CN108421039B - 金纳米团簇组装体、靶标标记自组装材料和肿瘤药物 - Google Patents
金纳米团簇组装体、靶标标记自组装材料和肿瘤药物 Download PDFInfo
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Abstract
本发明涉及一种金纳米团簇组装体、靶标标记自组装材料和肿瘤药物,所述的金纳米团簇组装体由金纳米团簇和二氢卟吩e6组装结合形成GNCs‑Ce6NPs,金纳米团簇组装体与CD3‑Ab结合后形成靶标标记自组装材料,当靶标标记自组装材料进入CIK细胞后即可组成肿瘤药物并用于肿瘤的成像治疗等。与现有技术相比,本发明的制备步骤简单,反应条件温和,易于操作,且不用任何表面活性剂,生物相容性好,最后制得的肿瘤药物成像效果明显且能够抑制肿瘤的生长,因此在肿瘤的诊断与治疗方面具有良好的发展前景。
Description
技术领域
本发明涉及生物医药、细胞治疗、肿瘤治疗领域,尤其是涉及一种金纳米团簇组装体、靶标标记自组装材料和肿瘤成像治疗药物及其制备和应用。
背景技术
目前的癌症治疗手段通常包括手术、化疗和放疗,但它们仍然面临着长期的挑战,因为它们不足以彻底根除癌细胞,尤其是对晚期癌症患者。因此,越来越多的研究关注肿瘤的诊断和治疗,以提高成像和治疗药物的靶向特异性。光动力疗法(PDT)对治疗各种癌症有很大的希望,因为它在本质上是非侵入性的,并且已经被批准用于临床使用。PDT利用光敏剂(PS)和光与氧结合,产生细胞毒素单线态氧(1O2),通过坏死或凋亡诱导癌细胞死亡。光动力试剂在没有激光照射的情况下,有微弱的荧光和光毒性,但在接收适当波长的激光照射,它的荧光会变强,且产生光毒性。因此,在非特异性组织中,光敏剂的积累显示的系统毒性很小。此外,许多光敏剂能够发射近红外荧光,这种特性有助于检测光敏剂的位置。因此,PDT试剂可通过成像介导治疗。
尽管该技术具有优势,但PDT具有严重的局限性,包括水溶解度低、非特异性分布以及低生物可利用性。为了解决这些问题,我们必须找到一种新的策略,把PS靶向递送到肿瘤部位,以提高肿瘤治疗的效率。金纳米团簇(GNCs)的独特物理化学特性,如超小尺寸、良好的光物理性能和生物相容性,使它们成为生物传感、药物输送和成像的理想平台。最近,GNCs被作为自我组装的基石,因为自组装的纳米粒子被认为是一种为临床应用提供药物的有效策略。不同的药剂被用来将GNCs与大的组件连接起来,例如Gd2+离子、Gd3+离子、Zn2+离子、Cu2+离子和阳离子聚合物。开发组装GNCs的新方法对改进它们的生物应用具有极大的必要。作为一种PDT试剂,二氢卟吩e6(Ce6)用于GNCs自组装中未见报道。因此,将Ce6整合到纳米粒子的递送系统中,可能会扩大GNCs的治疗应用。
目前,肿瘤细胞(包括间质干细胞、诱导多能干细胞(iPS细胞)和免疫细胞)已经引起了纳米医学领域的极大兴趣。具体来说,细胞因子诱导的杀伤细胞(CIK)细胞治疗(ACT)已经成为引发抗肿瘤免疫反应的最有效方法之一。CIK细胞是自然杀伤细胞(NK)的一种,具有非MHC限制的细胞毒性,它们可以很容易地在体外扩展,并且显示出比淋巴细胞激活杀伤(LAK)细胞更强的细胞增殖率。更重要的是,CIK细胞具有较低的抗宿主病(GVHD)风险。它们已被应用于实体瘤和血液瘤的治疗,并表现出显著的抗肿瘤活性。以前的研究表明,CIK细胞主要通过对NKG2D(NKGroup 2,成员D)和穿孔素介导的途径对恶性肿瘤细胞进行抗肿瘤活动。NKG2D属于II型c型凝集素家族,通过与它所表达的配体的相互作用,在发现和消灭肿瘤细胞方面起着重要作用。与此同时,使用CIK细胞的临床试验证明了CIK细胞不仅具有良好的治疗效果,而且可以抑制复发,提高患者的生活质量。
发明内容
本发明的目的就是为了克服上述现有技术存在的缺陷而提供一种金纳米团簇组装体、靶标标记自组装材料和肿瘤药物。
本发明的目的可以通过以下技术方案来实现:
本发明的目的之一在于提出一种金纳米团簇组装体,由金纳米团簇和二氢卟吩e6(即Ce6)组装结合形成GNCs-Ce6NPs。
本发明的金纳米团簇可以采用现有技术制得,如采用文献(Xia F,etal.ActaBiomaterialia,2017.)中记载的方法制备得到。金纳米团簇作为载体负载Ce6,Ce6可以用荧光成像和光动力治疗。
优选的,上述金纳米团簇组装体中,金纳米团簇上的金元素(Au)约22个,谷胱甘肽(GSH)约18个。
优选的,Ce6与金纳米团簇上的谷胱甘肽的摩尔比约为0.08:1。
同时,本发明还公开了一种金纳米团簇组装体的制备方法,具体为:取金纳米团簇分散于水溶液中,形成金纳米团簇溶液,再滴加二氢卟吩e6,室温搅拌,即得到金纳米团簇组装体GNCs-Ce6NPs。
在上述制备过程中,金纳米团簇的浓度约为1.25mg/mL。同时,水溶液的pH值约为7.4左右。此外,最后制得的自组装纳米材料的粒径约为128nm。
本发明的目的之二在于提出一种靶标标记自组装材料,由CD3-Ab标记在上述GNCs-Ce6NPs上并组成Ce6-GNCs-Ab。
CD3-Ab即为CD3抗体(Ab)(可购自ebioscience)。同时,本发明还提出了一种靶标标记自组装材料的制备方法,包括以下步骤:
(1):取NHS-PEG2000-NHS超声分散于PBS溶液中,得到NHS-PEG2000-NHS溶液;
(2):再取CD3-Ab加入步骤(1)得到的NHS-PEG2000-NHS溶液中摇晃过夜,即得到NHS-PEG2000-Ab;
(3):最后,将GNCs-Ce6NPs分散于PBS溶液中,再加入步骤(2)制得的NHS-PEG2000-Ab,避光搅拌过夜,得到最终产物Ce6-GNCs-Ab,即为靶标标记自组装材料。
优选的,步骤(2)中,NHS-PEG2000-NHS(可以从上海炎怡生物科技有限公司购买得到)与CD3-Ab的添加质量比为5:(0.4-0.8)。
优选的,步骤(3)中,GNCs-Ce6NPs与NHS-PEG2000-Ab的加入量之比满足:GNCs-Ce6NPs与Ab的质量比为50:1。
优选的,步骤(3)中GNCs-Ce6在PBS溶液中分散的方式为超声分散,超声分散的功率为50~100W,时间为1~2分钟。上述制备方法中,Ce6和与金纳米团簇上的谷胱甘肽的摩尔比过小,无法形成组装体,过大则形成很大的颗粒,不利于细胞摄取。NHS-PEG2000-NHS过多则造成浪费,过少则影响不能保证接到每个组装体上。本发明的目的之三在于提出了一种肿瘤药物,其由药物载体CIK细胞(细胞因子诱导的杀伤细胞)负载如上述的靶标标记自组装材料Ce6-GNCs-Ab形成。
上述肿瘤药物的制备方法,优选为将靶标标记自组装材料Ce6-GNCs-Ab和CIK细胞置于培养基中孵育,得到Ce6-GNCs-Ab标记的CIK细胞,即为肿瘤药物。
更优选的,培养基中Ce6-GNCs-Ab的浓度满足Ce6的等效浓度为3-6μg/mL。
本发明的目的之四还在于提出上述肿瘤药物在制备肿瘤成像与治疗试剂中的应用。
优选的,所述的肿瘤为胃癌MGC-803细胞构建的皮下肿瘤。
本发明首次报告了一种利用二氢卟吩e6分子将水溶液中的金纳米团簇组装成单分散和稳定的自组装纳米粒子(GNCs-Ce6NPs)的简易方法。与单独的金纳米团簇相比,形成的金纳米团簇组装体的荧光增强约4倍。而且可以与抗体或其他靶标结合,以提高细胞的摄取效率。所以,我们将自组装的纳米材料与CD3抗体(Ab)结合,制备了Ce6-GNCs-Ab NPs。而CIK细胞则作为一种药物载体,将Ce6-GNCs-Ab NPs递送到肿瘤部位,从而用于肿瘤的诊断与治疗。
本发明所要解决的技术问题是利用二氢卟吩e6分子将水溶液中的金纳米团簇组装成单分散和稳定的自组装纳米粒子(GNCs-Ce6NPs)并用细胞因子诱导的杀伤细胞进行靶向递送到肿瘤部位且用于成像和联合治疗的方法。该方法具有制备步骤简单,反应条件温和,易于操作,且不用任何表面活性剂,因此制备的纳米材料生物相容性好,且充分利用了细胞因子诱导的杀伤细胞的归巢行为递送自组装的纳米材料。该细胞因子诱导的杀伤细胞负载二氢卟吩e6诱导的金纳米团簇的自组装材料能够靶向到肿瘤部位,成像效果明显且能够抑制肿瘤的生长,因此在肿瘤的诊断与治疗方面具有良好的发展前景。
与现有技术相比,本发明具有以下优点:
(1)制备方法简单,易于合成。
(2)自组装的纳米材料合成方法,不需添加表面活性剂,生物相容性好。
(3)自组装纳米材料的合成方法中,可以直接将Ce6包入自组装材料中,方法简单,无需添加其他试剂。
(4)本发明制备的自组装纳米材料,生物相容性好。
(5)本发明制备的自组装纳米材料是用细胞因子诱导的杀伤细胞(即CIK细胞)作为靶向递送的介质,具有低宿主免疫排斥性。且细胞因子诱导的杀伤细胞不仅可以用于递送纳米材料,其本身又可以通过免疫释放穿孔素等方式杀伤肿瘤细胞,因此本发明制备的细胞因子诱导的杀伤细胞介导的靶向主动递送自组装纳米材料的方法可用于肿瘤的成像与治疗。
附图说明
图1为本发明合成的金纳米团簇组装体的TEM图片;
图2为本发明合成的金纳米团簇组装体的SEM图片;
图3为本发明合成的金纳米团簇组装体的STEM图片;
图4为本发明合成的Ce6-GNCs-Ab颗粒的TEM图片;
图5为本发明合成的Ce6-GNCs-Ab颗粒的水动力粒径分布图片;
图6为本发明合成的Ce6-GNCs-Ab颗粒的荧光图片;
图7为本发明合成的Ce6-GNCs-Ab颗粒的细胞的CCK-8测试结果图;
图8为本发明合成的Ce6-GNCs-Ab进入CIK细胞的共聚焦图片;
图9为MGC-803细胞的SEM图片;
图10为CIK细胞攻击MGC-803细胞的SEM图片;
图11为CIK细胞递送合成的纳米材料的荧光活体成像图片。
具体实施方式
以下通过具体实施例结合附图对本发明的应用作进一步阐述说明,但本发明并不仅限于以下的实施例。
下述各实施例中所采用的表征方法有透射电子显微镜(TEM),扫描电子显微镜(SEM),扫描透射电子显微镜(STEM),动态光散射,荧光光谱等。同时,还通过了CCK-8检测合成的材料的生物相容性,以及用小动物活体成像仪来检测最后的肿瘤药物在用于肿瘤的靶向成像效果。
实施例1
Ce6诱导的金纳米团簇自组装,即金纳米团簇组装体的形成:
首先将金纳米团簇溶于pH7.4的水溶液中并超声分散(1.25mg/mL),随后将配置的Ce6滴加如金纳米团簇水溶液中,室温温和搅拌60分钟,形成GNCs-Ce6NPs。然后通过透析纯化,经冷冻干燥后获得最终产品金纳米团簇组装体。
最后制得的金纳米团簇组装体的TEM照片、SEM照片和STEM照片分别如图1-图3所示,可知,图1的TEM图片表明,分散于水中的GNCs-Ce6NPs的粒径约为100nm,且基本为球形分布。图2的SEM图片进一步证明了合成的自组装纳米为球形分布。且大小与TEM的图片一致。图3的STEM表明金元素均匀的分布在合成的金纳米颗粒中。
实施例2
自组装纳米材料Ce6-GNCs NPs与CD3抗体连接,提高细胞因子诱导的杀伤细胞对自组装纳米材料的摄取率,即靶标标记自组装材料的合成。
首先,将NHS-PEG2000-NHS与CD3-Ab反应生成NHS-PEG-CD3-Ab(NHS-PEG-Ab)。具体步骤为,将5mg NHS-PEG2000-NHS溶于pH为7.4的1mL PBS溶液中,并用50-100W的功率超声混匀。随后将300μL的CD3-Ab(2mg/mL)缓慢滴加到NHS-PEG2000-NHS溶液中,并于室温温和摇晃过夜。反应的产物NHS-PEG2000-Ab通过3000的超滤管超滤纯化。
然后将GNCs-Ce6NPs(10mg)溶于1mL PBS溶液中,并与NHS-PEG2000-Ab(Ab=200μg)温和混匀搅拌过夜,从而形成Ce6-GNCs-PEG2000-Ab(Ce6-GNCs-Ab)。终产物通过10000的超滤管纯化。
最后制得的靶标标记自组装材料Ce6-GNCs-Ab的TEM图片、水动力粒径分布图片和荧光图片分别如图4-6所示。图4中合成的Ce6-GNCs-Ab分散于水中的TEM图片表明,表明,抗体连接到了GNCs-Ce6NPs上,且在外围有较弱的光晕。图5的动态光散射测量则表明了Ce6诱导的金纳米团簇自组装颗粒在水溶液中的粒径分布较窄,证明了合成的纳米材料较为均一。图6中的荧光图片则表明了Ce6在合成的纳米材料中,且280nm处的抗体锋表明抗体连接到了GNCs-Ce6NPs上。
实施例3
细胞水平上Ce6-GNCs-Ab的生物相容性。
将GES-1细胞,MGC-803细胞和CIK细胞分别种在96孔板(5000个/孔)上,37℃,5%CO2培养24小时。上述细胞用100μL培养基处理,其中含有Ce6-GNCs-Ab(Ce6的等效浓度,范围从0到5μg/mL)。孵育24小时后,每孔加入10μL的CCK-8试剂继续在37℃培养4小时。然后用酶标仪测量其在450nm处的吸光值。图7表明Ce6-GNCs-Ab(5μg/mL)对GES-1细胞,MGC-803细胞,和CIK细胞几乎没有毒性,这种情况说明在没有激光照射的情况下,Ce6-GNCs-Ab具有良好的生物相容性。
细胞因子诱导的杀伤细胞(CIK)或负载Ce6-GNCs-Ab的CIK细胞对胃癌细胞MGC-803的活性的影响。
步骤如下:将MGC-803细胞以5000个每孔种于96孔板上培养24小时后去掉培养液。加入100μL含CIK细胞或者负载Ce6-GNCs-Ab的CIK细胞的X-Vivo15培养液。培养12小时后,一板继续培养12小时,另外一板用633nm的红外激光照射3分钟(功率为100mW/cm2)后再培养12小时。然后去掉培养液,并用PBS洗3次。加入100μL的新鲜培养液(含10μL CCK-8试剂)。用酶标仪测量450nm处的吸光值然后计算细胞的存活率。
结果发现,MGC-803细胞在Ce6-GNCs-Ab-CIK(633nm,3min)处理后的活性为51.18%,显著低于其他组。说明Ce6-GNCs-Ab-CIK对MGC-803细胞具有较强的杀伤效果,包括免疫杀伤和激光照射后产生的单线态1O2对细胞的杀伤。
实施例4
为了研究纳米颗粒在CIK细胞内的分布情况,我们将CIK细胞按照1×104个细胞每孔种于24孔板并加入含有单独Ce6,GNCs-Ce6NPs或Ce6-GNCs-Ab NPs的培养液并培养12小时。然后收集CIK细胞用PBS洗2次后,加入4%的多聚甲醛固定30分钟。除去多聚甲醛后,用Hoechst 33342染色20分,接着用PBS洗两次后将细胞滴到干净的爬片上。然后用TCS SP8共焦激光扫描显微镜观察单独Ce6,GNCs-Ce6NPs或Ce6-GNCs-Ab NPs在CIK细胞内的分布。图8表明,自组装的纳米材料与抗体连接后,其进入CIK细胞的效率明显高于不加抗体的GNCs-Ce6NPs组。此结果可以证明CD3抗体的加入可以显著提高自组装的纳米材料进入CIK细胞的效率和摄取量。
实施例5
CIK细胞对MGC-803细胞的靶向攻击实验。将CIK细胞和MGC-803细胞按照效靶比10:1的比例共同培养24小时后。用4%的多聚甲醛固定30分钟后,不同百分含量的乙醇脱水,滴到硅片上喷金。样品制备好之后,通过扫描电子显微镜SEM观察CIK细胞对MGC-803细胞影响(图9和图10)。结果发现,MGC-803细胞单独培养的情况下,细胞的形态比较规则,状态良好。然而,当MGC-803细胞与CIK细胞共同培养后,MGC-803细胞的形态发生了明显变化,细胞皱缩,破坏,甚至死亡,生长受到了显著抑制。和文献报道一致,CIK细胞可以显著抑制癌细胞的生长。
实施例6
CIK细胞对纳米材料Ce6-GNCs-Ab NPs的靶向递送通过活体动物成像实验证明。为了建立皮下肿瘤模型,MGC-803细胞(100Μl,5×106个细胞)被注射到老鼠的右侧。当肿瘤的大小达到200mm3时,这些小鼠被随机选择进行生物分布和成像研究。Ce6-GNCs-Ab NPs(Ce6 2.5mg/kg),或Ce6-GNCs-Ab-CIK(100μL,1×106细胞)通过尾静脉注入裸鼠体内。材料在裸鼠体内的分布通过Bruker In-Vivo FPRO成像系统拍摄。从图11可以看出,在肿瘤组织中,Ce6-GNCs-Ab-CIK处理的裸鼠的近红外荧光强度在24小时后达到最强,且其荧光强度显著高于Ce6-GNCs-Ab NPs组的小鼠。由此可以看出,CIK细胞可以有效地将Ce6-GNCs-Ab NPs递送到裸鼠的肿瘤部位。
上述的对实施例的描述是为便于该技术领域的普通技术人员能理解和使用发明。熟悉本领域技术的人员显然可以容易地对这些实施例做出各种修改,并把在此说明的一般原理应用到其他实施例中而不必经过创造性的劳动。因此,本发明不限于上述实施例,本领域技术人员根据本发明的揭示,不脱离本发明范畴所做出的改进和修改都应该在本发明的保护范围之内。
Claims (8)
1.一种肿瘤药物,其特征在于,其由药物载体CIK细胞负载靶标标记自组装材料Ce6-GNCs-Ab形成,其中,靶标标记自组装材料Ce6-GNCs-Ab由CD3-Ab标记在GNCs-Ce6 NPs上组成,而GNCs-Ce6 NPs由金纳米团簇和二氢卟吩e6组装结合形成。
2.根据权利要求1所述的一种肿瘤药物,其特征在于,GNCs-Ce6 NPs的具体制备过程为:取金纳米团簇分散于水溶液中,形成金纳米团簇溶液,再滴加二氢卟吩e6,室温搅拌,即得到金纳米团簇组装体GNCs-Ce6 NPs。
3.根据权利要求1所述的一种肿瘤药物,其特征在于,靶标标记自组装材料Ce6-GNCs-Ab的具体制备过程包括以下步骤:
(1):取NHS-PEG2000-NHS超声分散于PBS溶液中,得到NHS-PEG2000-NHS溶液;
(2):再取CD3-Ab加入步骤(1)得到的NHS-PEG2000-NHS溶液中摇晃过夜,即得到NHS-PEG2000-Ab;
(3):最后,将GNCs-Ce6 NPs分散于PBS溶液中,再加入步骤(2)制得的NHS-PEG2000-Ab,避光搅拌过夜,得到最终产物Ce6-GNCs-Ab,即为靶标标记自组装材料。
4.根据权利要求3所述的一种肿瘤药物,其特征在于,步骤(2)中,NHS-PEG2000-NHS与CD3-Ab的添加质量比为5:(0.4-0.8);
步骤(3)中,GNCs-Ce6 NPs与NHS-PEG2000-Ab的加入量之比满足:GNCs-Ce6NPs与Ab的质量比为50:1。
5.如权利要求1所述的肿瘤药物的制备方法,其特征在于,将靶标标记自组装材料Ce6-GNCs-Ab和CIK细胞置于培养基中孵育,得到Ce6-GNCs-Ab标记的CIK细胞,即为肿瘤药物。
6.根据权利要求5所述的肿瘤药物的制备方法,其特征在于,培养基中Ce6-GNCs-Ab的浓度满足Ce6的等效浓度为3-6μg/mL。
7.如权利要求1所述的肿瘤药物在制备肿瘤成像与治疗试剂中的应用。
8.根据权利要求7所述的肿瘤药物的应用,其特征在于,所述的肿瘤为胃癌MGC-803细胞构建的皮下肿瘤。
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