CN114796151A - 一种具有靶向肿瘤微环境控制释放的纳米药物水凝胶互穿网络体系微胶囊 - Google Patents
一种具有靶向肿瘤微环境控制释放的纳米药物水凝胶互穿网络体系微胶囊 Download PDFInfo
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Abstract
一种具有靶向肿瘤微环境控制释放的纳米药物水凝胶互穿网络体系微胶囊,涉及纳米药物水凝胶技术领域。利用京尼平合成一种依赖于pH和温度的互穿水凝胶,再与纳米药物合成纳米药物水凝胶互穿网络体系。京尼平交联的海藻酸钠和聚乙二醇‑接枝‑壳聚糖为水凝胶模型。充分发挥有机药物‑无机纳米颗粒的协同效果,获得高疗效、低或无毒副作用的原创型纳米药物,同时利用壳聚糖和海藻酸盐水凝胶良好的相容性,构建互穿网络体系,拥有pH和温度响应,可以自主靶向肿瘤微环境,非常适合口服给药。
Description
技术领域
本发明涉及纳米药物水凝胶技术领域,具体涉及一种自主靶向肿瘤微环境的纳米药物水凝胶微互穿网络体系微胶囊。
背景技术
水凝胶是一种亲水的三维聚合物网络,可以吸收和保留大量的水,膨胀而不溶解或失去其结构特征。这是因为水凝胶具有很高的透水性,适合于药物传递系统,嵌入的蛋白质或药物可以通过其多孔的微观结构被释放。水凝胶可以由天然或合成聚合物制备。多糖和天然提取物由于其生物相容性、生物降解性和大规模可用性,是制备水凝胶的首选材料。由于其官能团可以经过特定的化学修饰,因此设计的水凝胶的性能可以根据目标应用进行调整。纳米复合水凝胶是由嵌有功能性纳米颗粒或纳米结构的聚合物网络组成,它不仅改善了机械性能,而且表现出了生物活性,例如嵌入式纳米材料的可控释放,可以调节细胞行为或组织功能。在过去的几十年里,纳米复合水凝胶在生物医学工程的各个领域取得了前所未有的发展,包括药物传递(N.Hanafy,S.Leporatti,M.A.El-Kemary,Mucoadhesivehydrogel nanoparticles as smart biomedical drug delivery system.AppliedSciences,9.5(2019).)伤口愈合(H.L.Deng,Z.P.Yu,S.G.Chen,L.T.Fei,Q.Y.Sha,N.Zhou,Z.T.Chen,C.Xu,Facile and eco-friendly fabrication of polysaccharides-basednanocomposite hydrogel for photothermal treatment of wound infection,Carbohydr.Polym.230(2020).)、成骨(N.Cui,K.Han,M.Li,J.L.Wang,J.M.Qian,Purepolylysine-based foamy scaffffolds and their interaction with MC3T3-E1 cellsand osteogenesis,Biomed.)、和生物传感(F.N.Muya,P.G.L.Baker,E.I.Iwuoha,Polysulfone Hydrogel Nanocomposite Alkaline Phosphatase Biosensor for theDetection of Vanadium,ElectrocatalysisUs,(2020):1-9.)。
但是水凝胶的一些局限性降低了直接给药到肿瘤组织的抗癌药物的疗效,如药物释放失控导致的短暂的循环时间和高浓度,药物分子不稳定和在局灶区分散差,以及缺乏靶向性。2016年,Chan等人分析了近十年来纳米粒子对肿瘤部位的输送效率,发现纳米粒子的输送效率较低,实体肿瘤平均为0.7%,渗透深度特别低。Leong等人报道,静脉注射TiO2、SiO2和Au纳米粒子均加速了乳腺癌的外渗、转移和转移部位的发展。这一对比结果似乎与血管内皮钙粘蛋白的相互作用有关,表明惰性纳米粒子仅作为药物载体,没有抗癌作用,但可优先被癌细胞用于逃逸、迁移、肿瘤转移和复发。为了克服这一挑战,除了适当选择材料外,最大限度地减少药物在转移到病灶中的损失和对周围组织的毒性是至关重要的。特别是,需要一个安全的给药途径,尽可能减少暴露于循环系统,并作为可靠的载体或介质给药,或增加药物系统的运输稳定性。
为了实现高效给药和制备高效治疗抗癌纳米药物,需要在所需的细胞微环境下采用大比表面积、适当的孔径和高载药量控释的纳米药物给药系统,以增强药物在病灶区的穿透和滞留。纳米材料作为药物载体的应用得到了广泛的研究。然而,从载体生物材料过量或突然释放可能会增加细胞毒性,降低药物疗效。纳米粒子或纳米药物与包埋在水凝胶中的生物活性成分或前药物偶联后形成,由于水凝胶系统的保护,在运输到局灶区域的过程中可降低其细胞毒性。Shi等报道了一种掺有MgSiO3纳米粒子多孔和中空结构的纳米复合水凝胶,可以装载抗癌药物阿霉素(L.Shi,Y.Han,J.Hilborn,D.Ossipov,Smart”drugloaded nanoparticle delivery from a self-healing hydrogel enabled by dynamicmagnesium-biopolymer chemistry,Chem.Commun.52(74)(2016)11151–11154.)。封装后的阿霉素在酸性肿瘤微环境下可快速释放。Kim等人基于双膦酸盐和带正电的硅酸镁锂纳米之间的相互作用,开发了一种自组装水凝胶,由于硅酸镁锂独特的电荷分布(表面负电荷和边缘正电荷),该水凝胶介导正电或负电模型蛋白可持续释放(K.Y.Zhang,Z.F.Jia,B.G.Yang,Q.Feng,X.Xu,W.H.Yuan,X.F.Li,X.Y.Chen,L.Duan,D.P.Wang,L.M.Bian,Adaptable hydrogels mediate cofactor-assisted activation of biomarker-responsive drug delivery via positive feedback for enhanced tissueregeneration,Adv.Sci.5(12)(2018).)。因此,探索有效的控释方法及相关水凝胶体系对开发生物相容性纳米药物包封体系具有重要意义。
天然聚合物水凝胶可以由多糖组成,如琼脂糖、海藻酸盐、葡聚糖、壳聚糖、甲基纤维素、透明质酸和蛋白质。天然聚合物海藻酸钠或壳聚糖水凝胶因其生物相容性好、毒性低、可降解性好而受到广泛关注。这些类型的水凝胶具有pH敏感性膨胀,并允许药物通过其固有的微孔扩散。但海藻酸钠力学性能差,水溶性过高,必须进行化学交联才能提高其在水介质中的稳定性。海藻酸钠的羟基和羧基官能团可以通过钙、钡、锶、镁等二价或高价离子进行交联,形成互穿网络聚合物。并可形成具有优良载药性能的微孔载体,可根据转运环境和病变微环境对pH和温度的响应进行可调的控释速率。壳聚糖比带正电荷的海藻酸盐具有更高的机械强度,它可以通过静电相互作用吸引带负电荷的蛋白质,导致药物释放不佳。带正电荷的壳聚糖也加重了附着在凝胶界面上的炎症细胞,这被认为是纤维包裹的来源。溶胶的聚合物浓度低,导致水凝胶机械强度差。研究表明,接枝聚乙二醇可以改善壳聚糖的机械性能和亲水性。聚乙二醇可接枝到壳聚糖骨架上,得到聚乙二醇接枝壳聚糖(PEG-g-CS)。PEG-g-CS水凝胶在植入和给药方面具有一定的优势。接枝聚乙二醇可减少蛋白质与炎症细胞之间的静电相互作用,有利于药物释放,不利于纤维包封。PEG-g-CS水凝胶可用于药物缓释。壳聚糖上的氨基和羟基可以形成多个键,但在酸性介质中解聚阻碍了控制口服给药。这一问题可以通过与戊二醛、甲醛、三聚磷酸盐、京尼平和香兰素等试剂进行化学交联来解决。然而,戊二醛和甲醛在一定浓度下是有毒的。因此,使用无毒有效的交联剂是必不可少的。
发明内容
为解决现有技术中存在的问题,本发明的一个目的在于提供一种自主靶向肿瘤微环境的纳米药物水凝胶互穿网络体系,利用京尼平合成一种依赖于pH和温度的互穿水凝胶,再与纳米药物合成纳米药物水凝胶互穿网络体系。其中,Au@CoFeB-Rg3为纳米药物模型,京尼平交联的海藻酸钠和聚乙二醇-接枝-壳聚糖为水凝胶模型。
根据本发明的纳米药物水凝胶互穿网络体系,在一种具体实施方案中,所述纳米药物采用包含以下步骤的方法制备:
(1)制备Au@CoFeB纳米颗粒;
(2)制备Au@CoFeB-Rg3纳米药物;
(3)研制液滴微流控装置:
a)使用UV光刻技术在硅片上制备SU-8模具;
b)将二甲基硅氧烷与交联剂混合物倒在SU-8模具上,固化后提取二甲基硅氧烷微流控设备,进行穿孔-结合-加热-疏水处理。
(4)封装Au@CoFeB-Rg3纳米药物:
a)将步骤(2)得到的纳米颗粒放入缓冲液中;
b)将权利要求2中的交联剂添加到步骤4(a)中的纳米粒子缓冲液中,再将交联剂京尼平加入到纳米药物聚合物混合物中;
c)将纳米药物胶囊采用微流控装置形成水凝胶液滴。
根据本发明的纳米药物,步骤(4)中所用缓冲液可以为基于本领域技术人员所公知的缓冲液,例如所述缓冲液可以为磷酸盐PBS缓冲液、柠檬酸–Na2HPO4缓冲液、Trizma缓冲液、胎牛血清FBS缓冲液、碳酸钠-碳酸氢钠缓冲溶液、和醋酸钠-醋酸缓冲液中的至少一种,优选为磷酸盐缓冲液、胎牛血清FBS缓冲液和柠檬酸-Na2HPO4缓冲液中的至少一种,进一步优选为磷酸盐PBS缓冲液。
本发明提供的纳米药物水凝胶互穿网络体系可以充分利用无机,特别是金属基纳米颗粒的多模态和表面数层原子层的活性和量子效应产生的疗效,以及有机药物的疗效和对金属内层及生命有机体的保护作用,构建无机-有机复合纳米药物,充分发挥有机药物-无机纳米颗粒的协同效果,获得高疗效、低或无毒副作用的原创型纳米药物,同时利用壳聚糖和海藻酸盐水凝胶良好的相容性,构建互穿网络体系,拥有pH和温度响应,可以自主靶向肿瘤微环境,非常适合口服给药。
附图说明
图1是合成纳米药物微胶囊的多结液滴微流控反应器。
图2结构图;其中A是把水凝胶微滴封装成纳米药物的液滴微流控装置的微观结构图;B是合成纳米药物微胶囊的明场光学图像。
图3性能图;A和B是纳米药物水凝胶不同截面的SEM图像,插入图B中的为尺寸分布直方图;C是纳米药物水凝胶的溶胀性能图。
图4是通过模拟胃液(37℃时pH=1.2)、小肠(37℃时pH=7.4)、癌细胞微环境(37℃时pH=5.5)的pH值和温度,以及不同pH(1.2和7.4)条件下口服给药的环境储存温度(20℃),来测试不同pH值和温度下PBS中水凝胶薄膜的受控纳米药物释放效果。
图5是模拟的在温度37℃时pH值为1.2,5.5,7.4时的扩散系数曲线。
图6是模拟的在温度20℃时pH值为1.2,7.4时的扩散系数曲线。
图7释放效率图;A是纳米药物水凝胶中Au纳米粒子在温度为37℃时,分别在pH1.2、5.5和7.4缓冲液中的释放效率;B是纳米药物水凝胶中Co纳米粒子在温度为37℃时,分别在pH 1.2、5.5和7.4缓冲液中的释放效率;C是纳米药物水凝胶中Fe纳米粒子在温度为37℃时,分别在pH 1.2、5.5和7.4缓冲液中的释放效率。
附图标记说明
I、第一通道;II、第二通道;III、第三通道。
具体实施方式
下面结合具体实施例,进一步阐述本发明。应理解,这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法,通常按照常规条件,或按照制造厂商所建议的条件。
纳米药物水凝胶的合成
实施例1:
(1)制备Au@CoFeB纳米颗粒:
核心壳Au@CoFeB@CoxFe(1-x)(OH)2通过金属盐还原和共沉淀反应,采用我们的测序简单程序微流控工艺合成了纳米粒子。简单地说,两步微流控法被用于制备纳米粒子。首先,采用简单的程序微流控方法制备了一种超小型CoFeB纳米粒子溶液。通过表面涂层和外延生长在Au纳米粒子表面沉积CoFeB纳米粒子,得到Au@CoFeB纳米粒子。在第一步中,金属盐溶液被吸引到注射器中再注入引水系统联合,减少快速反应,推迟瞬时成核,形成超薄CoFeB纳米颗粒和控制增长。微流控合成在氮气保护下,温度为120℃,流速为3mL/min,有利于完成还原反应并快速成核。溶液被收集,称取相应比例的氯金酸,以相同体积的N-甲基-2-吡咯烷酮(NMP)作为溶液溶解。然后通过微流控合成Au@CoFeB纳米粒子。在此步骤之前,将一定量的NaBH4溶解在产物接收器中,加入过量还原剂。纳米粒子表面的Co和Fe在水溶液中容易氧化,在其表面形成若干羟基配体(OH),导致生成Au@CoFeB@CoxFe(1-x)(OH)2纳米粒子。
(2)Au@CoFeB-Rg3纳米药物的合成:
Au@CoFeB-Rg3纳米药物的合成采用顺序表面和配体修饰或活化和原位偶联。简单地说,用氨基硅烷偶联剂(3-氨基丙基)三甲氧基硅烷(APTMS)和双功能胺活性交联剂二丁二酰亚胺酯(DSS)对纳米粒子进行了表面改性和活化。然后,利用APTMS对药物人参皂苷Rg3进行预修饰和活化原位偶联。通过APTMS将Au@CoFeB@CoxFe(1-x)(OH)2纳米粒子上的表面羟基修饰为氨基,然后用DSS活化。通过APTMS将人参皂苷Rg3与预活化羟基原位偶联表面活化的纳米粒子,从而形成Au@CoFeB-Rg3纳米药物。
(3)液滴微流控装置的研制:
聚(二甲基硅氧烷)(PDMS)器件是使用基于SU-8(一种负性光刻胶,MicroChem)模具的传统软光刻技术制造的。为了制造微流控装置,首先使用UV光刻技术在硅片上制备SU-8模具。然后,将硅酮树脂PDMS(Dow Corning,MI,USA)和交联剂以10:1的比例均匀预混,再将混合物倒在SU-8模具上,真空除气后在65℃的烤箱中固化2小时以上。使用金属手术刀提取PDMS微设备,并用0.75mm或1.0mm活检穿孔机(Harris unicore,Ted Pella,Inc.,Redding,CA)进行穿孔,以创建入口和出口。然后,将PDMS微器件结合到玻璃载玻片上,在65℃下加热1小时。最后,该器件通过乙烯酮二聚物胶料(PPG Industries,Pittsburgh,PA,USA)进行疏水处理,使通道表面疏水。
(4)封装Au@CoFeB-Rg3纳米药物:
首先将20mg Au@CoFeB-Rg3溶于4-mL磷酸盐缓冲盐水(PBS)中制备纳米药物水凝胶微胶囊聚合物溶液。然后,20毫克海藻酸钠和20毫克聚乙二醇-接枝-壳聚糖晶体,被添加到包含Au@CoFeB-Rg3的4ml PBS中。最后将0.68mg的交联剂京尼平加入纳米药物聚合物混合物中,均匀混合,4℃保存。
Au@CoFeB-Rg3纳米药物微胶囊采用微流控装置形成水凝胶液滴。外相(图1中的通道III)是HFE-7500(3M,MN,美国),含1.0%表面活性剂(全氟聚醚-聚乙二醇,RainDanceTechnologies,MA,美国)油。内相(图1中的通道I)包括用于形成水凝胶液滴的纳米药物-聚合物-京尼平溶液。内相的流动在交叉点(红点圆)处被外油相剪切,在通道I与孔板连接的端部形成单分散的水凝胶滴。将水凝胶液滴收集在一个小瓶中,并在室温下与纳米药物水凝胶交联2天以上。交联后加入全氟辛醇滴(1H,1H,2H,2H,全氟辛醇(CF3(CF2)5(CH2)2OH))确定交联。如果没有观察到水凝胶液滴的显著损失(水凝胶微胶囊的合并),交联水凝胶作为微胶囊口服被认为是足够的。然后在样品瓶中加入更多的PFO和一些水。涡旋混合物,离心1-2分钟,用移液管小心地除去底部的PFE油。向样品中加入更多的水;样品被旋转和离心得到水凝胶滴。底部的PFE油用吸管除去。洗涤步骤重复三次,以确保PFE油的去除,得到纯化的水凝胶滴。将纳米药物水凝胶滴一滴置于载玻片上,通过光学显微镜观察干燥过程中纳米药物水凝胶微胶囊的稳定性和分散性。
对通过实施例1中制备的典型的纳米颗粒和纳米药物水凝胶微胶囊的微观结构以及pH和温度依赖性释放动力学特性进行表征。图2A是使用光学显微镜观察显示了使用液滴微流体制备的Au@CoFeB-Rg3纳米药物水凝胶微胶囊的形成。在连续外部HFE-7500油相(图1中的通道III)和纳米型聚合物-京尼平水性缓冲液(图1中的通道I)之间形成均匀的水凝胶纳米粒子,然后进行剪切从而通过外部剪切至液滴油相。这些微胶囊在油相中具有良好的稳定性和分散性。图2B是合成的纳米药物微胶囊的光学图像,其在交联后转移到水相超过2天后。它们也稳定且分散在水溶液中,显示均匀直径大约是10μm。纳米药物被成功包封在每个水凝胶微胶囊中(每个微胶囊中的暗点:右上放大图像),尽管它们在形成水凝胶微胶囊期间形成聚集体,但由于增强的局部浓度和交联效应而形成了交联磁性偶极效应。
(5)制备Au@CoFeB-Rg3纳米药物水凝胶互穿网络体系:
首先将20mg Au@CoFeB-Rg3溶于4-mL磷酸盐缓冲盐水(PBS)中制备纳米药物水凝胶聚合物溶液。然后,20毫克海藻酸钠和20毫克聚乙二醇-接枝-壳聚糖晶体,被添加到包含Au@CoFeB-Rg3的4ml PBS中。最后将0.68mg的交联剂京尼平加入纳米药物聚合物混合物中,均匀混合,4℃保存。将纳米药物水凝胶溶液置于培养皿中,在60℃下在空气循环烘箱中干燥2天以上,形成10个20μm的薄膜,然后将其切成3个10毫米的薄片供未来使用。所制备的互穿网络体系干燥薄膜可模拟口服后的消化过程,研究互穿网络体系的再膨胀特性。此外,纳米药物胶囊干燥后的成本效益和长期存储得到了改善,类似于干燥食品。
纳米药物水凝胶在去离子水中溶胀平衡后,用扫描电镜观察图像。如图3A-B所示,水凝胶薄膜保留了PEG-g-壳聚糖和海藻酸盐通过京尼平交联形成的微孔互穿网络。通过对薄膜横截面上200多个随机选择的孔隙进行统计分析(图3B),得出平均直径为1.63μm±0.30μm(如图3B插入的图像所示)。图3C为纳米药物水凝胶薄膜的溶胀率。溶胀速率取决于凝胶材料之间的交联程度。随着纳米药物水凝胶交联度的增加,水凝胶薄膜的溶胀率将显著降低。当pH值为7.4时,纳米药物水凝胶的溶胀率为23%,负载率为33%,这是以纳米药物水凝胶总干质量为基础的。
如图4所示,为了模拟药物在胃中的存在,将药物在37℃下pH为1.2时释放,此时纳米药物水凝胶互穿网络体系的释放效率仅在30分钟内就达到15%。为了模拟血液和组织中药物的存在,该药物在37℃下以7.4的受控pH释放。释放效率在30分钟内高达55%。整个过程符合菲克的第二定律。同时,当药物达到肿瘤部位时,pH值为5.5,释放效率高达95%。药物在胃中的停留时间约为30分钟,比较前30分钟的释放速率显示非常少量的药物会被释放到胃中。因此,药物可以通过小肠,到达肿瘤部位大量释放。有趣的是,当pH为5.5时,37℃的释放百分比高于100%,因为水凝胶在该pH下开始分解,从而导致交联网络(非交联藻酸盐和/或PEG-g-壳聚糖分子)作为药物释放。海藻酸钠和/或PEG-g-壳聚糖将溶于水性缓冲溶液中,从而使总释放的材料的量比混合到水凝胶中的总纳米药物的量大。这导致累积释放百分比超过100%。药物逐渐变灰,最终呈絮凝状。这种现象是理想的,因为水凝胶的快速降解会加速纳米药物释放到肿瘤微环境中,并增加它们在肿瘤细胞周围的浓度以及它们的一般利用效率。当药物在模拟室温下(20℃)到达胃和小肠的pH环境时,在前200分钟中,释放率下降,在pH 1.2下小于10%,pH 7.4的少于15%。与37℃相比,释放效率远低得多。整个释放过程与菲克的第二定律也相匹配,说明药物可在室温下很好的保存。
我们还利用ICP光谱法直接测量纳米药物水凝胶的金属释放效率。如图7所示,不同pH条件下,金属在水凝胶中的释放效率趋势与之前的测试结果相似。我们的纳米颗粒是核壳结构,金纳米颗粒包裹在里面,所以与Co和Fe纳米颗粒相比,其释放效率较低。金属颗粒的总体趋势是pH为5.5时释放效率相比于pH为1.2时释放效率较高。这再次证明了我们的纳米药物水凝胶互穿网络体系能够顺利通过胃、肠,最终到达肿瘤部位进行大规模释放。
应用实施例
纳米药物水凝胶互穿网络体系的pH依赖性释放动力学研究
应用实施例1
以Au@CoFeB-Rg3为纳米药物模型,以京尼平交联的海藻酸钠和聚乙二醇-壳聚糖的混合物为水凝胶模型,结合了壳聚糖和海藻酸盐的优点,构建了纳米药物水凝胶微互穿网络体系。通过模拟药物转运过程中消化道的pH值和温度以及靶病理细胞微环境,评价纳米药物在水凝胶中的释放动力学。
为了研究纳米药物水凝胶互穿网络体系的控释性能,我们采用加权法考察了纳米药物水凝胶干燥薄膜的释放速率。这是因为使用目前的单线液滴微流体来合成足够量的纳米药物水凝胶样品很难进行精确的研究。将纳米药物水凝胶溶液置于培养皿中,在60℃下在空气循环烘箱中干燥2天以上,形成10个20μm的薄膜,然后将其切成3个10毫米的薄片供未来使用。所制备的互穿网络体系干燥薄膜可模拟口服后的消化过程,研究互穿网络体系的再膨胀特性。此外,纳米药物胶囊干燥后的成本效益和长期存储得到了改善,类似于干燥食品。
将干燥的30-50毫克的纳米药物水凝胶薄膜添加到不同pH值的PBS溶液中,pH值分别为1.2,5.5,和7.4,(分别模拟的是胃,癌症细胞的肿瘤微环境,肠道微环境的pH值),分别在一定温度(在小型恒温器中,储存温度为20℃,健康人体温为37℃),放置在一个瓶中5分钟,10分钟、20分钟,30分钟,40分钟,60分钟,90分钟,120分钟,150分钟,240分钟,180 280360分钟,420分钟,620分钟。然后用移液管将缓冲液完全去除,纳米药物水凝胶片在室温下用纳米水晃动下快速洗涤3次,在60℃空气循环烘箱中干燥2h,直至恒重。(在10分钟的干燥间隔内,几乎相同重量至少3次,误差小于±5%)。在一定的温度和pH下,通过绘制释放时间相关的累积质量损失曲线,研究了它们的释放动力学。如图5显示了在37℃的质量变化的扩散系数的变化趋势。随着时间的推移,质量变化率等于具有距离的扩散通量变化的负值,这与菲克扩散第二定律相一致。如图6显示了在20℃的质量变化的扩散系数的变化趋势。前期的药物扩散释放后,后期的药物浓度降低,并在水凝胶和药物的非物理作用(京尼平交联时,也把部分药物给固定在水凝胶分子上了)使其扩散出水凝胶趋于稳定。而纳米药物只有伴随水凝胶降解才能释放出进入溶液。基于当前数据估计纳米药物水凝胶互穿网络体系所需的激活能量为2.26×104J/mol,这表示所需的激活能量越多,药物释放越慢。从该结果,可以推导出药物可以储存在环境条件下,即使在高湿度条件下也没有损失交联。因此,通过使用京尼平作为交联剂,纳米药物可以安全地包封在交联的藻酸盐/聚乙二醇-接枝-壳聚糖中以形成相对稳定的纳米药物互穿网络体系,非常适合口服给药。采用ICP-MS(Aglient7800,Aglient)进一步研究其释放动力学。
应用实施例2
以Au@CoFeB-Rg3为纳米药物模型,以京尼平交联的海藻酸钠和聚乙二醇-壳聚糖的混合物为水凝胶模型,结合了壳聚糖和海藻酸盐的优点,构建了纳米药物水凝胶互穿网络体系。通过模拟药物转运过程中消化道的pH值和温度以及靶病理细胞微环境,评价纳米药物在水凝胶中的释放动力学。
ICP光谱法可以对材料中的多种元素进行定性、半定量和定量分析。其定性分析通常准确可靠,是原子光谱学中唯一可用于定性分析的方法。将纳米药物水凝胶溶液置于培养皿中,在60℃下在空气循环烘箱中干燥2天以上,形成10个20μm的薄膜,然后将其切成3个10毫米的薄片供未来使用。
将干燥的30-50毫克的纳米药物水凝胶薄膜添加到不同pH值的PBS溶液中,pH值分别为1.2,5.5,和7.4,(分别模拟的是胃,癌症细胞的肿瘤微环境,肠道微环境的pH值),在一定温度(在小型恒温器中,健康人体温为37℃),放置在一个瓶中10min、20min、40min、60min、120min、180min、300min。然后用移液管将缓冲液吸取干净,最后采用ICP-MS直接测定上清液中金属元素的释放量,计算释放效率。
应用实施例3
(1)制备FePtB@FePtOx纳米颗粒:
核心壳FePtB@FePtOx通过金属盐还原和共沉淀反应,采用我们的测序简单程序微流控工艺合成了纳米粒子。简单地说,两步微流控法被用于制备纳米粒子。首先,采用简单的程序微流控方法制备了一种超小型FePtOx纳米粒子溶液。通过表面涂层和外延生长在FePtB纳米粒子表面沉积FePtOx纳米粒子,得到FePtB@FePtOx纳米粒子。在第一步中,金属盐溶液被吸引到注射器中再注入引水系统联合,减少快速反应,推迟瞬时成核,形成超薄FePtOx纳米颗粒和控制增长。微流控合成在氮气保护下,温度为150℃,流速为5mL/min,有利于完成还原反应并快速成核。溶液被收集,称取相应比例的氯金酸,以相同体积的N-甲基-2-吡咯烷酮(NMP)作为溶液溶解。然后通过微流控合成FePtB@FePtOx纳米粒子。在此步骤之前,将一定量的NaBH4溶解在产物接收器中,加入过量还原剂。
(2)FePtB@FePtOx-PTX纳米药物的合成:
FePtB@FePtOx-PTX纳米药物的合成采用顺序表面和配体修饰或活化和原位偶联。简单地说,用氨基硅烷偶联剂(3-氨基丙基)三甲氧基硅烷(APTMS)和双功能胺活性交联剂二丁二酰亚胺酯(DSS)对纳米粒子进行了表面改性和活化。通过APTMS将FePtB@FePtOx-PTX纳米粒子上的表面羟基修饰为氨基,然后用DSS活化。
(3)制备FePtB@FePtOx-PTX纳米药物水凝胶互穿网络体系:
首先将60mgFePtB@FePtOx-PTX溶于10mL磷酸盐缓冲盐水(PBS)中制备纳米药物水凝胶聚合物溶液。然后60毫克海参皂苷和60毫克蚕丝多肽被添加到包含FePtB@FePtOx-PTX的10ml PBS中。最后将15mg的交联剂CaCl2溶液加入纳米药物聚合物混合物中,均匀混合,4℃保存。将纳米药物水凝胶溶液置于培养皿中,在60℃下在空气循环烘箱中干燥2天以上,形成10个20μm的薄膜,然后将其切成3个10毫米的薄片供未来使用。所制备的互穿网络体系干燥薄膜可模拟口服后的消化过程,研究互穿网络体系的再膨胀特性。此外,纳米药物胶囊干燥后的成本效益和长期存储得到了改善,类似于干燥食品。
应用实施例4
(1)制备FeB@Fe3O4纳米颗粒:
核心壳FeB@Fe3O4通过金属盐还原和共沉淀反应,采用我们的测序简单程序微流控工艺合成了纳米粒子。简单地说,两步微流控法被用于制备纳米粒子。首先,采用简单的程序微流控方法制备了一种超小型Fe3O4纳米粒子溶液。通过表面涂层和外延生长在FeB纳米粒子表面沉积Fe3O4纳米粒子,得到FeB@Fe3O4纳米粒子。在第一步中,金属盐溶液被吸引到注射器中再注入引水系统联合,减少快速反应,推迟瞬时成核,形成超薄Fe3O4纳米颗粒和控制增长。微流控合成在氮气保护下,温度为150℃,流速为1.5mL/min,有利于完成还原反应并快速成核。溶液被收集,称取相应比例的氯金酸,以相同体积的N-甲基-2-吡咯烷酮(NMP)作为溶液溶解。然后通过微流控合成FeB@Fe3O4纳米粒子。在此步骤之前,将一定量的NaBH4溶解在产物接收器中,加入过量还原剂。
(2)FeB@Fe3O4-Rg3纳米药物的合成:
FeB@Fe3O4-Rg3纳米药物的合成采用顺序表面和配体修饰或活化和原位偶联。简单地说,用氨基硅烷偶联剂(3-氨基丙基)三甲氧基硅烷(APTMS)和双功能胺活性交联剂二丁二酰亚胺酯(DSS)对纳米粒子进行了表面改性和活化。然后,利用APTMS对药物人参皂苷Rg3进行预修饰和活化原位偶联。通过APTMS将FeB@Fe3O4-Rg3纳米粒子上的表面羟基修饰为氨基,然后用DSS活化。通过APTMS将人参皂苷Rg3与预活化羟基原位偶联表面活化的纳米粒子,从而形成FeB@Fe3O4-Rg3纳米药物。
(3)制备FeB@Fe3O4-Rg3纳米药物水凝胶互穿网络体系:
首先将20mgFeB@Fe3O4-Rg3溶于4-mL磷酸盐缓冲盐水(PBS)中制备纳米药物水凝胶聚合物溶液。然后20毫克海藻酸钠和20毫克氨基化聚乙二醇晶体,被添加到包含FeB@Fe3O4-Rg3的4ml PBS中。最后将5mg的交联剂京尼平加入纳米药物聚合物混合物中,均匀混合,4℃保存。将纳米药物水凝胶溶液置于培养皿中,在60℃下在空气循环烘箱中干燥2天以上,形成10个20μm的薄膜,然后将其切成3个10毫米的薄片供未来使用。所制备的互穿网络体系干燥薄膜可模拟口服后的消化过程,研究互穿网络体系的再膨胀特性。此外,纳米药物胶囊干燥后的成本效益和长期存储得到了改善,类似于干燥食品。
应用实施例5
利用应用实施例3的步骤制备FePtB@FePtOx纳米颗粒。
(1)FePtB@FePtOx-Rg3纳米药物的合成:
FePtB@FePtOx-Rg3纳米药物的合成采用顺序表面和配体修饰或活化和原位偶联。简单地说,用氨基硅烷偶联剂(3-氨基丙基)三甲氧基硅烷(APTMS)和双功能胺活性交联剂二丁二酰亚胺酯(DSS)对纳米粒子进行了表面改性和活化。然后,利用APTMS对药物人参皂苷Rg3进行预修饰和活化原位偶联。通过APTMS将FePtB@FePtOx-Rg3纳米粒子上的表面羟基修饰为氨基,然后用DSS活化。通过APTMS将人参皂苷Rg3与预活化羟基原位偶联表面活化的纳米粒子,从而形成FePtB@FePtOx-PTX纳米药物。
(2)制备FePtB@FePtOx-Rg3纳米药物水凝胶互穿网络体系:
首先将20mgFePtB@FePtOx-Rg3溶于4-mL蒸馏水中制备纳米药物水凝胶聚合物溶液。然后,20毫克聚乙烯亚胺和20毫克羧基化聚乙二醇,被添加到包含FePtB@FePtOx-Rg3的4ml蒸馏水中。最后将20mg的交联剂戊二醛加入纳米药物聚合物混合物中,均匀混合,4℃保存。将纳米药物水凝胶溶液置于培养皿中,在60℃下在空气循环烘箱中干燥2天以上,形成10个20μm的薄膜,然后将其切成3个10毫米的薄片供未来使用。所制备的互穿网络体系干燥薄膜可模拟口服后的消化过程,研究互穿网络体系的再膨胀特性。此外,纳米药物胶囊干燥后的成本效益和长期存储得到了改善,类似于干燥食品。
应用实施例6
利用应用实施例4的步骤制备FeB@Fe3O4纳米颗粒。
(1)FeB@Fe3O4--DOC纳米药物的合成:
FeB@Fe3O4--DOC纳米药物的合成采用顺序表面和配体修饰或活化和原位偶联。简单地说,用氨基硅烷偶联剂(3-氨基丙基)三甲氧基硅烷(APTMS)和双功能胺活性交联剂二丁二酰亚胺酯(DSS)对纳米粒子进行了表面改性和活化。通过APTMS将FeB@Fe3O4--DOC纳米粒子上的表面羟基修饰为氨基,然后用DSS活化。
(2)制备FeB@Fe3O4--DOC纳米药物水凝胶互穿网络体系:
首先将20mgFeB@Fe3O4-DOC溶于4-mL蒸馏水中制备纳米药物水凝胶聚合物溶液。然后20毫克甲基丙烯酸酰化明胶和20毫克聚乙烯亚胺,被添加到包含FeB@Fe3O4--DOC的4ml蒸馏水中。最后将20mg的交联剂苯基(2,4,6-三甲基苯甲酰基)磷酸锂盐加入纳米药物聚合物混合物中,均匀混合,4℃保存。将纳米药物水凝胶溶液置于培养皿中,在60℃下在空气循环烘箱中干燥2天以上,形成10个20μm的薄膜,然后将其切成3个10毫米的薄片供未来使用。所制备的互穿网络体系干燥薄膜可模拟口服后的消化过程,研究互穿网络体系的再膨胀特性。此外,纳米药物胶囊干燥后的成本效益和长期存储得到了改善,类似于干燥食品。
应用实施例7
利用实施例1的步骤制备Au@CoFeB纳米颗粒。
(1)Au@CoFeB-克唑替尼纳米药物的合成:
Au@CoFeB-克唑替尼纳米药物的合成采用顺序表面和配体修饰或活化和原位偶联。简单地说,用氨基硅烷偶联剂(3-氨基丙基)三甲氧基硅烷(APTMS)和双功能胺活性交联剂二丁二酰亚胺酯(DSS)对纳米粒子进行了表面改性和活化。通过APTMS将Au@CoFeB-克唑替尼纳米粒子上的表面羟基修饰为氨基,然后用DSS活化。
(2)制备Au@CoFeB-克唑替尼纳米药物水凝胶互穿网络体系:
首先将60mgAu@CoFeB-克唑替尼溶于10mL蒸馏水中制备纳米药物水凝胶聚合物溶液。然后30毫克甲基丙烯酸酰化明胶和30毫克聚乙烯亚胺,被添加到包含Au@CoFeB-克唑替尼的10ml蒸馏水中。最后将16mg的交联剂琥珀酰-亚胺丁二酸酯加入纳米药物聚合物混合物中,均匀混合,4℃保存。将纳米药物水凝胶溶液置于培养皿中,在60℃下在空气循环烘箱中干燥2天以上,形成10个20μm的薄膜,然后将其切成3个10毫米的薄片供未来使用。所制备的互穿网络体系干燥薄膜可模拟口服后的消化过程,研究互穿网络体系的再膨胀特性。此外,纳米药物胶囊干燥后的成本效益和长期存储得到了改善,类似于干燥食品。
Claims (7)
1.一种具有靶向肿瘤微环境控制释放的纳米药物水凝胶互穿网络体系微胶囊,其特征在于,利用交联剂合成一种具有pH和温度响应控制释放功能的互穿水凝胶,再与纳米药物合成纳米药物水凝胶互穿网络体系;其中,Au@CoFeB-Rg3、FeB@Fe3O4-Rg3、FePtB@FePtOx-Rg3、FePtB@FePtOx-紫杉醇(PTX,Paclitaxel)、FeB@Fe3O4-PTX、Au@CoFeB-PTX、Au@CoFeB-DOC(Docetaxel)、FePtB@FePtOx-DOC、FeB@Fe3O4-DOC、Au@CoFeB-克唑替尼为纳米药物模型。
2.根据权利要求1所述的一种具有靶向肿瘤微环境控制释放的纳米药物水凝胶互穿网络体系微胶囊,其特征在于,纳米药物水凝胶互穿网络体系,是由海藻酸钠、聚乙二醇-接枝-壳聚糖、壳聚糖、海参皂苷、羧基化聚乙二醇、氨基化聚乙二醇、低分子量聚丙烯酰胺、水凝胶互穿网络体系聚丙烯酸、甲基丙烯酸酰化明胶(GelMA)、甲基丙烯酸酰化猪皮冻胶原蛋白、甲基丙烯酸酰化阿胶、甲基丙烯酸酰化牛皮冻胶原蛋白、丙烯酰胺、丙烯酸、聚乙烯亚胺(PEI)、蚕丝多肽其中的两种或两种以上构建。
3.根据权利要求1所述的一种具有靶向肿瘤微环境控制释放的纳米药物水凝胶互穿网络体系微胶囊,其特征在于,其中所述交联剂选以化学型交联剂:京尼平、CaCl2(0.5mol-L-1)、戊二醛、辛二酸(N-羟基琥珀酰亚胺酯)、乙二醇双(丁二酸N-羟基琥珀酰亚胺酯)、聚乙二醇二琥珀酰亚胺琥珀酸酯、琥珀酰-亚胺丁二酸酯、聚乙二醇琥珀酰-亚胺丁二酸酯和氮丙啶交联剂XR-100;或紫外交联剂:苯基(2,4,6-三甲基苯甲酰基)磷酸锂盐Lithiumphenyl-(2,4,6-trimethylbenzoyl)phosphinate(LAP,a photoinitiator,PI)、光引发剂Irgacure 2959(BASF)中的一种来交联上述水凝胶互穿网络体系,海藻酸钠并与聚乙二醇-接枝-壳聚糖的混合物作为水凝胶模型;交联剂浓度为水凝胶互穿网络体系浓度的0.1wt%-20wt%。
4.权利要求1-3任一项所述的一种具有靶向肿瘤微环境控制释放的纳米药物水凝胶互穿网络体系微胶囊的制备方法,其特征在于,包括以下步骤:
(1)制备Au@CoFeB纳米颗粒;
(2)制备Au@CoFeB-Rg3纳米药物;
(3)研制液滴微流控装置:
a)使用UV光刻技术在硅片上制备SU-8模具;
b)将二甲基硅氧烷与交联剂混合物倒在SU-8模具上,固化后提取二甲基硅氧烷微流控设备,进行穿孔-结合-加热-疏水处理。
(4)封装Au@CoFeB-Rg3纳米药物:
a)将步骤(2)得到的纳米颗粒放入缓冲液中;
b)将权利要求2中的水凝胶添加到步骤4(a)中的纳米粒子缓冲液中,再将交联剂京尼平加入到纳米药物聚合物混合物中;
c)将纳米药物胶囊采用微流控装置形成水凝胶液滴。
5.根据权利要求4所述的方法,其特征在于,步骤(1)中的Au@CoFeB纳米颗粒采用微流控法、水热法、磁控溅射法或电沉积法制备。
6.根据权利要求4所述的方法,其特征在于,纳米颗粒为核壳结构,核壳结构的金属内核为面心立方晶体结构的Au;核壳结构的壳层为面心立方晶体结构的CoFeB;
所述纳米药物的整体结构为6-7.2nm的超小纳米药物单元偶联在一起构建的尺寸为250-350nm的纳米药物聚集体;纳米颗粒的动力学半径约100-200nm;
所述纳米颗粒表面带有+7-12mV;所述纳米药物表面带有+25-30mV的正电势。
7.根据权利要求4所述的方法,其特征在于,步骤(4)中将纳米药物利用微流控装置封装成水凝胶包含以下步骤的方法制备:
a)外相含有表面活性剂全氟聚醚-聚乙二醇,内相含有纳米药物聚合物混合物,该混合物在微流控器件交叉点被剪切,形成单分散的水凝胶液滴;
b)将收集好的水凝胶液滴在室温下交联两天以上;
c)交联后加入全氟辛醇滴确定交联,将交联的水凝胶加入更多的1H,1H,2H,2H-全氟-辛醇和水,最后将得到的水凝胶混合物进行离心-洗涤,得到纯化的水凝胶液滴。
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