CN115025238B - 一种尺寸可控的线粒体靶向型光敏性纳米颗粒及其制备方法 - Google Patents
一种尺寸可控的线粒体靶向型光敏性纳米颗粒及其制备方法 Download PDFInfo
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Abstract
本发明公开了一种尺寸可控的线粒体靶向型光敏性纳米颗粒及其制备方法，所述光敏性纳米颗粒由光敏剂和增加局部氧含量的蛋白通过共价键连接之后组装而成，所述纳米颗粒的平均粒径介于5～1000nm之间。本发明所得的尺寸可控的线粒体靶向型光敏性纳米颗粒生物相容性好，尺寸可控，稳定性高，颗粒活性好，具有靶向细胞线粒体的能力，并且能调节病灶部位微环境，如氧气含量、过氧化物水平及酸碱度，结合光动力疗法，能够提高肿瘤的治疗效果。
Description
技术领域
本发明属于生物医用材料领域，具体涉及一种尺寸可控的线粒体靶向型光敏性纳米颗粒及其制备方法。
背景技术
与化疗、放疗等传统治疗方法相比，光动力疗法(Photodynamic therapy,PDT)已经成为最有前景的医学技术之一。光动力疗法侵入性小，生物毒性低，病灶组织选择性强，在皮肤病、痤疮、尖锐湿疣和肿瘤治疗中具有独特的优势。光动力疗法以在光敏剂、氧气和特定波长的光三者之间发生的光动力反应为基础。富集在病灶部位的光敏剂在特定波长激发光的照射下，与周围氧气或生物大分子之间发生能量传递，生成氧化性很强的活性氧，如单线态氧，从而氧化腺苷、氨基酸等细胞成分，破坏蛋白质、脂质和核苷酸等细胞组分，使细胞发生不可逆转的损伤而死亡，达到治疗疾病的效果。目前在临床上，PDT已成功用于治疗人体多种疾病，并且取得了很好的疗效。
然而，PDT中也存在着诸多局限。病灶部位的氧含量较低，大大限制了活性氧特别是单线态氧的产量。为提高病灶区域的氧气含量，很多研究设计具有催化产氧功能的无机纳米粒子或者制备催化过氧化氢分解生成氧气的纳米蛋白反应器，用来改善乏氧问题。但是无机纳米粒子的生物毒性与纳米蛋白反应器对蛋白的损伤都无法避免，大大限制了其在临床上的应用。同时单线态氧的寿命与扩散半径都非常短，具有时空局限性，限制了其在肿瘤中的作用区域。近年来利用亲脂性阳离子如三苯基膦(TPP)等设计线粒体等细胞器靶向性的药物成为一大热点(参见Angew.Chem.Int.Ed.2020,59,2634-2638)，但是并非所有的光敏剂都能通过与靶向小分子的连接而起到靶向效果。而且在激发光的选择上其也具有自身的局限性，生物组织对激发光具有吸收和散射作用，导致激光强度到达疾病部位时出现严重的衰减。若选择波长较长的激发光，但由于其能量较低，使用时需要提高光照强度。除此之外，光敏剂的亲脂性和亲水性直接决定了纳米颗粒药物的传输和设计方式。脂溶性的光敏剂尽管容易透过细胞膜但容易发生聚集导致单线态氧的产量下降，水溶性光敏剂不被细胞吸收，因此设计合适的载体是关键。
分子共组装的方法在纳米颗粒制备中得到了广泛的应用，其形状多样、粒径可控，操作简单。通过分子间的非共价作用，如氢键、静电吸附、π-π堆积，设计多种自组装的纳米粒子。自组装得到的纳米粒子在完成药物传递、增强渗透性和滞留性、缓解抗癌药物副作用和提高疾病治疗效果等方面比单个成分之和具有更大的作用(参见Adv.HealthcareMater.2018,7,1800670)。药物的传递方式有很多种，如通过磷脂分子、聚乙二醇或者人血清白蛋白包封，其主要功能是完成药物传递而不能直接提高单线态氧产量。理想的给药载体不仅能给药，还能作为药物，提高治疗效果。
发明内容
本发明内容针对光动力过程中病灶部位乏氧的不利条件，选择合适的蛋白载体与光敏药物，通过分子组装的方式合成具有产氧能力且尺寸可控制备的线粒体靶向的光敏性纳米颗粒。本发明所制备的纳米颗粒在过氧化物存在的条件下和特定波长的照射下，产生更多的氧气和单线态氧，并且靶向线粒体等细胞器，提高的对病灶细胞的杀伤能力，增强光动力治疗效果。
本发明涉及一种尺寸可控的线粒体靶向型光敏性纳米颗粒及其制备方法，为了实现本发明的目的，拟采用如下技术方案：
本发明一方面涉及一种尺寸可控的线粒体靶向型光敏性纳米颗粒，其特征在于，所述光敏性纳米颗粒由光敏剂和增加局部氧含量的蛋白通过共价键连接之后组装而成，所述纳米颗粒的平均粒径介于5～1000nm之间。
在本发明的一个优选实施方式中，所述光敏剂和所述增加局部氧含量的蛋白通过酰胺键、腙键或希夫碱进行连接。
在本发明的一个优选实施方式中，所述的光敏性纳米颗粒中，所述增加局部氧含量的蛋白包括但不限于超氧化物歧化酶、过氧化氢酶、肌红蛋白、脑红蛋白、血红蛋白或血蓝蛋白。为了更高效率地提高肿瘤氧含量，所述增加局部氧含量地蛋白优选为过氧化氢酶，过氧化物酶相对于其他蛋白的优势是可直接催化肿瘤处富集的过氧化氢分解为氧气且为目前在生物蛋白中催化过氧化氢分解为氧气效率最高的一种方式。
在本发明的一个优选实施方式中，所述的光敏性纳米颗粒中，所述光敏剂包括但不限于卟啉类、卟吩类、5-氨基酮戊酸及其衍生物、孟加拉红、竹红菌素、酞菁类、叶绿素类光敏剂。
在本发明的一个优选实施方式中，所述纳米颗粒的平均粒径为200nm以下，进一步优选为100nm以下。通过将纳米颗粒的尺寸控制在200nm以下，有助于细胞吸收药物，而小于100nm的纳米颗粒更有助于在病灶区域富集从而达到更好的治疗效果。综合来看，尺寸可控的且具有产氧能力的、能够靶向病灶细胞器的光敏性纳米颗粒在特定光的照射下，能够大大地提高单线态氧的产量，达到更好的疾病治疗效果。
本发明另一方面还涉及上述光敏性纳米颗粒的制备方法，包括如下步骤：
1)将所述光敏剂和所述增加局部氧含量的蛋白分别溶解；
2)在光敏剂的溶液中加入共价键连接的催化剂进行反应；
3)将步骤2)的溶液与所述增加局部氧含量的蛋白溶液进行混合完成组装；
4)将步骤3)的体系纯化即可得到光敏性纳米颗粒。
在本发明的一个优选实施方式中，步骤1)中，所述光敏剂溶解的浓度为1～10mg/mL，具体可为2、4、6、8mg/mL；特别优选为5-7mg/mL。通过将光敏剂的浓度限定到5-7mg/mL，有助于控制光敏性纳米颗粒的尺寸在20-30nm之间。
在本发明的一个优选实施方式中，步骤1)中，所述蛋白溶解的浓度为1～100mg/mL，具体可为5、10、15、20mg/mL。
本发明所述的“尺寸可控”指的是通过改变光敏剂和蛋白的初始反应浓度比例，可以改变最终产物的尺寸，可在5～1000nm之间调控纳米颗粒的粒径。
上述的制备方法中，步骤1)中，使用二次水或有机溶剂配制所述光敏剂溶液，并且采用PBS磷酸缓冲液或二次水配制所述增加局部氧含量的蛋白溶液；
所述PBS缓冲液pH为7.2～7.4，离子强度为0.01mol/L。
上述的制备方法中，步骤2中采用合适浓度的碱性溶液调节所述光敏剂溶液的pH；
所述催化剂为1-乙基-(3-二甲基氨基丙基)碳酰二亚胺和N-羟基琥珀酰亚胺；
催化时间为20～40min。
上述的制备方法中，步骤3)中所述反应在2～8℃条件反应6～12h。
步骤4中所述纯化包括以下步骤：
根据体系不同，选择透析、超滤洗涤、冷冻干燥、色谱柱分离等方法纯化
本发明所提供的光敏性纳米颗粒可用于肿瘤的光动力疗法，如抑制乳腺癌细胞的生长。
以所述光敏性药物为活性成分的光动力治疗剂也属于本发明的保护范围。
有益效果
本发明将光敏剂与具有分解过氧化物和产氧能力的蛋白以共价键相连，通过组装形成不同尺寸的纳米颗粒。该纳米颗粒克服了单纯的光敏剂不容易被细胞吸收的缺陷，可以更好地被细胞吸收，通过分解病灶部位的过氧化物增加病灶部位的氧气含量，提高单线态氧产量，改善疾病的光动力治疗效果。
本发明首次提出利用共价组装的制备方法，通过改变反应物的比例，实现了对蛋白负载水光敏剂的纳米颗粒的颗粒尺寸调控，可以靶向细胞的线粒体，是一种新型具有药物作用的纳米颗粒。本发明提供的光敏性纳米颗粒，具有一定的产氧功能，能极大增强肿瘤细胞附近的氧气含量，改善肿瘤部位的乏氧环境，增加单线态氧的产量，靶向细胞的线粒体。与传统的光敏药物相比，该纳米颗粒同时实现了尺寸的可控制备与调节，并且更好的负载水溶性光敏剂，光动力效果更加明显，有望用于肿瘤的光动力治疗。
附图说明
图1是本发明实施例1所制备的光敏性纳米颗粒CAT-RB NPs的粒径分布图和形貌图，左图中的曲线分别对应RB不同初始反应浓度0、2、4、6mg/mL时的纳米颗粒粒径分布。
图2是CAT-RB NPs和RB的单线态氧的相对产量。
图3是CAT-RB NPs和RB的溶解氧的相对浓度。
图4是CAT-RB NPs和RB孵育的细胞的激光共聚焦显微镜图。
图5是CAT-RB NPs和CAT分别与细胞线粒体的共定位分析。
图6是CAT-RB NPs、RB和CAT孵育的细胞在光照与黑暗条件下的细胞存活率，*P<0.05。
图7是CAT-RB NPs孵育的细胞在光照后不同时间的ATP相对含量。
图8是分别静脉注射CAT-RB NPs和PBS的小鼠的生化指标。
图9是分别静脉注射CAT-RB NPs和RB的小鼠不同时间后的生物荧光成像。
图10是治疗过程中不同治疗组的老鼠肿瘤体积的变化，***P<0.001。
图11是治疗过程中不同治疗组的老鼠肿瘤的照片。
图12是治疗结束后不同治疗组的老鼠肿瘤的照片。
图13是治疗过程中不同治疗组的老鼠体重的变化。
图14是不同治疗组的老鼠的主要器官和肿瘤的苏木精-伊红的染色图。
具体实施方式
下列实施例中所使用的实验方法如无特殊说明，均为常规方法。
下列实施例中所使用的材料、试剂等如无特殊说明，均可从商业途径得到。
本实例采用的增加局部氧含量的蛋白为过氧化氢酶(CAT)，分解水生成氧气和水。本实例采用的过氧化氢酶是以铁卟啉为辅基结合酶，分子量为250000左右，并且通常以四聚体的形式存在，是过氧化物酶体的标志酶。
本发明所采用光敏剂为孟加拉红(RB)，其分子量为1018。在549nm激发光照射下能产生具有细胞毒性的单线态氧。
本实例选用PBS缓冲液配制蛋白溶液，其pH为7.4，浓度为0.01mol/L，能最大程度维持蛋白活性。
实施例1
按照下述步骤制备尺寸可控的线粒体靶向的光敏性纳米颗粒(CAT-RB NPs)：
利用去离子水分别配制浓度分别为0、2、4、6mg/mL的RB溶液，并且用0.01mol/L氢氧化钠溶液调节溶液pH在5～10之间。
向其中先后逐滴加入EDC和NHS反应20min。
利用PBS缓冲液配制10mg/mL的CAT溶液，分别加入上述制备的不同浓度的RB水溶液，4℃过夜共价组装12h。
将上述生成物利用透析袋4℃条件下透析去除未组装的反应物，得到共价组装体CAT-RB NPs，4℃保存。
图1为不同RB浓度下共价组装得到的纳米颗粒的粒径图和特定浓度下的形貌图。由图1可知，本实施例制备的纳米颗粒尺寸随RB的浓度变化而变化，尺寸均一，控制在在20nm～100nm之间。当RB浓度为6mg/mL时，通过冷冻透射电镜图可得，纳米颗粒为球状，分布均匀，尺寸在25nm左右。
实施例2
分别配制5μg/mL的单纯RB和CAT-RB NPs溶液，向其中加入9,10-Dipheylanthracene(DPA)的DMSO饱和溶液，两者混合均匀后，密封于石英皿中，向其中注射加入10μL 0.03％H2O2,再次密封，给予10mW/cm2,560nm左右激光照射，利用紫外-可见分光光度计测量体系200-600nm范围内吸光度，记录380nm处吸光度随时间的变化情况。
DPA是常见的单线态氧捕获剂，与单线态氧反应后其吸光度下降。利用DPA的吸光度下降表示单线态氧的产量。由图2可知，与单纯RB相比，CAT-RB NPs中DPA下降值更多，证明产生了更多的单线态氧，分析可得产量是RB的1.65倍。
实施例3
分别配制5μg/mL的单纯RB和CAT-RB NPs溶液于烧杯中，并将溶解氧电极插在烧杯中，用封口膜密封,利用注射器分别向其中加入10μL 0.03％H2O2。在10mW/cm 2,560nm左右激光照射下，记录溶液中单线态氧随时间的变化情况。由图3可知，与RB相比，组装体中溶解氧含量较高且激光条件下消耗量更大，这说明CAT-RB NPs可提高氧气的含量和利用率。
实施例4
将乳腺癌细胞(MCF-7)接种在20mm的共聚焦培养皿中，并且分别用含有5μg/mL的单纯RB和CAT-RB NPs培养液与细胞共孵育1.5h，PBS清洗3次。随后用Alexsa488和Hoechest33342分别给细胞膜和细胞核染色。在405nm、488nm和561nm激光条件下，通过激光共聚焦显微镜(CLSM)观察细胞成像。由图4可知，与单纯RB相比，CAT-RB NPs在细胞内部有明显红色光发射。这说明CAT作为药物载体将RB递送到细胞内部，提高了细胞内吞水溶性光敏剂的效率。在同样实验条件下，细胞经过CAT-RB NPs孵育后，利用线粒体染料染色30分钟，PBS清洗3次，随后对细胞核染色，CLSM观察细胞成像。由图5可知，CAT-RB NPs在细胞中所处的位置与线粒体有很好的重叠，CLSM分析后发现共定位系数大于0.75，这说明CAT-RB NPs对线粒体有很好的选择性。同样条件下，CAT与线粒体的共定位系数小于0.15，说明CAT不具有线粒体靶向性，可见对线粒体的靶向性是CAT-RB NPs的特性。
实施例5
将MCF-7接种到96孔板中，分别用含有不同浓度的RB、CAT和CAT-RB NPs培养液与细胞共孵育1.5h，PBS清洗三次后，细胞在在2mW/cm2,560nm激光条件下照射5min。24h后，利用CCK-8试剂盒检测细胞活性，不给予光照的细胞作为对照组。由图6可知组装体RB含量为5μg/mL时，细胞存活率约为5％，CAT-RB NPs具有明显的细胞光毒性无暗毒性，对照组CAT和RB均不具有细胞光毒性和暗毒性。通过student’s t-test显著性检验得出CAT-RB NPs与RB,CAT相比P值<0.01,说明他们之间存在显著性差异，进一步地证实了CAT-RB NPs的细胞毒性。利用细胞ATP检测试剂盒测定给药光照后0h，4h，8h，16h，24h细胞的ATP含量，由图7可得，ATP含量逐渐下降，光照后24h细胞ATP含量仅为对照组的5％，表明该颗粒光照条件下产生的单线态氧引起了线粒体的功能紊乱，降低了细胞ATP的浓度，最终导致肿瘤细胞的凋亡。
实施例6
将PBS和CAT-RB NPs通过尾静脉注射的方式分别给药至小鼠体内，48h后采用腹部静脉取血的方式对收集的血清进行生化分析检测。由图8可得，CAT-RB NPs处理后的老鼠的生化分析参数与注射了PBS的对照组小鼠基本一致，证明该粒子对小鼠的肾脏和肝脏没有明显的生理毒性，具有较好的生物相容性，可用于下一步的抗肿瘤测试。
实施例7
MCF-7细胞接种到Balb/c nude小鼠身上，构建荷瘤小鼠模型。当肿瘤长至约80mm3，测试CAT-RB NPs的抗肿瘤性能。将1mg/kg,100μL(按RB浓度计)剂量的Cy7标记的RB和CAT-RB NPs通过尾静脉注射的方式分别给药至小鼠体内。利用生物成像仪观察给药后不同时间内纳米颗粒在体内的分布。由图9可得，与游离的RB相比，CAT-RB NPs更多地富集在肿瘤部位，并在注射后1h富集量达到最大值，这极大地提高了水溶性光敏剂在肿瘤部位的浓度，为增强肿瘤的PDT效果提供了有利条件。
实施例8
将16只小鼠平均分为4组，建立MCF-7肿瘤模型，分别对它们进行以下四种治疗方案：PBS组(对照组)，CAT-RB NPs组，RB+Laser组，CAT-RB NPs+Laser组(治疗方案中Laser代表给予激光照射，下同)，每天通过游标卡尺测量和拍照的方式记录小鼠的肿瘤体积，并称量小鼠监测其体重变化。对RB+Laser组，CAT-RB NPs+Laser组，尾静脉注射0.5mg/kg,100μL(按RB浓度计)的RB和CAT-RB NPs后的1h，对肿瘤部位实施160mW/cm2,10min的560nm的激光照射，PBS和CAT-RB NPs组则不实施光照。由图10和11可以看到，与其他三组相比，CAT-RBNPs+Laser组对小鼠肿瘤的抑制效果最好，治疗后的14天肿瘤完全被抑制且最终体积为0。通过student’s t-test显著性检验得出CAT-RB NPs+Laser组与其他三组数据相比P值<0.001,说明他们之间存在显著性差异，进一步地证实了CAT-RB NPs+Laser组的优异的抑制肿瘤生长性能。在治疗结束后，收集每组小鼠的肿瘤，如图12所示，该肿瘤变化也证实了CAT-RB NPs具有较高的抗肿瘤活性。图13显示在治疗期间小鼠的体重没有发生明显的变化，说明了该粒子具有较好的生物相容性。另外我们将实施了PBS，CAT-RB NPs以及CAT-RBNPs+Laser治疗方案的小鼠的主要器官进行了苏木精-伊红(H&E)染色分析。如图14所示，这三组小鼠的心，肝，脾，肺，肾并没有发生明显的结构变化，而CAT-RB NPs+Laser处理的小鼠的肿瘤细胞结构异常，出现了明显的细胞死亡，这证实了该粒子在非光照条件下的生物安全性以及较高的PDT肿瘤杀伤效果。
由上述测试可以看出，CAT-RB NPs的催化过氧化氢产生氧气的能力解决了肿瘤的乏氧问题，该粒子的EPR效应使得其更容易在肿瘤部位富集，其对线粒体的靶向打破了单线态氧的时空局限性，光照条件下造成线粒体功能紊乱，降低了细胞ATP的水平，表现出优异的抗肿瘤性能。基于其优异的生物安全性和生物相容性，该粒子在未来的肿瘤PDT疗法中具有广阔的应用前景。
本发明已经对实施例和附图进行了说明，但是，对于本领域的技术人员来说，依据本申请实例的思想，本发明的具体实施方式与应用范围可以有各种更改和变化。本发明的各种更改、变化和等同物由所附的权利要求书的内容涵盖。
Claims (4)
1.一种光敏性纳米颗粒的制备方法，其特征在于，所述光敏性纳米颗粒由光敏剂和增加局部氧含量的蛋白通过共价键连接之后组装而成，所述纳米颗粒的平均粒径为100nm以下，所述增加局部氧含量的蛋白为过氧化氢酶，所述光敏剂为孟加拉红；
所述制备方法，包括如下步骤：
1)将所述光敏剂和所述增加局部氧含量的蛋白分别溶解；
2)在光敏剂的溶液中加入共价键连接的催化剂进行反应；
3)将步骤2)的溶液与所述增加局部氧含量的蛋白溶液进行混合完成组装；
4)将步骤3)的体系纯化即可得到光敏性纳米颗粒；
步骤1)中，所述光敏剂溶解的浓度为1～10mg/mL，所述蛋白溶解的浓度为1～100mg/mL；
所述步骤2)的催化剂为1-乙基-(3-二甲基氨基丙基)碳酰二亚胺和N-羟基琥珀酰亚胺，催化时间为20～40min；
步骤4)中所述纯化选自透析、超滤洗涤、冷冻干燥、色谱柱分离中的一种或者多种的组合。
2.权利要求1所述的制备方法所制备得到的光敏性纳米颗粒。
3.权利要求2所述的光敏性纳米颗粒在制备抑制肿瘤的光动力药物中的应用。
4.根据权利要求3所述的应用，所述光动力药物为线粒体靶向性药物。
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