CN112168964A - 一种线粒体靶向牛血清白蛋白@硫化铜纳米复合物及其制备方法和应用 - Google Patents
一种线粒体靶向牛血清白蛋白@硫化铜纳米复合物及其制备方法和应用 Download PDFInfo
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Abstract
本发明公开了一种线粒体靶向牛血清白蛋白@硫化铜纳米复合物及其制备方法和应用，属于纳米医药技术领域。本发明利用牛血清白蛋白BSA为模板原位合成了硫化铜CuS纳米粒子，制得了具有高效近红外光热转换效率的BSA@CuS纳米复合物；随后，将罗丹明110分子与BSA@CuS共价偶联，构建了R‑BSA@CuS纳米复合物，可被乳腺癌细胞MCF‑7有效地内吞。本申请制备的线粒体靶向的R‑BSA@CuS纳米复合物与非靶向的BSA@CuS纳米复合物相比，在相同的近红外激光照射下，光热特性更优良，且R‑BSA@CuS纳米复合物的抗癌效果显著增强，在肿瘤光热治疗中具有重要的应用前景。
Description
技术领域
本发明属于纳米医药技术领域，具体涉及一种线粒体靶向牛血清白蛋白@ 硫化铜纳米复合物及其制备方法和应用。
背景技术
线粒体是真核细胞必不可少的亚细胞器，它通过氧化磷酸化产生大部分细胞能量，并调节其凋亡途径。线粒体的缺陷或功能失调可导致癌症的发生、转移或复发，因此，针对线粒体的特异性治疗方法已被开发出来，以提高癌症治疗的疗效。在过去的几十年里，随着线粒体靶向配体(如亲脂性阳离子、肽或适配体)的修饰，多功能纳米材料已被构建用于癌症诊断或治疗。特别是高温引起的热应激可严重干扰高热敏线粒体的细胞功能或直接破坏线粒体，导致癌细胞凋亡或坏死途径的激活。与传统热疗方法相比，光热纳米制剂可有效地将近红外(NIR)光转换为热能，并热烧蚀肿瘤，同时将对周围健康组织的损伤降至最低。然而，这些非靶向性光热纳米颗粒被肿瘤细胞内吞后，主要分布在亚细胞胞浆、内含体或溶酶体中，限制了光热治疗的疗效。因此，同时具有线粒体靶向和光热特性的纳米复合材料被设计来精确控制它们在线粒体中的特异性富集，然后在近红外光照射下急剧提高局部温度，从而显著提高癌症光热疗法的疗效。这种创新的线粒体靶向光热疗法是一种很有前途的策略，可以更高的效率对抗癌症。
发明内容
针对现有技术存在的上述问题，本发明所要解决的第一技术问题是提供一种线粒体靶向牛血清白蛋白@硫化铜纳米复合物的制备方法；本发明所要解决的第二技术问题是提供上述制备方法所制备的线粒体靶向牛血清白蛋白@硫化铜纳米复合物；本发明所要解决的第三技术问题是提供线粒体靶向牛血清白蛋白@硫化铜纳米复合物对肿瘤细胞的光热治疗作用以及在制备光热治疗肿瘤药物中的应用。
为了解决上述技术问题，本发明所采用的技术方案如下：
一种线粒体靶向牛血清白蛋白@硫化铜纳米复合物的制备方法，包括以下步骤：
1)将牛血清白蛋白BSA溶于去离子水中，然后依次加入CuSO4、氢氧化钠和硫化钠，在80℃～100℃下连续搅拌0.4～0.6h，颜色由棕色变为深绿色，用透析膜MWCO＝12kDa透析制得BSA@CuS纳米复合材料；
2)将罗丹明110、NHS和EDC溶解在DMF溶液中，先在黑暗中连续搅拌 3～5h，将所得混合物添加到BSA@CuS纳米复合材料分散的水溶液中，然后在黑暗中连续搅拌10～14h，最后用透析膜MWCO＝12kDa透析得到R-BSA@CuS 纳米复合物。
进一步的，步骤1)中，牛血清白蛋白BSA用量以去离子水体积计为33.3g/L。
进一步的，步骤1)中，CuSO4、氢氧化钠和硫化钠的摩尔比为2∶5∶4。
进一步的，步骤1)中，在90℃下连续搅拌0.5h。
进一步的，步骤2)中，罗丹明110、NHS和EDC溶解在DMF溶液中的浓度比为70：43：36(w/v)。
进一步的，步骤2)中，先在黑暗中连续搅拌4h，然后在黑暗中连续搅拌 12h。
上述方法制备得到的线粒体靶向牛血清白蛋白@硫化铜纳米复合物。
进一步的，当线粒体靶向牛血清白蛋白@硫化铜纳米复合物的浓度为400 μg/mL时，在功率密度为1.6～3.2w/cm2的近红外激光下，温度增高15.5～32.9 ℃。
线粒体靶向牛血清白蛋白@硫化铜纳米复合物在制备光热治疗肿瘤药物中的应用。
进一步的，使用功率密度为3.2w/cm2的近红外激光对肿瘤区域进行照射。
有益效果：相比于现有技术，本发明的优点为：
本发明利用牛血清白蛋白(BSA)为模板原位合成了硫化铜(CuS)纳米粒子，制得了具有高效(42.0％)近红外光热转换效率的BSA@CuS纳米复合物。随后，将罗丹明110分子(rhodamine 110)与BSA@CuS共价偶联，构建了 R-BSA@CuS纳米复合物，可被乳腺癌(MCF-7)细胞有效地内吞，然后在亚细胞线粒体中特异性富集且线粒体靶向的R-BSA@CuS与非靶向的BSA@CuS相比，在相同的近红外激光照射下，光热特性更优良，且R-BSA@CuS的抗癌效果显著增强(***p＜0.001)，R-BSA@CuS纳米复合物在肿瘤光热治疗中具有重要的应用前景。
附图说明
图1中，(a)、(b)是R-BSA@CuS的透射电镜成像图；(c)是R-BSA CuS的高分辨率TEM成像图，双线条标记的晶面；
图2中，(a)是去离子水，0.8mg/mL的BSA，BSA@CuS以及R-BSA@CuS 水溶液在1.6W/cm2近红外激光照射15min后的T-t曲线图；(b)是0.8mg/mL R-BSA@CuS溶液在重复近红外激光照射下(1.6W/cm2，15min)的光热稳定性图；(c)是辐照时间与R-BSA@CuS的ln(θ)的关系图；
图3是0.4mg/mL R-BSA@CuS与MCF-7细胞共孵育12h分别用lyso tracker 红染料和mito tracker橙色染料染色后的共聚焦成像及Pearson相关分析图，图中，比例尺＝40μm。
图4是与BSA@CuS或R-BSA@CuS共孵育的MCF-7细胞在不同功率强度近红外激光辐照的存活率图。
具体实施方式
下面结合具体实施例对本发明进一步进行描述。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。以下实施例中如无特殊说明，所用实验方法均为常规方法。
以下实施例中所使用的材料和仪器如下：
BSA、CuSO4·5H2O(中国国药化学试剂有限公司)。N-羟基丁二酰亚胺(NHS) 和N-(3-二甲基氨基丙基)-N-乙基碳二亚胺盐酸盐(EDC)(中国上海麦克林生化有限公司)。罗丹明-110氯化物和聚甲基丙烯酸2-羟乙基酯(PHEMA)(美国西格玛-奥尔德里奇化学试剂有限公司)。3-(4，5-二甲基-2-噻唑烷基)-2，5-二苯基-2-H-四唑溴化铵(MTT，KGA311)，5，5′，6，6′-四氯-1，1′3，3′-四乙基苯并咪唑碘化碳氰酸盐(JC-1，KGA601)，DMEM培养基(KGM2800SH-500)、4′，6- 二氨基-2-苯基吲哚(DAPI，KGA215)、lyso tracker red探针(KGMP006)和mito tracker orange探针(KGMP0073)(中国凯基生物技术有限公司)。去离子水(自制)。
用lambda 950分光光度计记录了UV-Vis-NIR吸附光谱。用Perkin Elmer LS55 荧光光谱仪进行了光致发光(PL)光谱分析。用X射线衍射(XRD)分析了样品的晶体参数。在真空度＜4×10-9Pa的条件下，用单色Al KαX射线束(1486.6ev) 在150W下用Kratos轴超DLD系统记录了X射线光电子能谱(XPS)200千伏。采用Zetasizer NanoZS动态光散射(DLS)测量(英国马尔文仪器公司)在25℃下分析了BSA基纳米复合材料的尺寸和zeta电位。
以下实施例采用SPSS统计软件进行统计分析。所有数据均为平均值±标准差。采用Tukey后验的方差分析确定具有统计学意义的差异(***p＜0.001， **p＜0.01，*p＜0.05或NS(无显著性差异，p＞0.05))。
实施例1 R-BSA@CuS纳米复合材料的合成和表征
先将250mg BSA溶于7.5mL去离子水中，然后依次加入1mL 0.2mol/L CuSO4、0.5mL1mol/L氢氧化钠和2mL 0.2mol/L硫化钠。上述混合物在90℃下连续搅拌0.5小时，颜色由棕色变为深绿色。用透析膜(MWCO＝12kDa)反复透析制得BSA@CuS纳米复合材料。
然后，将14.0mg罗丹明110、8.6mgNHS和7.2mg EDC溶解在1.5mL DMF 溶液中，在黑暗中连续搅拌4h。将所得混合物逐滴添加到4.5mL(15.6mg/mL) 中BSA@CuS水溶液，然后在黑暗中连续搅拌12h。最后用透析膜(MWCO＝12 kDa)反复透析得到R-BSA@CuS纳米复合材料，冷冻干燥并在4℃下储存。
将50mg BSA@CuS纳米复合材料溶解于10mL碳酸盐缓冲液(pH 9-9.5)，然后滴加0.25mL 1mg/mL异硫氰酸荧光素(FITC)二甲基亚砜溶液，在4℃下在黑暗中搅拌。24h后，反复透析反应液得到F-BSA@CuS纳米复合材料，然后冷冻干燥并在4℃下储存。
由于BSA中-NH2、-COOH和-SH部分与Cu2+离子有较强的配位作用，选择 BSA作为模板原位合成CuS纳米粒子。此外，使用的碱性反应条件可以展开BSA 的结构以捕获更多的Cu2+离子，并且在90℃的持续加热条件可以改善CuS纳米颗粒的结晶形成，同时增加近红外吸收强度。在此基础上，通过EDC/NHS活化将罗丹明110分子共价修饰到BSA@CuS，制备R-BSA@CuS纳米复合材料。对制得的R-BSA@CuS采用紫外-可见-近红外吸收光谱、荧光光谱、XPS、TEM和 DLS等测试手段对纳米复合材料进行了逐步表征。
用透射电镜分析了R-BSA@CuS样品的尺寸、形貌和晶体结构，如图1(a)所示，R-BSA@CuS平均尺寸(36.5±11.3nm)比BSA@CuS(24.7±5.4nm)或裸BSA(13.5±4.6nm)大，这是由于反应条件诱导BSA模板的聚集。此外，在图1(b)中，尺寸为3.9±2.2nm的CuS纳米粒子(箭头标记)随机分布在 R-BSA@CuS样品中。此外，还记录了CuS纳米粒子的高分辨率TEM成像，以分析其晶体结构。在图1(c)中，可以清晰地观察到R-BSA@CuS样品中CuS(102) 晶格平面(用双线条标记)，可见BSA模板中原位形成了CuS纳米晶。
实施例2
(1)R-BSA@CuS纳米复合材料的光热性能
采用波长为808nm的光纤耦合功率可调半导体激光器(Hi-Techoptoselectronics，China)作为近红外激光光源，照射距离为～2.5cm，面积为～0.8 cm2。在近红外激光照射(1.6W/cm2，15min)下，用红外热像仪(FLK-Ti32， Fluke，USA)分别对1mL去离子水，浓度为0.8mg/mL的BSA，BSA@CuS，和R-BSA@CuS水溶液观察热成像和升温。不同浓度(0.1、0.2、0.4、0.8和1.6 mg/mL)的R-BSA@CuS以及用不同功率密度(0.8、1.6、2.4和3.2w/cm2)的条件下辐照15min，以评价其光热性能。为测试其光热稳定性，0.8mg/mL R-BSA@CuS溶液在1.6w/cm2的近红外激光照射15min，无激光照射下自然冷却至室温，即为“一次激光开/关周期”。最后，BSA@CuS以及R-BSA@CuS的光热转换效率(η)根据“J.Li，W.Zhang，Y.Gao，H.Tong，Z.Chen，J.Shi，H.A. Santos and B.Xia，J.Mater.Chem.B.，2020，8，546”进一步计算。
为了测试BSA基纳米复合材料在水溶液中的光热效应，利用红外热成像仪测量了其在808nm激光照射下的温度变化(T-t曲线)。从图2(a)可以看出，随着1.6w/cm2近红外激光的照射时间从0增加到15min，0.8mg/mL的 R-BSA@CuS和BSA@CuS溶液温度急剧增加，分别为ΔT＝25.0℃；ΔT＝29.3℃。但是，在相同的辐照下，去离子水(ΔT＝2.1℃)或0.8mg/mLBSA溶液(ΔT＝2.3 ℃)的温度变化不明显。在图2(c)中，R-BSA@CuS的近红外光热转换效率(η) 为22.8％。结果表明，在BSA模板中制备的CuS纳米粒子仍保持了良好的光热效应。此外，R-BSA@CuS溶液的升温可以通过改变浓度或近红外激光功率进行调节。最后，0.8mg/mLR-BSA@CuS溶液被近红外激光照射(1.6W/cm2，15 分钟，激光打开)，然后通过关闭近红外激光冷却到室温，作为“一个循环”，以评估其光热稳定性。在图2(b)中，分别记录了连续三个循环后，温度升高分别为 24.4、24.3、24.7和24.9℃。以上结果表明，与小分子光热剂相比，R-BSA@CuS 纳米复合材料对近红外激光的多次照射具有稳定、高效的光热效应。
(2)R-BSA@CuS纳米复合材料的生物相容性
MCF-7细胞在添加了10％胎牛血清和1％青霉素链霉素DMEM培养基中在 37℃下，在5％CO2的增湿气氛中培养。
MTT染色观察其细胞活性。用磷酸盐缓冲液(PBS)洗涤三次后，加入含有 10μLMTT，浓度为5mg/mL的新培养基100μL，孵育4h，小心取出培养基，加入100μL DMSO，用以下方法记录溶液在每孔570nm处的吸光度使用filter Max F5微型板光度计(MolecularDevices)。细胞活力值按下式计算：细胞活力 (％)＝实验组吸光度/空白对照组吸光度×100％。
评价R-BSA@CuS纳米复合材料的生物相容性，MCF-7细胞(约1.5×105个 /mL)分散在96孔板中，总体积为100μL/孔，在含有25、50、100、200和400 μg/mLR-BSA@CuS分别培养24小时和48小时，用MTT法检测细胞活力。
MCF-7细胞(人乳腺癌)与浓度范围为0-400μg/mL的R-BSA@CuS纳米复合材料共孵育。然后用MTT法测定细胞存活率。在与R-BSA@CuS共孵育24h 以及48h后，MCF-7细胞的存活率仍保持在90％以上，说明R-BSA@CuS纳米复合材料的细胞毒性可以忽略不计。
(3)R-BSA@CuS纳米复合材料的细胞摄取和亚细胞分布
观察细胞摄取R-BSA@CuS纳米复合材料，将细胞接种于6孔培养板中，每孔细胞数约为1.5×105个细胞(每孔放置一个无菌玻片)。培养12h后，用含0.4 mg/mL R-BSA@CuS的培养基代替细胞培养基。在0、2、4、8和12h后，用PBS 冲洗这些细胞样本，并用DAPI探针染色进行激光共焦成像(德国蔡司LSM710 NLO)。
观察其亚细胞分布R-BSA@CuS纳米复合材料，将细胞接种于6孔培养板中，每孔细胞数约为1.S×105个细胞(每孔放置一个无菌玻片)。培养12h后，用含 0.4mg/mL R-BSA@CuS或者F-BSA@CuS的培养基代替细胞培养基。12h后，用PBS冲洗这些细胞样本，分别用mitotracker orange或lyso tracker red探针染色，进行共焦成像。
MCF-7细胞与400μg/mL R-BSA@CuS共孵育12h。然后将这些细胞样本与线粒体探针mito tracker orange进行共聚焦成像，如图3所示。除了上述罗丹明分子的绿色荧光通道外，另一个红色荧光通道(Ex＝543nm，Em＝556-683nm) 用于mito tracker探针。根据图3中的叠加图像，R-BSA@CuS的绿色荧光与来自mito tracker探针的红色荧光大部分重叠。此外，还计算了绿荧光和红光荧光之间的皮尔逊系数，以定量评估这些纳米复合材料与亚细胞线粒体的共定位效应。R-BSA@CuS在线粒体中的皮尔逊系数达到了0.68。这意味着近70％内吞的R-BSA@CuS可以进入胞浆中的内含体，然后在线粒体中特异性地富集。证实了罗丹明110分子作为特异性配体将BSA@CuS靶向到MCF-7细胞的线粒体中。
(4)线粒体靶向的R-BSA@CuS的光热疗法对癌细胞的治疗作用
为评价光热疗法的疗效，将MCF-7细胞(约1.5×105个/mL)分散在96孔板中，总体积为100μL/孔，含400μg/mL R-BSA@CuS或者BSA@CuS分别持续 12h。然后用新鲜培养基反复洗涤细胞样品，分别用0、1.6、2.4和3.2w/cm2的近红外激光照射10min。培养12h后，用MTT法检测细胞活力。
为监测线粒体损伤，将细胞置于6孔培养板中，每孔细胞数约为1.5×105个细胞(每孔放置一个无菌玻片)。培养12h后，用含0.4mg/mL R-BSA@CuS或者BSA@CuS的培养基代替细胞培养基，培养12h后，用新鲜培养基洗涤细胞，用3.2w/cm2近红外激光照射10min，用JC-1探针染色共聚焦成像。并用流式细胞仪(BD Biosciences，USA)定量分析上述细胞样品的荧光强度。
用MTT法检测MCF-7细胞在不同处理后的存活率，结果如图4所示。MCF-7 细胞分别与400μg/mL BSA@CuS、R-BSA@CuS孵育12小时，可以让足够多的纳米材料通过内吞作用进入细胞。随后，用新鲜培养基反复洗涤这些细胞样品，以消除环境中非内吞的纳米组分产生的光热效应。最后，在NIR激光照射后，将细胞培养12h进行MTT分析。培养基中含400μg/mL R-BSA@CuS在1.6、 2.4和3.2W/cm2的近红外激光照射下，温度增高分别为15.5℃、24.4℃和32.9 ℃。由图4可知，当近红外激光照射的功率强度从0增加到3.2w/cm2时，不加材料的MCF-7细胞作为对照组的存活率分别为100.0±9.6％、116.4±31.4％、 91.5±8.4％和117.2±2.7％。但是，对于BSA@CuS组，MCF-7细胞经体外与 BSA@CuS共孵育后在相同的近红外激光辐照后的存活率，依次为94.2±7.8％、 76.9±10.7％、70.8±9.2％、67.2±3.3％。用1.6、2.4和3.2W/cm2激光照射的 MCF-7细胞与未经NIR激光照射的MCF-7细胞相比，细胞活力的显著差异(以星号表示)分别为NS、*p＜0.05和**p＜0.01。结果表明，细胞存活率与BSA@CuS 激光辐照下引起的温度升高有关联性。对与R-BSA@CuS共孵育的各组细胞，在相同的近红外激光辐照后存活率依次为114.6±31.3％、90.8±17.9％、48.9± 2.9％、40.4±4.9％，2.4和3.2W/cm2激光照射条件下差异有显著性(***p＜0.001)。特别是在3.2w/cm2的近红外激光照射下，添加R-BSA@CuS组的细胞存活率与 BSA@CuS组的相比，由原来的67.2±3.3％急剧下降至40.4±4.9％，两组间差异有显著性(***p＜0.001)。根据以上结果，BSA@CuS纳米复合材料表现出对癌细胞良好的光热疗法。但是，与非靶向性BSA@CuS纳米复合物相比，通过罗丹明110分子共轭形成的线粒体靶向R-BSA@CuS纳米复合材料具有显著增强的功效。制得的R-BSA@CuS纳米复合材料主要聚集在线粒体内，在相同的近红外激光照射下产生较高的局部温度，有效地诱导线粒体损伤，提高了纳米复合材料对癌细胞增殖的抑制作用。
综上所述，在BSA模板中原位合成CuS纳米粒子，然后与罗丹明110染料偶联制备R-BSA@CuS纳米复合物。制得的R-BSA@CuS纳米复合材料具有良好的线粒体靶向能力和光热效应。此外，与非靶向BSA@CuS纳米复合物相比，针对线粒体靶向R-BSA@CuS体外细胞实验说明其能显著提高光热疗法对癌细胞的疗效。因此，这些R-BSA@CuS纳米复合材料在肿瘤光热治疗中具有重要的应用前景。
Claims (10)
1.一种线粒体靶向牛血清白蛋白@硫化铜纳米复合物的制备方法，其特征在于，包括以下步骤：
1)将牛血清白蛋白BSA溶于去离子水中，然后依次加入CuSO4、氢氧化钠和硫化钠，在80℃～100℃下连续搅拌0.4～0.6h，颜色由棕色变为深绿色，用透析膜MWCO＝12kDa透析制得BSA@CuS纳米复合材料；
2)将罗丹明110、NHS和EDC溶解在DMF溶液中，先在黑暗中连续搅拌3～5h，将所得混合物添加到BSA@CuS纳米复合材料分散的水溶液中，然后在黑暗中连续搅拌10～14h，最后用透析膜MWCO＝12kDa透析得到R-BSA@CuS纳米复合物。
2.根据权利要求1所述的线粒体靶向牛血清白蛋白@硫化铜纳米复合物的制备方法，其特征在于，步骤1)中，所述牛血清白蛋白BSA用量以去离子水体积计为33.3g/L。
3.根据权利要求1所述的线粒体靶向牛血清白蛋白@硫化铜纳米复合物的制备方法，其特征在于，步骤1)中，CuSO4、氢氧化钠和硫化钠的摩尔比为2∶5∶4。
4.根据权利要求1所述的线粒体靶向牛血清白蛋白@硫化铜纳米复合物的制备方法，其特征在于，步骤1)中，在90℃下连续搅拌0.5h。
5.根据权利要求1所述的线粒体靶向牛血清白蛋白@硫化铜纳米复合物的制备方法，其特征在于，步骤2)中，罗丹明110、NHS和EDC溶解在DMF溶液中的浓度比为70∶43∶36(w/v)。
6.根据权利要求1所述的线粒体靶向牛血清白蛋白@硫化铜纳米复合物的制备方法，其特征在于，步骤2)中，先在黑暗中连续搅拌4h，然后在黑暗中连续搅拌12h。
7.权利要求1至6任一项所述方法制备得到的线粒体靶向牛血清白蛋白@硫化铜纳米复合物。
8.根据权利要求7所述的线粒体靶向牛血清白蛋白@硫化铜纳米复合物，其特征在于，当线粒体靶向牛血清白蛋白@硫化铜纳米复合物的浓度为400μg/mL时，在功率密度为1.6～3.2w/cm2的近红外激光下，温度增高15.5～32.9℃。
9.权利要求7所述的线粒体靶向牛血清白蛋白@硫化铜纳米复合物在制备光热治疗肿瘤药物中的应用。
10.根据权利要求9所述的线粒体靶向牛血清白蛋白@硫化铜纳米复合物在制备光热治疗肿瘤药物中的应用，其特征在于，使用功率密度为3.2w/cm2的近红外激光对肿瘤区域进行照射。
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