CN113262309B - 一种负载抗肿瘤药物的超支化-嵌段共接枝药物载体及其制备方法和应用 - Google Patents
一种负载抗肿瘤药物的超支化-嵌段共接枝药物载体及其制备方法和应用 Download PDFInfo
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Abstract
本发明公开了一种负载抗肿瘤药物的超支化‑嵌段共接枝药物载体:包括超支化‑嵌段共接枝载体,以及包埋于超支化‑嵌段共接枝载体中的抗肿瘤药物;超支化‑嵌段共接枝载体为亲水核‑疏水桥接‑亲水PEG嵌段共接枝载体。本发明还公开了上述药物载体的制备方法:通过酯交换方法合成HPG‑MA;利用巯基‑烯基点击反应合成HPG‑SDP;通过双相萃取‑真空冻干联用法将抗肿瘤药物封装在HPG‑SDP中,得到药物载体。本发明还公开了上述药物载体在制备抗肿瘤治疗药物中的应用。该药物载体提高了抗肿瘤药物的理化稳定性并赋予药物肿瘤靶向性,解决了抗肿瘤药物在生物体中利用率低的问题和减少了药物治疗的毒副作用;本发明提供的制备方法简单并得到高负载量抗肿瘤药物的药物载体。
Description
技术领域
本发明涉及靶向载体,具体涉及一种负载抗肿瘤药物的超支化-嵌段共接枝药物载体及其制备方法和应用。
背景技术
恶性肿瘤的临床治疗效果尚不理想。药物组合治疗、纳米医学等领域的研究进展为肿瘤治疗带来了新思路和新方法。通过筛选新型药物组合方案,采用有针对性的纳米药物载体,可以为恶性肿瘤治疗提供新策略,提升临床疗效。
超支化聚缩水甘油(HPG)是一类分子内部富含醚键而分子表面富含羟基的超支化聚合物,其起始单元一般为三羟甲基丙烷,重复单元为缩水甘油。HPG的特殊结构和化学键,赋予了其优良的水溶性与生物相容性。而且,其中的空腔可满足载药的需要,其独特的单分子胶束可以起到药物增溶的效果。经过特殊的改性,还可以令HPG变成具有靶向作用的药物载体。因此,HPG是理想的药物载体。
索拉非尼是一种分子靶向药物,其主要靶点为VEGFR、PDGFR、RAF/MEK/ERK等。在临床上,索拉非尼可用于肝细胞癌等多种恶性肿瘤的治疗。近些年的研究发现,索拉非尼还可以通过诱导肿瘤细胞铁死亡,抑制肿瘤生长。
肿瘤单药靶向治疗的效果尚不理想,通过构建适当的纳米药物载体,可以增加药物在生物体内的稳定性,增加药物在生物体内的有效循环时间,促进肿瘤内部的药物投递,从而有效增强药物的治疗效果、减轻副作用。
综上所述,超支化聚缩水甘油是一种理想的药物载体,通过适当的改进,可以有效增进所搭载药物的治疗效果;基于超支化聚缩水甘油的药物载体,可以促进药物靶向投递,增强肿瘤区域药物浓度,增强治疗效果,减轻药物副作用。
发明内容
本发明的目的在于提供了一种负载抗肿瘤药物的超支化-嵌段共接枝药物载体及制备方法。本发明提供的方法提高了药物的理化稳定性;本发明提供的方法赋予了超支化聚缩水甘油以pH响应性,并可赋予药物肿瘤靶向性,从而解决了药物在肿瘤治疗过程中利用率低的问题,在增强治疗效果的同时,减少了药物治疗的毒副作用;本发明提供的制备方法简单,可以得到具有高负载量的纳米药物。
本发明所提供的技术方案为:
一种负载抗肿瘤药物的超支化-嵌段共接枝药物载体,所述药物载体包括超支化-嵌段共接枝载体,以及包埋于超支化-嵌段共接枝载体中的抗肿瘤药物;所述超支化-嵌段共接枝载体为亲水核-疏水桥接-亲水PEG嵌段共接枝载体。
作为优选,所述抗肿瘤药物为索拉非尼(Sorafenib,标记为SRF)。
作为优选,所述药物载体中索拉非尼的负载量为12.48-20.36%。
本发明还提供了一种负载抗肿瘤药物的超支化-嵌段共接枝药物载体的制备方法,所述制备方法包括:
(1)通过酯交换方法合成端基含双键的超支化聚缩水甘油HPG-MA;
(2)利用了巯基-烯基点击反应,在紫外光条件下,合成出具有pH响应性的超支化-嵌段共接枝载体HPG-SDP;
(3)通过双相萃取-真空冻干联用法将抗肿瘤药物封装在超支化-嵌段共接枝载体中,得到抗肿瘤药物-超支化-嵌段共接枝药物载体(负载抗肿瘤药物的药物载体)。
作为优选,通过双相萃取-真空冻干联用法将索拉非尼(标记为SRF)封装在超支化-嵌段共接枝载体中,得到索拉非尼-超支化聚缩水甘油载体(标记为SRF@HPG-SDP);
作为优选,所述合成方法包括:
首先以三羟甲基丙烷(TMP)为起始剂,在无水无氧条件下加入甲醇钾粉末活化TMP,以生成活性的阴离子。经过真空除去生成的甲醇后,在氮气保护下,以注射泵缓慢以24小时逐滴加入单体缩水甘油的方法,最后经过阳离子交换树脂处理及丙酮中沉淀,最后合成超支化聚缩水甘油(HPG)。
进一步优选,合成HPG过程中,TMP、甲醇钾和缩水甘油的使用量的物质的量比例为1:1:50-100,HPG的相对数均分子质量为3000-25000。
而后使用酯交换方法合成端基含双键的超支化聚缩水甘油(标记为HPG-MA):将超支化聚缩水甘油溶解于有机溶剂中添加4-二甲基氨基吡啶,再加入甲基丙烯酸缩水甘油酯后室温下反应得到产物,记为HPG-MA。具体方法为:取超支化聚缩水甘油,溶解分散于适量DMSO中,添加4-二甲基氨基吡啶于其中,通入氮气保护,逐滴加入甲基丙烯酸缩水甘油酯(GMA),室温下搅拌过夜后倾入适量乙醚中搅拌,可观察得到橙黄色液体沉于下层,用乙醚洗涤3遍后弃去上层乙醚层后得到黏稠液体,真空烘去乙醚得到产物,记为HPG-MA。进一步优选,HPG、4-二甲基氨基吡啶与GMA的质量比为1-10:10-50:20-200。
利用了巯基-烯基点击反应,在紫外光条件下,快速地合成出具有pH响应性的超支化-嵌段共接枝载体(标记为HPG-SDP)。HPG-SDP属于亲水核-疏水桥接-亲水PEG嵌段共接枝载体,其上含有双亲性结构,在弱碱性环境中可进行自组装成为搭载药物的胶束,胶束在弱酸性的环境中可以发生变化,胶束发生分解,从而令搭载在其中的药物得到释放。大分子结构中的天然空穴一来可捕捉索拉非尼分子,同时利用其上的疏水的十二烷基与索拉非尼记性上的相亲性,实现索拉非尼分子在HPG-SDP的富集;二来可通过EDC/NHS处理,实现荧光蛋白的固载,从而用于指示细胞吞噬作用。相对HPG来说,HPG-SDP具有了pH响应性与更丰富的功能性。具体的合成方法是:将HPG-MA溶于DMSO中,而后加入适当量的正十二硫醇和端基同时含有巯基和羟基的巯基-聚乙二醇-羟基(SH-PEG-OH),充分搅拌均匀后,添加适量的二苯甲酮,经充分鼓入氮气后,在紫外光条件下快速地合成出具有pH响应性的超支化-嵌段共接枝载体(HPG-SDP)。
作为优选,所使用的SH-PEG-OH的数均相对分子质量为3000及以上,HPG-MA、正十二硫醇和SH-PEG-OH的质量比为:1-10:10-50:20-200。
作为优选,所述双相萃取-真空冻干联用法包括:
HPG-SDP与抗肿瘤药物(如索拉非尼)分别配制成水溶液和氯仿溶液,室温下以磁力搅拌法充分搅拌一定时间,得到抗肿瘤药物(如索拉非尼)富集的载药新体系,如SRF@HPG-SDP;进一步优选,所述混合是指搅拌0.5-3h;所述HPG-SDP和超纯水的质量比、抗肿瘤药物(如SRF)和氯仿的质量比分别设为1-10:100和20-50:100。
具体为:先将抗肿瘤药物(如索拉非尼)溶于氯仿中,将HPG-SDP溶于超纯水中。经过充分的高速搅拌后,先旋蒸除去氯仿;水相部分经抽滤除去不溶物后,转移至透析袋中充分透析3天,每天更换透析液超纯水3次以除去游离的索拉非尼及其他杂质。最后转移至冻干机中充分冻干,即可获得负载抗肿瘤药物的超支化-嵌段共接枝药物载体。
本发明提供的制备方法合成方法简单,制备的药物载体中抗肿瘤药物(如索拉非尼)的负载量最高可达20%以上,提高了药物的利用率和药效。
本发明还提供一种上述的负载抗肿瘤药物的超支化-嵌段共接枝载体药物载体在抗肿瘤治疗中的应用。
同现有技术相比,本发明的有益效果体现在:
(1)本发明中超支化-嵌段共接枝药物载体对抗肿瘤药物具有保护作用,能够减缓药物在体内非肿瘤部位的降解速度,从而延长了药物在血液循环系统中高浓度存在的时间。
(2)本发明中超支化-嵌段共接枝药物载体直径为20-100nm,能够通过细胞膜的内吞作用进入细胞,且其结构稳定,能够通过人体代谢排除,无明显细胞毒性。
(3)本发明中,超支化-嵌段共接枝药物载体具有pH靶向性,将抗肿瘤药物封装在该药物载体内,可以使其具有针对肿瘤组织的靶向性,能使其选择性降解于肿瘤组织部位,从而靶向针对肿瘤细胞,促进肿瘤内化疗药物投递,增强肿瘤治疗效果。
附图说明
图1为实施例1-3中HPG-SDP的制备路径;
图2为实施例1-3分别制备的HPG、HPG-MA和HPG-SDP的核磁共振氢谱分析图;
图3为实施例1-4分别制备的HPG、HPG-MA、HPG-SDP和SRF@HPG-SDP的红外图谱图;
图4为实施例3制备的HPG-SDP的透射电镜图;
图5为实施例4制备的SRF@HPG-SDP的透射电镜图;
图6为不同pH下实施例4制备的SRF@HPG-SDP的药物释放曲线图;
图7为实施例3、4分别制备的HPG-SDP、SRF@HPG-SDP在抑制肿瘤细胞活性中的作用分析图;
图8为实施例3、4分别制备的HPG-SDP、SRF@HPG-SDP在诱导肿瘤细胞凋亡中的作用分析图。
具体实施方式
下面结合具体的实施例对本发明作进一步说明。
实施例1:制备HPG
首先,以三羟甲基丙烷(TMP)为起始剂,在75℃无水无氧条件下加入甲醇钾粉末活化TMP,以生成活性的阴离子。经过真空除去生成的甲醇后,在氮气保护下,以注射泵缓慢以24小时逐滴加入单体缩水甘油的方法,最后经过阳离子交换树脂处理及500mL丙酮中沉淀,最后合成超支化聚缩水甘油(HPG)。合成HPG过程中,所使用的TMP、甲醇钾和缩水甘油的物质的量之比为1:1:50-100,获得的HPG的数均相对分子质量为3000-25000。
实施例2:制备HPG-MA
而后,使用酯交换方法合成端基含双键的超支化聚缩水甘油(标记为HPG-MA)。具体方法为:取超支化聚缩水甘油,溶解分散于20mL的DMSO中,添加4-二甲基氨基吡啶于其中,通入氮气保护,逐滴加入甲基丙烯酸缩水甘油酯(GMA),室温下搅拌12小时后倾入1L乙醚中搅拌,可观察得到橙黄色液体沉于下层,用乙醚洗涤3遍后弃去上层乙醚层后得到黏稠液体,25℃真空烘去乙醚得到产物。制备过程中,控制HPG、4-二甲基氨基吡啶与GMA的质量比为1-10:10-50:20-200。
实施例3:制备HPG-SDP
利用了巯基-烯基点击反应,在紫外光条件下,快速地合成出具有pH响应性的超支化-嵌段共接枝载体:将HPG-MA溶于DMSO中,而后加入正十二硫醇和端基同时含有巯基和羟基的巯基-聚乙二醇-羟基(SH-PEG-OH),充分搅拌均匀后,添加适量的二苯甲酮,经充分鼓入氮气5min后,在356nm的紫外光条件下,辐照30min后,经过在氯仿中透析3天,每天更换透析液3次,在40℃的旋蒸除去氯仿后即可得到具有pH响应性的超支化-嵌段共接枝载体(HPG-SDP)。控制所使用的SH-PEG-OH的数均相对分子质量为3000及以上,HPG-MA、正十二硫醇和SH-PEG-OH的质量比为:1-10:10-50:20-200。
其中,HPG-SDP制备路径如图1所示。即,本发明的具有pH响应性的超支化-嵌段共接枝载体的合成方法,其合成路线简图见图1。
实施例4:制备SRF@HPG-SDP
HPG-SDP与索拉非尼分别配制成水溶液和氯仿溶液,室温下以磁力搅拌法充分搅拌一定时间,得到索拉非尼富集的载药新体系SRF@HPG-SDP。
实施例4制备的SRF@HPG-SDP载体中SRF的负载量为20%。
HPG-SDP与索拉非尼分别配制成10wt%水溶液和40wt%的氯仿溶液,室温下以磁力搅拌法充分搅拌一定时间,得到索拉非尼富集的载药新体系SRF@HPG-SDP;进一步优选,所述混合是指搅拌3h。
表征试验1:核磁共振氢谱分析
基于“巯基-烯基”点击化学反应对HPG改性需要经过两个步骤,首先是HPG与甲基丙烯酸缩水甘油酯(GMA)的酯交换反应,得到含有烯基的HPG改性物HPG-MA。而后HPG-MA与正十二硫醇和HS-PEG-OH在光引发条件下发生点击反应,得到端基为羧酸的产物HPG-SDP。HPG-SDP为淡黄色粘稠液态物质,同样具有良好的水溶性,可有效溶于生理盐水中。分别以氘代DMSO和重水为溶剂,检测HPG-MA和HPG-SDP的核磁共振氢谱,并将HPG、HPG-MA和HPG-SDP的1H NMR作对比如图2所示。对HPG-MA的1H NMR而言,δ=3.25~4.0ppm之间的宽峰为HPG-MA中聚醚结构的信号峰,δ=6.0ppm与δ=5.5ppm两处为双键上携带的两类氢的信号。由结果可知,聚缩水甘油的甲基丙烯酸酯化是成功进行的。再观察HPG-SDP的1H NMR,经“巯基-烯基”点击反应后,HPG-MA的δ=6.0ppm与δ=5.5ppm两处的双键信号峰消失,而在δ=1.4~1.8ppm处出现了长链烷基的特征信号峰,和δ=3.0~4.0ppm处的醚键信号峰显著增强,相互证明了点击反应的成功进行。
表征试验2:红外光谱检测
给出了HPG、HPG-MA和HPG-SDP的红外谱图(图3)。谱图中显示,经过“巯基-烯基”反应后,HPG-MA所含的C=C键被完全反应,双键信号峰消失。在717cm-1处有一弱峰,为C-S键的信号峰,证明“巯基-烯基”反应后形成了C-S键,结合2558cm-1处并未检测到S-H的伸缩振动峰,同时在1045处的C-O信号峰显著增强,均可以证实点击反应的成功进行,所收集到的产物为目标产物HPG-SDP。
经过载药过程后,可以发现在1550-1800cm-1处和1200cm-1处索拉非尼的特征信号峰较为显著地出现,证实了索拉非尼的成功搭载。详见图3。
表征试验3:透射电镜分析
图4和图5分别为搭载SRF前后的HPG-SDP的透射电子显微镜图像,从这些图像中可以分析得到,HPG-SDP在电子显微镜下呈现出团聚的情况,这是因为由于其上的亲水性官能团互相吸引而导致的。经过粒径分析,可以推断出,HPG-SDP的粒径在5~15nm之间,经过载药后,HPG-SDP的粒径分布在20~100nm之间,可以推断,载药的过程是多个大分子相互作用建立起来的载体,因而赋予了载体更大的载药量。
表征试验5:粒径分析
利用动态光散射(DLS法)测定20℃时,不同分子量的HPG和HPG-DSP在水中的粒径分布情况。经过整理,得到如表1所示的结果。表1给出了所制备的三种HPG及其对应的HPG-SDP样品的相对分子质量及其相关物性参数。可以看出,所选用的HPG分子量在3500-45000之间,其粒径随着相对分子质量的增加而有所增加,单分子粒径在5-8nm之间。搭载了索拉菲尼后,观测到的粒径变大。这是由于在药物搭载过程中,在药物的作用下,大分子之间产生互相聚集交联,从而使观察到的粒径增加。
表1 HPG、HPG-SDP样品的合成条件及相关理化性质表征
a.由凝胶渗透色谱GPC获得,以DMF为流动相,PAMAM为标准品
b.以差式扫描量热法获得
c.以动态光散射法获得
性能试验1:药物载体在不同pH环境下的释放曲线分析
从图6的结果可以看到,SRF@HPG-SDP在不同的pH环境下,均表现出了缓慢释放的现象,其中pH对缓释的速度有较大的影响,在pH=5.4的环境下,SRF@HPG-SDP在6天内达到了80%的释放量,而在pH=8.0的环境中,相同时间下仅有45%左右的释放量。
性能试验2:药物载体在杀伤肿瘤中的作用
将SRF@HPG-SDP在中性液体环境中(pH 7.4,MEM培养基)测试细胞毒性。采用人源性肝癌细胞株HCC-LM3为对象,通过CCK-8试验分析药物对细胞的杀伤作用。如图7所示,在中性环境中,SRF@HPG-SDP具有良好的肿瘤细胞杀伤功能,而HPG-SDP无明显细胞毒性。
采用人源性肝癌细胞株Huh7为对象,通过细胞凋亡试验分析药物对细胞的杀伤作用。如图8所示,SRF@HPG-SDP具有促肿瘤凋亡功能,而HPG-SDP无明显细胞毒性。
Claims (10)
1.一种负载抗肿瘤药物的超支化-嵌段共接枝药物载体的制备方法,其特征在于,所述制备方法包括:
(1)通过酯交换方法合成端基含双键的超支化聚缩水甘油HPG-MA,其中HPG指代超支化聚缩水甘油,MA指代其取代上的碳碳双键端基;
(2)利用了巯基-烯基点击反应,在紫外光条件下,合成出具有pH响应性的超支化-嵌段共接枝载体HPG-SDP,其中HPG指代超支化聚缩水甘油,SDP指代通过点击反应后接枝上的-硫-正十二烷基-聚乙二醇嵌段;
(3)通过双相萃取-真空冻干联用法将抗肿瘤药物封装在超支化-嵌段共接枝载体中,得到抗肿瘤药物-超支化-嵌段共接枝药物载体;
其中HPG-MA的结构式为:
HPG-SDP的结构式为:
2.根据权利要求1所述的负载抗肿瘤药物的超支化-嵌段共接枝药物载体的制备方法,其特征在于,在步骤(1)中:将超支化聚缩水甘油溶解于有机溶剂中添加4-二甲基氨基吡啶,再加入甲基丙烯酸缩水甘油酯后室温下反应得到产物,记为HPG-MA。
3.根据权利要求2所述的负载抗肿瘤药物的超支化-嵌段共接枝药物载体的制备方法,其特征在于,所述超支化聚缩水甘油、4-二甲基氨基吡啶与甲基丙烯酸缩水甘油酯的质量比为1-10:10-50:20-200。
4.根据权利要求1所述的负载抗肿瘤药物的超支化-嵌段共接枝药物载体的制备方法,其特征在于,在步骤(2)中:将HPG-MA溶于DMSO中,而后加入正十二硫醇和端基同时含有巯基和羟基的巯基-聚乙二醇-羟基SH-PEG-OH,充分搅拌均匀后,添加二苯甲酮,经充分鼓入氮气后,在紫外光条件下快速地合成出具有pH响应性的超支化-嵌段共接枝载体HPG-SDP。
5.根据权利要求4所述的负载抗肿瘤药物的超支化-嵌段共接枝药物载体的制备方法,其特征在于,所述SH-PEG-OH的数均相对分子质量为3000及以上,所述HPG-MA、正十二硫醇和SH-PEG-OH的质量比为:1-10:10-50:20-200。
6.根据权利要求1所述的负载抗肿瘤药物的超支化-嵌段共接枝药物载体的制备方法,其特征在于,在步骤(3)中:所述双相萃取-真空冻干联用法包括:HPG-SDP与抗肿瘤药物分别配制成水溶液和氯仿溶液,室温下以磁力搅拌法充分搅拌一定时间,得到抗肿瘤药物-超支化-嵌段共接枝药物载体。
7.根据权利要求6所述的负载抗肿瘤药物的超支化-嵌段共接枝药物载体的制备方法,其特征在于,所述超支化-嵌段共接枝载体和超纯水的质量比、抗肿瘤药物和氯仿的质量比分别设为1-10:100和20-50:100。
8.根据权利要求1所述的负载抗肿瘤药物的超支化-嵌段共接枝药物载体的制备方法,其特征在于,所述药物载体包括超支化-嵌段共接枝载体,以及包埋于超支化-嵌段共接枝载体中的抗肿瘤药物;所述超支化-嵌段共接枝载体为亲水核-疏水桥接-亲水PEG嵌段共接枝载体。
9.根据权利要求1所述的负载抗肿瘤药物的超支化-嵌段共接枝药物载体的制备方法,其特征在于,所述抗肿瘤药物为索拉非尼,所述药物载体中索拉非尼的负载量为12.48-20.36%。
10.一种根据权利要求1-9任一所述的制备方法得到的负载抗肿瘤药物的超支化-嵌段共接枝药物载体在制备抗肿瘤治疗药物中的应用。
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