CN108992418A - 药物组合物、制备方法及其用途 - Google Patents
药物组合物、制备方法及其用途 Download PDFInfo
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- CN108992418A CN108992418A CN201810581905.0A CN201810581905A CN108992418A CN 108992418 A CN108992418 A CN 108992418A CN 201810581905 A CN201810581905 A CN 201810581905A CN 108992418 A CN108992418 A CN 108992418A
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Abstract
本发明提供一种药物组合物包括一个或多个金属纳米颗粒及治疗剂。每一金属纳米颗粒包括内核及包覆于所述内核的表面的稳定剂。所述治疗剂与金属纳米颗粒上的稳定剂结合。所述治疗剂是两亲化合物,每一治疗剂具有至少一个与所述稳定剂相互作用的疏水链。所述药物组合物可进一步包括一包封金属纳米颗粒和治疗剂的聚合物壳,所述聚合物壳用于控制所述治疗剂的释放。所述的药物组合物具有双重功能,可用于诊断及治疗癌症。本发明还提供了一种应用该药物组合物的制备方法及其用途。
Description
技术领域
本发明涉及一种医药领域,尤其涉及一种药物组合物、制备方法及其用途。
背景技术
纳米技术已越来越广地应用于肿瘤的临床诊断与治疗,以实现癌症的早期诊断与治疗。计算机断层扫描(Computed Tomography,CT)或核磁共振(Magnetic resonanceimaging,MRI)可以使用纳米颗粒作为诊断的工具,其中纳米颗粒可以是氧化铁颗粒(IronOxide)、金纳米颗粒(Nano-gold)、量子点颗粒(Quantum dots)及铁铂纳米颗粒(FePt),或是其他的组合合金等。由此,医生就可以诊断病人是否患癌。
在现有的临床应用中,病人在CT成像之前需要注射造影剂(如碘剂)或是在MRI成像之前注射其他类型的造影剂。之后,主治医生可以诊断病人是否患癌,患何种类型的癌症,以及如何进行有效治疗。例如,对于肿瘤的治疗,可结合化学疗法与放射疗法来治疗癌细胞。
然而,病人完成专门的疗程可能需要5至10年连续不间断的跟踪治疗,如此长时间的治疗可能由诊断与治疗之间的异步性所导致的。另外,单一的造影剂可能只适用于对应的工具,因而,对于需要多种工具来进行诊断时,可能需要注射多种不同的对比剂到病人的体内,如此使得给诊断与治疗带来一定的不便。而在后续的治疗中,化学治疗或放射性治疗并不与影像诊断同步,而药物药效的释放也无法同步控制。因而,病人在治疗的后期可能会产生不适或有副作用的产生。
发明内容
有鉴于此,有必要提供一种药物组合物、制备方法及其用途,可以提高放射疗法的治疗效果。
一种药物组合物,包括:
一个或多个金属纳米颗粒,每一金属纳米颗粒包括:
内核;及
涂覆于所述内核的表面的稳定剂;及
至少一依附于所述稳定剂的治疗剂;
其中所述治疗剂是两亲化合物,每一治疗剂具有至少一个与所述稳定剂相互作用的疏水链。
进一步地,所述药物组合物中,所述金属纳米颗粒是FePt纳米颗粒。
进一步地,所述药物组合物中,所述FePt纳米颗粒的平均直径位于3纳米至13纳米的范围内。
进一步地,所述药物组合物中,所述稳定剂包括油酸。
进一步地,所述药物组合物中,所述治疗剂包括至少一个抗癌药物、抗炎剂、或其一种或多种的组合物。
进一步地,所述药物组合物中,所述治疗剂为2-氨基-2-[2-(4-辛基苯基)乙基]-1、3-丙二醇(FTY720)、FTY720之衍生物、2-氨基-N-(3-辛基苯基)-3-(磷酰氧基)-丙酰胺(VPC 23019)、VPC 23019之衍生物、[(3R)-3-氨基-4-[(3-己基苯基)氨基]-4-氧代丁基]磷酸(W146)、W146之衍生物、或以上任选之组合。
进一步地,所述药物组合物中,所述金属纳米颗粒与所述治疗剂的质量比位于1:0.01至1:100的范围内。
进一步地,所述药物组合物还包括一包封金属纳米颗粒和治疗剂的聚合物壳。
进一步地,所述药物组合中,所述聚合物壳用于控制所述治疗剂的释放。
进一步地,所述药物组合中,所述聚合物壳的组成包括聚乙烯醇、聚乳酸-共-聚乙醇酸、聚乙二醇、维生素E聚乙二醇琥珀酸酯、以上任选之共聚物、或以上任选之组合。
进一步地,所述药物组合中,所述聚合物的含量占药物组合物总重量的比值位于0.1%至10%的范围内。
进一步地,所述药物组合物还包括一用于将所述治疗剂与所述金属纳米颗粒的稳定剂连接的适配剂。
进一步地,所述药物组合物还包括一用于将所述治疗剂与所述金属纳米颗粒的稳定剂连接的适配剂。
一种制备如上述所述的药物组合物的制备方法,包括:
将所述金属纳米颗粒溶解在有机溶剂中,以获得金属纳米颗粒溶液;
将金属纳米颗粒溶液与所述至少一两亲治疗剂混合,以获得混合物;及
从混合物中除去有机溶剂。
一种如上述所述的药物组合物在制备用于诊断及治疗癌症的双重功能的药物中的用途。
进一步地,所述的用途中,所述癌症为肺癌或乳癌。
一种如上述所述的药物组合物在制备用于治疗癌症的药物中的用途,其中
向对象施用一治疗有效量的药物组合物。
进一步地,所述用途还包括
向对象施用一有效量的放射剂量,所述有效量的放射剂量足以治疗该对象的疾病。
进一步地,所述用途还包括
对对象进行核磁共振成像或CT扫描,确定对象是否患有癌症。
进一步地,所述用途还包括
对对象进行核磁共振成像或CT扫描,确定对象是否患有癌症;
向对象施用一有效量的放射剂量,所述有效量的放射剂量足以治疗该对象的疾病。
一种如上述所述的药物组合物在制备用于治疗癌症的药物中的用途,其中
向对象施用一治疗有效量的药物组合物。
进一步地,所述用途还包括
向对象施用一有效量的放射剂量,所述有效量的放射剂量足以治疗该对象的疾病。
进一步地,所述用途还包括
对对象进行核磁共振成像或CT扫描,确定对象是否患有癌症。
进一步地,所述用途还包括
对对象进行核磁共振成像或CT扫描,确定对象是否患有癌症;
向对象的癌细胞施用一放射剂量。
进一步地,所述用途还包括
向对象施用一有效量的放射剂量,所述有效量的放射剂量足以让所述药物组合物中的治疗剂被释放。
进一步地,所述的用途中,所述有效量的放射剂量足以治疗该对象的疾病。
进一步地,所述用途还包括
对对象进行核磁共振成像或CT扫描,确定对象是否患有癌症;
向对象施用一有效量的放射剂量,所述有效量的放射剂量足以让所述药物组合物中的治疗剂被释放。
进一步地,所述的用途中,所述有效量的放射剂量足以治疗该对象的疾病。
上述药物组合物制备方法及用途中药物组合物包含金属纳米颗粒(FePt NPs)和治疗剂,该药物组合物可以同时用于诊断和治疗癌症。另外,药物组合物可以是用于CT或MRI扫描的造影剂,用于通过产生自由基来破坏肿瘤细胞以提高放射疗法的治疗效果的增强剂和/或用于增强肿瘤细胞的敏感性的敏化剂辐射或化学疗法。在FePt NPs中使用的含有FTY720药物的药物组合物也可以明显增加癌细胞的辐射敏感性,从而为癌细胞放射治疗起到治疗效果。
另外,所述药物组合物可包括金属纳米颗粒(FePt NPs)、治疗剂和聚合物壳。所述聚合物壳可由聚合物制成,并且覆盖于药物组合物外侧。因此,药物组合物的稳定性可以明显增加,以避免治疗剂在患者的正常组织中释放。当施加辐射能量到肿瘤组织上,聚合物壳的聚合度会降低,促进由金属纳米颗粒携带的治疗剂在肿瘤组织中释放,治疗剂也可以积聚在肿瘤组织中。另外,聚合物壳可以避免治疗剂在正常组织释放所引起的相关副作用。
附图说明
图1A提供了本发明药物组合物的第一较佳实施方式的示意图。
图1B是图1A中药物组合物中单一颗金属纳米复合材料的较佳实施方式的示意图。
图2A提供了本发明药物组合物的第二较佳实施方式的示意图。
图2B是图2A中药物组合物中单一颗金属纳米复合材料的较佳实施方式的示意图。
图3提供了本发明药物组合物的第三较佳实施方式的示意图。
图4提供了本发明药物组合物的第四较佳实施方式的示意图。
图5是本发明药物组合物中金属纳米颗粒制备方法的一较佳实施方式的流程图。
图6提供了一种根据第一较佳实施方式的药物组合物制备的较佳实施方式流程图。
图7提供了一种根据第三较佳实施方式的药物组合物制备的较佳实施方式流程图。
图8是图FePt@FTY720NPs及FePt@FTY720-PVA NPs的药物组合物的制备过程的较佳实施方式的示意图。
图9A和图9B示出了一示例性对应FePt@FTY720NPs的透射电子显微镜(TEM)照片。
图9C和图9D示出了一示例性对应FePt@FTY720NPs的低温电子显微镜(Cryo-EM)照片。
图10A和图10B示出了示例三的FePt@FTY720-PVA NPs的TEM图。
图10C和图10D示出了示例三的FePt@FTY720-PVA NPs的Cryo-EM图。
图11提供了一种根据第二较佳实施方式的药物组合物制备的较佳实施方式流程图。
图12提供了一种根据第四较佳实施方式的药物组合物制备的较佳实施方式流程图。
图13示出了一示例性实施方式中的药物组合物在制备用于递送治疗剂至一对象的药物中的用途的流程图。
图14示出了一示例性实施方式中的药物组合物在制备用于治疗癌症的药物中的用途的流程图。
图15A示出了通过使用不具或具有聚合物殼的药物组合物和每种药物组合物的特定浓度所对应肿瘤细胞的存活部分的测定结果的示意图。
图15B示出了通过使用不具或具有聚合物殼的药物组合物和每种药物组合物的特定浓度并施加辐射所对应肿瘤细胞的存活部分的测定结果的示意图。
图16示出了细胞质模拟缓冲***对治疗剂释放程度的测定结果的示意图。
主要元件符号说明
药物组合物 100、200、300、400
金属纳米复合材料 10、20
金属纳米颗粒 11、21、31、41
治疗剂 13、23、33、43
稳定剂 112、212、312、412
内核 111、211、311、411
适配剂 25、45
聚合物壳 301、401
如下具体实施方式将结合上述附图进一步说明本发明。
具体实施方式
下面将结合本发明实施例中的附图,对本发明实施例中的技术方案进行清楚、完整地描述,显然,所描述的实施例仅仅是本发明一部分实施例,而不是全部的实施例。基于本发明中的实施例,本领域普通技术人员在没有做出创造性劳动前提下所获得的所有其他实施例,都属于本发明保护的范围。
现在将说明贯穿本文适用的几个定义。
如术语“基本上”意思是基本符合该术语修改的特定尺寸,形状或其他特征,使得该部件不必是精确的。当使用时,术语“包括”或“包含”意思是“包括但不一定限于”,它具体可表示在所描述的组合、组、系列等中的开放式包含或所属的成员。
术语“施用”是指对一对象所进行的处置,该处置可以是一种治疗,例如使该对象服用、施打特定药物或进行放射治疗,或者提供一诊断。
如本文所使用的,术语“对象”和“患者”可互换使用并且指哺乳动物,通常是人。
如本文所使用的术语“治疗有效量”是指产生其给药所需效果的剂量。确切的剂量可由本领域技术人员使用已知技术来确定,并且,功效可以常规方式测量。例如,对于癌症治疗来说,可以通过评估退化或进展时间,确定治疗反应率,复发时间,肿瘤大小等来测量功效。如本文所使用的术语“有效量”是指是指产生特定效果的剂量,所述剂量可以是一药物的剂量或一放射线剂量,所述特定效果可以是治疗效果、诊断效果、药物释放效果等。
如本文所用,术语“药学上可接受的”意指由联邦或州政府的管理机构批准或在美国药典或其他公认的药典中列出的用于动物且更具体地用于人的术语。
如本文所用,术语“第一、第二、第三、第四”等词语用来表示名称,而并不表示任何或用于限定特定的顺序。
在一实施方式中,本发明提供了一种药物组合物。所述药物组合物可用于癌症的诊断与治疗,所述药物组合物可包括若干种金属纳米颗粒及至少一治疗剂。每种金属纳米颗粒可包括内核及涂覆于所述内核外的稳定剂,所述稳定剂可用于增加所述金属纳米颗粒的稳定性。所述治疗剂可以是两亲化合物,所述治疗剂可具有至少一个与稳定剂相互作用的疏水链。
在可选的实施方案中,药物组合物还可包含用于将治疗剂与金属纳米颗粒的稳定剂连接的适配剂。
在一实施方式中,公开了药物组合物。该药物组合物可用于癌症的诊断与治疗,所述药物组合物可包括多个金属纳米颗粒、至少一治疗剂和聚合物。每个金属纳米颗粒包括内核及涂覆于所述内核外的稳定剂。所述稳定剂可以增加金属纳米颗粒的稳定性。所述聚合物可包封金属纳米颗粒和治疗剂形成一聚合物壳。所述治疗剂可以是两亲化合物,可具有至少一个与稳定剂相互作用的疏水链。所述聚合物壳可用于控制治疗剂的特异性释放并防止治疗剂的非特异性释放。
在一实施方式中,所述药物组合物还包含配置用于连接治疗剂与金属纳米颗粒的稳定剂连接的适配剂。
所公开的用于制备药物组合物的制备方法的一个实例可包括以下步骤:
将一个或多个金属纳米颗粒溶解在有机溶剂中,以获得金属纳米颗粒溶液;
将金属纳米颗粒溶液与两亲治疗剂混合,以获得混合物;
从混合物中除去有机溶剂。
在一实施方式中,用于制备药物组合物的方法还可包括在将金属纳米颗粒溶液与治疗剂混合之前加入适配剂以促进金属纳米颗粒与治疗剂之间的组合的步骤。
所公开的用于制备药物组合物的方法的另一个实例还可包括以下步骤:
将一个或多个金属纳米颗粒溶解在有机溶剂中,以获得金属纳米颗粒溶液;
将金属纳米颗粒溶液与两亲治疗剂混合,以获得混合物;
在混合物中加入聚合物;
从混合物中除去有机溶剂。
在一个可替代实施方案中,用于制备药物组合物的方法还包括在将金属纳米颗粒溶液与治疗剂混合之前加入配置剂以促进金属纳米颗粒与治疗剂之间的组合的步骤。
在一实施方式中,药物组合物在制备可用于诊断及治疗癌症的双重功能的药物中的用途。所述癌症,较佳的,可以为肺癌或乳癌。
较佳地,请参阅图1A,本发明药物组合物100的第一较佳实施方式可包括若干金属纳米复合材料10及药物载体(图未示)。本实施方式中,所述药物组合物100的微粒直径可位于10纳米至1000纳米之间,较佳地,所述药物组合物100的微粒直径大约在10纳米至200纳米之间。所述药物组合物的粒度可适应于纳米药物的临床应用,可使其具有更好的生物吸收性和安全性。所述药物组合物100可通过口服、静脉注射、皮下注射或肌肉注射等方式进入体内。
请参阅图1B,每一金属纳米复合材料10可包括金属纳米颗粒11及至少一治疗剂13。所述金属纳米颗粒11可包括内核111及涂覆于所述内核111表面的稳定剂112。所述稳定剂112可用于增加所述金属纳米颗粒11的稳定性。所述至少一治疗剂13可依附于所述金属纳米颗粒11的稳定剂112,以与所述稳定剂112进行交互作用。
在第一较佳实施方式中,所述药物组合物100可包括若干金属纳米复合材料11及位于每一金属纳米颗粒11表面上的所述治疗剂13。本实施方式中,所述金属纳米颗粒11与所述治疗剂13之间质量比可位于1:0.01至1:100之间。
可以理解地,所述金属纳米颗粒11的内核11可由对应的材质得到,所述材质包括但不限于金属、合金、金属氧化物、类金属(Metalloid)、类金属氧化物(Metalloid Oxide)、磁性纳米颗粒(Magnetic Nanoparticle)或其组合。
可以理解地,当所述金属纳米颗粒11的材质为金属时,所述金属包括但不限于金、银、铜、钛、镍、铂、钯或者及其组合;所述金属亦可包括但不限于镧系元件;当所述金属纳米颗粒11的材质为金属氧化物时,所述金属氧化物包括但不限于TiO2。当所述金属纳米颗粒11的材质为磁性纳米颗粒时,所述磁性纳米颗粒包括但不限于铁纳米颗粒、铁复合材料的纳米颗粒或者及其组合。所述铁复合材料的纳米颗粒包括但不限于Fe2O3、Fe3O4、FePt、FeCo、FeAl,、FeCoAl、CoFe2O4、MnFeO4、CoPt或者及其组合。
在第一较佳实施方式中,所述金属纳米颗粒11可为FePt纳米颗粒(以下简称FePtNPs)。
所述FePt纳米颗粒的晶体结构可为面心立方(face-centered cubic,FCC)结构。所述FePt纳米颗粒的平均直径可位于3纳米(nanometer,nm)至13纳米之间,优选的平均直径约6纳米至7纳米。所述FePt纳米颗粒的一般式为Fe58Pt42。
所述FePt纳米颗粒可同时用于癌症的诊断与治疗,特别是针对于恶性肿瘤;所述癌症,较佳的,可以为肺癌或乳癌。所述FePt纳米颗粒可用于为CT或MRI扫描的造影剂,也就是说,所述FePt纳米颗粒拥有CT/MRI的双造影特征。另外,所述FePt纳米颗粒可具有在肿瘤组织累和积吸收放射线能量的功能,因此,所述FePt纳米颗粒可通过吸收放射线能量进而在体内达到放射线聚焦,从而更有效地杀死肿瘤组织的效果。
可以理解地,所述FePt纳米颗粒可用作药物载体,如用于运载癌症药物,因此,通过携带癌症治疗药物,进而达到放射线与药物治疗的加成效果。
当所述FePt纳米颗粒吸收放射线能量时,所述FePt纳米颗粒可***其附近的水分子,之后通过产生自由基来摧毁肿瘤细胞。因此,所述FePt纳米颗粒可用作放射治疗的增强剂。
所述金属纳米颗粒11的稳定剂112可用于稳定所述金属纳米颗粒,所述稳定剂可为表面活性剂(Surfactant)。所述表面活性剂包括但不限于阴离子型表面活性剂、中性表面活性剂或阳离子型表面活性剂。所述阴离子型表面活性剂可包括但不限于卤化烷基三甲铵(alkyl trimethylammonium halide)。所述中型表面活性剂可包括但不限于饱和脂肪酸(saturated fatty acid)或不饱和脂肪酸,如油酸,月桂酸或十二烷酸,三烷基磷化合物或三烷基磷氧化物如三辛基氧化磷(TOPO),三辛基磷(TOP)或三丁基磷,烷基胺如十二烷基胺,油胺,三辛胺或辛胺,或烷基硫醇。所述阴离子表面活性剂可以包括但不限于烷基磷酸钠。
为保持所述金属纳米颗粒11的稳定性及较统一的大小,所述表面活性剂可优选为包括但不限于饱和脂肪酸,不饱和脂肪酸和/或烷基胺。
所述稳定剂112可优选为油酸,以根据需要金属纳米颗粒的疏水性来选用。
所述至少一治疗剂13可以是两亲化合物。所述至少一种治疗剂13具有至少一个与稳定剂112相互作用的疏水链。
所述治疗剂13可以包括但不限于抗代谢药,抗真菌药,抗炎剂,抗肿瘤药,抗感染药,抗生素,营养素,激动剂和拮抗剂。
所述至少一种治疗剂13可以优选地包括抗癌药物,抗炎剂和它们的组合。
所述治疗剂13可优选包括2-氨基-2-[2-(4-辛基苯基)乙基]-1、3-丙二醇(FTY720)、2-氨基-N-(3-辛基苯基)-3-(磷酰氧基)-丙酰胺(VPC23019)、[(3R)-3-氨基-4-[(3-己基苯基)氨基]-4-氧代丁基]磷酸(W146)及其衍生物(如FTY720之衍生物、VPC 23019之衍生物、W146之衍生物)、或以上任选之组合。
由于FTY720可以作为敏化剂,其可以增强肿瘤细胞对辐射的易感性,因此,所述治疗剂13也可以优选为FTY720。
在本实施方式中,FTY720可以作为治疗剂13。FTY720可形成于每个FePt纳米颗粒的表面,以形成药物组合物100(在此表示为:FePt@FTY720NPs)。可以理解地,所述FePt纳米颗粒与FTY720的质量比在1:0.01至1:100的范围内。
请参阅图2A,在第二较佳实施方式中,药物组合物200可包括多个金属纳米复合材料20和药物载体(图未示)。
可以理解地,所述药物组合物200中的颗粒直径可以在10纳米至1000纳米的范围内。所述药物组合物200的粒径可以优选在约10纳米至200纳米的范围内。所述药物组合物的粒度可适应于纳米药物的临床应用,可使其具有更好的生物吸收性和安全性。
请参阅图2B,每一金属纳米复合材料20可包括金属纳米颗粒21和至少一种治疗剂23。所述金属纳米颗粒21可包括内核211和涂覆在所述内核211的表面上的稳定剂212。所述稳定剂212可用于增加所述金属纳米颗粒21的稳定性。所述金属纳米颗粒21及至少一治疗剂23在结构上与第一较佳实施方式大致相同。在与第一较佳实施方式中不在之处在于,第二较佳实施方式的金属纳米复合材料20还包括连接稳定剂212与治疗剂23的适配剂25。
可以理解地,所述适配剂25可以是但不限于聚合物。例如,所述适配剂25可包括但不限于纤维素,聚乙二醇(PEG),聚(N-乙烯基吡咯烷酮),聚(氰基丙烯酸烷基酯),聚-ε-己内酯,其衍生物及其组合。
在第二实施例中,所述药物组合物200可包括多个金属纳米颗粒21。所述治疗剂23可形成在每个金属纳米颗粒21的表面,所述适配剂25可使得所述金属纳米颗粒21与治疗剂23连接。所述金属纳米颗粒21与治疗剂23的质量比可以位于1:0.01至1:100的范围内。
较佳地,所述金属纳米颗粒21可以选择FePt NPs(FePt纳米颗粒),所述治疗剂23可以选择FTY720,所述适配剂25可以选择PEG。可以理解地,所述PEG可形成于所述FePt纳米颗粒的表面上,以形成亲水性FePt纳米颗粒(在此表示为:FePt@PEG NPs)。更进一步地,所述FTY720可形成于FePt@PEG NPs的表面,以形成药物组合物200(在此表示为:FePt@PEG-FTY720NPs)。
请参阅图3,在第三较佳实施方式中,所述药物组合物300包括多个金属纳米颗粒31及至少一治疗剂33。每个金属纳米颗粒31可包括内核311和涂覆于所述内核311的表面上的稳定剂312。所述稳定剂312可用于增加所述金属纳米颗粒31的稳定性。所述金属纳米颗粒31及至少一治疗剂33在结构上与第一较佳实施方式大致相同。与第一较佳实施方式相比,第三较佳实施中,所述药物组合物300还可包括包封所述金属纳米颗粒31及至少一治疗剂33的聚合物壳301。
可以理解地,所述聚合物壳301可以优选由可生物降解的聚合物制成。所述聚合物壳301由选自但不限于聚乙烯醇(PVA),聚乳酸-共-聚乙醇酸(PLGA),聚乙二醇(PEG),维生素E聚乙二醇琥珀酸酯(TPGS),以及以上任选的组合。所述药物组合物300中聚合物壳301的含量的范围可在0.1%至10%之间。所述药物组合物300中聚合物壳301的含量可以优选在0.25%至5%之间。
在本实施实施方式中,所述聚合物壳301的材料可优选聚乙烯醇。
所述聚合物壳301可用于控制所述治疗剂33在肿瘤部位的释放,并且还可以防止药物发生非特异性释放,从而有效避免由于治疗剂33释放到正常组织时而产生的副作用。
可以理解地,所述药物组合物300的颗粒直径可以在10纳米至1000纳米的范围内。
较佳地,所述药物组合物300的粒径可以优选在10纳米至200纳米的范围内。所述药物组合物的粒度可适应于纳米药物的临床应用,可使其具有更好的生物吸收性和安全性。
在第三较佳实施方式中,所述金属纳米颗粒31可以选择FePt NPs(FePt纳米颗粒),所述治疗剂33可以选择FTY720,所述聚合物可以选择聚乙烯醇(PVA)。可以理解地,所述PVA可形成于在所述FePt@FTY720NPs的表面,进而形成药物组合物300(在此表示为:FePt@FTY720-PVA NP)。较佳地,所述FePt纳米颗粒与FTY720的质量比可在1:0.01至1:100的范围内。所述药物组合物300中PVA的含量占在总重量的比值可在0.1%至10%的范围内。本实施方式中,所述药物组合物300中PVA的优选的含量占总重量比较约在0.25%至5%的范围内。
请参阅图4,在第四较佳实施方式中,所述药物组合物400可包括多个金属纳米颗粒41及至少一治疗剂43。每个金属纳米颗粒41包括内核411和涂覆在内核411的表面上的稳定剂412。所述稳定剂412可用于增加金属纳米颗粒41的稳定性。所述金属纳米颗粒41及至少一治疗剂43在结构上与第二较佳实施方式大致相同。与第二较佳实施方式的不同之处在于,第四较佳实施方式中的药物组合物400还可包括包封所述金属纳米颗粒41及至少一种治疗剂43的聚合物壳401。
第四较佳实施方式中的聚合物外壳401与第三较佳实施方式中的聚合物外壳301的构造基本相同。
在第四较佳实施方式,所述聚合物壳401的材料可优选为聚乙烯醇。所述药物组合物400中聚乙烯醇的含量占总重量比值可在0.1%至10%的范围内。本实施方式中,所述药物组合物400的聚乙烯醇中的优选含量占总重量的比值可在0.25%至5%的范围内。
可以理解地,所述药物组合物400的颗粒直径(粒径)可以在10纳米至1000纳米的范围内。
较佳地,所述药物组合物400的粒径可以优选在10纳米至200纳米的范围内。所述药物组合物的粒度可适应于纳米药物的临床应用,可使其具有更好的生物吸收和安全性。
以下,将提供示例来说明本公开的实施例。以下实施例旨在为本领域普通技术人员提供关于如何制造和使用该方法以及使用本文所述的方法和组合物的完整公开和描述,并且不旨在限制。
请参阅图5,实施例一,本发明金属纳米颗粒的制备方法的第一较佳实施方式可包括以下步骤:
步骤S110,将含铂化合物、含铁化合物和稳定剂混合,并溶解在有机溶剂中以获得反应溶液。
步骤S120,从反应溶液中除去有机溶剂以分离沉淀物。
步骤S130,洗涤沉淀物并离心,以将分离的金属纳米颗粒作为目标产物。
在一较佳的实施方式中,所述金属纳米颗粒可以是被油酸涂覆的FePt纳米颗粒。由于被油酸涂覆前,FePt内核是疏水性的,涂覆油酸可使得FePt纳米颗粒具有亲水性。较佳地,所述含铁化合物可以是Fe(CO)5。所述稳定剂可以是油酸。所述有机溶剂可以是二辛基醚、1,2-十六烷二醇和油胺。所述含铂化合物可以是Pt(acac)2。
在第一种方式中,制备粒径为3纳米至4纳米的FePt纳米颗粒的制备方法可以包括:将97mg Pt(acac)2,195mg 1,2-十六烷二醇和将10mL二辛基醚混合并在氮气环境下10分钟内加热至100℃。在100℃下,注入66μLFe(CO)5,80μL油胺和80μL油酸。将反应混合物以15℃/分钟的加热速率加热至297℃。30分钟后,移除加热源并让产物冷却至室温。用己烷/乙醇洗涤颗粒三次,并通过离心收集以分离出粒径为3纳米至4纳米的FePt纳米颗粒。
在第二种方式中,制备粒径为6纳米至7纳米的FePt纳米颗粒的制备方法可以包括:采用化学还原法制备FePt纳米颗粒。具体地说,将97mg Pt(acac)2,4mL二辛基醚,66μLFe(CO)5,195mg 1,2-十六烷二醇,100μL油胺和100μL油酸在氮气下混合。将反应混合物以15℃/分钟的加热速率加热至240℃。在240℃以15℃/分钟的加热速率加热反应混合物30分钟后,移除加热源,然后使产物冷却至室温。用己烷/乙醇洗涤颗粒三次,并通过离心收集以分离出粒径为6纳米至7纳米的FePt纳米颗粒。
在第三种方式中,制备粒径为12纳米至13纳米的FePt纳米颗粒的制备方法可以包括:将195mg Pt(acac)2,1.05g 1,2-十六烷二醇,4mL二辛基醚,66μL Fe(CO)5,4mL油胺和4mL油酸在氮气下混合,然后将混合物在15℃/分钟的加热速率下加热至240℃。之后,将混合物在240℃保持60分钟。然后,移除加热源,将反应混合物冷却至室温。用己烷/乙醇洗涤颗粒三次,并通过离心收集以分离出粒径为12纳米至13纳米的FePt纳米颗粒。
请参阅图6,根据第一较佳实施方式制备纳米颗粒的制备方法的较佳实施方式可包括以下步骤:
步骤S210,将金属纳米颗粒溶解在有机溶剂中,以获得金属纳米颗粒溶液。
步骤S220,将金属纳米颗粒溶液与至少一两亲性的治疗剂混合,以获得混合物。
步骤S230,从混合物中除去有机溶剂以获得沉淀物。
步骤S240,洗涤沉淀物并离心,以分离得到期望的药物组合物。
请参阅图7,根据第三较佳实施方式制备金属纳米颗粒的制备方法的较佳实施方式可包括以下步骤:
步骤S310,将金属纳米颗粒溶解在有机溶剂中,以获得金属纳米颗粒溶液。
步骤S320,将金属纳米颗粒溶液与两亲治疗剂混合,以获得混合物。
步骤S330,在混合物中加入聚合物。
步骤S340,从混合物中除去有机溶剂,以获得沉淀物。
步骤S350,洗涤并离心沉淀物,以分离得到所期望的药物组合物。
请参阅图8,以FePt@FTY720NPs及FePt@FTY720-PVA NPs为例的药物组合物的制备方法中,所述药物组合物可通过纳米沉淀法合成的。具体而言,可将5mg粒径为6纳米的FePtNPs溶解于100ul二氯甲烷(dichloromethane methylene chloride,DCM)溶液中,以制备第一反应溶液;将3mg FTY720溶解于900ul水中,以制备第二反应溶液。然后,将第一反应溶液和第二反应溶液通过吸液混合方式进行混合,直到混合物均匀化。之后,将混合物注入9ml水中或含有1%PVA溶液的水,并通过超声波震荡处理5分钟,然后将经超声波处理后混合物放置真空中15分钟以蒸发DCM溶液。由于溶剂疏水性的突然降低,从而可以使得FTY720和包封所述FePt纳米颗粒的疏水片段的聚集,从而生成载有FTY720的金属纳米颗粒的沉淀。之后,可使用离心机分离多余的FTY720和PVA,并用水溶液洗涤两次,以获得最终产物FePt@FTY720NPs和FePt@FTY720-PVA NPs。
于上述实施例中,所述FePt金属纳米颗粒与FTY720的质量比可在1:0.01至1:100的范围内。所述药物组合物中聚乙烯醇的含量可以占总重量的0.1%至10%的范围内。较佳地,所述FePt@FTY720-PVA NPs中聚乙烯醇的优选含量占总重量的0.25%至5%的范围内。更佳地,所述FePt@FTY720-PVA NPs中聚乙烯醇的含量约为1%。在有机溶剂的真空蒸发过程中,由于溶剂疏水性的突然降低导致治疗剂和包封金属纳米颗粒的疏水片段的聚集,进而可以使得所述治疗剂加载在金属药物组合物上。
请一并参阅图9A至9D,根据上述实施例的步骤所制备的FePt@FTY720NPs可通过透射电子显微镜(TEM)及低温电子显微镜(Cryo-EM)进行观察与测定。此处的测定结果显示,FePt@FTY720NPs的平均直径基本上在84.4±12.3纳米的范围内。
请一并参阅图10A至图10D,根据上述实施例的步骤所制备的FePt@FTY720-PVANPs可通过透射电子显微镜及低温电子显微镜进行观察与测定。此处的测定结果显示,FePt@FTY720-PVA NPs的平均直径基本上在71.7±23.6纳米的范围内。
请参阅图11,根据第二较佳实施方式制备FePt@PEG-FTY720NPs纳米颗粒的制备方法的较佳实施方式可包括以下步骤:
步骤S410,将金属纳米颗粒溶解在有机溶剂中,以获得金属纳米颗粒溶液。
步骤S420,向金属纳米颗粒溶液添加适配剂,以获得亲水性的金属纳米颗粒溶液。
步骤S430,将亲水性的金属纳米颗粒溶液与至少一两亲性治疗剂混合,以获得混合物。
步骤S440,从混合物中除去有机溶剂,以获得沉淀物。
步骤S450,洗涤沉淀物并离心,以分离得到所期望的药物组合物。
据上述实施例四的步骤制备的药物组合物(FePt@PEG-FTY720NPs)中可包括金属纳米颗粒、至少一治疗剂和适配剂。较佳地,所述金属纳米颗粒的粒径可为6纳米。所述至少一治疗剂可以是FTY720,其可以溶于水中。所述适配剂可由PEG的材料制成。所述FePt纳米颗粒与FTY720的质量比可位于1:0.01至1:100的范围内。
请参阅图12,根据第四较佳实施方式制备FePt@PEG-FTY720-PVA NPs的制备方法的较佳实施方式可包括以下步骤:
步骤S510,将金属纳米颗粒溶解在有机溶剂中,以获得金属纳米颗粒溶液。
步骤S520,向金属纳米颗粒溶液添加适配剂,以获得亲水性金属纳米颗粒溶液。
步骤S530,将亲水性金属纳米颗粒溶液与至少一两亲性治疗剂混合,以获得混合物。
步骤S540,在混合物中添加聚合物。
步骤S550,从混合物中除去有机溶剂,以获得沉淀物。
步骤S560,洗涤并离心沉淀物,以分离得到所期望的药物组合物。
上述实施例五的步骤制备的药物组合物(FePt@PEG-FTY720-PVA NPs)中可包括金属纳米颗粒、至少一治疗剂、适配剂及聚合物壳。较佳地,所述金属纳米颗粒平均粒径可为6纳米。所述种治疗剂可为FTY720,其可以溶于水中。所述适配剂可由PEG的材料制成。所述聚合物壳可由PVA材料制成。所述FePt NPs与FTY720的质量比可位于1:0.01至1:100的范围内。所述药物组合物中PVA的含量占总重量的比值可位于0.1%至10%的范围内。所述FePt@FTY720-PVA NP中PVA的含量占总重量的比值可优选为0.25%至约5%的范围内。
请参阅图13,在一个实例中,使用根据第一至第四较佳实施方式制备的药物组合物(FePt@FTY720NPs,FePt@FTY720-PVA NPs,FePt@PEG-FTY720NPs或FePt@PEG-FTY720-PVANPs)的较佳实施方式可包括以下步骤:
步骤S610,向对象施用一治疗有效量的药物组合物。所述药物组合物可以口服、静脉注射、皮下注射或肌肉注射等方式给予一对象。可以理解地,在向一对象施用药物组合物之前,可以进一步包括配置药物组合物的步骤,例如将药物组合物与药物载体结合。
在一个实例中,上述使用方法进一步包含步骤S620,对对象进行核磁共振成像或CT扫描,以诊断该对象是否患有癌症;或者步骤S630,向对象施用一有效量的放射剂量,所述有效量的放射剂量足以治疗该对象的疾病。在另一个实例中,上述使用方法进一步包含步骤S620以及步骤S630,因此可同时针对对象的癌细胞组织进行诊断与治疗。
请参阅图14,在另一实施方式中,使用根据第三至第四较佳实施方式制备的药物组合物(如FePt@FTY720-PVA NPs或FePt@PEG-FTY720-PVANPs)的较佳实施方式可包括以下步骤:
步骤S710,向对象施用一治疗有效量的药物组合物。所述药物组合物可以口服、静脉注射、皮下注射或肌肉注射等方式给予一对象。可以理解地,在向一对象施用药物组合物之前,可以进一步包括配置药物组合物的步骤,例如将药物组合物与药物载体结合。
在一个实例中,上述使用方法进一步包含步骤S720,对对象进行核磁共振成像或CT扫描,以诊断该对象是否患有癌症。在另一实施方式中,上述药物组合物之使用方法,可进一步包含步骤S730,向药物组合物提供一有效量的放射剂量,所述有效量的放射剂量足以让所述药物组合物中的治疗剂被释放。所述有效量的放射剂量可能同时足以治疗该对象的疾病,因此可利用所述治疗剂与放射剂量同时治疗癌症。在另一实施方式中,上述使用方法进一步包含步骤S720以及步骤S730,因此可同时针对对象的癌细胞组织进行诊断与治疗。
请一并参阅图15A及图15B,其显示了施用不同FePt纳米颗粒药物组合物对癌细胞的治疗效果。具体而言,实验分别将两种药物组合物,FePt@FTY720NPs和FePt@FTY720-PVANPs,依不同浓度施用于人类肺癌细胞SR3A-13,在未施用或施用放射能量(图中以IR表示有施用放射能量)的情况下,分析不同药物组合物对癌细胞存活率之影响。将SR3A-13癌细胞与浓度范围从0、0.25、0.5及1.0mg/ml的FePt@FTY720NPs或FePt@FTY720-PVA NPs药物组合物于体外进行培养,并持续进行25小时后,将SR3A-13癌细胞分为2组,其中一组进一步以6Gy辐射剂量进行照射。最后,将SR3A-13癌细胞利用胰蛋白酶悬浮,并在10cm大小培养皿中以不同细胞密度(500~10000个细胞/培养皿)再培养10-14天,以形成细胞群落。计算每个实验组的细胞群落后计算得到存活率(Surviving Fraction,SF),从而可以观察如图15A及图15B所述的细胞存活结果。
如图15A及图15B所示,FePt@FTY720NPs具有治疗癌症的加乘作用。具体而言,以FePt@FTY720NPs处理的SR3A-13癌细胞经由辐射能量照射后,其癌细胞的存活率明显地下降。在FePt@FTY720NPs浓度为0.25mg/ml时,照射辐射能量后癌细胞存活率大约降低至30%-50%。由以上结果可知FePt@FTY720NPs对癌症放射治疗具有一加乘治疗效果。
除此之外,以FePt@FTY720NPs处理的实验组别显示了随着增加药物组合物的浓度,不论有没有照射辐射能量,癌细胞存活率都显著的下降;相对的,以FePt@FTY720-PVANPs处理的实验组别随着增加药物组合物的浓度,癌细胞存活率的下降只在有照射辐射能量时较为显著。此外,以FePt@FTY720-PVA NPs处理的实验组别在照射辐射能量后,对癌细胞所产生的毒杀作用与FePt@FTY720NPs相似。如此,可以说明了,金属纳米颗粒药物组合物被聚乙烯醇包封时(FePt@FTY720-PVA NPs),聚乙烯醇(PVA)壳可抑止FTY720药物的释放,使得FTY720药物的释放速率明显降低;并且所述聚乙烯醇壳可透过辐射能量照射来控制FTY720药物释放。
请参阅图16,其显示了不同缓冲液***对药物组合物的治疗剂释放度的测定结果。实验中的所述药物组合物分别使用FePt@FTY720NPs和FePt@FTY720-PVA NPs,分别以水和细胞质模拟缓冲液(CMB)进行测试,其中所述CMB由KCl(120mM),CaCl2(0.15mM),K2HPO4/KH2PO4(10mM),HEPES(25mM),EGTA(2mM),MgCl2(5mM),ATP(2mM)和谷胱甘肽(5mM)组合。所述CMB的pH值可基本上为7.6。可以理解,药物组合物分散在CMB缓冲***中的环境条件与分散在肿瘤组织的环境条件相类似。所述药物组合物在不同缓冲液***中被静置于室温24小时,再分别观察各组的FePt纳米颗粒的聚集程度
如图16所示,当FePt@FTY720NPs和FePt@FTY720-PVA NPs被放至于水中时,在试管中没有沉淀形成,表示在水中FePt@FTY720NPs和FePt@FTY720-PVA NPs的FTY720不会被释放。相对的,当FePt@FTY720NPs被放至于CMB环境时,在试管中有金属颗粒沉淀物形成,表示在CMB环境中FePt@FTY720NPs中的FTY720被释放;然而,当FePt@FTY720-PVANPs被放至于CMB环境时,在试管中没有沉淀形成,说明了FePt@FTY720-PVA NPs在未被辐射能量照射的情形下,FTY720的释放会受到抑止。
本公开的药物组合物包含金属纳米颗粒(FePt NPs)和治疗剂(FTY720),因此该药物组合物可以同时用于诊断和治疗癌症。另外,药物组合物可以是用于CT或MRI扫描的造影剂,用于通过产生自由基来破坏肿瘤细胞以提高放射疗法的治疗效果的增强剂和/或用于增强肿瘤细胞的敏感性的敏化剂辐射或化学疗法。在FePt NPs中使用的含有FTY720药物的药物组合物也可以明显增加癌细胞的辐射敏感性,从而为癌细胞放射治疗起到治疗效果。
根据本公开的另一种药物组合物,包括金属纳米颗粒(FePt NPs)、治疗剂(FTY720)和聚合物壳。所述聚合物壳可由聚合物制成,并且覆盖于药物组合物外侧。因此,药物组合物的稳定性可以明显增加,以避免治疗剂(FTY720)在患者的正常组织中释放。当施加辐射能量到肿瘤组织上,聚合物壳的聚合度会降低,促进由金属纳米颗粒携带的治疗剂在肿瘤组织中释放,治疗剂也可以积聚在肿瘤组织中。另外,聚合物壳可以避免治疗剂在正常组织释放所引起的相关副作用。
以上示出和描述的实施例仅是示例。本领域经常会发现许多细节,例如药物组合物的其他特征,以及制备和使用该药物组合物的方法。因此,许多这样的细节既没有示出也没有描述。尽管在前面的描述中已经阐述了本技术的众多特征和优点以及本公开的结构和功能的细节,但是本公开仅仅是说明性的,并且可以在细节上做出改变,特别是在事项在本公开内容的原理范围内的部件的形状,尺寸和布置,直到并且包括由权利要求中使用的术语的广泛一般含义所确定的全部范围。因此可以理解,上述实施例可以在权利要求的范围内进行修改。
对于本领域的普通技术人员来说,可以根据本发明的技术构思做出其它各种相应的改变与变形,而所有这些改变与变形都应属于本发明权利要求的保护范围。
Claims (28)
1.一种药物组合物,其特征在于,所述药物组合包括:
一个或多个金属纳米颗粒,每一金属纳米颗粒包括:
内核;及
涂覆于所述内核的表面的稳定剂;及
至少一依附于所述稳定剂的治疗剂;
其中所述治疗剂是两亲化合物,每一治疗剂具有至少一个与所述稳定剂相互作用的疏水链。
2.如权利要求1所述的药物组合物,其特征在于,所述金属纳米颗粒是FePt纳米颗粒。
3.如权利要求2所述的药物组合物,其特征在于,所述FePt纳米颗粒的平均直径位于3纳米至13纳米的范围内。
4.如权利要求1所述的药物组合物,其特征在于,所述稳定剂包括油酸。
5.如权利要求1所述的药物组合物,其特征在于,所述治疗剂包括至少一个抗癌药物、抗炎剂、或其一种或多种的组合物。
6.权利要求5所述的药物组合物,其特征在于,所述治疗剂为2-氨基-2-[2-(4-辛基苯基)乙基]-1、3-丙二醇(FTY720)、FTY720之衍生物、2-氨基-N-(3-辛基苯基)-3-(磷酰氧基)-丙酰胺(VPC 23019)、VPC 23019之衍生物、[(3R)-3-氨基-4-[(3-己基苯基)氨基]-4-氧代丁基]磷酸(W146)、W146之衍生物、或以上任选之组合。
7.如权利要求1所述的药物组合物,其特征在于,所述金属纳米颗粒与所述治疗剂的质量比位于1:0.01至1:100的范围内。
8.如权利要求1所述的药物组合物,其特征在于,所述药物组合物还包括一包封金属纳米颗粒和治疗剂的聚合物壳。
9.如权利要求8所述的药物组合物,其特征在于,所述聚合物壳用于控制所述治疗剂的释放。
10.如权利要求8所述的药物组合物,其特征在于,所述聚合物壳的组成包括聚乙烯醇、聚乳酸-共-聚乙醇酸、聚乙二醇、维生素E聚乙二醇琥珀酸酯、以上任选之共聚物、或以上任选之组合。
11.如权利要求8所述的药物组合物,其特征在于,所述聚合物的含量占药物组合物总重量的比值位于0.1%至10%的范围内。
12.如权利要求8所述的药物组合物,其特征在于,所述药物组合物还包括一用于将所述治疗剂与所述金属纳米颗粒的稳定剂连接的适配剂。
13.如权利要求1所述的药物组合物,其特征在于,所述药物组合物还包括一用于将所述治疗剂与所述金属纳米颗粒的稳定剂连接的适配剂。
14.一种制备如权利要求1-13中任意一项所述的药物组合物的制备方法,其特征在于,所述制备方法包括:
将所述金属纳米颗粒溶解在有机溶剂中,以获得金属纳米颗粒溶液;
将金属纳米颗粒溶液与所述至少一两亲治疗剂混合,以获得混合物;及
从混合物中除去有机溶剂。
15.一种如权利要求1-13中任意一项所述的药物组合物在制备用于诊断及治疗癌症的双重功能的药物中的用途。
16.如权利要求15所述的用途,其特征在于,所述癌症为肺癌或乳癌。
17.一种如权利要求1所述的药物组合物在制备用于治疗癌症的药物中的用途,其中
向对象施用一治疗有效量的药物组合物。
18.如权利要求17所述的用途,其特征在于,所述用途还包括
向对象施用一有效量的放射剂量,所述有效量的放射剂量足以治疗该对象的疾病。
19.如权利要求17所述的用途,其特征在于,所述用途还包括
对对象进行核磁共振成像或CT扫描,确定对象是否患有癌症。
20.如权利要求17所述的用途,其特征在于,所述用途还包括
对对象进行核磁共振成像或CT扫描,确定对象是否患有癌症;
向对象施用一有效量的放射剂量,所述有效量的放射剂量足以治疗该对象的疾病。
21.一种如权利要求8所述的药物组合物在制备用于治疗癌症的药物中的用途,其中
向对象施用一治疗有效量的药物组合物。
22.如权利要求21所述的用途,其特征在于,所述用途还包括
向对象施用一有效量的放射剂量,所述有效量的放射剂量足以治疗该对象的疾病。
23.如权利要求21所述的用途,其特征在于,所述用途还包括
对对象进行核磁共振成像或CT扫描,确定对象是否患有癌症。
24.如权利要求21所述的用途,其特征在于,所述用途还包括
对对象进行核磁共振成像或CT扫描,确定对象是否患有癌症;
向对象的癌细胞施用一放射剂量。
25.如权利要求21所述的用途,其特征在于,所述用途还包括
向对象施用一有效量的放射剂量,所述有效量的放射剂量足以让所述药物组合物中的治疗剂被释放。
26.如权利要求25所述的用途,其特征在于,所述有效量的放射剂量足以治疗该对象的疾病。
27.如权利要求21所述的用途,其特征在于,所述用途还包括
对对象进行核磁共振成像或CT扫描,确定对象是否患有癌症;
向对象施用一有效量的放射剂量,所述有效量的放射剂量足以让所述药物组合物中的治疗剂被释放。
28.如权利要求27所述的用途,其特征在于,所述有效量的放射剂量足以治疗该对象的疾病。
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