CN116327967A - 一种铂纳米粒子/石墨烯量子点复合纳米材料及其制备方法和在抗肿瘤药物中的应用 - Google Patents
一种铂纳米粒子/石墨烯量子点复合纳米材料及其制备方法和在抗肿瘤药物中的应用 Download PDFInfo
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Abstract
本申请公开了一种铂纳米粒子/石墨烯量子点复合纳米材料及其制备方法和在抗肿瘤药物中的应用,属于生物医药材料制备领域。所述复合纳米材料包括铂纳米粒子和石墨烯量子点;所述铂纳米粒子以聚集体形式分散于所述石墨烯量子点中;所述石墨烯量子点与所述纳米氧化铪络合。该材料溶解性高、物化性能稳定且化疗效果显著。该制备方法为简便的热还原合成方法,克级别合成高溶解性的铂纳米粒子/石墨烯量子点化疗药物。在制备过程中,不需要额外加入有毒还原剂,石墨烯量子点同时作为具有化疗作用的超细铂纳米粒子的多功能辅助基质和稳定剂。
Description
技术领域
本申请涉及一种铂纳米粒子/石墨烯量子点复合纳米材料及其制备方法和在抗肿瘤药物中的应用,属于生物医药材料制备领域。
背景技术
癌症是危害人类生命健康的全球性疾病,预计将取代心血管疾病成为全球第一大致死疾病。随着患癌率越来越高,人们对各类癌症早已不陌生。世界卫生组织国际癌症研究机构(IARC)发布了全球癌症负担数据,2021年全球新发癌症病例超过2000万例,癌症死亡病例达到1002万例,其中,中国新发癌症和死亡病例均位居全球第一。国家癌症中心最新数据显示:2022年中国癌症新发病例约482万例,癌症死亡病例约321万例。癌症治疗方法包括手术、放疗、化疗、光动力治疗、光热治疗、磁热治疗、基因治疗和免疫治疗等。每种方法的适用范围不一样,各有优点和局限性,但是,由于癌细胞的易转移特性,通常的治疗方案中都会采用化疗药物。化疗是利用化学药物阻止癌细胞的增殖、浸润和转移,直至最终杀灭癌细胞的一种全身性治疗方式。
近年来,铂纳米粒子(Platinum nanoparticles,PtNPs)的化疗作用受到广泛关注。在肿瘤特殊微环境下(如酸性偏高、过氧化氢浓度偏高等),具有表面效应的高活性PtNPs被氧化分解,释放出癌细胞毒性的离子铂或相关二价铂配合物,产生化疗作用,另一方面,在正常中性或弱碱性体液中,PtNPs难以被氧化分解,而且通过肿瘤的增强渗透滞留效应(Enhanced permeability and retention effect,EPR)蓄集于肿瘤组织,从而呈现出相比于铂类分子药物更小的毒副作用。此外,PtNPs是一种多功能抗肿瘤药物,还具有人工酶、高能射线增敏、高效光热转换等特殊性能。所以,相对于临床常用的顺铂、奥沙利铂等铂类分子药物,具有化疗作用的PtNPs表现出更低的毒副作用,对铂类分子药物耐药的一些肿瘤也表现出明显的抑制作用,PtNPs化疗药物有望成为下一代铂类抗癌药物。
PtNPs化疗药物的临床应用仍然面临着巨大挑战,原因主要有:1)在稳定剂和还原剂(如硼氢化钠、水合肼、抗坏血酸等)存在下,通过直接湿法还原得到超细PtNPs是广泛使用的一种合成方法,在合成过程中,稳定剂、还原剂、高价铂化合物、有机溶剂、反应副产物、以及毒素或细菌污染都可能是体内毒副作用的来源,导致纳米药物的纯化过程比较繁杂;2)静脉注射的纳米药物需经过体内血液循环、肿瘤蓄积、肿瘤内渗透、被癌细胞内吞和在胞内释放五步级联过程才能在肿瘤细胞内发挥药效,在肿瘤组织中渗透能力的缺失是大多数纳米药物的“短板”,它们在肿瘤的递送效率少于0.7%,主要原因是分散性和溶解性差;3)药物的物理化学稳定性、药理学、药代动力学、毒理学需要综合评估,以验证药物的有效性和安全性。
发明内容
针对现有技术中具有化疗作用的铂纳米粒子难以批量合成、稳定性差、溶解性低等癌症临床治疗上的用药问题,为解决现有技术的不足,本发明提供一种铂纳米粒子/石墨烯量子点化疗药物,提供上述纳米材料的高剂量绿色制备方法。所合成的上述纳米药物的化疗效果稳定且显著,具有很好应用前景。利用高生物相容的GQDs保护具有化疗作用的PtNPs,可有效提高药物的分散性和溶解性,并通过EPR效应加大PtNPs@GQDs化疗药物在肿瘤组织中的蓄积,使之被动靶向于癌细胞。此外,作为纳米载体的GDQs可以负载靶向分子(生物素、叶酸、RGD肽、透明质酸、TAT穿膜肽等),提高复合药物对肿瘤和癌细胞的主动靶向能力,增强抗肿瘤效果。
根据本申请的第一个方面,提供了一种复合纳米材料。该材料由石墨烯量子点络合保护超细铂纳米粒子得到的产物。具体的,利用石墨烯量子点中的羧基、羟基、氨基等基团增加纳米复合物的分散性和溶解性,石墨烯量子点作为超细铂纳米粒子的多功能辅助基质和稳定剂,有力保护高活性超细铂纳米粒子,使之在肿瘤特殊微环境下析出抗癌活性组分并有效杀灭癌细胞。超细铂纳米粒子(粒径为1.5-3nm)以聚集体形式分散于无定形石墨烯量子点基质中,此复合物高效溶解于去离子水中,全部溶质能通过220nm孔径的微孔滤膜,水溶解度大于80mg/mL,放置2个月后无沉集现象。
一种复合纳米材料,所述复合纳米材料包括铂纳米粒子和石墨烯量子点;
所述铂纳米粒子以聚集体形式分散于所述石墨烯量子点中;
所述石墨烯量子点与所述纳米氧化铪络合。
可选地,所述石墨烯量子点中含有氮、硫、氧。
可选地,所述石墨烯量子点中相互堆叠形成纳米片。
可选地,所述铂纳米晶的粒径为1.5-3nm。
可选地,在所述复合纳米材料中,铂的含量为10%-20%。
可选地,在所述复合纳米材料中,铂的含量独立地选自10%、11%、12%、13%、14%、15%、16%、17%、18%、19%、20%中的任意值或任意两者之间的范围值。
可选地,所述复合纳米材料的水溶液中,全部溶质能通过220nm孔径的微孔滤膜。
可选地,所述复合纳米材料的水溶解度大于80mg/mL。
可选地,所述复合纳米材料的水溶解度独立地选自80mg/mL、85mg/mL、90mg/mL、95mg/mL、100mg/mL、110mg/mL、120mg/mL、130mg/mL、140mg/mL、150mg/mL、160mg/mL、170mg/mL、180mg/mL、190mg/mL、200mg/mL中的任意值或任意两者之间的范围值。
可选地,所述石墨烯量子点含有羧基、羟基、氨基。
所述石墨烯量子点作为所述铂纳米粒子的辅助基质和稳定剂。
根据本申请的第二个方面,提供了一种复合纳米材料的制备方法。该方法为简便的热还原法,克级别合成高溶解性的PtNPs@GQDs化疗药物。在制备过程中,不需要额外加入有毒还原剂,所加入的还原剂(甲醇或乙醇)可以通过旋蒸、冻干等工艺去除。由于PtNPs与GQDs的协同作用,所合成的复合药物具有高分散性和高水溶性。
一种复合纳米材料的制备方法,包括以下步骤:
S1、获得石墨烯量子点;
S2、将含有所述石墨烯量子点、铂源、还原剂的混合物,热还原得到所述复合纳米材料;
所述还原剂选自甲醇、乙醇中的至少一种。
可选地,所述铂源选自氯亚铂酸钠、氯亚铂酸钾、氯亚铂酸铵、四氯化铂、氯铂酸、氯铂酸钠中的至少一种。
可选地,所述石墨烯量子点的质量与所述铂源的摩尔比为7g/mmol-8g/mmol。
可选地,所述石墨烯量子点的质量与所述铂源的摩尔比独立地选自7g/mmol、7.1g/mmol、7.2g/mmol、7.3g/mmol、7.4g/mmol、7.5g/mmol、7.6g/mmol、7.7g/mmol、7.8g/mmol、7.9g/mmol、8g/mmol中的任意值或任意两者之间的范围值。
可选地,所述石墨烯量子点的质量与所述还原剂的体积比为0.04g/ml-0.08g/ml。
可选地,所述石墨烯量子点的质量与所述还原剂的体积比独立地选自0.040、0.045、0.050、0.055、0.060、0.065、0.070、0.075、0.080中的任意值或任意两者之间的范围值。
可选地,热还原的条件如下:
第一阶段的温度为45-55℃;
时间为0.3-0.7h;
可选地,第一阶段的温度独立地选自45℃、46℃、47℃、48℃、49℃、50℃、51℃、52℃、53℃、54℃、55℃中的任意值或任意两者之间的范围值。
可选地,时间独立地选自0.3h、0.35h、0.40h、0.45h、0.50h、0.55h、0.60h、0.65h、0.70h中的任意值或任意两者之间的范围值。
第二阶段的温度为55-65℃;
时间为0.8-1.2h。
可选地,第二阶段的温度独立地选自55℃、56℃、57℃、58℃、59℃、60℃、61℃、62℃、63℃、64℃、65℃中的任意值或任意两者之间的范围值。
可选地,时间独立地选自0.8h、0.85h、0.90h、0.95h、1.00h、1.05h、1.10h、1.15h、1.20h中的任意值或任意两者之间的范围值。
可选地,热还原后还包括纯化、冷冻干燥。
可选地,步骤S2中,将含有铂源的溶液加入到含有所述石墨烯量子点的溶液中,再加入还原剂。
可选地,步骤S1中,石墨烯量子点的制备如下:
将含有单一小分子的混合物置于密闭容器中,反应得到所述石墨烯量子点;
所述单一小分子选自柠檬酸铵、柠檬酸氢二铵、柠檬酸、叶酸、尿素、硫脲、二氰二胺中的至少一种。
可选地,所述单一小分子的浓度为0.2mmol/ml-0.4mmol/ml。
可选地,所述单一小分子的浓度独立地选自0.2mmol/ml、0.25mmol/ml、0.30mmol/ml、0.35mmol/ml、0.40mmol/ml中的任意值或任意两者之间的范围值。
可选地,反应的条件如下:
温度为180-250℃;
时间为8-12h。
可选地,温度独立地选自180℃、185℃、190℃、195℃、200℃、205℃、210℃、215℃、220℃、225℃、230℃、235℃、240℃、245℃、250℃中的任意值或任意两者之间的范围值。
可选地,时间独立地选自8h、8.5h、9.0h、9.5h、10.0h、10.5h、11.0h、11.5h、12.0h中的任意值或任意两者之间的范围值。
可选地,所述单一小分子为0.2mmol/ml-0.4mmol/ml的柠檬酸氢二胺。
可选地,所述单一小分子为0.2mmol/ml-0.3mmol/ml的柠檬酸和0.3mmol/ml-0.35mmol/ml的二氰二胺。
可选地,所述单一小分子为0.2mmol/ml-0.3mmol/ml的柠檬酸和0.45mmol/ml-0.55mmol/ml的尿素。
根据本申请的一个实施方式,上述铂纳米粒子/石墨烯量子点化疗药物的制备方法,基本步骤包括:1)石墨烯量子点前体的合成和纯化;2)利用石墨烯量子点配位锚定高价铂化合物,并在石墨烯量子点基质上原位热还原高价铂化合物,形成超细铂纳米粒子/石墨烯量子点复合物;3)铂纳米粒子/石墨烯量子点复合物的纯化和冷冻干燥。
石墨烯量子点前体的合成包括由上而下法和由下而上法,优选的,采用由下而上法合成高水溶性、高生物相容性的石墨烯量子点。具体的,由柠檬酸铵、柠檬酸氢二铵、柠檬酸、叶酸、尿素、硫脲、二氰二胺等单一小分子或混合物作为起始原料,采用溶剂热法缩合成石墨烯量子点。优选的,合成含氮、硫、氧等的石墨烯量子点,以便有利于配位锚定高价铂化合物并进行原位还原。近一步优选的,采用高温水热合成石墨烯量子点,有利于形成石墨烯纳米片,使之对超细铂纳米粒子具有适中的保护能力,有利于超细铂纳米粒子在肿瘤微环境下发挥化疗作用。
铂纳米粒子/石墨烯量子点化疗药物的高剂量合成方法,原位热还原锚定在含氮、硫、氧等石墨烯量子点的铂离子,精确控制温度,使铂离子缓慢还原形成超细铂纳米粒子/石墨烯量子点复合物。热还原合成所用溶剂为高纯度去离子水,还原剂选用挥发性的有机溶剂乙醇或甲醇(优选乙醇)。加入的高价铂化合物为溶于水的氯亚铂酸钠、氯亚铂酸钾、氯亚铂酸铵、四氯化铂、氯铂酸、氯铂酸钠等中一种,优选同时溶于水和乙醇的氯亚铂酸钠、氯铂酸、氯铂酸钠等中一种。
随着还原反应的进行,溶液颜色逐渐加深,由黄色-棕色-棕黑色变化,说明铂纳米粒子缓慢形成。在制备过程中,不需要额外加入有毒还原剂,所加入的还原剂(甲醇或乙醇)可以通过旋蒸、冻干等工艺去除。未反应的氯亚铂酸钠、氯铂酸、氯铂酸钠等铂化合物可以通过乙醇洗涤去除。此绿色合成方法适合于铂纳米粒子化疗药物的可控高剂量合成。
根据本申请的第三个方面,提供了一种复合纳米材料在抗肿瘤药物中的应用。该复合材料可以高效杀灭各种人癌细胞,在人癌小鼠移植瘤模型试验中表现出良好的抗肿瘤效果。各种体外人癌细胞增殖抑制试验表明,所述铂纳米粒子/石墨烯量子点复合物的半数抑制浓度IC50小于0.6μgPt/mL(以铂含量计算),而且放置1-2月后样品的化疗效果并未改变。作为对比,合成的石墨烯量子点前体具有良好生物相容性,无细胞毒性。以上说明所述铂纳米粒子/石墨烯量子点化疗药物具有优越的溶解性、物化稳定性及药效稳定性。
本申请能产生的有益效果包括:
1)本申请所提供的一种复合纳米材料,其溶解性高、物化性能稳定且化疗效果显著。利用高生物相容的石墨烯量子点保护具有化疗作用的铂纳米粒子,可有效提高药物的分散性和溶解性,并通过增强的渗透滞留效应加大铂纳米粒子/石墨烯量子点复合药物在肿瘤组织中的蓄积,被动靶向于癌细胞。此外,作为纳米载体的石墨烯量子点可以负载生物活性剂和靶向剂(抗体、叶酸、RGD肽、透明质酸、TAT穿膜肽等),提高复合药物的主动靶向能力,增强肿瘤治疗效果并减少毒副作用。
2)本申请所提供的一种复合纳米材料的制备方法,通过简便的热还原合成方法,克级别合成高溶解性的铂纳米粒子/石墨烯量子点化疗药物。在制备过程中,不需要额外加入有毒还原剂,石墨烯量子点同时作为具有化疗作用的超细铂纳米粒子的多功能辅助基质和稳定剂。所述超细铂纳米粒子/石墨烯量子点化疗药物具有优越的溶解性和物理化学稳定性,并且高效杀灭各种人癌细胞,在人癌小鼠移植瘤模型试验中表现出良好的抗肿瘤效果。此外,由于铂纳米粒子与石墨烯量子点的协同作用,其纳米复合材料在催化领域也具有潜在应用价值。铂纳米粒子/石墨烯量子点纳米材料将成为抗肿瘤治疗和催化有应用前景的平台,同时也将在其它领域得到广泛的应用。
附图说明
图1为本申请实施例1中的GQDs的粉末衍射。
图2为本申请实施例1中的GQDs的透射电镜图,其中,a的标尺为100nm,b的标尺为5nm。
图3为本申请实施例1中的PtNPs@GQDs的高分辨透射电镜,标尺为5nm。
图4为本申请实施例1中的PtNPs@GQDs化疗药物对人结肠癌HT-29小鼠移植瘤的治疗作用。
具体实施方式
下面结合实施例详述本申请,但本申请并不局限于这些实施例。
如无特别说明,本申请的实施例中的原料均通过商业途径购买。
如无特别说明,采用常规的测试方法或者仪器推荐的测试方法。
实施例1
GQDs前体制备:称取柠18mmol柠檬酸三胺(4.37g)于反应釜聚四氟乙烯材质内衬中(容积为100毫升),加入60毫升去离子水,超声溶解10分钟,然后210℃水热反应10小时。反应液自然冷却至室温后,高速离心(12000r/min)5分钟,除去溶液中的橙黄色大颗粒残渣。之后,60℃真空旋蒸离心液至近干,除去溶液中的挥发性小分子。旋蒸得到的橙黄色粘稠物通过冷冻干燥除去溶剂水,之后用无水乙醇多次洗涤离心,得到不溶于乙醇的淡黄色石墨烯量子点,真空冷冻干燥得到1.2克GQDs产物。通过测试证实了石墨烯量子点的特征:粉末衍射在2θ=26°出现石墨烯量子点的特征峰(图1);透射电镜测试看到15-30nm的石墨烯量子点相互堆叠形成纳米片(图2)。
PtNPs@GQDs化疗药物制备:称取1.2克上述GQDs前体于圆底烧瓶中,加入20毫升去离子水溶解。配制600毫克Na2PtCl4(铂含量>48%)的20毫升去离子水溶液,缓慢滴加于GQDs水溶液中,搅拌反应,再加入20毫升无水乙醇。此时的溶液颜色为黄色,并伴有少量沉淀。缓慢升温反应溶液至50℃,恒温反应0.5小时,溶液颜色由黄色变为棕色,沉淀也完全溶解,表明铂纳米粒子缓慢形成。再次缓慢升温反应溶液至60℃,恒温反应1小时,溶液颜色逐渐变深,最终呈现出棕黑色的澄清液。停止反应后,真空旋蒸(50℃)除去乙醇至水溶液体积约20毫升,用NaOH调节溶液pH值至7-7.5。高速离心溶液(12000r/min)4分钟,除去溶液中的极少量黑色大颗粒。棕黑色澄清液真空冷冻干燥得到黑色固体,用乙醇洗涤离心,再次真空冷冻干燥除去乙醇和水,得到黑色PtNPs@GQDs固体产物1.5克。通过透射电镜测试看到超细铂纳米晶(粒径为1.5-3nm)以聚集体形式分散于无定形石墨烯量子点基质中(图3),ICP测试得到固体样品中铂和钠的含量分别为16.05%和8.54%。
PtNPs@GQDs化疗药物的体外癌细胞增殖抑制试验:将不同浓度PtNPs@GQDs受试物对人肿瘤细胞(细胞数为3K)作用3天后,采用磺酰罗丹明B(SRB)法测定吸光度值,计算半数抑制浓度IC50。表1为所述PtNPs@GQDs化疗药物对不同人肿瘤细胞的IC50值(以铂含量计算,小于0.6μg Pt/mL),所述PtNPs@GQDs化疗药物具有高效化疗作用。
PtNPs@GQDs化疗药物的人癌小鼠移植瘤模型试验:人肿瘤细胞系传3代后接种于Balb/c裸鼠或NOD-SCID小鼠皮下,建立人癌异体移植瘤模型,评估PtNPs@GQDs的体内抗肿瘤活性。待移植瘤生长至少达100mm3后,将小鼠随机分组(每组10只)尾静脉给药,包括高、中、低3个剂量的给药组、阳性对照组和阴性对照组。图4给出了所述PtNPs@GQDs化疗药物对人结肠癌HT-29小鼠移植瘤的治疗作用。在此试验中,以医用顺铂(DDP,包含聚乙二醇400和氯化钠)为阳性对照药物。PtNPs@GQDs受试物剂量的选择体现出量效关系,高剂量药物的最终肿瘤抑制率为90.19%,高于医用顺铂的最终肿瘤抑制率(66.97%)。而且,在治疗过程中,注射入PtNPs@GQDs化疗药物的三组小鼠未见死亡,但是,注射入医用顺铂的一组小鼠中,中途有两只小鼠死亡。人癌小鼠移植瘤模型试验表明,所述PtNPs@GQDs是有应用前景的化疗药物。
表1
实施例2
石墨烯量子点的组成结构及合成条件直接影响PtNPs@GQDs药物的化疗作用。不改变实施例1中制备合成中所有方案及配比,唯一改变的是石墨烯量子点前体合成中的小分子,我们得到了一系列具有高效化疗作用的PtNPs@GQDs药物,其化疗效果不再赘述,在此公开石墨烯量子点前体制备中加入的初始小分子,由18mmol柠檬酸三胺分别改为:1)18mmol柠檬酸氢二胺;2)15mmol柠檬酸和20mmol二氰二胺;3)15mmol柠檬酸和30mmol尿素。
以上所述,仅是本申请的几个实施例,并非对本申请做任何形式的限制,虽然本申请以较佳实施例揭示如上,然而并非用以限制本申请,任何熟悉本专业的技术人员,在不脱离本申请技术方案的范围内,利用上述揭示的技术内容做出些许的变动或修饰均等同于等效实施案例,均属于技术方案范围内。
Claims (10)
1.一种复合纳米材料,其特征在于,所述复合纳米材料包括铂纳米粒子和石墨烯量子点;
所述铂纳米粒子以聚集体形式分散于所述石墨烯量子点中;
所述石墨烯量子点与所述纳米氧化铪络合。
2.根据权利要求1所述的复合纳米材料,其特征在于,所述石墨烯量子点中含有氮、硫、氧;
优选地,所述石墨烯量子点相互堆叠形成纳米片;
优选地,所述铂纳米晶的粒径为1.5-3nm;
优选地,在所述复合纳米材料中,铂的含量为10%-20%。
3.根据权利要求1所述的复合纳米材料,其特征在于,所述复合纳米材料的水溶液中,全部溶质能通过220nm孔径的微孔滤膜;
优选地,所述复合纳米材料的水溶解度大于80mg/mL;
优选地,所述石墨烯量子点含有羧基、羟基、氨基。
4.一种复合纳米材料的制备方法,其特征在于,包括以下步骤:
S1、获得石墨烯量子点;
S2、将含有所述石墨烯量子点、铂源、还原剂的混合物,热还原得到所述复合纳米材料;
所述还原剂选自甲醇、乙醇中的至少一种。
5.根据权利要求4所述的制备方法,其特征在于,所述铂源选自氯亚铂酸钠、氯亚铂酸钾、氯亚铂酸铵、四氯化铂、氯铂酸、氯铂酸钠中的至少一种;
优选地,所述石墨烯量子点的质量与所述铂源的摩尔比为7g/mmol-8g/mmol;
优选地,所述石墨烯量子点的质量与所述还原剂的体积比为0.04g/ml-0.08g/ml;
优选地,热还原的条件如下:
第一阶段的温度为45-55℃;
时间为0.3-0.7h;
第二阶段的温度为55-65℃;
时间为0.8-1.2h;
优选地,热还原后还包括纯化、冷冻干燥。
6.根据权利要求4所述的制备方法,其特征在于,步骤S2中,将含有铂源的溶液加入到含有所述石墨烯量子点的溶液中,再加入还原剂。
7.根据权利要求4所述的制备方法,其特征在于,步骤S1中,石墨烯量子点的制备如下:
将含有单一小分子的混合物置于密闭容器中,反应得到所述石墨烯量子点;
所述单一小分子选自柠檬酸铵、柠檬酸氢二铵、柠檬酸、叶酸、尿素、硫脲、二氰二胺中的至少一种。
8.根据权利要求7所述的制备方法,其特征在于,所述单一小分子的浓度为0.2mmol/ml-0.4mmol/ml;
优选地,反应的条件如下:
温度为180-250℃;
时间为8-12h;
优选地,所述单一小分子为0.2mmol/ml-0.4mmol/ml的柠檬酸氢二胺;
优选地,所述单一小分子为0.2mmol/ml-0.3mmol/ml的柠檬酸和0.3mmol/ml-0.35mmol/ml的二氰二胺;
优选地,所述单一小分子为0.2mmol/ml-0.3mmol/ml的柠檬酸和0.45mmol/ml-0.55mmol/ml的尿素。
9.权利要求1-3中任一项所述的复合纳米材料和/或权利要求4-8中任一项所述的制备方法得到的复合纳米材料在抗肿瘤药物中的应用。
10.根据权利要求9所述的的应用,其特征在于,所述复合纳米材料中的石墨烯量子点作为载体,负载有靶向分子;
优选地,所述靶向分子选自生物素、叶酸、RGD肽、透明质酸、TAT穿膜肽中的至少一种。
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