CN117838886A - 一种基于介孔聚多巴胺的靶向性纳米抗衰剂及其制备方法和应用 - Google Patents

一种基于介孔聚多巴胺的靶向性纳米抗衰剂及其制备方法和应用 Download PDF

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CN117838886A
CN117838886A CN202410135257.1A CN202410135257A CN117838886A CN 117838886 A CN117838886 A CN 117838886A CN 202410135257 A CN202410135257 A CN 202410135257A CN 117838886 A CN117838886 A CN 117838886A
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nano
tmpda
solution
mesoporous polydopamine
mesoporous
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史丽云
徐晓玲
张海瑞
寿鑫
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Zhejiang Shuren University
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Abstract

本发明公开了一种基于介孔聚多巴胺的靶向性纳米抗衰剂的制备方法和应用。所述制备方法包括：1)运用Tempo改良和PEG修饰法，构建具有介孔的聚多巴胺—TMPDA作为载体；2)根据π‑π堆叠或氢键相互作用，由水溶性的TMPDA载体包裹疏水性的混合型“Senolytics”，即达沙替尼+槲皮素(D+Q)；3)运用氢键吸附的方式在介孔纳米颗粒上包裹一层可被β‑半乳糖苷酶分解的半乳聚糖，最终得到GTMPDA@D+Q。本发明所构建的多功能纳米抗衰剂具有衰老细胞特异性靶向、药物缓释、生物利用度高、生物安全性好等优势。经过静脉注射，可高效清除衰老的肺泡二型上皮细胞，缓解特发性肺纤维化；或结合PTT光热疗法来清除由于化疗诱导的衰老肿瘤细胞，防止肿瘤复发和转移。

Description

一种基于介孔聚多巴胺的靶向性纳米抗衰剂及其制备方法和 应用
技术领域
本发明属于生物医学材料领域，具体涉及一种基于介孔聚多巴胺的多功能纳米抗衰剂及其制备方法和应用。
背景技术
随着医疗技术的进步和生活质量的提高，全球人口老龄化现象日益明显。老龄化是一个全球性挑战，衰老疾病的发病率和负担随之增加。因此，研究治疗衰老疾病对于应对人口老龄化具有重要意义。研究发现，衰老是导致多种慢性疾病的主要风险因素之一。通过研究衰老疾病，可以深入了解疾病的发生机制和影响因素，从而提供预防和早期干预的策略。这有助于延缓疾病的发展，减少疾病的发病率和病情的严重程度。
特发性肺纤维化是一种不可逆转的、慢性、进行性的肺部疾病。近年来，越来越多的研究发现特发性肺纤维化发生早期伴随着肺泡二型上皮细胞的衰老，进而影响其向肺泡一型上皮细胞转化，减少气体交换；其释放的细胞因子刺激成纤维细胞向肌成纤维细胞的转化，使得胶原增加，肺泡壁增厚。故，在疾病初期对衰老的肺泡二型上皮细胞的清除可作为一种可行治疗手段。
肿瘤放化疗以及某些靶向药物可诱导细胞衰老。尽管细胞衰老作用具有多重性，但作为细胞的自我保护性机制，其在肿瘤的复发、转移、耐药等方面有重要意义。已有研究显示，Palbociclib等化疗药物治疗乳腺癌可引起肿瘤细胞衰老，治疗诱导的肿瘤细胞衰老并不是永久的细胞衰老，反而可能引起肿瘤细胞往“干性细胞”转化，并在某些情况下重新进入细胞周期，引起肿瘤的复发和转移。如何克服治疗引起的肿瘤细胞衰老引发的不利影响，通过清除衰老细胞以达到彻底治疗目的，是肿瘤治疗和细胞衰老研究的重要瓶颈问题。
达沙替尼+槲皮素(D+Q)的药物联合是目前被公认的Senolytics抗衰老药物，目前D+Q大多以口服方式给药用来治疗衰老相关疾病，达沙替尼和槲皮素的生物利用度低的问题一直存在，且通过口服方式给药后药物快速被肠道吸收，药物在短时间内可被非衰老细胞捕获，通过血液循环达到衰老部位的药物不足，影响清除效率。故迫切需要一种新的给药方式或者载体来提高D+Q的生物利用度，实现对衰老细胞的靶向、进行药物的缓慢释放，以提高清除效率。
靶向纳米给药系统的出现，为肿瘤的安全高效治疗提供了新的策略。聚多巴胺(PDA)是一种仿生材料，具有和贻贝粘附蛋白相似的黏附特性和生物相容性，并且有着例如高金属离子螯合性、良好光热转换性等独特物理化学性质，是一种优良无害的靶向药物递送平台。PDA表面由于存在丰富的官能基团，使其易于吸附药物或功能修饰，D+Q很容易通过π-π堆叠或氢键相互作用吸附于PDA表面。
Tempo作为一种自由基捕获剂，一方面，它可以与介孔聚多巴胺结合，发挥出更大的光热转化作用，与常规“Senolytics”协同作用，提高衰老细胞杀伤效率；另一方面，它可以清除衰老细胞中的ROS，使得衰老细胞抵抗外界刺激导致的DNA损伤能力下降，加快衰老细胞的凋亡。
衰老细胞中的β-半乳糖苷酶含量是正常细胞的5～10倍，基于β-Gal响应性的靶向衰老细胞前药被设计。利用半乳聚糖的包封，用其来实现纳米粒对衰老细胞的定向递送。
发明内容
本发明所要解决的技术问题是针对现有技术的不足，提供一种基于介孔聚多巴胺的靶向性纳米抗衰剂及其制备方法和应用。
为了实现上述目的，本发明提供了一种基于介孔聚多巴胺的靶向性纳米抗衰剂的制备方法，包括如下步骤：
(1)制备未修饰的介孔聚多巴胺(TMPDA)纳米颗粒：在乙醇水溶液中加入盐酸多巴胺、Tempo和1,3,5-三甲苯(TMB)，碱性条件下搅拌反应，离心，洗涤，得到未修饰的TMPDA纳米颗粒。
(2)制备介孔聚多巴胺(TMPDA)纳米颗粒：将所述的未修饰的TMPDA纳米颗粒重悬于水中，加入PEG-2000，搅拌反应，离心，洗涤，得到TMPDA纳米颗粒。
(3)将所述的TMPDA纳米颗粒与药物达沙替尼和槲皮素混合，搅拌反应，得到含有TMPDA@D+Q纳米颗粒的溶液。
(4)在步骤(3)制得的溶液中加入半乳聚糖，搅拌反应，离心，得到GTMPDA@D+Q纳米颗粒，即为基于TMPDA的靶向性纳米抗衰剂。
其中，步骤(1)中，所述的Tempo为2,2,6,6-四甲基哌啶氧化物。
其中，步骤(1)中，所述的乙醇水溶液浓度为20％～40％v/v；所述的盐酸多巴胺加入量以每100mL乙醇水溶液加入100～125mg的盐酸多巴胺计；所述的Tempo加入量以每100mL乙醇水溶液加入100～125mg的Tempo计；所述的TMB加入量以每100mL乙醇水溶液加入2～8mL的TMB计。优选地，所述的乙醇水溶液浓度为40％v/v；所述的盐酸多巴胺加入量以每100mL乙醇水溶液加入112.5mg的盐酸多巴胺计；所述的Tempo加入量以每100mL乙醇水溶液加入112.5mg的Tempo计；所述的TMB加入量以每100mL乙醇水溶液加入5mL的TMB计。更优选地，所述的TMB以TMB溶液的形式加入，所述的TMB溶液的浓度为97％。
其中，步骤(1)中，所述的碱性条件为PH＝12；所述的搅拌，其转速为400～800rpm；所述的离心，其转速为6000～10000rpm，时间为6～10min。所述的搅拌反应在室温下进行。优选地，所述的搅拌，其转速为800rpm，时间为4h；所述的离心，其转速为10000rpm，时间为10min。
其中，步骤(1)中，所述的洗涤方法为：用与未修饰的介孔聚多巴胺纳米颗粒相同体积的水和无水乙醇溶液分别洗涤三次。
优选地，步骤(1)的具体方法为：将40～80mL无水乙醇加入到120～160mL水中，然后加入200～250mg盐酸多巴胺、200～250mg的Tempo，水浴超声溶解，再加入5～15mL TMB溶液(TMB浓度为97％)，使得生成均匀的介孔，在pH为12条件下，以400～800rpm磁力室温搅拌4h，然后在6000～10000rpm，6-10min离心，去上清，得到未修饰的介孔聚多巴胺纳米颗粒。加入同体积的水溶液超声溶解，再离心，6000～10000rpm，6～10min离心，去上清，重复洗涤三次。再加入同体积的无水乙醇溶液重复洗涤三次，得到未修饰的介孔聚多巴胺纳米颗粒。
其中，步骤(2)中，所述的TMPDA纳米颗粒，直径为100～200nm，介孔尺寸为1～30nm。优选地，所述的直径为147.20nm，介孔尺寸为26.03nm。
其中，步骤(2)中，所述的未修饰的TMPDA纳米颗粒与PEG-2000的质量比为1:2。优选地，所述的搅拌，其温度为室温，其时间为12h。所述的加入PEG-2000用于增加纳米颗粒亲水性。
其中，步骤(3)中，TMPDA纳米颗粒、达沙替尼、槲皮素的质量比为1:0.02:0.052。
其中，步骤(3)中，所述的药物达沙替尼和槲皮素以达沙替尼和槲皮素的DMSO溶液的形式加入；所述的达沙替尼和槲皮素的DMSO溶液中达沙替尼浓度为10mg/mL，槲皮素浓度为26mg/mL。
其中，步骤(3)中，所述的搅拌反应，其条件为室温避光搅拌24h。
其中，步骤(4)中，所述的半乳聚糖分子量为532.49。
其中，步骤(4)中，所述的半乳聚糖和所述的TMPDA纳米颗粒质量比为2:1。
其中，步骤(4)中，所述的搅拌反应，其条件为室温避光搅拌24h。
本发明的第二方面在于，提供了一种上述的制备方法制备得到的基于TMPDA的靶向性纳米抗衰剂。所述的TMPDA负载“Senolytics”药物。
本发明的第三方面在于，还提供了所述的靶向性纳米抗衰剂在制备抗衰老药物和/或治疗乳腺癌药物中的应用
优选地，所述的抗衰老药物可以靶向衰老细胞，包括但不限于在局部抗衰老治疗、治疗特发性肺纤维化中的应用。
有益效果：
本发明在TMPDA纳米颗粒合成中加入Tempo，使得清除衰老细胞ROS、治疗乳腺癌的光热效果增加，加强对衰老细胞的清除。然后将PEG-2000修饰于所述未修饰TMPDA纳米颗粒的表面，制得TMPDA纳米颗粒。提高负载量的目的的同时，能够更加有利于药物的缓释。最后通过半乳聚糖的包封，使得纳米颗粒对β-Gal的响应性更强，做到D+Q的靶向释放。本发明制备得到的纳米抗衰剂可实现化学疗法、PTT光热疗法、“Senolytics”抗衰老协同靶向衰老部位，实现对衰老细胞的高效清除，减少对正常组织的毒副作用。
本发明的有益之处在于采用经过Tempo改良、PEG修饰、具有介孔的聚多巴胺——TMPDA作为载体，根据π-π堆叠或氢键相互作用将D+Q载入纳米粒介孔中，运用氢键吸附的方式在纳米颗粒介孔上包裹上一层可以被β-半乳糖苷酶分解的半乳聚糖，最终得到GTMPDA@D+Q。通过静脉注射GTMPDA@D+Q，利用其靶向、缓释、生物利用度高、生物安全性好等优势清除衰老的肺泡二型上皮细胞，有效缓解特发性肺纤维化；或结合PTT光热疗法来清除由于化疗诱导的衰老肿瘤细胞，防止肿瘤复发和转移。
附图说明
下面结合附图和具体实施方式对本发明做更进一步的具体说明，本发明的上述和/或其他方面的优点将会变得更加清楚。
图1为基于TMPDA靶向性纳米抗衰剂的制备及应用过程。
图2为TMPDA的透射电镜图和动态光散射粒径分布图。其中图2a为实施例1合成的TMPDA的透射电镜图；图2b为实施例2合成的TMPDA的透射电镜图；图2c为实施例3合成的TMPDA的透射电镜图；图2d为实施例1合成的TMPDA的动态光散射粒径分布图；图2e为实施例2合成的TMPDA的动态光散射粒径分布图；图2f为实施例3合成的TMPDA的动态光散射粒径分布图。
图3为GTMPDA@D+Q水溶液在不同条件下的光热升温图。图3a为不同浓度；图3b为不同激光功率；图3c为不同制剂。
图4为GTMPDA@D+Q与不同细胞孵育24h后的细胞活性。图4a衰老A549细胞；图4b衰老4T1细胞。
图5为小鼠的体重变化和肿瘤体积变化。图5a为经过各组治疗后的特发性肺纤维化小鼠的体重变化；图5b为经过各组治疗后的乳腺癌小鼠的肿瘤体积变化。
图6为经过各组治疗后的肺部切片H&E染色。
图7为经过各组治疗后的肿瘤切片H&E染色。
具体实施方式
下述实施例中所述实验方法，如无特殊说明，均为常规方法；所述试剂和材料，如无特殊说明，均可从商业途径获得。
下列实施例中，所述的半乳聚糖的分子量为532.49。
下列实施例中，所述的Tempo为2,2,6,6-四甲基哌啶氧化物。所述的TMB溶液为1,3,5-三甲苯溶液，其中TMB浓度为97％，购买于麦克林公司。
下列实施例中，所述的DMEM培养基和1640完全培养基均购买于武汉普诺赛生命科技有限公司。
下列实施例所述的基于TMPDA靶向性纳米抗衰剂的制备和应用过程如图1所示。
实施例1：制备介孔聚多巴胺(TMPDA)纳米颗粒
将40mL无水乙醇加入到160mL水中，然后加入200mg盐酸多巴胺、250mgTempo，水浴超声溶解，再加入5mL TMB溶液，使得生成均匀的介孔，在碱性条件(pH＝12)下，以400rpm磁力室温搅拌4h，然后6000rpm离心10min，去上清，得到未修饰的介孔聚多巴胺纳米颗粒。加入与未修饰的介孔聚多巴胺纳米颗粒同体积的水溶液超声溶解，6000rpm离心10min，去上清，重复洗涤三次。接着再用相同体积的无水乙醇溶液重复洗涤三次，洗涤后重悬于与未修饰的介孔聚多巴胺纳米颗粒同体积的水溶液中，得到未修饰的介孔聚多巴胺纳米颗粒-1溶液。
将所述的未修饰的介孔聚多巴胺纳米颗粒-1溶液在室温下按照未修饰的介孔聚多巴胺纳米颗粒-1与PEG-2000质量比为1:2的比例加入PEG-2000来增加其亲水性，室温搅拌12h，得到TMPDA纳米颗粒-1溶液。
实施例2：制备TMPDA纳米颗粒
将60mL无水乙醇加入到140mL水中，然后加入250mg盐酸多巴胺、200mgTempo，水浴超声溶解，再加入15mL TMB溶液，使得生成均匀的介孔，在碱性条件下(pH＝12)，以600rpm磁力室温搅拌4h，然后8000rpm离心10min，去上清，得到未修饰的介孔聚多巴胺纳米颗粒。加入与未修饰的介孔聚多巴胺纳米颗粒同体积的水溶液超声溶解，8000rpm离心10min，去上清，重复洗涤三次。接着再用相同体积的无水乙醇溶液重复洗涤三次，洗涤后重悬于与未修饰的介孔聚多巴胺纳米颗粒相同体积的水溶液中，得到未修饰的介孔聚多巴胺纳米颗粒-2溶液。
将所述的未修饰的介孔聚多巴胺纳米颗粒-2溶液在室温下按照未修饰的介孔聚多巴胺纳米颗粒-2与PEG-2000质量比为1:2的比例加入PEG-2000来增加其亲水性，室温搅拌12h，得到TMPDA纳米颗粒-2溶液。
实施例3：制备TMPDA纳米颗粒
将80mL无水乙醇加入到120mL水中，然后加入225mg盐酸多巴胺、225mgTempo，水浴超声溶解，再加入10mL TMB溶液，使得生成均匀的介孔，在碱性条件下(pH＝12)，以800rpm磁力室温搅拌4h，然后10000rpm离心10min，去上清，得到未修饰的介孔聚多巴胺纳米颗粒。加入与未修饰的介孔聚多巴胺纳米颗粒同体积的水溶液超声溶解，10000rpm离心10min，去上清，重复洗涤三次。接着再用同体积的无水乙醇溶液重复洗涤三次，洗涤后重悬于与未修饰的介孔聚多巴胺纳米颗粒相同体积的水溶液中，得到未修饰的介孔聚多巴胺纳米颗粒-3溶液。
将所述的未修饰的介孔聚多巴胺纳米颗粒-3溶液在室温下按照未修饰的介孔聚多巴胺纳米颗粒-3与PEG-2000质量比为1:2的比例加入PEG-2000来增加其亲水性，室温搅拌12h，得到TMPDA纳米颗粒-3溶液。
实施例4：TMPDA负载“Senolytics”的靶向性纳米抗衰剂GTMPDA@D+Q的合成
(1)收集实施例1-3制备得到的TMPDA纳米颗粒溶液，9500rpm离心10min，过滤，用60mL体积的水溶液洗涤，得到TMPDA纳米颗粒。称取60mg所述的TMPDA纳米颗粒与含达沙替尼(D)+槲皮素(Q)的DMSO溶液(120μL；10mg/mL D；26mg/mL Q)混合，室温避光搅拌800rpm，24h，分别得到TMPDA@D+Q-1/TMPDA@D+Q-2/TMPDA@D+Q-3溶液；
(2)在步骤(1)所述的TMPDA@D+Q-1/TMPDA@D+Q-2/TMPDA@D+Q-3溶液中投入120mg半乳聚糖，继续避光800rpm搅拌24h，9500rpm离心10min，弃上清，重悬于60mL水溶液中，得到GTMPDA@D+Q-1、GTMPDA@D+Q-2、GTMPDA@D+Q-3。
实施例5：TMPDA的表征
(1)透射电镜(TEM)观察TMPDA形貌：取10μL TMPDA纳米颗粒溶液，滴加在表面碳涂层铜网上，室温条件下自然风干。200kV电压条件下，透射电子显微镜观察纳米颗粒的形貌和粒径。根据实施例1、2、3制备的纳米颗粒TMPDA-1、TMPDA-2、TMPDA-3的透射电镜结果如图2a、图2b、图2c所示，可以看出基于实施例3方法合成的纳米颗粒TMPDA-3呈球形且粒径均一，有规则分布的孔道结构，且纳米颗粒TMPDA-1、TMPDA-2、TMPDA-3的介孔尺寸分别为20.24±4.33nm、14.39±0.57nm和26.03±6.43nm
(2)马尔文纳米粒度仪测量TMPDA粒径与稳定性：取1mL根据实施例1、2、3制备的纳米颗粒TMPDA-1、TMPDA-2、TMPDA-3溶液加入样品池中，测量其粒径，分别为93.59±14.07nm、269.23±40.48nm、147.20±22.17nm，并得到如图2d、图2e、图2f的动态光散射粒径分布图。由图中可见，采用实施例3方法制得的TMPDA-3粒径分布范围较窄，其粒径分布指数(PDI)仅为0.161，表明粒径比较均一。下列实施例中有关TMPDA/GTMPDA@D+Q的性质研究均采用TMPDA-3/GTMPDA@D+Q-3纳米颗粒溶液。
实施例6：GTMPDA@D+Q体外光热性质研究
(1)配制不同浓度(0μg/mL、50μg/mL、100μg/mL、200μg/mL)的TMPDA-3溶液，将溶液移至样品池中，采用功率为1.5W/cm2的808nm激光器对溶液进行照射5分钟，同时每30s用电子温度计记录材料进行激光照射时的温度变化情况。绘制成温度-时间曲线，分析溶液温度变化与溶液浓度的关系。
(2)配制浓度为100μg/mLTMPDA-3溶液，将溶液移至样品池中，分别采用不同功率(0.5W/cm2、1.0W/cm2、1.5W/cm2)的808nm激光器对分散液进行照射5分钟，每30s用电子温度计记录激光照射时分散液的温度变化情况。绘制成温度-时间曲线，分析溶液温度变化与激光功率的关系。
(3)配制浓度为100μg/mL的各组溶液(GTMPDA@D+Q-3、TMPDA-3、Free D+Q、水)，将溶液移至样品池中，采用功率为1.5W/cm2的808nm激光器对溶液进行照射5分钟，同时每30s用电子温度计记录材料进行激光照射时的温度变化情况。绘制成温度-时间曲线，分析各组之间溶液温度变化。
(4)如图3a～c所示，在808nm激光照射下，TMPDA-3溶液温度升高呈浓度和激光功率依赖性。由此可以看出，本发明制备得到的TMPDA-3有着良好的光热转化能力。
实施例7：GTMPDA@D+Q对衰老细胞的杀伤效果评价
衰老细胞的构建：对于A549细胞，采用含0.01U/mL博来霉素的DMEM培养基诱导2天；对于4T1细胞，采用含5μM的帕博西尼的1640培养基诱导14天。(所述的A549细胞和4T1细胞均购买于武汉普诺赛生命科技有限公司)
将上述构建的两种不同的衰老细胞以4000个/孔的数量分别接种在2块96孔细胞培养板中。待细胞贴壁后，将所述的A549细胞中分别加入含PBS(pH＝7.4)、Free D+Q(D:2.9μM,Q:17.2μM)和100μg/mL(GTMPDA@D+Q、TMPDA、)各组溶液的DMEM培养基200μL，与细胞共孵育24小时；将所述的4T1细胞中分别加入含PBS(pH＝7.4)、Free D+Q(D:2.9μM,Q:17.2μM)和100μg/mL(GTMPDA@D+Q、TMPDA)各组溶液的1640完全培养基200μL，与细胞共孵育24小时。CCK8实验检测各组溶液对细胞活性的影响。如图4所示，图4a的A549细胞和图4b的4T1细胞实验结果表明，TMPDA在一定程度上抑制了衰老细胞的增殖，其细胞抑制率约为20％，D+Q的清除效果明显，Free D+Q溶液的细胞抑制率约为40％，而GTMPDA@D+Q的细胞抑制率达到了60％。
此外，对4T1细胞进行了近红外光照射实验，在上述含GTMPDA@D+Q溶液的1640培养基培养4T1细胞24h后，采用1.0W/cm2的808nm的近红外光照射3min，后续进行CCK8实验检测各组溶液对细胞活性的影响。实验结果表明，如图4b所示，近红外光的照射下，GTMPDA@D+Q/R的细胞抑制率增加到85％。
实施例8：GTMPDA@D+Q的衰老治疗情况及疗效监测
对于特发性肺纤维化小鼠而言，采用C57BL/6J品系的6～8周小鼠(20g)，在博来霉素(Bleo)气管滴注(2U/kg)第6天、第12天、第18天尾静脉注射200μL的PBS、Free D+Q(D：0.7mg/kg Q：2.6mg/kg)、TMPDA(5mg/mL)、GTMPDA@D+Q(5mg/mL)，第21天处死小鼠并收集肺脏。期间每三天记录一次体重数据。如图5a结果显示，博来霉素造模使得小鼠体重下降明显；TMPDA、Free D+Q组则是在治疗后期缓解了这种体重的下降；GTMPDA@D+Q组与其他组相比，体重开始回升，其相比博来霉素造模对照组，体重回升了10％，治疗效果更显著。
对于乳腺癌小鼠而言，采用Balb/C品系的6～8周小鼠(20g)，在第0天时将5×105个4T1细胞接种在乳垫处，第7天开始进行帕博西尼(Pab)口服(100mg/kg)化疗，持续7天。在第15天、第18天、第21天尾静脉注射200μL的PBS、Free D+Q(D：0.7mg/kg Q：2.6mg/kg)、TMPDA(5mg/mL)、GTMPDA@D+Q(5mg/mL)，其中GTMPDA@D+Q两组中选出一组在给药24h后进行光热治疗，总的来说，采用1.0W/cm2的808nm的近红外光照射肿瘤部位3min。第24天处死小鼠并收集肿瘤。期间每三天记录一次肿瘤体积数据。如图5b结果所示，随着天数的增长，肿瘤体积呈指数型增长，最终达到1300mm3；在口服帕博西尼后，肿瘤增长得到了小幅度的抑制，达到938mm3；而TMPDA(910mm3)、Free D+Q(750mm3)、GTMPDA@D+Q(702mm3)均有着不同程度的抑制效果，而加了光照的GTMPDA@D+Q/R组肿瘤大小下降最大，降低到100cm3，消融效果明显。
实施例9：GTMPDA@D+Q体内治疗后脏器和肿瘤的H&E染色
将收集到的特发性肺纤维化小鼠肺脏和乳腺癌小鼠肿瘤使用4％多聚甲醛(购买于上海碧云天生物技术有限公司，P0099)固定，24h后进行石蜡包埋，切片，H&E染色。
肺脏结果显示(图6)：Bleo组造模使得肺组织肿大肺泡壁增厚，大量炎症细胞浸润，TMPDA组显示出一定的治疗效果，Free D+Q已经明显缓解了肺泡壁的增厚和炎症细胞浸润，GTMPDA@D+Q因其良好的衰老靶向和缓释效果更好，肺泡壁结构完整，治疗最为显著。
肿瘤结果显示(图7)：Pab组通过帕博西尼化疗使得肿瘤细胞变大，密集程度下降，出现了一定程度上的衰老，其他组之间均有一定的治疗效果。其中，GTMPDA@D+Q/R组细胞核溶解，细胞质增多，治疗最为显著。
本发明提供了一种基于介孔聚多巴胺的纳米抗衰剂及其制备方法和应用的思路及方法，具体实现该技术方案的方法和途径很多，以上所述仅是本发明的优选实施方式，应当指出，对于本技术领域的普通技术人员来说，在不脱离本发明原理的前提下，还可以做出若干改进和润饰，这些改进和润饰也应视为本发明的保护范围。本实施例中未明确的各组成部分均可用现有技术加以实现。

Claims (10)

1.一种基于介孔聚多巴胺的靶向性纳米抗衰剂的制备方法，其特征在于，包括如下步骤：
(1)制备未修饰的介孔聚多巴胺纳米颗粒：在乙醇水溶液中加入盐酸多巴胺、Tempo和1,3,5-三甲苯，碱性条件下搅拌反应，离心，洗涤，得到未修饰的介孔聚多巴胺纳米颗粒；
(2)制备介孔聚多巴胺纳米颗粒：将所述的未修饰的介孔聚多巴胺纳米颗粒重悬于水中，加入PEG-2000，搅拌反应，离心，洗涤，得到介孔聚多巴胺纳米颗粒；
(3)将所述的介孔聚多巴胺纳米颗粒与药物达沙替尼和槲皮素混合，搅拌反应，得到含有TMPDA@D+Q纳米颗粒的溶液；
(4)在步骤(3)制得的溶液中加入半乳聚糖，搅拌反应，离心，得到GTMPDA@D+Q纳米颗粒，即为所述的基于介孔聚多巴胺的靶向性纳米抗衰剂。
2.根据权利要求1所述的制备方法，其特征在于，步骤(1)中，所述的乙醇水溶液浓度为20％～40％v/v；所述的盐酸多巴胺加入量以每100mL乙醇水溶液加入100～125mg的盐酸多巴胺计；所述的Tempo加入量以每100mL乙醇水溶液加入100～125mg的Tempo计；所述的1,3,5-三甲苯加入量以每100mL乙醇水溶液加入2～8mL的1,3,5-三甲苯计。
3.根据权利要求1所述的制备方法，其特征在于，步骤(1)中，所述的碱性条件为pH为12；所述的搅拌，其转速为400～800rpm；所述的离心，其转速为6000～10000rpm。
4.根据权利要求1所述的制备方法，其特征在于，步骤(2)中，所述的介孔聚多巴胺纳米颗粒，直径为100～200nm，介孔尺寸为1～30nm。
5.根据权利要求1所述的制备方法，其特征在于，步骤(2)中，所述的未修饰的介孔聚多巴胺纳米颗粒与所述的PEG-2000的质量比为1:2。
6.根据权利要求1所述的制备方法，其特征在于，步骤(3)中，所述的介孔聚多巴胺纳米颗粒、达沙替尼、槲皮素的质量比为1:0.02:0.052。
7.根据权利要求1所述的制备方法，其特征在于，步骤(3)中，所述的药物达沙替尼和槲皮素以达沙替尼和槲皮素的DMSO溶液的形式加入；所述的达沙替尼和槲皮素的DMSO溶液中达沙替尼浓度为10mg/mL，槲皮素浓度为26mg/mL。
8.根据权利要求1所述的制备方法，其特征在于，步骤(4)中，所述的半乳聚糖和介孔聚多巴胺纳米颗粒质量比为2:1。
9.权利要求1～8中任意一项所述的制备方法制备得到的基于介孔聚多巴胺的靶向性纳米抗衰剂。
10.权利要求9所述的基于介孔聚多巴胺的靶向性纳米抗衰剂在制备抗衰老药物和/或治疗乳腺癌药物中的应用。
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