CN115364236B - 一种细胞膜锚定的ros响应壳聚糖凝胶前药体系、制备方法及其应用 - Google Patents
一种细胞膜锚定的ros响应壳聚糖凝胶前药体系、制备方法及其应用 Download PDFInfo
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Abstract
本发明涉及响应性凝胶制备技术领域,具体涉及一种细胞膜锚定的ROS响应壳聚糖前药凝胶体系、制备方法及其应用,新制备的壳聚糖凝胶前药释放体系中环氧丙基三甲基氯化铵具有的正电基团可以与细胞膜表面的带负电的磷酸基团结合,将药物小分子固载在细胞膜表面,顺铂‑吡啶基硫缩酮苯乙酸具有ROS响应,而结构中肉桂醛可以在酸性条件下释放并进入细胞产生ROS,进一步切断硫缩酮键释放顺铂,从而实现顺铂在癌细胞中选择性释放,降低对正常细胞的损伤,实现选择性化疗。本发明制备的壳聚糖凝胶体系可以长时间粘附在癌细胞表面,实现长效持续性药物释放,从而增强对癌细胞的杀伤,同时降低顺铂对正常细胞的损伤,具有较好的应用前景。
Description
技术领域
本发明涉及凝胶制备技术领域,具体涉及一种细胞膜锚定的ROS响应壳聚糖凝胶前药体系、制备方法及其应用。
背景技术
化疗作为现在最有效的治疗方式,被广泛用于初期肿瘤治疗当中。但静脉注射的传统方法具有药物传递效率低、毒性高、需要多次注射等弊端。而瘤内注射可以将抗肿瘤药物直接注射到肿瘤内部,避免了体内的长循环对药物的稀释,减少了药物对于正常组织的影响。直接在肿瘤原位注射抗肿瘤药物的溶液,因药物流失和吸收过快而无法有效的提高给药效率,为了提高注射效率我们需要一种可注射并能对于抗肿瘤药物进行原位长效响应缓释的载体。
甲壳素作为自然界中广泛存在的一种天然多糖,经过脱乙酰化处理可以得到壳聚糖。其具有抗菌性和生物降解性、生物相容性,被广泛应用于食品和医疗行业。壳聚糖是目前自然界中已知的唯一带有正电荷的碱性多糖,可以与细胞膜表面磷酸根离子交联,形成具有三维网状结构的凝胶。水凝胶是一种高分子经过交联形成的具有空间网状结构的材料,可以作为一种药物载体,负载药物并被植入患者病灶处,对药物进行长期缓释,提高递送效率,降低给药频率同时也降低了高浓度药物对于正常组织的毒性。但是目前基于壳聚糖制备的凝聚用于运载药物,大部分是基于壳聚糖表面正电荷与药物负电荷吸引进行负载,又或者是通过凝聚网络吸附,这样运输药物容易导致药物泄漏,并且对药物在癌细胞中的释放不能控制,此外以往报道的pH响应的凝胶,在正常细胞的溶酶体中也会释放出药物,导致对正常细胞产生损伤,因此为解决壳聚糖凝胶体系在载药过程中容易泄漏以及选择性差的难题,需要重新构建能够锚定癌细胞并且响应性释放药物的凝胶体系。
含铂抗肿瘤药物,是一种十分有效与有力的化疗试剂,其中顺铂是目前应用广泛的一类抗肿瘤药物,又被称之为癌症中的青霉素,用于治疗多种不同的癌症。顺铂具有抗癌谱广、作用强、与多种抗肿瘤药有协同作用、且无交叉耐药等特点。但是,顺铂同样存在着毒副作用大,血液中半衰期短等问题,尤其是肾脏毒性,使顺铂的剂量限制,大大制约了其运用的有效性。因此需要开发能够特异性锚定在癌细胞表面,选择性响应释放顺铂的凝胶载药体系,来解决顺铂运载困难和毒副作用大的难题。
鉴于上述缺陷,本发明创作者经过长时间的研究和实践终于获得了本发明。
发明内容
本发明的目的在于解决顺铂存在着毒副作用大,血液中半衰期短等问题,尤其是肾脏毒性,使顺铂的剂量限制,大大制约了其运用的有效性的问题,提供了一种细胞膜锚定的ROS响应壳聚糖凝胶前药体系、制备方法及其应用。
为了实现上述目的,本发明公开了一种细胞膜锚定的ROS响应壳聚糖凝胶前药体系,所述壳聚糖前药凝胶体系包括细胞膜锚定的壳聚糖凝胶,所述细胞膜锚定的壳聚糖凝胶结构式如下所示:
上述细胞膜锚定的壳聚糖凝胶的合成路线如下:
本发明还公开了上述细胞膜锚定的ROS响应壳聚糖凝胶前药体系的制备方法,包括以下步骤:
S1,将顺铂,三氟甲基磺酸银以水做溶剂,加热反应;过滤,除去氯化银沉淀,冻干,得到前体1;
S2,将醛基苯乙酸,4-吡啶乙硫醇盐酸盐以N,N-二甲基甲酰胺为溶剂,三氟乙酸为催化剂,冷凝回流;反应结束后,旋蒸浓缩,加入饱和碳酸氢钾中和,旋干后用无水乙醇洗涤,过滤得到溶液旋干后过中性氧化铝柱子,最后得到前体2;
S3,向壳聚糖中加入盐酸调节pH为3-4之间,55℃加热30min,得到溶解的壳聚糖,用DMSO和水的混合溶液(体积比1:1)把前体2进行溶解,随后加入NHS、EDC·HCl对羧基进行活化,再将溶解的壳聚糖加入到活化后的前体2中,加热反应,透析,冻干得到前体3;
S4,将步骤S3中得到的前体3溶解于水中,盐酸调节pH在3-4之间;将环氧丙基三甲基氯化铵用水溶解后滴加至前体3的溶液中,加热反应,离心除去未溶物,丙酮萃取,透析提纯,冷冻干燥出前体4;
S5,将步骤S4中得到的前体4、步骤S1中得到的前体1溶于水中,加热反应,透析,冻干得到前体5;
S6,将步骤S5中得到的前体5溶于水中,将肉桂醛用无水乙醇溶解之后滴加至前体5的溶液中,加热反应,透析,冻干得到壳聚糖-环氧丙基三甲基氯化铵-肉桂醛-对醛基苯乙酸-4-吡啶乙硫醇-铂配合物。
所述步骤S1中顺铂和三氟甲基磺酸银的摩尔比为1:1,加热温度为60℃,反应时间为12h。
所述步骤S2中对醛基苯乙酸和4-吡啶乙硫醇盐酸盐的摩尔比为1:2,催化剂三氟乙酸的量为300μL,加热温度为60℃,反应时间为24h。
所述步骤S3壳聚糖中氨基和前体2中羧基摩尔比为10:1,羧基活化时-COOH、EDC·HCl和NHS摩尔比为1:1:1.5,DMSO和水的体积比1:1,加热温度为60℃,反应时间为24h。
所述步骤S4中壳聚糖上氨基:环氧丙基三甲基氯化铵摩尔比为2:1,加热温度为55℃,反应时间为15h。
所述步骤S5中吡啶基团与前体1摩尔比为1:1,反应过程避光,加热温度为60℃,反应时间为48h。
所述步骤S6中前体5中氨基:肉桂醛摩尔比为5:1,反应过程避光,加热温度为80℃,反应时间为12h。
本发明还公开了上述细胞膜锚定的ROS响应壳聚糖凝胶前药体系在选择性进行ROS响应、持续释放抗肿瘤药物中的应用。
本发明中壳聚糖凝胶前药体系的ROS响应性机制如下:
壳聚糖链上偶联的季铵盐基团可以和细胞膜中磷酸酯键静电结合,从而使壳聚糖凝胶前药体系锚定在细胞膜表面,而细胞膜周围的肿瘤微环境中呈现出弱酸性,导致壳聚糖上偶联的肉桂醛断裂,游离出肉桂醛,当肉桂醛进入细胞后,可以在细胞中可以产生高活性的ROS,高活性的ROS进一步切割壳聚糖链上的顺铂吡啶前药中的TK接头,把顺铂吡啶释放出来,顺铂进入细胞进行化疗。但是在正常细胞中,正常细胞膜周围环境是中性环境,因此肉桂醛不能从壳聚糖链上断裂,进入细胞去产生高活性的ROS,从而TK接头在正常细胞中不能断裂,顺铂也不能从壳聚糖链上游离,被牢靠的锚定在细胞膜上,从而保护正常细胞免受顺铂的毒副作用。因此本发明专利通过细胞膜锚定的壳聚糖前药体系,利用ROS响应的键,可以降低顺铂对正常细胞的损伤。
与现有技术比较本发明的有益效果在于:壳聚糖表面接枝季铵盐阳离子可以把凝胶锚定在癌细胞膜上,阻止药物从癌细胞中外排,另一方面在壳聚糖上偶联能够ROS响应的TK接头去和顺铂配位交联,能够使顺铂牢靠的在纳米凝胶中,防止药物提前泄漏,同时ROS响应的键又能够保证顺铂在癌细胞中释放,起到化疗的目的。和以往壳聚糖凝胶载体相比,本发明提供的细胞膜锚定的凝胶载体能够牢靠稳定在细胞膜上起到长效释放化疗药物顺铂,同时又能阻止顺铂从细胞中外排,另一方面利用ROS响应的原理,可以选择性的在癌细胞中释放顺铂,而在正常细胞中,壳聚糖凝胶虽然也能锚定在正常细胞膜上,但是正常细胞微环境较低的ROS环境不足以触发顺铂的释放。本发明提供的一种细胞膜锚定的ROS响应的壳聚糖凝胶制备方法和pH响应的凝胶制备方法,和解决的实际问题都不同。
附图说明
图1为link的质谱谱图;
图2为link的核磁共振波谱图;
图3为link的红外光谱图;
图4为CS的红外光谱图;
图5为CS-link的红外光谱图;
图6为CS-O-CA-link-Pt的红外光谱图;
图7为link-H2O2的质谱图;
图8为CS-link-H2O2的红外光谱图;
图9活性氧探针检测的共聚焦图像,(a)不加药的细胞的共聚焦图像,(b)加CS-O-CA-link-Pt细胞的共聚焦图像。
具体实施方式
以下结合附图,对本发明上述的和另外的技术特征和优点作更详细的说明。
实施例1
细胞膜锚定的壳聚糖凝胶体系的合成
称取500mg顺铂,429mg三氟甲基磺酸银于圆底烧瓶中,加入10mL超纯水做溶剂,60℃反应12h后;过滤,除去氯化银沉淀;冻干,得到421mg前体1。(对应反应路线1)
首先取对醛基苯乙酸1000mg,4-吡啶乙硫醇盐酸盐4708mg于圆底烧瓶中,加入30mL的N,N-二甲基甲酰胺作为溶剂,300μL三氟乙酸作为催化剂,反应温度60℃,冷凝回流,反应时间为48h;反应结束后,旋蒸浓缩,加入饱和碳酸氢钾中和;旋干后用无水乙醇洗涤;过滤得到溶液旋干后过中性氧化铝柱子,最后得到1291mg前体2(link)。(对应反应路线2)
link的质谱谱图,1H NMR谱图,红外谱图分别见图1,图2和图3所示,link的理论分子量为424,实际为425,质谱图中在425处有峰;对link的结构进行分析,其结构中总共含有24个H,从核磁图中的可以看到H的积分个数为24;link的红外光谱图上在1685.57cm-1处有羧基特征峰,在1508.30cm-1和1603.56cm-1处有苯环特征峰,在1419.70cm-1处有吡啶特征峰。综上,可确定link制备成功。
实施例2
壳聚糖配合物的合成
分别称取2175mg壳聚糖(相对分子质量100,000),500mg前体2于烧瓶1和烧瓶2中;烧瓶1中加入10mL超纯水,再加入盐酸调节pH在3-4之间,55℃加热30min;烧瓶2中加入1mLDMSO溶解,先加入227mg NHS,60℃反应10min后,再加入204mg的EDC·HCl活化1h;将烧瓶1中溶解的壳聚糖加入烧瓶2中,60℃反应24h;透析;冻干得到337mg前体3(CS-likn);(对应反应路线3)
称取337mg前体3溶解于水中,盐酸调节pH为3-4之间;将154mg环氧丙基三甲基氯化铵用水溶解后滴加至前体3的溶液中,55℃反应15h;离心除去未溶物;丙酮萃取;透析提纯;冷冻干燥出422mg前体4;(对应反应路线4)
称取300mg前体4,324mg前体1于烧瓶中,10mL超纯水作溶剂,60℃反应48h;透析;冻干得到548mg前体5;(对应反应路线5)
称取500mg前体5,66mg肉桂醛于烧瓶中,10mL超纯水作溶剂,加入200μL三氟乙酸作催化剂,60℃反应24h;透析;冻干得到110mg的壳聚糖凝体系(CS-O-CA-link-Pt)(对应反应路线6)
对比图3、图4和图5可以发现,CS-link的红外光谱图对比link的红外光谱图没有羧基特征峰,对比CS的红外光谱图在1560.88cm-1处多了吡啶的特征峰,由此基本可以确定合成了正确的产物。对比图5和图6可以看出,CS-O-CA-link-Pt的红外光谱图较CS-link的红外光谱图在1600cm-1处峰基本消失,这是由于壳聚糖上的氨基与肉桂醛中醛基反应导致N-H键减少产生的,1632.04cm-1为反应新生成的C═N键的伸缩振动峰。这表明肉桂醛已成功接枝在壳聚糖的氨基上。
实施例3
link和CS-link的过氧化氢响应之后的表征
取1mg的link溶解于500μL甲醇中,5mg的CS-link溶解于500μL的超纯水中,分别加入2μL的9.8M的过氧化氢,37℃孵育30min后测定质谱与红外光谱。
图7中出现了分子量为140.21和336.39的化合物,这表明link可以被H2O2切割。对比图5和图8可以发现,在加入H2O2后CS-link的红外光谱图上在1672.69cm-1位置出现了醛基的特征峰,这表明CS-link可以被H2O2切割。
实施例4
细胞中ROS水平加药前后的变化
按照1:1000用无血清培养液稀释DCFH-DA,使终浓度为10μM。共聚焦皿中培养细胞至贴壁,一组加药,一组不加药作为空白对照,48h后去除细胞培养液,用PBS洗涤细胞三次,去除残留的血清,加入2mL稀释好的DCFH-DA。37℃细胞培养箱内孵育30分钟。用无血清细胞培养液洗涤细胞三次,以充分去除未进入细胞内的DCFH-DA。
共聚焦显微镜下观察细胞的荧光强度,对比图9(a)和图9(b)可以看出加入CS-O-CA-link-Pt后细胞荧光明显变强,也就证明了CS-O-CA-link-Pt可以使细胞中活性氧浓度升高。
以上所述仅为本发明的较佳实施例,对本发明而言仅仅是说明性的,而非限制性的。本专业技术人员理解,在本发明权利要求所限定的精神和范围内可对其进行许多改变,修改,甚至等效,但都将落入本发明的保护范围内。
Claims (9)
1.一种细胞膜锚定的ROS响应壳聚糖前药凝胶体系,其特征在于,所述壳聚糖前药凝胶体系包括细胞膜锚定的壳聚糖凝胶,所述细胞膜锚定的壳聚糖凝胶结构式如下所示:
2.一种如权利要求1所述的细胞膜锚定的ROS响应壳聚糖前药凝胶体系的制备方法,其特征在于,反应路线包括以下六步:
路线一
路线二
路线三
路线四
路线五
路线六
3.如权利要求2所述的一种细胞膜锚定的ROS响应壳聚糖前药凝胶体系的制备方法,其特征在于,包括以下步骤:
S1,将顺铂,三氟甲基磺酸银以水做溶剂,加热反应;过滤,除去氯化银沉淀,冻干,得到前体1;
S2,将对醛基苯乙酸,4-吡啶乙硫醇盐酸盐以N,N-二甲基甲酰胺为溶剂,三氟乙酸为催化剂,冷凝回流;反应结束后,旋蒸浓缩,加入饱和碳酸氢钾中和,旋干后用无水乙醇洗涤,过滤得到溶液旋干后过中性氧化铝柱子,最后得到前体2;
S3,向壳聚糖中加入盐酸调节pH为3-4之间,55℃加热30min,得到溶解的壳聚糖,用DMSO和水的混合溶液将前体2溶解,随后加入NHS、EDC·HCl对羧基进行活化,再将溶解的壳聚糖将入活化后的前体2中,加热反应,透析,冻干得到前体3;
S4,将步骤S3中得到的前体3溶解于水中,盐酸调节pH在3-4之间;将环氧丙基三甲基氯化铵用水溶解后滴加至前体3的溶液中,加热反应,离心除去未溶物,丙酮萃取,透析提纯,冷冻干燥出前体4;
S5,将步骤S4中得到的前体4、步骤S1中得到的前体1溶于水中,加热反应,透析,冻干得到前体5;
S6,将步骤S5中得到的前体5溶于水中,将肉桂醛用无水乙醇溶解之后滴加至前体5的溶液中,加热反应,透析,冻干得到目标物,既壳聚糖-环氧丙基三甲基氯化铵-肉桂醛-对醛基苯乙酸-4-吡啶乙硫醇-铂配合物。
4.如权利要求3所述的一种细胞膜锚定的ROS响应壳聚糖前药凝胶体系的制备方法,其特征在于,所述步骤S1中顺铂和三氟甲基磺酸银的摩尔比为1:1,加热温度为60℃,反应时间为12h。
5.如权利要求3所述的一种细胞膜锚定的ROS响应壳聚糖前药凝胶体系的制备方法,其特征在于,所述步骤S2中对醛基苯乙酸和4-吡啶乙硫醇盐酸盐的摩尔比为1:2,催化剂三氟乙酸的量为300μL,加热温度为60℃,反应时间为24h。
6.如权利要求3所述的一种细胞膜锚定的ROS响应壳聚糖前药凝胶体系的制备方法,其特征在于,所述步骤S3壳聚糖中氨基和前体2中羧基摩尔比为10:1,羧基活化时-COOH、EDC·HCl和NHS摩尔比为1:1:1.5,DMSO和水的体积比1:1,加热温度为60℃,反应时间为24h。
7.如权利要求3所述的一种细胞膜锚定的ROS响应壳聚糖前药凝胶体系的制备方法,其特征在于,所述步骤S4中壳聚糖上氨基和环氧丙基三甲基氯化铵摩尔比为2:1,加热温度为55℃,反应时间为15h。
8.如权利要求3所述的一种细胞膜锚定的ROS响应壳聚糖前药凝胶体系的制备方法,其特征在于,所述步骤S5中吡啶基团与前体1摩尔比为1:1,反应过程避光,加热温度为60℃,反应时间为48h。
9.如权利要求3所述的一种细胞膜锚定的ROS响应壳聚糖前药凝胶体系的制备方法,其特征在于,所述步骤S6中前体5中氨基和肉桂醛摩尔比为5:1,反应过程避光,加热温度为80℃,反应时间为12h。
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