CN107970242A - 一种负载紫杉醇/厄洛替尼的介孔二氧化硅-透明质酸混合靶向纳米颗粒 - Google Patents
一种负载紫杉醇/厄洛替尼的介孔二氧化硅-透明质酸混合靶向纳米颗粒 Download PDFInfo
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
本发明公开了一种负载紫杉醇/厄洛替尼的介孔二氧化硅‑透明质酸混合靶向纳米颗粒及其在制备抗癌药物上的应用。所述靶向纳米颗粒是将介孔二氧化硅纳米颗粒经表面氨基化修饰后,将透明质酸共价偶联到其外表面上,再将紫杉醇、厄洛替尼分别负载在其内孔道中后,将两种介孔二氧化硅纳米颗粒按比例混合。本发明不仅可提高紫杉醇的稳定性,还可实现紫杉醇/厄洛替尼的靶向给药,并通过两者联用起到协同抗肿瘤转移的效果。
Description
技术领域
本发明属于抗肿瘤药物制备技术领域,具体涉及一种负载紫杉醇/厄洛替尼的介孔二氧化硅-透明质酸混合靶向纳米颗粒及其应用。
背景技术
近年来新型给药***一直是医药学领域研究的热点。纳米药物传递***可同时转运两种或多种药物,并可改善抗肿瘤药物的体内分布及药动学性质,提高药物对特定靶点的选择性,达到高效低毒的治疗目的。两种或多种抗肿瘤活性成分联合用药,其预后良好且不良反应较少,可减少耐药现象的发生,但联合用药易受不同药物体内代谢特性的影响,致到达肿瘤部位的药量较少。
紫杉醇(简称PTX)别名红豆杉醇、泰素、紫素、特素,结构式为:
。
紫杉醇是一种从裸子植物红豆杉的树皮中分离提纯的天然次生代谢产物,是目前已发现的最优秀的天然抗癌药物,在临床上已经广泛用于乳腺癌、卵巢癌和部分头颈癌和肺癌的治疗。紫杉醇作为一个具有抗癌活性的二萜生物碱类化合物,其新颖复杂的化学结构、广泛而显著的生物活性、全新独特的作用机制、奇缺的自然资源使其成为20世纪下半叶举世瞩目的抗癌明星和研究重点。紫杉醇是近年国际市场上最热门的抗癌药物,被认为是人类未来20年间最有效的抗癌药物之一。近年来地球人口和癌发率呈爆发性增长,对紫杉醇的需求量亦明显增大。发明专利(CN 102579449A)公开了一种可提高肿瘤对紫杉醇敏感性的联合用药,所述联合用药包括吡喹酮和紫杉醇,两者质量比为180~2200∶1。该联合用药可提高肿瘤对紫杉醇的敏感性,并可以有效提高紫杉醇对肿瘤的杀伤能力,极大地促进肿瘤细胞凋亡的发生,有效提高对紫杉醇不敏感或有抗药性的肿瘤细胞对紫杉醇的敏感性,并且大大降低肿瘤细胞对紫杉醇的抗药性。发明专利(CN 105982888A)公开了一种联合用药物,其含有第一活性成分青蒿素或其衍生物,和第二活性成分紫杉醇或其可药用盐、水合物,以及任选的药学可接受的辅料。青蒿素或其衍生物与紫杉醇联合应用可以用于治疗和/或预防黑色素瘤,二者具有很好的协同作用,同时大大降低了紫杉醇的用量。
厄洛替尼(Erlotinb,简称EL)作为EGFR小分子酪氨酸激酶抑制剂,其结构式为:
,可试用于两个或两个以上化疗方案失败的局部晚期或转移的非小细胞肺癌的三线治疗,且其口服简便、副作用小、易于被患者接受,临床应用广泛。厄洛替尼主要通过肝脏代谢和胆道分泌清除,因此厄洛替尼应慎用于肝脏功能障碍的患者。发明专利(CN 103933046A)公开了一种抗胰腺癌用药物组合物,其将治疗有效量的阿米洛利和治疗有效量的表皮生长因子酪氨酸激酶抑制剂厄洛替尼合用,能获得优于厄洛替尼单独使用的药效,提高临床化疗的效果。发明专利(CN 101300015A)公开了将N-辛二酰苯胺异羟肟酸和厄洛替尼联合使用用于肺癌、乳腺癌、胰腺癌等多种癌症的治疗。
介孔二氧化硅材料是一种具有超高比表面积、大孔容、形貌和尺寸可控的新型无机高分子药物载体。与传统的多孔材料相比,它的主要特点是:(1)长程有序结构;(2)均一可调的介孔孔径;(3)孔隙率高,比表面积大;(4)较好的热稳定性和水热稳定性;(5)表面富含不饱和的基团或者容易功能化上其他基团;(6)易于掺杂其他组分的无定形骨架组成;(7)有多种形貌结构。
透明质酸(hyaluronic acid,HA)是一种酸性粘多糖,其结构式为:
。透明质酸是一种体内广泛存在的糖胺聚糖,在细胞的增殖和转移等方面发挥重要作用。CD44是细胞表面最重要的透明质酸受体,利用透明质酸与其受体间的相互作用,使透明质酸可以作为抗恶性瘤药物的载体达到靶向治疗这类疾病的目的。发明专利(CN 107096034A)公开了一种载芹菜素透明质酸靶向纳米组装体,该***由亲水性多糖透明质酸钠和疏水药物芹菜素组成,该载药***显著提高了药物的溶出度,且物理稳定性良好;其另一突出优势是粒径较小,平均粒径小于200nm,可借助肿瘤部位EPR效应实现被动靶向;同时,以透明质酸为载体又可以实现主动靶向,降低毒副作用,提高抗肿瘤药物的治疗效率。
发明内容
本发明的目的在于提供一种具有靶向抗癌作用的负载有紫杉醇/厄洛替尼的介孔二氧化硅-透明质酸混合载药纳米颗粒,其利用透明质酸对癌细胞的靶向作用,提高紫杉醇/厄洛替尼的抗肿瘤活性。
为实现上述目的,本发明采用如下技术方案:
一种负载紫杉醇/厄洛替尼的介孔二氧化硅-透明质酸混合靶向纳米颗粒,其制备方法包括以下步骤:
1)将介孔二氧化硅纳米颗粒(MSN)溶于无水乙醇中,加入纳米颗粒重量0.4%的3-氨丙基三乙氧基硅烷,室温搅拌12h后离心,乙醇洗涤,冷冻干燥,得氨基化修饰的介孔二氧化硅(MSN-NH2);
2)将30mg透明质酸(HA)、100mg EDC和100mg NHS溶解在40mL 0.1mol/L的MES缓冲液中,室温下搅拌24小时,得到HA-NHS;将40mg MSN-NH2分散在20mL乙醇中并搅拌1小时,然后加入12mg HA-NHS,搅拌4小时,合成透明质酸修饰的介孔二氧化硅(MSN-HA);
3)将20mg的紫杉醇及20mg的厄洛替尼分别与60mg MSN-HA共同溶解在20mL乙醇中,室温下剧烈搅拌24小时,然后离心除去溶剂,用乙醇洗涤后于-50℃真空干燥器中干燥24小时,分别得到负载有紫杉醇的介孔二氧化硅(PTX@MSN-HA)及负载有厄洛替尼的介孔二氧化硅(EL@MSN-HA);
4)将PTX@MSN-HA与EL@MSN-HA按质量比1:1混匀,即得所述靶向纳米颗粒。
所用介孔二氧化硅纳米颗粒的粒径为150nm。
鉴于现有技术的不足,本发明通过共价键将透明质酸偶联到介孔二氧化硅外表面,再将紫杉醇/厄洛替尼负载到介孔二氧化硅的内孔道里。这一方面提高了紫杉醇/厄洛替尼的生物利用度;另一方面,透明质酸的高效靶向抗癌作用也可以提高紫杉醇/厄洛替尼的抗肿瘤效果。因此,本发明所得靶向纳米颗粒可用于制成肿瘤治疗的靶向药物。
本发明的优点在于:
1、本发明采用透明质酸为靶向分子,能使紫杉醇/厄洛替尼在癌细胞周围富集,并能显著提高癌细胞对药物的摄取率,从而在提高紫杉醇/厄洛替尼抗肿瘤效果的同时,降低紫杉醇/厄洛替尼对正常组织的毒副作用;
2、本发明所构建的纳米载药***也适用于除紫杉醇的其他毒副作用大或者难溶性的抗癌药;
3、本发明所设计的载药体系制备方法简单、材料易得,有利于进一步扩大制备。
附图说明
图1为实施例1所制备的介孔二氧化硅纳米颗粒(MSN)的TEM图(A)及DLS分析图(B)。
图2为介孔二氧化硅(MSN)、表面氨基化修饰的介孔二氧化硅(MSN-NH2)、透明质酸(HA)和透明质酸修饰的介孔二氧化硅(MSN-HA)的傅里叶变换红外光谱。
图3为介孔二氧化硅(MSN)、表面氨基化修饰的介孔二氧化硅(MSN-NH2)和透明质酸修饰的介孔二氧化硅(MSN-HA)的Zeta电位分析图。
图4为EL、PTX、EL@MSN、PTX@MSN和EL@MSN-HA、PTX@MSN-HA在pH 5.5(A)和pH 7.4(B)的PBS溶液中的药物释放速率。
图5为实施例7中细胞摄取实验的结果图。
图6为实施例8中MTT实验的结果图。
具体实施方式
为了使本发明所述的内容更加便于理解,下面结合具体实施方式对本发明所述的技术方案做进一步的说明,但是本发明不仅限于此。
实施例1 介孔二氧化硅纳米颗粒(MSN)的制备
将0.1g TEA(三乙醇胺)和20mL去离子水完全混合后,转移到含有2g CTAC(十六烷基三甲基氯化铵)的50mL烧瓶中,95℃下磁力搅拌1小时。随后通过注射器将1.5mL TEOS(硅酸四乙酯)滴加到烧瓶中,在该过程中,溶液的颜色逐渐变成乳白色。加完后在相同条件下继续搅拌1小时,之后将溶液以12000rpm离心15分钟。所得粗产物用20mL去离子水和20mL乙醇洗涤两次,然后溶于20mL甲醇中,加入2g NaCl,室温下磁力搅拌4小时以除去未反应的CTAC,然后将混合物离心15分钟,残余物用20mL乙醇洗涤三次后,在-50℃真空干燥器中干燥24小时,得介孔二氧化硅纳米颗粒(MSN)。
图1为所制备的介孔二氧化硅纳米颗粒的TEM图(A)及DLS分析图(B)。从图中可见,其粒径约为150nm。
实施例2 MSN-NH2纳米颗粒的合成
将100mg MSN加入到含有20mL乙醇的50mL烧瓶中,之后加入400μL的APTES(3-氨丙基三乙氧基硅烷),磁力搅拌12小时。反应完成后,将混合物以12000rpm离心15分钟以除去主要溶剂,残余物分别用20mL去离子水和20mL乙醇洗涤两次以除去未反应物质,然后在-50℃真空干燥器中干燥24h,得到约100mg MSN-NH2纳米粒子。
实施例3 MSN-HA纳米颗粒的合成
将30mg HA、100mg EDC和100mg NHS溶解在40mL 0.1mol/L MES缓冲液中,室温下搅拌24小时,得到HA-NHS。将40mg MSN-NH2分散在20mL乙醇中并搅拌1小时,然后加入12mg HA-NHS,搅拌4小时,合成MSN-HA。
实施例4 MSN、MSN-NH2和MSN-HA纳米颗粒的表征
根据KBr沉淀技术,在FT-IR光谱仪(Bruker IFS 55,Fällanden,Switzerland)上测量MSN、MSN-NH2、HA和MSN-HA的傅里叶变换红外(FT-IR)光谱。通过Zetasizer NanoZS90(Malvern,USA)测量MSN、MSN-NH2和MSN-HA在去离子水中的zeta电位。
图2为MSN、MSN-NH2、HA和MSN-HA的红外吸收光谱图。
图3为MSN、MSN-NH2和MSN-HA的Zeta电势图。如图3所示,MSN的ζ电位为-18.9±1.2mV的负值;在氨基化修饰后反向为+20.2±2.0 mV;修饰HA后,ζ电位反转至-26.8±1.6 mV的负值,这证实了HA成功的偶联到氨基化的介孔二氧化硅表面。
实施例5 EL或PTX负载的MSN-HA纳米颗粒的合成
将20mg的EL、20mg的PTX分别与60mg MSN-HA共同溶解在20mL乙醇中,室温下剧烈搅拌24小时,然后离心除去溶剂,用乙醇洗涤后在-50℃真空干燥器中干燥24小时获得产物,得EL@MSN-HA和PTX@MSN-HA。
实施例6 体外药物释放
为了确定EL和PTX从MSN-HA中的体外药物释放,将2mg游离的EL、游离PTX与EL@MSN、PTX@MSN、EL@MSN-HA、PTX@MSN-HA悬浮于50mL含有40%乙醇的PBS缓冲液(pH5.5或pH7.4)中。收集1mL悬浮液并以预定的时间间隔离心,在约233nm的紫外光谱处测定PTX的量,在约245nm的紫外光谱处测定的EL量,结果如图4所示。
如图4所示,在相同pH下,PTX和EL的溶解度差异无统计学意义。与游离的PTX和EL的释放相比,MSN和MSN-HA递送***在pH 7.4和pH 5.5下均可以持续的释放PTX和EL,且MSN和MSN-HA递送***在pH 5.5下的药物释放效率比pH 7.4下快。负载PTX或EL的MSN-HA载药***其药物释放百分比明显低于游离的药物和负载药物的MSN递送***。
该结果表明,与中性条件(如血液)相比,HA修饰的生物相容性MSN药物递送***在酸性环境(如肿瘤组织)中能更好的释放PTX或EL。
实施例7 细胞摄取
将A549细胞以2×105个细胞/孔的密度接种在24孔培养板上,培养过夜。之后,将培养板用PBS洗涤两次,在细胞中分别加入100 μg/mL FITC@MSN、FITC@MSN-HA和FITC@MSN-HA+HA,37℃下培养2 h。然后,每个孔中的细胞用冷PBS洗涤三次,用Hoechst 33342染色10分钟。最后将样品用共聚焦显微镜观测,结果如图5所示。
从图5可以看到,FITC@MSN-HA的荧光强度最大,说明细胞对它的摄取率最高。而FITC@MSN-HA+HA的荧光强度要稍低于FITC@MSN-HA,说明HA能够与FITC@MSN-HA竞争癌细胞上的受体,进一步证明了HA的靶向抗癌作用。
实施例8 MTT实验
分别培养A549细胞和H1975细胞,待其处于对数生长期且状态良好时,用胰蛋白酶消化后,血球计数板计数,调整细胞密度为1×105个/mL,配成细胞悬液;按每孔100µL接种到96孔板,周围用PBS封板,置于37℃、5 % CO2培养箱中隔夜培养;当细胞活性达到80%时加入用培养液稀释的不同浓度梯度的PTX、EL、PTX+EL、PE@MSN(EL@MSN和PTX@MSN按照1:1的比例混合)、PE@MSN-HA(EL@MSN-HA和PTX@MSN-HA按照1:1的比例混合)培养24 h;去除培养液,加入100 μL用无血清无酚红培养基稀释后的MTT溶液,37℃培养4 h;取出96孔板,吸出MTT溶液后加入100 μL DMSO,并在摇床上缓慢摇晃10 min,摇匀后多功能酶标仪于570 nm处检测OD值,使用GraphPad Prism 5计算细胞增殖抑制率,结果如图6所示。
由图6可见,PTX和EL呈浓度依赖性的抑制A549细胞和H1975细胞的增殖;当两者联合给药可以有效的提高两者的抗肿瘤的效果;与PTX+EL相比,PE@MSN、PE@MSN-HA均可以提高两者的抗肿瘤效果,且PE@MSN-HA的效果较PE@MSN显著,这说明,与PTX或EL单独用药相比,PTX与EL共负载到偶联有透明质酸分子的靶向纳米粒载体上,可以起到协同增效的治疗效果。
以上所述仅为本发明的较佳实施例,凡依本发明申请专利范围所做的均等变化与修饰,皆应属本发明的涵盖范围。
Claims (6)
1.一种负载紫杉醇/厄洛替尼的介孔二氧化硅-透明质酸混合靶向纳米颗粒,其特征在于:其制备方法包括以下步骤:
1)对介孔二氧化硅纳米颗粒表面进行氨基化修饰;
2)将透明质酸通过共价键偶联到氨基化修饰的介孔二氧化硅的外表面。
3)将紫杉醇、厄洛替尼分别负载到透明质酸修饰的介孔二氧化硅的内孔道;
4)将负载有紫杉醇的介孔二氧化硅与负载有厄洛替尼的介孔二氧化硅按质量比1:1混匀。
2.根据权利要求1所述负载紫杉醇/厄洛替尼的介孔二氧化硅-透明质酸混合靶向纳米颗粒,其特征在于:所用介孔二氧化硅纳米颗粒的粒径为150nm。
3.根据权利要求1所述负载紫杉醇/厄洛替尼的介孔二氧化硅-透明质酸混合靶向纳米颗粒,其特征在于:步骤1)的具体操作为:将介孔二氧化硅纳米颗粒溶于无水乙醇中,加入纳米颗粒重量0.4%的3-氨丙基三乙氧基硅烷,室温搅拌12h后离心,乙醇洗涤,冷冻干燥。
4. 根据权利要求1所述负载紫杉醇/厄洛替尼的介孔二氧化硅-透明质酸混合靶向纳米颗粒,其特征在于:步骤2)的具体操作为:将30mg透明质酸、100mg EDC和100mg NHS溶解在40mL 0.1mol/L的MES缓冲液中,室温下搅拌24小时,得到HA-NHS;将40mg氨基化修饰的介孔二氧化硅分散在20mL乙醇中并搅拌1小时,然后加入12mg HA-NHS,搅拌4小时,合成透明质酸修饰的介孔二氧化硅。
5.根据权利要求1所述负载紫杉醇/厄洛替尼的介孔二氧化硅-透明质酸混合靶向纳米颗粒,其特征在于:步骤3)的具体操作为:将20mg的紫杉醇及20mg的厄洛替尼分别与60mg透明质酸修饰的介孔二氧化硅共同溶解在20mL乙醇中,室温下剧烈搅拌24小时,然后离心除去溶剂,用乙醇洗涤后于-50℃下真空干燥24小时,得到负载有紫杉醇的介孔二氧化硅及负载有厄洛替尼的介孔二氧化硅。
6.一种如权利要求1所述的混合靶向纳米颗粒在制备抗癌药物上的应用。
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