CN113350289A - 一种聚多巴胺全氟己烷纳米脂质体及其制备方法与应用 - Google Patents
一种聚多巴胺全氟己烷纳米脂质体及其制备方法与应用 Download PDFInfo
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Abstract
一种聚多巴胺全氟己烷纳米脂质体及其制备方法与应用，涉及纳米材料和生物医用材料。制备：1)先将全氟己烷在超纯水中超声乳化分散成均匀纳米乳液；2)将纳米乳液与氨水和乙醇溶液共混，加入盐酸多巴胺溶液，搅拌，离心、清洗；3)将乳酸亚铁加入全氟己烷‑聚多巴胺纳米粒子溶液，搅拌，离心、清洗；4)将大豆卵磷脂、胆固醇和二硬脂酰基磷脂酰乙醇胺溶于二氯甲烷，用旋转蒸发仪合成脂质体薄膜，超声分散脂质体膜溶液；5)向步骤3)纳米粒子溶液中加入脂质体膜溶液超声分散自组装，离心、清洗，即得。改善全氟己烷不溶于水的不足，纳米粒子尺寸小，能通过高渗透长滞留效应被动靶向到肿瘤细胞，改善肿瘤微环境缺氧，触发肿瘤细胞铁死亡。
Description
技术领域
本发明属于纳米材料和生物医用材料技术领域，具体是涉及纳米脂质体能够到达肿瘤部位，释放氧气缓解肿瘤缺氧问题，同时释放亚铁离子驱动芬顿反应，触发肿瘤细胞铁死亡，从而达到抑制肿瘤的目的的一种聚多巴胺全氟己烷纳米脂质体及其制备方法与应用。
背景技术
癌症是对人类健康严重的威胁之一。肿瘤细胞的快速生长和扭曲的血管导致氧气供应不足。肿瘤微环境(TME)中的氧合不足会导致缺氧状态，缺氧不仅会促进肿瘤的快速增殖、血管生成和转移，而且也是放疗、化疗和免疫治疗中因耐药导致的治疗失败的原因。因此，改善肿瘤部位缺氧问题对肿瘤治疗有着至关重要的作用。
全氟化碳(PFCs)由于具有很高的氧键能力，可以作为一种生物医学应用材料，因此，全氟化碳作为血液替代品，作为缺氧治疗和器官保存的氧气输送系统，等引起人们的关注。在全氟化碳类别中，由于沸点较高，全氟己烷(PFH，BP 56℃)在体内的稳定性高于广泛使用的全氟戊烷(BP 29℃)。因此，PFH作为一种更好的体内供氧转运体受到越来越多的关注。PFH由于其储存活性氧(ROS)的能力，不仅能提高体内O2水平，而且还能延长肿瘤内活性氧(ROS)的寿命。
铁死亡是一种由铁依赖的脂质过氧化作用引起的提调节性细胞死亡(RCD)，在形态和机制上有别于其他调节性细胞死亡，如细胞凋亡、自噬和焦亡。这种独特的细胞死亡方式是由铁依赖的磷脂过氧化作用驱动的，除与疾病相关的各种信号通路外，还受多种细胞代谢途径的调控，包括氧化还原稳态、铁的处理、线粒体的活性以及氨基酸、脂质和糖的代谢。
目前还没有一种既能够解决肿瘤缺氧问题，又能同时触发肿瘤细胞铁死亡的纳米体系公开报道过。
发明内容
本发明的目的在于克服现有技术的不足，提供一种聚多巴胺全氟己烷纳米脂质体及其制备方法与应用；本发明提供的聚多巴胺全氟己烷纳米脂质体改善全氟己烷不溶于水的不足，并且纳米粒子尺寸足够小能够通过高渗透长滞留(EPR)效应被动靶向到肿瘤细胞，改善肿瘤微环境缺氧问题。同时纳米脂质体能够释放出亚铁离子与内源性的过氧化氢(H2O2)发生芬顿反应，产生大量的活性氧(ROS)，攻击磷脂产生磷脂自由基，触发肿瘤细胞铁死亡，从而达到抑瘤目的。另外，该纳米材料具有良好的生物相容性，制备方法安全简单，原料便宜易得。
一种聚多巴胺全氟己烷纳米脂质体的制备方法，包括如下步骤：
1)将全氟己烷在超纯水中用超声破碎机进行超声乳化分散成均匀的全氟己烷(PFH)纳米乳液；
2)将乳化好的全氟己烷(PFH)纳米乳液与氨水和乙醇溶液搅拌共混后，再加入盐酸多巴胺溶液，室温搅拌，离心、用超纯水分散离心管底部沉淀，得全氟己烷-聚多巴胺(PFH-PDA)纳米粒子溶液；
3)将乳酸亚铁加入到全氟己烷-聚多巴胺纳米粒子溶液中，室温搅拌，离心、清洗，得PFH-PDA-Fe2+纳米粒子溶液；
4)将大豆卵磷脂、胆固醇和二硬脂酰基磷脂酰乙醇胺(mPEG2000-DSPE)溶于二氯甲烷，用旋转蒸发仪合成脂质体薄膜，加入超纯水用超声清洗器进行分散后，再用超声破碎仪破碎，得脂质体膜溶液，备用；
5)将上述步骤4)制备的脂质体膜溶液和步骤3)制备的PFH-PDA-Fe2+纳米粒子溶液超声分散，搅拌，离心，用超纯水分散离心管底部沉淀，即得PFH-PDA-Fe2+-Lip纳米脂质体，即所述聚多巴胺全氟己烷纳米脂质体。
在步骤1)中，所述全氟己烷的用量为0.2～0.8mL，超纯水的用量为6mL，超声破碎的参数为240W，2s开、1s关，总时间为6min。
在步骤2)中，所述氨水的用量为0.4～0.8mL，乙醇的用量为4～8mL，盐酸多巴胺溶液中盐酸多巴胺用量为40～120mg，超纯水用量为10mL；所述共混的时间可为30min，室温搅拌的时间可为24h。
在步骤3)中，所述全氟己烷-聚多巴胺(PFH-PDA)纳米粒子的用量约为8mL，乳酸亚铁的用量为20～60mg；室温搅拌的时间可为6h。
在步骤4)中，所述大豆卵磷脂的用量40mg，胆固醇的用量为10mg，二硬脂酰基磷脂酰乙醇胺(mPEG2000-DSPE)的用量为10mg，二氯甲烷的用量为10mL；所述旋转蒸发仪温度为42℃，转速为50rpm/min，超纯水的用量为8mL，超声清洗器参数为800W，25℃恒温，超声破碎仪参数为200W，2s开、1s关，总时间为2min。
在步骤5)中，脂质体膜溶液用量为4～8mL，PFH-PDA-Fe2+纳米粒子溶液用量为4～8mL，超声分散自组装所用仪器为超声破碎仪其参数为功率100W，5s开、5关，总时间为20min。
在步骤2)、3)、5)中，所述搅拌均采用磁力搅拌，搅拌的转速均为100rpm/min。
在步骤2)、3)、5)中，所述超纯水的用量均为8mL，离心的速度均为10000～12000rpm，离心的时间均为10～15min。
一种聚多巴胺全氟己烷纳米脂质体，化学式为PFH-PDA-Fe2+-Lip，由上述制备方法得到。
一种聚多巴胺全氟己烷纳米脂质体在制备肿瘤治疗药物和缓解肿瘤乏氧问题药物中的应用。
与现有技术相比，本发明具有以下的明显有益效果：
(1)本发明的全氟己烷(PFH)本身是一种具有良好生物相容性、生物惰性的化学物质，并且由于其具有的独特的化学组成结构(分子上的氢原子全部被氟原子取代)，使得PFH具有高疏水性和低反应性，能够溶解大量的氧气。全氟己烷(PFH)溶解氧气是通过氧气浓度梯度差实现的，是一种物理过程，其溶解量是水的近20倍，甚至超过血红蛋白的氧溶解度，溶解的氧气通常可以释放到组织中。此外，PFH可以制备成纳米级乳液，如此小的尺寸能够让它们将氧气运输到身体各处，哪怕是毛细血管中；此外，全氟己烷还能够通过呼吸排出体外。
(2)本发明聚多巴胺全氟己烷纳米粒子的壳层材料为聚多巴胺和脂质体，聚多巴胺(PDA)外壳被广泛应用于生物医学和纳米材料等领域。PDA的儿茶酚结构使纳米粒带负电，强静电排斥力使PDA包裹的纳米粒表现出极强的稳定性。另外，儿茶酚结构是多价金属离子的强配位体，如铁离子、铜离子等。因此，PDA可通过金属离子配位间接吸附其他分子。脂质体(Liposomes)是由卵磷脂和神经酰胺等合成，具有的双分子层结构与细胞膜结构相同，因此能够有效的包封纳米粒子，增加材料稳定性，并且能够减缓药物释放达到缓释效果，被动或者主动靶向到肿瘤部位，另外，所包覆的磷脂能够为芬顿反应产生的活性氧(ROS)提供攻击位点，产生磷脂自由基，引发肿瘤细胞铁死亡。
(3)本发明使用的乳酸亚铁是一种很好的食品铁强化剂，吸收效果比无机铁好，作为食品和饲料添加剂，也是治疗贫血的药物。因此乳酸亚铁具有很好的生物安全性，另外，本发明中螯合亚铁离子(Fe2+)的纳米离子被动靶向到肿瘤部位后能够与内源性的过氧化氢(H2O2)发生芬顿反应，产生大量的活性氧(ROS)，攻击磷脂产生磷脂自由基，触发肿瘤细胞铁死亡，从而达到抑瘤目的。
附图说明
图1为本发明制备的聚多巴胺全氟己烷纳米脂质体示意图；
图2为本发明实施例1制备的聚多巴胺全氟己烷纳米脂质体透射电镜(TEM)图；
图3为本发明实施例3制备的聚多巴胺全氟己烷纳米脂质体粒径图；
图4为本发明实施例4制备的聚多巴胺全氟己烷纳米脂质体生物安全性实验图；
图5肿瘤细胞内脂质过氧化产物丙二醛(MDA)含量检测。
具体实施方式
以下实施例将结合附图进一步阐述本发明。下述实施例仅用于说明本发明而不用于限制本发明范围。
实施例1
一种聚多巴胺全氟己烷纳米脂质体的制备方法，包括如下步骤：
(1)全氟己烷(PFH)纳米乳液的制备：将400μL全氟己烷加入到6mL超纯水中，用超声破碎机(200W，2s开、1s关，总时间6min)进行超声乳化分散成均匀的纳米乳液；
(2)全氟己烷-聚多巴胺(PFH-PDA)纳米粒子的制备：向步骤(1)6mL全氟己烷乳液中加入400μL氨水和4mL乙醇溶液，磁力搅拌(100rpm/min)30min，用80mg盐酸多巴胺和10mL超纯水配置盐酸多巴胺溶液加入上述共混溶液中，室温搅拌24h，离心15min，转速10000rpm，用超纯水分散离心管底部沉淀，再次离心，反复3次即可得所述全氟己烷-聚多巴胺纳米粒子；
(3)PFH-PDA-Fe2+纳米粒子的制备：将40mg乳酸亚铁粉末加入到步骤(2)制备的8mL全氟己烷-聚多巴胺纳米粒子溶液中，室温搅拌6h，离心15min，转速10000rpm，用超纯水分散离心管底部沉淀，再次离心，反复3次即可得所述PFH-PDA-Fe2+纳米粒子；
(4)脂质体的制备：将40mg大豆卵磷脂、10mg胆固醇和10mg二硬脂酰基磷脂酰乙醇胺(mPEG2000-DSPE)溶于10mL二氯甲烷，用旋转蒸发仪合成脂质体薄膜，旋转蒸发仪温度为42℃，转速为50rpm/min，加入8mL超纯水用超声清洗器分散脂质体薄膜，再用超声破碎仪(200W，2s开、1s关，总时间2min)破碎备用；
(5)PFH-PDA-Fe2+-Lip纳米脂质体的制备：将上述步骤(4)制备的8mL脂质体膜溶液和步骤(3)制备的8mLPFH-PDA-Fe2+纳米粒子溶液超声(100W，5s开、5s关，总时间20min)分散20min，离心15min，转速10000rpm，用超纯水分散离心管底部沉淀，再次离心，反复3次即可得所述PFH-PDA-Fe2+-Lip纳米粒子。
图1给出本发明制备的聚多巴胺全氟己烷纳米脂质体示意图，将本实施例1制备的聚多巴胺全氟己烷纳米脂质体用透射电镜进行形貌表征，所得的透射电镜图如图2所示，从图2中可以看出，本实施例制备的纳米颗粒分散性好，粒径均一，具有明显的核壳结构，说明聚多巴胺成功包覆在PFH表面。
实施例2
一种聚多巴胺全氟己烷纳米脂质体的制备方法，包括如下步骤：
(1)全氟己烷(PFH)纳米乳液的制备：将200μL全氟己烷加入到3mL超纯水中，用超声破碎机(200W，2s开、1s关，总时间3min)进行超声乳化分散成均匀的纳米乳液；
(2)全氟己烷-聚多巴胺(PFH-PDA)纳米粒子的制备：向步骤(1)6mL全氟己烷乳液中加入200μL氨水和2mL乙醇溶液，磁力搅拌(100rpm/min)30min，用40mg盐酸多巴胺和5mL超纯水配置盐酸多巴胺溶液加入上述共混溶液中，室温搅拌24h，离心15min，转速10000rpm，用超纯水分散离心管底部沉淀，再次离心，反复3次即可得所述全氟己烷-聚多巴胺纳米粒子；
(3)PFH-PDA-Fe2+纳米粒子的制备：将20mg乳酸亚铁粉末加入到上述步骤(2)制备的8mL全氟己烷-聚多巴胺纳米粒子溶液中，室温搅拌6h，离心15min，转速10000rpm，用超纯水分散离心管底部沉淀，再次离心，反复3次即可得所述PFH-PDA-Fe2+纳米粒子；
(4)脂质体的制备：将40mg大豆卵磷脂、10mg胆固醇和10mg二硬脂酰基磷脂酰乙醇胺(mPEG2000-DSPE)溶于10mL二氯甲烷，用旋转蒸发仪合成脂质体薄膜，旋转蒸发仪温度为42℃，转速为50rpm/min，加入8mL超纯水用超声清洗器分散脂质体薄膜，再用超声破碎仪(200W，2s开、1s关，总时间2min)破碎备用；
(5)PFH-PDA-Fe2+-Lip纳米脂质体的制备：将上述步骤(4)制备的4mL脂质体膜溶液和步骤(3)制备的8mL PFH-PDA-Fe2+纳米粒子溶液超声(100W，5s开、5s关，总时间20min)分散20min，离心15min，转速10000rpm，用超纯水分散离心管底部沉淀，再次离心，反复3次即可得所述PFH-PDA-Fe2+-Lip纳米粒子。
实施例3聚多巴胺全氟己烷纳米脂质体的粒径表征
用动态光散射(DLS)检测实施例1制备的聚多巴胺全氟己烷纳米脂质体(浓度为1.55mg/mL)的粒径，取1mL稀释液用马尔文电位粒度仪检测，所得粒径结果如图3所示，纳米粒子粒径大约为200nm。
实施例4聚多巴胺全氟己烷纳米脂质体的生物安全性检测
为检验纳米脂质体的细胞毒性，本实施例采用小鼠胚胎成纤维细胞(NIH 3T3)模型，考察不同浓度条件下，由实施例1制备的纳米脂质体的细胞毒性。将NIH 3T3细胞以8000个/孔的细胞密度接种于96孔板，过夜培养使细胞贴壁生长。将PFH-PDA-Fe2+-Lip纳米脂质体用培养基按照浓度梯度稀释，每孔加入100μL不同浓度的材料，每个浓度设置6个平行组，加入材料后培养24h，吸走材料，用pH为7.4的PBS溶液清洗2次。用cck-8溶液检测细胞存活率，每孔加入10μL cck-8溶液并加入90μL培养基，用酶标仪检测450nm和650nm处的吸光值，以未处理的细胞作为对照组，计算细胞存活率。如图4所示，不同浓度下细胞存活率均为90％以上，说明该纳米脂质体具有良好的生物安全性。
实施例5肿瘤细胞内脂质过氧化产物丙二醛(MDA)含量检测
为检测肿瘤细胞内脂质过氧化水平，本实施例采用小鼠乳腺癌细胞(4T1)模型，实验步骤：
1、取1000×104个细胞，加入样品(DMEM培养基，PFH-PDA，PFH-PDA-Fe2+，PFH-PDA-Fe2+-Lip，浓度为100μg/mL，用DMEM培养基稀释)，孵育6h后，离心后弃上清，加入1mL MDA提取液超声破碎(200W on：3s，off：10s，6.5min)，8000g 4℃离心10min，取上清。
2、按照MDA检测试剂盒配置混合液，样品检测混合液配方表见表1。将混合液在100℃水浴中保温60min后(盖紧，防止水分散失)，置于冰浴中冷却，10000g，常温，离心10min。吸取200uL上清液于96孔板中，测定各样品在450nm、532nm和600nm处的吸光度。分别计算ΔA450＝A450测定-A450空白，ΔA532＝A532测定-A532空白，ΔA600＝A600测定-A600空白。
MDA含量(nmol/104cell)＝(12.9×(ΔA532-ΔA600)-2.58×ΔA450)×V总÷(500×V样本÷V提取)＝0.02×(12.9×(ΔA532-ΔA600)-2.58×ΔA450)。
表1
| 试剂名称 | 测定管 | 空白管 |
| MDA检测工作液(μL) | 450 | 450 |
| 蒸馏水(μL) | - | 150 |
| 样本(μL) | 150 | - |
| 试剂三(μL) | 150 | 150 |
结果如图5所示，本发明的聚多巴胺全氟己烷纳米脂质体能够产生脂质过氧化，触发肿瘤细胞铁死亡，由此可见，本发明制备的聚多巴胺全氟己烷纳米脂质体可在制备肿瘤治疗药物和缓解肿瘤乏氧问题药物中的应用。
Claims (10)
1.一种聚多巴胺全氟己烷纳米脂质体的制备方法，其特征在于包括如下步骤：
1)将全氟己烷在超纯水中用超声破碎机进行超声乳化分散成均匀的PFH纳米乳液；
2)将乳化好的PFH纳米乳液与氨水和乙醇溶液搅拌共混后，再加入盐酸多巴胺溶液，室温搅拌，离心、用超纯水分散离心管底部沉淀，得PFH-PDA纳米粒子溶液；
3)将乳酸亚铁加入到PFH-PDA纳米粒子溶液中，室温搅拌，离心、用超纯水分散离心管底部沉淀，得PFH-PDA-Fe2+纳米粒子溶液；
4)将大豆卵磷脂、胆固醇和二硬脂酰基磷脂酰乙醇胺溶于二氯甲烷，用旋转蒸发仪合成脂质体薄膜，加入超纯水用超声清洗器进行分散后，再用超声破碎仪破碎，得脂质体膜溶液，备用；
5)将上述步骤4)制备的脂质体膜溶液和步骤3)制备的PFH-PDA-Fe2+纳米粒子溶液超声分散，搅拌，离心，用超纯水分散离心管底部沉淀，即得PFH-PDA-Fe2+-Lip纳米脂质体，即所述聚多巴胺全氟己烷纳米脂质体PFH-PDA-Fe2+-Lip。
2.如权利要求1所述一种聚多巴胺全氟己烷纳米脂质体的制备方法，其特征在于在步骤1)中，所述全氟己烷的用量为0.2～0.8mL，超纯水的用量为6mL，超声破碎的参数为240W，2s开、1s关，总时间为6min。
3.如权利要求1所述一种聚多巴胺全氟己烷纳米脂质体的制备方法，其特征在于在步骤2)中，所述氨水的用量为0.4～0.8mL，乙醇的用量为4～8mL，盐酸多巴胺溶液中盐酸多巴胺用量为40～120mg，超纯水用量为10mL；所述共混的时间可为30min，室温搅拌的时间可为24h。
4.如权利要求1所述一种聚多巴胺全氟己烷纳米脂质体的制备方法，其特征在于在步骤3)中，全氟己烷-聚多巴胺(PFH-PDA)纳米粒子的用量约为8mL，乳酸亚铁的用量为20～60mg；室温搅拌的时间可为6h。
5.如权利要求1所述一种聚多巴胺全氟己烷纳米脂质体的制备方法，其特征在于在步骤4)中，所述大豆卵磷脂的用量40mg，胆固醇的用量为10mg，二硬脂酰基磷脂酰乙醇胺(mPEG2000-DSPE)的用量为10mg，二氯甲烷的用量为10mL；所述旋转蒸发仪温度为42℃，转速为50rpm/min，超纯水的用量为8mL，超声清洗器参数为800W，25℃恒温，超声破碎仪参数为200W，2s开、1s关，总时间为2min。
6.如权利要求1所述一种聚多巴胺全氟己烷纳米脂质体的制备方法，其特征在于在步骤5)中，脂质体膜溶液用量为4～8mL，PFH-PDA -Fe2+纳米粒子溶液用量为4～8mL，超声分散自组装所用仪器为超声破碎仪其参数为功率100W，5s开、5关，总时间为20min。
7.如权利要求1所述一种聚多巴胺全氟己烷纳米脂质体的制备方法，其特征在于在步骤2)、3)、5)中，所述搅拌均采用磁力搅拌，搅拌的转速均为100rpm/min。
8.如权利要求1所述一种聚多巴胺全氟己烷纳米脂质体的制备方法，其特征在于在步骤2)、3)、5)中，所述超纯水的用量均为8mL，离心的速度均为10000～12000rpm，离心的时间均为10～15min。
9.如权利要求1～8中任一所述制备方法制备的聚多巴胺全氟己烷纳米脂质体。
10.如权利要求1～8中任一所述制备方法制备的聚多巴胺全氟己烷纳米脂质体在制备肿瘤治疗药物和缓解肿瘤乏氧问题药物中的应用。
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| CN114983965A (zh) * | 2022-05-05 | 2022-09-02 | 上海市第十人民医院 | 一种聚多巴胺纳米囊泡递送系统及其制备方法和应用 |
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| CN114983965B (zh) * | 2022-05-05 | 2023-06-20 | 上海市第十人民医院 | 一种聚多巴胺纳米囊泡递送系统及其制备方法和应用 |
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