CN115317515A - 氯尼达明/牛血清白蛋白/磷酸铁多效协同仿生矿化纳米制剂及制备方法和应用 - Google Patents
氯尼达明/牛血清白蛋白/磷酸铁多效协同仿生矿化纳米制剂及制备方法和应用 Download PDFInfo
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Abstract
本发明公开了氯尼达明/牛血清白蛋白/磷酸铁多效协同仿生矿化纳米制剂及制备方法和应用，属于纳米制剂技术领域。本发明的纳米制剂通过在牛血清白蛋白(BSA)内部载入己糖激酶抑制剂氯尼达明(LND)，之后引入三价铁离子(Fe3+)和磷酸根离子(PO4 3‑)通过仿生矿化手段形成非晶态磷酸铁矿化物。本发明制备的纳米制剂可以实现抑制糖酵解通路、提高氧化应激水平、阻断保护性自噬、诱导凋亡和铁死亡的协同增效，达到高效抗肿瘤的效果。
Description
技术领域
本发明属于纳米制剂技术领域，具体涉及一种氯尼达明/牛血清白蛋白/磷酸铁多效协同仿生矿化纳米制剂及制备方法和应用。
背景技术
近年来，肿瘤的发病率和死亡率不断上升，癌症已经成为威胁人们健康的头号杀手。肿瘤发病机制复杂、治疗效果差、复发转移率高且治疗副作用大、精准性差等原因导致肿瘤治疗难度大。
肿瘤代谢重编程和肿瘤保护性自噬是多种肿瘤的重要生物学特征，主要体现在具有高度糖酵解表型，其不仅提供细胞增殖所需大量ATP和生物大分子合成中间原料，还可降低氧化应激水平从而下调失巢凋亡敏感性，促进循环肿瘤细胞存活和生长，在肿瘤的发生发展、侵袭转移过程中扮演重要角色。而保护性自噬使肿瘤细胞不断调整以适应外界不良环境，如低氧、能量应激、氧化应激等，重塑胞内生理平衡，从而造成治疗抵抗，严重影响治疗效果。因此，研究开发一种可以在阻断糖酵解、提升肿瘤细胞氧化应激的同时阻断其保护性自噬的制剂，进而达到高效抗肿瘤效果显得尤为重要。
生物矿化是指生物体在有机质的调控下形成矿化物的过程，它将自然界中的有机物和无机物复合在一起。而仿生矿化是以有机物为模板，将生物矿化机理引入到材料合成领域，调控无机物的成核和生长，从而制得具有特殊性能及优异生物相容性的纳米复合物。
发明内容
针对肿瘤因高度糖酵解表型、高度侵袭转移性及保护性自噬导致治疗难度较大这一技术问题，本申请提供一种氯尼达明/牛血清白蛋白/磷酸铁多效协同仿生矿化纳米制剂及制备方法和应用，本发明从改变肿瘤细胞代谢及生物学行为角度出发，采用原位仿生矿化手段，在DMEM培养基中将BSA与LND共混合后与Fe3+、PO4 3-进行孵育，精确调控矿化过程及后处理过程，诱导形成氯尼达明-牛血清白蛋白-非晶态磷酸铁(LND-BSA@FePO4)多效协同纳米制剂，创新性构筑氯尼达明/牛血清白蛋白/磷酸铁多效协同仿生矿化纳米制剂，阻断肿瘤细胞糖酵解通路、提高氧化应激水平、防止发生保护性自噬，从而诱导细胞死亡达到治愈目的。
本发明提供如下技术方案：
本发明提供一种氯尼达明/牛血清白蛋白/磷酸铁多效协同仿生矿化纳米制剂的制备方法，主要包括如下步骤：
(1)将氯尼达明溶于缓冲溶液中，制得氯尼达明溶液；
(2)将铁盐溶于去离子水中，得到铁盐水溶液；
(3)将牛血清白蛋白溶于DMEM培养基，30～40℃水浴孵育，加入步骤(1)所得的氯尼达明溶液，30～40℃水浴搅拌，再加入步骤(2)所得的铁盐水溶液，30～40℃水浴孵育；
(4)将步骤(3)所得的溶液超声形成均一溶液，并加入稳定剂，搅拌均匀；
(5)将步骤(4)得到的溶液装入截留分子量为3500～4500的透析袋中，在去离子水中透析；
(6)低速离心去除步骤(5)得到的溶液中的游离药物，得到氯尼达明/牛血清白蛋白/磷酸铁多效协同仿生矿化纳米制剂。
基于上述技术方案，进一步地，步骤(1)中所述的缓冲溶液为Tris缓冲溶液，所述Tris缓冲溶液的浓度为0.01～5mol/L，氯尼达明溶液的浓度为1～10mg/mL。
基于上述技术方案，进一步地，步骤(2)中所述铁盐包括氯化铁、硝酸铁、硫酸铁及其水合物，所述铁盐水溶液中铁离子的浓度为0.1～5mol/L。
基于上述技术方案，进一步地，步骤(3)中牛血清白蛋白与DMEM的质量比为1:0.1～5，孵育时间为1～8小时。
基于上述技术方案，进一步地，步骤(3)中加入氯尼达明溶液的体积与牛血清白蛋白与DMEM的总体积的体积比为1:1～50，搅拌时间为1～8小时。
基于上述技术方案，进一步地，步骤(3)中加入的铁盐水溶液的体积与牛血清白蛋白与DMEM的总体积的体积比为1:20～200，孵育时间为2～24小时。
基于上述技术方案，进一步地，步骤(3)中加入的稳定剂为PVP、海藻酸钠、聚乙二醇、TPGS、普朗尼克、磷脂中的一种或两种以上的组合，稳定剂在溶液中的浓度为1～10mg/mL。
基于上述技术方案，进一步地，步骤(6)中所述离心的转速为500～4000rpm，时间1～20分钟。
本发明另一方面提供上述制备方法制得的氯尼达明/牛血清白蛋白/磷酸铁多效协同仿生矿化纳米制剂。
基于上述技术方案，进一步地，所述纳米制剂中氯尼达明的包封率为40～80％，载药量为5～25％。
基于上述技术方案，进一步地，所述纳米制剂的水动力学直径为200～300nm，Zeta电位为(-10)～(-20)。
本发明还提供上述氯尼达明/牛血清白蛋白/磷酸铁多效协同仿生矿化纳米制剂在制备治疗肿瘤药物中的应用。
基于上述技术方案，进一步地，所述的肿瘤包括B16黑色素瘤。
基于上述技术方案，进一步地，纳米制剂通过瘤内注射注入肿瘤中，纳米制剂中己糖激酶抑制剂氯尼达明调控糖酵解通路，切断细胞能量及生物合成供给来源，提高氧化应激水平；另一方面，纳米制剂中磷酸铁矿化物在肿瘤酸性微环境中可逐步解离生成Fe3+和PO4 3-，其中Fe3+在胞内将还原型谷胱甘肽(GSH)转化为氧化型谷胱甘肽(GSSG)，所生成的Fe2 +与H2O2发生芬顿反应，产生大量高毒性羟基自由基(·OH)，进一步提升氧化应激水平，恢复肿瘤细胞失巢凋亡敏感性，抑制肿瘤转移并实现化学动力学联合增效；PO4 3-调控自噬通路中溶酶体渗透压，防止肿瘤细胞能量应激和氧化应激保护性自噬，加速肿瘤细胞死亡进程；此外，由于过量铁负载和抗氧化体系的功能丧失，该纳米制剂还可启动膜内脂质过氧化，诱导铁死亡实现联合增效，该纳米制剂中各组分多效协同发挥作用并相互促进有望达到肿瘤高效治疗目的。
本发明相对于现有技术具有的有益效果如下：
1、本发明的制备方法简单便捷，易操作，制备周期快。
2、本发明制备的多效协同仿生矿化纳米制剂具有生物相容性好、生物安全性高等特点。
3、本发明制备的多效协同仿生矿化纳米制剂通过抑制糖酵解、提升氧化应激、阻断保护性自噬、诱导凋亡和铁死亡等多效协同作用，进而达到高效治疗肿瘤的目的。
附图说明
为了更清楚地说明本发明实施例，下面将对实施例涉及的附图进行简单地介绍。
图1是LND-BSA@FePO4多效协同纳米制剂的透射电镜(TEM)图；
图2是LND-BSA@FePO4多效协同纳米制剂的元素分析能谱图(a)以及能谱图的局部放大图(b-f)；
图3是LND-BSA@FePO4多效协同纳米制剂在不同pH缓冲液(a)和不同pH值及HPO4 3-双重影响因子缓冲液中(b)的铁离子释放性能考察图；
图4是LND-BSA@FePO4多效协同纳米制剂的活性氧生成考察图；
图5是LND-BSA@FePO4多效协同纳米制剂的细胞铁死亡检测考察图；
图6是LND-BSA@FePO4多效协同纳米制剂的细胞乳酸水平考察图。
图7是LND-BSA@FePO4多效协同纳米制剂的细胞脂质过氧化水平考察图。
图8是LND-BSA@FePO4多效协同纳米制剂的抗肿瘤效果图。
具体实施方式
下面结合实施例对本发明进行详细的说明，但本发明的实施方式不限于此，显而易见地，下面描述中的实施例仅是本发明的部分实施例，对于本领域技术人员来讲，在不付出创造性劳动性的前提下，获得其他的类似的实施例均落入本发明的保护范围。
本发明设计一种氯尼达明/牛血清白蛋白/磷酸铁多效协同仿生矿化纳米制剂的制备和应用。所述多效协同仿生矿化纳米制剂是将己糖激酶抑制剂氯尼达明载入牛血清白蛋白内部，并以牛血清白蛋白为模板进行原位仿生矿化形成磷酸铁矿化物，加入适当的稳定剂处理后得到粒径均一的复合纳米粒子。本发明制备的多效协同纳米制剂可以实现通过抑制糖酵解、提升氧化应激、阻断保护性自噬、诱导凋亡和铁死亡多种途径高效治疗肿瘤瘤的目的。
本发明的氯尼达明/牛血清白蛋白/磷酸铁多效协同仿生矿化纳米制剂(简称为LND-BSA@FePO4多效协同仿生矿化纳米制剂或LND-BSA@FePO4)包括氯尼达明(LND)、牛血清白蛋白(BSA)以及矿化磷酸铁(FePO4)。
实施例1
一种氯尼达明/牛血清白蛋白/磷酸铁多效协同仿生矿化纳米制剂的制备方法，包括：
(1)将氯尼达明(LND)溶于Tris溶液(浓度为0.1mol/L)，制得LND(Tris)溶液(LND含量为5mg/mL)；
(2)将六水合氯化铁溶于去离子水形成氯化铁水溶液(浓度为0.33mol/L)；
(3)将牛血清白蛋白(BSA)溶于DMEM培养基(BSA与DMEM的质量比为2:1)，37℃水浴孵育2小时；加入步骤(1)所得的LND(Tris)溶液(LND溶液与BSA与DMEM溶液总体积的体积比为1:6)，37℃水浴搅拌2小时；再加入步骤(2)所得的氯化铁溶液(氯化铁溶液与BSA与DMEM溶液总体积的体积比为1:100)，37℃水浴4小时；
(4)将步骤(3)所得的溶液超声形成均一溶液，并加d-α琥珀酸生育酚聚乙二醇酯(TPGS)稳定剂(TPGS在溶液中的浓度为2mg/mL)，搅拌1.5小时；
(5)将上述溶液装入截留分子量为3500-4500的透析袋中，在去离子水中透析两小时；
(6)低速离心去除游离药物得到所述氯尼达明/牛血清白蛋白/磷酸铁多效协同仿生矿化纳米制剂。
本实施例制备的LND-BSA@FePO4多效协同仿生矿化纳米制剂中LND的包封率为40～80％，载药量为5～25％；纳米制剂的水动力学直径为200～300nm，Zeta电位为(-10)～(-20)mv。
图1为本实施例制备的LND-BSA@FePO4多效协同仿生矿化纳米制剂的TEM图。
图2为本实施例制备的LND-BSA@FePO4多效协同仿生矿化纳米制剂的Fe、N、C和O元素的分布图，结果表明各组分间的有机结合。
实施例2
实施例1制备的LND-BSA@FePO4多效协同仿生矿化纳米制剂中铁离子释放性能评价，本实施例使用1,10-菲咯啉检测二价铁离子，1,10-菲咯啉是一种金属螯合剂，可与Fe2+络合而形成红色配合物，此配合物在510nm处有最大吸收峰。在本发明中，纳米制剂离心所得的上清液中Fe3+被还原为Fe2+后再与1,10-菲咯啉反应，通过测定溶液中Fe2+的含量来评价纳米制剂铁离子释放性能。
将等量的LND-BSA@FePO4多效协同纳米制剂分别置于不同pH的缓冲溶液中(pH为3.0、4.0、4.8的柠檬酸-柠檬酸钠缓冲溶液和pH为5.5、6.0、6.5的磷酸二氢钠-磷酸氢二钠缓冲溶液)，加入2mg谷胱甘肽，加入1mg 1,10-菲咯啉，在37℃恒温下震荡，分别在0、15、30、45、60、90min后10000rpm离心3min，收集上清液，在300-800nm波长范围内进行光谱扫描。
图3为LND-BSA@FePO4多效协同纳米制剂在不同pH缓冲溶液中的铁离子释放曲线，表明Fe3+的释放受介质中pH值及HPO4 3-双重影响。在pH3.0、4.0、4.8的柠檬酸-柠檬酸钠缓冲溶液中，Fe3+的释放只受H+浓度影响，pH越小，释放速率越快。而在pH5.5、6.0、6.5的磷酸盐缓冲液中，Fe3+的释放受pH值及HPO4 3-双重影响，随着pH值的升高释放逐渐加快；在模拟肿瘤细胞内微环境的pH6.5磷酸盐缓冲液中，本发明的纳米制剂可以在90min内迅速释放Fe3+。
实施例3
实施例1制备的LND-BSA@FePO4多效协同仿生矿化纳米制剂生成活性氧的能力的评价，本实施例使用亚甲基蓝检测LND-BSA@FePO4生成活性氧的能力。亚甲基蓝是常用的染料及化学指示剂，在664nm有最大吸收峰；谷胱甘肽具有很强的还原能力，可将Fe3+还原为Fe2+，Fe2+与H2O2发生链式催化反应，使体系中生成氧化性极强的羟基自由基(·OH)，与亚甲基蓝反应而使其降解，体系蓝色褪去。
将LND-BSA@FePO4与10mM H2O2置于pH6.5的磷酸盐缓冲溶液中，加入指示剂MB(浓度为50μg/mL)，共同反应0、0.5、1、2、3、4h后，分别在UV/Vis 664nm下测定上清液中剩余MB浓度。
图4为LND-BSA@FePO4多效协同仿生矿化纳米制剂的活性氧生成结果，表明LND-BSA@FePO4所释放的Fe3+经还原后生成Fe2+，可通过芬顿反应释放大量·OH，使体系中MB的含量随着孵育时间的延长逐渐降低，证明该纳米制剂可以在体内肿瘤环境下产生活性氧。
实施例4
实施例1制备的LND-BSA@FePO4多效协同仿生矿化纳米制剂对细胞谷胱甘肽水平的影响，本实施例以B16黑色素瘤细胞作为模型细胞，传代两次后，经消化以密度为1×105个/mL的细胞悬液加入6孔板中，在5％CO2，37℃培养箱中培养24小时。加入不同浓度纳米制剂，继续培养12小时。通过GSH检测试剂盒检测制剂孵育后的细胞内GSH水平。
图5是LND-BSA@FePO4孵育后的细胞内GSH水平，随着纳米制剂浓度增加，GSH水平降低，证明LND-BSA@FePO4多效协同仿生矿化纳米制剂在细胞内可以消耗还原型谷胱甘肽，提升氧化应激。
实施例5
实施例1制备的LND-BSA@FePO4多效协同仿生矿化纳米制剂对细胞上清液乳酸水平的影响，本实施例以B16黑色素瘤细胞作为模型细胞，传代两次后，经消化以密度为1×105个/mL的细胞悬液加入6孔板中，在5％CO2，37℃培养箱中培养24小时。加入不同浓度纳米制剂，继续培养12小时。通过乳酸检测试剂盒检测细胞上清液培养基中的乳酸水平。
图6是LND-BSA@FePO4孵育后细胞上清液培养基中的乳酸水平，随着纳米制剂浓度增加，培养基中乳酸水平降低，证明纳米制剂释放的LND可以抑制糖酵解，减少了葡萄糖的消耗，可以达到切断细胞能量及生物合成供给来源，提高氧化应激水平的效果。
实施例6
实施例1制备的LND-BSA@FePO4多效协同仿生矿化纳米制剂对细胞内MDA水平的影响，本实施例以B16黑色素瘤细胞作为模型细胞，传代两次后，经消化以密度为1×105个/mL的细胞悬液加入6孔板中，在5％CO2，37℃培养箱中培养24小时。加入不同浓度纳米制剂，继续培养12小时。通过MDA检测试剂盒检测细胞中的MDA水平。
图7是LND-BSA@FePO4孵育后细胞中的MDA水平，随着纳米制剂浓度增加，细胞中MDA水平降低，证明纳米制剂可以在肿瘤细胞内高效释放Fe3+，启动膜内脂质过氧化，诱导肿瘤细胞铁死亡的发生。
实施例7
本实施例检测实施例1制备的LND-BSA@FePO4多效协同仿生矿化纳米制剂的抗肿瘤效果。以B16黑色素瘤细胞作为模型细胞，传代两次后，经消化以密度为3×104个/mL的细胞悬液加入96孔板中，在5％CO2，37℃培养箱中培养24小时。分别加入PBS(control)和不同浓度的Na3PO4溶液、FeCl3溶液、LND(Tris)溶液、LND-BSA@FePO4纳米制剂，继续培养12小时。通过MTT细胞增殖及细胞毒性检测试剂盒检测细胞存活率，以评价纳米制剂的抗癌效果。
图8为不同药物孵育后的细胞存活率，LND-BSA@FePO4组的细胞存活率明显低于Na3PO4组、FeCl3组和LND组，表明纳米制剂的各组分之间可以发挥协同作用，达到了高效抗肿瘤的目的。
最后应说明的是：以上各实施例仅用以说明本发明的技术方案，而非对其限制；尽管参照前述各实施例对本发明进行了详细的说明，本领域的普通技术人员应当理解：其依然可以对前述各实施例所记载的技术方案进行修改，或者对其中部分或者全部技术特征进行等同替换；而这些修改或者替换，并不使相应技术方案的本质脱离本发明各实施例技术方案的范围。
Claims (10)
1.一种氯尼达明/牛血清白蛋白/磷酸铁多效协同仿生矿化纳米制剂的制备方法，其特征在于，主要包括如下步骤：
(1)将氯尼达明溶于缓冲溶液中，制得氯尼达明溶液；
(2)将铁盐溶于去离子水中，得到铁盐水溶液；
(3)将牛血清白蛋白溶于DMEM培养基，30～40℃条件下孵育，加入步骤(1)所得的氯尼达明溶液，30～40℃条件下搅拌，再加入步骤(2)所得的铁盐水溶液，30～40℃条件下孵育；
(4)将步骤(3)所得的溶液超声形成均一溶液，加入稳定剂，搅拌均匀；
(5)将步骤(4)得到的溶液装入截留分子量为3500～4500的透析袋中，在去离子水中透析；
(6)离心去除步骤(5)得到的溶液中的游离药物，得到氯尼达明/牛血清白蛋白/磷酸铁多效协同仿生矿化纳米制剂。
2.根据权利要求1所述的制备方法，其特征在于，步骤(1)中所述的缓冲溶液为Tris缓冲溶液，所述Tris缓冲溶液的浓度为0.01～5mol/L，氯尼达明溶液的浓度为1～10mg/mL。
3.根据权利要求1所述的制备方法，其特征在于，步骤(2)中所述铁盐包括氯化铁、硝酸铁、硫酸铁及其水合物，所述铁盐水溶液中铁离子的浓度为0.1～5mol/L。
4.根据权利要求1所述的制备方法，其特征在于，步骤(3)中牛血清白蛋白与DMEM的质量比为1:0.1～5，孵育时间为1～8小时。
5.根据权利要求1所述的制备方法，其特征在于，步骤(3)中加入氯尼达明溶液的体积与牛血清白蛋白与DMEM的总体积的体积比为1:1～50，搅拌时间为1～8小时。
6.根据权利要求1所述的制备方法，其特征在于，步骤(3)中加入的铁盐水溶液的体积与牛血清白蛋白与DMEM的总体积的体积比为1:20～200，孵育时间为2～24小时。
7.根据权利要求1所述的制备方法，其特征在于，步骤(3)中加入的稳定剂为PVP、海藻酸钠、聚乙二醇、TPGS、普朗尼克、磷脂中的一种或两种以上的组合，稳定剂在溶液中的浓度为1～10mg/mL。
8.根据权利要求1所述的制备方法，其特征在于，步骤(6)中所述离心的转速为500～4000rpm，时间1～20分钟。
9.权利要1-8任一项所述的制备方法制得的氯尼达明/牛血清白蛋白/磷酸铁多效协同仿生矿化纳米制剂。
10.权利要求9所述的氯尼达明/牛血清白蛋白/磷酸铁多效协同仿生矿化纳米制剂在制备治疗肿瘤药物中的应用。
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