CN106581674A - 一种多功能纳米载药系统及其制备方法 - Google Patents
一种多功能纳米载药系统及其制备方法 Download PDFInfo
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- CN106581674A CN106581674A CN201610980576.8A CN201610980576A CN106581674A CN 106581674 A CN106581674 A CN 106581674A CN 201610980576 A CN201610980576 A CN 201610980576A CN 106581674 A CN106581674 A CN 106581674A
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- drug
- dopamine
- hyaluronic acid
- poly
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- KIUKXJAPPMFGSW-DNGZLQJQSA-N (2S,3S,4S,5R,6R)-6-[(2S,3R,4R,5S,6R)-3-Acetamido-2-[(2S,3S,4R,5R,6R)-6-[(2R,3R,4R,5S,6R)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2-carboxylic acid Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 KIUKXJAPPMFGSW-DNGZLQJQSA-N 0.000 claims abstract description 27
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Classifications
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- A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
- A61K41/0052—Thermotherapy; Hyperthermia; Magnetic induction; Induction heating therapy
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- A—HUMAN NECESSITIES
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
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- A—HUMAN NECESSITIES
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- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
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- A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
- A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
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- A61K49/22—Echographic preparations; Ultrasound imaging preparations ; Optoacoustic imaging preparations
- A61K49/221—Echographic preparations; Ultrasound imaging preparations ; Optoacoustic imaging preparations characterised by the targeting agent or modifying agent linked to the acoustically-active agent
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- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/51—Nanocapsules; Nanoparticles
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- A61K9/5115—Inorganic compounds
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- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/51—Nanocapsules; Nanoparticles
- A61K9/5107—Excipients; Inactive ingredients
- A61K9/513—Organic macromolecular compounds; Dendrimers
- A61K9/5146—Organic macromolecular compounds; Dendrimers obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyamines, polyanhydrides
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/51—Nanocapsules; Nanoparticles
- A61K9/5107—Excipients; Inactive ingredients
- A61K9/513—Organic macromolecular compounds; Dendrimers
- A61K9/5161—Polysaccharides, e.g. alginate, chitosan, cellulose derivatives; Cyclodextrin
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Epidemiology (AREA)
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- Nanotechnology (AREA)
- Biomedical Technology (AREA)
- Optics & Photonics (AREA)
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Abstract
本发明提供一种多功能纳米载药系统,所述多功能纳米载药系统为透明质酸修饰的载药复合纳米材料,透明质酸吸附在负载药物的复合纳米材料表面,复合纳米材料的结构为氨基化介孔二氧化硅、聚多巴胺包覆还原氧化石墨烯、氨基化介孔二氧化硅复合的三明治结构。本发明还提供所述功能纳米载药系统的制备方法。本发明提供的多功能纳米载药系统,在还原氧化石墨烯外包覆聚多巴胺,提高生物相容性的同时可以提高药物载体的光热吸收性能。通过再修饰介孔硅层可以提高此类材料的光热性能和光声成像性能,以及提高药物负载量,同时硅基材料有利于多功能化修饰,使该基于石墨烯的药物载体可以与透明质酸静电组装,实现靶向成像和治疗以及负载药物的多种功能。
Description
技术领域
本发明属于生物医药材料领域,具体涉及一种以纳米石墨烯材料修饰的载药系统及其制备的方法。
背景技术
光热治疗是通过联合运用近红外光吸收剂和对于人体组织穿透力较强的近红外光使局部组织温度升高,从而使得细胞变性、坏死,达到治疗目的的一种绿色治疗方法。热能可以对细胞产生不同的影响,低剂量热处理有助于损伤的恢复,高剂量热处理可导致细胞死亡,而中等、温和、非致死性剂量的热处理则可使肿瘤细胞对放疗和许多药物变得敏感。光热治疗得以成功实现的关键是选择性能优异的近红外光吸收材料。光吸收材料不仅要求对近红外光有高强吸收,并且需要将吸收的光能转化成热量释放出来的。此外,这些材料必须具备良好的生物相容性,拥有适当的尺寸,可通过主动靶向在肿瘤部位富集。
联合化学-光热治疗被视为癌症治疗的新策略。在化疗的同时给予热疗,能在一定程度上增强化疗药的效果。加热后拓扑异构酶I类抑制剂(喜树碱),拓扑异构酶II类抑制刺,铂类(顺铂),蒽环类药物(阿霉素),紫杉醇等抗肿瘤药物的细胞毒性增强。以及,肿瘤部位的局部温度升高后血液循环加速,肿瘤组织对药物的摄取量大大增加。此外,加热后细胞膜的稳定性被破坏,细胞膜呈现出高通透性,提高药物的摄入量。而且,加热后某些蛋白质变性,基于P-糖蛋白的肿瘤细胞多药耐药性在一定程度上被克服。
为了确保化疗药物和光热试剂能够被同时传输到肿瘤部位发挥多重协同功能,开发安全高效的传输系统颇受青睐。然而联合化学-光热治疗仍然存在许多未解决问题,包括光热治疗试剂的选择、纳米载体的构建、纳米载体的尺寸问题,以及靶向、生物相容性和生物毒性问题。联合化学-光热治疗并不仅仅是单纯的功能集成,还应该避免功能原件增加导致部分效果牺牲的现象,理想状态是通过巧妙的设计使得各部分元件相互协同放大。因此,构建具有良好生物相容性与生物可降解性的载体系统,是光热治疗发展应用的关键。
发明内容
本发明所要解决的技术问题在于克服现有技术的缺陷,提供一种多功能纳米载药系统。
本发明的另一目的是提出所述多功能纳米载药系统的制备方法。
实现本发明上述目的的技术方案为:
一种多功能纳米载药系统,所述多功能纳米载药系统为透明质酸修饰的载药复合纳米材料,透明质酸吸附在负载药物的复合纳米材料表面,所述复合纳米材料的结构为氨基化介孔二氧化硅、聚多巴胺包覆还原氧化石墨烯、氨基化介孔二氧化硅复合的三明治结构;
其中,氨基化介孔二氧化硅层的厚度为2~50nm,聚多巴胺层的厚度为1~30nm,负载的药物为阿霉素、盐酸表阿霉素、紫杉醇、长春新碱、羟基喜树碱中的一种或多种,所述透明质酸的重均分子量为2000~20000Da。
还原氧化石墨烯相比于氧化石墨烯体系,降低了毒性,但仍保持其光热性能。聚多巴胺包覆修饰,提高了系统的光热性能。
优选地,被包覆的所述还原氧化石墨烯的尺寸为20~100nm,所述介孔二氧化硅层的厚度为5~20nm,聚多巴胺层的厚度为5~20nm,所述透明质酸的重均分子量为500~10000Da。
所述的多功能纳米载药系统的制备方法,包括步骤:
S1:将氧化石墨烯分散在pH值为8.0-9.0的缓冲溶液中,再加入多巴胺盐酸盐,50~90℃反应4~48小时,得聚多巴胺包覆还原氧化石墨烯;
S2:将所述聚多巴胺包覆还原氧化石墨烯分散在水溶液中,加入表面活性剂,调节pH值为10~12,加入正硅酸乙酯和3-氨丙基三乙氧基硅烷,反应12~36h,离心洗涤,获得聚多巴胺包覆还原氧化石墨烯的药物载体;
S3:将所述石墨烯药物载体加入到药物溶液中,加入透明质酸,搅拌,离心,获得多功能纳米载药系统。
进一步地,步骤S1中,所述氧化石墨烯的尺寸为20~300nm,所述pH值为8.0-9.0的缓冲溶液为tris缓冲溶液,加入多巴胺盐酸盐后在敞开的环境下反应,即保证反应体系在有氧环境下进行。
其中,步骤S1中再加入多巴胺盐酸盐后,60~70℃反应12~24小时。
其中,步骤S2中,所述聚多巴胺包覆还原氧化石墨烯分散在水溶液中的浓度为0.05~1mg/mL。
其中,步骤S2中,所述表面活性剂为阳离子表面活性剂,选自十六烷基三甲基溴化铵或十六烷基三甲基氯化铵,所述表面活性剂的浓度为0.002~0.2mol/L。
其中,步骤S2中,所述正硅酸乙酯和3-氨丙基三乙氧基硅烷的质量比为1~50:1。所述3-氨丙基三乙氧基硅烷与聚多巴胺包覆还原氧化石墨烯的质量比为0.1~1;所述离心洗涤用乙醇和/或甲醇洗涤去除表面活性剂模板。
当所述药物为亲水药物时,步骤S3中,药物载体加入到药物溶液中,再加透明质酸溶液,所述的药物的浓度为1~5mg/mL,所述透明质酸和石墨烯药物载体的质量比为0.1~5:1。
当所述药物为疏水药物时,步骤S3中,药物载体加入到药物溶液中,搅拌,离心,再分散到水溶液中,滴加透明质酸溶液;所述的药物的浓度为1~5mg/mL。
透明质酸与表面的氨基静电作用,形成复合物。所述透明质酸可以为透明质酸钠或者透明质酸,所述透明质酸和石墨烯药物载体的质量比为0.1~5:1。
本发明的有益效果在于:
本发明提供的多功能纳米载药系统,在还原氧化石墨烯外包覆聚多巴胺,提高生物相容性的同时可以提高药物载体的光热吸收性能。通过聚多巴胺包覆还原氧化石墨烯外部再修饰介孔硅层可以提高此类材料的光热性能和光声成像性能,以及提高药物负载量,同时硅基材料有利于多功能化修饰,使该基于石墨烯的药物载体可以与透明质酸静电组装,实现靶向成像和治疗以及负载药物的多种功能。
进一步,该多功能纳米载药系统修饰透明质酸具有防止孔内药物提前释放的功能。
本发明的基于石墨烯的药物载体制备方法简单,反应条件温和,成本低。
附图说明
图1是本发明实施例1多功能纳米载药系统与不同对照的细胞存活率图;
图2是本发明实施例1多功能纳米载药系统与相同浓度的阿霉素药物的细胞存活率对照;
图3是本发明实施例1多功能纳米载药系统与不同对照的裸鼠治疗后肿瘤生长曲线;
图4是本发明实施例1多功能纳米载药系统与不同对照的裸鼠治疗中的体重变化曲线。
具体实施方式
以下通过具体实施例来举例说明多功能纳米载药系统以及其性能等方面。下面实施例中的材料为根据现有方法直接制备而得,或直接从市场上购得。
实施例中使用的透明质酸为山东福瑞达公司产品。氧化石墨烯购自南京先丰纳米材料有限公司。
实验例1
在制备多功能纳米载药系统的试验之前,先摸索试验了负载系统的制备和优化。
将10mL氧化石墨烯(2mg/mL)和10mg多巴胺盐酸盐混合,加入0.1mL 1M的tris缓冲溶液,60℃反应24小时,得聚多巴胺包覆还原氧化石墨烯。通过原子力显微镜观察到聚多巴胺层的厚度小于10nm。0.8mL 0.2mol/L的十六烷基三甲基溴化铵溶液,再加入0.18mL的NaOH(0.1mol/L),加入0.06mL正硅酸乙酯和0.06mL 3-氨丙基三乙氧基硅烷,反应24h,离心洗涤,获得聚多巴胺包覆还原氧化石墨烯的药物载体。
实施例1:
将10mL氧化石墨烯(2mg/mL)和10mg多巴胺盐酸盐混合,加入0.1mL 1M的tris缓冲溶液,60℃反应24小时,得聚多巴胺包覆还原氧化石墨烯;
将所述聚多巴胺包覆还原氧化石墨烯分散在10mL水溶液中,浓度为0.2mg/mL,0.8mL 0.2mol/L的十六烷基三甲基溴化铵溶液,再加入0.18mL的NaOH(0.1mol/L),加入0.06mL正硅酸乙酯,反应24h,乙醇和水离心洗涤,获得所述基于石墨烯的药物载体。
将1mg基于石墨烯的药物载体加入到2mg/mL的盐酸阿霉素水溶液中,搅拌,加入4mg透明质酸,搅拌离心,用水洗涤,获得多功能纳米载药系统。
实施例2:
将10mL氧化石墨烯(1mg/mL)和10mg多巴胺盐酸盐混合,加入0.1mL 1M的tris缓冲溶液,90℃反应12小时,得聚多巴胺包覆还原氧化石墨烯;
将所述聚多巴胺包覆还原氧化石墨烯分散在10mL水溶液中,浓度为0.2mg/mL,0.8mL 0.2mol/L的十六烷基三甲基溴化铵溶液,再加入0.18mL的NaOH(0.1mol/L),加入0.1mL正硅酸乙酯,反应24h,离心洗涤,获得所述基于石墨烯的药物载体。
将2mg基于石墨烯的药物载体加入到2mg/mL的紫杉醇的有机溶液中,搅拌,离心,沉淀再分散到水溶液中,加入4mg透明质酸,搅拌离心,用水洗涤,获得所述多功能纳米载药系统。
试验例2
将实施例1制得的多功能纳米载药系统物用PBS进行稀释,以阿霉素总质量计,配制成不同浓度的药液,图1中DOX浓度为5μmol/L。同时,将阿霉素配成不同浓度的药液作为对照。培养宫颈癌细胞Hela,温度为37℃,将处于对数生长期的Hela细胞分别按1000个/孔的密度接种于96孔培养板,12小时后,分别加入不同种类的药液以及多功能纳米载药系统,每种浓度平行6孔。不同种类的药液分别是:空白blank,磷酸盐缓冲液PBS,附着了透明质酸的氨基化介孔二氧化硅-聚多巴胺包覆还原氧化石墨烯-氨基化介孔二氧化硅复合的三明治结构(pRGO@MS-HA)(有光照和无光照);阿霉素(DOX),实施例1制得的多功能纳米载药系统pRGO@MS(DOX)-HA(有光照和无光照)。对加有pRGO@MS-HA和pRGO@MS(DOX)-HA的孔进行近红外照射NIR,即加入药液后培养12h,用808nm的激光(1.5W/cm2)照射5分钟,再继续培养12h。
分别采用含有10重量%胎牛血清的DMEM培养基,每孔加100μL,培养24h,使用CCk-8试剂盒对细胞活性进行测定。具体操作完全按照试剂盒的说明进行。
图1为不同材料和不同治疗方式的细胞存活率,所述多功能纳米载药系统将化疗和光热治疗结合,具有非常好的肿瘤细胞抑制作用。
图2为相同阿霉素浓度下,有机药物和多功能纳米载药系统的肿瘤抑制效果,说明药物负载到多功能纳米载药系统中没有影响其药效。图3为不同治疗方式下的肿瘤生长曲线,可以看出多功能纳米载药系统的光热治疗联合化疗,具有很好的肿瘤抑制效果。
不同种类的药液:空白saline,附着了透明质酸的氨基化介孔二氧化硅-聚多巴胺包覆还原氧化石墨烯-氨基化介孔二氧化硅复合的三明治结构pRGO@MS-HA(有光照和无光照);阿霉素DOX,实施例1制得的多功能纳米载药系统pRGO@MS(DOX)-HA(有光照和无光照)。用不同种类的药液注射到小鼠体内,图4是注射一次后,观察20日的裸鼠的体重曲线,可以看出,本发明的多功能纳米载药系统毒性较低,基本没有影响裸鼠的生长。
以上的实施例仅仅是对本发明的优选实施方式进行描述,并非对本发明的范围进行限定,在不脱离本发明设计精神的前提下,本领域普通工程技术人员对本发明的技术方案作出的各种变型和改进,均应落入本发明的权利要求书确定的保护范围内。
Claims (10)
1.一种多功能纳米载药系统,其特征在于,所述多功能纳米载药系统为透明质酸修饰的载药复合纳米材料,透明质酸吸附在负载药物的复合纳米材料表面,所述复合纳米材料的结构为氨基化介孔二氧化硅、聚多巴胺包覆还原氧化石墨烯、氨基化介孔二氧化硅复合的三明治结构;
其中,氨基化介孔二氧化硅层的厚度为2~50nm,聚多巴胺层的厚度为1~30nm,负载的药物为阿霉素、盐酸表阿霉素、紫杉醇、长春新碱、羟基喜树碱中的一种或多种,所述透明质酸的重均分子量为2000~20000Da。
2.根据权利要求1所述的多功能纳米载药系统,其特征在于,被包覆的所述还原氧化石墨烯的尺寸为20~300nm,所述介孔二氧化硅层的厚度为3~20nm,聚多巴胺层的厚度为5~20nm,所述透明质酸的重均分子量为500~10000Da。
3.权利要求1或2所述的多功能纳米载药系统的制备方法,其特征在于,包括步骤:
将氧化石墨烯分散在pH值为8.0-9.0的缓冲溶液中,再加入多巴胺盐酸盐,50~90℃反应4~48小时,得聚多巴胺包覆还原氧化石墨烯;
将所述聚多巴胺包覆还原氧化石墨烯分散在水溶液中,加入表面活性剂,调节pH值为10~12,加入正硅酸乙酯和3-氨丙基三乙氧基硅烷,反应12~36h,离心洗涤,获得聚多巴胺包覆还原氧化石墨烯的药物载体;
将所述药物载体加入到药物溶液中,加入透明质酸,搅拌,离心,获得多功能纳米载药系统。
4.根据权利要求3所述的制备方法,其特征在于,步骤S1中,所述氧化石墨烯的尺寸为20~300nm,所述pH值为8.0-9.0的缓冲溶液为tris缓冲溶液,加入多巴胺盐酸盐后在敞开的环境下反应。
5.根据权利要求3所述的制备方法,其特征在于,步骤S1中再加入多巴胺盐酸盐后,60~70℃反应12~24小时。
6.根据权利要求3所述的制备方法,其特征在于,步骤S2中,所述聚多巴胺包覆还原氧化石墨烯分散在水溶液中的浓度为0.05~1mg/mL。
7.根据权利要求3所述的制备方法,其特征在于,步骤S2中,所述表面活性剂为阳离子表面活性剂,选自十六烷基三甲基溴化铵或十六烷基三甲基氯化铵,所述表面活性剂的浓度为0.5~3mg/mL。
8.根据权利要求3所述的制备方法,其特征在于,步骤S2中,所述正硅酸乙酯和3-氨丙基三乙氧基硅烷的质量比为1~50:1;所述3-氨丙基三乙氧基硅烷与聚多巴胺包覆还原氧化石墨烯的质量比为0.1~1;所述离心洗涤用乙醇和/或甲醇洗涤去除表面活性剂模板。
9.根据权利要求3所述的制备方法,其特征在于,步骤S3中,所述药物载体加入到药物溶液中,再加透明质酸溶液,所述的药物的浓度为1~5mg/mL,所述透明质酸和石墨烯药物载体的质量比为0.1~5:1。
10.根据权利要求3所述的制备方法,其特征在于,步骤S3中,所述药物载体加入到药物溶液中,搅拌,离心,再分散到水溶液中,滴加透明质酸溶液;所述药物的浓度为1~5mg/mL,所述透明质酸和石墨烯药物载体的质量比为0.1~5:1。
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