CN115317624A - 一种主动靶向骨肿瘤的液态金属-金属有机框架纳米载药材料及其制备方法和应用 - Google Patents
一种主动靶向骨肿瘤的液态金属-金属有机框架纳米载药材料及其制备方法和应用 Download PDFInfo
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Abstract
本发明涉及一种主动靶向骨肿瘤的液态金属‑金属有机框架纳米载药材料及其制备方法和应用,属于载药材料制备技术领域。本发明将抗肿瘤药物吸附在液态金属‑金属有机框架纳米载体内(LMSZ),表面再修饰透明质酸(hyaluronic acid,HA)和阿仑膦酸钠(alendronate,ALN)形成的复合物(HA/ALN),即可形成具有骨和肿瘤双靶向作用、光热治疗联合化疗的金属有机框架纳米载药递送系统(LMSZ@HA/ALN)。该载药材料可以将药物主动靶向骨转移病灶处的肿瘤细胞,可以实现肿瘤酸性环境下更快释放药物,联合化疗和光热治疗发挥良好的抗肿瘤效果;同时骨靶向配体阿仑膦酸钠具有抑制破骨细胞活性的作用,进而抑制骨吸收。
Description
技术领域
本发明属于载药材料制备技术领域,涉及一种主动靶向骨肿瘤的液态金属-金属有机框架纳米载药材料及其制备方法和应用。
背景技术
目前,临床针对原发或转移性骨肿瘤尚无满意的治疗策略。在临床各种治疗方式中,化疗仍然被认为是治疗晚期及发生转移癌症的主要方法,但目前临床使用的大部分化疗药物选择性低,对机体正常组织或细胞产生毒副作用,且大部分化疗药物为疏水性药物,血浆清除快,限制了其在临床上的应用。因此,将药物有效靶向递送至骨组织病灶尤其是骨组织病灶处的肿瘤细胞是解决问题的关键。纳米递送系统为解决上述问题提供了思路。近年来,已研发出多种结构和性能优良的载体材料,包括各种高分子聚合物、脂质体等有机材料,介孔二氧化硅、磁性纳米颗粒、碳纳米管等无机材料。这些无机和有机纳米材料均有其独特的优势,但也各有缺点。例如脂质体和聚合物的生物相容性较好,但载药率通常较低;无机金、铁纳米颗粒具有载药率低及不易表面修饰等缺点。因此,迫切需要寻找一种高载药量、易修饰的纳米载药递送系统治疗骨肿瘤。
金属有机框架材料(Metal organic frame materials,MOFs)由于具有丰富的纳米孔结构、孔径可调、载药量高和环境敏感等特性,在药物递送方面展现出广阔的应用前景和经济价值(Peng S,Liu J,Qin Y,Wang H,Cao B,Lu L,Yu X.Metal-organic frameworkencapsulating hemoglobin as a high-stable and long-circulating oxygencarriers to treat hemorrhagic shock.ACS Appl Mater Interfaces,2019,11(39):35604-35612)。纳米载药递送系统可较大提升化疗药物在肿瘤治疗方面的作用,但癌症的高复发率、化疗药物不敏感及化疗导致的多药耐药等难题严重阻碍了肿瘤的治疗进程(Gottesman MM,Lavi O,Hall MD,Gillet JP.Toward a better understanding of thecomplexity of cancer drug resistance.Annu Rev Pharmacol Toxicol,2016,56:85-102),因此,亟需开发新型安全的肿瘤诊疗手段联合化疗治疗骨肿瘤。
光热治疗(Photothermal therpy,PTT)较传统的癌症治疗方法来说是一种新型肿瘤治疗手段,具有无侵入性、独特选择性的优势。化疗与光热治疗联合治疗肿瘤较大的提升了治疗疗效。为了适应肿瘤治疗的需要,研究者开发了各种类型的光热治疗的纳米材料。但常用的光热转换材料各有优缺点,例如,碳基纳米材料在体内难以降解,且在制备的过程中可能产生潜在的毒性;贵金属纳米颗粒虽有优异的光热转换效率,但价格较为昂贵。因此,寻找一种制备简单、价格低廉、优异光热性能的材料治疗肿瘤具有重要意义。
近年来,液态金属由于价格低廉、具有良好的导电性、优异的导热性和低毒性特性,吸引了大量科研人员的关注。液态金属可以通过搅拌或超声的方式制备成液态金属小颗粒,静脉注射后通过近红外的激光辐照可以明显抑制小鼠肿瘤的生长(Hu JJ,Liu MD,Chen Y,Gao F,Peng SY,Xie BR,Li CX,Zeng X,Zhang XZ.Immobilized liquid metalnanoparticles with improved stability and photothermal performance forcombinational therapy of tumor[J].Biomaterials,2019,207:76-88)。但对于骨肿瘤来说,由于骨组织环境的复杂性,裸的液态金属纳米颗粒难以累积在骨组织病灶甚至骨组织病灶处的肿瘤细胞。
因此,利用ZIF-8优异的装载性能,如何将化疗药物与液态金属纳米颗粒共包载入MOF载体中联合光热治疗和化疗有效治疗骨肿瘤,具有重要意义。
发明内容
有鉴于此,本发明的目的之一在于提供一种主动靶向骨肿瘤的液态金属-金属有机框架纳米载药材料;本发明的目的之二在于提供一种主动靶向骨肿瘤的液态金属-金属有机框架纳米载药材料的制备方法;本发明的目的之三在于提供一种主动靶向骨肿瘤的液态金属-金属有机框架纳米载药材料在原发性骨肿瘤及转移性骨转移治疗方面的应用。
为达到上述目的,本发明提供如下技术方案:
1.一种主动靶向骨肿瘤的液态金属-金属有机框架纳米载药材料,所述纳米载药材料包括包载二氧化硅修饰的液态金属纳米粒的金属有机框架纳米载体、吸附在所述纳米载体上的药物以及表面修饰的由透明质酸(hyaluronic acid,HA)和阿仑膦酸钠(alendronate,ALN)形成的复合物(HA/ALN)。
优选的,所述载体包括羧基化二氧化硅修饰的液态金属纳米粒和其表面形成的金属有机框架沸石咪唑酯骨架材料。
进一步优选的,所述羧基化二氧化硅修饰的液态金属纳米粒按照如下方法制备:
(1)将液态金属滴入无水乙醇中,冰浴条件下进行超声处理形成混悬液,所得混悬液即为液态金属纳米粒的乙醇溶液;
(2)将所述液态金属纳米粒的乙醇溶液用三蒸水稀释,调节反应体系为碱性,超声条件下,滴加正硅酸乙酯,超声完成后滴加提供羧基的化合物,继续超声处理,完成后离心收集,洗涤后真空干燥得到羧基化二氧化硅修饰的液态金属纳米粒(LMS)。
优选的,步骤(1)中所述液态金属为镓基合金,所述液态金属和无水乙醇的体积比为1:100~400;
步骤(2)中所述三蒸水的体积与步骤(1)中的无水乙醇的体积相等,所述调节反应体系为碱性具体为:向三蒸水稀释的液态金属纳米粒的乙醇溶液中添加0.5倍体积的氨水,所述氨水的重量百分比浓度为7%,所述液态金属与正硅酸乙酯的体积比为1:0.5~6,所述提供羧基的化合物与正硅酸乙酯的的体积比为1~2:10,所述提供羧基的化合物为二氢-3-[3-(三乙氧基硅基)丙基]呋喃-2,5-二酮、硅烷三醇丙酸钠或丁二酸酐中的任意一种;
所述超声处理为在400W的功率下超声处理0.5~2h。
进一步优选的,在所述羧基化二氧化硅修饰的液态金属纳米粒表面形成金属有机框架沸石咪唑酯骨架材料(zeolitic imidazolate framework-8,ZIF-8)的方法具体为:将分散于甲醇中的羧基化二氧化硅修饰的液态金属纳米粒(LMS)与分散于甲醇中的六水合硝酸锌混合,搅拌下加入2-甲基咪唑甲醇溶液,在0~50℃下搅拌5~20min后离心收集,分别用甲醇和三蒸水反复洗涤即可得到纳米载体(LMSZ)。
优选的,所述羧基化二氧化硅修饰的液态金属纳米粒(LMS)、六水合硝酸锌与2-甲基咪唑的质量比为1:1:1.65~10。
优选的,所述药物为抗肿瘤药物,所述抗肿瘤药物包括姜黄素、阿霉素、顺铂或紫杉醇中的任意一种;
所述复合物(HA/ALN)中透明质酸(hyaluronic acid,HA)和阿仑膦酸钠(alendronate,ALN)的制备方法为:将N-(3-二甲氨基丙基)-N-乙基碳二亚胺盐酸盐和N-羟基琥珀酰亚胺加入至透明质酸(hyaluronic acid,HA)水溶液中搅拌1~12h,然后加入阿仑膦酸钠(alendronate,ALN)搅拌反应,通过透析纯化并冷冻干燥得到复合物(HA/ALN);
所述透明质酸(HA)和阿仑膦酸钠(ALN)的质量比为5:1~2,所述N-(3-二甲氨基丙基)-N-乙基碳二亚胺盐酸盐、N-羟基琥珀酰亚胺和透明质酸(HA)的质量比为57:34:50~200。
2.上述纳米载药材料的制备方法,所述制备方法包括如下步骤:
(1)将药物溶解在水或有机溶剂中,加入包载羧基化二氧化硅修饰的液态金属纳米粒的金属有机框架纳米载体,搅拌使其混合均匀,离心得到负载药物的纳米颗粒;
(2)将所述负载药物的纳米颗粒分散到三蒸水中,与复合物(HA/ALN)混合搅拌,离心后用三蒸水反复洗涤得到主动靶向骨肿瘤的液态金属-金属有机框架纳米载药材料。
优选的,所述有机溶剂为乙醇或甲醇;
所述药物与纳米载体的质量比为1~4:20;
所述负载药物的纳米颗粒与复合物(HA/ALN)的质量比为2:1~4。
3.上述纳米载药材料在原发性骨肿瘤及转移性骨转移治疗中的应用。
本发明的有益效果在于:本发明公开了一种主动靶向骨肿瘤的液态金属-金属有机框架纳米载药材料,将抗肿瘤药物吸附在上述靶向骨肿瘤的液态金属-金属有机框架纳米载体(主要是将羧基化二氧化硅修饰的液态金属纳米粒作为载体内核、将金属有机框架沸石咪唑酯骨架材料生长在内核表面,由于羧基化二氧化硅修饰的液态金属纳米粒具有光热性能,金属有机框架沸石咪唑酯骨架材料具有高载药率和pH敏感释药性能,因此本发明公开的液态金属-金属有机框架纳米载体具有高载药率、pH敏感释药和光热性能)上,表面再修饰透明质酸(hyaluronic acid,HA)和阿仑膦酸钠(alendronate,ALN)形成的复合物(HA/ALN),该纳米载药材料同时结合了液态金属纳米颗粒具有的光热性能、药物对原发性或者转移性骨肿瘤的治疗效果以及复合物(HA/ALN)具有的骨和肿瘤双靶向性能,具有的按需释放药物的特性可以降低药物对病灶周围正常组织的毒副作用,因此将该纳米载药材料应用于骨肿瘤疾病治疗可以显著抑制骨肿瘤的生长,且同时可以抑制破骨细胞的活性,进而抑制骨吸收。
本发明的其他优点、目标和特征在某种程度上将在随后的说明书中进行阐述,并且在某种程度上,基于对下文的考察研究对本领域技术人员而言将是显而易见的,或者可以从本发明的实践中得到教导。本发明的目标和其他优点可以通过下面的说明书来实现和获得。
附图说明
为了使本发明的目的、技术方案和优点更加清楚,下面将结合附图对本发明作优选的详细描述,其中:
图1为本发明制备靶向骨肿瘤的液态金属-金属有机框架纳米载药材料(CLMSZ@HA/ALN)的流程图;
图2为实施例1中制备的靶向骨肿瘤的液态金属-金属有机框架纳米载药材料(CLMSZ@HA/ALN)结构图;
图3为实施例1中制备的靶向骨肿瘤的液态金属-金属有机框架纳米载药材料(LMSZ)SEM图;
图4为实施例1中靶向骨肿瘤的液态金属-金属有机框架纳米载药材料(LMSZ@HA/ALN)制备过程中的Zeta电位图;
图5为实施例1中靶向骨肿瘤的液态金属-金属有机框架纳米载药材料(CLMSZ@HA/ALN)的细胞摄取实验;
其中1为液态金属,2为正硅酸乙酯,3为二氢-3-[3-(三乙氧基硅基)丙基]呋喃-2,5-二酮,4为羧基化二氧化硅修饰的液态金属纳米粒(LMS),5为六水合硝酸锌,6为2-甲基咪唑,7为包载二氧化硅修饰的液态金属纳米粒的金属有机框架纳米载体,8为药物,9为载药液态金属金属有机框架纳米复合物(CLMSZ),10为复合物(HA/ALN),11为主动靶向骨肿瘤的液态金属-金属有机框架纳米载药材料(CLMSZ@HA/ALN)。
具体实施方式
以下通过特定的具体实例说明本发明的实施方式,本领域技术人员可由本说明书所揭露的内容轻易地了解本发明的其他优点与功效。本发明还可以通过另外不同的具体实施方式加以实施或应用,本说明书中的各项细节也可以基于不同观点与应用,在没有背离本发明的精神下进行各种修饰或改变。需要说明的是,以下实施例中所提供的图示仅以示意方式说明本发明的基本构想,在不冲突的情况下,以下实施例及实施例中的特征可以相互组合。
实施例1
一种靶向骨肿瘤的液态金属-金属有机框架纳米载药材料,具体的制备方法包括如下步骤:
1、制备包载二氧化硅修饰的液态金属纳米粒的金属有机框架纳米载体(LMSZ):
(1)制备羧基化二氧化硅修饰的液态金属纳米粒(LMS):
a、称取74.5g镓和25.5g铟,置于玻璃烧杯中,加热至200℃,玻璃棒搅拌直至完全混合,得到镓铟合金;
b、将100μL镓铟合金滴入10mL无水乙醇中,冰浴条件下将混合物在400W下超声处理2h形成混悬液,即为所需要的液态金属纳米粒(LM NPs)的乙醇溶液;
c、将液态金属纳米粒(LM NPs)的乙醇溶液用等量三蒸水稀释,加入10mL重量浓度百分比为7%的氨水,超声条件下,滴加500μL正硅酸乙酯溶液,在400W下超声2h,滴加100μL二氢-3-[3-(三乙氧基硅基)丙基]呋喃-2,5-二酮,继续超声1h,离心收集,无水乙醇和三蒸水分别洗涤三次得到羧基化二氧化硅修饰的液态金属纳米粒(LMS)。
(2)制备靶向骨肿瘤的液态金属-金属有机框架纳米载体(LMSZ):将100mg羧基化二氧化硅修饰的液态金属纳米粒(LM@SiO2-COOH,LMS)分散在10mL甲醇中,加入2mL六水合硝酸锌甲醇溶液(含有100mg六水合硝酸锌)混合,搅拌30min后加入2mL 2-甲基咪唑甲醇溶液(含有245mg 2-甲基咪唑),在25℃下继续搅拌20min,离心收集,甲醇和三蒸水分别洗涤三次得到包载二氧化硅修饰的液态金属纳米粒的金属有机框架纳米载体(LMSZ)。
2、制备主动靶向骨肿瘤的液态金属-金属有机框架纳米载药材料
(1)将2mg姜黄素溶于乙醇中,加入10mg的包载二氧化硅修饰的液态金属纳米粒的金属有机框架纳米载体(LMSZ),在室温下搅拌24h,离心收集后用乙醇和三蒸水分别洗涤三次得到负载药物的纳米颗粒(CLMSZ);
(2)将100mg透明质酸(hyaluronic acid,HA)溶于20mL三蒸水中,溶解后加入34mg的N-羟基琥珀酰亚胺和57mg的N-(3-二甲氨基丙基)-N’-乙基碳二亚胺盐酸盐,搅拌混合1h,加入30mg阿仑膦酸钠(alendronate,ALN),继续搅拌24h后用透析袋(8000MWCO)透析三天,每隔一天更换一次水,得到复合物(HA/ALN),冷冻干燥保存;
(3)称取10mg复合物(HA/ALN)溶于三蒸水中,滴入15mg步骤(1)中制备的负载药物的纳米颗粒(CLMSZ),搅拌24h,离心收集,三蒸水洗涤两次得到靶向骨肿瘤的液态金属-金属有机框架纳米载药材料(CLMSZ@HA/ALN)。
实施例2
一种靶向骨肿瘤的液态金属-金属有机框架纳米载药材料,具体的制备方法包括如下步骤:
1、制备包载二氧化硅修饰的液态金属纳米粒的金属有机框架纳米载体(LMSZ):
(1)制备羧基化二氧化硅修饰的液态金属纳米粒(LMS):
a、称取100g镓置于玻璃烧杯中,加热至200℃,玻璃棒搅拌直至完全混合;
b、将100μL镓滴入10mL无水乙醇中,冰浴条件下将混合物在400W下超声处理0.5h,混悬液即为所需要的液态金属纳米粒(LM NPs)的乙醇溶液;
c、将液态金属纳米粒(LM NPs)的乙醇溶液用等量的三蒸水稀释,加入10mL 7%的氨水,超声条件下,滴加10μL 3-氨基丙基三甲氧基硅烷和500μL正硅酸乙酯溶液,在400W下超声2h,离心收集后用无水乙醇和三蒸水分别洗涤三次得到氨基化LM@SiO2。
d、将100mg氨基化LM@SiO2分散于50mL N,N-二甲基甲酰胺中,随后磁力搅拌条件下,逐滴加入2mL预先配制的溶解有0.15g丁二酸酐的N,N-二甲基甲酰胺溶液。随后加入300μL三乙醇胺催化反应。混合溶液在室温下搅拌反应12h,离心收集,无水乙醇和三蒸水分别洗涤三次得到羧基化二氧化硅修饰的液态金属纳米粒(LMS)。
(2)制备包载二氧化硅修饰的液态金属纳米粒的金属有机框架纳米载体(LMSZ):将100mg羧基化二氧化硅修饰的液态金属纳米粒(LM@SiO2-COOH,LMS)分散在10mL甲醇中,加入2mL六水合硝酸锌甲醇溶液(含有100mg六水合硝酸锌)混合,搅拌30min后加入2mL 2-甲基咪唑甲醇溶液(含有245mg 2-甲基咪唑),在25℃下继续搅拌10min,离心收集,甲醇和三蒸水分别洗涤三次得到靶向骨肿瘤的液态金属-金属有机框架纳米载体(LMSZ)。
2、制备主动靶向骨肿瘤的液态金属-金属有机框架纳米载药材料
(1)将2mg姜黄素溶于乙醇中,加入8mg的包载二氧化硅修饰的液态金属纳米粒的金属有机框架纳米载体(LMSZ),在室温下搅拌24h,离心收集后用乙醇和三蒸水分别洗涤三次得到负载药物的纳米颗粒(CLMSZ);
(2)将100mg透明质酸(hyaluronic acid,HA)溶于20mL三蒸水中,溶解后加入34mg的N-羟基琥珀酰亚胺和57mg的N-(3-二甲氨基丙基)-N’-乙基碳二亚胺盐酸盐,搅拌混合1h,加入40mg阿仑膦酸钠(alendronate,ALN),继续搅拌24h后用透析袋(8000MWCO)透析三天,每隔一天更换一次水,得到复合物(HA/ALN),冷冻干燥保存;
(3)称取10mg复合物(HA/ALN)溶于三蒸水中,滴入20mg步骤(1)中制备的负载药物的纳米颗粒(CLMSZ),搅拌24h,离心收集,三蒸水洗涤两次得到靶向骨肿瘤的液态金属-金属有机框架纳米载药材料(CLMSZ@HA/ALN)。
实施例3
一种靶向骨肿瘤的液态金属-金属有机框架纳米载药材料,具体的制备方法包括如下步骤:
1、制备包载二氧化硅修饰的液态金属纳米粒的金属有机框架纳米载体(LMSZ):
(1)制备羧基化二氧化硅修饰的液态金属纳米粒(LMS):
a、称取74.5g镓和25.5g铟,置于玻璃烧杯中,加热至200℃,玻璃棒搅拌直至完全混合,得到镓铟合金;
b、将100μL镓铟合金滴入10mL无水乙醇中,冰浴条件下将混合物在400W下超声处理2h,混悬液即为所需要的液态金属纳米粒(LM NPs)的乙醇溶液;
c、将液态金属纳米粒(LM NPs)的乙醇溶液用等量三蒸水稀释,加入10mL 7%的氨水,超声条件下,滴加600μL正硅酸乙酯溶液,在400W下超声2h,完成后滴加100μL硅烷三醇丙酸钠,60℃下,搅拌24h,离心收集,无水乙醇和三蒸水分别洗涤三次得到羧基化二氧化硅修饰的液态金属纳米粒(LMS)。
(2)制备靶向骨肿瘤的液态金属-金属有机框架纳米载体(LMSZ):将100mg羧基化二氧化硅修饰的液态金属纳米粒(LMS,LM@SiO2-COOH)分散在1mL甲醇中,加入2mL六水合硝酸锌甲醇溶液(含有100mg六水合硝酸锌)混合,搅拌30min后加入2mL 2-甲基咪唑甲醇溶液(含有245mg 2-甲基咪唑),在25℃下继续搅拌20min,离心收集,甲醇和三蒸水分别洗涤三次得到包载二氧化硅修饰的液态金属纳米粒的金属有机框架纳米载体(LMSZ)。
2、制备主动靶向骨肿瘤的液态金属-金属有机框架纳米载药材料
(1)将2mg姜黄素溶于乙醇中,加入40mg的包载二氧化硅修饰的液态金属纳米粒的金属有机框架纳米载体(LMSZ),在室温下搅拌24h,离心收集后用乙醇和三蒸水分别洗涤三次得到负载药物的纳米颗粒(CLMSZ);
(2)将100mg透明质酸(hyaluronic acid,HA)溶于20mL三蒸水中,溶解后加入34mg的N-羟基琥珀酰亚胺和57mg的N-(3-二甲氨基丙基)-N’-乙基碳二亚胺盐酸盐,搅拌混合1h,加入20mg阿仑膦酸钠(alendronate,ALN),继续搅拌24h后用透析袋(8000MWCO)透析三天,每隔一天更换一次水,得到复合物(HA/ALN),冷冻干燥保存;
(3)称取10mg复合物(HA/ALN)溶于三蒸水中,滴入10mg步骤(1)中制备的负载药物的纳米颗粒(CLMSZ),搅拌24h,离心收集,三蒸水洗涤两次得到靶向骨肿瘤的液态金属-金属有机框架纳米载药材料(CLMSZ@HA/ALN)。
上述实施例中制备的主动靶向骨肿瘤的液态金属-金属有机框架纳米载药材料(CLMSZ@HA/ALN)的制备过程如图1所示,其中1为液态金属,2为正硅酸乙酯,3为二氢-3-[3-(三乙氧基硅基)丙基]呋喃-2,5-二酮,4为羧基化二氧化硅修饰的液态金属纳米粒(LMS),5为六水合硝酸锌,6为2-甲基咪唑,7为包载二氧化硅修饰的液态金属纳米粒的金属有机框架纳米载体,8为药物,9为载药液态金属金属有机框架纳米复合物(CLMSZ),10为复合物(HA/ALN),11为主动靶向骨肿瘤的液态金属-金属有机框架纳米载药材料(CLMSZ@HA/ALN)。
利用扫描电镜观察上述实施例1中制备的主动靶向骨肿瘤的液态金属-金属有机框架纳米载药材料,其结构如图2所示,SEM图如图3所示。从图3可以看出,包载羧基化二氧化硅修饰的液态金属纳米粒的金属有机框架纳米载体(LMSZ)为类球形,大小较为均一。
利用多角度粒径和高灵敏度Zeta电位分析仪检测制备靶向骨肿瘤的液态金属-金属有机框架纳米载药材料(LMSZ@HA/ALN)过程中的Zeta电位,与LMS相比,当被带正电荷ZIF-8包载后,LMSZ的Zeta电位为正值,说明ZIF-8成功修饰;当使用带负电位的HA/ALN复合物修饰后,LMSZ@HA/ALN电位为负值,说明LMSZ@HA/ALN成功制备,具体如图4所示。
图5为主动靶向骨肿瘤的液态金属-金属有机框架纳米载药材料(CLMSZ@HA/ALN)的细胞摄取实验(DAPI为细胞核染料荧光,Cur为姜黄素荧光,Merged为两种荧光信号的重叠)。通过血液相容性实验可知,靶向骨肿瘤的液态金属-金属有机框架纳米载药材料(CLMSZ@HA/ALN)在较高浓度时的溶血较低,说明生物相容性良好;通过摄取实验可知,靶向骨肿瘤的液态金属-金属有机框架纳米载药材料(CLMSZ@HA/ALN)可被乳腺肿瘤4T1细胞摄取,且随着时间的延长,乳腺肿瘤4T1细胞摄取量进一步增多。
同样的,对实施例2和3中制备的靶向骨肿瘤的液态金属-金属有机框架纳米载药材料(CLMSZ@HA/ALN)进行性能检测,其结果与实施例1中制备的靶向骨肿瘤的液态金属-金属有机框架纳米载药材料(CLMSZ@HA/ALN)性能相同。
综上所述,本发明公开了一种主动靶向骨肿瘤的液态金属-金属有机框架纳米载药材料,将抗肿瘤药物吸附在上述靶向骨肿瘤的液态金属-金属有机框架纳米载体(将羧基化二氧化硅修饰的液态金属纳米粒作为载体内核、将金属有机框架沸石咪唑酯骨架材料生长在内核表面,由于羧基化二氧化硅修饰的液态金属纳米粒具有光热性能,金属有机框架沸石咪唑酯骨架材料具有高载药率和pH敏感释药性能,因此该液态金属-金属有机框架纳米载体具有高载药率、pH敏感释药和光热性能)上,表面再修饰透明质酸(hyaluronicacid,HA)和阿仑膦酸钠(alendronate,ALN)形成的复合物(HA/ALN),该纳米载药材料同时结合了液态金属纳米颗粒具有的光热性能、药物对原发性或者转移性骨肿瘤的治疗效果以及复合物(HA/ALN)具有的骨和肿瘤双靶向性能,具有的按需释放药物的特性可以降低药物对病灶周围正常组织的毒副作用,因此将该纳米载药材料应用于骨肿瘤疾病治疗可以显著抑制骨肿瘤的生长,且同时可以抑制破骨细胞的活性,进而抑制骨吸收。
最后说明的是,以上实施例仅用以说明本发明的技术方案而非限制,尽管参照较佳实施例对本发明进行了详细说明,本领域的普通技术人员应当理解,可以对本发明的技术方案进行修改或者等同替换,而不脱离本技术方案的宗旨和范围,其均应涵盖在本发明的权利要求范围当中。
Claims (10)
1.一种主动靶向骨肿瘤的液态金属-金属有机框架纳米载药材料,其特征在于,所述纳米载药材料包括包载羧基化二氧化硅修饰的液态金属纳米粒的金属有机框架纳米载体、吸附在所述纳米载体上的药物以及表面修饰的由透明质酸和阿仑膦酸钠形成的复合物。
2.根据权利要求1所述的纳米载药材料,其特征在于,所述载体包括羧基化二氧化硅修饰的液态金属纳米粒和其表面形成的金属有机框架沸石咪唑酯骨架材料。
3.根据权利要求2所述的纳米载药材料,其特征在于,所述羧基化二氧化硅修饰的液态金属纳米粒按照如下方法制备:
(1)将液态金属滴入无水乙醇中,冰浴条件下进行超声处理形成混悬液,所得混悬液即为液态金属纳米粒的乙醇溶液;
(2)将所述液态金属纳米粒的乙醇溶液用三蒸水稀释,调节反应体系为碱性,超声条件下,滴加正硅酸乙酯,超声完成后滴加提供羧基的化合物,继续超声处理,完成后离心收集,洗涤后真空干燥得到羧基化二氧化硅修饰的液态金属纳米粒。
4.根据权利要求3所述的纳米载药材料,其特征在于,步骤(1)中所述液态金属为镓基合金,所述液态金属和无水乙醇的体积比为1:100~400;
步骤(2)中所述三蒸水的体积与步骤(1)中的无水乙醇的体积相等,所述调节反应体系为碱性具体为:向三蒸水稀释的液态金属纳米粒的乙醇溶液中添加0.5倍体积的氨水,所述氨水的重量百分比浓度为7%,所述液态金属与正硅酸乙酯的体积比为1:0.5~6,所述提供羧基的化合物与正硅酸乙酯的的体积比为1~2:10,所述提供羧基的化合物为二氢-3-[3-(三乙氧基硅基)丙基]呋喃-2,5-二酮、硅烷三醇丙酸钠或丁二酸酐中的任意一种;
所述超声处理为在400W的功率下超声处理0.5~2h。
5.权利要求2所述的纳米载药材料,其特征在于,在所述羧基化二氧化硅修饰的液态金属纳米粒表面形成金属有机框架沸石咪唑酯骨架材料的方法具体为:将分散于甲醇中的羧基化二氧化硅修饰的液态金属纳米粒与分散于甲醇中的六水合硝酸锌混合,搅拌下加入2-甲基咪唑甲醇溶液,在0~50℃下搅拌5~20min后离心收集,分别用甲醇和三蒸水反复洗涤即可得到纳米载体。
6.根据权利要求5所述的纳米载药材料,其特征在于,所述羧基化二氧化硅修饰的液态金属纳米粒、六水合硝酸锌与2-甲基咪唑的质量比为1:1:1.65~10。
7.根据权利要求1所述的纳米载药材料,其特征在于,所述药物为抗肿瘤药物,所述抗肿瘤药物包括姜黄素、阿霉素、顺铂或紫杉醇中的任意一种;
所述复合物中透明质酸和阿仑膦酸钠的制备方法为:将N-(3-二甲氨基丙基)-N-乙基碳二亚胺盐酸盐和N-羟基琥珀酰亚胺加入至透明质酸水溶液中搅拌1~12h,然后加入阿仑膦酸钠搅拌反应,通过透析纯化并冷冻干燥得到复合物;
所述透明质酸和阿仑膦酸钠的质量比为5:1~2,所述N-(3-二甲氨基丙基)-N-乙基碳二亚胺盐酸盐、N-羟基琥珀酰亚胺和透明质酸的质量比为57:34:50~200。
8.权利要求1~7任一项所述纳米载药材料的制备方法,其特征在于,所述制备方法包括如下步骤:
(1)将药物溶解在水或有机溶剂中,加入包载羧基化二氧化硅修饰的液态金属纳米粒的金属有机框架纳米载体,搅拌使其混合均匀,离心得到负载药物的纳米颗粒;
(2)将所述负载药物的纳米颗粒分散到三蒸水中,与复合物混合搅拌,离心后用三蒸水反复洗涤得到主动靶向骨肿瘤的液态金属-金属有机框架纳米载药材料。
9.根据权利要求8所述的制备方法,其特征在于,所述有机溶剂为乙醇或甲醇;
所述药物与纳米载体的质量比为1~4:20;
所述负载药物的纳米颗粒与复合物的质量比为2:1~4。
10.权利要求1~7任一项所述的纳米载药材料在原发性骨肿瘤及转移性骨转移治疗中的应用。
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