CN114053227A - 一种表面镶有金属化合物颗粒的多功能纳米粒及其制备方法和抗肿瘤中的应用 - Google Patents
一种表面镶有金属化合物颗粒的多功能纳米粒及其制备方法和抗肿瘤中的应用 Download PDFInfo
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Abstract
本发明属于生物医药领域,公开了一种表面镶有金属化合物颗粒的多功能纳米粒及其制备方法和抗肿瘤中的应用。具体公开了使用一种操作简便的工艺技术使嵌段共聚物载体上负载疏水性功能物质,得到表面镶有金属Mn化合物颗粒的嵌段共聚物纳米粒,并将该多功能纳米粒应用于声动力治疗和化疗抗肿瘤。本发明可有效解决现阶段抗肿瘤药物生物相容性差,生物利用度低,药物副作用大以及两亲性分子自组装形成纳米粒子时的诸多缺陷。同时,该方法构建的肿瘤靶向递释系统提高了疏水性药物的体内行为和肿瘤靶向性,起到增强的抗肿瘤效果,具有良好的抗肿瘤治疗应用前景。
Description
技术领域
本发明属于生物医药领域,涉及一种表面镶有金属化合物颗粒的多功能纳米粒及其制备方法和抗肿瘤中的应用。
背景技术
癌症的标准化治疗包括手术、化学疗法、放射疗法和免疫疗法,但以手术、化疗、放疗这些方法的治疗常伴有治疗不彻底、易复发、易转移、易引起多种并发症的缺点,往往给患者带来较为严重的毒副作用和极大的痛苦,同时也不利于癌症患者的康复,所以需要寻找更有效、更安全的替代治疗方法。
声动力疗法(sonodynamic treatment,SDT)是一种由光动力学疗法(photodynamic treatment,PDT)发展而来的新兴、无创的治疗方法,由于具有更深的辐射距离且无光毒性特点逐渐替代传统的PDT,且相较于传统的放化疗,SDT具有良好的时间及空间选择性、无创性等优势。SDT主要包括两个步骤,先是将声敏剂递送至肿瘤组织,随后给予超声辐射激发声敏剂,产生声动力治疗。声敏剂在超声辐射时无细胞毒性,仅在超声辐射下才在辐射区域产生具有细胞毒性的活性氧,对周边正常组织损伤小,安全性高。但大部分声敏剂水溶性和靶向性差,在肿瘤部位的富集效果极低,且肿瘤长期处于缺氧微环境中,极大限制了疗效及进一步临床转化。
纳米材料不仅具有靶向性好、载药量高,有效地避免对其他组织的毒性,还可优化肿瘤的靶向治疗,使更多的声敏剂稳定、靶向地递送至肿瘤组织并发挥作用,被广泛用于药物的载体。纳米声动力治疗(nano-SDT)可为声敏剂设计开辟新的途径,可以最大程度地发挥声动力治疗靶向性好、副作用小的优点,改善肿瘤缺氧增强SDT。
肿瘤缺氧是由氧气供应与消耗间的不平衡引起的,其对癌症的生长、转移具有至关重要的影响。由缺氧引起的代谢变化会促进酸中毒(肿瘤中的酸性pH)和增加的活性氧(ROS)产生速率,从而导致更异常的肿瘤微环境,微环境的多因素性质仍然是治疗实体瘤以及复发和转移性癌症的主要挑战。目前技术已经研究了几种方法来专门针对肿瘤部位个体微环境因子以改善治疗效果,特别是与放射疗法(RT)结合使用时,但是由于安全性问题和反应不一致,许多先前的方法尚未取得临床成功。
通过文献查阅表明,肿瘤微环境内还原型GSH浓度约是正常细胞的7倍-10倍,肿瘤细胞通过上调还原型谷胱甘肽(GSH)适应了所处氧化应激状态。因此,若通过一种新的抗肿瘤药物递释平台与肿瘤微环境的相互作用,改善肿瘤乏氧特质的同时又能耗竭微环境中还原型GSH,降低ROS的消耗,使得ROS蓄积增多,进而扫除ROS发挥作用的障碍,对于增强肿瘤SDT治疗具有重要价值。
声动力-化学联合治疗的方法(SDT-CT)被认为是一种强有力的肿瘤治疗策略。一方面,SDT能够很好地抑制肿瘤生长但非完全消除肿瘤,因此可作为一种临床治疗癌症方法与其它治疗方法联合使用;另一方面,尽管化学治疗在癌症治疗方面取得了长足进步,但是囿于化疗制剂的组织和细胞靶向性不足,对正常组织有毒性从而用药剂量受限,导致化疗药物对肿瘤杀伤性不足。抗肿瘤化学药物的有效递送需达到:离开体循环、克服组织-肿瘤屏障、渗透到细胞质中、摆脱溶酶体的包裹和降解,而SDT及超声的使用被证明可以有效地克服以上障碍。在研究中发现,将SDT和CT联合应用(比如联合阿霉素、博来霉素、5-氟尿嘧啶等抗肿瘤化学药物)以实现对癌症的协同治疗方案,作为一种新的肿瘤治疗策略,显示出巨大潜力。以上研究结果提示我们,nano-SDT-CT是一条颇具前景和价值的抗肿瘤治疗研究方向。
但目前nano-SDT-CT的实施方案依赖于SDT和CT的分别进行,又或只是递送声敏剂和化学治疗药物载体系统的简单拼接,操作繁琐、时空同步性不佳;有些递送系统制备步骤繁多、结构复杂、稳定性差,从而加大了实施难度。
近年来,二氧化锰纳米材料由于其多样的结构、肿瘤微环境响应的降解途径以及催化特性在肿瘤诊断一体化应用中不断被报道,有改善乏氧、肿瘤微环境成像和强大的载药特性等方面的优势,正在成为肿瘤递药系统研究的热点材料之一。
基于上述诸多论述,我们拟开发一种制备方法简单、结构简洁且具有肿瘤靶向性的多功能的集成化纳米制剂系统,实现声敏性物质的肿瘤组织蓄积和响应(超声激发ROS生成能力)、抗肿瘤药物的负载以及肿瘤靶向递送和释放,在超声条件下达到增强的声动力-化学治疗协同效应。同时该纳米制剂系统中镶嵌的MnO2一方面与肿瘤微环境中H2O2相互作用产生O2进而改善肿瘤乏氧特质,另一方面与高水平还原型GSH发生氧化还原反应,耗竭GSH,使ROS含量增多,大大的提高了nano-SDT-CT开发中的实操性,有效推进nano-SDT-CT在抗肿瘤治疗中的应用。
发明内容
为克服目前肿瘤治疗存在的缺陷,本发明构建了一种简便快速的制备方法,来构建多功能的集成化纳米制剂系统,并将该纳米制剂系统首次应用于抗肿瘤领域。将美国FDA批准上市的生物相容性良好的聚乳酸-羟基乙酸(PLGA)作为载体,制备得到负载有声敏剂HMME和化疗药物DTX且表面镶有金属化合物MnO2颗粒的多功能纳米粒,在改善肿瘤乏氧环境达到抑制肿瘤生长的同时,也将声动力治疗与化疗抗肿瘤相结合,协同发挥杀伤肿瘤的功效。
此外,该纳米平台的构建不仅改善了HMME和DTX疏水性功能物质水溶性差的问题,也提高了疏水性功能物质被动靶向肿瘤的能力。
一种表面镶有金属化合物颗粒的多功能纳米粒,在嵌段共聚物载体上负载疏水性功能物质,负载后表面还镶有金属Mn化合物颗粒的多功能纳米粒;
所述嵌段共聚物载体包含天然两亲性化合物中的藻类、磷脂、胆固醇、阿拉伯胶、动物胶,或者合成两亲性化合物中的PVP、PEG、海藻酸、海藻酸钠、明胶或聚乳酸类;
所述疏水性功能物质包括血卟啉单甲醚、光卟啉、脱镁叶绿酸a、原卟啉IX、顺铂、环磷酰胺、阿霉素、丝裂霉素、氮介、甲氨蝶呤、氟尿嘧啶、长春新碱、紫杉醇、喜数碱、多西他赛、姜黄素、吲哚菁绿、吖啶橙、竹红菌素B、竹红菌素或金丝桃素中的一种或几种。
一种表面镶有金属化合物颗粒的多功能纳米粒的制备方法,包括以下步骤:
(1)将嵌段共聚物载体,与疏水性功能物质溶解在有机溶剂中,持续搅拌1-4h,即得到嵌段共聚物载体和疏水性功能物质的混合溶液,作为有机相;
(2)将KMnO4与聚乙烯醇PVA溶于超纯水中,得到的混合物质水溶液作为水相;
(3)将步骤(1)和(2)中的有机相和水相分别置于FNP装置中的两个独立腔室中,同时快速按压,使得水相和有机相同时进入混合腔室,相互混合反应,混合腔下接口处即会射出成功负载有疏水性功能物质的纳米粒混悬液;
(4)将2-(N-吗啡啉)乙磺酸MES和十二烷基硫酸钠SDS溶于超纯水中,得到MES-SDS混合水溶液;
将MES-SDS混合水溶液与步骤(3)中所得的纳米粒混悬液在避光状态下进行30-50min氧化还原反应,透析后,离心,去上清,沉淀用超纯水重悬,得到重悬液,即为表面镶有金属化合物颗粒的负载疏水性功能物质的多功能纳米粒。
步骤(1)中,嵌段共聚物载体,包括天然两亲性化合物中的藻类、磷脂、胆固醇、阿拉伯胶、动物胶;或者合成两亲性化合物中的PVP、PEG、海藻酸、海藻酸钠、明胶、聚乳酸类。
步骤(1)中,疏水性功能物质,包括血卟啉单甲醚、光卟啉、脱镁叶绿酸a、原卟啉IX、顺铂、环磷酰胺、阿霉素、丝裂霉素、氮介、甲氨蝶呤、氟尿嘧啶、长春新碱、紫杉醇、喜数碱、多西他赛、姜黄素、吲哚菁绿、吖啶橙、竹红菌素B、竹红菌素或金丝桃素中的一种或几种;
有机相中用到的有机溶剂能够与水完全互溶,是乙腈、四氢呋喃、乙醇、N-N-二甲基甲酰胺、二甲基亚砜或N-甲基吡咯烷酮中的一种。
步骤(1)的有机相中,嵌段共聚物载体的浓度为5-10mg/mL,疏水性功能物质的浓度为20-200μg/mL。
步骤(2)的水相中,KMnO4的浓度为3-6mM,PVA的质量浓度为2%-4%。
步骤(3)中,水相和有机相的体积比为1:1;按压速度为0.6-1.2mL/s;透析时间为12-16h,离心速率为12000-30000rpm。
步骤(4)中,MES-SDS混合水溶液中,MES的浓度为0.1-0.5M,SDS的浓度为1-5mg/mL;MES-SDS混合水溶液与纳米粒混悬液的体积比为5:1。
将本发明所述的一种表面镶有金属Mn化合物颗粒的多功能纳米粒用在制备抗肿瘤制剂中的应用。
所述的抗肿瘤制剂包括抗脑胶质瘤、淋巴癌、黑色素瘤、肾癌、皮肤癌、肺癌、颈癌、骨癌、前列腺癌、结肠癌、子宫颈癌、乳癌、脑癌、肝癌、胰腺癌、喉癌、甲状腺癌、膀胱癌、舌癌或食道癌的制剂。
本发明的有益效果为:
首次将制备得到的多功能纳米制剂系统应用于抗肿瘤治疗,制备工艺技术简单,操作简便,生产成本低,毒副作用小,对肿瘤细胞的增殖具有很好的抑制效果,对肿瘤细胞杀伤力很强,有良好的应用价值和社会效益。
附图说明
图1为多功能纳米粒荧光光谱;
图2为多功能纳米粒TEM形貌图;
图3 MCF-7细胞对多功能纳米粒的摄取;
图4不同超声功率对MCF-7细胞存活率的影响;
图5使用MTT法测定评估与各制剂组共孵育下MCF-7细胞存活率;
图6激光共聚焦显微镜检测的细胞内ROS产量;
图7各实验组别肿瘤和邻近组织的H&E染色切片。
具体实施方式
下面结合附图和具体实施例对本发明的技术方案做进一步详细说明。
实施例1:多功能纳米粒的制备
本发明中多功能纳米粒的制备,是使用一种新工艺负载声敏剂HMME和化疗药物DTX,并利用氧化还原反应使得PLGA纳米粒表面镶有二氧化锰颗粒,构建一体化的纳米系统。其制备方法是,使用具有两个腔室的FNP装置,水相为高锰酸钾(KMnO4)和聚乙烯醇(PVA)混合水溶液,高锰酸钾为3-6mM,聚乙烯醇质量浓度为2%-4%。有机相为乙腈溶解的疏水性声敏剂HMME和化疗药物DTX,制备装置下方混合流腔室处的容器中装有2-(N-吗啡啉)乙磺酸和十二烷基硫酸钠(SDS)水溶液。准备工作完成后,按照水相和有机相体积1:1的比例同时按压水相和有机相腔室的注射器,混合腔室中射出的流体与FNP下接口处容器中水系反应环境发生氧化还原反应,避光反应40min后,装进透析袋中,在超纯水中透析16h,再离心除去上清,取1mL超纯水重新分散得到的纳米粒沉淀,即得到负载有HMME和DTX功能性物质,且PLGA载体表面镶有二氧化锰颗粒的PLGA-HMME-DTX@MnO2多功能纳米粒。
所述方法制备的表面镶有金属化合物颗粒的多功能纳米粒为球形形貌,粒径约为200nm左右,电位大约为-38mV,分散系数PDI在0.2左右。
所述方法制备的表面镶有金属化合物颗粒的多功能纳米粒在抗肿瘤声动力药物中的应用。
所述方法制备的表面镶有有金属化合物颗粒的多功能纳米粒声动力治疗与化疗协同引起ROS的产生,在增强杀伤恶性肿瘤细胞中的应用。
所述方法制备的表面镶有金属化合物颗粒的多功能纳米粒表面的二氧化锰可结合肿瘤微环境特性,催化肿瘤细胞内过氧化氢产生氧气用于改善肿瘤乏氧环境,同时二氧化锰可与肿瘤微环境中高浓度GSH反应,有利于肿瘤微环境中ROS的蓄积,达到进一步辅助抗肿瘤药物功效的应用。
本发明所述的一种表面镶有金属化合物颗粒的多功能纳米粒的制备方法及其在肿瘤领域的应用,其制备工艺简便,制备时间极短,粒径可控,包封率高,十分适合可控制备功能性的纳米粒,且制备出的纳米粒具有作用时间长、疗效好、毒副作用低、靶向性好等优点。
本发明所述的一种表面镶有金属化合物颗粒的多功能纳米粒的制备方法及其在肿瘤领域的应用,将该法制备出来的多功能纳米粒首次应用于抗肿瘤治疗,在超声照射下能有效地产生活性氧或其他活性物质,利用所产生的活性氧或其他活性物质有效地杀伤肿瘤细胞,有助于声动力和化疗结合,达到协同增强抗肿瘤治疗。
实施例2:多功能纳米粒基本性质的测定
(1)多功能纳米粒的荧光光谱
取制备的多功能纳米粒溶液,稀释,采用日本岛津公司的荧光分光光度计检测多功能纳米粒荧光光谱,选择395nm作为荧光激发波长,发射波长的扫描范围为400nm-800nm。得出的扫描结果如图1,表明多功能纳米粒在620nm和650nm处左右有荧光发射,可以证明HMME成功的被包入到了纳米粒中。
(2)多功能纳米粒的TEM表征
取100μL重悬后的多功能纳米粒,加超纯水到1mL,摇匀,滴一滴于铜网上,晾干后再滴加一滴,滴加三次后用透射电子显微镜观察纳米粒形貌。图2的TEM图表征显示,本发明方法制备出多功能纳米粒呈球形,且球形纳米粒周边成功的镶有金属化合物颗粒。
实施例3:MCF-7细胞对多功能纳米粒的摄取情况
取处于对数生长期的MCF-7细胞,经胰蛋白酶消化后,按每个约5×104个细胞的密度接种至铺有盖玻片的35mm单个细胞培养皿中,每个1mL,继续培养24h。待细胞贴壁后吸去培养液,加入1mL用DMEM高糖培养基稀释的多功能纳米粒,放入细胞培养箱,继续培养0.5、1、2、3和4h后,用溶酶体绿色荧光探针,即LysoGreen(1μmol/L)染细胞质30min,PBS洗涤三遍后采用10μg/mL的Hoechst 33342染核15min,PBS洗涤三遍后采用4%多聚甲醛固定30min,PBS轻缓洗涤三次以除去多余的多聚甲醛。取出盖玻片,50%甘油封片,最后采用荧光显微镜进行观察。
图3结果显示,在最初0.5h时少量多功能纳米粒摄取进入细胞,HMME对应的0.5h处红色荧光较弱,随着摄取时间的增加,红色荧光逐渐增加。在2h时能看到多功能纳米粒大部分已经进入细胞,MCF-7细胞继续摄取,3h-4h时HMME的红色荧光亮度更强,说明多功能纳米粒已完全进入细胞。该摄取结果表明,声动力治疗可在细胞摄取3h-4h时开始进行。
实施例4:不同超声功率对MCF-7细胞存活率的影响
取处于对数生长期的MCF-7细胞,经胰蛋白酶消化后,按每孔板约5×104个细胞的密度接种至铺有盖玻片的35mm单个细胞培养皿中,每个1mL,继续培养24h。待细胞贴壁后吸去培养基,更换上清液为无血清培养基,利用超声治疗仪对每孔分别进行0W/cm2、0.75W/cm2、1W/cm2、1.25W/cm2、1.5W/cm2、1.75W/cm2、2W/cm2超声处理,超声的深度为4cm。超声处理后,每孔添加1mL 1mg/mL的MTT溶液,培养箱中培养4h后,弃去培养基,每孔分别加入1.5mLDMSO溶液,振荡10min,转移至96孔细胞培养板后利用酶标仪测定OD490,按照上述公式计算细胞存活率,每个设置5个复孔。
图4实验结果表明,随着超声功率的增强,细胞的存活率出现降低趋势,当超声功率为2W/cm2时,细胞存活率仅为85%左右。但结合不同超声功率下,MCF-7细胞产生ROS能力的强弱,选择1.75W/cm2作为最优超声功率进行超声治疗。
实施例5:不同药物制剂对MCF-7细胞存活率的影响。
采用MTT法测定不同药物制剂对MCF-7细胞存活率的影响,结果如图5所示。取处于对数生长期的MCF-7细胞,经胰蛋白酶消化后,按每孔约5×104个细胞的密度接种至96孔板中,每孔100μL,继续培养24h。待细胞贴壁后吸去培养液,将96孔板细胞分成空白对照组(PBS)、单纯超声组(US)、血卟啉单甲醚组(HMME)、血卟啉单甲醚+超声组(HMME+US)、血卟啉单甲醚纳米粒组(PH NPs)、血卟啉单甲醚纳米粒+超声组(PH NPs+US)、多功能纳米粒子组(PHD@MnO2 NPs)、多功能纳米粒子+超声组(PHD@MnO2 NPs+US),分别加入相应的药物制剂,继续培养24h后将原培养液吸出,用无菌PBS洗3遍。避光加入100μL 1mg/mL的MTT溶液,置于培养箱继续培养4小时,去除MTT溶液,每孔加入150μL DMSO溶液,振荡10min,酶标仪测定OD490,按照下述公式计算细胞存活率。每个浓度设置5个复孔。
细胞存活率(%)=(实验组OD/对照组OD)×100%
图5实验结果显示,在所有药物制剂组别中,多功能纳米粒+超声治疗组对MCF-7细胞的抑制率达到最高,细胞杀伤率达到了50%左右,同时可以看出,当无超声作用时,多功能纳米粒对细胞的暗毒性小,有利于后续细胞的声动力治疗。
实施例6:多功能纳米粒产生ROS的能力
以MCF-7为模型,利用DCFH-DA检测空白对照组(PBS)、单纯超声组(US)、血卟啉单甲醚组(HMME)、血卟啉单甲醚+超声组(HMME+US)、血卟啉单甲醚纳米粒组(PH NPs)、血卟啉单甲醚纳米粒+超声组(PH NPs+US)、多功能()纳米粒子组(PHD@MnO2NPs)、多功能纳米粒子+超声组(PHD@MnO2 NPs+US)产生ROS的能力。具体步骤操作如下:取处于对数生长期的MCF-7细胞,经胰蛋白酶消化后,按每个约5×104个细胞的密度接种至铺有盖玻片的35mm单个细胞培养皿中,每个1mL,继续培养24h。待细胞贴壁后,除空白对照组和单纯超声组外,分别给各组加入1mL相应的药物制剂,继续培养4h后,将细胞培养液换成10μM的DCFH-DA溶液并在37℃孵育30min,无菌PBS洗涤三遍后采用无血清培养基对对应组给予声动力治疗,接着采用10μg/mL的Hoechst 33342染色15min,PBS洗涤三遍后采用4%多聚甲醛固定30min,PBS轻缓洗涤三次后取出盖玻片,50%甘油封片,最后采用激光共聚焦显微镜进行观察。
图6结果表明,当细胞处于空白对照情况下(PBS),无DCFH-DA绿色荧光出现。单纯超声细胞(US)产生了微弱的绿色荧光,说明单纯超声也能够使细胞内产生微量的活性氧。结合实验结果中荧光强度的变化,可以看出当超声联合多功能纳米粒作用时,即多功能纳米粒子+超声组(PHD@MnO2 NPs+US)绿色荧光明显增强,表明该组别产生了大量的ROS。
实施例表明多功能纳米粒可以安全有效的作为药物递送平台达到化疗协同超声,并结合肿瘤微环境特性,抑制肿瘤细胞的增殖。
实施例7:多功能纳米粒体内抗肿瘤研究
首先构建荷S180肉瘤小鼠模型,待小鼠肉瘤体积达到100mm3时,将小鼠分为4组,每组5只,分别为对照组(PBS)、单纯超声组(US)、血卟啉单甲醚+超声组(HMME+US)、血卟啉单甲醚纳米粒+超声组(PH NPs+US)、血卟啉单甲醚-多西他赛纳米粒组(PHD NPs)、血卟啉单甲醚-多西他赛纳米粒组+超声组(PHD NPs+US)、多功能纳米粒子组(PHD@MnO2 NPs)、多功能纳米粒子+超声组(PHD@MnO2 NPs+US),游离药物血卟啉单甲醚(HMME)按3mg/kg给药,各纳米粒组按照游离药物载药量百分比进行制备,将各组药物制剂分别进行尾静脉注射,4h后进行180s的超声处理,隔天重复上述操作,共进行12天治疗,同时监测各组小鼠体重的变化,根据瘤体积计算公式:肿瘤体积=短径2×长径/2计算瘤体积,探究体内多功能纳米粒联合SDT的抗肿瘤研究。
由于超声具有较强的组织穿透能力,能够很好地杀伤肿瘤细胞。通过图7的HE组织染色可以看出,对照组(PBS)与单纯超声组(US)均无抑瘤作用,各组药物制剂在无超声作用下毒性较小,抑制肿瘤效果不明显,但各药物制剂联合应用超声时可以观察到明显的肿瘤组织杀伤性,说明多功能纳米粒作为一种抗肿瘤药物递送平台在超声的激发下产生更多的ROS起到抗肿瘤的作用。
Claims (10)
1.一种表面镶有金属化合物颗粒的多功能纳米粒,其特征在于:在嵌段共聚物载体上负载疏水性功能物质,负载后表面还镶有金属Mn化合物颗粒的多功能纳米粒;
所述嵌段共聚物载体包含天然两亲性化合物中的藻类、磷脂、胆固醇、阿拉伯胶、动物胶,或者合成两亲性化合物中的PVP、PEG、海藻酸、海藻酸钠、明胶或聚乳酸类;
所述疏水性功能物质包括血卟啉单甲醚、光卟啉、脱镁叶绿酸a、原卟啉IX、顺铂、环磷酰胺、阿霉素、丝裂霉素、氮介、甲氨蝶呤、氟尿嘧啶、长春新碱、紫杉醇、喜数碱、多西他赛、姜黄素、吲哚菁绿、吖啶橙、竹红菌素B、竹红菌素或金丝桃素中的一种或几种。
2.根据权利要求1所述的一种表面镶有金属化合物颗粒的多功能纳米粒的制备方法,其特征在于,包括以下步骤:
(1)将嵌段共聚物载体,与疏水性功能物质溶解在有机溶剂中,持续搅拌1-4h,即得到嵌段共聚物载体和疏水性功能物质的混合溶液,作为有机相;
(2)将KMnO4与聚乙烯醇PVA溶于超纯水中,得到的混合物质水溶液作为水相;
(3)将步骤(1)和(2)中的有机相和水相分别置于FNP装置中的两个独立腔室中,同时快速按压,使得水相和有机相同时进入混合腔室,相互混合反应,混合腔下接口处即会射出成功负载有疏水性功能物质的纳米粒混悬液;
(4)将2-(N-吗啡啉)乙磺酸MES和十二烷基硫酸钠SDS溶于超纯水中,得到MES-SDS混合水溶液;
将MES-SDS混合水溶液与步骤(3)中所得的纳米粒混悬液在避光状态下进行30-50min氧化还原反应,透析后,离心,去上清,沉淀用超纯水重悬,得到重悬液,即为表面镶有金属化合物颗粒的负载疏水性功能物质的多功能纳米粒。
3.根据权利要求2所述的制备方法,其特征在于:步骤(1)中,嵌段共聚物载体,包括天然两亲性化合物中的藻类、磷脂、胆固醇、阿拉伯胶、动物胶;或者合成两亲性化合物中的PVP、PEG、海藻酸、海藻酸钠、明胶、聚乳酸类。
4.根据权利要求2所述的制备方法,其特征在于:步骤(1)中,疏水性功能物质,包括血卟啉单甲醚、光卟啉、脱镁叶绿酸a、原卟啉IX、顺铂、环磷酰胺、阿霉素、丝裂霉素、氮介、甲氨蝶呤、氟尿嘧啶、长春新碱、紫杉醇、喜数碱、多西他赛、姜黄素、吲哚菁绿、吖啶橙、竹红菌素B、竹红菌素或金丝桃素中的一种或几种;
有机相中用到的有机溶剂能够与水完全互溶,是乙腈、四氢呋喃、乙醇、N-N-二甲基甲酰胺、二甲基亚砜或N-甲基吡咯烷酮中的一种。
5.根据权利要求2所述的制备方法,其特征在于:步骤(1)的有机相中,嵌段共聚物载体的浓度为5-10mg/mL,疏水性功能物质的浓度为20-200μg/mL。
6.根据权利要求2所述的制备方法,其特征在于:步骤(2)的水相中,KMnO4的浓度为3-6mM,PVA的质量浓度为2%-4%。
7.根据权利要求2所述的制备方法,其特征在于:步骤(3)中,水相和有机相的体积比为1:1;按压速度为0.6-1.2mL/s;透析时间为12-16h,离心速率为12000-30000rpm。
8.根据权利要求2所述的制备方法,其特征在于:步骤(4)中,MES-SDS混合水溶液中,MES的浓度为0.1-0.5M,SDS的浓度为1-5mg/mL;MES-SDS混合水溶液与纳米粒混悬液的体积比为5:1。
9.将权利要求1所述的一种表面镶有金属Mn化合物颗粒的多功能纳米粒用在制备抗肿瘤制剂中的应用。
10.如权利要求9所述的应用,其特征在于,所述的抗肿瘤制剂包括抗脑胶质瘤、淋巴癌、黑色素瘤、肾癌、皮肤癌、肺癌、颈癌、骨癌、前列腺癌、结肠癌、子宫颈癌、乳癌、脑癌、肝癌、胰腺癌、喉癌、甲状腺癌、膀胱癌、舌癌或食道癌的制剂。
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