CN105078900B - 一种多西紫杉醇纳米载药颗粒、其制备方法和应用 - Google Patents
一种多西紫杉醇纳米载药颗粒、其制备方法和应用 Download PDFInfo
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Abstract
本发明公开了一种多西紫杉醇纳米载药颗粒、其制备方法和应用,多西紫杉醇纳米载药颗粒包括纳米颗粒、包裹在所述的纳米颗粒内的多西紫杉醇、通过共价键修饰于所述的纳米颗粒表面的巯基化的EGF1蛋白,所述的纳米颗粒是由马来酰亚胺‑聚乙二醇‑聚乳酸‑羟基乙醇酸聚合物形成。本发明公开的纳米颗粒生物靶向性良好,能够主动靶向过度表达组织因子的肿瘤细胞或肿瘤血管细胞,可以有效地提高药物在肿瘤部位的聚集浓度,降低药物的毒副作用。
Description
技术领域
本发明涉及生物材料与纳米技术领域,具体涉及一种具有较高包封率和载药量、高生物安全性,并且能够缓慢释放药物多西紫杉醇的多西紫杉醇纳米载药颗粒、其制备方法和应用。
背景技术
癌症是世界范围内仅次于心血管疾病的第二大严重威胁人类健康和生命的疾病。而乳腺癌的发病率在整个癌症中排名第二,是我国女性最常见的恶性肿瘤,且发病率呈逐年上升趋势。目前对于乳腺癌的治疗手段包括手术治疗、放射治疗、化学治疗、内分泌治疗和分子靶向治疗,但仍以手术切除为主。分子靶向治疗能够提高肿瘤化疗药物疗效,降低其毒副作用,是近年来乳腺癌治疗研究领域最为活跃的部分,对于提高乳腺癌临床治疗效果具有极其重要的意义,并有可能成为今后乳腺癌药物研发的主要方向(http://www.haodf.com/jibing/ruxianai.htm)。
多西紫杉醇(docetaxel,DTX)又名多西他赛,是新一代紫杉醇烷类抗肿瘤药物。它通过作用于细胞微管与聚合的管蛋白作用并抑制其解聚,使肿瘤细胞停止在有丝分裂期而死亡,有效抑制肿瘤细胞的复制。临床研究表明,多西紫杉醇可以单独或与其他抗肿瘤药物合用治疗非小细胞性肺癌、乳腺癌、卵巢癌、胃癌等癌症。由于多西紫杉醇具有亲脂性,基本不溶于水,因此上市的静脉注射剂多西紫杉醇浓溶液中含有大量的吐温80,且需要用13%乙醇稀释后方能注射。由于吐温80具有溶血性且黏度较大,临床试验中大多数患者产生明显的过敏反应,并且药物本身也具有一定的毒副作用,容易引起骨髓抑制,神经毒性反应,心脏毒性反应,关节或者肌肉疼痛,肝脏肾脏毒性反应等。因此近年来开发新型多西紫杉醇制剂一直是研究的热点。
纳米药物载体通过将药物包封于亚微粒中,可以调节释药的速度,能增加生物膜的透过性,改变在体内的分布,提高生物利用度等,为改善抗肿瘤药物疗效和降低肿瘤耐药性提供了新的思路。而且纳米载药颗粒还有另一优势,实现纳米粒介导的靶向治疗。纳米粒介导的靶向治疗是通过纳米粒子作为载体,包裹药物(核苷酸、蛋白或小分子化合物),同时在纳米粒表面连接具有导向功能的靶头,将药物递送到靶向部位,提高药物在局部的浓集和释放,从而实现靶向干预治疗。靶向释药系统能够克服或部分的解决抗肿瘤药物毒副作用大、水溶性差、半衰期短、生物利用度低等传统化疗中存在的问题,在改善化疗药物的体内分布特性和药代动力学特性,增加药物效力,降低药物毒性,减少肿瘤多药耐药性产生从而提高治疗指数和肿瘤化疗效果方面有着独特的优势,在肿瘤治疗中有着非常良好的应用前景。
组织因子(tissue factor,TF)又称凝血因子Ⅲ,是外源性凝血系统的启动因子,是人体内活性最强的促凝物质之一。经研究发现TF除了在正常生理状态下表现的功能外,在肿瘤的发展过程中起着重要的作用。TF的过度表达经常被与肿瘤的发生相关联,TF在转移性癌细胞比在非转移癌细胞表达水平可高达1000倍以上,提示TF在肿瘤转移的直接作用。目前已知的TF在人脑胶质瘤、转移性乳腺癌、大肠癌、胰腺癌等癌症细胞上过度表达。肿瘤细胞上过度表达的TF与肿瘤的血管生成、肿瘤发生转移、肿瘤侵袭以及肿瘤患者预后等有密切关联。根据TF在肿瘤细胞及肿瘤血管细胞表面的高表达状态,其作为肿瘤分子靶向治疗的靶点已经收到了广泛关注。目前有关TF 及其配体FⅦ的研究发现,FⅦ上类表皮生长因子I 区多肽(First epidermal growth factor-likedomain,EGF1)是与TF 结合的重要配体,该肽段具有结合TF 功能而无促凝活性,因此EGF1 肽可基于配/受体的相互作用而成为靶向TF 制剂的导向功能基。
目前已有很多研究以FⅦ突变体(其中氨基酸突变)作为靶向功能基修饰于载药纳米颗粒表面或者与细胞免疫蛋白融合表达,靶向癌细胞表面过表达的组织因子,从而达到治疗的目的。另外也有以EGF1作为靶向多肽,修饰于紫杉醇纳米颗粒表面用于脑胶质瘤的治疗。但是EGF1-多系紫杉醇纳米载药颗粒的研究尚未见报道。因此本专利是在该方面的创新,制备了一种新颖的靶向纳米载药颗粒。
发明内容
本发明的目的是提供通过超声乳化/溶剂挥发法,构建针对药物包裹多西紫杉醇的纳米载药系统,解决多西紫杉醇水溶性、缓释性、吸收性、存在的问题,同时在该纳米颗粒表面修饰一种靶向性多肽,直接靶向肿瘤细胞,提高对肿瘤的治疗效果。
为达到上述目的,本发明采用的技术方案是:
一种多西紫杉醇纳米载药颗粒,其包括纳米颗粒、包裹在所述的纳米颗粒内的多西紫杉醇、通过共价键修饰于所述的纳米颗粒表面的巯基化的EGF1蛋白,所述的纳米颗粒是由马来酰亚胺-聚乙二醇-聚乳酸-羟基乙醇酸聚合物形成。
具体地,所述的马来酰亚胺-聚乙二醇-聚乳酸-羟基乙醇酸聚合物中的马来酰亚胺基与所述的巯基化的EGF1蛋白中的巯基形成所述的共价键。
一种所述的多西紫杉醇纳米载药颗粒的制备方法,包括依次进行的如下步骤:
步骤(1)、采用挥发性有机溶剂将所述的马来酰亚胺-聚乙二醇-聚乳酸-羟基乙醇酸聚合物与所述的多西紫杉醇溶解,得到有机相,而后在超声乳化仪超声的条件下将所述的有机相分散至水相中,得到水包油型乳液,搅拌使所述的有机溶剂挥发,得到纳米颗粒,离心后制得包裹有多西紫杉醇的纳米颗粒;
步骤(2)、将步骤(1)制得的包裹有多西紫杉醇的纳米颗粒与所述的巯基化的EGF1蛋白在孵育条件下以所述的共价键连接,制得所述的多西紫杉醇纳米载药颗粒。
具体地,所述的挥发性有机溶剂为二氯甲烷,所述的水相为质量浓度为0.5wt%~2wt%的聚乙烯醇水溶液,所述有机相与水相的体积之比为15~25:1。
具体地,所述的马来酰亚胺-聚乙二醇-聚乳酸-羟基乙醇酸聚合物与所述的多西紫杉醇的投料质量比为40~60:1。
具体地,步骤(1)中还包括在离心操作后,采用超纯水将包裹有多西紫杉醇的纳米颗粒洗涤干净、冻干的步骤。
具体地,步骤(2)中,所述的包裹有多西紫杉醇的纳米颗粒中的马来酰亚胺-聚乙二醇-聚乳酸-羟基乙醇酸聚合物与所述的巯基化的EGF1蛋白中的巯基的投料摩尔比为1:0.5~1.5。
具体地,步骤(2)的具体实施方式为:将所述的包裹有多西紫杉醇的纳米颗粒加入到磷酸盐缓冲液中,混匀后,加入所述的巯基化的EGF1蛋白,在10~35℃下避光、充氮气的情况下磁力搅拌10~16小时,然后在2~6℃、13500~14500rpm的条件离心,除去上清液后,加入磷酸盐缓冲液混匀,经Sepharose CL-4B 柱,除去未结合的游离蛋白,收集洗脱液,所述的洗脱液经冷冻干燥得到所述的多西紫杉醇纳米载药颗粒。
更具体地,所述的磷酸盐缓冲液的浓度为0.008~0.012mol/L。
一种所述的多西紫杉醇纳米载药颗粒在制备治疗过度表达组织因子的肿瘤的药物中的应用。
优选地,一种所述的多西紫杉醇纳米载药颗粒在制备治疗乳腺癌的药物中的应用。
由于上述技术方案的运用,本发明与现有技术相比具有下列优点:采用简单易行的超声乳化溶剂挥发法制备纳米载药颗粒,该方法成本低廉,可重复性好,不需要超洁净实验环境,并可以大批量制备,具有操作方便、简单易行、成本低廉以及可重复性好等优势,这些优势可被广泛应用于多种疏水性药物的纳米载药颗粒制备。同时在制备的纳米颗粒表面修饰靶向性多肽,能够主动靶向肿瘤细胞,且与组织因子的胞外区具有较高的亲和力,不会引起凝血效应,提高药物在肿瘤部位的浓度,降低药物的毒性,生物安全性良好,且能有效延长药物释放时间,有效地提高多西紫杉醇的生物利用度,提供了一种新颖的肿瘤靶向药物治疗方式。
附图说明
附图1 为多西紫杉醇纳米载药颗粒的制备流程示意图;
附图2 为EGF1 蛋白的诱导表达鉴定的SDS-PAGE电泳图,其中:M:Marker;带1为诱导后工程菌BL21;带2为未诱导菌;带3,4为纯化后洗脱液;
附图3 为包裹有多西紫杉醇的纳米颗粒的粒径分布图;
附图4为多西紫杉醇纳米载药颗粒的粒径分布图。
具体实施方式
以下结合具体实施例对上述方案作进一步说明,应理解,这些实施例是用于说明本发明而不限于限制本发明的范围。实施例中所采用的实施条件可以根据具体厂家的条件做进一步调整,未注明的实施条件通常为常规实验中的条件。以下实施例中表示含量的百分比“%”均指的是质量百分含量。
实施例1:包裹多西紫杉醇的的纳米颗粒的制备包括以下步骤:
1)称取1mg多西紫杉醇和50mg的马来酰亚胺-聚乙二醇-聚乳酸-羟基乙醇酸聚合物(Malemide-PEG-PLGA)溶于1ml二氯甲烷,振荡使其充分溶解,得到有机相。
)在冰浴超声的条件下,在持续超声90s内将有机相用注射器缓慢均匀的加入到20ml的1%聚乙烯醇水溶液中,继续设置超声12min(参数设置,功率为300w,1s开1s关)得到O/W型乳液。
)保鲜膜扎孔封口,磁力搅拌10h,使二氯甲烷缓慢的挥发,纳米颗粒均匀的固化。
)将纳米颗粒混悬液进行高速离心(仪器参数设置:16000rpm,25℃,60min),将上清液倾倒出,得到包裹多西紫杉醇的的纳米颗粒。
)超纯水洗涤包裹多西紫杉醇的的纳米颗粒,除去游离的药物,取部分添加5%(w/v) 蔗糖作为冻干保护剂混合均匀,于冷冻干燥机中冻干,称量质量。
)包裹多西紫杉醇的的纳米颗粒尺寸表征:取一定量的冻干纳米颗粒,加入适量的双蒸馏水中,搅拌使其重悬。用马尔文粒度仪测定纳米颗粒的粒径(参见附图3),得到该纳米颗粒的平均粒径为(90.4±11.4)nm,分散系数为0.134。
)纳米颗粒的包封率和载药量的测定:采用高相液相色谱法(参数设置:流动相:乙腈:水=60::40;流速:1ml/min;检测波长:230nm;色谱柱:AltimaC18,250mm×4.6mm,5um)测定纳米颗粒的包封率为(83.56±1.23)%,载药量为(1.35±0.12)%。
实施例2:EGF1蛋白的制备及巯基化修饰
一:EGF1蛋白的制备过程包括pET28a-EGF1质粒的构建,转化、蛋白诱导表达以及纯化鉴定。
)用EcoRⅠ酶和HindⅢ酶切EGF1的编码基因和pET28a质粒,然后将具有相同酶切位点的线性DNA进行连接,得到pET28a-EGF1质粒。
)将pET28a-EGF1质粒转化BL21(DE3)菌株,用含100ug/ml氨苄青霉素的琼脂平板筛选阳性菌落,挑取阳性菌落,接种于5ml含100ug/ml氨节青霉素的LB培养基中,摇菌24h;
3)按照1:100接种于lL新鲜LB培养液中(含有100mg/L卡那),摇床250rpm摇菌培养6h;
4)加入IPTG至终浓度1mmol/L,23℃ 200rpm诱导表达4h,收获BL21菌液;4℃,10000g,离心10min收集菌体,0.01M PBS缓冲液重悬沉淀,4℃ 6000rpm 离心10min收集沉淀;
5)取50g菌体用50ml,0.01M PBS分散,冰浴下超声2min、间隔2min共超声40min,4℃ 21000g 离心30min,收集上清;
6)将上清过已用pH8.0含有50mM Tris.Cl/50mM Arg/l0mM咪唑/5%甘油的平衡液(NiA)平衡的Ni Sepharose亲和层析柱;
7)用pH8.0含有50mM Tris.Cl/50mM Arg/60mM咪唑/5%甘油的平衡液(NiB)洗脱杂蛋白;
8)用pH8.0含有50mM Tris.Cl/50mM Arg/300mM咪唑/5%甘油的平衡液(NiC)洗脱并收集产物;
9)将洗脱物过1L Sephacry S-100 HR层析柱(S100),用2L pH8.0含有50mMTris.Cl/500Mm NaCl(S100冲洗液)冲洗,根据蛋白纯化仪实时监测分5部分收集蛋白;
10)SDS-PAGE电泳分析确定纯度最高的目的蛋白(参见图2),切胶、胰酶消化并将消化产物通过肽段质量指纹谱鉴定,最终得到目的EGF1蛋白;
二:EGF1蛋白的巯基化:
通过巯基化反应,采用2-iminothiolane(Traut’s试剂)将巯基引入到EGF1蛋白上。
)将EGF1蛋白溶解于0.15 mol/L的硼酸钠/ 0.1 mmol/L的EDTA缓冲液(pH 8.5)中;
2)以EGF1: 2-iminothiolane摩尔比为1:40 加入Traut’s试剂,室温搅拌1 h;
3)经Sephadex G-100 凝胶层析柱分离除去2-iminothiolane,洗脱液为0.01mol/L PBS(pH 7.0),即得巯基化EGF1 蛋白。
实施例3:EGF1蛋白修饰于包裹多西紫杉醇的纳米颗粒表面
1)取5 ml 0.01 mol/L PBS,加入冷冻干燥得到的多西紫杉醇纳米载药颗粒,用移液器吹打分散,混匀后转移入小烧杯中;
2)按照-SH: MAL一PEG一PLGA的摩尔比为1:1加入巯基化的EGF1蛋白至上述溶液中;
3)室温、避光、充N2和低速磁力搅拌过夜;
4)将搅拌后的溶液在4℃下14000 rpm 离心60 min,除去上清;
5)加入2.0 ml 0.01 mol/L PBS,吹打分散使混匀;
6)将上述步骤5所得溶液过Sepharose CL-4B 柱,除去未结合的游离蛋白,收集含DTX-EGF1-NP的洗脱液。
)DTX-EGF1-NP进行冷冻干燥,得到纳米颗粒冻干粉。
)DTX- EGF1-NP 的表征:将该纳米颗粒粉末重新混悬于0.001 mol/L NaCl 介质,利用马尔文粒度仪测定该纳米颗粒的粒径为112.3±7.3 nm,分散系数为0.142(参见图4)。
该DTX- EGF1-NP在癌症治疗中的应用:
由于多西紫杉醇可以用于非小细胞性肺癌、乳腺癌、卵巢癌、胃癌等癌症的治疗,而且在晚期和转移性乳腺癌细胞表面过表达组织因子,因此本发明制备的纳米载药颗粒可以用于乳腺癌的靶向治疗,较好的提高多西紫杉醇在乳腺癌病灶部位的聚集浓度,降低毒副作用,提高其生物利用度,在癌症的治疗中有良好的应用前景。
上述实施例只为说明本发明的技术构思及特点,其目的在于让熟悉此项技术的人士能够了解本发明的内容并加以实施,并不能以此限制本发明的保护范围,凡根据本发明精神实质所作的等效变化或修饰,都应涵盖在本发明的保护范围内。
Claims (3)
1.一种多西紫杉醇纳米载药颗粒,其特征在于:其包括纳米颗粒、包裹在所述的纳米颗粒内的多西紫杉醇、通过共价键修饰于所述的纳米颗粒表面的巯基化的EGF1蛋白,所述的纳米颗粒是由马来酰亚胺-聚乙二醇-聚乳酸-羟基乙醇酸聚合物形成,所述的马来酰亚胺-聚乙二醇-聚乳酸-羟基乙醇酸聚合物中的马来酰亚胺基与所述的纳米颗粒表面的EGF1蛋白的巯基通过共价键结合;所述的多西紫杉醇纳米载药颗粒的制备方法包括依次进行的如下步骤:
步骤(1)、采用挥发性有机溶剂将所述的马来酰亚胺-聚乙二醇-聚乳酸-羟基乙醇酸聚合物与所述的多西紫杉醇溶解,得到有机相,而后在超声乳化仪超声的条件下将所述的有机相分散至水相中,得到水包油型乳液,搅拌使所述的有机溶剂缓慢挥发,得到纳米颗粒,离心后制得包裹有多西紫杉醇的纳米颗粒;所述的挥发性有机溶剂为二氯甲烷,所述的水相为质量浓度为0.5wt%~2wt%的聚乙烯醇水溶液,所述有机相与水相的体积之比为15~25:1;所述的马来酰亚胺-聚乙二醇-聚乳酸-羟基乙醇酸聚合物与所述的多西紫杉醇的投料质量比为40~60:1;
步骤(2)、将步骤(1)制得的所述的包裹有多西紫杉醇的纳米颗粒加入到磷酸盐缓冲液中,混匀后,加入所述的巯基化的EGF1蛋白,在10~35℃下避光、充氮气的情况下磁力搅拌10~16小时,然后在2~6℃、13500~14500rpm的条件离心,除去上清液后,加入磷酸盐缓冲液混匀,经Sepharose CL-4B 柱,除去未结合的游离蛋白,收集洗脱液,所述的洗脱液经冷冻干燥得到所述的多西紫杉醇纳米载药颗粒;所述的包裹有多西紫杉醇的纳米颗粒中的马来酰亚胺-聚乙二醇-聚乳酸-羟基乙醇酸聚合物与所述的巯基化的EGF1蛋白中的巯基的投料摩尔比为1:0.5~1.5;所述的磷酸盐缓冲液的浓度为0.008~0.012mol/L;
步骤(1)中还包括在离心操作后,采用超纯水将包裹有多西紫杉醇的纳米颗粒洗涤干净、冻干的步骤。
2.一种如权利要求1所述的多西紫杉醇纳米载药颗粒的制备方法,其特征在于:包括依次进行的如下步骤:
步骤(1)、采用挥发性有机溶剂将所述的马来酰亚胺-聚乙二醇-聚乳酸-羟基乙醇酸聚合物与所述的多西紫杉醇溶解,得到有机相,而后在超声乳化仪超声的条件下将所述的有机相分散至水相中,得到水包油型乳液,搅拌使所述的有机溶剂挥发,得到纳米颗粒,离心后制得包裹有多西紫杉醇的纳米颗粒;所述的挥发性有机溶剂为二氯甲烷,所述的水相为质量浓度为0.5wt%~2wt%的聚乙烯醇水溶液,所述有机相与水相的体积之比为15~25:1;所述的马来酰亚胺-聚乙二醇-聚乳酸-羟基乙醇酸聚合物与所述的多西紫杉醇的投料质量比为40~60:1;
步骤(2)、将步骤(1)制得的所述的包裹有多西紫杉醇的纳米颗粒加入到磷酸盐缓冲液中,混匀后,加入所述的巯基化的EGF1蛋白,在10~35℃下避光、充氮气的情况下磁力搅拌10~16小时,然后在2~6℃、13500~14500rpm的条件离心,除去上清液后,加入磷酸盐缓冲液混匀,经Sepharose CL-4B 柱,除去未结合的游离蛋白,收集洗脱液,所述的洗脱液经冷冻干燥得到所述的多西紫杉醇纳米载药颗粒;所述的包裹有多西紫杉醇的纳米颗粒中的马来酰亚胺-聚乙二醇-聚乳酸-羟基乙醇酸聚合物与所述的巯基化的EGF1蛋白中的巯基的投料摩尔比为1:0.5~1.5;所述的磷酸盐缓冲液的浓度为0.008~0.012mol/L;
步骤(1)中还包括在离心操作后,采用超纯水将包裹有多西紫杉醇的纳米颗粒洗涤干净、冻干的步骤。
3.一种如权利要求1所述的多西紫杉醇纳米载药颗粒在制备治疗过度表达组织因子的肿瘤的药物中的应用。
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