CN112533641A - 药物递送产品、组合物和系统 - Google Patents
药物递送产品、组合物和系统 Download PDFInfo
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- CN112533641A CN112533641A CN201980051763.XA CN201980051763A CN112533641A CN 112533641 A CN112533641 A CN 112533641A CN 201980051763 A CN201980051763 A CN 201980051763A CN 112533641 A CN112533641 A CN 112533641A
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Abstract
本发明公开了一种缀合物,所述缀合物包含:(a)纳米金刚石;(b)通过物理吸附粘附在纳米金刚石表面上的人血清白蛋白(HSA);和(c)与所述人血清白蛋白化学地连接的药物分子,其中所述药物分子具有治疗效果。
Description
技术领域
本发明涉及一种药物递送产品、组合物和系统,特别是本发明提供了用于向受试者递送具有降低的毒性副作用的药物的一种药物递送产品、组合物和系统。
背景技术
化学疗法目前被认为是世界上最常见的癌症治疗方法,然而药物典型地带来相关的副作用。
在临床实践中,副作用仍然是癌症疗法和治疗中具有挑战性的问题。减少与药物或疗法相关的副作用是一个重要的问题,因为这还涵盖药物的实际治疗效果。
可以利用药物递送系统(DDS)的设计来解决或至少改善这些副作用问题中的一些。DDS可以包括特定的药物靶向/递送、在维持治疗效果的同时降低毒性,以及开发新的且更安全的药物。
已经开发的大多数先进药物递送系统(DDS)的目的是改善药物产品或活性药物成分(API)的生物利用度,包括通过防止或减少过早降解以及增强药物吸收,这可以通过控制药物释放速率来显示出将药物浓度保持在必需的治疗窗口内,这已经显示出通过靶向患病部位和靶细胞来减少副作用。
在现有技术中,已经进行了许多尝试和开发,例如,通过组合新的或新型材料以便携带和递送抗癌药物、从而使药物递送过程中的任何副作用最小化的靶向癌症疗法。
在现有技术中,已经提出了用于生物学和医学、用于生物成像以及用于药物递送的各种纳米结构材料。
在现有技术中,将纳米颗粒载体用于药物递送以进行药物靶向运输和药物及API的释放。
例如,已经显示纳米颗粒刺激耐药细胞的内吞作用,从而提高细胞内药物浓度。
然而,人们一直关注递送颗粒(诸如纳米颗粒)的使用,所述递送颗粒存在与受试者体内的毒性和积累有关的问题、以及聚集在一起形成此类递送颗粒的问题,并且因此需要将药物有效地加载到颗粒中以及有效且持续地递送到受试者体内。
此外,药物递送系统应该能够适当地控制API向受试者的释放和递送,以便具有适合于特定应用的释放曲线,例如出于治疗目的向受试者提供必需的血浆浓度。
因此,为了克服现有技术的这种缺点,改善受试者的生活质量,需要一种改进的药物递送产品、组合物和系统。
发明目的
本发明的目的是提供克服或至少部分改善与现有技术相关的至少一些缺陷的药物递送产品、组合物和系统。
发明内容
在第一方面,本发明提供了缀合物,所述缀合物包含纳米金刚石、通过物理吸附粘附在纳米金刚石表面上的人血清白蛋白(HSA)、和与所述人血清白蛋白化学地连接的药物分子,其中所述药物分子具有治疗效果。
优选地,所述药物分子是抗癌药物分子。癌症可以是淋巴结、肝、肺、骨、肾、脑、胃、肝或结肠组织的癌症。
药物分子可以是盐酸多柔比星C27H29NO11(DOX)。
药物分子可以是甲氨蝶呤C20H22N8O5(MTX)。
优选地,纳米金刚石具有在25nm至80nm范围内、更优选地在35nm至65nm范围内的尺寸,并且更优选地,纳米金刚石具有约50nm的尺寸。
在第二方面,本发明提供了一种药物溶液,所述药物溶液包含多种缀合物和液体载体,其中所述缀合物包含(a)纳米金刚石;(b)通过物理吸附粘附在纳米金刚石表面的人血清白蛋白(HSA);和(c)与所述人血清白蛋白化学地连接的药物分子,其中所述药物分子具有治疗效果。
优选地,所述药物分子是抗癌药物分子。癌症可以是淋巴结、肝、肺、骨、肾、脑、胃、肝或结肠组织的癌症。
药物分子可以是盐酸多柔比星C27H29NO11(DOX)。
药物分子可以是甲氨蝶呤C20H22N8O5(MTX)。
优选地,纳米金刚石具有在25nm至80nm范围内、更优选地在35nm至65nm范围内的尺寸,并且更优选地,纳米金刚石具有约50nm的尺寸。
在第三方面,本发明提供了缀合物用于制造用于预防或治疗受试者的药物的用途,其中所述缀合物包含(a)纳米金刚石、(b)通过物理吸附粘附在纳米金刚石表面的人血清白蛋白(HSA)、和(c)与所述人血清白蛋白化学地连接的药物分子,其中所述药物分子具有治疗效果。
优选地,所述药物分子是抗癌药物分子。癌症可以是淋巴结、肝、肺、骨、肾、脑、胃、肝或结肠组织的癌症。
药物分子可以是盐酸多柔比星(DOX)。
药物分子可以是甲氨蝶呤C20H22N8O5(MTX)。
在第四方面,本发明提供了一种向有需要的受试者提供治疗性治疗的方法,所述方法包括向所述受试者递送治疗量的药物溶液的步骤,其中所述药物溶液包含多种缀合物和液体载体,其中所述缀合物包含(a)纳米金刚石、(b)通过物理吸附粘附在纳米金刚石表面的人血清白蛋白(HSA)、和(c)与所述人血清白蛋白化学地连接的药物分子,其中所述药物分子具有治疗效果。
优选地,所述药物分子是抗癌药物分子。癌症可以是淋巴结、肝、肺、骨、肾、脑、胃、肝或结肠组织的癌症。
药物分子可以是盐酸多柔比星(DOX)。
药物分子可以是甲氨蝶呤C20H22N8O5(MTX)。
附图说明
为了可以获得对上述发明的更精确的理解,将通过参考附图中示出的本发明的具体实施方案来使得对上面简要描述的本发明有更具体的描述。本文呈现的附图可能不是按比例绘制的,并且附图中对尺寸的任何提及或以下描述对于所公开的实施方案而言是特定的。
图1(a)显示了在不同pH值(即pH7、pH8和pH9)下ND-HAS-DOX缀合物的UV-可见光谱;
图1(b)显示了在不同pH值(即pH7、pH8和pH9)下ND-HAS-DOX的吸收的图示;
图1(c)显示了ND、ND-HAS、DOX、ND-DOX和ND-HAS-DOX的FTIR光谱;
图1(d)显示了在不同pH值(即pH7、pH8和pH9)下50ND-DOX的释放速率的图示;
图1(e)显示了在不同pH值(即pH7、pH8和pH9)下50ND-HAS-DOX的释放速率的图示;
图2(I)显示了SAS细胞与游离DOX孵育4小时的相互作用的共焦图像;
图2(II)显示了SAS细胞与ND-HAS DOX复合物孵育4小时的相互作用的共焦图像;
图3(a)显示了在不同浓度的DOX下用游离DOX和50ND-HAS-DOX处理24小时之后的细胞活力的图示;
图3(b)显示了在不同浓度的DOX下用游离DOX和50ND-HAS-DOX处理48小时之后的细胞活力的图示;
图3(c)显示了在不同浓度的DOX下用游离DOX和50ND-HAS-DOX处理72小时之后的细胞活力的图示;
图4(a)显示了MCTS与DOX孵育1天之后的共焦图像;
图4(b)显示了MCTS与ND-DOX孵育1天之后的共焦图像;
图4(c)显示了MCTS与ND-HAS-DOX孵育1天之后的共焦图像;
图4(d)显示了MCTS与DOX孵育2天之后的共焦图像;
图4(e)显示了MCTS与ND-DOX孵育2天之后的共焦图像;
图4(f)显示了MCTS与ND-HAS-DOX孵育2天之后的共焦图像;
图5(I)显示了用ND、DOX和50ND-HAS-DOX处理4天的MCTS的光学图像;并且
图5(II)显示了在处理期间的MCTS体积变化的图示。
具体实施方式
发明(1.)
本发明人已经鉴定了药物递送系统的缺点,并且已经提供了具有以下优点的药物递送产品、组合物和系统:
(a)没有毒性的药物递送载体/颗粒,
(b)减少的颗粒聚集,
(c)增加的递送系统药物加载;
(d)在癌症部位提供释放机制;
(e)药物化合物或治疗剂在位点特异性治疗部位的递送和卸载;以及
(f)改进的API向受试者递送的释放速率和一致性。
在这个背景下,本发明人已经利用纳米金刚石(ND)开发了一种纳米药物产品,所述纳米药物产品可以通过使用酸敏感性来减少不良副作用,并增强药物递送的效率。
根据本发明,通过物理吸附将人血清白蛋白(HSA)粘附在纳米金刚石(ND)的表面上,并将HAS与抗癌药物盐酸多柔比星(DOX)化学地连接以形成缀合物。
纳米金刚石(ND)已被提议作为将活性药物成分递送至有需要的受试者的手段,或者在一些情况下用于预防目的。已经发现纳米金刚石是无毒和生物相容的,并且因此,被认为是既适用又适合于体内使用的。
纳米金刚石(ND)的用途(2.)
纳米金刚石(ND)是碳族中相对较新的一类纳米材料,具有优异的物理和化学特性来用于这些目的,有用于在药物递送系统中使用的潜力。
ND的光谱信号(拉曼和荧光)可以用于生物标记或成像。ND晶格结构的碳sp3性质提供了既强又孤立的独特拉曼信号(约1332cm-1)。
来自晶格缺陷以及纳米尺寸效应的ND天然荧光进一步为生物成像提供了另一种标记。
已经表明,ND的生物相容性在过去几年已经得到了深入的研究,并且已经研究了不同生物系统的ND毒性。
对于纯的/表面官能化的ND与生物分子的缀合物,研究了ND与不同种类的细胞培养物和生物组织的相互作用。通过利用ND的表面特性,ND表面可以被各种分子和离子基团官能化,随后通过物理吸附或化学连接与感兴趣的生物分子进一步缀合,从而使ND成为理想的药物递送平台。
提出了将生物分子或药物固定在ND上的各种方法,并且现有技术中已经证明了成功的药物和基因递送[26-31]。然而,尤其是对于宽度小于50nm的纳米金刚石,纳米颗粒聚集(诸如纳米金刚石(ND)聚集)在药物递送应用中可能是有问题的。
这可能是因为纳米金刚石的表面积与体积之比较大,由此它们倾向于聚集并形成更大的聚集颗粒,从而降低表面能和容量。
因此,这些大的聚集的纳米金刚石可能不会均匀地扩散到靶向区域上,并且纳米金刚石与靶向区域之间的接触面积可能会减小和受损。
这导致以下问题,诸如:
(i)需要高得多的药物剂量/量来实现具有纳米金刚石聚集的药物的相同效果;
(ii)举例来说,大的聚集的纳米金刚石作为诊断剂可能不会正常工作,因为错过任何阳性结果的机会很高或增加了;以及
(iii)聚集的纳米金刚石的尺寸可能太大,无法在人体体液中顺畅流动,并且在一些情况下可能危及受试者的安全。
生物学方面、测定和方法(3.)
已知,几十年来,二维(2D)单层细胞培养模型一直被用作评价纳米颗粒生物性能的药物代谢、毒性的工具。
这样的平台易于操作,具有成本效益,提供良好的可再现性,并且能够使无数不同的细胞类型生长,这使得2D培养成为最常用的临床前体外化学疗法开发方法之一。
然而,这些2D模型有严重的局限性,因为它们缺乏生物模拟,并且它们不能提供体内存在的三维(3D)细胞信息。
此外,这样的2D培养的细胞是异常的基因和蛋白质表达,这是由获得人工极性的拉伸和经历细胞骨架重排引起的。
最近,有新的临床前方法,即用于检测药物效果和纳米毒性评估的3D组织样培养系统。3D培养系统在不同的方法(诸如支架、生物芯片和球状体)中在具有各种细胞类型的情况下仅促进癌细胞生长,从而鼓励非常类似于肿瘤自然环境的细胞-细胞和细胞-基质相互作用。这些相互作用导致3D培养细胞获得与体内肿瘤相关的形态和细胞特征。
为了形成肿瘤,癌细胞的一个特征是形成球状体。球状体模型(也称为多细胞肿瘤球状体(MCTS)),类似于组织,但不具有帮助细胞附着的人工基底。它们是在液体中形成的,其中将琼脂糖涂覆在培养瓶上防止细胞粘附。由于细胞特征和培养条件,球状体显示出多种形态诸如圆形、块状、葡萄状、星形。
在药物设计和药物递送方面有许多研究使用MCTS模型来证明药物效果。MCTS由坏死细胞的最内层(有凋亡细胞位于坏死区周围),包围最内层的静止的活细胞中间层和高度增殖和迁移细胞的最外层构成。
由于细胞形态不同于单层细胞,所述药物效率可能会降低。MCTS是一种模拟模型,其不仅能够帮助改进化学疗法药物或开发药物,而且还能有利地减少动物实验模型中所需的动物量。
科学家已经证明,药物靶向递送是通过不同的方法(诸如pH响应释放药物、抗体缀合)靶向的。人血清白蛋白(HSA)是血浆中具有许多重要生理功能的最丰富的蛋白质,已被证明、被证明能够通过pH响应释放药物来靶向癌症[42-45]。
研究已经表明,通过与HSA结合将药物递送至其靶向器官/组织[46,47]。此外,HSA还直接或通过结合和携带自由基清除剂占据了人血清的大部分抗氧化能力。HSA不仅抗氧化和影响体内药物分布,而且还影响药物的药代动力学[46]。因此,HSA已被本发明人鉴定为具有作为药物载体的良好潜力的物质。
本发明—概述和解释(4.)
根据所描述和要求保护的本发明,提供了对比研究,其显示ND-药物复合物在2D和3D人口腔鳞状癌细胞(SAS)细胞模型中的效率。
使用UV/可见光谱和FTIR光谱来表征ND-HAS-DOX缀合。还测量了不同pH下从ND-HSA-DOX的DOX释放。
可以通过在2D和3D细胞模型中的激光共焦荧光图像测量ND、ND-药物的细胞摄取和渗透,以确认检测到ND和DOX的共定位。
使用SAS细胞系进行细胞活力测试,以比较DOX和ND-HSA-DOX复合物的细胞毒性作用。
通过MTT测定在2D和3D SAS细胞模型中评估DOX和ND-HSA-DOX复合物的细胞毒性作用,并计算多细胞肿瘤球状体(MCTS)体积。
结果表明,证明了从ND-HSA-DOX复合物的pH依赖性药物释放,并且ND-HSA-DOX在3D培养细胞中比在2D培养细胞中更有效。
因此,实验研究支持并证明了酸敏感性ND-药物复合物拥有作为本发明提供的纳米尺度药物的广泛药物功能化平台技术的潜力,并且3D细胞模型呈现了药物递送至人体或动物体内肿瘤的真实效果。
ND-HSA、ND-HSA-DOX和ND-DOX的合成、表征和分散(5.)
根据本发明的细节进行了研究,使用从Kay Diamond,USA购买的平均直径为50nm的合成纳米金刚石粉末,然后进行羧基化。
根据诸如在Chung PH,Perevedentseva E,Tu JS,Chang CC,Cheng CL:Spectroscopic study of bio-functionalized nanodiamonds.Diam Relat Mater 2006,15(4-8):622-625中详细描述的方法对ND进行羧基化[48]。
在将抗癌药物盐酸多柔比星(DOX)涂覆到ND上之前,为了提供ND表面的修饰和避免ND聚集,首先将人血清白蛋白(HSA)吸附在ND表面上。
使用UV-可见光谱来表征吸附在ND表面上的人血清白蛋白(HSA)。
HSA的吸收光谱典型地在280nm处具有吸收带,对应于三种类型的芳香族残基的UV光吸收:(1)色氨酸(Trp),(2)苯丙氨酸(Phe)和(3)酪氨酸(Tyr)。
在所列举的三种芳香族氨基酸中,有最强的吸收和发射是Trp,它比酪氨酸和苯丙氨酸两者具有更高的摩尔吸收率和固有荧光量子产率[49]。
已经证明,HSA已经被物理吸附到纳米金刚石的表面上,由此HSA吸附在纳米金刚石上的机制是由疏水性吸引、氢键和离子吸引引起的(Lee JW,Lee S,Jang S,Han KY,KimY,Hyun J,Kim SK,Lee Y:Preparation of non-aggregated fluorescent nanodiamonds(FNDs)by non-covalent coating with a block copolymer and proteins forenhancement of intracellular uptake.Mol Biosyst 2013,9(5):1004-1011)[50]。
HSA与带负电荷的ND表面之间的净负电荷可以诱导它们之间的排斥相互作用,但是疏水性相互作用和氢键可以诱导它们之间的吸引相互作用[51,52]。
在没有缀合HSA的情况下,50nm ND颗粒的尺寸大于1um(在2100nm左右)。50ND-HSA复合物显著减小,平均尺寸为约144nm。“ζ-电位显示50nm ND在表面上带负电荷,为-22mV。阴离子氨基酸残基导致HSA在中性pH环境下带负电荷[53,54]。
与HSA缀合之后,50ND-HSA的ζ-电位为-15mV左右。ND显示出较少的负ζ-电位,这是相当合理的。在每天同一时间制备五个ND-HSA样品,每个样品测量5天。
ND-HSA复合物的尺寸和表面电荷在5天内尺寸保持稳定,因此聚集程度低并且实现了分散良好的ND溶液。
在确认ND-HSA在磷酸盐缓冲盐水(PBS)中稳定之后,将ND-HSA与DOX在PBS缓冲液中缀合。将未吸附在纳米金刚石上的DOX洗掉(通过两次离心和用PBS洗涤)。
ND-HSA-DOX复合物已通过离心沉淀。为了比较HSA的功能,还通过相同的方法但是在没有HSA处理的情况下制备了ND-DOX。
在与DOX缀合之后,确定了ND、ND-DOX、ND-HSA-DOX的尺寸和ζ电位。发现50ND、50ND-HSA的平均尺寸在2100nm和144nm左右。
在与DOX缀合之后,ND、ND-HSA在PBS中的尺寸分别增加到2966nm和155nm。50ND-HSA-DOX和50ND-DOX的ζ-电位被发现在-15mV左右。在结合HSA的情况下,ND-HSA-DOX仍然足够小,足以通过胞吞途径被摄取[55]。
盐酸多柔比星(DOX)的加载和释放(6.)
在利用根据本发明的HAS中间体时,ND表面上的DOX吸附可以利用ND上的羧酸基团和DOX分子上的质子化胺之间的静电相互作用。
然而,DOX与ND-HSA复合物的缀合是化学连接的,因为HSA含有半胱氨酸34结构,这有助于HSA缀合到DOX上[49,56]。
ND-HSA复合物上的DOX加载和药物加载效率可能受到不同pH条件的影响。将UV-可见光谱用于分析药物加载的优化。
如图1(a)所示,已证明DOX在PBS溶液的不同pH值下可能具有不同的加载效率。
相应地,DOX加载分别估计为107.4μg(pH 7)、191.2μg(pH 8)和187.4μg(pH 9)。
参考图1(b),DOX加载的比率显示在pH 7、8和9下分别为54.2%、95.5%和93.6%。通过使用线性回归将UV-可见吸光度转换为浓度来确定吸附的DOX。
因此,这些图1(a)和(b)显示了通过利用ND-HSA复合物的pH响应特性实现的药物加载和加载效率。已经显示ND-HSA展现出pH响应性药物吸附特性。
为了确认DOX、ND、ND-HSA、ND-DOX、ND-HSA-DOX复合物的表面化学,通过FTIR光谱对它们进行表征。
图1(c)表示FTIR光谱很复杂,并且最强的峰位于1000-1700cm-1的范围内。DOX的振动光谱揭示了醇基团的C-O拉伸(1072、1119和1206cm-1)、N-H平面弯曲(1612和1581cm-1)、C-C拉伸(1405cm-1)、C-O-C拉伸(1284和992cm-1)[57]。如图1(d)和图1(e)所示,通过分别在pH 6.0、7.0和8下针对PBS溶液进行透析来评估ND-DOX和ND-HSA-DOX的DOX释放特征。
从数据中清楚地看出,ND-DOX和ND-HSA-DOX的DOX释放特征是pH依赖性的,并且在所有pH值下都具有类似的结果。
为了通过经由酸敏感性由ND-HSA-DOX复合物缓慢释放DOX来限制在有益效果的范围内,当ND或ND-HSA加载有抗癌药物DOX时,它们被释放以协同地杀死癌细胞。
如图2I和2II的图像所示,通过使用共焦激光扫描显微镜检查(CLSM),将DOX在SAS细胞内的细胞内运输和分布用于进一步研究所述结果。
如图所示,用发出蓝色荧光(440nm-484nm)202的Hoechst 33324对细胞核染色,并且游离DOX或从ND-HSA-DOX复合物中释放的DOX表现出红色荧光(565-620nm)204。
50nm ND荧光用488nm激发,并在500-515nm范围内进行收集。此范围内的ND荧光主要对应于来自金刚石H3缺陷中心的发射,其中发射峰在505nm附近,显示为绿色206。还提供了所证明的亮场来揭示SAS细胞的形态。
在用相同剂量的DOX(20μg/ml)孵育4小时后,如图2(I)所示为对照组,图2(I)(b)未显示ND的绿色荧光。
如图2(I)(c)所示,相对红色的荧光204出现在细胞质中,为被SAS细胞吞噬的少数DOX,并且发现DOX的强红色荧光开始出现在细胞核中。
然而,许多游离DOX分布在细胞质中,因为游离DOX在细胞中分布更均匀并逐渐渗透到细胞核中,如图2(I)(e)所示。
图2(II)显示了ND-HSA-DOX组,其中显示了SAS与ND-HSA-DOX相互作用的图像。图2(II)(b)显示了ND的绿色荧光206。观察到ND定位于细胞质中和细胞核附近,但从未渗透到细胞核中。这证明了文献[17,58]中以前观察到的ND在细胞质中的分布。
如图2(II)(c)和图2(II)-(e)所示,ND-HSA-DOX复合物也定位在细胞质中,来自DOX和ND的信号没有观察到共定位,并且观察到的DOX的强红色荧光204开始出现在细胞核中,ND仅在细胞核附近,表明许多ND-HSA-DOX已经进入细胞,并且许多DOX从ND-HSA-DOX复合物中释放。
Zhu H,Wang Y,Hussain A,Zhang ZP,Shen YY,Guo SR:Nanodiamond mediatedco-delivery of doxorubicin and malaridine to maximize synergistic anti-tumoreffects on multi-drug resistant MCF-7/ADR cells.J Mater Chem B 2017,5(19):3531-3540已证明ND-药物在细胞中的途径,其中ND-药物复合物表明溶酶体的形成、以及ND-药物加载通过胞内体/溶酶体途径的内化、以及药物进入溶酶体或细胞核中[59]。
重要地并且根据本发明,这些结果表明,ND-HSA-DOX复合物可以进入溶酶体的酸性环境,以有效地释放抗癌药物DOX。
发现DOX在ND-HSA-DOX组的红色荧光相对强于游离DOX组,表明在ND-HSA-DOX组中DOX在细胞内部的摄取和释放增强,并且DOX主要分布在细胞核中。
本发明人注意到,Chan MS,Liu LS,Leung HM,Lo PK:Cancer-Cell-SpecificMitochondria-Targeted Drug Delivery by Dual-Ligand-FunctionalizedNanodiamonds Circumvent Drug Resistance.ACS Appl Mater Interfaces 2017,9(13):11780-11789发现DOX的大多数定位高度依赖于其剂量,DOX分子通过内吞途径被细胞摄取并定位于溶酶体中,当使用高剂量的DOX时,它们中的一些可能从溶酶体中释放,进入细胞质中,并且然后进入细胞核,随后杀死肿瘤细胞。
在本研究中,建议将作为载体的ND进行修饰以递送低剂量的DOX从而杀死癌细胞,而不是用高剂量的DOX来完成同样的任务。因此,本研究的结果表明,根据本发明,可以通过ND-HSA复合物平台来调节DOX的细胞内递送。
有文献出版物报道,游离DOX在处理5h之后已被定位于HeLa细胞的细胞核中(LiYQ,Zhou XP,Wang DX,Yang BS,Yang P:Nanodiamond mediated delivery ofchemotherapeutic drugs.J Mater Chem2011,21(41):16406-16412)[60],并且从图2(II)看出,如预期的那样,在ND-HSA-DOX处理4h后DOX主要更集中地分布在细胞核中,由此表明本发明对运输非细胞渗透的化学治疗剂非常有帮助并且通过这样的ND-HSA递送系统将它们引导至特定的细胞内细胞器。
因此并且重要地,本研究支持本发明,因为其证明了可以通过ND-HSA-DOX复合物将DOX有效地递送至癌细胞中以进行化学疗法。
参考图3(a)至(c),图3(a)显示了在不同浓度的DOX下用游离DOX和50ND-HAS-DOX处理24小时之后的细胞活力的图示;图3(b)显示了在不同浓度的DOX下用游离DOX和50ND-HAS-DOX处理48小时之后的细胞活力的图示;图3(c)显示了在不同浓度的DOX下用游离DOX和50ND-HAS-DOX处理72小时之后的细胞活力的图示。
在平的塑料或玻璃表面上生长的2D单层细胞不能反映真实组织的基本生理学,因为在人体中细胞生长在3D环境中。
为了获得关于ND-药物相互作用的更充分和详细的信息,本发明人继续使用3DMCST模型作为体外评价功效的手段,表明3D培养可以减少细胞培养物与活组织之间的差距,因为它非常类似于肿瘤自然环境。
为了研究不同配方的DOX(ND-DOX和ND-HSA-DOX)在体外组织模型中的渗透,使用SAS MCTS来与ND、游离DOX、ND-DOX和ND-HSA-DOX一起孵育。
通过使用CLSM监测ND和不同配方的DOX复合物在SAS MCTS模型中的摄取和分布。据发现MCTS在培养基中均匀地呈球状体和对称的形状,尺寸为约400μm。
将细胞核用发出蓝色荧光(440nm-484nm)的Hoechst 33324染色,并且将细胞膜用3,3’-二戊基氧杂碳菁碘化物(DIOC’5)染色,在520-555nm范围内收集信号,显示为红色。
DOX表现出青色荧光(565-620nm),用488nm激发并在500-515nm范围内收集50nmND荧光,显示为绿色。
参考图4(a)至4(f),显示了SAS MCTS与DOX、ND-DOX和ND-HSA-DOX组一起孵育的X-Z和Y-Z共焦图像,其中图4(a)显示了MCTS与DOX一起孵育1天后的共焦图像;图4(b)显示了MCTS与ND-DOX一起孵育1天后的共焦图像;图4(c)显示了MCTS与ND-HAS-DOX一起孵育1天后的共焦图像;图4(d)显示了MCTS与DOX一起孵育2天后的共焦图像;图4(e)显示了MCTS与ND-DOX一起孵育2天后的共焦图像,并且图4(f)显示了MCTS与ND-HAS-DOX一起孵育2天后的共焦图像。
尽管ND-DOX和ND-HSA-DOX的强荧光在孵育1天之后也出现在SAS MCTS的外细胞层中,但是在1天孵育时间之后,ND和游离DOX在SAS MCTS中的渗透限于球状体的外细胞层。此外,从SAS MCTS中间层发出的ND和DOX的弱荧光信号表明,一些ND-DOX和ND-HSA-DOX复合物可以更有效地渗透球状体。
纳米金刚石、纳米金刚石-多柔比星和纳米金刚石-白蛋白-多柔比星复合物的制
备(7.)
使用购买来的和在表面修饰之后的平均直径为50nm的金刚石纳米颗粒(KayDiamond,USA)研究了盐酸多柔比星(DOX)与纳米金刚石的相互作用。ND的详细处理方法已在其他地方报道过。
简言之,将纳米金刚石用强酸H2SO4:HNO3(1:3)的混合物处理,以去除非金刚石混合物和污染物,并且用COOH表面官能团修饰颗粒(羧基化纳米金刚石,cND)以进一步与期望的分子缀合。贯穿全文,ND表示羧基化纳米金刚石。
ND-HSA(7.1)
为了避免ND聚集,将人血清白蛋白(HSA)吸附在ND表面上。对于吸附HSA的表面修饰,使用通过功率约40W的超声波处理5min的在900ml双蒸(D.D.)水中的2mg ND粉末(50、100nm)。
然后将2mg HSA粉末(Sigma,USA)添加到100μl D.D.水中,与50nm ND溶液混合,并将溶液在室温(Tr)下搅拌2小时。
搅拌后,将ND-HSA复合物在11,000rcf下离心10min,并且除去上清液。然后添加1ml D.D.水以分散50nm ND-HSA复合物。
ND-DOX(7.2)
盐酸多柔比星从Sigma-Aldrich(USA)获得。为了制备复合物,首先将5mg多柔比星溶解于4ml二甲亚砜(DMSO,Sigma-Aldrich,USA)中。
然后将多柔比星在1ml标准磷酸盐缓冲盐水(PBS:NaCl 4g;KCl 0.1g,Na2HPO40.72g,KH2PO4 0.21g,H2O 500ml;pH 7.4)中稀释至400μg/ml。此外,向多柔比星溶液中等量添加4mg/ml的ND,获得其浓度为2mg/ml的混悬液。
将混合物充分搅拌2h,以便更好地吸附多柔比星。搅拌后,将混合物在室温下以11,000rcf的速度离心15分钟,以沉淀出纳米金刚石,包括吸附多柔比星的ND。
然后,向含有ND-多柔比星复合物的沉淀物中添加1ml PBS溶液(pH值为7.4)。
对复合物进行弱的超声波处理以崩解沉淀物,并且然后涡旋30分钟。从溶液中洗涤ND-多柔比星复合物以除去非相互作用的多柔比星,重复3次。
ND-HSA、ND-DOX和ND-HSA-DOX复合物的表征(8.)
使用来自Malvern Instruments,Malvern,UK的、具有基于动态光散射法组件的4mW、633nm波长He-Ne激光器的Zetasizer Nano ZS以173°的检测角度来分析颗粒尺寸和ζ电位。
将纳米金刚石、ND-HSA、DOX、ND-DOX和ND-HSA-DOX复合物用PBS稀释来测量尺寸和表面电荷以获得浓度。
在稀释至20μg/ml之后,在25℃下的pH为7.4。
使用Titan(Taiwan)的SENTRON pH计测量pH值。对于FTIR光谱表征,将20μl的ND、DOX、ND-HSA、ND-DOX、ND-HSA-DOX复合物溶液各自置于硅基底(1cm×1cm)上,并且在室温下在空气中干燥。
采用FTIR光谱法(使用具有氘化三甘氨酸硫酸盐(DTGS)检测器的瑞士ABB BomemMB 154FTIR光谱仪)获得样品的红外光谱,以确认在空气中在25℃的温度下分别形成了ND、DOX、ND-DOX和ND-HSA-DOX复合物。光谱分辨率为4cm-1。
ND-HSA、ND-DOX和ND-HSA-DOX功能化及药物加载效率的UV-可见光谱分析(9.)
在室温下使用UV-可见光谱仪JASCO V-550(JASCO,US)测量在与ND相互作用之前和之后DOX溶液的吸收光谱。在495nm处发现了DOX吸收峰。
DOX吸附峰的强度与溶液中DOX的浓度成正比,因此使用通过从指定的DOX浓度稀释并绘制495nm处的吸光度获得的标准曲线,各种浓度定量了DOX浓度。由于吸光度和药物浓度遵循比尔-朗伯定律(Beer-Lambert’s law),吸附后的DOX浓度通过线性回归进行转换。
DOX从ND-DOX和ND-HSA-DOX复合物中的pH依赖性释放(10.)
使用pH 6、pH 7和pH 8的PBS缓冲液观察到ND-DOX复合物的pH响应性释放特征。
在制备ND-DOX之后,将样品重悬于1ml的PBS中,并在室温下孵育2h、4h、24h、48h的累积时间段以便模拟体外药物释放。
孵育后,将样品以11,000rpm离心10min。然后,将样品重悬于新鲜的PBS中,以累积剩余的持续时间。收集含有释放的DOX的上清液用于UV-可见光分析。
ND、ND、DOX和ND-DOX复合物的单层2D SAS细胞摄取(11.)
将人口腔鳞状癌细胞(SAS)细胞在DMEM培养基(Gibco,Invitrogen,UK)中培养。培养基中补充有2mM L-谷氨酰胺(Invitrogen,USA)、1.5g/L碳酸氢钠(Sigma,UK)、10%胎牛血清(Gibco/Life Technologies,Carlsbad,CA,USA)。
将细胞保持在37℃潮湿环境下在含有95%空气和5%CO2的孵育箱(Galaxy 170S,Eppendorf,USA)中的标准细胞培养条件下。
每48或72小时将培养基用新鲜培养基替换。通过用0.5%胰蛋白酶和2.6mM乙二胺四乙酸(EDTA)(来自Gibco/Life Technologies,Carlsbad,CA,USA)处理来分离细胞,将培养物在大约80%融合下进行常规继代培养。
将SAS细胞(30,000个细胞/孔)在含盖玻片6孔培养皿上培养2天。用DOX和ND-HSA-DOX复合物处理细胞以观察它们的相互作用。
将每个样品添加到培养基中,培养基中的样品浓度为20μg/ml,并且将细胞与样品一起孵育4h。
通过洗涤除去未反应的样品。将盖玻片上粘附有DOX和ND-HSA-DOX复合物的细胞用3.7%甲醛固定15min,并用于显微镜检查。DOX的发射在570-590nm下被吸收,并且ND在500-515nm下被检测到。
ND-DOX复合物在2D单层细胞模型中的细胞毒性(12.)
使用MTT测定来确定ND、DOX和ND-DOX复合物对细胞活力的影响。
MTT测定是一种定量和快速的比色方法,基于活细胞的线粒体脱氢酶将黄色四唑鎓盐切割成不溶性紫色甲臜晶体。
将SAS细胞以每孔5000个细胞/孔的密度接种在96孔板中,并孵育24h以允许细胞附着。将用空白媒介物处理的细胞用作对照。用不同浓度的ND、DOX、ND-DOX复合物(10、20、30、40和0.5μg/ml)处理细胞,并将细胞在5%CO2和37℃下孵育24h和48h。孵育完成后,向每个孔中添加MTT染料储备溶液(20μl,5mg/ml),并且将细胞再孵育4h。除去上清液,并将所形成的MTT-甲臜晶体溶解于100μl的DMSO中,并使用微板读数器记录在570nm下的吸光度。计算IC50值,并使用最佳剂量进行进一步研究。
SAS多细胞肿瘤球状体(MCTS)形成和生长抑制研究(13.)
为了促进多细胞肿瘤球状体(MCTS)形成,在药物处理之前,将SAS细胞以每孔5,000个细胞的密度接种在Gravity TRAP ULA板(Insphero)中,并在37℃、5%CO2下培养3天。
通过共焦激光显微镜检查确定了在MCTS内ND、DOX、ND-DOX和ND-HSA-DOX的分布。
将SAS MCTS用ND、DOX、ND-DOX和ND-HSA-DOX处理4天。每天收获一个处理的MCTS,并且将其用3.7%甲醛固定24h。用PBS洗涤MCTS 3次,并且将MCTS与DIOC’5一起孵育24h。在洗涤3次之后,将Hoechst 33342与MCTS一起孵育24h。然后通过共焦显微镜检查观察MCTS。
测量了ND、DOX、ND-DOX复合物对MCTS的生长抑制作用。将直径约300μm的MCTS与每个样品共培养4天。通过解剖显微镜观察MCTS。将MCTS的体积计算如下:
其中a代表每个MCTS的最大直径,并且b代表最小直径。图5(I)显示了用ND、DOX和50ND-HAS-DOX处理4天的MCTS的光学图像;并且图5(II)显示了治疗期间MCTS体积变化的图示,其中n=9(三个实验重复三次)。
统计分析(14.)
如上面所分析和描述的实验结果用平均值±标准偏差(SD)表示。两组之间的统计差异使用双尾学生t检验进行。P值<0.05被认为是统计学上显著的。
抗癌化合物(15.)
已经在实验实施方案中使用盐酸多柔比星(C27H29NO11,被称为DOX)描述了本发明。DOX是用于治疗癌症的化学疗法药物。所述癌症包括乳腺癌、膀胱癌、卡波西肉瘤、淋巴瘤和急性淋巴细胞性白血病。DOX通常与其他化学疗法药剂一起使用,并且本发明适用于组合疗法。
如将理解的,可以使用其他抗癌药物,诸如甲氨蝶呤(经验式:C20H22N8O5,被称为MTX)。甲氨蝶呤是一种化学疗法剂和免疫系统抑制剂。其用于治疗癌症、自身免疫性疾病、异位妊娠,和用于药物流产。其用于的癌症类型包括乳腺癌、白血病、肺癌、淋巴瘤和骨肉瘤。其用于的自身免疫性疾病的类型包括银屑病、类风湿性关节炎和克罗恩病。其可以通过口服或通过注射给予。
如还将理解的,在替代性实施方案中,本发明的缀合物可以具有超过一种类型的药物分子与其附接。
此外,在又进一步的实施方案中,药物溶液可以包含第一多个具有与其连接的第一药物的缀合物、和第二多个具有与其连接的第二药物的缀合物。
本发明及其实施方案适用于各种癌症类型,包括肺癌、结肠直肠癌、胃癌、黑色素瘤、胰腺癌、乳腺癌、肝癌和/或前列腺癌。
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发明优势(17.)
本发明人已经鉴定了药物递送系统的缺点,并且已经提供了具有以下优点的解决方案:
(a)无毒性,
(b)减少的颗粒聚集,和
(c)增加的递送系统药物加载;
(d)在癌症部位提供释放机制;
(e)药物化合物或治疗剂在位点特异性治疗部位的递送和卸载;以及
(f)改进的API向受试者递送的释放速率和一致性。
Claims (32)
1.一种缀合物,所述缀合物包含:
(a)纳米金刚石
(b)通过物理吸附粘附在纳米金刚石表面上的人血清白蛋白(HSA);和
(c)与所述人血清白蛋白化学地连接的药物分子,其中所述药物分子具有治疗效果。
2.根据权利要求1所述的缀合物,其中所述药物分子是抗癌药物分子。
3.根据权利要求2所述的缀合物,其中所述癌症是淋巴结、肝、肺、骨、肾、脑、胃、肝或结肠组织的癌症。
4.根据前述权利要求中任一项所述的缀合物,其中所述药物分子是盐酸多柔比星C27H29NO11(DOX)。
5.根据权利要求1至3中任一项所述的缀合物,其中所述药物分子是甲氨蝶呤C20H22N8O5(MTX)。
6.根据前述权利要求中任一项所述的缀合物,其中所述纳米金刚石具有在25nm至80nm范围内的尺寸。
7.根据前述权利要求中任一项所述的缀合物,其中所述纳米金刚石具有在35nm至65nm范围内的尺寸。
8.根据前述权利要求中任一项所述的缀合物,其中所述纳米金刚石具有约50nm的尺寸。
9.一种药物溶液,包含多种缀合物和液体载体,其中所述缀合物包含:
(a)纳米金刚石;
(b)通过物理吸附粘附在纳米金刚石表面上的人血清白蛋白(HSA);和
(c)与所述人血清白蛋白化学地连接的药物分子,其中所述药物分子具有治疗效果。
10.根据权利要求9所述的药物溶液,其中所述药物分子是抗癌药物分子。
11.根据权利要求9或权利要求10所述的药物溶液,其中所述癌症是淋巴结、肝、肺、骨、肾、脑、胃、肝或结肠组织的癌症。
12.根据权利要求9至11中任一项所述的药物溶液,其中所述药物分子是盐酸多柔比星C27H29NO11(DOX)。
13.根据权利要求9至11中任一项所述的药物溶液,其中所述药物分子是甲氨蝶呤C20H22N8O5(MTX)。
14.根据权利要求9至13中任一项所述的药物溶液,其中所述纳米金刚石具有在25nm至80nm范围内的尺寸。
15.根据权利要求9至14中任一项所述的药物溶液,其中所述纳米金刚石具有在35nm至65nm范围内的尺寸。
16.根据权利要求9至15中任一项所述的药物溶液,其中所述纳米金刚石具有约50nm的尺寸。
17.缀合物在制备用于预防或治疗受试者的药物中的用途,其中所述缀合物包含:
(a)纳米金刚石
(b)通过物理吸附粘附在纳米金刚石表面上的人血清白蛋白(HSA);和
(c)与所述人血清白蛋白化学地连接的药物分子,其中所述药物分子具有治疗效果。
18.根据权利要求17所述的用途,其中所述药物分子是抗癌药物分子。
19.根据权利要求18所述的用途,其中所述癌症是淋巴结、肝、肺、骨、肾、脑、胃、肝或结肠组织的癌症。
20.根据权利要求17至19中任一项所述的用途,其中所述药物分子是盐酸多柔比星C27H29NO11(DOX)。
21.根据权利要求17至19中任一项所述的用途,其中所述药物分子是甲氨蝶呤C20H22N8O5(MTX)。
22.根据权利要求17至21中任一项所述的用途,其中所述纳米金刚石具有在25nm至80nm范围内的尺寸。
23.根据权利要求17至22中任一项所述的用途,其中所述纳米金刚石具有在35nm至65nm范围内的尺寸。
24.根据权利要求17至23中任一项所述的用途,其中所述纳米金刚石具有约50nm的尺寸。
25.一种向有需要的受试者提供治疗性治疗的方法,所述方法包括向所述受试者递送治疗量的药物溶液的步骤,其中所述药物溶液包含多种缀合物和液体载体,其中所述缀合物包含:
(a)纳米金刚石
(b)通过物理吸附粘附在纳米金刚石表面上的人血清白蛋白(HSA);和
(c)与所述人血清白蛋白化学地连接的药物分子,其中所述药物分子具有治疗效果。
26.根据权利要求25所述的方法,其中所述药物分子是抗癌药物分子。
27.根据权利要求26所述的方法,其中所述癌症是淋巴结、肝、肺、骨、肾、脑、胃、肝或结肠组织的癌症。
28.根据权利要求25至27中任一项所述的方法,其中所述药物分子是盐酸多柔比星C27H29NO11(DOX)。
29.根据权利要求25至27中任一项所述的方法,其中所述药物分子是甲氨蝶呤C20H22N8O5(MTX)。
30.根据权利要求25至29中任一项所述的方法,其中所述纳米金刚石具有在25nm至80nm范围内的尺寸。
31.根据权利要求25至30中任一项所述的方法,其中所述纳米金刚石具有在35nm至65nm范围内的尺寸。
32.根据权利要求25至31中任一项所述的方法,其中所述纳米金刚石具有约50nm的尺寸。
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HK18110301.3 | 2018-08-10 | ||
HK18110301A HK1256428A2 (zh) | 2018-08-10 | 2018-08-10 | 藥物輸送製品,組成和系統 |
PCT/CN2019/100255 WO2020030191A1 (en) | 2018-08-10 | 2019-08-12 | Drug delivery product, composition and system |
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US (1) | US20210316010A1 (zh) |
EP (1) | EP3833396A4 (zh) |
CN (1) | CN112533641A (zh) |
HK (1) | HK1256428A2 (zh) |
WO (1) | WO2020030191A1 (zh) |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
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CN102008733A (zh) * | 2010-11-24 | 2011-04-13 | 首都医科大学 | 一种抗肿瘤控释纳米复合物及制备方法 |
CN104524594A (zh) * | 2015-01-06 | 2015-04-22 | 山西大学 | 纳米钻石表面修饰负载甲氨蝶呤的药物及其制备方法 |
-
2018
- 2018-08-10 HK HK18110301A patent/HK1256428A2/zh unknown
-
2019
- 2019-08-12 US US17/266,889 patent/US20210316010A1/en not_active Abandoned
- 2019-08-12 EP EP19845949.7A patent/EP3833396A4/en not_active Withdrawn
- 2019-08-12 WO PCT/CN2019/100255 patent/WO2020030191A1/en unknown
- 2019-08-12 CN CN201980051763.XA patent/CN112533641A/zh active Pending
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
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CN102008733A (zh) * | 2010-11-24 | 2011-04-13 | 首都医科大学 | 一种抗肿瘤控释纳米复合物及制备方法 |
CN104524594A (zh) * | 2015-01-06 | 2015-04-22 | 山西大学 | 纳米钻石表面修饰负载甲氨蝶呤的药物及其制备方法 |
Non-Patent Citations (2)
Title |
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YUZHOU WU等: "Programmable Biopolymers for Advancing Biomedical Applications of Fluorescent Nanodiamonds", 《ADV. FUNCT. MATER.》, vol. 25, pages 6576 - 6585, XP055684789, DOI: 10.1002/adfm.201502704 * |
ZHE RUI LIN等: "Nanodiamond-mediated drug delivery in 2D- and 3D-cultured cellular models", 《JOURNAL OF BIOTECHNOLOGY》, vol. 256, pages 94 * |
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US20210316010A1 (en) | 2021-10-14 |
HK1256428A2 (zh) | 2019-09-20 |
EP3833396A1 (en) | 2021-06-16 |
EP3833396A4 (en) | 2022-05-18 |
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