CN108514565B - 磷基材料在制备治疗肿瘤的药物中的应用 - Google Patents
磷基材料在制备治疗肿瘤的药物中的应用 Download PDFInfo
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Abstract
本发明公开了一种磷基材料在制备治疗肿瘤的药物中的应用,其中,磷基材料包括在酸性环境下可转化产生磷酸根离子的材料,且磷基材料通过被肿瘤细胞吞噬后转化产生大量磷酸根离子以改变细胞内外环境,进而抑制肿瘤细胞增殖及诱导肿瘤细胞死亡。而此过程对正常细胞活性无明显影响。通过以上方式,将磷基材料应用于制备治疗肿瘤的药物中,可有效抑制肿瘤细胞的扩增和转移,从而更有效地防止肿瘤细胞的转移和肿瘤的复发,提高治疗肿瘤效果,且在治疗过程中,对正常细胞和组织影响较小,安全可靠。
Description
技术领域
本发明涉及医药技术领域,具体涉及一种磷基材料在制备治疗肿瘤的药物中的应用。
背景技术
化学药物疗法及其与手术疗法和放射疗法相结合的介入手段是目前肿瘤、癌症临床治疗的主要方式。然而,由于化疗药物分子对癌细胞和正常细胞具有类似的毒性作用,实际治疗过程往往伴随着严重的毒副作用,损害人体器官和造血功能,有些会引发脱发、严重贫血、消化功能障碍及免疫功能损伤等。同时,目前的治疗手段及化疗药物尚未从根本上有效解决癌症治疗的难点问题,如癌症的复发、转移及免疫功能的严重受损仍然是导致死亡的主要原因。
专利“一种硒掺杂黑磷前药及其制备方法”(申请号CN107496444A),具体披露了一种利用硒掺杂的黑磷纳米薄片构建硒元素可控释放的前药及其制备方法和应用,其构建二维黑磷负载抗肿瘤药物,并对其表面采用聚乙二醇胺修饰,实现硒的可控释放、提高药物的生物相容性。该前药中黑磷纳米片是作为抗癌药物载体,其本身的抗癌效果未提及,且对肿瘤的治疗无靶向性和特异性。
专利“一种黑磷纳米片-抗肿瘤化合物的复合材料及其制备方法和应用”(申请号CN106267204A),具体披露了一种黑磷纳米片和带伯氨基和/或酚羟基的抗肿瘤复合材料及其制备方法和应用,其构建二维黑磷负载抗肿瘤药物,实现协同抗癌效果。同样,该复合材料中黑磷纳米片起到的是抗癌药物载体的作用,黑磷本身不作为一种抗癌药物,且药物无靶向性和特异性。
发明内容
为了解决上述技术问题,本发明提供一种磷基材料在制备治疗肿瘤的药物中的应用,其可有效抑制肿瘤细胞的扩增和转移,从而更有效防止癌症细胞的转移和肿瘤的复发,以提高治疗肿瘤效果,且在整个治疗过程中,磷基材料对正常组织和细胞影响较小,安全可靠。
本发明所采用的技术方案是:本发明提供了一种磷基材料在制备治疗肿瘤的药物中的应用,所述磷基材料为在酸性环境下可转化产生磷酸根离子的材料,所述磷基材料通过被肿瘤细胞吞噬后转化产生磷酸根离子以改变所述肿瘤细胞内外环境,进而抑制肿瘤细胞增殖及诱导肿瘤细胞死亡。
优选地,所述磷基材料包括在酸性环境下可转化产生磷酸根离子的单质磷和/或含磷化合物,含磷化合物包括含磷氧化物、卤化物及其他在酸性环境下可转化产生磷酸根离子的含磷化合物(如磷酸盐等)。磷基材料具体包括但不限于黑磷、红磷、白磷、紫磷等磷单质,三氧化磷、五氧化磷等磷氧化物,五卤化磷、三卤化磷、四卤化磷等磷卤化物,以及基于正磷酸、偏磷酸、亚磷酸、焦磷酸、三磷酸、次磷酸、连二磷酸、聚磷酸等磷酸盐化合物中的一种或多种。
优选地,所述磷基材料为磷基微纳材料,包括纳米和微米级别的材料。其中,纳米级别材料利于静脉给药,减少器官累计毒性;微米级别材料用于原位给药,具有更强的生物学效应。
优选地,所述磷基材料经过表面修饰以用于增强靶向性和/或稳定性。其中,用于增强稳定性的表面修饰包括但不限于基于脂质体或聚合物分子等的被动包裹修饰、基于配位键的配体修饰以及共价修饰等手段;用于增强靶向性的表面修饰包括但不限于利用叶酸等化合物修饰、穿膜肽等肽类物质修饰、以及靶向癌细胞的适配体、抗体等的修饰。通过对磷基材料的表面进行靶向性修饰,可更有效地抑制癌细胞或肿瘤细胞的扩散和转移,从而更有效地防止癌细胞或肿瘤细胞的复发,以更进一步提高治疗效果。
优选地,所述磷基材料可作为单一制剂;或者以所述磷基材料作为活性成分,加入药学可接受的助剂一同制备治疗肿瘤的药物;此外,还可加入其他抗肿瘤活性成分,以达到协同作用。具体可按照常规工艺,制成临床接受的剂型,包括片剂、胶囊剂、丸剂、颗粒剂、缓释制剂、控释制剂或注射制剂等,应用于临床。其中,磷基材料在组合药物中所占的比例因具体情况而定,磷基材料的具体添加量可为0.01%–99.99%,优选20%-99.99%,进一步优选30%-80%。
将以上磷基材料应用于制备治疗肿瘤的药物中,所制得药物的给药方式可通过静脉给药,或肿瘤体内和肿瘤周围直接放置的方式。具体可用于制备治疗起源于人及动物大脑、血液、乳腺、胰腺、子宫、子宫内膜、子宫颈、肾脏、肝、胆囊、头颈部、口腔、甲状腺、皮肤、黏膜、腺体、血管、肝脏、肺脏、食管、卵巢、前列腺、骨组织、淋巴结、膀胱、结肠或直肠的原发或继发的癌、肉瘤或癌肉瘤的药物。其具体作用涉及的肿瘤细胞包括但不限于人乳腺癌细胞MCF-7、人宫颈癌细胞Hela、肝癌细胞HepG2、人非小细胞肺癌细胞A549、急性早幼粒白血病细胞NB4、人脑胶质瘤细胞A172、人神经胶质瘤细胞LN-18等。治疗过程中的具体用药量可根据药物中所含磷基材料的类型、所针对的肿瘤类型及用药方式等情况进行确定。
本发明的有益技术效果是:本发明提供了一种磷基材料在制备治疗肿瘤的药物中的应用,其中,磷基材料为在酸性环境下可转化产生磷酸根离子的材料,其具有特定的生物活性,在被肿瘤细胞吞噬后可转化产生大量磷酸根离子,改变细胞内外环境,进而抑制肿瘤细胞增殖及诱导肿瘤细胞死亡。具体地,由于肿瘤组织的高渗透长滞留效应(enhancedpermeability and retention effect,EPR)和/或由于其表面的靶向作用等原因在肿瘤组织微环境中积累,和/或被肿瘤细胞通过内吞作用摄取后,由于肿瘤细胞内及胞外所具有的偏酸性微环境加速其转化,并在其快速转化过程中瞬时产生大量磷酸根离子及其他活性产物(即不稳定的中间产物,如活性自由基、活性氧等),该过程可称为“离子炸弹效应(IonicBomb Effect)”,进而可进一步诱导肿瘤细胞内外微环境的改变,并促使蛋白发生非特异性磷酸化作用,从而扰乱肿瘤细胞的有丝分裂,抑制肿瘤细胞增殖,并最终诱导肿瘤细胞死亡。同时,对于正常细胞而言,由于其较慢的分裂活性以及偏中性的胞内胞外微环境,磷基材料在正常组织及细胞中的转化较为缓慢,在这一温和转化过程中被缓慢地释放的磷酸根离子具有极高的生物相容性,因此,对正常组织细胞的影响非常小。综上,整个方案简单、高效,磷基材料在治疗肿瘤过程中具有特异性和靶向性,可将这一针对肿瘤细胞的特异性杀伤过程称为“生物活性磷基药物疗法(Bioactive Phosphorus-based Therapy)”,简称为“活性磷疗(BPT)”。
附图说明
为了更清楚的说明本发明实施例中的技术方案,下面将对实施例描述中所需要使用的附图做简单说明。
图1是本发明一实施例中的黑磷纳米薄片抑制乳腺癌细胞增殖曲线图;
图2是图1中实施例所采用的黑磷纳米薄片诱导乳腺癌细胞凋亡图;
图3是图1中实施例所采用的黑磷纳米薄片抑制宫颈癌细胞增殖曲线图;
图4是图1中实施例所采用的黑磷纳米薄片诱导宫颈癌细胞凋亡图;
图5是图1中实施例所采用的黑磷纳米薄片抑制非小肺癌细胞增殖曲线图;
图6是图1中实施例所采用的黑磷纳米薄片诱导非小肺癌细胞凋亡图;
图7是图1中实施例所采用的黑磷纳米薄片抑制人正常细胞增殖曲线图;
图8是图1中实施例所采用的黑磷纳米薄片诱导人正常细胞凋亡图;
图9是图1中实施例所采用的黑磷纳米薄片被人乳腺癌细胞内吞后,在细胞中逐步转化的拉曼扫描图。
具体实施方式
下面结合具体实施例,进一步阐述本发明。应理解,这些实施例仅用于说明本发明而不用于限制本发明的范围。此外应理解,在阅读了本发明讲授的内容之后,本领域技术人员可以对本发明作各种改动或修改,这些等价形式同样落于本申请所附权利要求书所限定的范围。
先通过液相剥离方法制备具有生物活性的黑磷纳米薄片。具体步骤包括:在隔绝空气的环境下,将一定量的黑磷晶体研磨后分散于溶剂中并密封,溶剂可采用各种有机溶剂,如N-甲基吡咯烷酮(NMP)、二甲基甲酰胺(DMF)、二甲基亚砜(DMSO)中、无水乙醇、异丙醇等;而后采用探头超声、水浴超声或者两者依次作用的方式,对黑磷溶液进行超声剥离,以制备具有生物活性的黑磷薄片。可通过改变超声的作用方式、超声频率等调节剥离的效果,也可结合其他的剥离技术如热分离技术、离子插层技术等,提高剥离的效率和产率。
按如上液相剥离方法制得黑磷薄片,此外,还可对所制得黑磷薄片进行表面配位或靶向修饰,以增强黑磷薄片的稳定性和靶向性,得到的二维黑磷(包括裸露的二维黑磷以及经修饰的二维黑磷)分散于适当溶剂中,如N-甲基吡咯烷酮(NMP)、二甲基甲酰胺(DMF)、二甲基亚砜(DMSO)中、无水乙醇、异丙醇等有机溶剂,以便于材料的长期保存。
再将所制得的黑磷纳米薄片作用于肿瘤细胞和正常细胞,进行细胞增殖检测实验和细胞凋亡检测实验。具体如下:
(一)细胞增殖检测实验方法
预先培养不同类型的人癌细胞(包括宫颈癌细胞、乳腺癌细胞和非小肺癌细胞)和正常细胞(选用人骨髓间充质干细胞),将细胞计数后种植于多孔板内,加入培养基,培养细胞至生长。具体地,可将人癌细胞株按5000个/孔的密度种植于96孔板,每组做四个复孔,每孔培养基为100μL包含有10%FBS的DMEM,细胞置于37℃培养箱,5%CO2,饱和湿度条件下培养24h。
选择适宜尺寸的黑磷薄片进行清洗,具体可选择厚度为2-10nm;长宽尺寸为20-300nm的黑磷纳米薄片,以利于细胞内吞。而后按照释放的稀释方法进行稀释,使得培养孔中体积为100μL时的药物浓度分别为0.125、0.25、0.5、1、2、4、8、16μg/mL,对照组为不加黑磷薄片药物的培养基。细胞置于37℃培养箱,5%CO2,饱和湿度条件下培养24h和48h后,弃去原培养基,加入100μL CCK8工作液孵育1h后,检测A450nm处的OD值,通过各孔OD值计算细胞存活率。
(二)细胞凋亡检测实验方法
预先培养不同类型的人癌细胞(包括宫颈癌细胞、乳腺癌细胞和非小肺癌细胞)和正常细胞(选用人骨髓间充质干细胞),将细胞计数后种植于多孔板内,加入培养基,培养细胞至生长。具体地,将人癌细胞株按5×104个/孔的密度种植于24孔板,每组做三个复孔,每孔培养基为1mL包含有10%FBS的DMEM,细胞置于37℃培养箱,5%CO2,饱和湿度条件下培养24h。
选择适宜尺寸的黑磷薄片进行清洗,具体可选择厚度为2-10nm;长宽尺寸为20-300nm的黑磷纳米薄片,以利于细胞内吞。而后按照释放的稀释方法进行稀释,使得培养孔中体积为1mL时的药物浓度分别为2、4、8μg/mL,对照组为不加黑磷薄片药物的培养基。细胞置于37℃培养箱,5%CO2,饱和湿度条件下培养48h后,用胰蛋白酶处理并收集细胞,1000g离心5min,弃上清,收集细胞,用PBS轻轻重悬细胞并计数。取5-10万重悬的细胞,1000g离心5min,弃上清,加入195μL Annexin V-FITC结合液轻轻重悬细胞,再加入5μL Annexin V-FITC和10μL碘化丙啶(PI)轻轻混匀,室温避光染色15min,用流式细胞仪上机检测。
对黑磷纳米薄片进行如上体外应用研究,所得结果如图1-8所示。
请参阅图1、3、5、7,图1是本发明一实施例中的黑磷纳米薄片抑制乳腺癌细胞增殖曲线图,图3是黑磷纳米薄片抑制宫颈癌细胞增殖曲线图,图5是黑磷纳米薄片抑制非小肺癌细胞增殖曲线图,图7是黑磷纳米薄片抑制人正常细胞增殖曲线图。在以上细胞增殖曲线图中,横坐标为黑磷浓度,纵坐标为细胞存活率。
如图1、3、5、7所示,在细胞增殖检测实验中,黑磷纳米薄片作用于乳腺癌细胞、宫颈癌细胞和非小肺癌细胞三种癌细胞24h和48h后,黑磷纳米薄片对三种癌细胞呈浓度依赖性的细胞增殖作用,即黑磷纳米薄片浓度越高,其对癌细胞的抑制效果越明显。培养48h后,当黑磷纳米薄片的浓度为0.5μg/mL时,乳腺癌细胞的增殖率被抑制了50%左右(如图1所示);当黑磷纳米薄片的浓度为1μg/mL左右时,宫颈癌细胞的增殖抑制率达到了50%(如图3所示);黑磷纳米薄片浓度为2μg/mL左右时,非小肺癌细胞增殖抑制率达到50%左右(如图5所示)。而对于正常细胞人骨髓间充质干细胞,在培养24h后,各浓度黑磷纳米薄片处理的细胞其细胞存活率均在90%以上。培养48h后,较低浓度的黑磷纳米薄片(4μg/mL以下)对正常细胞的增殖无显著抑制,细胞存活率在80%以上(如图7所示)。由此可见,黑磷纳米薄片在较低的剂量下便可显著抑制癌细胞的增殖;在相同剂量下黑磷纳米薄片对正常细胞的增殖抑制作用远远小于癌细胞。
请参阅图2、4、6、8,图2是黑磷纳米薄片诱导乳腺癌细胞凋亡图,图4是黑磷纳米薄片诱导宫颈癌细胞凋亡图,图6是黑磷纳米薄片诱导非小肺癌细胞凋亡图,图8是黑磷纳米薄片诱导人正常细胞凋亡图。在以上细胞凋亡图中,横坐标为Annexin V荧光强度;纵坐标为PI荧光强度;Q4区域为活性正常的细胞;Q3为早期凋亡细胞;Q2为晚期凋亡细胞;Q1为坏死细胞,可忽略不计。
在细胞凋亡检测实验中,黑磷纳米薄片浓度为2μg/mL时乳腺癌细胞中正常细胞比例(Q1)显著下降,凋亡细胞比例(Q2+Q3)显著提高,且随着黑磷纳米薄片浓度增大,凋亡细胞比例明显提高;当黑磷纳米薄片浓度为8μg/mL时正常细胞的比例由90%下降到33%(如图2所示)。同样,黑磷纳米薄片浓度为2μg/mL时宫颈癌细胞中正常细胞比例(Q1)下降了30%,凋亡细胞比例(Q2+Q3)显著提高;当黑磷纳米薄片浓度为8μg/mL时,正常细胞比例从93.1%下降到15.7%(如图4所示)。对于非小肺癌细胞,浓度为8μg/mL的黑磷纳米薄片可诱导凋亡细胞的比例增加21%左右(如图6所示)。而对于正常细胞人骨髓间充质干细胞,各浓度黑磷纳米薄片作用48h后未观察凋亡细胞的比例显著增大,各组中正常细胞的比例均在94%以上。证明黑磷纳米薄片在可以有效诱导癌细胞凋亡的同时,对正常细胞无显著毒性。
以上结果证明黑磷纳米薄片可显著有效地抑制癌细胞的增殖,并诱导其凋亡,但在相同剂量下对正常细胞的杀伤作用远小于癌细胞。黑磷纳米薄片这种对肿瘤细胞和正常癌细胞的选择性杀伤作用证明磷基材料非常适用于作为“活性磷疗”抗癌药物的开发,即将磷基材料应用于制备治疗肿瘤的药物。
除此,还对以上所制得黑磷纳米薄片作用于人乳腺癌细胞(MCF-7),被细胞内吞后,黑磷纳米材料在细胞中转化过程进行了观察实验。结果如图9所示,图9是黑磷纳米薄片被人乳腺癌细胞内吞后,在细胞中逐步转化的拉曼扫描图,图(Ⅰ)(Ⅱ)(Ⅲ)分别表示黑磷纳米材料分别作用于MCF-7细胞4h、24h和48h所得到的拉曼扫描图,其中,检测的荧光强度为黑磷纳米薄片的拉曼特征峰Ag l峰的信号,从小到大表示Ag l峰的强度从弱到强,黑磷纳米薄片的含量从低到高。
由图9可知,黑磷纳米薄片作用于MCF-7细胞4h时,细胞中可观察到大量的黑磷纳米薄片信号峰,24h后明显减弱,48h后几乎观察不到黑磷纳米薄片的信号峰。这一结果证明黑磷纳米薄片被癌细胞内吞后,可在细胞内快速转化。
由上,黑磷纳米薄片具有生物活性,在与肿瘤细胞接触后,可被肿瘤细胞吞噬,并在肿瘤细胞内转化产生磷酸根离子,由于肿瘤细胞内及胞外所具有的偏酸性微环境可加速其转化,在其快速转化过程中瞬时产生大量磷酸根离子及其他活性产物(即不稳定的中间产物),可进一步诱导肿瘤细胞内外微环境的改变,破坏肿瘤细胞内外微环境的离子平衡,并促使肿瘤细胞的蛋白发生非特异性磷酸化作用,从而扰乱肿瘤细胞的有丝分裂,抑制肿瘤细胞增殖,并最终诱导肿瘤细胞死亡。根据以上黑磷纳米薄片针对肿瘤细胞的作用机理,可推断其他在酸性环境下可转化产生磷酸根离子的磷基材料,包括其他单质磷和/或含磷化合物,也可应用于制备治疗肿瘤的药物,以通过以上类似的作用机理作用于肿瘤细胞,抑制肿瘤细胞的增殖及诱导肿瘤细胞死亡,实现对肿瘤的治疗。
尽管结合优选实施方案具体展示和介绍了本发明,但所属领域的技术人员应该明白,在不脱离所述权利要求书所限定的本发明的精神和范围内,在形式上和细节上可以对本发明做出各种变化,均为本发明的保护范围。
Claims (7)
1.磷基材料在制备治疗肿瘤的药物中的应用,其特征在于,所述磷基材料为在酸性环境下可转化产生磷酸根离子的材料,所述磷基材料通过被肿瘤细胞吞噬后转化产生磷酸根离子以改变所述肿瘤细胞的内外环境,进而抑制肿瘤细胞增殖及诱导肿瘤细胞死亡;所述药物的给药方式为静脉给药,或肿瘤体内和肿瘤周围直接放置的方式;所述磷基材料为黑磷纳米薄片。
2.根据权利要求1所述的应用,其特征在于,所述磷基材料经过表面修饰以用于增强靶向性和/或稳定性;所述用于增强稳定性的表面修饰包括基于脂质体或聚合物分子的被动包裹修饰、基于配位键的配体修饰和共价修饰中的一种或多种;所述用于增强靶向性的表面修饰包括化合物修饰、肽类物质修饰和靶向癌细胞的适配体或抗体修饰中的一种或多种。
3.根据权利要求1所述的应用,其特征在于,所述磷基材料应用于制备所述治疗肿瘤的药物时的添加量为0.01%–99.99%。
4.根据权利要求3所述的应用,其特征在于,所述磷基材料应用于制备所述治疗肿瘤的药物时的添加量为30%-80%。
5.根据权利要求1所述的应用,其特征在于,所述肿瘤包括乳腺癌、宫颈癌、肺癌、肝癌、脑胶质瘤。
6.根据权利要求1-5中任一项所述的应用,其特征在于,所述治疗肿瘤的药物还包括药学可接受的助剂。
7.根据权利要求6所述的应用,其特征在于,所述治疗肿瘤的药物为片剂、胶囊剂、丸剂、颗粒剂、缓释制剂、控释制剂、注射制剂中的任一种。
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