CN107737348B - 一种肺癌靶向自组装纳米粒的制备方法 - Google Patents
一种肺癌靶向自组装纳米粒的制备方法 Download PDFInfo
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Abstract
本发明公开了一种具有肺癌靶向性的厄洛替尼修饰的壳聚糖与药物DOX和ICG的自组装纳米制剂。该纳米制剂是先通过化学偶联将肺癌分子靶向药物厄洛替尼连接到经过化学结构改造的壳聚糖上,再用厄洛替尼修饰的壳聚糖自组装包载吲哚菁绿ICG和多柔比星DOX而得到CEDI纳米制剂。本发明制备纳米粒,既利用了壳聚糖无毒、生物相容性高的特性,又大大提高了厄洛替尼的水溶性和生物利用度;同时利用厄洛替尼的分子靶向作用,可使包载的细胞毒药物和光敏剂选择性靶向到肺癌细胞,降低药物毒副作用;此外该纳米粒还可以同时进行分子靶向治疗、化疗和光动力治疗,并具有近红外荧光成像能力,提高治疗效果。
Description
技术领域
本发明属于生物医药技术领域,具体涉及一种厄洛替尼修饰的壳聚糖共同包载DOX和ICG的自组装纳米制剂。
背景技术
肺癌是严重威胁人类健康的常见恶性肿瘤,居我国恶性肿瘤发病率和死亡率第一位。按照组织学特点,肺癌可分为非小细胞肺癌(NSCLC)和小细胞肺癌(SCLC),其中NSCLC占肺癌总量的85%以上,大多数患者在确诊时已处于中晚期。从传统药物治疗到现代靶向药物治疗的不断发展,肺癌患者的生存期在不断延长,加上个体化治疗理念的引入,肺癌的治疗方式正在不断地扩大与更新,为广大肺癌患者带来福音。
厄洛替尼(Erlotinib)是癌症药物治疗的常用药物。厄洛替尼商品名特罗凯(Tevceva)。厄洛替尼的作用途径与传统化疗药物不同,它是一种靶向治疗药物,可特异性地针对肿瘤细胞作用,抑制肿瘤的形成和生长。它是一种小分子化合物,可抑制人表皮生长因子受体(EGFR)的信号传导途径,是表皮生长因子(又可称HER1)信号传导通路的关键组分,在多种肿瘤细胞的形成及生长中都扮演了重要的角色。厄洛替尼通过抑制酪氨酸激酶的活性的方式来抑制肿瘤生长,酪氨酸激酶是EGFR细胞内的重要组成部分之一。因此我们利用厄洛替尼来达到主动靶向的作用。
壳聚糖(Chitosan,Cs)是一种无毒、在体内可生物降解的天然多糖,由于制备方法和原料的不同,其相对分子量大大不同。Cs外观为白色或淡黄色半透明状固体,化学稳定性良好。由于Cs对皮肤和黏膜无刺激性,所以与人体具有很好的生物相容性。Cs既有氨基又有羟基,其结构易于化学修饰,是一种具有广泛应用前景的新型药物载体。此外,Cs本身具有确切的抗肿瘤作用,可能通过多种作用机制达到抑制肿瘤的作用。我们还可以将Cs制备为纳米载药微粒,将药物制备成纳米粒以后可以提高药物的稳定性,防止药物被生物酶降解,并可以实现药物的控释和靶向治疗的作用。
近红外(NIR)荧光染料由于具有了良好的组织渗透性,吸收的近红外光在生物组织中的穿透深度较大,而激发的荧光受生物组织本身的影响较小,所以可检测到深层组织的荧光信号。该类染料作为非侵入性的分子影像试剂在癌症的早期检测中具有良好的应用前景。其中最具代表性的为近红外菁染料,能够被肿瘤细胞摄取并富集,从而特异性成像。吲哚菁绿ICG是一种带负电荷的聚甲基菁染料,在近红外光谱范围内有较强吸收、毒性小、不参与体内生物转化、排泄迅速等优点,比CY3,CY5,CY7这些菁染料有着更高的吸收和发射波长,因此,我们选择吲哚菁绿ICG作为监测药物作用于活体动物的荧光标记和光动力治疗的光敏剂。
多柔比星DOX是一种抗肿瘤抗生素,可抑制RNA 和DNA的合成,对RNA的抑制作用最强,抗瘤谱较广,对多种肿瘤均有作用,属周期非特异性药物,对各种生长周期的肿瘤细胞都有杀灭作用。因此,我们选择多柔比星DOX来增强抗肿瘤效果。
基于以上背景,本发明利用连接了肺癌分子靶向药物厄洛替尼的壳聚糖自组装包载吲哚菁绿ICG和多柔比星DOX。由于纳米粒连接了分子靶向药物厄洛替尼,因而具有靶向输送的能力,并且纳米粒同时包载了DOX和ICG,使纳米粒具有协同分子靶向治疗、化疗和光动力治疗的能力以及ICG的近红外成像功能。
发明内容
本发明的目的在于提供一种具有肺癌靶向性的厄洛替尼修饰的壳聚糖共同包载DOX和ICG的自组装纳米制剂CEDI,该纳米粒主动靶向肺癌,进行近红外成像和协同分子靶向治疗、化疗和光动力治疗。
本发明制备纳米制剂CEDI的方法,包括如下步骤:
步骤a:称取取壳聚糖(Cs),溶于无水DMF,加入4-溴邻苯二甲酸酐,氮气保护,125℃油浴搅拌加热。反应体系澄清后,结束反应,将反应液直接倒入冰水中,析出黄白色沉淀。抽滤,固体用乙醚、丙酮洗涤,干燥,得到N-4-溴邻苯二甲亚胺基壳聚糖(Cs-Br);
步骤b:称取步骤a所得产物,溶于 N-甲基吡咯烷酮(NMP),加入叠氮化钠(NaN3),氮气保护,80℃反应24小时。反应体系呈红棕色液体,结束反应,将反应液倒入乙醇中,析出固体。离心,收集产物,产物先后用乙醇、二次水、丙酮各洗涤三遍。干燥得到棕色固体叠氮化的壳聚糖(Cs-N3);
步骤c:称取步骤b所得产物,将其溶于二甲基亚砜(DMSO),室温搅拌,然后加入厄洛替尼(Erlotinib),避光,氮气保护,将无水硫酸铜和维生素C钠盐分别溶于水,之后慢慢滴加入烧杯。50℃反应72 h。反应结束后,将反应液加到透析袋中,用纯水透析72h,收集固体,冷冻干燥,得到产物厄洛替尼修饰的壳聚糖(CE);
步骤d:称取步骤c所得产物,将其溶于DMSO,将溶解液加入纯水中,室温搅拌24h。在超声条件下,向上述溶液中加入多柔比星(DOX)和吲哚菁绿(ICG)的二甲基亚砜溶液,反应4h。反应液于去离子水中透析处理24h,即得载药自组装纳米微粒溶液(CEDI纳米微粒溶液)。
其中Cs的重均分子量为10~1000千道尔顿。
步骤d中,步骤c所得产物CE和药物(DOX与ICG之和)的质量比为40∶1~10∶1,ICG和DOX的质量比为:2∶1~0.5∶1。
本发明中所述的纳米粒CEDI的制备方法包括以下步骤:在超声条件下,向所述的CE溶液中缓慢加入DOX和ICG的二甲基亚砜溶液,一段时间后,反应液于去离子水中透析处理合适的时间,即得载药自组装纳米微粒溶液。
本发明的纳米粒CEDI用于肺癌细胞的靶向近红外荧光成像和分子靶向、化疗和光动力联合治疗。
本发明的有益效果在于:
1.本发明的纳米粒CEDI,既具备了厄洛替尼的靶向治疗特点,还具有DOX的抗肿瘤作用和ICG的近红外成像功能,提高治疗效果。
2.本发明的纳米粒CEDI既保留了壳聚糖无毒、生物相容性高的特性,又大大提高了厄洛替尼的水溶性和生物利用度。
3.本发明的纳米粒CEDI利用厄洛替尼的分子靶向作用,可使包载的细胞毒药物和光敏剂选择性靶向到肺癌细胞,降低药物毒副作用。
附图说明
图1为本发明实施例1处理的步骤b、步骤c的产物的红外谱图。
图2为本发明实施例5处理的DOX的荧光强度标准曲线。
图3为本发明实施例5处理的ICG的荧光强度标准曲线。
图4为本发明实施例2,实施例4,实施案例5制备的CEDI,CEI和ICG的荧光光谱图。
图5为本发明实施例2,实施例3,实施案例5制备的CEDI,CED和DOX的荧光光谱图。
图6为本发明实施例6的CED,CEI和CEDI的粒径分布图;
图7为本发明实施例6的CED,CEI和CEDI的表面Zeta电势图;
图8为本发明实施例7的细胞毒性结果图。
具体实施方式
下面结合具体实施例,对本发明进行进一步说明,有助于本领域的普通技术人员进一步理解本发明,但不以任何形式限制本发明。
实施例1
厄洛替尼修饰的壳聚糖(CE)的合成:
步骤a:称取200 mg壳聚糖Cs(壳聚糖购于上海伯奥生物科技有限公司,分子量为60千道尔顿,脱乙酰度为90%)溶于20 mL无水DMF中,随后加入800mg 4-溴邻苯二甲酸酐,氮气保护,125℃油浴搅拌加热。当反应液变澄清,溶液呈黄色时,终止反应。趁热过滤,然后直接将热滤液倒入适量冰水中,析出白色固体。抽滤,固体用乙醚、丙酮分别洗涤3次,除去多余的4-溴邻苯二甲酸酐,通风处干燥得产物N-4-溴邻苯二甲亚胺基壳聚糖(Cs-Br)。
步骤b:称取60 mg 产物Cs-Br,加入6 mL N-甲基吡咯烷酮(NMP),加热搅拌,使其完全溶解,加入100 mg 叠氮化钠(NaN3),氮气保护,油浴80℃下搅拌加热24小时。反应结束后,将反应液倒在60 mL 乙醇中,析出固体。通过离心(12000 r/min)收集产物,产物先后用乙醇、二次水、丙酮各洗涤三遍。得到固体通风处干燥后得到棕色产物Cs-N3。
步骤c:称取30mg产物Cs-N3,溶于3 mL二甲亚砜,加入烧瓶,再加入25 mg 厄洛替尼。烧瓶用橡胶塞密封,抽真空后,氮气保护,用1 mL注射器往烧瓶先滴加4 mg五水硫酸铜(溶于200 μL二次水中),后滴加3 mg抗坏血酸钠(溶于200 μL二次水中)。反应物在50℃下,避光反应72 h。反应结束后将反应液用透析袋在二次水中透析72 h。透析后,将产物冻干,得到CE。步骤b、步骤c的产物的红外谱图如图1所示。与Cs-N3的红外谱图相比,CE红外谱图上位于2100-1处的叠氮特征峰消失,表明厄洛替尼(Er)已通过“点击化学”反应偶联到壳聚糖上。
实施例2
CEDI的制备:
称取80 mg CE分散于4 mL DMSO中,然后缓慢滴加到40 mL二次水中,室温条件下振荡24 h。超声条件下,向20 mL空白微粒溶液中缓慢滴加0.6 mL的DOX和0.6 mL的ICG的二甲基亚砜溶液(1.5 mg DOX溶于0.9 mL DMSO中,1.5 mg ICG溶于0.9 mL DMSO中)。先超声振荡0.5 h,再磁力搅拌4 h。反应液于去离子水中透析处理24 h,每6 h换水一次,除去DMSO,即得载药自组装纳米微粒溶液。透析后,将产物放于-80℃的冰箱中结冰,冻干,得到纳米粒CEDI。
实施例3
厄洛替尼修饰的壳聚糖包载DOX纳米粒(CED)的制备:
称取80 mg CE分散于4 mL DMSO中,然后缓慢滴加到40 mL二次水中,室温条件下振荡24h。超声条件下,向10 mL空白微粒溶液中缓慢滴加0.3 mL的DOX的二甲基亚砜溶液(1.5 mg DOX溶于0.9 mL DMSO中)。先超声振荡0.5 h,再磁力搅拌4 h。反应液于去离子水中透析处理24 h,每6h换水一次,除去DMSO,即得载药自组装纳米微粒溶液。透析后,将产物放于-80℃的冰箱中结冰,冻干,得到纳米粒CED。
实施例4
厄洛替尼修饰的壳聚糖包载ICG纳米粒(CEI)的制备:
称取80 mg CE分散于4 mL DMSO中,然后缓慢滴加到40mL二次水中,室温条件下振荡24h。超声条件下,向10ml空白微粒溶液中缓慢滴加0.3 mL的ICG的二甲基亚砜溶液(1.5mg ICG溶于0.9 mL DMSO中)。先超声振荡0.5 h,再磁力搅拌4h。反应液于去离子水中透析处理24 h,每6 h换水一次,除去DMSO,即得载药自组装纳米微粒溶液。透析后,将产物放于-80℃的冰箱中结冰,冻干,得到纳米粒CEI。
实施例5
DOX和ICG的载药量检测:
称取1 mg DOX用DMSO配置成1 mg/mL 的母液,备用。取DOX母液用DMSO稀释成4、2、1、0.5、0.25、0.125μg/mL的浓度梯度,以DMSO为溶剂,用荧光分光光度计以激发波长479nm、发射波长606 nm测量不同浓度下DOX的荧光光谱及荧光强度,处理数据得到DOX的荧光强度标准曲线。称取CED和CEDI用DMSO配置成10 μg/mL的溶液,荧光分光光度计以同样的激发波长和发射波长测量其荧光光谱及荧光强度。如图2、图5所示,DOX的载药量采用荧光法检测。CED中DOX的载药量为:0.6027 g/g;CEDI中DOX的载药量为:0.2196 g/g。
称取1 mg ICG用DMSO配置成1 mg/mL 的母液,备用。取ICG母液用DMSO稀释成4、2、1、0.5、0.25、0.125 μg/mL的浓度梯度,以DMSO为溶剂,用荧光分光光度计以激发波长633nm、发射波长826 nm测量不同浓度下ICG的荧光光谱及荧光强度,处理数据得到ICG的荧光强度标准曲线。称取CEI和CEDI用DMSO配置成10 μg/mL的溶液,荧光分光光度计以同样的激发波长和发射波长测量其荧光光谱及荧光强度。如图3、图4所示,ICG的载药量采用荧光法检测。CEI中ICG的载药量为:0.3776 g/g;CEDI中ICG的载药量为:0.3652 g/g。
实施例6
纳米粒的粒径和表面电位测定:
将所制备的纳米粒CED,CEI和CEDI用超纯水稀释,将其分别配制成一定浓度的悬浮液,采用动态光散射粒度测定仪(DLS)测定纳米粒CED,CEI和CEDI的粒径分布和表面Zeta电势。如图6、图7所示,纳米粒CED,CEI和CEDI的粒径和表面Zeta电势采用动态光散射粒度测定仪(DLS)测定。粒径和电势的数据如表一所示。
实施例7
以人肺癌细胞A549细胞(EGFR野生型)为测试细胞(细胞购自中国科学院上海生命科学研究所细胞资源中心)。
细胞培养方法:从液氮罐中取出A549细胞保种管,在37℃水浴锅中快速溶化解冻,然后1000 rpm离心5 min,吸弃上清液,取1 mL DMEM完全培养液将细胞沉淀吹打均匀,转移至培养瓶中使得瓶中培养基为4 mL,置于37℃,5% CO2培养箱中培养。
细胞毒性实验:取对数期生长且状态良好的A549细胞经胰蛋白酶消化后,配制成细胞悬液。96孔板中每孔加入100ul细胞悬液(5胞悬液4细胞/孔)。在37。、5%CO2的培养箱中孵育24h后,分别加入5种不同的药物:ICG、DOX(DOX的浓度为2 μg/mL)、EC、ECDI、ECD,其中,ICG和ECDI用近红外光照射,用于比较光动力的治疗效果。每个药物设五个复孔。药物作用48 h后,用PBS洗两遍,每孔加入100 ul MTT溶液(5mg/mL,即0.5%MTT),继续培养4h后终止培养,小心吸去孔内培养液。每孔加入100 ul DMSO,置摇床上低速振荡10 min,使结晶物充分溶解。在酶联免疫检测仪OD570 nm 处测量各孔的吸光值。并按下式计算细胞的存活率。存活率(%)=(实验组吸收值-溶剂对照组吸收值)/(空白组吸收值-溶剂对照组吸收值)。
细胞毒性结果如图8所示。从图8中可以看出:ICG(细胞活性数据为115.15%)对A549细胞没有毒性,当A549细胞暴露在红外灯下时,ICG+NIR(细胞活性数据为95.35%)有了毒性。DOX(细胞活性数据为20%)对A549细胞的毒性非常强。CE(细胞活性数据为65.90%)和CED(细胞活性数据为48.60%)均可以在不同程度上杀死A549细胞,且CED的毒性强于CE。当细胞暴露在红外灯下时,ECDI+NIR(细胞活性数据为23.38%)的毒性比ECDI(细胞活性数据为39.30%)的毒性强。这表明:虽然DOX对肺癌细胞的毒性很强,但是单独使用该药物没有主动靶向治疗的效果,而厄洛替尼修饰的壳聚糖共同包载DOX和ICG的自组装纳米制剂CEDI对肺癌细胞的毒性相对较强,也能主动靶向肺癌细胞,从而提高了抗肿瘤的治疗效果。ECDI的毒性比CED的毒性强,这也表明加入ICG的纳米制剂CEDI可进行光动力治疗,且对肺癌细胞的毒性更强。
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 (3)
1.一种肺癌靶向自组装纳米粒的制备方法,其特征在于:包括如下具体步骤:
步骤(a):称取壳聚糖,与4-溴邻苯二甲酸酐反应取代氨基,得到N-4-溴邻苯二甲亚胺基壳聚糖;
步骤(b):将步骤(a)所得产物上的溴基进行叠氮基取代反应,得到叠氮化的壳聚糖;
步骤(c):将步骤(b)所得产物与厄洛替尼在无水硫酸铜和维生素C钠盐的催化作用下进行反应,得到产物厄洛替尼修饰的壳聚糖;
步骤(d):将步骤(c)所得产物与多柔比星、吲哚菁绿在超声的条件下进行混合,得到产物CEDI溶液;
步骤(e):将步骤(d)所得产物CEDI溶液进行透析,除去溶剂,得到自组装纳米微粒溶液;
步骤(f):将步骤(e)所得纳米微粒溶液冻干,得到CEDI纳米粒;
步骤(d)中,步骤(c)所得产物厄洛替尼修饰的壳聚糖与药物多柔比星和吲哚菁绿之和的质量比为40∶1~10∶1,吲哚菁绿和多柔比星的质量比为2∶1~0.5∶1。
2.根据权利要求1所述的制备方法,其特征在于:所述的壳聚糖的重均分子量为10~1000千道尔顿。
3.根据权利要求1所述的制备方法,其特征在于:步骤(d)和步骤(e)的具体操作为:在超声条件下,向所述的厄洛替尼修饰的壳聚糖溶液中缓慢加入多柔比星和吲哚菁绿的二甲基亚砜溶液,一段时间后,反应液于去离子水中透析处理,即得自组装纳米微粒溶液。
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Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN105193831A (zh) * | 2015-09-14 | 2015-12-30 | 郑州大学 | 一种负载吲哚菁绿的自组装多功能纳米靶向系统的制备方法及其应用 |
CN106832059A (zh) * | 2017-03-08 | 2017-06-13 | 福州大学 | 一种具有肿瘤靶向性的厄洛替尼‑Cy7‑壳聚糖聚合物 |
-
2017
- 2017-12-11 CN CN201711305094.3A patent/CN107737348B/zh active Active
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN105193831A (zh) * | 2015-09-14 | 2015-12-30 | 郑州大学 | 一种负载吲哚菁绿的自组装多功能纳米靶向系统的制备方法及其应用 |
CN106832059A (zh) * | 2017-03-08 | 2017-06-13 | 福州大学 | 一种具有肿瘤靶向性的厄洛替尼‑Cy7‑壳聚糖聚合物 |
Non-Patent Citations (1)
Title |
---|
Free DOX and chitosan-N-arginine conjugate stabilized indocyaninegreen nanoparticles for combined chemophotothermal therapy;Pei-Ru Jheng et al.;《Colloids and Surfaces B: Biointerfaces》;20150921;第136卷;第402-412页 * |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
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