALL、T细胞ALL)、急性骨髓性白血病(AML)(例如,B细胞AML、T细胞AML)、双表型急性白血病、慢性骨髓性白血病(CML)(例如,B细胞CML、T细胞CML)和慢性淋巴细胞性白血病(CLL)(例如,B细胞CLL、T细胞CLL));淋巴瘤,例如霍奇金淋巴瘤(Hodgkin lymphoma,HL)(例如,B细胞HL、T细胞HL)和非霍奇金淋巴瘤(NHL)(例如B细胞NHL,例如弥漫性大细胞淋巴瘤(DLCL)(例如,弥漫性大B细胞淋巴瘤)、滤泡性淋巴瘤、慢性淋巴细胞性白血病/小淋巴细胞性淋巴瘤(CLL/SLL)、外套细胞淋巴瘤(MCL)、边缘区B细胞淋巴瘤(例如,粘膜相关淋巴组织(MALT)淋巴瘤、结节性边缘区B细胞淋巴瘤、脾边缘区B细胞淋巴瘤)、原发性纵膈B细胞淋巴瘤、伯基特淋巴瘤(Burkittlymphoma)、淋巴浆细胞性淋巴瘤(例如瓦登斯特隆巨球蛋白血症(macroglobulinemia))、多毛细胞白血病(HCL)、免疫母细胞性大细胞淋巴瘤、前体B淋巴母细胞性淋巴瘤和原发性中枢神经系统(CNS)淋巴瘤;和T细胞NHL,例如前体T淋巴母细胞性淋巴瘤/白血病、外周T细胞淋巴瘤(PTCL)(例如,皮肤T细胞淋巴瘤(CTCL)(例如,蕈样真菌病、塞扎里综合症(Sezary syndrome))、血管免疫母细胞性T细胞淋巴瘤、结节外天然杀手T细胞淋巴瘤、肠病变型T细胞淋巴瘤、皮下脂膜炎样T细胞淋巴瘤和退行性大细胞淋巴瘤);一或多种如上文所述白血病/淋巴瘤的混合病症;和多发性骨髓瘤(MM))、重链疾病(例如,α链疾病、γ链疾病、μ链疾病);血管母细胞瘤;下咽癌;炎症性肌纤维母细胞肿瘤;免疫细胞淀粉样变性;肾癌(例如肾母细胞瘤,即威尔姆氏肿瘤(Wilms’tumor)、肾细胞癌);肝癌(例如,肝细胞癌(HCC)、恶性肝细胞瘤);肺癌(例如,支气管原癌、小细胞肺癌(SCLC)、非小细胞肺癌(NSCLC)、肺腺癌);平滑肌肉瘤(LMS);肥大细胞增多症(例如,全身性肥大细胞增多症);肌癌症;骨髓发育不良综合症(MDS);间皮瘤;骨髓增生性病症(MPD)(例如,真性红细胞增多症(PV)、原发性血小板增多症(ET)、原因不明性髓样化生(AMM),即骨髓纤维化(MF)、慢性特发性骨髓纤维化、慢性骨髓细胞性白血病(CML)、慢性嗜中性白血病(CNL)、嗜酸细胞增多综合症(HES));神经母细胞瘤;神经纤维瘤(例如,1型或2型神经纤维瘤病(NF)、神经鞘瘤病);神经内分泌癌(例如,胃胰脏神经内分泌肿瘤(GEP NET)、类癌肿瘤);骨肉瘤(例如,骨癌);卵巢癌(例如,囊腺癌、卵巢胚胎癌、卵巢腺癌);乳头状腺癌;胰脏癌(例如,胰脏腺癌、导管内乳头状粘液性赘瘤(IPMN)、胰岛细胞肿瘤);阴茎癌(例如,阴茎和阴囊柏哲德氏病(Paget’s disease));松果体瘤;原始神经外胚层肿瘤(PNT);浆细胞赘瘤;赘瘤相关综合症;上皮内赘瘤;前列腺癌(例如,前列腺腺癌);直肠癌;横纹肌肉瘤;唾腺癌;皮肤癌(例如,鳞状细胞癌(SCC)、角质棘皮瘤(KA)、黑色素瘤、基底细胞癌(BCC));小肠癌(例如,阑尾癌);软组织肉瘤(例如,恶性纤维组织细胞瘤(MFH)、脂肪肉瘤、恶性外周神经鞘肿瘤(MPNST)、软骨肉瘤、纤维肉瘤、粘液肉瘤);皮脂腺癌;小肠癌;汗腺癌;滑膜瘤;睾丸癌(例如,精原细胞瘤、睾丸胚胎癌);甲状腺癌(例如,甲状腺乳头状癌、乳头状甲状腺癌(PTC)、骨髓性甲状腺癌);尿道癌;阴道癌;和外阴癌(例如,外阴柏哲德氏病)。
“载剂”:如本文所用“载剂”是指与化合物一起投与的稀释剂、佐剂、赋形剂或媒剂。所述医药载剂可为无菌液体,例如水和油,包括石油、动物、植物或合成来源的那些,例如花生油、大豆油、矿物油、芝麻油等。优选地使用水或水溶液盐水溶液和水性右旋糖和甘油溶液作为载剂,尤其用于可注射溶液。适宜医药载剂描述于E.W.马丁(E.W.Martin)的“雷明顿医药科学(Remington's Pharmaceutical Sciences)”中。
“化学治疗剂”:如本文所用术语“化学治疗剂”(例如,抗癌药物)在提到一或多种促细胞凋亡剂、细胞生长抑制剂和/或细胞毒性剂(例如明确包括用于和/或经推荐用于治疗一或多种与不需要的细胞增殖相关的疾病、病症或病况的药剂)时具有其业内所理解的含义。在许多实施例中,化学治疗剂可用于治疗癌症。在一些实施例中,化学治疗剂可为或包含一或多种烷基化剂、一或多种蒽环、一或多种细胞骨架干扰剂(例如微管靶向剂,例如紫杉烷(taxane)、美登素(maytansine)和其类似物)、一或多种埃博霉素(epothilone)、一或多种组蛋白脱乙酰基酶抑制剂(HDAC)、一或多种拓扑异构酶抑制剂(例如,拓扑异构酶I和/或拓扑异构酶II的抑制剂)、一或多种激酶抑制剂、一或多种核苷酸类似物或核苷酸前体类似物、一或多种肽抗生素、一或多种基于铂的药剂、一或多种类视色素、一或多种长春花生物碱和/或以下(即共享相关抗增生活性)一或多种的一或多种类似物。在一些具体实施例中,化学治疗剂可为或包含以下中的一或多种:放线菌素(Actinomycin)、所有反式视黄酸、奥里斯他汀(Auristatin)、阿扎胞苷(Azacitidine)、硫唑嘌呤(Azathioprine)、博来霉素(Bleomycin)、硼替佐米(Bortezomib)、卡铂(Carboplatin)、卡培他滨(Capecitabine)、顺铂(Cisplatin)、苯丁酸氮芥(Chlorambucil)、环磷酰胺(Cyclophosphamide)、姜黄素(curcumin)、阿糖胞苷(Cytarabine)、柔红霉素(Daunorubicin)、多西他赛(Docetaxel)、去氧氟尿苷(Doxifluridine)、多柔比星(Doxorubicin)、表柔比星(Epirubicin)、埃博霉素、依托泊苷(Etoposide)、氟尿嘧啶(Fluorouracil)、吉西他滨(Gemcitabine)、羟基脲(Hydroxyurea)、伊达比星(Idarubicin)、伊马替尼(Imatinib)、伊立替康(Irinotecan)、美坦辛(Maytansine)和/或其类似物(例如,DM1)、氮芥(Mechlorethamine)、巯嘌呤(Mercaptopurine)、甲氨蝶呤(Methotrexate)、米托蒽醌(Mitoxantrone)、类美登素(Maytansinoid)、奥沙利铂(Oxaliplatin)、紫杉醇(Paclitaxel)、培美曲塞(Pemetrexed)、替尼泊苷(Teniposide)、硫鸟嘌呤(Tioguanine、托泊替康(Topotecan)、戊柔比星(Valrubicin)、长春碱(Vinblastine)、长春新碱(Vincristine)、长春地辛(Vindesine)、长春瑞滨(Vindesine)和其组合。在一些实施例中,化学治疗剂可用于抗体-药物偶联物背景下。在一些实施例中,化学治疗剂是在选自由以下组成的群组的抗体-药物偶联物中发现的化学治疗剂:hLL1-多柔比星、hRS7-SN-38、hMN-14-SN-38、hLL2-SN-38、hA20-SN-38、hPAM4-SN-38、hLL1-SN-38、hRS7-Pro-2-P-Dox、hMN-14-Pro-2-P-Dox、hLL2-Pro-2-P-Dox、hA20-Pro-2-P-Dox、hPAM4-Pro-2-P-Dox、hLL1-Pro-2-P-Dox、P4/D10-多柔比星、吉妥珠单抗奥佐米星(gemtuzumabozogamicin)、贝伦妥单抗维多汀(brentuximab vedotin)、曲妥珠单抗艾坦辛(trastuzumab emtansine)、英妥珠单抗奥佐米星(inotuzumab ozogamicin)、格巴妥莫单抗维多汀(glembatumomab vedotin)、SAR3419、SAR566658、BIIB015、BT062、SGN-75、SGN-CD19A、AMG-172、AMG-595、BAY-94-9343、ASG-5ME、ASG-22ME、ASG-16M8F、MDX-1203、MLN-0264、抗PSMA ADC、RG-7450、RG-7458、RG-7593、RG-7596、RG-7598、RG-7599、RG-7600、RG-7636、ABT-414、IMGN-853、IMGN-529、沃妥珠单抗马佛多汀(vorsetuzumab mafodotin)和洛妥珠单抗美坦辛(lorvotuzumab mertansine)。在一些实施例中,化学治疗剂可为或包含以下中的一或多种:法呢基-硫代水杨酸(FTS)、4-(4-氯-2-甲基苯氧基)-N-羟基丁酰胺(CMH)、雌二醇(E2)、四甲氧基二苯乙烯(TMS)、δ-生育三烯酚、沙利霉素(salinomycin)或姜黄素。
“组合疗法”:如本文所用术语“组合疗法”是指其中个体同时暴露于两种或更多种治疗方案(例如,两种或更多种治疗剂)的那些情形。在一些实施例中,可同时投与两种或更多种药剂;在一些实施例中,所述药剂可相继投与;在一些实施例中,所述药剂是以重叠投药方案投与。
“肽”或“多肽”:术语“肽”或“多肽”是指通过肽键连接在一起的至少两个(例如,至少三个)氨基酸串。在某些实施例中,多肽包含天然氨基酸;或者或另外,在某些实施例中,多肽包含一或多个非天然氨基酸(即在自然界中不存在但可纳入多肽链中的化合物;参见例如http://www.cco.caltech.edu/~dadgrp/Unnatstruct.gif,其展示已成功地纳入功能离子通道中的非天然氨基酸的结构)和/或或者可采用如业内已知的氨基酸类似物)。在某些实施例中,蛋白质中的一或多个氨基酸可通过例如添加用于偶联、官能化或其它修饰等的化学实体(例如碳水化合物基团、磷酸酯基团、法呢基、异法呢基、脂肪酸基团、连接体)来修饰。
“放射性标记”:如本文所用术语“放射性标记”是指包含至少一种元素的放射性同位素的部分。实例性适宜放射性标记包括(但不限于)本文描述的那些。在某些实施例中,放射性标记是用于正电子发射断层摄影术(PET)中的放射性标记。在某些实施例中,放射性标记是用于单光子发射计算机断层扫描摄影术(SPECT)中的放射性标记。在某些实施例中,放射性同位素包含99mTc、111In、64Cu、67Ga、186Re、188Re、153Sm、177Lu、67Cu、123I、124I、125I、11C、13N、15O、18F、186Re、188Re、153Sm、166Ho、177Lu、149Pm、90Y、213Bi、103Pd、109Pd、159Gd、140La、198Au、199Au、169Yb、175Yb、165Dy、166Dy、67Cu、105Rh、111Ag、89Zr、225Ac和192Ir。
“个体”:如本文所用术语“个体”包括人类和哺乳动物(例如,小鼠、大鼠、猪、猫、狗和马)。在许多实施例中,个体是哺乳动物,尤其灵长类动物,尤其人类。在某些实施例中,个体是家畜,例如牛、绵羊、山羊、母牛、猪等;家禽,例如鸡、鸭、鹅、火鸡等;和家养动物,尤其宠物,例如狗和猫。在某些实施例中(例如,尤其在研究背景下),标的哺乳动物将为例如啮齿类动物(例如,小鼠、大鼠、仓鼠)、兔、灵长类动物或猪(例如近交系猪等)。
“大体上”:如本文所用术语“大体上”是指展现所关注特征或性质的全或近全范围或程度的定性条件。生物领域技术人员应理解,生物和化学现象(如果有)很少进行到完成和/或进展到完成或实现或避免绝对结果。因此,术语“大体上”在本文中用于捕获许多生物和化学现象中固有的完成的潜在缺乏。
“治疗剂”:如本文所用片语“治疗剂”是指在投与个体时具有治疗作用和/或引发所需生物和/或药理学作用的任何药剂。
“治疗”:如本文所用术语“治疗(treatment)”(还为“治疗(treat)”或“治疗(treating)”)是指部分或完全减轻、改善、缓解、抑制特定疾病、病症和/或病况的一或多种症状、特征和/或病因、延迟其发作、降低其严重程度和/或降低其发生率的物质的任一投与。所述治疗可用于不展现相关疾病、病症和/或病况的体征的个体和/或仅展现所述疾病、病症和/或病况的早期体征的个体。或者或另外,所述治疗可用于展现相关疾病、病症和/或病况的一或多种已确立体征的个体。在某些实施例中,治疗可用于已经诊断患有相关疾病、病症和/或病况的个体。在某些实施例中,治疗可用于已知具有一或多种在统计学上与增加的罹患相关疾病、病症和/或病况风险相关联的易感因素的个体。
本文呈现图式用于说明目的而非用来限制。
附图说明
通过结合附图一起参考以下描述将更明了且更好地理解本发明的前述和其它目标、方面、特征和优点,其中:
图1A-1K显示,在氨基酸剥夺条件中基于二氧化硅和超小α-MSH-PEG-C’点粒子诱导细胞死亡。
图1A显示,实例性α-MSH-PEG-C'点是基于二氧化硅的超小的6nm直径粒子,其具有荧光(例如,经囊封的Cy5)核心和聚乙二醇(PEG)涂层以及α黑色素细胞刺激激素(αMSH)修饰的外壳。
图1B显示,α-MSH-PEG-C'点定位于细胞中的溶酶体网络。用α-MSH-PEG-C'点(15μM)将表达LAMP1-GFP的M21黑色素瘤细胞处理24小时。应注意,纳米粒子(Cy5荧光,假着色)与LAMP1-GFP之间的共定位合并于图像中。棒=10μm。
图1C-1E显示,α-MSH-PEG-C’点在营养素充足培养基中充分耐受且M21细胞经所指示α-MSH-PEG-C'点浓缩物处理并培养40小时。纳米粒子对细胞存活率(图1D)或细胞增殖(图1E)不具显著作用。棒指示平均值+/-平均值的标准误差。N=3次生物实验,其中每一实验具有5个独立视野。关于个别实验值参见图10A和10B。刻度误差棒指示S.D.棒=10μm。
图1F-1H显示,经纳米粒子处理的细胞的自体吞噬和溶酶体功能未受扰乱。墨点显示在溶酶体抑制剂刀豆素A(ConA,1小时,100nM)存在(+)和不存在(-)下,与未经处理和氨基酸饥饿(AA-st)细胞相比经递增剂量的α-MSH-PEG-C'点处理24小时的细胞中的LC3-I和-II。LC3-II的水平(图1G)未因纳米粒子处理而发生变化,且经处理与对照细胞之间的ConA诱导性LC3-II积累(图1H)(自体吞噬更新的量度)相似。SEM棒指示平均值+/-平均值的标准误差。对于每组N=3。关于个别实验值参见图10C和10D。
图1I-1J显示,纳米粒子处理诱导在无氨基酸培养基中培养的M21细胞的细胞死亡。图像显示在AA-st条件中活的对照细胞和死(Sytox绿阳性经纳米粒子处理的)细胞。刻度尺=10μm。
图1I显示50小时后完全培养基(完全)或AA-st条件中的Sytox绿阳性细胞%,如通过时差显微术所测定(图1J)。棒指示平均值+/-标准偏差。对于每组N=4。每一重复来自一次生物实验,经量化有5个独立视野。
图1K显示相对于未经处理的细胞(圆形),在完全培养基中培养72小时的经15μMα-MSH-PEG-C'点处理的M21细胞在免疫缺陷(SCID/Beige)小鼠中产生异种移植物之前展示生长抑制(倒三角)。示意图显示工作流程,其包含(1)对培养物中的M21黑色素瘤细胞负载粒子和(2)将负载有粒子的M21细胞注射至小鼠中以分析相对于对照细胞的异种移植物肿瘤生长。数据显示每组三个肿瘤的22天生长内的平均肿瘤体积。棒指示平均值+/-平均值的标准误差。经粒子处理的M21细胞显示在研究区间内与对照相比统计学上显著的(p<0.001)生长抑制。P值来自通过广义估计方程式估计的回归模型中的沃德测试(Wald test)以将数据的纵向性质考虑在内。
图2A-2F显示,α-MSH-PEG-C’点粒子诱导的细胞死亡并非细胞凋亡、程序性坏死或自死亡(autosis)。
图2A显示在氨基酸不存在下与15μMα-MSH-PEG-C’点一起培养的MCF10A人类乳腺上皮细胞在30小时后经历具有坏死特征的细胞死亡。插图显示由箭头指示的正在死亡的细胞。荧光图像显示死细胞核的Sytox绿标记。棒=10μm。
图2B-2F显示在完全培养基或氨基酸饥饿(AA-st)条件中在15μMα-MSH-PEG-C’点存在或不存在下、和40小时后(MCF10A)(图2B)或45小时后(MEF)(图2C),MCF10A和小鼠胚胎成纤维细胞(MEF)培养物中细胞死亡(Sytox绿+)的量化,如通过时差显微术所测定。棒指示平均值+/-标准偏差。N=5/组。每一重复来自一次生物实验,经量化有5个独立视野。
图2D-2F显示,细胞死亡分析(与图2B-2C中所显示的分析类似)指示,MCF10A中的Bcl2过表达对细胞凋亡的抑制(图2D)(在38小时时差实验后量化),或缺失MEF中的Bax和Bak对细胞凋亡的抑制(图2E)(在45小时后量化),或缺失MEF中的ripk3对程序性坏死的抑制(图2F)(在45小时后量化),或敲除MEF中的Atg5在45小时后对自体吞噬的抑制(图2F)不会抑制通过氨基酸饥饿和15μMα-MSH-PEG-C’点处理诱导的细胞死亡。棒指示平均值+/-标准偏差。N=5/组。每一重复来自一次生物实验,经量化有5个独立视野。
图3A-3G显示,铁死亡是α-MSH粒子诱导的细胞死亡的潜在机制。
图3A-3C显示在完全培养基(完全)或氨基酸饥饿(AA-st)条件中在以下各项存在或不存在下培养的MCF10A细胞的细胞死亡(Sytox绿+)的量化:15μMα-MSH-PEG-C’点和(图3A)1μM菲乐斯他镇-1(Ferrostatin-1)(Fer-1)在40小时后、(图3B)100μM去铁胺(deferoxamine,DFO)在38小时后、和(图3C)50μM丁羟茴醚(BHA)、200μM抗坏血酸(AA)、100μM Trolox、10mM N-乙酰基半胱氨酸(NAC)或5mM谷胱甘肽(GSH)在40小时后。棒指示平均值+/-标准偏差。N=5/组。每一重复来自一次生物实验,经量化有5个独立视野。
图3D和3E显示在氨基酸饥饿条件中在15μMα-MSH-PEG-C’点下经历铁死亡的MCF10A的时差分析的图像。应注意,死亡(Sytox绿阳性)自图像左侧至右侧细胞至细胞扩展。刻度尺=10μm。
图3F-3G显示在经15μMα-MSH-PEG-C’点和氨基酸抽除处理的细胞死亡前的脂质ROS积累。
图3F显示在检测脂质ROS的C11-BODIPY存在下培养的经处理细胞。应注意,C11-BODIPY的荧光强度在细胞死亡前的几小时有所增加(细胞死亡之前的时间指示于每一图像上的底部图像中)。
图3G显示经粒子处理和氨基酸饥饿细胞(虚线)或经爱拉斯汀(erastin)处理的细胞(黑线)中C11-BODIPY荧光的量化。显示一次生物实验的5个细胞的平均强度+/-标准偏差。时间0指示通过DIC显微术测定的细胞死亡时间。应注意,C11-BODIPY染色的强度在细胞死亡前的3小时与4小时之间有所增加。
图4A-4G显示,α-MSH-PEG-C’点可诱导不同类型癌细胞的细胞死亡。
图4A-4F显示在完全培养基(完全)或无氨基酸培养基(AA-st)中、在15μMα-MSH-PEG-C’点存在或不存在下,(图4A-4B)40小时后BxPC3胰脏癌细胞、(图4C-4D)45小时后H1650肺癌细胞、和(图4E-4F)65小时后HT1080纤维肉瘤细胞的细胞死亡(Sytox绿+)的量化。棒指示平均值+/-标准偏差。N=5/组。每一重复来自一次生物实验,经量化有5个独立视野。刻度尺=10μm。
图4G显示α-MSH-PEG-C’点纳米粒子诱导的铁死亡的实例性模型。氨基酸剥夺(I)和纳米粒子摄入于溶酶体中(II)均会消耗谷胱甘肽(参见图7D-7E),此共同帮助诱导依赖于溶酶体铁(活性氧类(ROS)的一种已知诱导剂)的铁死亡和被菲乐斯他镇-1和立普妥他汀(liporoxstatin)-1阻断的脂质过氧化作用。
图5A-5K显示,在HT1080和786-O异种移植物模型中α-MSH-PEG-C’点抑制肿瘤生长。
图5A、5B和5K各自显示经α-MSH-PEG-C’点处理(T;n=5)和盐水处理(C;n=3)的小鼠中的786-O(图5K)和HT1080(图5B)平均肿瘤体积测量值的图解汇总;误差棒指示标准偏差。在10天时段内i.v.注射(a;箭头)三次高剂量α-MSH-PEG-C’点(或对照媒剂)处理。来自部分(图5A)的个别HT-1080肿瘤体积测量值显示于图5B中。相对于对照肿瘤体积,数据显示在粒子处理后肿瘤生长的显著抑制和部分肿瘤消退(HT-1080:p<0.001;786-OL P<0.01)。P值来自通过广义估计方程式估计的回归模型中的沃德测试以将数据的纵向性质考虑在内。
图5C显示代表性H1080肿瘤异种移植物的代表性全身Cy5荧光成像。
图5D显示,代表性对照和经处理肿瘤的H&E染色组织切片的低倍视图揭露对照样本的大小不成比例地大于相应经处理的样本。
图5E-5H显示,使用Mac-2的肿瘤切片的免疫组织化学染色显示在(图5E)低倍和(图5G)高倍视图上对照肿瘤切片(T)周围的分散的巨噬细胞(箭头),而经Mac-2染色的经处理切片的相应(图5F)低倍和(图5H)高倍视图显示在类似位置(框,d,f;箭头)划定肿瘤界限的大量Mac-2阳性细胞。还注意到少量肿瘤内Mac-2阳性细胞。
图5I显示经历组合抑制剂和粒子处理(T+L;n=3)对单独粒子处理(T;n=3)的小鼠中个别HT1080肿瘤体积测量值的图解汇总。在10天时段内三次高剂量α-MSH-PEG-C’点处理(具和不具i.p.注射的抑制剂)。相对于单独粒子处理,在组合抑制剂和粒子处理后观察到肿瘤生长的显著进展(p<0.001)。
图5J显示,当另外用利普司他汀-1(Liproxstatin-1)处理(右侧肿瘤)时,代表性粒子暴露的肿瘤揭露样本的大小不成比例地较大。刻度尺:1mm(图5D、图5E和图5F);50μm(图5G、图5H);1cm(图5J)。
图6A-6C显示786-O和HT-1080细胞中纳米粒子诱导的细胞死亡和HT-1080肿瘤的血管化。(图6A)50小时后SKOV3卵巢癌细胞和(图6B)5天后HT1080纤维肉瘤细胞的细胞死亡(Sytox绿+)的量化。在完全培养基(完全)或无氨基酸培养基(AA-st)中在所指示浓度的α-MSH-PEG-C’点存在或不存在下培养细胞。棒指示平均值+/-标准偏差。N=5/组。
图6C-6E显示在15μMα-MSH-PEG-C’点存在或不存在下氨基酸饥饿786-O肾癌细胞的细胞死亡(Sytox绿+)的量化。棒指示平均值+/-标准偏差。N=5/组。每一重复来自一次生物实验,经量化有5个独立视野。刻度尺=10μm。与细胞凋亡性死亡(图6E)相比,坏死性细胞死亡是通过形态和快速Sytox绿阳性(图6D)来测定。
图7A-7K显示,纳米粒子影响铁摄取和谷胱甘肽水平。
图7A-7C显示,通过流式细胞术检查在完全培养基中经15μMα-MSH-PEG-C’点处理24小时的MCF10A细胞的细胞溶质ROS水平(使用25μM HDCFDA)(图7B)和脂质过氧化作用(使用2μM C11-BODIPY(581/591))(图7C)。图7A显示经粒子处理的细胞(蓝色群体)的Cy5荧光。
图7D显示在15μMα-MSH-PEG-C’点或400μM丁硫氨酸亚钒胺(BSO)(γ-谷氨酰基半胱氨酸合成酶(谷胱甘肽的限速酶)的一种抑制剂)存在或不存在下,在完全培养基(完全)或无氨基酸培养基(AA-st)中培养24小时的MCF10A细胞中还原谷胱甘肽(GSH)水平的量化。应注意,单独和组合的纳米粒子处理和氨基酸剥夺会降低谷胱甘肽水平,此与用BSO处理类似。棒指示三次独立实验中平均值+/-平均值的标准误差。关于个别实验值参见图12D。
图7E显示,24小时后,经纳米粒子处理的细胞中的总谷胱甘肽水平以及氨基酸饥饿细胞、经纳米粒子处理的细胞(αMSH)和经谷胱甘肽产生抑制剂BSO处理的细胞中的总谷胱甘肽的相对水平有所下降。
图7F显示在40小时和68小时,在AA-st条件中在15μMα-MSH-PEG-C’点(白色棒)或缺少αMSH肽的PEG-C’点(阴暗棒)存在下培养的MCF10A细胞的细胞死亡(Sytox绿+)的量化。棒指示平均值+/-标准偏差。N=5/组。每一重复来自一次生物实验,经量化有5个独立视野。
图7G显示,α-MSH-PEG-C’点结合铁且经处理细胞具有增加的铁水平。数据显示自αMSH纳米粒子原料样品和未经处理细胞(二者为“对照”,低于检测限值)、自培养基(NP+培养基)纯化的α-MSH-PEG-C’点和经纳米粒子处理的细胞(NP+细胞)测定的铁浓度。铁浓度标准以红色数据点显示。所有测量值是以一式三份进行的一个生物实验的平均值。原始数据显示于表1中。
图7H显示铁蛋白重链表达在氨基酸饥饿(AA-st)细胞中通过用15μMα-MSH-PEG-C’点处理或通过用柠檬酸铁铵(FAC)处理而增加,且通过用DFO处理而减少。西方墨点(western blot)显示在用所指示试剂处理后24小时,与肌动蛋白负载对照相比的铁蛋白重链(FTH1)表达。
图7I显示在氨基酸饥饿(AA-st)条件中用铁(FAC)处理细胞足以模拟α-MSH-PEG-C’点诱导的死亡。图表显示如所指示处理的细胞的细胞死亡%(Sytox绿+)的量化。
图7J显示,用爱拉斯汀预处理对纳米粒子诱导的铁死亡敏感。图表显示在所指示处理后18小时(白色棒)或24小时(阴暗棒)的HT-1080细胞死亡%(Sytox绿+细胞)。用爱拉斯汀预处理4小时指示为‘-’或‘+’。应注意,爱拉斯汀预处理自身不会诱导细胞死亡(‘不处理’),但对持续爱拉斯汀处理(‘爱拉斯汀’)和α-MSH-PEG-C’点(15μM)和氨基酸饥饿的组合(‘AA-st+αMSH’)二者敏感,这是因为经预处理的培养物(‘+’)在18小时和24小时经历更多细胞死亡。棒指示平均值+/-标准偏差。N=5/组。每一重复来自一次生物实验,经量化有5个独立视野。
图7K显示,粒子处理不会抑制GPX4活性。数据显示在所指示处理后收集的细胞溶解物的特异性GPX4活性。数据来自三次独立生物实验;棒表示平均值+/-平均值的标准误差。
图8A-8G显示细胞凋亡和程序性坏死受抑制的细胞和利普司他汀-1的对照分析。
图8A显示在无氨基酸培养基中培养且经100nM刀豆素A(ConA)处理的MCF10A细胞经历具有涉及细胞起泡和片段化的细胞凋亡的形态特征的细胞死亡。
图8B显示在完全培养基(完全)或氨基酸饥饿(AA-st)条件中、在Bcl2过表达存在或不存在下培养且经ConA处理的MCF10A细胞的细胞死亡(Sytox绿+)的量化。应注意,在AA-st条件中,Bcl2抑制由ConA处理诱导的细胞凋亡。棒指示平均值+/-标准偏差。N=5/组。每一重复来自一次生物实验,经量化有5个独立视野。
图8C显示敲除RIPK3抑制程序性坏死。图表显示用100ng/ml TNFα、1μg/ml环己酰亚胺(CHX)和20μM zVAD的组合处理以诱导程序性坏死的野生型(wt)和RIPK3-/-MEF的细胞死亡%(Sytox绿+)。应注意,RIPK3-/-MEF不经历细胞死亡,此与经30μM坏死他汀-1(necrostatin-1,Nec-1)(一种程序性坏死抑制剂)处理的wt细胞类似。棒指示平均值+/-标准偏差。N=5/组。每一重复来自一次生物实验,经量化有5个独立视野。
图8D显示响应50μg/ml环己酰亚胺处理而经历细胞凋亡的MCF10A细胞展现细胞死亡的非同步模式。左侧图像显示已经历细胞凋亡的细胞的时差显微术的图像(亮=Sytox绿)。右侧图像显示左侧图像的Sytox绿阳性核,其经假着色以表示个别细胞死亡的时间。时间细胞死亡模式在此处与图3D和3E相比是非同步的。所有刻度尺=10μm。
图8E显示在完全培养基中在15μMα-MSH-PEG-C’点不存在(左图)和存在(右图)下培养72小时的M21细胞(粒子荧光以青色显示)。
图8F显示在完全培养基中在72小时粒子处理后3天和10天时对照和经粒子处理的细胞的细胞死亡%(Sytox绿+细胞)。应注意,完全培养基条件中的粒子处理并不抑制细胞活力。棒指示平均值+/-标准偏差。N=5/组。每一重复来自一次生物实验,经量化有5个独立视野。
图8G显示,利普司他汀-1处理抑制粒子诱导的细胞死亡。在氨基酸饥饿(AA-st)条件中在15μMα-MSH-PEG-C’点和1μM利普司他汀-1存在或不存在下培养的MCF10A细胞40小时后的细胞死亡(Sytox绿+)的量化。棒指示平均值+/-标准偏差。N=5/组。每一重复来自一次生物实验,经量化有5个独立视野。
图8H显示,利普司他汀-1处理抑制由爱拉斯汀处理诱导的C11-BODIPY染色。图像显示如在图3F-3G中在对照细胞经历细胞死亡后6小时,经爱拉斯汀(5μM)处理的C11-BODIPY培育的细胞。应注意,在经爱拉斯汀+利普司他汀-1处理的细胞中不存在C11-BODIPY染色。
图9A-9C显示经粒子处理的肿瘤的图像。
图9A显示经不同大小的PEG-C’点处理的HT-1080细胞的细胞死亡测量值。在完全培养基或AA-st条件中在15μM缺少αMSH肽的PEG-C’点6nm或10nm不存在或存在下培养48小时的HT-1080细胞死亡(Sytox绿+)的量化。误差棒代表S.D.棒指示平均值+/-标准偏差。N=5/组。
图9B显示,HT-1080肿瘤充分血管化。图像显示在粒子注射后10天收获且通过免疫组织化学针对内皮标记物CD31染色的代表性HT-1080异种移植物样本。整个肿瘤的低放大倍数(4×)显微图像(顶部图像)和肿瘤区域的高放大倍数(40×)图像(底部图像)。应注意血管存在于整个肿瘤中。刻度尺=500μm(低倍);50μm(高倍)。
图9C显示,经α-MSH-PEG-C’点处理的786-O肿瘤显示较大数量的招募巨噬细胞。经Mac-2染色处理的切片的低倍(顶部图像)和高倍(底部图像)视图显示在类似位置(框)划定肿瘤界限的显著Mac-2阳性细胞。
图10A-10J显示图1C-1F和图2A-2E的图表的个别数据点。
图10A显示图1C中的细胞存活率图表(在左侧)的数据。N=3次生物实验,每一数据点代表5个独立视野的平均值。
图10B显示图1C中的细胞增殖图表(在右侧)的数据。N=3次生物实验,每一数据点代表5个独立视野的平均值。
图10C显示图1D左图的个别LC3-II/肌动蛋白值。对于每组N=3次西方墨点。应注意,15μm条件具有两个在0.79处绘制的值。
图10D显示图1D右图的个别LC3-II更新值。对于每组N=3次西方墨点。
图10E显示图1E中的细胞死亡图表的数据。N=4次生物实验,每一数据点代表5个独立视野的平均值。
图10F显示图2B左侧的细胞死亡图表的数据,对于每组N=5。每一重复为同一生物实验的独立视野。
图10G显示图2B右侧的细胞死亡图表的数据,对于每组N=5。每一重复为同一生物实验的独立视野。
图10H显示图2C中的细胞死亡图表的数据,对于每组N=5。每一重复为同一生物实验的独立视野。
图10I显示图2D中的细胞死亡图表的数据,对于每组N=5。每一重复为同一生物实验的独立视野。
图10J显示图2E中的细胞死亡图表的数据,对于每组N=5。每一重复为同一生物实验的独立视野。
图11A-11I显示图3A-3F、4A-4C和8A-8G的图表的个别数据点。
图11A显示图3A中的细胞死亡图表的数据。N=3次生物实验,每一数据点代表5个独立视野的平均值。
图11B显示图3C中的细胞死亡图表的数据。对于每组N=5。每一重复为同一生物实验的独立视野。
图11C显示图3B中的细胞死亡图表的数据。N=3次生物实验,每一数据点代表5个独立视野的平均值。
图11D显示图4A中的细胞死亡图表的数据。对于每组N=5。每一重复为同一生物实验的独立视野。
图11E显示图4B中的细胞死亡图表的数据。对于每组N=5。每一重复为同一生物实验的独立视野。
图11F显示图4C中的细胞死亡图表的数据。N=3次生物实验,每一数据点代表5个独立视野的平均值。
图11G显示图8B中的细胞死亡图表的数据。对于每组N=5。每一重复为同一生物实验的独立视野。
图11H显示图8C中的细胞死亡图表的数据。对于每组N=5。每一重复为同一生物实验的独立视野。
图11I显示图8F中的细胞死亡图表的数据。对于每组N=5。每一重复为同一生物实验的独立视野。
图12A-12E显示图6B-6C和7B-7H的图表的个别数据点。
图12A显示图6B中的细胞死亡图表的数据。对于每组N=5。每一重复为同一生物实验的独立视野。
图12B显示图7C中的细胞死亡图表的数据。对于每组N=5。每一重复为同一生物实验的独立视野。
图12C显示图7F中的细胞死亡图表的数据。对于每组N=5。每一重复为同一生物实验的独立视野。
图12D显示图7B(顶部图表)的谷胱甘肽量化的数据。N=3次独立生物实验。
图12E显示图7G中的细胞死亡图表的数据。对于每组N=5。每一重复为同一生物实验的独立视野。
具体实施方式
在本说明书通篇中,当将组合物描述为具有、包括或包含特定组分时,或当将方法描述为具有、包括或包含特定步骤时,另外预期存在基本上由所列举的组分组成或由其组成的本发明组合物,且存在基本上由所列举的处理步骤组成或由其组成的本发明方法。
应理解,只要本发明保持可操作,各步骤的顺序或执行某些动作的顺序并不重要。此外,可同时实施两个或更多个步骤或动作。
本文中所提到的例如[背景技术]章节中的任何公开案并非承认所述公开案充当关于本文中所呈现的任一技术方案的现有技术。[背景技术]章节是出于清楚目的而呈现且并非意指为对关于任一技术方案的现有技术的描述。
本文所述的各个实施例使用经FDA-IND批准的超小纳米粒子,例如C和C’点。本文所述的各个实施例展示其适用于药物递送应用且进行检查以下各项的详细细胞生物学分析:(1)细胞和异种移植物模型如何响应一系列浓度和时间(例如,数天至数周)内的黑色素瘤靶向C'点(例如,α-MSH-PEG-C'点)处理,和(2)粒子摄入是否影响细胞路径。
本文描述用α-MSH-PEG-C’点处理细胞和饥饿氨基酸的组合协同作用以诱导细胞死亡程序铁死亡。另外,本文展示使用适应黑色素瘤靶向肽的亚10nm直径荧光(含有Cy5染料)二氧化硅纳米粒子(例如,C'点)对细胞的浓度和时间依赖性处理作用。本发明描述高浓度的超小纳米粒子(例如直径小于10nm,例如C点或C’点)通过铁死亡机制诱导细胞死亡的方式,其涉及铁、活性氧类和细胞死亡执行的同步模式。在某些实施例中,高浓度是个体的肿瘤组织中在0.18μM至1.8μM范围内的局部浓度(其中此范围是基于本文所述的小鼠研究的估计值)。在某些实施例中,高浓度是在肿瘤组织中至少0.18μM、至少0.3μM、至少0.4μM、至少0.5μM或至少0.6μM的局部浓度;例如,其中纳米粒子是基于二氧化硅的,例如其中纳米粒子是C点或C’点。在某些实施例中,局部浓度依赖于肿瘤类型和/或个体。
本发明描述,高浓度的这些粒子通常在营养素充足培养基中培养的非癌细胞和癌细胞二者中充分耐受。粒子处理和代谢(例如,氨基酸)剥夺的组合协同作用以高速率杀死癌细胞。不受限于理论,摄入的纳米粒子定位于溶酶体网络,但并不抑制溶酶体功能,且纳米粒子诱导的死亡独立于自体吞噬路径发生。
为确定这些作用是否延伸至体内营养素耗尽条件,自粒子暴露的癌细胞或使用粒子多投药策略静脉内处理来产生异种移植物。为此,观察到浓度依赖性持续生长抑制,且发生与部分肿瘤消退偶合的肿瘤生长动力学阻抑。因此,这些数据展示,在高浓度和营养素剥夺条件下使用的基于二氧化硅的超小表面官能化纳米粒子通过铁死亡机制诱导细胞死亡。
在某些实施例中,纳米粒子包含二氧化硅、聚合物(例如,聚(乳酸共乙醇酸)(PLGA))、生物剂(例如,蛋白质载剂)和/或金属(例如,金、铁)。在某些实施例中,纳米粒子是如布莱伯利(Bradbury)等人的美国公开案第2013/0039848 A1号中所述的“C点”,所述公开案以引用方式并入本文中。
在某些实施例中,纳米粒子为球状。在某些实施例中,纳米粒子是非球状。在某些实施例中,纳米粒子为或包含选自由以下组成的群组的材料:金属/半金属/非金属、金属/半金属/非金属-氧化物、-硫化物、-碳化物、-氮化物、脂质体、半导体和/或其组合。在某些实施例中,金属选自由以下组成的群组:金、银、铜和/或其组合。
纳米粒子可包含金属/半金属/非金属氧化物,包括二氧化硅(SiO2)、二氧化钛(TiO2)、氧化铝(Al2O3)、氧化锆(ZrO2)、氧化锗(GeO2)、五氧化二钽(Ta2O5)、NbO2等;和/或非氧化物,包括金属/半金属/非金属硼化物、碳化物、硫化物和氮化物,例如钛和其组合(Ti、TiB2、TiC、TiN等)。
纳米粒子可包含一或多种聚合物,例如一或多种根据21 C.F.R.§177.2600已经美国食品药品管理局(U.S.Food and Drug Administration,FDA)批准用于人类中的聚合物,包括(但不限于)聚酯(例如,聚乳酸、聚(乳酸共乙醇酸)、聚己酸内酯、聚戊内酯、聚(1,3-二噁烷-2-酮));聚酸酐(例如,聚(癸二酸酐));聚醚(例如,聚乙二醇);聚氨基甲酸酯;聚甲基丙烯酸酯;聚丙烯酸酯;聚氰基丙烯酸酯;PEG和聚(环氧乙烷)(PEO)的共聚物。
纳米粒子可包含一或多种可降解聚合物,例如某些聚酯、聚酸酐、聚原酸酯、聚磷腈、聚磷酸酯、某些聚羟酸、聚富马酸丙酯、聚己酸内酯、聚酰胺、聚(氨基酸)、聚缩醛、聚醚、生物可降解聚氰基丙烯酸酯、生物可降解聚氨基甲酸酯和多糖。例如,可使用的特定生物可降解聚合物包括(但不限于)聚赖氨酸、聚(乳酸)(PLA)、聚(羟乙酸)(PGA)、聚(己酸内酯)(PCL)、聚(丙交酯-共-乙交酯)(PLG)、聚(丙交酯-共-己酸内酯)(PLC)和聚(乙交酯-共-己酸内酯)(PGC)。另一实例性可降解聚合物是聚(β-氨基酯),其可适用于本申请案中。
在某些实施例中,纳米粒子可具有或经修饰具有一或多个官能基。所述官能基(在纳米粒子表面内或上)可用于与任何药剂(例如,可检测实体、靶向实体、治疗实体或PEG)缔合。除通过引入或修饰表面官能基改变表面电荷外,引入不同官能基容许偶联连接体(例如,(可裂解或(生物)可降解)聚合物,例如(但不限于)聚乙二醇、聚丙二醇、PLGA等)、靶向/归巢剂和/或其组合。
在某些实施例中,纳米粒子包含一或多个靶向配体(或部分)(例如,与其附接),例如(但不限于)小分子(例如,叶酸盐、染料等)、适体(例如,A10、AS1411)、多糖、小生物分子(例如,叶酸、半乳糖、二碳磷酸盐化合物、生物素)、寡核苷酸和/或蛋白质(例如,(多)肽(例如,αMSH、RGD、奥曲肽、AP肽、表皮生长因子、氯毒素、转铁蛋白等)、抗体、抗体片段、蛋白质等)。在某些实施例中,纳米粒子包含一或多种对比/成像剂(例如,荧光染料、(螯合)放射性同位素(SPECT、PET)、MR活性剂、CT剂)和/或治疗剂(例如,小分子药物、治疗(多)肽、治疗抗体、(螯合)放射性同位素等)。
在某些实施例中,使用PET(质子发射断层摄影术)示踪剂作为成像剂。在某些实施例中,PET示踪剂包含89Zr、64Cu、[18F]氟脱氧葡萄糖。在某些实施例中,纳米粒子包括这些和/或其它放射性标记。在某些实施例中,一或多个靶向配体(或部分)可具有相同类型或可为不同种类。
在某些实施例中,纳米粒子包含一或多个荧光团。荧光团包含荧光染料、荧光染料猝灭剂分子、任何有机或无机染料、金属螯合物或任何荧光酶底物,包括蛋白酶可激活酶底物。在某些实施例中,荧光团包含长链嗜碳酸气酞菁。在其它实施例中,荧光团包含DiI、DiR、DiD等。荧光染料包含远红和近红外荧光染料(NIRF)。荧光染料包括(但不限于)碳菁和靛菁荧光染料。在某些实施例中,成像剂包含市售荧光染料,包括(但不限于)Cy5.5、Cy5和Cy7(GE医疗(GE Healthcare));AlexaFlour660、AlexaFlour680、AlexaFluor750和AlexaFluor790(英杰(Invitrogen));VivoTag680、VivoTag-S680和VivoTag-S750(维森医药(VisEn Medical));Dy677、Dy682、Dy752和Dy780(戴欧米克斯(Dyomics));DyLight547、DyLight647(皮尔斯(Pierce));HiLyte Fluor 647、HiLyte Fluor 680和HiLyte Fluor750(阿钠拜客(AnaSpec));IRDye 800CW、IRDye 800RS和IRDye 700DX(拉哥(Li-Cor));以及ADS780WS、ADS830WS和ADS832WS(美国染料来源(American Dye Source))和Kodak X-SIGHT 650、Kodak X-SIGHT 691、Kodak X-SIGHT 751(锐珂医疗(Carestream Health))。
在某些实施例中,纳米粒子包含(例如,已附接)一或多个例如用于靶向所关注癌症组织/细胞的靶向配体。
可治疗的癌症包括例如前列腺癌、乳癌、睾丸癌、子宫颈癌、肺癌、结肠癌、骨癌、神经胶质瘤、胶质母细胞瘤、多发性骨髓瘤、肉瘤、小细胞癌、黑色素瘤、肾癌、肝癌、头颈癌、食管癌、甲状腺癌、淋巴瘤、胰脏(例如,BxPC3)、肺(例如,H1650)和/或白血病。
在某些实施例中,纳米粒子包含治疗剂,例如药物(例如,化学治疗药物)和/或治疗性放射性同位素。如本文所用“治疗剂”是指在投与个体时具有治疗作用和/或引发所需生物和/或药理学作用的任一药剂。
在例如使用组合疗法的某些实施例中,实施例治疗方法包括投与纳米粒子和投与一或多种药物(例如,单独或偶联至纳米粒子),例如一或多种化学治疗药物,例如索拉菲尼(sorafenib)、紫杉醇、多西他赛、MEK162、依托泊苷、拉帕替尼(lapatinib)、尼罗替尼(nilotinib)、克唑替尼(crizotinib)、氟维司群(fulvestrant)、威罗菲尼(vemurafenib)、贝沙罗汀(bexorotene)和/或喜树碱(camptotecin)。
可调整纳米粒子的表面化学、涂层均匀性(当存在涂层时)、表面电荷、组合物、浓度、投与频率、形状和/或大小以产生所需治疗作用,例如癌细胞的铁死亡。
在某些实施例中,将纳米粒子药物偶联物(NDC)用于药物递送应用。关于NDC的细节描述于例如国际公开案WO 2015/183882 A1中,所述公开案的内容的全文以引用方式并入本文中。
实例
如本文所述,使用MC1-R靶向C'点来增强细胞摄取(图1A)。经粒子处理24小时的表达MC1-R的人类黑色素瘤细胞(M21)的实时成像揭露α-MSH-PEG-C'点与溶酶体的共定位。共定位通过加GFP标签的溶酶体缔合的膜蛋白1(LAMP1)的表达可视化以指示经摄入粒子驻留于溶酶体或次级胞内体网络中(图1B)。经递增浓度的α-MSH-PEG-C'点粒子(至多15μM)处理的M21细胞显示与在对照细胞中所观察到的速率相似的存活和增殖速率(图1C-1E)。这些结果展示与高浓度的这些纳米粒子一起培育为细胞充分耐受。随后检查溶酶体在经α-MSH-PEG-C’点处理的细胞内是否正确地发挥功能。为确定此,检查靶向用于溶酶体降解的细胞内底物的自体吞噬路径。自体吞噬是通过量化自体吞噬蛋白微管相关蛋白1轻链3(LC3)的基底水平和更新速率来检查,所述自体吞噬蛋白微管相关蛋白1轻链3脂化至自体吞噬体膜上且在自体吞噬体与溶酶体融合后变得降解。通过西方墨点,将LC3的自体吞噬体相关脂化形式(称为LC3-II)的积累量化为相对于细胞溶质非脂化形式(称为LC3-I)通过溶酶体的通量的量度或自体吞噬诱导的量度(图1F-1H)。
以溶酶体依赖性方式出现的LC3-II的更新还可测量为溶酶体功能的读数。当溶酶体正确地发挥功能时,用抑制溶酶体空泡型H+-ATPase(V-ATPase)的溶酶体抑制剂(例如刀豆素A(ConA))处理因缺少降解而引起LC3-II积累。相比之下,如果溶酶体功能失调,那么用ConA处理不会改变LC3-II水平。经递增浓度的α-MSH-PEG-C'点(自0.15μM至15μM)处理24小时的细胞具有与对照细胞相比相似的相对LC3-II水平,此表明纳米粒子处理并不诱导或扰乱自体吞噬。用通过增加pH抑制溶酶体功能且阻断自体吞噬体降解的溶酶体抑制剂ConA处理细胞产生经粒子处理的细胞中与对照相比相似的LC3-II积累,此展示即使在细胞负载有高浓度的α-MSH-PEG-C’点时,溶酶体仍正确地发挥功能(图1F-1H)。
随后,将纳米粒子投与在营养素剥夺条件下培养的细胞以诱导自体吞噬。用α-MSH-PEG-C'点处理在无氨基酸培养基中培养的细胞且通过时差成像来检查。尽管在粒子不存在下M21细胞对氨基酸剥夺充分耐受,但用15μM对营养素充足培养基中的细胞不具作用的α-MSH-PEG-C'点处理氨基酸剥夺细胞会引起高速细胞死亡。通过Sytox绿(一种标记具有破裂的质膜的细胞的膜可渗透核酸染料)的摄取来检测细胞死亡(图1I-1J)。此展示尽管α-MSH-PEG-C'点通常是充分耐受的,但营养素剥夺癌细胞对处理敏感。为确定此发现是否对体内肿瘤生长具有影响,将M21黑色素瘤细胞与α-MSH-PEG-C'点一起培育于对细胞活力不具作用的营养素充足条件下的培养物中(图1C-1E和图8E-8F),且然后将粒子暴露的细胞以及粒子未暴露的细胞作为侧腹肿瘤异种移植物注射至小鼠中以促进营养素剥夺状态。负载有αMSH-PEG-C’点的M21黑色素瘤细胞展示相对于非粒子暴露细胞统计学上显著的生长抑制(p<0.001)。直至在细胞注射后10天未发现粒子暴露细胞的可测量肿瘤生长。不受限于理论,这些发现表明,在营养素剥夺条件下在培养物中和体内用高浓度的α-MSH-PEG-C'点处理可诱导细胞死亡。
随后,研究在营养素剥夺条件下经α-MSH-PEG-C'点处理的细胞如何经历细胞死亡的机制。不受限于理论,正在死亡的细胞的形态检验表明坏死的形式,此导致细胞膨胀并质膜破裂但无通常在细胞凋亡期间所观察到的细胞起泡和片段化(图2A和图8A)。为更明确地鉴别细胞死亡的机制,使用两个非肿瘤细胞系MCF10A人类乳腺上皮细胞和小鼠胚胎成纤维细胞(MEF)且在无氨基酸培养基中在α-MSH-PEG-C'点存在下培养时也观察到高速死亡(图2B-2C)。细胞通过过表达抗细胞凋亡蛋白Bcl-2(MCF10A-Bcl2)来抵抗细胞凋亡(图8B)或通过基因缺失Bax和Bak(Bax/Bak-/-MEF)以与对照细胞相似的速率经历细胞死亡,此表明α-MSH-PEG-C'点诱导的细胞死亡并非通过细胞凋亡进行(图2D和图2E)。
随后,确定细胞死亡是否通过程序性坏死(一种需要RIPK3激酶的程序性坏死形式)发生。与Bax/Bak-/-MEF相似,对程序性坏死有抗性的Ripk3-/-敲除MEF(图8C)还以与对照相比相似的速率经历细胞死亡。不受限于理论,此结果表明,纳米粒子处理不会诱导程序性坏死(图2F)。
随后,确定通过在氨基酸不存在下用α-MSH-PEG-C'点处理完全缺失自体吞噬的自体吞噬相关基因5敲除MEF(Atg5-/-MEF)是否可涉及最近描述的涉及自体吞噬路径的细胞死亡形式(称为自死亡)。Atg5-/-MEF以与对照细胞相似的速率经历细胞死亡,此展示α-MSH-PEG-C'点诱导的细胞死亡并不涉及自体吞噬,且并非自死亡(图2F)。总之,这些数据展示由α-MSH-PEG-C'点处理和氨基酸剥夺的组合诱导的细胞死亡独立于细胞凋亡、程序性坏死和自死亡发生。
随后确定铁死亡(最近描述的通过铁和脂质活性氧类(ROS)依赖性过程发生的细胞死亡机制)是否由谷胱甘肽耗尽诱导且参与α-MSH-PEG-C'点诱导的细胞死亡。首先确定在此背景下菲乐斯他镇-1和利普司他汀-1(铁死亡的药理学抑制剂,其为脂质ROS的清除剂)是否可阻断细胞死亡。用菲乐斯他镇-1或利普司他汀-1处理会拯救细胞活力,从而使细胞死亡减少至在氨基酸剥夺条件下在纳米粒子不存在下出现的水平(图3A、图8G)。
还通过用其它抗氧化剂(包括丁羟茴醚(BHA)、抗坏血酸(Asc Acid)和trolox)或或者通过添加谷胱甘肽或N-乙酰基半胱氨酸(NAC)(谷胱甘肽的前体)使谷胱甘肽过饱来抑制纳米粒子诱导的细胞死亡(图2B-2C)。为检查脂质ROS是否在纳米粒子诱导的细胞死亡期间积累,使粒子暴露的细胞在脂质氧化指示剂C11-BODIPY存在下成像。在细胞死亡之前观察到增加的染色响应已知铁死亡诱导剂爱拉斯汀以利普司他汀-1可抑制方式发生(图3F-G、图8H)。与由爱拉斯汀处理诱导的细胞死亡一样,通过C11-BODIPY染色检测的脂质ROS在无氨基酸条件下通过纳米粒子处理诱导细胞死亡之前几小时积累(图3F-3G)。为进一步检查纳米粒子诱导的死亡是否依赖于铁(铁死亡的一个必要条件),发现经去铁胺(DFO)(用于处理铁过载的铁螯合剂)和经报道阻断铁死亡的药剂处理的细胞几乎完全抑制细胞死亡(图3B)。这些数据展示用高α-MSH-PEG-C'点浓度处理氨基酸饥饿细胞诱导铁死亡(图3C)。应注意,还观察到在此背景下铁死亡以波形方式自细胞至细胞扩散(图3D和3E),此与对经历其它类型的死亡(例如细胞凋亡)的细胞所发现不同(图8D)。不受限于理论,此表明死亡诱导信号的细胞至细胞通信。
在确定MCF10A细胞和MEF通过铁死亡经历细胞死亡后,确定在较宽癌细胞组中是否可以此方式通过氨基酸剥夺和纳米粒子处理诱导细胞死亡。例如,在氨基酸不存在下用α-MSH-PEG-C'点处理时,MCF10A、MEF和M21细胞、BxPC3胰脏癌细胞、H1650肺癌细胞、HT1080纤维肉瘤细胞和786-O肾癌细胞也经历高速坏死。此数据指示,可在多个不同癌细胞类型中在氨基酸不存在下通过纳米粒子诱导细胞死亡(图4A-4F、图6C-6E)。
应注意,在完全培养基中(图4E-4F)和在饥饿培养基中在10倍较低粒子浓度下(图6B)培养时,HT-1080细胞响应纳米粒子处理经历坏死,此表明这些细胞对此形式的细胞死亡尤其敏感。
基于这些结果,进一步确定在786-O肾癌和HT1080纤维肉瘤异种移植物模型中是否可产生粒子诱导的治疗反应。使用多投药递送方案,在带有侧腹786-O或HT-1080肿瘤的免疫阻抑小鼠中在靶向粒子探针(n=5)或0.9%盐水溶液(n=3)的三次高剂量静脉内(i.v.)治疗后10天时段内评价肿瘤生长。相对于在注射盐水媒剂后测量的随时间快速增加的肿瘤体积,在实验区间内利用多剂量粒子处理对于两个肿瘤类型观察到统计学上显著的肿瘤生长抑制(图5A、5B、5I、5K),但对于HT-1080异种移植物观察到更大的肿瘤生长抑制。应注意,此是通过在初始注射后4至5天区间内对于所有经粒子处理的HT-1080肿瘤超过50%(例如,57%-78%的部分肿瘤消退的范围;具有约64%的平均部分肿瘤消退)的部分肿瘤消退来实现(图5B)。在实验区间的剩余时间,经粒子处理的肿瘤体积减小。例如,截至10天实验时段结束时,经处理的HT-1080肿瘤体积显示相对于对照体积统计学上显著的约85%减小(p<0.001),且经处理的786-O肿瘤体积显示统计学上显著的约73%减小(p<0.01)(图5A、5B)。在初始αMSH-PEG-C’点注射后,带有HT1080侧腹异种移植物的小鼠的代表性全身光学成像展示肿瘤放置位点处强烈的荧光信号,此表明静脉内注射粒子的定位(图5C)。
代表性对照(n=1)和经处理(n=2)肿瘤(图5D)的相应H&E染色组织切片揭露展现多病灶坏死的致密细胞和侵入性赘瘤。对照肿瘤平均显著大于经处理肿瘤且无明显形态差异。针对巨噬细胞标记物Mac-2的免疫组织化学染色揭露,在低和高放大倍数二者下,相对于在对照肿瘤周围所见较大数量的经处理肿瘤周围的招募巨噬细胞(图5E-5H)。肿瘤内Mac-2阳性细胞以类似地少量存在于所有肿瘤中。
为进一步检查由纳米粒子处理引起的肿瘤生长抑制是否可与铁死亡相关,在10天时段内用每日利普司他汀-1腹膜内(i.p.)给药治疗带有肿瘤的小鼠以确定对粒子诱导的肿瘤皱缩的作用。在随后投与三次高剂量粒子处理的HT1080异种移植小鼠(n=3)中,利普司他汀-1使生长抑制显著减少至几乎等效于在未暴露于粒子的肿瘤中所见的水平的水平(图5I)。经利普司他汀-1处理的粒子暴露肿瘤的平均每日生长为14.6mm3(95%CI:10.1-18.9)与单独粒子处理的-0.87mm3(95%CI:-1.06至-0.69)相比差15.3mm3(CI:13.1至17.6;p<0.001)。相应粒子暴露的肿瘤样本平均显著小于接受每日利普司他汀-1的经粒子处理的肿瘤(图5J)。
α-MSH-PEG-C’点和氨基酸饥饿对细胞的组合处理协同作用以诱导细胞死亡程序铁死亡且高剂量递送纳米粒子可抑制肿瘤生长并引起肿瘤消退;这些作用在利普司他汀-1存在下可发生逆转。例如,在此背景下铁死亡诱导对营养素剥夺和纳米粒子处理的组合需要可接合体内肿瘤细胞,同时保留正常细胞(例如,这是因为已知与正常组织相比肿瘤组织经历代谢应激且营养素受限)。还显示,当用促进靶向的配体修饰时,超小靶向二氧化硅纳米粒子自身优先在肿瘤组织中比非肿瘤组织更有效地积累。
如本文所述,发现在静脉内递送后纳米粒子在HT1080异种移植物内的积累显著抑制肿瘤生长且诱导部分肿瘤消退。再添加利普司他汀-1使这些作用逆转至几乎等效于在未暴露于粒子的肿瘤中所见的水平的水平。这些发现强调在所选癌症类型中所观察到的粒子处理与营养素剥夺之间的潜在协同作用,且不必受限于理论,通过利用所述代谢策略,铁死亡的接合可保持治疗潜能。
经粒子处理的肿瘤周围的巨噬细胞数相对于对照肿瘤周围显著增加的重要性并不完全清楚,但已充分确立其通过吞没细胞碎片在疾病保护和伤口修复中的作用。可进一步认为,高度巨噬细胞可塑性可响应来自肿瘤微环境的局部线索而存在,且在激活时,巨噬细胞可假设维持组织稳态所需的一系列作用,包括其与肿瘤皱缩相关的功能的转变。这些数据呈现分子靶向C’点的治疗应用,已在临床试验中用于癌症成像和检测,但例如无需表面附接的细胞毒性剂。
在某些实施例中,本文所述的纳米粒子诱导铁死亡。用靶向癌症的αMSH肽对粒子表面修饰会增强细胞内化(数据未显示)。使用αMSH的粒子表面修饰并非所测试细胞系的铁死亡所必需,这是因为其使用未经αMSH靶向配体修饰的PEG涂布的C’点的诱导已出现,但速率较缓慢,此可反映基底粒子相对于α-MSH修饰平台的较缓慢内化(图7F)。
因此,在某些实施例中,天然二氧化硅粒子自身具有铁死亡诱导活性,这是因为去质子化表面硅烷醇基团和/或分形内部结构可引起铁吸附和/或纳入其结构内。发现与双去离子水制剂相比与培养基一起培育的α-MSH-PEG-C'点纳米粒子的铁负载(图7G、图8A-8F)。当与氧化铁溶液一起培育时,增加的铁负载以浓度依赖性方式出现,此通过减小铁负载能力实现(图8A-8F)。另外,对经α-MSH-PEG-C'点纳米粒子处理的细胞发现与未经处理的细胞相比增加的细胞内铁水平(图7G,表1)。另外,经粒子处理的细胞使结合细胞溶质铁的铁蛋白重链(FTH1)的表达上调(图7H)。还发现在氨基酸饥饿细胞中通过用柠檬酸铁铵(FAC)处理使铁负载至细胞中足以模拟粒子处理且诱导铁死亡(图7I),此表明这些基于二氧化硅的纳米粒子可通过将铁负载至细胞中接合铁死亡。增加的铁摄取可耗尽谷胱甘肽,认为此归因于增加的ROS产生。发现在经粒子处理的细胞中谷胱甘肽水平受阻(图7D-7E),且用通过阻断胱氨酸摄取抑制谷胱甘肽产生的爱拉斯汀预处理使细胞对粒子诱导的铁死亡敏感,此表明谷胱甘肽耗尽对粒子诱导的死亡有限速作用(图7J)。
表1显示通过微波等离子体原子发射光谱(MP-AES)测量的铁浓度。
表1
BDL,低于检测限值;NA,不适用
*存在于未经稀释的完全和无AA培养基中的铁为8.6μM
总之,本文所述的实例性数据支持由粒子处理诱导的铁死亡涉及铁摄取至细胞中、引起谷胱甘肽阻抑和脂质ROS积累从而执行铁死亡的模型(图4G)。脂质ROS可在谷胱甘肽阻抑细胞中积累,此归因于保护细胞免于脂质过氧化作用且抑制铁死亡的谷胱甘肽过氧化物酶4(GPX4)的降低的活性。未发现在经处理细胞溶解物的酶分析中粒子处理抑制GPX4活性(图7K)。同样未发现,粒子处理的模型不会通过直接抑制GPX4引起脂质过氧化作用。
一些癌症(例如,HT1080、786-0)也可对此细胞死亡机制尤其敏感,此可降低实现抗肿瘤作用所需的粒子浓度的阈值。发现HT-1080癌细胞即使在营养素充足条件下仍经历α-MSH-PEG-C'点诱导的铁死亡(图4E-4F),且这些细胞还在氨基酸剥夺条件中在10倍较低纳米粒子浓度下被杀死(图6B)。HT-1080肿瘤充分血管化(图9B),此表明即使在营养素充足条件下,这些癌细胞对粒子诱导的死亡的敏感性(图4E-4F)仍可有助于在静脉内粒子递送后所观察到的强抗肿瘤作用。
尽管本文所用纳米粒子的浓度经选择以诱导体外细胞死亡(例如,15μM)或抑制体内肿瘤生长抑制和消退(例如,60μM)且比当前人类个体中用于基于单一剂量成像的分析的浓度高至少四个数量级,但作为多投药策略、组合治疗方案的一部分和/或通过靶位点的直接导管输注,肿瘤位点处的局部浓度可被推动到更高水平。所述投药时间表可经设计以产生最大肿瘤对背景比率,同时降低脱靶毒性且促进有效肾清除。应注意,肿瘤脉管系统的泄露可容许全身注射的纳米粒子在肿瘤组织中积累且还有助于肿瘤内的营养素剥夺。不受限于理论,此进一步表明,纳米粒子和营养素剥夺的协同作用可限于体内肿瘤位点。还发现,不同肿瘤细胞系在表观上对铁死亡诱导机制的敏感性可不同。例如,发现通过氨基酸剥夺和α-MSH-PEG-C'点的组合处理,卵巢癌细胞系SKOV3显示对细胞死亡的抗性(图6A)。相比之下,HT1080纤维肉瘤细胞即使在营养素充足条件下(图4E-4F)和在氨基酸剥夺条件中在10倍较低纳米粒子浓度(1.5μM)下仍经历α-MSH-PEG-C'点纳米粒子诱导的铁死亡(图6B)。在此情况下,靶向粒子摄取至HT1080细胞中可能通过非特异性胞吞途径进行。由于铁死亡是铁依赖性细胞死亡,不受限于理论,不同易感性可部分归因于可用于细胞中的铁量。例如,铁是细胞稳态的必需组分,但还可产生可损害细胞器的ROS。细胞可通过摄取、输出或自储存器移位至不稳定铁池(LIP)调控铁利用度且这些过程中的一些在癌症中发生变化。癌基因c-myc和E1a降低主要细胞溶质铁储存蛋白铁蛋白的水平,所述铁蛋白可使铁自储存器移位至代谢活性LIP,且抑制铁蛋白可通过激活DNA合成刺激Ras依赖性增殖。铁死亡诱导药物最初是在小分子筛选中发现,其赋予选择性杀死Ras驱动的肿瘤细胞。另外,在上述所测试癌细胞系中,HT1080是唯一具有Ras突变的细胞系。因此,确定具有突变体Ras的癌细胞通常是否对纳米粒子处理更敏感。
已显示一些纳米材料(例如,直径约63nm(例如,数量级大于C'点)的未经涂布的二氧化硅粒子)诱导细胞中的ROS。相比之下,在经亚10-nm直径的α-MSH-PEG-C'点处理24小时的细胞中未检测到增加的细胞溶质或脂质ROS水平(图7A-7C)。如上文所述,发现氨基酸饥饿和纳米粒子处理均降低细胞中的谷胱甘肽水平,且还具有加和作用(图7D-7E)。不受限于理论,此数据表明,在此背景下可至少部分地通过谷胱甘肽耗尽触发细胞死亡,此与通过限制半胱氨酸摄取抑制谷胱甘肽产生的铁死亡诱导剂爱拉斯汀相似。
在体内用靶向癌症的αMSH肽对本文所用的纳米粒子进行表面修饰。还显示此修饰增强细胞摄取(数据未显示)。此粒子表面修饰似乎并不参与铁死亡,这是因为利用未经αMSH靶向配体修饰的PEG涂布的C’点也观察到铁死亡诱导。然而,由不具αMSH修饰的PEG涂布的C’点引起的死亡在细胞群体内以较缓慢动力学发生,此归因于基底粒子与表达MC1-R的黑色素瘤细胞中为α-MSH修饰平台的粒子相比降低的摄取速率(图7F)。另一方面,发现粒子大小在氨基酸剥夺条件下诱导铁死亡方面起关键作用。相对于在暴露于较小直径(约6nm)聚乙二醇化C’点后48小时发现的Sytox绿标记的HT1080细胞的高百分比(例如,80%),在与较大直径(约10nm)粒子一起培育后发现的经标记细胞的百分比低得多,约为25%,仅比未经处理的细胞稍有增加(图9A-9C)。
尽管认为一些癌症的敏感性可降低发挥抗肿瘤作用所需的粒子浓度,但还发现多个高剂量治疗是充分耐受的。在实验实例结束时进行经粒子和媒剂处理的带有HT-1080-和786-O的小鼠的肝、肾和血液学肿瘤样本的评估。未发现与对照动物相比全血计数、血清化学以及肝和肾组织病理学方面的显著组差异,只是间接和总胆红素血清浓度在经粒子处理的小鼠中适当升高(表2、表3)。然而,鉴于缺少溶血作用(关于全血计数)且不存在肝损伤(关于组织病理学和血清化学),没有机制可解释此发现。因此,这些发现表明,多个高剂量α-MSH-PEG-C'点处理是充分耐受的。还汇总经粒子处理(显著)和经媒剂处理(轻度)的肿瘤样本中巨噬细胞染色的程度(表4)。
表2显示带有肿瘤的小鼠中的代谢浓度特征、肾特征和肝功能特征。
表2
Na,钠;K,钾;Cl,氯;TC02,总二氧化碳;Ca,钙;P,磷;GLU,葡萄糖;BUN,血尿素氮;Crea,肌酸酐;ALP,碱性磷酸酶;AST,天冬氨酸氨基转移酶;ALT,丙氨酸氨基转移酶;GGT,γ-谷氨酰基转移酶;TBIL,总胆红素;DBIL,直接胆红素;IBIL,间接胆红素;TP,总蛋白质;ALB,白蛋白;GLOB,球蛋白;CHOL,胆固醇;TRIG,三酸甘油酯;CK,肌酸激酶;*,相对于正常值升高
表3显示带有肿瘤的小鼠中的血液学特征
表3
RBC,红血细胞;HGB,血红蛋白浓度;HCT,血细胞比容;MCV,平均血细胞体积;MCH,平均血细胞血红蛋白;MCHC,平均血细胞血红蛋白浓度;ROW-SD和ROW-CV,红血细胞分布宽度标准偏差和变异系数;RET,网织红细胞相对和绝对计数;PLT,血小板计数;POW,血小板分布宽度;MPV,平均血小板体积;WBC,白血细胞;和NEUT,中性白细胞,LYMPH,淋巴细胞,MONO,单核细胞,EO,嗜酸性粒细胞,BASO,嗜碱性粒细胞的相对和绝对计数
表4显示带有肿瘤的小鼠的组织病理学特征。
表4
SQ,皮下;N,正常;Mac2,巨噬细胞免疫组织化学标记物;N:正常,F:病灶,FE:病灶广泛,MF:多病灶,MFR:多病灶随机,D:弥漫,U:单向,1:最轻,2:轻度,3:中度,4:显著。
可确定C点帮助铁死亡的机制以鉴别出其它种类的纳米材料是否可具有类似作用以诱导此形式的细胞死亡以及粒子结构、组成或表面化学性质的其它受控变化是否可改变或甚至消除铁死亡的诱导。不希望受限于任一理论,纳米粒子诱导的铁死亡作为细胞命运的氧化还原作用调节剂以及肿瘤消退和生长抑制的调介剂的能力表明,可在治疗上利用此过程以同步且选择性杀死最易受此机制影响的那些癌症敏感的癌症。
在某些实施例中,肿瘤血管化影响粒子递送、营养素和氧状况以及治疗反应。在某些实施例中,跨越多个临床前肿瘤类型评价肿瘤血管化提供改良的适于通过铁死亡诱导细胞死亡的模型的筛选。在某些实施例中,评价鉴别出适宜组合治疗范例。
在某些实施例中,C’点性质(例如,结构、组成或表面化学)的受控变化增强或消除铁死亡的诱导。发现例如,C’点大小在氨基酸剥夺条件下所观察到的作用量值中起关键作用(图9A)。较小直径(约6nm)聚乙二醇化C’点产生与对较大直径(约10nm)C’点所发现(约25%)相比显著较高的Sytox绿标记的HT-1080细胞百分比(约80%)。
另外,尽管对利普司他汀-1的反应为铁死亡提供实例作为体内抗肿瘤机制,但其它机制可有帮助,包括(但不限于)调节肿瘤微环境,给予经粒子处理的肿瘤显著巨噬细胞招募(图5G和5H,HT-1080;图9C,786-O)。
在某些实施例中,可将组合疗法投与个体以促进铁诱导。例如,可将药物(例如,TAS-102)投与肿瘤细胞,且然后可投与足够高浓度的纳米粒子以诱导铁死亡。关于TAS-102的细节可参见“用于难治性转移性结肠直肠癌的TAS-102的随机化试验”,R.J.梅尔(R.J.Mayer)等人,新英格兰医学杂志(NEJM),2015年5月14日,所述参考文献的内容以引用方式并入本文中。另外,可剥夺肿瘤的激素(例如,阉割),且相对于未暴露于激素或抑制剂治疗的肿瘤,将足够高浓度的纳米粒子投与肿瘤可诱导和/或甚至增强铁细胞死亡程序。
不希望受限于任一具体理论,假定激素阉割(和/或营养素,例如氨基酸剥夺)通过过表达内化附近粒子的受体使细胞得以补偿。在某些实施例中,可另外利用铁对铁死亡的作用。例如,在替代性实施例中,某些细胞类型可不需要在代谢或激素方面经剥夺来内化纳米粒子用于诱导铁死亡。
肿瘤微环境和巨噬细胞可塑性/激活的纳米粒子调节
不同巨噬细胞子集与癌症中的保护或致病作用相关。经典激活的“促炎症”M1表型巨噬细胞具有抗肿瘤免疫作用,从而在肿瘤发生中提供保护作用。这些巨噬细胞激活肿瘤杀死机制且拮抗肿瘤相关巨噬细胞和骨髓源阻抑细胞的阻抑活性。M1巨噬细胞被类铎受体配体(例如脂多糖)和干扰素-γ激活,其放大辅助T细胞亚型TH1反应,提供抗肿瘤反应中的正反馈回路。另外,M1巨噬细胞尤其表达促炎症细胞因子和诱导性一氧化氮合酶。或者,激活的“促消退”巨噬细胞(M2巨噬细胞)具有抗炎症功能,从而调控伤口愈合。另外,其阻抑适应性肿瘤特异性免疫反应且促进肿瘤生长、侵入、转移、间质重塑和血管发生。
继续在动物模型中测试具和不具肿瘤靶向部分(例如,α黑色素细胞刺激激素)的二氧化硅纳米粒子以评价细胞死亡程序(例如,铁死亡)和药物疗法。如本文所述,少量Mac-2阳性巨噬细胞(一种鼠类巨噬细胞标记物)通过免疫组织化学染色显示于对照肿瘤周围的软组织中,同时经粒子处理的肿瘤被低和高放大倍数二者下的相同位置的更大量的Mac-2阳性细胞划定界限。经粒子处理的肿瘤周围相对于对照病灶周围的巨噬细胞数的此显著增加通过吞没细胞碎片在疾病保护和伤口修复中具有作用。可进一步认为,已知巨噬细胞响应来自肿瘤微环境的局部线索而展示高度可塑性(例如,代表一系列激活表型而非离散的稳定亚群)且可假设在激活时为维持组织稳态所需的一系列作用,包括其与肿瘤皱缩相关的功能的转变。
上述结果以及相关肿瘤生长抑制和皱缩对于组合超小二氧化硅纳米粒子大小(例如,6nm)与不同净电荷、大小和构象的表面官能基的此杂合无机-有机平台是完全出人意料的。在某些实施例中,可确定关于这些结果是否可仅归因于铁死亡或免疫调节和/或肿瘤微环境内的其它激活的代谢/非免疫过程是否起作用的机制。不希望受限于任一理论,C点物理化学性质(例如,大小、电荷、附接的表面化学部分)可响应来自肿瘤微环境的局部线索调节所述过程。
在某些实施例中,蛋白质冠(例如,IgG、白蛋白等)经测定是在全身性投与后在粒子表面周围形成,从而引起巨噬细胞(例如,促炎症(M1)和/或促消退(M2))的表型激活。在某些实施例中,确定在血液/等离子体样本、鼠类肿瘤组织、离体人类肿瘤组织样本中提取的粒子之间的巨噬细胞表型激活的特征差异。
在某些实施例中,确定和/或控制单核细胞/巨噬细胞对粒子存在的反应。在某些实施例中,确定和/或控制肿瘤微环境的其它组分的反应以实现杀肿瘤行为。在某些实施例中,治疗性纳米粒子的表面化学影响单核细胞/巨噬细胞反应。在某些实施例中,治疗性纳米粒子的表面化学经设计以控制单核细胞/巨噬细胞反应。
在某些实施例中,天然和/或表面官能化超小二氧化硅纳米粒子(例如,C点)激活巨噬细胞(例如,M1巨噬细胞)。在某些实施例中,存在高IL-12水平,这是因为IL-12刺激TH1细胞的IFNγ产生(例如,IL-10水平应较低)。在某些实施例中,测量iNOS表达以及TNFα、GM-CSF和LPS的水平。在某些实施例中,测量转录因子(例如,IRF-5、STAT-1)。在某些实施例中,测量M1细胞分泌的细胞因子(例如,IL-1、IL-6、Il-15、IL-18和IL-23)。M1巨噬细胞分泌吸引其它类型的免疫细胞和整合/协调免疫反应的促炎症细胞因子和趋化因子。M1巨噬细胞还表达高水平的主要组织相容性复合体(MHC)、共刺激分子和FcγR。
在某些实施例中,存在与M1表型相关的基因的上调和/或下调。在某些实施例中,信号传导路径和/或免疫效应物(例如p38MAPK、p44/p42MAPK、JNK)、CD40、CD80、CD86上调(例如,共刺激分子)和I-A/I-E激活标记物(例如,B细胞激活)由天然和/或表面官能化超小二氧化硅纳米粒子效应。
在某些实施例中,巨噬细胞激活依赖于TLR4(类铎受体4)和ROS信号传导以杀死细胞。在某些实施例中,LPS诱导的表型(例如,表达剖析)出现在暴露于天然和/或表面官能化超小二氧化硅纳米粒子时。
在某些实施例中,可测定C点对巨噬细胞伪足小体(例如,富含肌动蛋白的细胞表面结构,其使得能够通过细胞外基质降解形成和细胞外基质降解活性所需的递送因子迁移和侵入)的功能作用。
在某些实施例中,可使用表面官能化C点靶向患者的癌症相关炎症。
在某些实施例中,通过C点物理化学性质改变‘坏的’和‘好的’炎症过程以促进适应性免疫而非肿瘤发育。
在某些实施例中,药物递送(或其它疗法)与C点的天然免疫调节性质组合以增加C点在癌症治疗和/或组织修复过程(例如,伤口愈合)中的治疗潜能。
在某些实施例中,使用具有双模式粒子探针的剂量递增研究来研究PDGFB驱动的神经胶质瘤模型中的达沙替尼(dasatinib)-NDC和EGFRmt+临床前侧腹/脑异种移植物模型中的吉非替尼(dasatinib)-NDC二者在靶向治疗递送、穿透和最大治疗反应方面相对于天然药物的改良;在组织学上确认成像发现。还使用这些药剂进行药物代谢动力学研究以评价出人意料的毒性并评估粒子放射量测定。可向单独小鼠队列注射双模式粒子探针来追踪药物对粒子递送和分布以监测平台的稳定性。在肿瘤位点处预期增加的有效药物浓度是基于先前所观察到的优先肿瘤驻留和定量估计治疗投药需求的能力。
细胞培养物和构筑物
将MEF和HT1080细胞培养于补充有10%胎牛血清(FBS,西格玛(Sigma),圣路易斯,密苏里州)和青霉素(penicillin)/链霉素(streptomycin)(康宁(Corning),康宁市,纽约州)的达尔伯克氏改良伊格尔培养基(Dulbecco's modified Eagle's medium,DMEM)(MSKCC培养基制备设施(MSKCC Media Preparation Facility))中。将MCF10A细胞培养于补充有5%马血清(亚特兰大生物制品(Atlanta Biologicals),弗劳沃利布兰奇,乔治亚州)、20ng/ml EGF(派普泰克(Peprotech),罗基希尔(Rocky Hill),新泽西州)、10μg/ml胰岛素(西格玛)、0.5μg/ml氢化可的松(hydrocortisone)(西格玛)和100ng/ml霍乱毒素(西格玛)和青霉素/链霉素的DMEM/F12(Gibco,格兰德岛,纽约州)中。将M21、BxPC3、H1650和786-O细胞培养于补充有10%FBS和青霉素/链霉素的RPMI-1640(Gibco)中。将SKOV3细胞培养于补充有10%FBS和青霉素/链霉素的McCoy's 5a改良培养基(Gibco)中。通过以下方式制备无氨基酸培养基:将热灭活的FBS(对于MEF、HT1080、M21、BxPC3、H1650和SKOV3细胞)或马血清(对于MCF10A细胞)透析4h,然后在4℃下在磷酸盐缓冲盐水(PBS)中在MWCO 3500透析管(21-152-9;Fisherbrand,匹兹堡,宾夕法尼亚州)中培育过夜并添加至在无氨基酸下制备的基础培养基中。通过逆转录病毒转导将PRetro-Lamp1-GFP引入M21细胞中,且用嘌呤霉素(puromycin)(2μg ml-1)选择稳定细胞系。
试剂
使用所指示浓度的以下试剂:刀豆素A(ConA)(西格玛)100nM;SYTOX绿核酸染色(S7020;英杰,卡尔斯巴德,加利福尼亚州)5nM;菲乐斯他镇-1(Fer-1)(EMD密理博(EMDMillipore),比尔里卡,马萨诸塞州)1μM;利普司他汀-1(艾克索(Selleckchem)),对于体外和体内分别为1μM和125mg/kg;去铁胺(DFO)(西格玛)100μM;丁羟茴醚(BHA)(西格玛)50μM;抗坏血酸(Asc Acid)(西格玛)200μM;Trolox(西格玛)100μM;N-乙酰基半胱氨酸(NAC)(西格玛)10mM;谷胱甘肽(GSH)(西格玛)5mM;TNFα(西格玛)100ng/ml;环己酰亚胺(CHX)(西格玛)1μg/ml和50μg/ml以分别诱导程序性坏死和细胞凋亡;zVAD(西格玛)20μM;坏死他汀-1(西格玛)30μM;丁硫氨酸亚钒胺(BSO)(西格玛)400μM;柠檬酸铁铵(FAC)(西格玛,F5879)400μM;爱拉斯汀(西格玛),5μM,C11-BODIPY(581/591)2μM(英杰)。在生物分析开始时将试剂添加至培养物中,只是在溶解前1小时添加ConA用于西方墨点。
肽合成
使用标准固相Fmoc肽化学合成具有双氨基己酸(Ahx2)脂肪族连接体和N-Ac-Cys的经修饰黑皮质素-1受体靶向肽Re(Arg11)CCMSH。分析铼环化αMSH肽类似物Ac-Cys1-(Ahx)2-dLys2-Re[Cys-Cys-Glu-His-dPhe-Arg-Trp-Cys]-Arg-Pro-Val-NH2且在与LCQFLEET离子阱质谱仪(赛默飞世尔科学(Thermo Fisher Scientific))耦合的贝克曼库尔特(Beckman Coulter)高效液相色谱(HPLC)系统上纯化并最终通过冻干回收。
α-MSH-PEG-C’点的合成和表征
αMSH是神经免疫调节剂,且其受体MC1-R存在于巨噬细胞上。在某些实施例中,αMSH肽附接至纳米粒子(例如,C’点)。在某些实施例中,α-MSH-PEG-C’点用于组合疗法。例如,α-MSH-PEG-C’点诱导铁死亡且通过αMSH肽提供免疫调节。
在水中合成囊封有机染料Cy5的不同大小的荧光二氧化硅纳米粒子(C’点)。将αMSH肽通过其N末端乙酰化半胱氨酸硫醇偶联至马来酰亚氨基封端甲硅烷-聚乙二醇(PEG)以形成α-MSH-PEG。在聚乙二醇化步骤中将偶联物附接至粒子表面以产生αMSH官能化C'点或α-MSH-PEG-C’点。在水中透析合成的粒子样品且在进一步表征之前通过凝胶渗透色谱(GPC,美国伯乐有限公司(Bio-Rad Laboratories,Inc),海克利斯,加利福尼亚州)来纯化。使用瓦里安(Varian)Cary 5000分光光度计(瓦里安,帕罗奥图,加利福尼亚州)和荧光分光光度计(光子技术国际有限公司(Photon Technology International,Inc),伯明翰,新泽西州)获得经囊封和天然Cy5染料的吸收和发射光谱特征。使用配置有固态633nm激发的自制荧光相关光谱(FCS)设置与游离Cy5染料相对照测定α-MSH-PEG-C’点的流体动力学半径、亮度和浓度。
西方墨点
将细胞刮至冰冷RIPA缓冲液(50mM Tris(pH 7.4)、150mM NaCl、2mM EDTA、1%NP40、0.1%SDS和蛋白酶抑制剂混合物)中且在冰上溶解10min。然后在4℃下在15,870g下将溶解物离心20min且通过BCA分析(皮尔斯,沃尔瑟姆,马萨诸塞州)量化蛋白质。在15%聚丙烯酰胺SDS-PAGE凝胶上分离样品且转移至聚偏氟乙烯膜,所述聚偏氟乙烯膜用TBST加5%BSA封阻且在4℃下与稀释于封阻缓冲液中的一级抗体(抗LC3A/B(4108;细胞信号传导,丹弗斯,马萨诸塞州)、抗FTH1(3998;细胞信号传导)和抗肌动蛋白(A1978;西格玛))一起培育过夜。将墨点与偶联至二级抗体的辣根过氧化物酶一起培育且使用增强的化学发光检测(英杰)检测蛋白质。使用ImageJ软件(NIH)实施光密度测定分析。
时差显微术
将细胞平铺于玻璃底皿(马特克(MatTek),亚什兰(Ashland),马萨诸塞州)上。使用尼康(Nikon)TI-E倒置显微镜、CoolSNAP HQ2CCD(电荷耦合装置)照相机(Photometrics,土桑,亚利桑那州)针对所指示时间每30min获取过夜和荧光以及微分干涉对比(DIC)图像。活细胞培育室将细胞维持在37℃和5%CO2下。使用NIS元素软件(尼康,梅尔维尔,纽约州)。使用NIS元素软件和Image J手工量化和处理细胞命运,包括细胞存活率、死亡和增殖。
谷胱甘肽量化
对于谷胱甘肽测量,将HT-1080细胞平铺于6cm细胞培养皿上,与15μM加α-MSH标签的纳米粒子于无氨基酸DMEM+10%透析的FBS中一起培育且在预期死亡时间之前约2小时收获。作为对照,用mix of 3份完全或无氨基酸DMEM和1份H2O的混合物或完全培养基中的100μM BSO处理细胞。用冷PBS将细胞洗涤3×且通过50μL冷溶解缓冲液中的细胞刮擦收获。使用BCA分析测量蛋白质浓度且调整样品体积以使得各自具有相同的最终蛋白质浓度。根据制造商的说明书,使用谷胱甘肽分析试剂盒(卡曼化学品(Cayman Chemicals),703002)测量总谷胱甘肽且使用QuantiChromTM谷胱甘肽分析试剂盒(生物分析系统(BioAssaySystems),DIGT-250)测量还原谷胱甘肽。
活性氧类的分析
用或不用15μMα-MSH-PEG-C’点将细胞处理24小时,然后收获且重悬浮于500μL补充有H2DCFDA(25μM)或C11-BODIPY(581/591)(2μM)(二者均来自英杰)的汉克氏平衡盐溶液(Hanks Balanced Salt Solution,HBSS)(Gibco)中且在37℃下培育15分钟。然后将细胞重悬浮于500μL新鲜HBSS中且使用流式细胞仪的FL1通道(MoFlo,贝克曼库尔特)分析。收集最少10,000个细胞/条件的数据。
铁测量
对于C’点的铁负载能力测量,将50μLα-MSH-PEG-C’点(60μM)添加至在一系列铁(Fe3+)浓度范围(2μM至2mM,表1)内制备的150μL含铁培养基(8.6μM)或150μL FeCl3溶液中。在室温下将溶液旋转(160rpm)48小时,然后使用PD-10柱并在水中洗脱分离游离铁与C’点。在培养基中将细胞样品与和不与粒子一起培育48小时,然后离心,沉淀并洗涤三次,随后重悬浮于磷酸盐缓冲盐水溶液中。使用微波等离子体-原子发射光谱测定铁测量值(每十亿份数,ppb)以及铁负载能力。铁负载能力计算为经纯化粒子暴露的C’点(或细胞)中的铁量除以在纯化之前测量的初始铁的总量的比率并乘以100。所有实验是以一式三份进行。
GPX4活性分析
根据罗韦里(Roveri)和同事进行GPX4特异性活性分析。简言之,将冷冻细胞沉淀物重悬浮于100μL溶解缓冲液(100mM KH2PO4/K2HPO4(pH 7.4)、1mM EDTA、150mM KCl、0.1%CHAPS、3mMβ-巯基乙醇和蛋白酶抑制剂混合物)中且通过50次研棒打击均质化。在冰上将样品培育15min且通过离心(20000g和10min,4℃)去除细胞碎片。在1ml分析缓冲液(100mMTrisHCl pH 7.8,含有5mM EDTA、0.1%Triton X、3mM GSH、200μM NADPH和0.6U/ml谷胱甘肽还原酶)中在20μM磷脂酰胆碱过氧化物(PCOOH)存在下使用来自均质化细胞的50μL上清液来测量酶活性。通过可通过SpectraMax读板仪(分子装置(Molecular Device)GmbH)中的340nm吸光度减少检测到的谷胱甘肽还原酶依赖性NADPH消耗来确定GPX4活性。通过比色660nm皮尔斯蛋白质分析方法(皮尔斯,沃尔瑟姆,马萨诸塞州)测定样品中的蛋白质含量。
动物模型和肿瘤接种
所有动物实验均是根据经纪念斯隆-凯特琳癌症中心(Memorial Sloan-Kettering Cancer Center)的本院实验动物照护和使用委员会(Institutional AnimalCare and Use Committee)批准的方案来进行且遵循动物福利的NIH指导方针。在免疫缺陷雄性SCID/Beige(C.B-17/IcrHsd-PrkdcscidLystbg-J)小鼠(6-8周龄;海兰实验室(HarlanLaboratories),南伊斯顿,马萨诸塞州)的剃毛侧腹上产生人类黑色素瘤(M21)异种移植物。使用同一模型另外产生人类肉瘤HT1080和786-O侧腹异种移植物(约2×106个细胞/100μl)用于静脉内粒子注射。将45-75mm3的平均初始肿瘤体积用于所有实验。
体内投药策略和检查
使用23号套针将在血清补充培养基中培养的5百万个M21细胞皮下植入小鼠的右侧腹中以在粒子暴露(n=3)或无暴露(n=3)后2天建立黑色素瘤异种移植物。在后续研究中,将小鼠分配至两个不同治疗组中的一个以评估HT-1080和786-O肿瘤对在10天时段内投与三次(即第0天、第4天、第7天)的高浓度(60μM)的i.v.注射的α-MSH-PEG-C’点(n=5只小鼠;200μl)的反应。在相同时间点向对照HT-1080和786-O小鼠(n=3)投与0.9%盐水媒剂。在第三治疗研究中,将HT-1080小鼠分配至两组中的一个以评估单独或在腹膜内投与利普司他汀-1(n=3只小鼠,125mg/kg)后在10天时段内对三个高浓度剂量(60μM)的i.v.注射的α-MSH-PEG-C’点(n=3只小鼠;200μl)的反应。在治疗区间内使用测径器测量肿瘤大小。通过触诊肿瘤细胞接种位点来检查所有小鼠,且每日观察发病率或死亡率的迹象直至肿瘤生长研究结束。在注射细胞后使用测径器每日测量用于计算肿瘤体积(V;4/3·π·d1 2·d2/8)的肿瘤的两个垂直直径(d1≤d2)。
荧光成像
使用异氟烷将动物麻醉且获取全身光学荧光成像以鉴别出肿瘤位点的纳米粒子荧光。使用IVIS光谱光子计数装置光学成像系统(精诺真(Xenogen),阿拉米达,加利福尼亚州)对小鼠扫描0.1至1秒,所述系统具有根据制造商的建议选择的用于Cy5荧光(激发650nm,发射680nm)和背景荧光(激发465nm,发射600nm)的遮挡块和滤光器。同样根据制造商的说明书减去荧光背景。荧光信号报告为辐射效率((光子/s/cm2/sr)/(mW/cm2)。
组织病理学分析
在结束体内成像研究后立即通过CO2吸入使HT-1080和786-O雄性和雌性小鼠安乐死,且在验尸时切除代表性粒子暴露的肿瘤(n=2)和对照肿瘤(n=1)以及肝和肾样本。另外获得血液学样本用于全血计数和血清化学。将切除的肿瘤、肝和肾于10%中性缓冲福马林中固定24小时,在酒精和二甲苯中处理,包埋于石蜡中,以5微米厚度制成切片,且用苏木素和曙红(H&E)染色。通过免疫组织化学法针对Mac-2(一级抗体Cedarlane CL8942B,其是在pH 6.0缓冲液中在热诱导的表位修复[HIER]后以1:100的浓度施加)、髓过氧化物酶(Dako A0398,1:1000,HIER pH 6.0)、裂解的半胱天冬酶-3(细胞信号传导技术(CellSignaling Technology)9661,1:250,HIER pH6.0)和Ki-67(艾博抗(Abcam)ab16667,1:100,HIER pH 9.0)对其它切片染色。Mac-2染色是使用抗生物素蛋白-生物素检测系统(Vectastain ABC Elite试剂盒,载体实验室(Vector Laboratories),PK-6100)手工进行。其它染色是在徕卡邦德(Leica Bond)RX自动化染色机上使用邦德聚合物精制检测试剂盒(徕卡生物系统(Leica Biosystem)DS9800)进行。还如先前所述通过TUNEL方法对肿瘤切片进行染色。由经认证的兽医病理学家检查所有载玻片。
肿瘤血管化评价
通过在徕卡邦德RX自动化染色平台(徕卡生物系统)上通过免疫组织化学法针对CD31对HT-1080肿瘤染色来评价肿瘤血管化。在pH 9.0下热诱导的表位修复后,以1:250的浓度施加一级抗体(大鼠单克隆抗体,目录号DIA-310;迪诺瓦(Dianova))且随后施加聚合物检测系统(诺法卡特邦德聚合物精制检测(Novocastra Bond Polymer RefineDetection),徕卡生物系统)。
统计学
使用通过广义估计方程式方法计算的稳健标准误差比较两个治疗组之间的体积-时间特征。使用线性模型比较具和不具铁死亡药理学抑制剂利普司他汀-1的经粒子处理的肿瘤生长特征。通过使用广义估计方程式将数据的纵向方位考虑在内。统计学显著性经分配为P<0.05。
Claims (19)
1.一种基于二氧化硅的纳米粒子于制造用于治疗个体的方法中的药剂的用途,所述方法包含:
投与基于二氧化硅的纳米粒子以大于1μM的足够高的浓度积累至肿瘤组织以诱导所述肿瘤组织的铁死亡,其特征在于与未处理的细胞相比,所述肿瘤组织中铁的细胞内浓度增加,
其中经投与纳米粒子具有不大于15nm的平均直径,并且
其中所述经投与纳米粒子包含有机聚合物涂层。
2.根据权利要求1所述的用途,其中所述有机聚合物涂层包含聚乙二醇。
3.根据权利要求1所述的用途,其中所述组织经氨基酸剥夺。
4.一种基于二氧化硅的纳米粒子于制造用于组合治疗个体的方法中的药剂的用途,所述方法包含:
剥夺肿瘤组织的激素;和
投与基于二氧化硅的纳米粒子以大于1μM的足够高的浓度积累至肿瘤组织以诱导铁所述肿瘤组织的死亡,其特征在于与未处理的细胞相比,所述肿瘤组织中铁的细胞内浓度增加,
其中经投与纳米粒子具有不大于15nm的平均直径,并且
其中所述经投与纳米粒子包含有机聚合物涂层。
5.根据权利要求4所述的用途,其中所述有机聚合物涂层包含聚乙二醇。
6.根据权利要求4所述的用途,其中所述组织通过阉割剥夺激素。
7.根权利要求4所述的用途,其中所述组织经氨基酸剥夺。
8.根据权利要求1所述的用途,其中所述肿瘤组织选自由以下组成的群组:肾肿瘤、前列腺肿瘤、黑色素瘤、胰脏肿瘤、肺肿瘤、纤维肉瘤、乳房肿瘤、脑肿瘤、卵巢肿瘤和结肠肿瘤组织。
9.根据权利要求8所述的用途,其中所述肿瘤胰脏组织包含BxPC3细胞。
10.根据权利要求8所述的用途,其中所述肿瘤肺组织包含H1650细胞。
11.根据权利要求1所述的用途,其中所述纳米粒子具有不大于10nm的平均直径。
12.根据权利要求1所述的用途,其中所述纳米粒子具有约5nm到约7nm的平均直径,其中术语“约”是指在写明的参考值的±25%以内的值范围。
13.根据权利要求1所述的用途,其中所述纳米粒子包含1到20个靶向部分,其中所述靶向部分结合至细胞上的受体。
14.根据权利要求13所述的用途,其中所述纳米粒子包含1到20个靶向部分,并且其中所述1到20个靶向部分包含α-黑色素细胞刺激激素。
15.根据权利要求1所述的用途,其中所述纳米粒子包含靶向部分。
16.根据权利要求1所述的用途,其中所述纳米粒子在治疗过程中多次投与。
17.根据权利要求1所述的用途,其中所述方法进一步包含在所述治疗过程中每3天或4天投与所述纳米粒子。
18.根据权利要求1所述的用途,其中所述治疗与所述经投与纳米粒子的天然免疫调节性质组合以增加所述纳米粒子在癌症治疗和/或组织修复过程中的治疗潜能。
19.根据权利要求1所述的用途,其中所述组织包括营养素剥夺组织或肿瘤组织。
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