CN103845361A - 石墨烯量子点在制备肿瘤治疗敏化剂中的用途 - Google Patents
石墨烯量子点在制备肿瘤治疗敏化剂中的用途 Download PDFInfo
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Abstract
本发明涉及石墨烯量子点在制备肿瘤治疗敏化剂中的用途。本发明中石墨烯量子点能够进入肿瘤细胞的溶酶体引起溶酶体通透性增强,进而使化疗药物容易从溶酶体中释放出来,增强其对肿瘤细胞的杀伤作用。因此,本发明的石墨烯量子点能够作为肿瘤治疗敏化剂的活性成分使用,其具有稳定性高、靶向性强和副作用小的优势。
Description
技术领域
本发明涉及肿瘤治疗的敏化技术领域,尤其涉及石墨烯量子点在制备肿瘤治疗敏化剂中的用途。
背景技术
化疗作为癌症治疗中最常用的方法之一,却常常由于癌细胞对于化疗药物的抗性而效果不佳,克服癌细胞对化疗药物的抗性对于肿瘤治疗的成功往往起到关键作用。因此,针对肿瘤抗药性,亟需开发出提高化疗药效的新方法。
近年来,科学家提出多种克服肿瘤抗药性,提高疗效的方法,其中化疗敏化成为最为重要的方法之一。化疗敏化即应用某种方法或试剂使肿瘤细胞对于化疗药物更加敏感,更容易受到抗肿瘤药物的杀伤,从而降低抗药性,提高药效。用于敏化细胞的试剂包括一些病毒载体、小分子干扰核糖核酸和核酶等,还包括单克隆抗体以及小分子化合物等,例如某些蛋白酶抑制剂可以通过干扰细胞信号通路而达到敏化细胞的目的。然而无论大分子还是小分子敏化剂都存在稳定性差、副作用大的问题。例如小分子干扰核糖核酸和核酶等都属于核酸类分子,它们进入血液循环,很容易被降解,所以不稳定;小分子蛋白酶抑制剂缺少靶向性,进入体内很有可能损伤正常细胞,也就是说副作用大。这些问题制约着敏化剂的应用。
随着纳米科技的发展,纳米材料在生物医学中的应用受到了研究者的广泛关注。已经证明一些纳米材料可以敏化细胞。如Wason发现氧化铈纳米颗粒可以通过诱导细胞产生活性氧簇来敏化癌细胞,Mackey等人发现细胞核靶向的金纳米颗粒可以通过调节细胞周期来敏化癌细胞,提升化疗药物5-氟尿嘧啶的效果。
但是以上纳米材料中都含有重金属元素,其潜在的毒性限制了实际应用。最近几年兴起的石墨烯量子点因为生物相容性好、水溶性好、易合成及易修饰等特点,具有很好的生物医学应用前景。石墨烯量子点还可利用实体瘤的高通透性和滞留效应(EPR)发挥被动靶向作用,提高其在实体肿瘤中的积累浓度,增加对肿瘤的效应同时减小对正常细胞的损伤,因此其靶向性强、副作用小。阿霉素等化疗抗癌药被癌细胞摄取后容易停留在溶酶体中而难以大量到达其发挥毒性作用的细胞核,药效降低,还会因而产生抗药性。利用石墨烯量子点引起溶酶体通透性增强来敏化癌细胞还未有报道。
发明内容
针对现有技术的不足,本发明人经过深入研究发现石墨烯量子点能够进入肿瘤细胞的溶酶体引起溶酶体通透性增强,进而使化疗药物容易从溶酶体中释放出来,增强其对肿瘤细胞的杀伤作用。因此,本发明的石墨烯量子点能够作为肿瘤治疗敏化剂的活性成分使用,其具有稳定性高、靶向性强和副作用小的优势。
本发明提供石墨烯量子点在制备肿瘤治疗敏化剂中的用途,所述敏化剂包括作为活性成分的石墨烯量子点,用于增强化疗药物对肿瘤的杀伤作用。
作为本发明的优选实施方案,所述石墨烯量子点为水溶性石墨烯量子点。所述石墨烯量子点可以是羟基、羧基、氨基和/或聚乙二醇修饰的水溶性石墨烯量子点,优选为羟基和/或羧基修饰的水溶性石墨烯量子点,更优选为羟基和羧基修饰的水溶性石墨烯量子点。
制备上述水溶性石墨烯量子点的方法是本领域技术人员公知的,比如Pan,D等人在Adv Mater2010,22(6),734-8中报道了将石墨烯片切割成发蓝光的石墨烯量子点的水热法路径;Tetsuka,H等人在Adv Mater2012,24(39),5333-8中报道了光可调谐氨基功能化石墨烯量子点;Peng,J等人在Nano Lett2012,12(2),844-9中报道了由碳纤维衍生出石墨烯量子点。上述方法以及现有的其它方法和未来将要开发出来的方法制备的石墨烯量子点可用于本发明中。
虽然如此,本发明还提供一种制备所述石墨烯量子点的方法供本领域技术人员参考,所述方法是以氧化石墨烯为前体通过水热法制备得到石墨烯量子点。
本发明提供的制备所述石墨烯量子点的方法,包括以石墨粉为原料,经过氧化、超声剥离、水热处理和分离纯化等基本步骤。优选地,所述氧化步骤包括用浓硫酸、过硫酸钾和/或五氧化二磷处理石墨粉,反应产物用水稀释,经过过滤、洗涤和干燥得到氧化石墨烯。优选地,所述超声剥离步骤包括将干燥的氧化石墨烯加入超纯水中,用氢氧化钠调节pH至8-10(优选为9),超声处理30-50分钟(优选为40分钟),氧化石墨烯浓度为1-10mg/mL(优选为5mg/mL)。优选地,所述水热处理步骤是以所述氧化石墨烯为前体在碱性环境下经超声剥离后,在180-220℃(优选200℃)水热处理4-6小时(优选5小时)。优选地,所述分离纯化步骤包括微孔滤膜过滤、透析除盐和干燥的步骤,其中所述微孔滤膜孔径优选为0.22μm,透析除盐优选先用盐酸将pH调至7,再用孔径500-1000KDa(优选500KDa)的透析袋透析除盐。
采用本发明提供的方法制备的石墨烯量子点呈片层状,所述片层横向大小为1-6nm、厚度为0.5-1.5nm。
本领域的技术人员知晓,石墨烯量子点的形状和尺寸不是其发挥生理生化功能的关键因素,因此本发明的石墨烯量子点并不局限于上述形状和尺寸。
经研究发现,所述石墨烯量子点能够进入肿瘤细胞的溶酶体引起溶酶体通透性增强,这是其能够使化疗药物容易从溶酶体中释放出来,增强化疗药物对肿瘤细胞的杀伤作用的关键。
能够适用于本发明的化疗药物包括但不限于阿霉素(doxorubicin)、道诺霉素(daunorubicin)、长春新碱(vincristine)、舒尼替尼(sunitinib)、顺铂(cis-platin)、喜树碱(camptothecin)、紫杉醇(paclitaxel)、博来霉素(bleomycin)、5-氟尿嘧啶(5-FU)、埃博霉素(epothilones)、吉非替尼(gefitinib)、拉帕替尼(lapatinib)、伊达比星(idarubicin)、表柔比星(epirubicin)、多西他赛(docetaxel)和卡铂(carboplatin)中的至少一种,优选包括阿霉素。
本发明人以化疗药物阿霉素为例研究了石墨烯量子点能够增强阿霉素杀伤作用的机理在于石墨烯量子点能够进入肿瘤细胞的溶酶体引起溶酶体通透性增强,使阿霉素容易从溶酶体中释放出来。上述药物与阿霉素相似,它们被癌细胞摄取后都容易停留在溶酶体中而难以大量到达其发挥毒性作用的细胞核从而药效减低。因此本领域的技术人员知晓本发明的石墨烯量子点引起溶酶体通透性增强,必然能够使这些化疗药物容易从溶酶体中释放出来,增强它们对肿瘤细胞的杀伤作用。
目前上述药物适用治疗的肿瘤包括但不限于胃癌、肝癌、直肠癌、结肠癌、小细胞肺癌、鳞状细胞肺癌、肺腺癌、细支气管腺癌、甲状腺癌、宫颈癌、卵巢癌、前列腺癌、食管癌、头颈癌、淋巴上皮癌、黑色素瘤、乳腺癌、导管癌、骨肉瘤、基底鳞状细胞癌、膀胱癌、神经母细胞瘤和胶质母细胞瘤中的至少一种,其中所述头颈癌包括眼癌、口癌、舌癌、咽癌、喉癌、鼻癌和唇癌中的至少一种。因此,本发明的石墨烯量子点能够用于这些肿瘤的治疗中,作为敏化剂来敏化上述药物对这些肿瘤的治疗作用。
本发明中,所述石墨烯量子点与所述化疗药物联合施用。联合施用的方式可以是同时施用所述石墨烯量子点和所述化疗药物,也可以是间隔施用所述石墨烯量子点和所述化疗药物,比如先施用所述石墨烯量子点1分钟-2小时之后再施用所述化疗药物,或者相反。优选地,联合施用时,所述石墨烯量子点的用量以质量计为所述化疗药物用量的1-100倍,优选50倍。
需要说明的是,本发明中的敏化剂以所述石墨烯量子点为关键性活性成分之一,并不排除其它不影响所述石墨烯量子点药效功能的其它敏化剂活性成分或辅料。
本发明的有益效果为:本发明的石墨烯量子点能够进入肿瘤细胞的溶酶体引起溶酶体通透性增强,进而使化疗药物容易从溶酶体中释放出来,增强其对肿瘤细胞的杀伤作用。因此,可以作为肿瘤治疗敏化剂的活性成分使用。相比现有技术中的小分子干扰核糖核酸和核酶等核酸类分子,石墨烯量子点进入血液循环不会被降解,可以稳定存在至被代谢出体外,因此其稳定性高;相比小分子蛋白酶抑制剂,石墨烯量子点可利用实体瘤的高通透性和滞留效应(EPR)发挥被动靶向作用,提高其在实体肿瘤中的积累浓度,增加对肿瘤的效应同时减小对正常细胞的损伤,因此其靶向性强、副作用小。
附图说明
图1示出了本发明的石墨烯量子点的透射电子显微镜图像及其尺寸分布图,其中a为石墨烯量子点的透射电子显微镜图像,可见其呈片层状;b为其尺寸分布图,可见其片层横向大小(直径)为1-6nm。
图2示出了本发明的石墨烯量子点及阿霉素单独或共同孵育HeLa细胞的存活率变化(a),以及细胞形态、阿霉素细胞核内浓度变化(b)的结果。
图3示出了本发明的石墨烯量子点与溶酶体和线粒体共定位情况,显示石墨烯量子点主要定位于溶酶体(a),而非线粒体(b)。
图4示出了本发明的石墨烯量子点导致溶酶体膜通透性增强的结果,石墨烯量子点处理的细胞吖啶橙红色荧光相比未处理的细胞(对照组)强度明显下降,图中箭头指示点即为吖啶橙红色荧光点。
具体实施方式
下面通过具体实施方式描述本发明的技术方案。
本发明中,研究所述石墨烯量子点引起癌细胞对化疗药物敏化的方法,包括步骤:1)将石墨烯量子点和化疗药物(优选阿霉素)共同或单独加入细胞培养基孵育细胞1-24小时,石墨烯量子点浓度为10-100μg/mL(优选50μg/mL),化疗药物浓度为0.3-2μg/mL(1μg/mL),并设置平行对照组(不加石墨烯量子点或化疗药物);2)检测细胞存活率并对细胞核荧光染色后用荧光显微镜观测细胞。
本发明还在细胞层面上研究了石墨烯量子点敏化细胞的机理,包括石墨烯量子点的细胞内定位研究和溶酶体通透性的研究。
其中,所述细胞内定位研究中,石墨烯量子点链接荧光素异硫氰酸荧光素(FITC)的步骤如下:1)1mL的浓度为100μg/mL石墨烯量子点加入3mgN-羟基琥珀酰亚胺(NHS)和0.5mg FITC,10分钟后加入8mg1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(EDC),室温避光反应4小时;2)用截留孔径500KD的透析袋避光透析两天,以除去未反应的小分子FITC。荧光标记的石墨烯量子点可以在蓝光的激发下发射出强绿色荧光。
用上述荧光标记的石墨烯量子点通过激光扫描共聚焦显微镜研究细胞内定位。用上述荧光标记的石墨烯量子点10-200μg/mL(优选100μg/mL)孵育细胞(优选HeLa细胞)2-24小时(优选6小时),再用溶酶体荧光探针LysoTracker Red-DND-99(Invitrogen)和线粒体荧光探针Mito Tracker RedCMXRos(Invitrogen)对细胞器进行标记,两种细胞器荧光探针均发红色荧光,用激光扫描共聚焦显微镜观察。
其中,石墨烯量子点影响溶酶体通透性变化的研究。优选用浓度为100μg/mL的石墨烯量子点处理HeLa细胞6小时,然后用荧光染料吖啶橙给细胞染色,用激光扫描共聚焦显微镜观察。吖啶橙在完整的溶酶体中富集成高浓度,可发出强烈红色荧光,若溶酶体通透性增强,则不能富集,红色荧光减弱,而低浓度的吖啶橙在细胞质基质及细胞核中,可发出绿色荧光。故可用吖啶橙荧光变化来表明溶酶体完整性。
试验结果证实,所述石墨烯量子点可使肿瘤细胞敏化,提高抗癌化疗药物阿霉素的杀伤效果。共定位实验图像表明石墨烯量子点主要分布在溶酶体中而非线粒体,也未进入细胞核中。所述石墨烯量子点引发溶酶体通透性增强,可增强进入溶酶体的化疗药物释放,从而增强杀伤性。预示着该石墨烯量子点在化疗敏化领域有广泛的应用。
下面将结合实施例对本发明的实施方案进行详细描述。本领域技术人员将会理解,以下实施例仅为本发明的优选实施例,以便于更好地理解本发明,因而不应视为限定本发明的范围。
下述实施例中的实验方法,如无特殊说明,均为常规方法;所用的实验材料,如无特殊说明,均为自常规生化试剂厂商购买得到的。
实施例1:石墨烯量子点的制备
将15mL浓硫酸加热到90℃,加入2.5g K2S2O8、2.5g P2O5和3g粉末状石墨(购自alfa aesar,325目)反应4.5小时。反应后,产物加入500mL去离子水稀释,过滤、洗涤,然后放入真空干燥箱。将120mL浓硫酸加入到干燥后的预处理氧化石墨中,搅拌均匀,于0℃冰浴中,缓慢加入15g高锰酸钾,待体系稳定之后撤掉冰浴,改为水浴,于35℃搅拌2h。然后改为冰浴,缓慢加入1000mL水进行稀释,溶液变为紫黑色,常温搅拌2h后,用玻璃滴管滴入20mL30%的H2O2,所得产物离心去掉上清液后用10%HCl溶液洗涤至完全除去硫酸根,再用去离子水洗至中性,最后得到的固体放入真空烘箱中进行干燥。
取100mg干燥后的氧化石墨加入30mL超纯水调节pH至8~9,经40min超声剥离后,转入到聚四氟乙烯反应釜中,于200℃下反应5小时后,自然冷却至室温。将上述过程中所得到的反应产物用0.22微米滤膜过滤除去黑色沉淀,得到淡黄棕色石墨烯量子点溶液,加盐酸调节pH至中性,透析除盐,再经旋转蒸发除去溶剂,得到石墨烯量子点固体。图1石墨烯量子点的透射电子显微镜图像表明其尺寸均一,集中分布在3.26nm左右。
实施例2:石墨烯量子点对癌细胞的敏化
对于细胞存活率实验,HeLa细胞接种在96孔板上,密度为4000个/孔,每组设三个复孔,先在37℃,5%CO2的条件下培养24小时。所选培养基为DMEM高糖,补充加10%胎牛血清以及青霉素/链霉素。24小时后,将培养基换为分别含有50μg/mL的石墨烯量子点,1μg/mL的阿霉素以及二者共有的培养基,孵育癌细胞HeLa,24小时后测细胞存活率发现石墨烯量子点与阿霉素共同使用比二者以相同浓度单独使用的细胞存活率显著下降(如图2a),说明了石墨烯量子点可以增强阿霉素的杀伤效果。对于荧光成像,HeLa细胞以5×105个/mL的密度接种在35mm玻璃底培养皿中培养24小时,然后分别换成含有50μg/mL的石墨烯量子点和1μg/mL的阿霉素以及只含有1μg/mL的阿霉素的培养基,孵育2小时。用细胞核探针Hoechst33342染细胞核,用荧光显微镜观察阿霉素在细胞内定位变化以及细胞形态变化。如图2b,明场显微图像显示了石墨烯量子点与阿霉素共同孵育癌细胞的形态变化,石墨烯量子点与阿霉素共同孵育的细胞比阿霉素单独孵育的细胞形态有变圆趋势,荧光显微镜则显示了共同孵育的细胞阿霉素更多进入细胞核。
实施例3:石墨烯量子点细胞定位
将HeLa细胞以5×105个/mL的密度接种在35mm玻璃底培养皿中培养24小时,然后换成含100μg/mL荧光标记的石墨烯量子点的培养基孵育细胞6小时后。将细胞标记溶酶体荧光探针和线粒体荧光探针,置于激光扫描共聚焦显微镜(Zeiss LSM710)进行成像,所得石墨烯量子点与细胞器共定位图片如图3所示。
石墨烯量子点分别于两种细胞器(溶酶体和线粒体)做荧光共定位研究,图3最右侧曲线图为融合图像中沿线段αω上红色(荧光探针的荧光)与绿色(石墨烯量子点的荧光)的荧光强度,可见石墨烯量子点与溶酶体探针的荧光发射位置重叠的很好,说明二者在同一位置,而石墨烯量子点与线粒体探针的荧光发射位置错开,说明二者不在同一位置。因此,石墨烯量子点主要定位于溶酶体(a),而非线粒体(b),也未进入细胞核。
实施例4:石墨烯量子点导致溶酶体通透性增强
将HeLa细胞以5×105个/mL的密度接种在35mm玻璃底培养皿中培养24小时,然后换成含100μg/mL荧光标记的石墨烯量子点的培养基孵育细胞6小时后。用5μg/mL的溶酶体极性染料吖啶橙染色,然后用共聚焦显微镜观察。吖啶橙在完整的溶酶体中富集成高浓度,可发出强烈红色荧光,若溶酶体通透性增强,则不能富集,红色荧光减弱,而低浓度的吖啶橙在细胞质基质及细胞核中,可发出绿色荧光。故可用吖啶橙荧光变化来表明溶酶体完整性。如图4所示,石墨烯量子点处理的细胞吖啶橙红色荧光相比未处理的细胞强度明显下降(图中箭头指示点即为吖啶橙红色荧光点)。
申请人声明,本发明通过上述实施例来说明本发明的详细特征以及详细方法,但本发明并不局限于上述详细特征以及详细方法,即不意味着本发明必须依赖上述详细特征以及详细方法才能实施。所属技术领域的技术人员应该明了,对本发明的任何改进,对本发明选用组分的等效替换及辅助成分的添加、具体方式的选择等,均落在本发明的保护范围和公开范围之内。
Claims (10)
1.石墨烯量子点在制备肿瘤治疗敏化剂中的用途,所述敏化剂包括作为活性成分的石墨烯量子点,用于增强化疗药物对肿瘤的杀伤作用。
2.根据权利要求1所述的用途,其特征在于,所述石墨烯量子点为水溶性石墨烯量子点。
3.根据权利要求1或2所述的用途,其特征在于,所述石墨烯量子点为羟基、羧基、氨基和/或聚乙二醇修饰的水溶性石墨烯量子点,优选为羟基和/或羧基修饰的水溶性石墨烯量子点,更优选为羟基和羧基修饰的水溶性石墨烯量子点。
4.根据权利要求1-3任一项所述的用途,其特征在于,所述石墨烯量子点呈片层状,所述片层横向大小为1-6nm、厚度为0.5-1.5nm。
5.根据权利要求1-4任一项所述的用途,其特征在于,所述石墨烯量子点能够进入肿瘤细胞的溶酶体引起溶酶体通透性增强。
6.根据权利要求1-5任一项所述的用途,其特征在于,所述石墨烯量子点是以氧化石墨烯为前体通过水热法制备得到的。
7.根据权利要求1-6任一项所述的用途,其特征在于,所述化疗药物包括阿霉素、道诺霉素、长春新碱、舒尼替尼、顺铂、喜树碱、紫杉醇、博来霉素、5-氟尿嘧啶、埃博霉素、吉非替尼、拉帕替尼、伊达比星、表柔比星、多西他赛和卡铂中的至少一种,优选包括阿霉素。
8.根据权利要求1-7任一项所述的用途,其特征在于,所述肿瘤包括胃癌、肝癌、直肠癌、结肠癌、小细胞肺癌、鳞状细胞肺癌、肺腺癌、细支气管腺癌、甲状腺癌、宫颈癌、卵巢癌、前列腺癌、食管癌、头颈癌、淋巴上皮癌、黑色素瘤、乳腺癌、导管癌、骨肉瘤、基底鳞状细胞癌、膀胱癌、神经母细胞瘤和胶质母细胞瘤中的至少一种。
9.根据权利要求1-8任一项所述的用途,其特征在于,所述头颈癌包括眼癌、口癌、舌癌、咽癌、喉癌、鼻癌和唇癌中的至少一种。
10.根据权利要求1-9任一项所述的用途,其特征在于,所述石墨烯量子点与所述化疗药物联合施用;
优选地,联合施用时,所述石墨烯量子点的用量以质量计为所述化疗药物用量的1-100倍,优选50倍。
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