CN111479593B - 奎尼酸-修饰的纳米粒子及其用途 - Google Patents
奎尼酸-修饰的纳米粒子及其用途 Download PDFInfo
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- CN111479593B CN111479593B CN201880045723.XA CN201880045723A CN111479593B CN 111479593 B CN111479593 B CN 111479593B CN 201880045723 A CN201880045723 A CN 201880045723A CN 111479593 B CN111479593 B CN 111479593B
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- selectin
- qanp
- nps
- quinic acid
- plga
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Abstract
本发明一般涉及靶向纳米粒子向E‑选择蛋白‑或P‑选择蛋白‑阳性细胞或组织的递送。特别地,本发明公开一种制备奎尼酸修饰的纳米粒子的方法,所述纳米粒子用于通过E‑选择蛋白或P‑选择蛋白介导的胞吞作用向癌细胞或组织的靶向药物递送。本文所述的发明还涉及用于治疗癌症的药物组合物和方法。
Description
相关申请的交叉引用
本美国专利申请涉及并要求2017年5月8日提交的美国临时专利申请序列号62/502,847的优先权,其全部内容通过引用合并于此。
政府支持条款
本发明是在美国国立卫生研究院(National Institute of Health)授予的EB017791赠款的政府支持下完成的。政府拥有本发明的某些权利。
技术领域
本发明一般涉及靶向纳米粒子递送至E-选择蛋白-阳性细胞或组织。特别地,本发明公开了一种制备奎尼酸修饰的纳米粒子的方法,该纳米粒子用于通过E-选择蛋白介导的胞吞作用将药物靶向递送至癌细胞或组织。本文所述的发明还涉及用于治疗癌症的药物组合物和方法。
背景技术
本节介绍可以帮助促进对本公开的更好理解的方面。因此,应从这些角度来阅读这些陈述,并且不应将其理解为对现有技术或非现有技术的承认。
癌症是一组涉及细胞异常生长的最多种疾病,目前已鉴定出100多种影响人类以及动物的癌症。在2016年,仅在美国,估计就诊断出1,685,210例新的人类癌症病例,并且有595,690例癌症死亡(Cancer Statistics 2016-American Cancer Society,Inc.)。对于对抗癌症的新的和新颖的疗法的需求未得到满足并且越来越多。
纳米粒子(NP)被认为是有前途的化疗药物载体。基于NP的化学疗法的前提是基于这样的观念,即肿瘤倾向于发展高脉管系统和较差的淋巴系统,这相对于正常组织为NP提供了选择性通路(Y Matsumura,Cancer Res.1986,46,6387-6392)。这种现象被称为增强的渗透性和保留(EPR)效果,已成为基于NP的药物递送的控制原理,而与肿瘤靶向机制无关。然而,由于肿瘤中NP积聚的百分比低,基于NP的化学疗法的前景最近受到挑战(S Wilhelm,et al.,Nature Review Materials 2016,1,1-12)以及缺乏支持NP益处的临床证据。限制NP向肿瘤的传递的潜在原因之一可能是疾病的多样性以及受试者之间和受试者之间的高差异,从而导致EPR效果的可变性(E Karathanasis,et al.,PLoS One 2009,4,e5843)。为了使基于NP的化学疗法在癌症治疗方面取得临床成功,还需要其他手段来利用EPR效应并提高NP的传递效率,使其超出当前可能的水平。
发明概述
在一些实施方案中,本发明涉及一种选择性靶向E-选择蛋白或P-选择蛋白阳性细胞或组织的奎尼酸修饰的纳米粒子(QANP),包含:
a.纳米粒子(NP);
b.多酚化合物;和
c.奎尼酸衍生物,其中所述NP被所述多酚化合物包覆,被所述奎尼酸衍生物进一步修饰。
在一些实施方案中,本发明涉及本文公开的选择性靶向E-选择蛋白或P-选择蛋白阳性细胞或组织的奎尼酸修饰的纳米粒子(QANP),其中所述NP选自聚(乳酸-co-羟基乙酸)(PLGA)、聚乙二醇-PLGA缀合物、D-α-生育酚聚乙二醇1000琥珀酸酯(TPGS)-PLGA缀合物、聚乳酸(PLA)、介孔二氧化硅、脂质体和多酚聚集体。
在一些实施方案中,本发明涉及本文公开的选择性靶向E-选择蛋白或P-选择蛋白阳性细胞或组织的奎尼酸修饰的纳米粒子(QANP),其中所述NP包含一种或多种封装的治疗药物。
在一些实施方案中,本发明涉及本文公开的选择性靶向E-选择蛋白或P-选择蛋白阳性细胞或组织的奎尼酸修饰的纳米粒子(QANP),其中所述治疗药物是选自紫杉醇、索拉非尼、伊曲康唑、多西他赛、阿霉素、硼替佐米、卡非佐米、喜树碱、顺铂、奥沙利铂、阿糖胞苷、长春新碱、伊立替康、两性霉素B、吉西他滨、多粘菌素、地塞米松和维生素D。
在一些实施方案中,本发明涉及本文公开的选择性靶向E-选择蛋白或P-选择蛋白阳性细胞或组织的奎尼酸修饰的纳米粒子(QANP),其中所述多酚化合物是聚合多巴胺(pD)。
在一些其他实施方案中,本发明涉及本文公开的选择性靶向E-选择蛋白或P-选择蛋白阳性细胞或组织的奎尼酸修饰的纳米粒子(QANP),其中所述奎尼酸衍生物是
在一些实施方案中,本发明涉及本文公开的选择性靶向E-选择蛋白或P-选择蛋白阳性细胞或组织的奎尼酸修饰的纳米粒子(QANP),其中所述P-选择蛋白或E-选择蛋白-阳性细胞或组织是癌细胞或组织、或者是癌细胞或组织周围的内皮细胞。
在一些其他实施方案中,本发明涉及包含本文公开的QANP以及一种或多种稀释剂、赋形剂或载体的药物组合物。
在一些实施方案中,本发明涉及包含本文公开的QANP以及一种或多种稀释剂、赋形剂或载体的药物组合物,其中所述药物组合物用于治疗患有癌症的患者。
在一些实施方案中,本发明涉及一种选择性靶向E-选择蛋白-或P-选择蛋白-阳性细胞或组织的奎尼酸-修饰的纳米粒子(QANP)的制备方法,包括以下步骤:
a.制备纳米粒子(NP);
b.使用多酚化合物包覆所述NP;和
c.使用奎尼酸衍生物修饰多酚包覆的NP以得到所述QANP。
在一些实施方案中,本发明涉及本文公开的选择性靶向E-选择蛋白或P-选择蛋白阳性细胞或组织的奎尼酸修饰的纳米粒子(QANP)的制备方法,其中所述NP包含一种或多种治疗药物。
在一些实施方案中,本发明涉及本文公开的选择性靶向E-选择蛋白或P-选择蛋白阳性细胞或组织的奎尼酸修饰的纳米粒子(QANP)的制备方法,其中所述多酚化合物是聚合多巴胺(pD)。
在一些实施方案中,本发明涉及本文公开的选择性靶向E-选择蛋白或P-选择蛋白阳性细胞或组织的奎尼酸修饰的纳米粒子(QANP)的制备方法,其中所述奎尼酸衍生物是
在一些实施方案中,本发明涉及本文公开的选择性靶向E-选择蛋白或P-选择蛋白阳性细胞或组织的奎尼酸修饰的纳米粒子(QANP)的制备方法,其中所述NP由PLGA、聚乙二醇-PLGA缀合物、D-α-生育酚聚乙二醇1000琥珀酸酯(TPGS)-PLGA缀合物、聚乳酸(PLA)、介孔二氧化硅、脂质体和多酚聚集体制成。
在一些实施方案中,本发明涉及根据本文公开的方法制造的药物产品、以及一种或多种稀释剂、赋形剂或载体。
在一些实施方案中,本发明涉及根据本文公开的方法制造的药物组合物、以及一种或多种稀释剂、赋形剂或载体。
在一些实施方案中,本发明涉及一种用于治疗癌症患者的方法,该方法包括以下步骤:向需要缓解所述癌症的患者施用治疗有效量的本文公开的药物组合物。
在一些实施方案中,本发明涉及本文公开的药物组合物在制备用于治疗受试者的癌症的药物中的用途。
在一些其他实施方案中,本发明涉及药物组合物,包含一种或多种本文公开的化合物的纳米粒子以及一种或多种稀释剂、赋形剂或载体。
附图简述
图1显示了PLGA NP的透射电子显微照片(左);PLGA-pD NP(中);QANP(右)。用乙酸铀酰进行负染色。比例尺:100nm。
图2描绘了与静息HUVEC和TNF-α活化的HUVEC一起孵育的裸NP和QANP的共聚焦图像。绿色:NP;蓝色:细胞核;红色:质膜。
图2B表示静止的HUVEC和TNF-α-活化的HUVEC的流式细胞术直方图。
图2C显示了与裸NP或QANP相互作用的HUVEC细胞的定量测量。
图3A通过游离QA-NH2竞争性抑制QANP与HUVEC的结合。
图3B证明了抗E-选择蛋白抗体对QANP与HUVEC结合的竞争性抑制。通过流式细胞术定量QANP-HUVEC结合。
图4A是跨内皮迁移测定的示意图。
图4B是HUVEC单层的代表性TEER图。
图4C显示了在有和没有TNF-α活化的情况下,跨汇合的HUVEC单层的NP转运百分比。
图4D显示了配体密度与QANP的跨内皮运输之间的关系。
图5A显示了在用各种人类癌细胞系条件化的培养基中生长的HUVEC的E-选择蛋白表达。#:单因素方差分析后,通过Dunnett的多重比较测试,与EGM-2组相比,p<0.001。
图5B显示了在用各种鼠癌细胞系条件化的培养基中生长的EOMA细胞的E-选择蛋白表达。#:p<0.001;*:通过单向方差分析,通过Dunnett的多重比较测试,与DMEM组相比,p<0.01。
图6示出了注射后24小时的动物的代表性全身成像。通过尾静脉向携带皮下MDA-MB-231肿瘤异种移植物的动物注射QANP(上)、NP-pD-PEG(中)和游离ICG(下)。
图7A描绘了在全身成像结束时取回的主要器官的离体图像的荧光强度。n=每组5只小鼠。#:根据双向方差分析,通过Bonferroni的多重比较测试,p<0.0001。
图7B示出了从主要器官提取的ICG的荧光强度。n=每组5只小鼠。#:根据双向方差分析,通过Bonferroni的多重比较测试,p<0.0001。
图8A显示了在具有MDA-MB-231异种移植的雌性裸鼠中以相当于PTX 20mg/kg的单剂量给予的治疗。一旦肿瘤体积(V)达到2000mm3或表现出动物方案中定义的任何发病迹象,处死小鼠。n=每组5。肿瘤特异性生长速率定义为ΔlogV/Δt(t:以天为单位的时间)。*:通过不成对的t检验,p<0.05。
图8B显示了在具有MDA-MB-231异种移植的雌性裸鼠中在2周内以五剂20mg PTX当量/kg/剂量给予的治疗。n=每组5。*:通过Gehan-Breslow-Wilcoxon检验,p<0.05。
图9A显示了PTX@QA-NP与盐水、空白PEG-NP、空白QA-NP和PTX@PEG-NP相比的抗癌功效。在2周内以10剂30mg PTX当量/kg/剂量的剂量给予治疗。n=每组5。
图9B显示了在单次注射PEG-NP、QA-NP或盐水(作为阴性对照)后5天,针对每个配体(PEG,QA)的抗体的检测,n=每组3。*:通过Log-rank(Mantel-Cox)测试得出p<0.05。
发明详述
尽管在附图和此处的描述中详细示出和描述了本公开的概念,但是附图中的结果及其描述应被认为是示例性的,而不是限制性的;应当理解,仅示出和描述了示例性实施例,并且希望保护落入本公开精神内的所有改变和修改。
在一些实施方案中,本发明涉及选择性靶向E-选择蛋白或P-选择蛋白阳性细胞或组织的奎尼酸修饰的纳米粒子(QANP),包含:
a.纳米粒子(NP);
b.多酚化合物;和
c.奎尼酸衍生物,其中所述NP被所述多酚化合物包覆,被所述奎尼酸衍生物进一步修饰。
在一些实施方案中,本发明涉及本文公开的选择性靶向E-选择蛋白或P-选择蛋白阳性细胞或组织的奎尼酸修饰的纳米粒子(QANP),其中所述NP选自聚(乳酸-co-羟基乙酸)(PLGA)、聚乙二醇-PLGA缀合物、D-α-生育酚聚乙二醇1000琥珀酸酯(TPGS)-PLGA缀合物、聚乳酸(PLA)、介孔二氧化硅、脂质体和多酚聚集体。
在一些实施方案中,本发明涉及本文公开的选择性靶向E-选择蛋白或P-选择蛋白阳性细胞或组织的奎尼酸修饰的纳米粒子(QANP),其中所述NP包含一种或多种封装的治疗药物。
在一些实施方案中,本发明涉及本文公开的选择性靶向E-选择蛋白或P-选择蛋白阳性细胞或组织的奎尼酸修饰的纳米粒子(QANP),其中所述治疗药物选自紫杉醇、索拉非尼、伊曲康唑、多西他赛、阿霉素、硼替佐米、卡非佐米、喜树碱、顺铂、奥沙利铂、阿糖胞苷、长春新碱、伊立替康、两性霉素B、吉西他滨、多粘菌素、地塞米松和维生素D。
在一些实施方案中,本发明涉及本文公开的选择性靶向E-选择蛋白或P-选择蛋白阳性细胞或组织的奎尼酸修饰的纳米粒子(QANP),其中所述多酚化合物是聚合多巴胺(pD)。
在一些其他实施方案中,本发明涉及涉及本文公开的选择性靶向E-选择蛋白或P-选择蛋白阳性细胞或组织的奎尼酸修饰的纳米粒子(QANP),其中所述奎尼酸衍生物是
在一些实施方案中,本发明涉及本文公开的选择性靶向E-选择蛋白或P-选择蛋白阳性细胞或组织的奎尼酸修饰的纳米粒子(QANP),其中所述P-选择蛋白或E-选择蛋白-阳性细胞或组织是癌细胞或组织、或者是癌细胞或组织周围的内皮细胞。
在一些其他实施方案中,本发明涉及包含本文公开的QANP以及一种或多种稀释剂、赋形剂或载体的药物组合物。
在一些实施方案中,本发明涉及包含本文公开的QANP以及一种或多种稀释剂、赋形剂或载体的药物组合物,其中所述药物组合物用于治疗患有癌症的患者。
在一些实施方案中,本发明涉及一种选择性靶向E-选择蛋白-或P-选择蛋白-阳性细胞或组织的奎尼酸-修饰的纳米粒子(QANP)的制备方法,包括以下步骤:
a.制备纳米粒子(NP);
b.使用多酚化合物包覆所述NP;和
c.使用奎尼酸衍生物修饰多酚包覆的NP以得到所述QANP。
在一些实施方案中,本发明涉及本文公开的选择性靶向E-选择蛋白或P-选择蛋白阳性细胞或组织的奎尼酸修饰的纳米粒子(QANP)的制备方法,其中所述NP包含一种或多种治疗药物。
在一些实施方案中,本发明涉及本文公开的选择性靶向E-选择蛋白或P-选择蛋白阳性细胞或组织的奎尼酸修饰的纳米粒子(QANP)的制备方法,其中所述多酚化合物是聚合多巴胺(pD)。
在一些实施方案中,本发明涉及本文公开的选择性靶向E-选择蛋白或P-选择蛋白阳性细胞或组织的奎尼酸修饰的纳米粒子(QANP)的制备方法,其中所述奎尼酸衍生物是
在一些实施方案中,本发明涉及本文公开的选择性靶向E-选择蛋白或P-选择蛋白阳性细胞或组织的奎尼酸修饰的纳米粒子(QANP)的制备方法,其中所述NP由PLGA、聚乙二醇-PLGA缀合物、D-α-生育酚聚乙二醇1000琥珀酸酯(TPGS)-PLGA缀合物、聚乳酸(PLA)、介孔二氧化硅、脂质体和多酚聚集体制成。
在一些实施方案中,本发明涉及根据本文公开的方法制造的药物产品、以及一种或多种稀释剂、赋形剂或载体。
在一些实施方案中,本发明涉及根据本文公开的方法制造的药物组合物、以及一种或多种稀释剂、赋形剂或载体。
在一些实施方案中,本发明涉及一种用于治疗癌症患者的方法,该方法包括以下步骤:向需要缓解所述癌症的患者施用治疗有效量的本文公开的药物组合物。
在一些实施方案中,本发明涉及本文公开的药物组合物在制备用于治疗受试者的癌症的药物中的用途。
在一些其他实施方案中,本发明涉及药物组合物,包含一种或多种本文公开的化合物的纳米粒子以及一种或多种稀释剂、赋形剂或载体。
参考以下附图、描述和权利要求,将更好地理解本发明的这些和其他特征、方面和优点。
如本文所使用,以下术语和短语应具有以下阐述的含义。除非另有定义,否则本文使用的所有技术和科学术语具有与本领域普通技术人员通常理解的相同含义。
在本公开中,术语“约”可以允许值或范围内的变化程度,例如,在所述值或范围的所述极限的10%以内、5%以内或1%以内。在本公开中,术语“基本上”可以允许值或范围内的一定程度的可变性,例如,在规定值或规定范围的极限值的90%之内,在95%、99%、99.5%、99.9%、99.99%或至少约99.999%或更高内。
在本文中,除非上下文另外明确指出,否则术语“一”、“一个”或“该”用于包括一个或多个。除非另有说明,否则术语“或”用于表示非排他性的“或”。另外,应当理解,本文中采用的,没有另外定义的措词或术语仅是出于描述的目的,而不是限制性的。本节标题的任何使用均旨在帮助阅读文档,而不应理解为限制性的。此外,与节标题相关的信息可能出现在该特定节之内或之外。此外,该文件中引用的所有出版物、专利和专利文件通过引用整体并入本文,就好像通过引用单独地并入。如果本文档与通过引用方式并入的那些文档之间用法不一致时,应将所引用的引用中的用法视为对本文档的补充;对于不一致的不一致之处,以本文档中的用法为准。
术语“药学上可接受的载体”是本领域公认的,并且是指药学上可接受的材料、组合物或媒介物,例如液体或固体填充剂、稀释剂、赋形剂、溶剂或包囊材料、参与运载或运输任何主题的成分或成分。每个载体在与主题组合物及其组分相容且对患者无害的意义上必须是“可接受的”。可用作药学上可接受的载体的材料的一些示例包括:(1)糖,例如乳糖、葡萄糖和蔗糖;(2)淀粉,例如玉米淀粉和马铃薯淀粉;(3)纤维素及其衍生物,例如羧甲基纤维素钠、乙基纤维素和醋酸纤维素;(4)黄芪粉;(5)麦芽;(6)明胶;(7)滑石;(8)赋形剂,例如可可脂和栓剂蜡;(9)花生油、棉籽油、红花油、芝麻油、橄榄油、玉米油、大豆油等油;(10)二醇,例如丙二醇;(11)多元醇,例如甘油、山梨糖醇、甘露糖醇和聚乙二醇;(12)酯,例如油酸乙酯和月桂酸乙酯;(13)琼脂;(14)缓冲剂,例如氢氧化镁和氢氧化铝;(15)海藻酸;(16)无热原水;(17)等渗盐水;(18)林格的解答;(19)乙醇;(20)磷酸盐缓冲溶液;(21)药物制剂中使用的其他无毒相容性物质。
如本文所用,术语“给药”包括将本文所述的化合物和组合物引入患者的所有方式,包括但不限于口服(po)、静脉内(iv)、肌内(im)、皮下(sc)、透皮、吸入、颊、眼、舌下、阴道、直肠等。本文所述的化合物和组合物可以以单位剂型和/或含有常规无毒的药学上可接受的载体、佐剂和赋形剂的制剂给药。
口服给药的说明性形式包括片剂、胶囊剂、elixirs、糖浆等。肠胃外施用的示例性途径包括静脉内、动脉内、腹膜内、硬膜外、尿道内、胸骨内、肌内和皮下以及任何其他本领域公认的肠胃外施用途径。
肠胃外给药的说明性手段包括针头(包括微针)注射器、无针注射器和输注技术、以及本领域公认的任何其他肠胃外给药手段。肠胃外制剂通常是水溶液,其可以包含赋形剂,例如盐、碳水化合物和缓冲剂(优选在约3至约9的pH范围内),但是对于某些应用,它们可以更合适地配制成无菌非水溶液或干燥形式,以与合适的载体(例如无菌,无热原的水)结合使用。肠胃外制剂在无菌条件下的制备,例如通过冻干,可以使用本领域技术人员众所周知的标准制药技术容易地完成。化合物的肠胃外给药以盐溶液形式或将化合物掺入脂质体中进行说明。在化合物本身不能充分溶解而不能溶解的情况下,可以使用诸如乙醇的增溶剂。
所要求保护的组合的每种化合物的剂量取决于几个因素,包括:给药方法、待治疗的病症、病症的严重程度、是否要治疗或预防该病症以及年龄、体重和被治疗的人的健康状况。另外,有关特定患者的药物基因组(基因型对治疗药物的药代动力学、药效动力学或功效的影响)学信息可能会影响所用剂量。
应该理解的是,在本文所述的方法中,可以通过任何合适的方式同时、一起、顺序、分开、或以单一药物制剂的形式共同给药或组合的各个组分。当共同施用的化合物或组合物以单独的剂型施用时,每种化合物每天施用的剂量数可以相同或不同。化合物或组合物可以通过相同或不同的给药途径来给药。化合物或组合物可以根据同时或交替方案在治疗过程中的相同或不同时间以分开或单一形式同时给药。
本文所用的术语“治疗有效量”是指研究人员、兽医、医生或其他临床医生所寻求的在组织系统、动物或人体内引起生物学或医学反应的活性化合物或药剂的量,包括减轻所治疗疾病或病症的症状。一方面,治疗有效量是可以以适用于任何医学治疗的合理的利益/风险比来治疗或减轻疾病或疾病症状的量。然而,应理解,本文所述的化合物和组合物的每日总用量可由主治医师在合理的医学判断范围内决定。任何特定患者的具体治疗有效剂量水平将取决于多种因素,包括所治疗的疾病和疾病的严重程度;所用特定化合物的活性;使用的具体组成;患者的年龄、体重、总体健康状况、性别和饮食;施用时间、施用途径和所用特定化合物的排泄率;治疗的持续时间;与所用特定化合物组合或同时使用的药物;以及研究人员、兽医、医生或其他普通技术人员众所周知的因素。
取决于给药途径,本文考虑了宽范围的容许剂量,包括落在约1μg/kg至约1μg/kg范围内的剂量。剂量可以是单一的或分开的,并且可以根据包括q.d.(一天一次)、b.i.d.(一天两次)、t.i.d.(一天3次)、甚至每隔一天一次、每周一次、每月一次、每季度一次等等在内的多种方案来施用。在这些情况的每一种中,应理解,本文所述的治疗有效量对应于给药实例,或替代地对应于由给药方案确定的每日、每周、每月或每季度的总剂量。
除了本文所述的示例性剂量和给药方案外,应理解,主治医生或医师可以使用已知技术和/或通过观察在类似情况下获得的结果确定本文所述化合物的任何一种或混合物的有效量。主治医生或医师在确定有效量或剂量时会考虑多种因素,包括但不限于哺乳动物的物种,包括人类,其大小、年龄和一般健康状况、所涉及的特定疾病或病症、疾病或病症的程度或程度或严重程度、单个患者的反应、给药的特定化合物、给药方式、给药制剂的生物利用度特征、所选的剂量方案、使用伴随药物以及其他相关情况。
术语“患者”包括人类和非人类动物,例如伴侣动物(狗和猫等)和牲畜。牲畜是为粮食生产而饲养的动物。待治疗的患者优选是哺乳动物,特别是人类。
纳米粒子(NP)被认为是有前途的化疗药物载体。基于NP的化学疗法的前提是基于这样的观念,即肿瘤倾向于发展高脉管系统和较差的淋巴系统,这相对于正常组织为NP提供了选择性通路。这种现象被称为增强的渗透性和保留(EPR)效果,已成为基于NP的药物递送的控制原理,而与肿瘤靶向机制无关。然而,由于NP在肿瘤中的累积百分比低以及缺乏支持NP益处的临床证据,最近基于NP的化学疗法的前景受到了挑战。限制NP向肿瘤的传递的潜在原因之一可能是疾病的多样性以及受试者之间和受试者内部的高差异,从而导致EPR效果的可变性。为了使基于NP的化学疗法在临床上取得成功,应该有其他手段来利用EPR效应并提高NP的递送效率,使其超出目前可能的水平。
在没有可靠的EPR效应的情况下,血管内皮-循环NP遇到的第一个细胞层-充当了潜在肿瘤的通行屏障;因此,能够与内皮屏障主动相互作用的NP将有更大的机会渗入肿瘤。在这方面,我们注意到在肿瘤周围内皮表面上调的独特粘附分子阵列(N Makrilia,etal.,Cancer Invest 2009,27,1023-1037)。例如,E-选择蛋白,其是促炎刺激后在内皮细胞上表达的跨膜糖蛋白(GS Kansas,Blood 1996,88,3259-3287),在肿瘤周围内皮上也过表达,促进血管生成(AE Koch,et al,Nature 1995,376,517)和肿瘤增殖。此外,E-选择蛋白可作为循环肿瘤细胞的粘附点,并帮助其扩散并形成转移灶(H Kobayashi,et al,CurrentMedicinal Chemistry 2007,14,377-386;GE Rice,et al,Science 1989,246,1303)。
E-选择蛋白的天然配体是碳水化合物部分-唾液酸Lewis-x(sLex),由唾液酸、半乳糖、岩藻糖和N-乙酰基-半乳糖胺组成的四糖(M Phillips等人,Science 1990,250,1130-1132)。考虑到E-选择蛋白在肿瘤进展和转移中的意义,已经研究了sLex及其类似物作为E-选择蛋白拮抗剂(S Pedatella等人,Carohydrate Research 2008,343,31-38)。已经提出了许多sLex的化学类似物以增强其对E-选择蛋白的特异性和亲和力(EE Simanek等人,Chemical Review 1998,98,833-862)。其中,奎宁酸(QA)及其衍生物由于其化学修饰的稳定性、简单性和易用性而被认为是很有前途的候选物(N Kaila等人,J.Med.Chem.2005,48,4346-4357)。这些E-选择蛋白配体也已经用作大分子和NP药物载体的靶向配体,用于将化疗药物递送至肿瘤周围内皮(Y Shamay等人,J.Controlled Release 2015,217,102-112)。最近,基于其与粘附分子的相互作用,产生了涂有炎性中性粒细胞膜的聚合NP,以解决转移前的内皮(T Kang等人,ACS Nano 2017,11,1397-1411)。
尽管这些研究证明了使用靶向内皮的配体来增强药物向肿瘤的递送的可行性,但新聚合物合成的复杂性和低效率可能会阻碍这一有希望的原理的临床翻译。为了解决这一挑战,我们采用了一种基于多巴胺聚合的简单表面官能化方法,该方法适用于各种NP平台,无论其化学反应性如何(J Park等人,ACS Nano 2014,8,3347-3356)。多巴胺聚合方法涉及在氧化条件下简单地在多巴胺溶液中孵育NP,这使多巴胺能够聚合并在NP表面形成化学反应层以容纳配体分子(H Lee等人,Science 2007,318,426-430)。该方法允许结合各种类型的配体,包括QA衍生物,并灵活控制NP表面的QA密度。这种多功能性和灵活性使我们能够研究通过QA增加NP跨内皮运输的最佳条件,并将QA修饰的NP与包含典型隐身涂层(例如聚乙二醇(PEG))的NP进行比较。在这项研究中,我们证明了通过聚合多巴胺(polydopamine,pD)可以容易地用QA修饰聚合物NP与活化的内皮细胞有效地相互作用,从而使内皮细胞层移位,并基于EPR效应,其到达肿瘤的范围比典型的隐形NP要大得多。
QA-NH2的合成,sLex的合成模拟物
QA-NH2是sLex的合成模拟物,是根据先前报道的方案进行合成的,并稍加修改。总产率为62%。lH质子NMR证实了该化合物的结构。电子喷雾电离质谱法发现该化合物的质荷比为预期的324.9(-MS模式)。
QANP的制备和表征
NP-pD-QA(QANP)用多巴胺介导的表面修饰方法制备(J Park等人,ACS Nano2014,8,3347-3356)。首先通过单乳液溶剂蒸发法制备PLGA NP,并覆盖pD层,然后通过Michael加成和/或Schiff碱反应将QA-NH2容纳在NP表面(H Lee等人,Science 2007,318,426-430)。根据动态光散射,QANP的平均直径为145nm,ζ电位为-6.5mV。QANP的电子喷雾电离质谱(MS-ESI)分析为QA-NH2在QANP上成功偶联提供了定性证据。简单地将QGA-NH2与没有pD功能化的PLGA NP孵育(PLGA/QA NP)在MS-ESI上没有QA-NH2的特征峰,证实了pD涂层作为QA-NH2偶联介体的重要作用。透射电子显微照片(TEM)(图1)确定了由于pD涂层(表1)而在PLGA核心NP的表面上形成了另外一层。但是,PLGA-pD NP和QANP之间没有可见的差异,这与使用其他配体的先前实例一致(J Park等人,ACS Nano 2014,8,3347-3356)。
通过从原始QA-NH2进料中减去残留在反应介质中的QA-NH2量,间接确定与QANP表面共轭的QA-NH2数量。与QANP单位表面积结合的QA-NH2随着QA-NH2进料线性增加,并且在受试饲料范围内未达到平稳状态。
表1.NP的粒径、ζ电位和多分散性指数(PDI)。
名称 | 大小(nm) | (mV)ζ电位 | PDI |
裸NP | 134±12 | -10.4±9.3 | 0.1±0.02 |
NP-pD | 142±17 | -11.2±8.1 | 0.2±0.06 |
PEG-NP | 163±11 | -10.7±6.2 | 0.2±0.04 |
QA-NP | 151±14 | -11.8±4.9 | 0.1±0.03 |
QA-NP(PLGA-FITC) | 149±7 | -9.3±5.5 | 0.1±0.03 |
QA-NP(PLGA-Alexa 555) | 147±11 | -10.4±6.1 | 0.1±0.05 |
QA-NP(PLGA-ICG) | 154±20 | -10.8±5.7 | 0.1±0.06 |
裸NP(PLGA-TPGS) | 171±33 | -12.3±6.6 | 0.2±0.09 |
PTX@PEG-NP(PLGA-TPGS) | 184±41 | -11.5±5.7 | 0.2±0.07 |
PTX@QA-NP(PLGA-TPGS) | 179±26 | -10.8±6.4 | 0.1±0.04 |
数据:平均值±s.d.(n=3个独立批次)
血清中QANP的稳定性
在对QANP进行生物学评估之前,以0.05mg/mL至0.2mg/mL的各种浓度测试了它们在50%FBS中的大小分布。无论浓度如何,QANP均在120nm处显示一致的峰。在10nm和80nm处的两个独特峰被鉴定为血清蛋白及其聚集体。在50%FBS中超过2小时,没有发生QANP的聚集或聚结。
QANP与活化的HUVEC的相互作用
用共聚焦显微镜和流式细胞术检查QANP-HUVEC相互作用(图2A-2C)。具体地,将HUVEC与荧光标记的QANP或具有或不具有TNF-α活化的裸NP一起孵育6小时。TNF-α处理可诱导HUVEC上E选择蛋白的表达。为了进行比较,裸露的PLGA NP也以相同的方式进行了测试。图2A显示QANP与HUVEC细胞膜相关,而裸NP显示最小的非特异性结合。为了量化保留在细胞中的NP,使用流式细胞仪测量细胞裂解液的荧光强度。与对照组(具有QANP(或裸NP)的未激活HUVEC或具有未修饰NP的激活HUVEC)相比,与QANP孵育的活化HUVEC表现出最大的荧光强度,与共聚焦成像一致(图2B,2C)。这些结果表明,QANP对活化的HUVEC具有亲和力,因此有可能集中在肿瘤周围内皮上。
为了确认QA-E-选择蛋白相互作用的介体,在游离QA-NH2或抗E-选择蛋白抗体的存在下进行孵育。游离QA-NH2(图3A)和抗E-选择蛋白抗体(图3B)以剂量依赖性方式降低了QANP与活化HUVEC的结合,这表明游离QA-NH2与QANP竞争,而E-选择蛋白的阻断分别干扰QANP与活化的HUVEC的结合。这些结果证实,QANP与活化的HUVEC的结合是通过与E-选择蛋白的QA相互作用来介导的。
跨内皮迁移试验可检测QANP的外渗潜力
QANP与肿瘤周围内皮之间的相互作用有助于将NP集中在肿瘤附近,并增加NP扩散并到达肿瘤的机会。我们评估了QANP跨Transwell插入物上生长的内皮细胞层运输的潜力(图4A),类似于博登室试验(S Boyden,J.Experiment Med.1962,March,453-466)。将QANP和对照NP置于含有汇合HUVEC层的Transwell的顶端(图4B),进行和不进行TNF-α预处理,并对残留在顶端并在基底外侧恢复的NP进行定量。如预期的那样,仅在QANP和TNF-α激活(=E-选择蛋白表达)HUVEC的情况下观察到了跨内皮层的转运(图4C)。
为了检查配体密度和跨内皮运输之间的关系,将各种配体密度的QANP与活化的HUVEC一起孵育(图4D)。随着QANP的配体密度从25QA-NH2/nm2增加到100QA-NH2/nm2,QANP转运增加。但是,当配体密度进一步增加到200QA-NH2/nm2时,穿过内皮层的细胞百分比降低。一个可能的解释是,随着配体密度的增加,QA-NH2可能由于氢键作用而形成了分子间簇,而不是与E-选择蛋白相互作用。总体而言,Transwell实验表明,具有最佳表面密度的QA配体有助于在活化的HUVEC上转运NP。
多种癌细胞在内皮细胞中诱导E-选择蛋白上调
E-选择蛋白的血管表达随肿瘤类型而变化。文献表明内皮细胞中的E-选择蛋白上调与肿瘤分泌的白介素-1α的量之间有很强的相关性(M Nguyen,Am J Pathol 1997,150,1307-1314)。我们筛选了几种人类癌细胞系的条件培养基,以查看它们是否在HUVEC中诱导E-选择蛋白表达。暴露于条件培养基的HUVEC表达不同水平的E-选择蛋白(图5A)。MDA-MB-231条件培养液诱导E-选择蛋白表达水平最高。用一组鼠细胞系获得了相似的观察结果(图5B)。以B16F10黑色素瘤细胞或4T1乳腺癌细胞为条件的培养基诱导E-选择蛋白表达,这表明E-选择蛋白靶向具有广泛的适用性。
为了研究QA-NP和E/P-选择蛋白之间的相互作用是否有助于QA-NP扩散并进入肿瘤,我们使用了活体显微镜观察了表达GFP的MDA-MB-231肿瘤小鼠的QA-NP。从注射后2小时在血管附近观察到QA-NP。QA-NP信号随时间进一步迁移到肿瘤中而增加。该观察结果与体外Transwell结果相吻合,并提供了体内概念证明,即QA-NP与E/P-选择蛋白的相互作用改善了外渗并增强了肿瘤的积累。
QANP的体内全身成像
由于MDA-MB-231对HUVEC上E-选择蛋白表达的积极影响,我们选择了MDA-MB-231异种移植小鼠模型来评估QANP分布。我们假设QANP将通过E-选择蛋白与肿瘤周围内皮发生主动相互作用,跨内皮细胞转移,并在MDA-MB-231肿瘤中比依赖EPR效应的长循环NP积累更大的NP。为了通过全身荧光成像系统追踪NP随时间的分布,QANP用吲哚菁绿(ICG)(一种近红外荧光染料)标记。ICG通过碳二亚胺化学共价缀合到PLGA。与物理包裹ICG(ICG/NP)的裸NP相比,用ICG-PLGA缀合物(ICG-NP)制得的裸NP在50%FBS中孵育的NP中保持稳定,这表明ICG-NP的ICG荧光将代表体内成像中的NP。
通过尾静脉注射QANP、NP-pD-PEG NP(代表PEG化的长循环NP)和游离ICG,并在24小时内成像(图6)。给药后立即释放出游离的ICG,并通过肝胆消除逐渐清除,而QANP和NP-pD-PEG NP在肝脏中出现。从注射后2小时开始,观察到QANP的大量肿瘤蓄积,而在用游离ICG和NP-pD-PEG处理的动物中几乎未检测到荧光(表2)。随着时间的流逝,累积在肿瘤中的QANP逐渐减少,但持续了整个24小时的实验阶段。接受NP-pD-PEG和游离ICG的动物在所有时间点均未在肿瘤中显示荧光。奇怪的是,在肿瘤中根本没有观察到NP-pD-PEG。尽管不像LS174T异种移植血管那样过度血管化,但根据伊文思蓝积累的程度(LS174T/肌肉=1.34,MDA-MB-231/肌肉=1.04),MDA-MB-231异种移植的血管化程度仍高于肌肉组织。文献也支持MDA-MB-231肿瘤的血管形成和长循环NP的积累。我们不怀疑NP-pD-PEG中的PEG修饰不足。荧光检测阈值设置得太高以至于可能没有捕获到弱荧光的可能性更高。对另一组动物重复该实验,以确认结果的可重复性。接受QANP和NP-pD-PEG的动物在肿瘤中显示出不同的荧光信号,与先前的实验一致。
表2.紫杉醇,PTX@PEG-NP和PTX@QA-NP的血浆药代动力学参数
QANP器官分布的离体分析
全身成像完成后立即进行离体分析。在最终成像时间点后(注射后24小时),处死动物,并取回所有主要器官进行成像。该发现与全身成像结果一致(图7A)。在接受NP-pD-PEG的动物中,肝脏显示出最大的荧光信号,其次是肺和脾脏。尽管QANP在RES器官中积累,但与NP-pD-PEG相比,它们在肿瘤中的信号明显更高,而在肺部的信号更低。注射后6小时(从第二组实验中获得)的离体图像显示,肿瘤中的QANP信号强于肝或脾中的QANP信号,而肝和脾中的QANP信号的强度低于NP-pD-PEG的信号。
通过从组织匀浆中提取ICG标记的聚合物来量化每个器官中的ICG含量。尽管这种趋势与体外成像的趋势一致,但肝脏中的ICG水平显着高于其他器官,并且每个器官中两个NP之间的差异在统计学上也不显着(图7B)。我们将差异归因于使用ICG提取方法(对ICG提取进行三维分析与对离体成像的二维表面分析)和/或从致密肿瘤中ICG提取不完全时考虑到的其他维度的存在。
抗癌功效:与紫杉醇的比较
首先在皮下MDA-MB-231肿瘤的雌性裸鼠模型中以单剂量(20mg/kg PTX当量)测试PTX@QA-NP的抗癌功效。紫杉醇,一种可溶于市场的表面活性剂PTX制剂,以与参考相同的剂量使用。如图8A所示,PTX@QA-NP比紫杉醇更有效地减弱了MDA-MB-231肿瘤的生长。PTX@QA-NP的中位生存时间为62天,明显比紫杉醇更长(44天,p<0.01,对数秩检验)。对患有同源B16F10肿瘤的雄性C57BL/6小鼠进行相同的治疗。反映了已知的侵袭性,肿瘤的生长速度比MDA-MB-231快得多,但是PTX@QA-NP在相同剂量下仍比紫杉醇具有更好的肿瘤衰减能力。接下来,在2周内每三天以20mg/kg/剂量给予PTX@QA-NP(共五次:q3d x 5)(图8B)。PTX@QA-NP具有显着的生存优势,每5只动物中就有3只显示出超过200天的完全缓解(截至本报告提交之时),而紫杉醇组中只有1只在同一时期存活。根据肿瘤的大小,用紫杉醇治疗的两只动物达到了终点,一只患有溃疡的健康状况恶化,另一只没有明显的原因死亡。这些结果共同证明,在相同剂量下,PTX@QA-NP具有比紫杉醇更大的抗癌功效。
抗癌功效:与PEG-NP的比较
我们在确定的最大耐受剂量下将PTX@QA-NP与PTX@PEG-NP进行了比较。健康雌性裸鼠在2周内以30mg/kg/剂量的剂量注射了10剂PTX@QA-NP,但没有明显的体重减轻。因此,在2周的时间内,对具有皮下MDA-MB-231动物的雌性裸鼠进行以下治疗之一10次:(i)盐水;(ii)空白的QA-NP;(iii)空白PEG-NP;(iv)30mg/kg/剂量的PTX@PEG-NP;(v)30mg/kg/剂量的PTX@QA-NP。与盐水组相比,只有PTX@QA-NP组显示出生存获益,>200天时40%完全缓解(图9A)。所有其他组均死亡,中位生存时间为68天(盐水)、86天(QA-NP空白)、80天(PEG-NP空白)和70天(PTX@PEG-NP)。令人惊讶的是,PTX@PEG-NP组没有没有存活动物的阴性对照组。我们认为PTX@PEG-NP可能已经诱导了抗PEG抗体的产生,这将加速随后给药的PTX@PEG-NP的清除,如PEG化脂质体所证明(Y Mima等人,Molecular Pharmaceutics 2015,12,2429-2435;T Ishida等人,Journal of controlled release 2003,88,35-42)。
为了研究这种可能性,我们用盐水、空白PEG-NP或空白QA-NP处理健康的裸鼠,并在5天后采血,然后将血清添加到涂有mPEG或QA的板上以检测抗体的存在。接受PEG-NP的动物产生的抗体与PEG装饰的表面结合,而其他治疗(盐水,QA-NP)则没有(图9B)。QA-NP注射不会诱导抗QA抗体的产生。这些结果证明,通过重复施用,QA-NP比PEG-NP更有效地将PTX递送至肿瘤。
方案1.sLex的合成模拟物奎宁酸(QA)衍生物4的合成
材料和方法
材料.PLGA(LA:GA=85:15,游离酸,MW:150kDa)、荧光素偶联的PLGA(LA:GA=48:52,MW:5kDa)和PLGA-乙二胺(PLGA-NH2,LA:GA=57:43,MW:5kDa)购自Akina,Inc.(美国印第安纳州西拉斐特)。吲哚菁绿-N-琥珀酰亚胺酯(ICG-NHS)购自Intrace medical(瑞士洛桑)。Hoechst 33342和重组人肿瘤坏死因子-α(TNF-α)购自Invitrogen(美国俄勒冈州尤金)。甲氧基-聚乙二醇-胺(mPEG-NH2,MW:5kDa)购自美国JenKem Technology(美国德克萨斯州艾伦市)。胶原I尾巴购自BD Biosciences(美国加利福尼亚州圣何塞)。盐酸多巴胺购自Alfa Aesar(美国马萨诸塞州沃德希尔)。CellMaskTM深红色膜染色染料购自ThermoFisher Scientific(美国马萨诸塞州沃尔瑟姆)。E-选择蛋白抗体(P2H3)FITC和E-选择蛋白抗体(UZ5)FITZ购自Santa Cruz(美国德克萨斯州达拉斯)。具有3.0μm孔的Transwell聚碳酸酯膜细胞培养插入物(6.5mm)从Corning(Corning,NY,USA)购买。所有其他材料均购自Sigma-Aldrich(美国密苏里州圣路易斯)。
QA-NH2的合成
(lS,3R,4S,5R)-1,3,4,5-四乙酰氧基环己烷-1-甲酸(化合物2):将奎宁酸(化合物1,961mg,5mmol)溶于12mL乙酸酐-吡啶1:2混合物。将该溶液与4-二甲基氨基吡啶(20mg,0.16mmol)混合,并在5℃下搅拌12小时。然后将氨苯反应混合物加入冰水中,酸化至pH 3,并用二氯甲烷(DCM)萃取。萃取液用硫酸钠干燥并浓缩,得到白色固体(1.75g,97%产率)。ESI:(M+H)+:361。
(lR,2S,3R,5S)-5-((3-氨基-5-(甲氧羰基)苯基)氨基甲酰基)环己烷-1,2,3,5-四乙酸四乙酸酯(化合物3):化合物2(958mg,将2.7mmol)溶解在15mL的二甲基甲酰胺中。将该溶液与N-羟基苯并三唑(432mg,3.2mmol)混合,并在0℃下搅拌5分钟。然后将(1-乙基-3-[3-二甲基氨基丙基]碳二亚胺(612mg,3.2mmol)和三乙胺(0.5mL,4.3mmol)加入到混合物中,并在0℃搅拌1小时。最后,将3,5-二氨基苯甲酸甲酯(1.7g,7.7mmol)在二甲基甲酰胺(5mL)中的溶液添加至该混合物中,将其温热至室温并搅拌72小时。然后将反应混合物加入冰水中,并用DCM萃取。萃取液用硫酸钠脱水,过滤并进一步蒸发。将残余物通过硅胶上的柱色谱法纯化(己烷-乙酸乙酯3:7),得到褐色固体化合物(1.3g,产率92%)。ESI:(M+H)+:509。
3-氨基-5-((1S,3R,4S,5R)-1,3,4,5-四羟基环己烷-1-羧酰胺基)苯甲酸(化合物4):在室温下,将化合物3(102mg,0.2mmol)在四氢呋喃(5mL)中的溶液与氢氧化锂一水合物(63mg,1.5mmol)一起搅拌48小时。然后使用Amberlite酸性树脂将反应混合物酸化至pH 5,过滤,并通过C18反相硅胶(水-乙腈1:2)上的反相柱色谱法纯化,得到白色固体化合物(45mg,收率69%)。ESI:(M+H)+:327。
ICG缀合PLGA的合成
室温下将200毫克PLGA-乙二胺溶解在2mL DMSO中。将1.5mg ICG-NHS在室温下通过剧烈涡旋混合溶解在1mL DMSO中。将一毫升N,N-二异丙基乙胺(DIPEA)添加到PLGA溶液中,然后逐滴添加ICG-NHS溶液。将混合物不断搅拌2小时,放入分子量为3500Da的再生纤维素透析袋中(SpectrumLabs,Rancho Dominguez,CA,美国),并用过量的DMSO透析3次和DCM透析3次。通过旋转蒸发收集纯化的样品,并储存在-20℃。
制备核心PLGA NP
核心PLGA NP通过单乳液溶剂蒸发法生产。简而言之,将100mg的PLGA溶解在4mL的DCM中。将该聚合物溶液添加到12mL的4%聚乙烯醇(PVA)溶液中,并使用Sonics Vibracell探针超声仪(Sonics,Newtown,CT,美国)进行乳化2分钟。将乳液添加至40mL的去离子水中,并搅拌4小时以蒸发DCM。然后通过使用Optima MAX-XP超速离心机(贝克曼库尔特公司,布雷亚,加利福尼亚,美国)离心收集NP,并用去离子(DI)水洗涤3次。对于共聚焦显微镜和流式细胞术,用荧光素缀合的PLGA制备NP。对于体内光学成像,用缀合了ICG的PLGA制备NP。
粒子表面修饰
通过在室温下旋转旋转于Tris缓冲液(10mM,pH 8.5)中的2mL多巴胺盐酸盐溶液中孵育3小时,用pD包被核心NP。通过超速离心收集涂有pD的PLGA NP(NP-pD),并用去离子水洗涤两次。为了进一步进行表面功能化,将NP-pD重悬在含有QA-NH2或mPEG的Tris缓冲液中,使NP-pD与配体的重量比保持在1:2。孵育30分钟后,通过超速离心收集NP,并用去离子水洗涤两次。将表面官能化的NP分别命名为NP-pD-QA(或QANP)和NP-pD-PEG。
QA-NH2配体密度的定量
将已知量的NP-pD重悬于含有已知量QA-NH2(QA-NH2进料)的Tris缓冲液(10mM,pH8.5)中。温育30分钟后,通过超速离心收集NP,并通过HPLC分析上清液以确定未缀合的游离QA-NH2的量。通过从QA-NH2进料中减去游离QA-NH2来计算表面缀合QA-NH2。通过将表面缀合的QA-NH2的数目除以NP-pD的总表面积来计算QA-NH2的配体密度。
颗粒表征
将NP分散在磷酸盐缓冲液(1mM,pH 7.4)中,并通过Malvern Zetasizer NanoZS90(英国伍斯特郡)测量其大小和ζ电势。在用乙酸铀酰进行负染后,通过TecnaiTM透射电子显微镜(FEI,Hillsboro,OR,美国)观察到NP形态。通过QANP的电喷雾电离质谱(ESI-MS)分析确认了QA-NH2的表面装饰。PEG-NH2表面装饰通过..
QANP的血清稳定性
为了评估尺寸稳定性,将5mg的QANP悬浮在5mL的50%FBS中,并在室温下孵育2小时。粒度分布通过Malvern Zetasizer Nano ZS90测量。为了评估荧光稳定性,将ICG标记的QANP悬浮在50%FBS中。在预定的时间点通过超速离心分离NP沉淀和上清液,并用IVISLumina成像以检测荧光强度。
细胞培养
在第4代中,人脐静脉内皮细胞(HUVEC,ATCC,Manassas,VA,美国)在EGM-2完全培养基中生长。在培养板上预先涂有5μg/cm2的I型大鼠尾胶原。将人乳腺腺癌细胞(MDA-MB-231,ATCC;MCF-7,ATCC)在补充了10%胎牛血清(FBS)的Dulbecco改良的Eagle培养基(DMEM)中培养。在补充了10%FBS的Eagle基本必需完全培养基(EMEM)中培养人结肠腺癌细胞(LS174T,ATCC)。在补充了10%FBS的GibcoTMRPMI1640培养基(RPMI)中培养人卵巢癌细胞(A2780,ATCC)。在补充有10%FBS的DMEM中培养人卵巢癌细胞(NCI/ADR-RES)。所有培养基均补充有100单位/mL的青霉素和100μg/mL的链霉素。当所有细胞融合到70-80%时,以1:7.5的比例继代培养。
共聚焦显微镜和流式细胞仪
将HUVEC接种在35mm培养皿中,该培养皿带有涂覆有I型大鼠尾胶原的玻璃窗(MatTek Corporation,Ashland,MA,USA),并在EGM-2Bullet Kit完全培养基中生长。当HUVEC融合约80%时,将细胞与含有10ng/mLTNF-α的EGM-2孵育4小时。用含有0.2mg/mL荧光标记的NP悬浮液的EGM-2代替培养基,并在37℃下孵育2小时。用含有0.5μMCellMask TM深红色膜染色染料的新鲜EGM-2培养基代替悬浮液。10分钟后,将细胞用PBS轻轻清洗两次。在成像前10分钟,加入Hoechst核染色剂(浓度为0.2mg/mL的10μL)。使用配备有SpectraPhysics 163C氩离子激光器和相干CUBE二极管激光器的Nikon AIR共聚焦显微镜进行共聚焦显微镜成像。使用346、633和649nm激光分别激发NP、细胞核和细胞膜。
对于流式细胞术,以与上述相同的方式用NP处理HUVEC,并用PBS轻轻洗涤两次以除去游离或松散结合的NP。然后将细胞用胰蛋白酶消化,在930×g离心5分钟后收集,在0℃下重悬于0.2mL PBS中,并用配备了FL-1检测器(λex/λem=488/525nm)的Accuri C6流式细胞仪(BD Biosciences,San Jose,CA,USA)进行分析。为了进行竞争分析,在进行NP处理和流式细胞术之前,将已知浓度的游离QA-NH2或E-选择蛋白抗体与HUVEC预孵育30分钟。
内皮迁移试验
将HUVEC接种在涂有I型鼠尾胶原的Corning Transwell插入物中,并在EGM-2Bullet Kit完全培养基中生长。每天都通过EVOM2TM上皮伏特计(世界精密仪器公司,萨拉索塔,佛罗里达州,美国)监测整个Transwell插入物的跨内皮电阻(TEER)。当整个插入片段的TEER值达到平稳时,将细胞用10ng/mLTNF-α处理4小时,然后与0.1mg/mL荧光标记的QANP孵育8小时。用FluoroMax 3分光荧光计(Horiba Scientific,Edison,NJ,美国)测量孵育前总NP的荧光强度和孵育后上下Transwell隔室的NP的荧光强度。
肿瘤介质对E-选择蛋白的内皮上调
将HUVEC以10,000个细胞/cm 2的密度接种在涂覆有I型大鼠尾胶原的6孔板中。当HUVEC融合约70-80%时,将细胞暴露于以MCF-7、MDA-MB-231、LS174T、A2780和NCI-ADR细胞为条件的培养基中4小时。用胰蛋白酶消化HUVEC,并通过离心收集。将细胞沉淀重悬于PBS中,并用20μL(相当于1×制造建议剂量)的FITC标记的抗E-选择蛋白抗体染色。E-选择蛋白上调的程度,如果有的话,通过流式细胞术定量。
体内全身成像
所有动物程序均已通过Purdue动物护理和使用委员会的批准,符合NIH关于实验室动物的护理和使用的准则。从Envigo(印第安纳州印第安纳州,IN,美国)购买6-7周龄的雌性无胸腺裸鼠(Foxnlnu),并在手术前适应1周。每只小鼠通过皮下注射在后腿侧面接收5×106MDA-MB-231细胞。当平均肿瘤体积达到200mm3时,每只小鼠通过尾静脉注射在PBS中接受6mg ICG标记的QANP或NP-pD-PEG。用IVIS Lumina系统(Caliper Life Sciences,霍普金顿,马萨诸塞州,美国)对动物进行成像,以检测48小时内的近红外荧光信号。48小时后,处死小鼠,取回肿瘤和主要器官并用IVIS Lumina系统成像。为了定量每个器官中的ICG含量,使用Tissue Master匀浆器(Omni International,肯尼索,GA,美国)在DMSO中匀浆肿瘤和主要器官。离心器官匀浆,并从每个匀浆中取样0.1mL上清液,并用IVIS Lumina系统进行分析。
在NP中封装用于癌症治疗的药物
通过遵循本领域技术人员已知的技术,可以容易地将疏水性和亲水性癌症治疗剂封装在NP中。特别地,以下提供了使用聚酯和多酚制成的NP来封装癌症治疗的示例。多酚化合物的实例包括单宁酸、连苯三酚、表儿茶素没食子酸酯、表没食子儿茶素没食子酸酯等。
(i)通过乳液法将疏水性药物包裹在聚酯NP中,将疏水性药物和聚酯溶解在二氯甲烷或乙酸乙酯中,然后在含有乳化剂的水溶液中进行乳化。在持续搅拌下通过旋转蒸发来蒸发溶剂。固化的NP用水洗涤并冻干直至使用。
(ii)将亲水性药物通过乳液法封装在聚酯NP中,然后将亲水性药物溶于水并在含有聚酯的有机溶液中进行乳化。如此形成的初级乳液在含有乳化剂的水溶液中乳化。在持续搅拌下通过旋转蒸发来蒸发溶剂。固化的NP用水洗涤并冻干直至使用。
(iii)将疏水性药物封装在多酚纳米胶囊中,将疏水性药物溶解在乙醇或其他合适的溶剂中,并与鞣酸的浓乙醇溶液混合。向该混合物中加入一定体积的含氯化铁的水,以形成在界面处涂覆有聚合单宁酸组件的富含药物的纳米核。通过离心和重悬于水中几次洗涤颗粒,以去除过量的鞣酸、氯化铁和未截留的药物。
(iv)将亲水性药物封装在多酚纳米胶囊中,将亲水性药物高浓度溶于水并与表面活性剂一起分散在甘油中。分散后,立即添加鞣酸和氯化铁以稳定界面。用水洗涤所得的NP以除去甘油。
(v)纳米晶体疏水性药物。将疏水性药物和表面活性剂溶于圆底烧瓶中的氯仿中。使用旋转蒸发仪蒸发有机溶剂以形成薄膜,然后在水中水合。将水合的药物-表面活性剂混合物超声处理以形成纳米晶体,与白蛋白温育并用水洗涤。
统计分析
所有统计分析均使用GraphPad Prism 7(位置)进行。所有数据均采用单向或双向方差分析进行分析,以确定各组之间均值的统计显着性,然后进行邓尼特或邦费罗尼的多重比较检验。小于0.05的p值被认为具有统计学意义。
本领域技术人员将认识到,可以对上述特定实现方式进行多种修改。实施方式不应限于所描述的特定限制。其他实施方式是可能的。
尽管已经在附图和前面的描述中详细示出和描述了本发明,但是本发明应被认为是示例性的,而不是限制性的,应理解,仅示出和描述了某些实施例,并且希望保护落入本发明的精神之内的所有改变和修改。
意图是,本方法和组合物的范围由所附权利要求书限定。然而,必须理解,可以在不脱离本发明的精神或范围的情况下以不同于具体解释和说明的方式来实践本公开。本领域技术人员应当理解,在不脱离所附权利要求书所限定的精神和范围的情况下,可以在实践权利要求书时采用本文所述实施例的各种替代方案。
Claims (17)
1.一种选择性靶向E-选择蛋白或P-选择蛋白阳性细胞或组织的奎尼酸修饰的纳米粒子(QANP),包含:
a.纳米粒子(NP);
b.包含聚合多巴胺(pD)的多酚化合物,pD包覆NP;和
c.奎尼酸衍生物,具有以下分子式:
其中通过以1∶2的被包覆的NP与奎尼酸衍生物的重量比孵育被包覆的NP,以使奎尼酸衍生物以能够结合选择蛋白的方向与被包覆的NP的表面结合,使得所述多酚化合物被所述奎尼酸衍生物修饰。
2.根据权利要求1所述的QANP,其中所述NP选自:聚(乳酸-co-羟基乙酸)(PLGA)、聚乙二醇-PLGA缀合物、D-α-生育酚聚乙二醇1000琥珀酸酯(TPGS)-PLGA缀合物、聚乳酸(PLA)、介孔二氧化硅、脂质体和多酚聚集体。
3.根据权利要求1所述的QANP,其中所述NP包含一种或多种封装的治疗药物。
4.根据权利要求3所述的QANP,其中所述治疗药物选自紫杉醇、索拉非尼、伊曲康唑、多西他赛、阿霉素、硼替佐米、卡非佐米、喜树碱、顺铂、奥沙利铂、阿糖胞苷、长春新碱、伊立替康、两性霉素B、吉西他滨、多粘菌素、地塞米松和维生素D。
5.根据权利要求1所述的QANP,其中QANP在被包覆的NP表面上具有25QA/nm2至100QA/nm2的奎尼酸衍生物(QA)密度。
6.根据权利要求1所述的QANP,其中所述P-选择蛋白或E-选择蛋白-阳性细胞或组织是癌细胞或组织,或者是癌细胞或组织周围的内皮细胞。
7.一种药物组合物,包含根据权利要求1-6中任一项所述的QANP,以及一种或多种赋形剂或载体。
8.根据权利要求7所述的药物组合物,其中所述药物组合物用于治疗患有癌症的患者。
9.一种选择性靶向E-选择蛋白-或P-选择蛋白-阳性细胞或组织的奎尼酸-修饰的纳米粒子(QANP)的制备方法,包括以下步骤:
a.制备纳米粒子(NP);
b.使用多酚化合物包覆所述NP,包含聚合多巴胺(pD);和
c.通过将被包覆的NP悬浮在含有奎尼酸衍生物的第一缓冲液中来提供所述QANP,其中被包覆的NP与奎尼酸衍生物的重量比为1∶2,由此使用奎尼酸衍生物修饰多酚包覆的NP以得到所述QANP;
其中奎尼酸衍生物具有以下结构:
10.根据权利要求9所述的方法,其中所述NP包含一种或多种治疗药物。
11.根据权利要求9所述的方法,其中用多酚化合物包覆所述NP还包括将NP悬浮在第二缓冲液中的多巴胺盐酸盐溶液中,第二缓冲液包含pH 8.5的10mM Tris缓冲液。
12.根据权利要求9所述的方法,其中所述NP由PLGA、聚乙二醇-PLGA缀合物、D-α-生育酚聚乙二醇1000琥珀酸酯(TPGS)-PLGA缀合物、聚乳酸(PLA)、介孔二氧化硅、脂质体和多酚聚集体制成。
13.根据权利要求9-12中任一项所述的方法制造的药物产品,以及一种或多种赋形剂或载体。
14.根据权利要求9-13中任一项所述的方法制造的药物组合物,以及一种或多种赋形剂或载体。
15.根据权利要求9所述的方法,其中所述P-选择蛋白或E-选择蛋白-阳性细胞或组织是癌细胞或组织,或者是癌细胞或组织周围的内皮细胞。
16.根据权利要求7、8、13和14中任一项所述的药物组合物在制备用于治疗受试者的癌症的药物中的用途。
17.根据权利要求9的方法,其中包覆所述NP的步骤独立于用奎尼酸衍生物修饰多酚包覆的NP的步骤并在其之前进行。
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