CN116395718A - 一种弱碱性钠盐纳米药物、其制备方法及其应用 - Google Patents
一种弱碱性钠盐纳米药物、其制备方法及其应用 Download PDFInfo
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Abstract
本发明提供了一种弱碱性钠盐纳米药物、其制备方法及其应用，由油酸钠和碳酸氢铵微乳液法制得。由油酸钠和碳酸氢铵微乳液法制得的弱碱性钠盐纳米药物，即NaHCO3，不仅可以和肿瘤微环境中乳酸进行酸碱中和，消耗乳酸，解除免疫抑制肿瘤微环境；同时可以在肿瘤细胞内降解释放大量离子，诱导细胞焦亡，激活免疫响应；从而通过两方面协同作用，激活全身抗肿瘤免疫反应，以对抗肿瘤复发和转移。本发明提供的弱碱性钠盐纳米药物的制备方法简单，反应条件温和，原料成本低廉，具有很大的应用前景。
Description
技术领域
本发明属于生物医用纳米材料技术领域，尤其涉及一种弱碱性钠盐纳米药物、其制备方法及其应用。
背景技术
肿瘤的“Warburg effect”使得瘤细胞即便在氧气充足的情况下依然将摄取的大量葡萄糖经糖酵解代谢生成乳酸。肿瘤微环境中积累的乳酸不仅可以促进肿瘤进程，高浓度的乳酸还会转运到细胞内作为燃料底物被代谢，同时促进肿瘤血管生成以及侵袭转移。除此之外，越来越多的研究表明，肿瘤微环境中的乳酸可以通过多种途径抑制机体免疫响应，极大影响肿瘤免疫治疗效果。例如，肿瘤细胞来源的乳酸可以通过低氧诱导因子1-α信号通路诱导血管内皮生长因子和精氨酸酶1表达，促进肿瘤相关巨噬细胞向M2型极化，以促进肿瘤生长；乳酸能够抑制树突细胞的抗原递呈过程和成熟分化；乳酸也能抑制细胞毒性T细胞糖酵解产生的乳酸排出，进而抑制其细胞毒性；同时，肿瘤来源的乳酸还可以降低CD8+T细胞的数量和活性。最近的研究还表明，肿瘤细胞不仅可以通过剥夺效应T细胞的营养来避免被杀死，还可以通过给免疫抑制的调节性T细胞供给乳酸来抗衡效应T细胞的杀伤作用。总之，乳酸作为一种糖酵解代谢物，在维持免疫抑制性肿瘤微环境中起着重要作用。
另外，在传统的肿瘤治疗过程中，如经典的化疗、放疗，往往是通过诱导肿瘤细胞凋亡来实现癌症治疗。而细胞凋亡通常被认为是非免疫原性的，因此凋亡介导的肿瘤治疗的体内免疫激活效果极为有限。细胞焦亡是一种程序性细胞坏死，是由Caspase激活且依赖于Gasdermins蛋白家族成员形成细胞质膜膜孔的可调控的炎症性细胞死亡。近来的研究表明细胞焦亡不仅可以有效杀死肿瘤细胞，而且其引发的强烈炎症反应可以高效诱导机体产生抗肿瘤免疫活性。但是目前常见的焦亡诱导剂如小分子化疗药物、活性蛋白等都面临着血液循环清除快和大剂量药物引起的全身不良反应等问题。其次，单一焦亡诱导的抗肿瘤免疫激活依然极大受限于免疫抑制的肿瘤微环境，免疫治疗效果有待进一步提升。
发明内容
有鉴于此，本发明的目的在于提供一种弱碱性钠盐纳米药物、其制备方法及其应用，该弱碱性钠盐纳米药物不仅可以和肿瘤微环境中乳酸进行酸碱中和，消耗乳酸，解除免疫抑制；还可以在肿瘤细胞内降解释放大量离子，诱导细胞焦亡，激活免疫响应。
本发明提供了一种弱碱性钠盐纳米药物，由油酸钠和碳酸氢铵微乳液法制得。
在本发明中，所述弱碱性钠盐纳米药物的粒径为10～200nm。
本发明提供了一种上述技术方案所述弱碱性钠盐纳米药物的制备方法，包括以下步骤：
将碳酸氢铵和油酸钠有机溶液混合，微乳液法反应，得到弱碱性纳盐纳米药物。
在本发明中，所述油酸钠有机溶液中的有机溶剂选自正己烷、无水乙醇和油胺的混合物。
在本发明中，所述混合物中正己烷、无水乙醇和油胺的体积比为(9～10):(2.5～3.5):1。
在本发明中，所述碳酸氢铵直接与油酸钠有机溶液混合；
或分散在水中后和油酸钠有机溶液混合，碳酸氢铵分散在水中后的浓度为10～200mg/mL。具体实施例中，碳酸氢铵分散在水中后的浓度为100mg/mL，或200mg/mL，或10mg/mL。
在本发明中，所述油酸钠有机溶液中油酸钠的浓度为0.5～2.5mg/mL。具体实施例中，所述油酸钠有机溶液中油酸钠的浓度为20mg/14mL，或0.5mg/mL，或35mg/14mL。
在本发明中，所述微乳液法反应的时间为3～60min；微乳液法反应的温度为20～40℃。具体实施例中，微乳液法反应的温度为室温，反应的时间为3min、10min、30min或60min。
在本发明中，在200～1000rpm的搅拌条件下，将碳酸氢铵和油酸钠有机溶液混合。若碳酸氢铵采用水溶液的方式加入，则优选将碳酸氢铵水溶液逐滴加入油酸钠有机溶液中。
本发明提供了一种肿瘤治疗药物，包括上述技术方案所述弱碱性钠盐纳米药物或上述技术方案所述制备方法制备的弱碱性钠盐纳米药物。
本发明提供了一种弱碱性钠盐纳米药物，由油酸钠和碳酸氢铵微乳液法制得。由油酸钠和碳酸氢铵微乳液法制得的弱碱性钠盐纳米药物，即NaHCO3，不仅可以和肿瘤微环境中乳酸进行酸碱中和，消耗乳酸，解除免疫抑制肿瘤微环境；同时可以在肿瘤细胞内降解释放大量离子，诱导细胞焦亡，激活免疫响应；从而通过两方面协同作用，激活全身抗肿瘤免疫反应，以对抗肿瘤复发和转移，提高肿瘤的治疗效果。本发明提供的弱碱性钠盐纳米药物的制备方法简单，反应条件温和，原料成本低廉，具有很大的应用前景。
附图说明
图1为本发明实施例1得到的弱碱性钠盐纳米药物的透射电镜照片；
图2为本发明实施例1得到的弱碱性钠盐纳米药物的X射线衍射图谱；
图3为本发明实施例9得到的弱碱性钠盐纳米药物的透射电镜照片；
图4为本发明实施例1得到的弱碱性钠盐纳米药物的pH值检测结果；
图5为本发明实施例1得到的弱碱性钠盐纳米药物对小鼠乳腺癌细胞(4T1)处理后的细胞形貌照片；
图6为本发明实施例1得到的弱碱性钠盐纳米药物对4T1细胞处理后的细胞毒性数据；
图7为本发明实施例8得到的弱碱性钠盐纳米药物的透射电镜照片。
具体实施方式
为了进一步说明本发明，下面结合实施例对本发明提供的一种弱碱性钠盐纳米药物、其制备方法及其应用进行详细地描述，但不能将它们理解为对本发明保护范围的限定。
实施例1
将20毫克油酸钠分散于含10毫升正己烷、3毫升乙醇和1毫升油胺的混合溶液中，同时将20毫克碳酸氢铵分散于200微升去离子水中。在室温下，搅拌速率为1000rpm的条件下，将200微升碳酸氢铵水溶液逐滴加入油酸钠混合溶液中，室温继续反应10分钟。离心收集沉淀，得到弱碱性钠盐纳米药物。
采用透射电子显微镜对弱碱性钠盐纳米药物进行形貌表征，结果如图1所示，可以看出微乳液法制得的弱碱性钠盐纳米药物为尺寸均一的球形颗粒。同时采用X射线衍射对弱碱性钠盐纳米药物进行结构表征，结果如图2所示，证明其具有NaHCO3纯相结构。
实施例2
将20毫克油酸钠分散于含10毫升正己烷、3毫升乙醇和1毫升油胺的混合溶液中，同时将20毫克碳酸氢铵分散于100微升去离子水中。在室温下，搅拌速率为1000rpm的条件下，将100微升碳酸氢铵水溶液逐滴加入油酸钠混合溶液中，室温继续反应10分钟。离心收集沉淀，得到弱碱性钠盐纳米药物。
实施例3
将20毫克油酸钠分散于含10毫升正己烷、3毫升乙醇和1毫升油胺的混合溶液中，同时将10毫克碳酸氢铵分散于1毫升去离子水中。在室温下，搅拌速率为1000rpm的条件下，将1毫升碳酸氢铵水溶液逐滴加入油酸钠混合溶液中，室温继续反应10分钟。离心收集沉淀，得到弱碱性钠盐纳米药物。
实施例4
将20毫克油酸钠分散于含10毫升正己烷、3毫升乙醇和1毫升油胺的混合溶液中，同时将20毫克碳酸氢铵分散于200微升去离子水中。在室温下，搅拌速率为1000rpm的条件下，将200微升碳酸氢铵水溶液逐滴加入油酸钠混合溶液中，室温继续反应3分钟。离心收集沉淀，得到弱碱性钠盐纳米药物。
实施例5
将20毫克油酸钠分散于含10毫升正己烷、3毫升乙醇和1毫升油胺的混合溶液中，同时将20毫克碳酸氢铵分散于200微升去离子水中。在室温下，搅拌速率为200rpm的条件下，将200微升碳酸氢铵水溶液逐滴加入油酸钠混合溶液中，室温继续反应60分钟。离心收集沉淀，得到弱碱性钠盐纳米药物。
实施例6
将7毫克油酸钠分散于含10毫升正己烷、3毫升乙醇和1毫升油胺的混合溶液中，同时将20毫克碳酸氢铵分散于200微升去离子水中。在室温下，搅拌速率为700rpm的条件下，将200微升碳酸氢铵水溶液逐滴加入油酸钠混合溶液中，室温继续反应10分钟。离心收集沉淀，得到弱碱性钠盐纳米药物。
实施例7
将35毫克油酸钠分散于含10毫升正己烷、3毫升乙醇和1毫升油胺的混合溶液中，同时将20毫克碳酸氢铵分散于200微升去离子水中。在室温下，搅拌速率为1000rpm的条件下，将200微升碳酸氢铵水溶液逐滴加入油酸钠混合溶液中，室温继续反应10分钟。离心收集沉淀，得到弱碱性钠盐纳米药物。
实施例8
将20毫克油酸钠分散于含10毫升正己烷、3毫升乙醇和1毫升油胺的混合溶液中。在室温下，搅拌速率为1000rpm的条件下，将20毫克碳酸氢铵加入油酸钠混合溶液中，室温继续反应10分钟。离心收集沉淀，得到弱碱性钠盐纳米药物。
实施例9
将20毫克油酸钠分散于含10毫升正己烷、3毫升乙醇和1毫升油胺的混合溶液中，同时将30毫克碳酸氢铵分散于300微升去离子水中。在室温下，搅拌速率为1000rpm的条件下，将300微升碳酸氢铵水溶液逐滴加入油酸钠混合溶液中，室温继续反应30分钟。离心收集沉淀，得到弱碱性钠盐纳米药物。
本发明对实施例1得到的弱碱性钠盐纳米药物进行pH值检测。检测结果如图4所示，证明合成的钠盐纳米药物呈现弱碱性。
本发明对实施例1得到的弱碱性钠盐纳米药物进行体外细胞焦亡检测实验，测试方法如下：4T1细胞以每孔10万个细胞的密度接种于12孔板，在RMPI培养基中培养12小时后，加入250微克每毫升的碳酸氢钠纳米药物孵育18小时，利用倒置荧光显微镜拍摄细胞形貌。检测结果如图5所示，弱碱性钠盐纳米药物处理的细胞出现明显的细胞鼓泡，证明了细胞焦亡的发生。
本发明对实施例1得到的弱碱性钠盐纳米药物进行体外细胞毒性分析的测试，测试方法如下：采用MTT法测定细胞毒性，4T1细胞以每孔5000个细胞的密度接种于96孔板，在RMPI培养基中培养12小时后，加入不同浓度的碳酸氢钠纳米药物(浓度范围为0-400μg·mL-1)共孵育24小时，利用MTT检测法检测细胞增殖。测试结果如图6所示，图6为实施例1得到的碳酸氢钠纳米药物对4T1细胞的抑制结果图。由图6可以看出，药物浓度低于100μg·mL-1时对小鼠癌细胞无明显毒性，药物浓度达到200μg·mL-1时4T1细胞存活率仅为40％左右，药物浓度增大到400μg·mL-1时4T1细胞存活率仅为不到10％，可以得出碳酸氢钠纳米药物能够对4T1细胞实现一定的抑制作用，并且具有剂量依赖性。
由以上实施例可知，本发明提供了一种弱碱性钠盐纳米药物，由油酸钠和碳酸氢铵微乳液法制得。由油酸钠和碳酸氢铵微乳液法制得的弱碱性钠盐纳米药物，即NaHCO3，不仅可以和肿瘤微环境中乳酸进行酸碱中和，消耗乳酸，解除免疫抑制肿瘤微环境；同时可以在肿瘤细胞内降解释放大量离子，诱导细胞焦亡，激活免疫响应；从而通过两方面协同作用，激活全身抗肿瘤免疫反应，以提高肿瘤的治疗效果。本发明提供的弱碱性钠盐纳米药物的制备方法简单，反应条件温和，原料成本低廉，具有很大的应用前景。
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。
Claims (10)
1.一种弱碱性钠盐纳米药物，由油酸钠和碳酸氢铵微乳液法制得。
2.根据权利要求1所述的弱碱性钠盐纳米药物，其特征在于，所述弱碱性钠盐纳米药物的粒径为10～200nm。
3.一种权利要求1所述弱碱性钠盐纳米药物的制备方法，包括以下步骤：
将碳酸氢铵和油酸钠有机溶液混合，微乳液法反应，得到弱碱性纳盐纳米药物。
4.根据权利要求3所述的制备方法，其特征在于，所述油酸钠有机溶液中的有机溶剂选自正己烷、无水乙醇和油胺的混合物。
5.根据权利要求4所述的制备方法，其特征在于，所述混合物中正己烷、无水乙醇和油胺的体积比为(9～10):(2.5～3.5):1。
6.根据权利要求3所述的制备方法，其特征在于，所述碳酸氢铵直接与油酸钠有机溶液混合；
或分散在水中后和油酸钠有机溶液混合，碳酸氢铵分散在水中后的浓度为10～200mg/mL。
7.根据权利要求3所述的制备方法，其特征在于，所述油酸钠有机溶液中油酸钠的浓度为0.5～2.5mg/mL。
8.根据权利要求3所述的制备方法，其特征在于，所述微乳液法反应的时间为3～60min；微乳液法反应的温度为20-40℃。
9.根据权利要求3所述的制备方法，其特征在于，在200～1000rpm的搅拌条件下，将碳酸氢铵和油酸钠有机溶液混合。
10.一种肿瘤治疗药物，其特征在于，包括权利要求1～2任一项所述弱碱性钠盐纳米药物或权利要求3～9任一项所述制备方法制备的弱碱性钠盐纳米药物。
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