CN109010902A - 一种具有抗肿瘤作用的肝素淀粉微球血管栓塞剂及制备方法 - Google Patents
一种具有抗肿瘤作用的肝素淀粉微球血管栓塞剂及制备方法 Download PDFInfo
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Abstract
本发明公开了一种具有抗肿瘤作用的肝素淀粉微球血管栓塞剂及制备方法,属于医药化工领域。具体涉及一种肝素淀粉微球血管栓塞剂及制备方法。本发明拟解决的技术问题是提供一种肝素淀粉微球血管栓塞剂及制备方法。该方法通过引入生物相容性好且具有抑制肿瘤生长和转移作用的肝素,制备出尺寸可控、粒径均匀的肝素淀粉微球。该肝素淀粉微球不仅具有栓塞效果,还能抑制肿瘤生长与转移,进而实现治癌的目的。本方法具有操作简便,重复性好,温度要求低等优点,能够通过控制反应条件,制备出具有良好的生物相容性、可降解性且无毒副作用的肝素淀粉微球,可广泛用于肿瘤血管栓塞与治疗,为其应用于医学领域奠定了基础。
Description
技术领域
本发明公开了一种具有抗肿瘤作用的肝素淀粉微球血管栓塞剂及制备方法,属于医药化工领域,具体涉及一种肝素淀粉微球血管栓塞剂及制备方法。
背景技术
作为近年来发展起来的新兴治疗方式,血管性介入疗法(Transcatcatheterarterial embolization,TAE)是在医学影像设备的引导下的一种微创医疗技术,具有创伤小、恢复快、疗效好的特点,已广泛应用于无法进行手术切除的肿瘤治疗中。经导管动脉栓塞(Transcatheter arterial chemoembolization, TACE)治疗是介入治疗中的重要技术,它是将血管栓塞材料和抗肿瘤药物在射线透视下插入靶动脉的导管灌注化疗药物,并用栓塞剂加以栓塞,既能阻断肿瘤血供,使得肿瘤缺少必要的营养供应,又增强了药物对肿瘤的杀伤力并降低了药物的系统毒性,达到控制出血、切断肿瘤血供营养、治疗血管性病变、以及消除病变器官功能的目的。但是,制得注意的是,TACE仍存在肿瘤耐药以及肿瘤新生血管需反复栓塞等不足。因此,探索进一步提高肿瘤介入治疗的远期疗效的栓塞剂,成为介入医学研究的重点课题之一。
目前,制备的栓塞剂种类繁多,性质各异。而理想的栓塞材料应具备以下条件:无毒、无抗原性、具有较好的生物兼容性,能迅速闭塞血管;能按需要栓塞不同口径、不同流量的血管,易经导管运送,使用便捷,安全可靠;能控制闭塞血管的时间长短,必要时可经动脉插管回收或使血管再通。目前制备栓塞微球所选用的基质材料一般分为不可降解型高分子材料和可降解型高分子材料两类。其中生物可降解材料由于其良好的生物相容性、生物降解性、理化及生物稳定性以及极低毒性而得到广泛关注。
作为最早使用的可降解微球原料,淀粉在非食用领域的开发具有极大的市场价值和社会意义。淀粉微球作为近些年来迅速发展的新型淀粉产品,不仅具有无毒性、无免疫原性,还具备较好的生物相容性、载药性、降解速度可控性、控释性、稳定性等优良性能,具有良好的工业化生产前景。
作为人体能自身合成的一种内源性产物,肝素首先从肝脏中发现而得名,是主要由肥大细胞和嗜碱性粒细胞产生的一种酸性黏多糖。肝素结构复杂,分子量在4000~20000之间,具有生物相容性、生物降解性以及水溶性等优点。除了抗凝作用外,对人体正常细胞并无杀伤作用。大量临床数据表明,肝素可以抑制肿瘤的生长和转移:癌症病人使用肝素进行治疗后,生存期明显延长,瘤体积得到控制,瘤转移几率大幅度降低(Wang Y,Xin D,LiuK,et al.Heparin -paclitaxel conjugates as drug delivery system:synthesis,self-assembly property, drug release,and antitumor activity.[J].BioconjugateChemistry,2009, 20(12):2214.)。与其他多糖类似,肝素可以快速被酶降解,体内清除时间相对较短。而且,由于其较化疗药物相比无毒性的特点,肝素在癌症治疗中日益得到重视。
淀粉微球作为肝癌栓塞剂在肝癌治疗中已显示出良好的前景,但其化学性质单一,只靠物理吸附载药也存在很多缺点,如药物与微球结合力弱。在淀粉微球中引入肝素,不仅能够克服淀粉微球的缺点,如形状不规整,性质不稳定,栓塞效果差等,制备出尺寸可控、粒径均匀的肝素淀粉微球,还可以在破坏肿瘤血供的情况下进一步抑制肿瘤的生长和转移,最终导致肿瘤细胞凋亡。
发明内容:
本发明拟解决的技术问题在于克服用作栓塞剂的淀粉微球的不足,通过引入生物相容性好且具有抑制肿瘤生长和转移作用的肝素,制备出尺寸可控、粒径均匀的肝素淀粉微球,不仅能够实现栓塞效果,还能抑制肿瘤生长与转移,进而实现治癌的目的。
技术方案:
本发明提供一种操作简便,重复性好的制备具有抗肿瘤作用肝素淀粉微球血管栓塞剂的方法,通过控制反应条件,制备出50μm-1000μm的肝素淀粉微球,本发明所提供的技术方案为:
1.水相的制备:将0.1mg~10mg淀粉和0.1mg~10mg肝素溶于1mL~10 mL去离子水中,溶解均匀后加入2mol/L的NaOH溶液,将pH值调节至8~14, 80℃~120℃油浴煮至淡黄色,将溶液冷却至35℃,待用。
2.油相的制备:以植物油为溶剂,向其中加入0.1mL~5mL的乳化剂, 50℃~70℃下搅拌至乳化剂完全溶解,将溶液冷却至50℃,待用。
3.单肝素淀粉微球的制备:将制备好的水相缓慢滴加到油相中,其中,搅拌速度为300r/min~800r/min,显微镜下观察乳化胶束尺寸达到要求后加入交联剂,30℃~60℃下反应2h~20h;离心分离出微球,并分别用环己烷、乙醇、丙酮反复洗涤1~5次,50℃~70℃真空干燥后得到肝素淀粉微球。
所述步骤1中淀粉为木薯淀粉、马铃薯淀粉、山芋淀粉、山药淀粉、藕淀粉、葛根淀粉等葡萄糖聚合物的一种或多种。
所述步骤1中肝素为标准肝素、低分子量肝素和超低分子量肝素的一种或多种。所述步骤1中肝素与淀粉的质量比为0∶1~1∶0。
所述步骤1中肝素淀粉溶液的浓度为0.1mg/mL~0.1mg/mL。
所述步骤1中植物油是玉米油、大豆油、花生油、橄榄油、蓖麻油等由脂肪酸和甘油化合而成的天然化合物的一种。
所述步骤2中乳化剂为Span60。
所述步骤2中乳化剂与水的体积比为1∶100~1∶5。
所述步骤3中油相与水相的体积比为1∶1~30∶1。
所述步骤3中交联剂为环氧氯丙烷。
所述步骤3中交联剂与水的体积比为1∶20~1∶1。
附图说明
图1为本发明肝素淀粉微球的扫描电镜图;
具体实施方式
实施例1:
(1)水相的制备:0.1g淀粉和0.1g肝素,加入到2ml去离子水中,溶解均匀后加入2mol/L的NaOH溶液,调节pH=12,100℃下油浴煮至淡黄色,溶液冷却至35℃,待用;
(2)油相的制备:向10ml大豆油中加入0.1gSpan60,60℃搅拌至Span60完全溶解,溶液冷却至50℃,待用;
(3)肝素淀粉微球的制备:将制备好的水相缓慢滴加到油相中,控制搅拌速度500r/min,显微镜观察乳化胶束尺寸达到要求后加入1ml环氧氯丙烷, 50℃下反应6h;离心分离出微球,并分别用环己烷、乙醇、丙酮反复洗涤3 次,60℃真空干燥后得到肝素淀粉微球。
实施例2∶
(1)水相的制备:0.5g淀粉和0.5g肝素,加入到2mL去离子水中,溶解均匀后加入2mol/L的NaOH溶液,调节pH=12,100℃下油浴煮至淡黄色,溶液冷却至 35℃,待用;
(2)油相的制备:向40ml大豆油中加入0.2g Span60,60℃搅拌至Span60完全溶解,溶液冷却至50℃,待用;
(3)肝素淀粉微球的制备:将制备好的水相缓慢滴加到油相中,控制搅拌速度500r/min,显微镜观察乳化胶束尺寸达到要求后加入1ml环氧氯丙烷, 50℃下反应6h;离心分离出微球,并分别用环己烷、乙醇、丙酮反复洗涤3 次,60℃真空干燥后得到肝素淀粉微球。
实施例3:
(1)水相的制备:0.8g淀粉和0.8g肝素,加入到4mL去离子水中,溶解均匀后加入2mol/L的NaOH溶液,调节pH=12,100℃下油浴煮至淡黄色,溶液冷却至 35℃,待用;
(2)油相的制备:向50ml大豆油中加入0.2g Span60,60℃搅拌至Span60完全溶解,溶液冷却至50℃,待用;
(3)肝素淀粉微球的制备:将制备好的水相缓慢滴加到油相中,控制搅拌速度500r/min,显微镜观察乳化胶束尺寸达到要求后加入1ml环氧氯丙烷, 50℃下反应6h;离心分离出微球,并分别用环己烷、乙醇、丙酮反复洗涤3 次,60℃真空干燥后得到肝素淀粉微球。
Claims (10)
1.一种具有抗肿瘤作用的肝素淀粉微球血管栓塞剂及制备方法,包括以下步骤:
1)水相的制备:将0.1mg~10mg淀粉和0.1mg~10mg肝素溶于1mL~10mL去离子水中,溶解均匀后加入2mol/L的NaOH溶液,将pH值调节至8~14,80℃~120℃油浴煮至淡黄色,将溶液冷却至35℃,待用;
2)油相的制备:以植物油为溶剂,向其中加入0.1mL~5mL的乳化剂,50℃~70℃下搅拌至乳化剂完全溶解,将溶液冷却至50℃,待用;
3)肝素淀粉微球的制备:将制备好的水相缓慢滴加到油相中,其中,搅拌速度为300r/min~800r/min,显微镜下观察乳化胶束尺寸达到要求后加入交联剂,30℃~60℃下反应2h~20h;离心分离出微球,并分别用环己烷、乙醇、丙酮反复洗涤1~5次,50℃~70℃真空干燥后得到肝素淀粉微球。
2.如权利要求1所述的一种具有抗肿瘤作用的肝素淀粉微球血管栓塞剂及制备方法,其特征在于步骤1)所述的淀粉为木薯淀粉、马铃薯淀粉、山芋淀粉、山药淀粉、藕淀粉、葛根淀粉等葡萄糖聚合物的一种或多种。
3.如权利要求1所述的一种具有抗肿瘤作用的肝素淀粉微球血管栓塞剂及制备方法,其特征在于步骤1)所述的肝素为标准肝素、低分子量肝素和超低分子量肝素的一种或多种。
4.如权利要求1所述的一种具有抗肿瘤作用的肝素淀粉微球血管栓塞剂及制备方法,其特征在于步骤1)所述的肝素与淀粉的质量比为0∶1~1∶0。
5.如权利要求1所述一种具有抗肿瘤作用的肝素淀粉微球血管栓塞剂及制备方法,其特征在于步骤1)所述的肝素淀粉溶液的浓度为0.1mg/mL~0.1mg/mL。
6.如权利要求1所述的一种具有抗肿瘤作用的肝素淀粉微球血管栓塞剂及制方法,其特征在于步骤2)所述的乳化剂为Span60。
7.根据权利要求1所述的一种具有抗肿瘤作用的肝素淀粉微球血管栓塞剂及制备方法,其特征在于步骤2)所述的乳化剂与水的体积比为1∶100~1∶5。
8.如权利要求1所述的一种具有抗肿瘤作用的肝素淀粉微球血管栓塞剂及制备方法,其特征在于步骤3)所述的油相与水相的体积比为1∶1~30∶1。
9.如权利要求1所述的一种具有抗肿瘤作用的肝素淀粉微球血管栓塞剂及制备方法,其特征在于步骤3)所述的交联剂为环氧氯丙烷。
10.如权利要求1所述的一种具有抗肿瘤作用的肝素淀粉微球血管栓塞剂及制备方法,其特征在于步骤3)所述的交联剂与水的体积比为1∶20~1∶1。
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