CN116159057A - 共载青蒿琥酯和氯喹的响应性纳米制剂及其制备方法和应用 - Google Patents
共载青蒿琥酯和氯喹的响应性纳米制剂及其制备方法和应用 Download PDFInfo
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- CN116159057A CN116159057A CN202310134354.4A CN202310134354A CN116159057A CN 116159057 A CN116159057 A CN 116159057A CN 202310134354 A CN202310134354 A CN 202310134354A CN 116159057 A CN116159057 A CN 116159057A
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Abstract
本发明公开了一种共载青蒿琥酯和氯喹的响应性纳米制剂及其制备方法,所述纳米制剂主要是由4‑羟甲基苯硼酸和PLGA合成的载体材料HPA与青蒿琥酯和氯喹组装而成。本发明制备的纳米制剂可利用苯硼酸与青蒿琥酯之间的氢键作用力,显著提高青蒿琥酯的包封率,并利用苯硼酸的ROS响应性促使药物释放,发挥青蒿琥酯和氯喹药物组合治疗作用。一方面,促使肿瘤相关巨噬细胞M2向M1表型的转变,激活抗肿瘤免疫;另一方面,上调胞内ROS水平,诱导结直肠癌细胞凋亡。从两方面抑制结直肠癌细胞的增殖、侵袭和转移,以达到对结直肠癌的治疗作用。
Description
技术领域
本发明属于药物制剂技术领域,具体涉及一种共载青蒿琥酯和氯喹的响应性纳米制剂及其制备方法。
背景技术
青蒿琥酯(Artesunate,AS)是从菊科植物黄花蒿中提取分离得到的青蒿素的半合成衍生物,在全球范围内广泛用作抗疟疾药物,无明显副作用。近年来研究表明,AS具有潜在的抗癌功效。由于肿瘤细胞中的亚铁离子水平较高,铁介导的AS内过氧化物桥断裂产生有毒自由基通常被认为是AS抗癌活性的关键机制。这些有毒自由基,尤其是活性氧(ROS)可产生氧化应激,导致细胞脂质、膜、蛋白质和DNA的损伤,诱导癌细胞凋亡、自噬和铁坏死,进而发挥抗结直肠癌作用。
氯喹(Chloroquine,CQ)是一种常用的自噬抑制剂。自噬是一种细胞在不利环境下维持自身稳态的机制,可以保护细胞防止代谢应激和氧化损伤,抑制ROS产生并减少DNA羟基化、组织损伤和染色体的不稳定性。此外,CQ还可以通过调节免疫反应,克服肿瘤细胞的耐药性,并抑制肿瘤转移的发生,并且CQ与化疗药物联合使用已被用于多项抗肿瘤临床试验。但是,由于缺乏组织和细胞特异性,临床上需要使用较大的剂量以实现治疗效果。
越来越多的证据表明,结直肠癌上皮内和间质区域肿瘤相关巨噬细胞M1和M2表型的比值与结直肠癌的死亡率密切相关。由于M2表型肿瘤相关巨噬细胞有助于免疫抑制肿瘤微环境的形成,因此通过调控肿瘤相关巨噬细胞由M2向M1型极化,重新编程肿瘤微环境,是一种潜在的结直肠癌治疗手段。
发明内容
发明目的:本发明提供了共载青蒿琥酯和氯喹的响应性纳米制剂及其制备方法,所述纳米制剂具有ROS响应性的特性,且所包裹的两种药物能在制剂的基础上产生协同作用,实现更优的结直肠癌治疗作用。
技术方案:为了达到上述发明目的,本发明所采用的技术方案如下:
一种共载青蒿琥酯和氯喹的响应性纳米制剂,所述纳米制剂主要是由4-羟甲基苯硼酸和PLGA(聚乳酸-羟基乙酸共聚物)合成的ROS响应性纳米载体材料HPA与青蒿琥酯和氯喹组装而成;
其中,所述的载体材料HPA通过以下方法合成:
①将PLGA、EDCI和DMAP溶解于氯仿中,冰浴搅拌活化;其中PLGA、EDCI和DMAP的摩尔比为1:(2~3):(2~3);
②将HPBA溶于DMSO中,并滴入步骤①的反应液中,50-60℃下冷凝回流反应,4-羟甲基苯硼酸与PLGA反应的摩尔比为(1~4):(1~4);
③反应结束后,离心除去未反应的HPBA,取上清加入石油醚中,振摇沉淀以得到产物,在产物中加入无水乙醇,涡旋混合后弃掉上清除去催化剂,将产物用乙醇和石油醚洗涤,干燥,得最终产物HPA。
作为优选:
高分子聚合物PLGA的分子量为5~50kDa,其乳酸:羟基乙酸的比例为75:25、50:50或25:75;所述PLGA选自上述比例中的一种或几种混合。
优选的,所述青蒿琥酯和氯喹的重量比为(1~3):(1~3),进一步优选(1~3):1。
优选的,所述纳米制剂主要是由如下重量份的原料制成:
优选的,所述纳米制剂主要是由如下重量份的原料制成:
进一步优选的,所述纳米制剂主要是由如下重量份的原料制成:
进一步优选的,所述乳化剂为吐温-80、司盘-80、聚乙烯醇(PVA)、十二烷基硫酸钠中的一种或几种材料混合,更进一步优选吐温-80、聚乙烯醇PVA。
所述的共载青蒿琥酯和氯喹的响应性纳米制剂,其制备方法,包括如下步骤:
取HPA、青蒿琥酯和氯喹溶解于有机溶剂中作为有机相,取乳化剂溶解于蒸馏水中作为外水相,将有机相加入外水相中,超声处理形成乳剂,蒸发除去有机溶剂,离心除去未包载的药物,得到所述共载青蒿琥酯和氯喹的ROS响应性纳米制剂。
优选,所述有机溶剂选自二氯甲烷,所述有机相:水相体积比为1:(4-6)。
最后所得纳米制剂为球形,直径为100~200nm。
本发明所述的共载青蒿琥酯和氯喹的响应性纳米制剂在制备治疗肿瘤的药物中的应用。
乳酸-羟基乙酸共聚物(PLGA)是经美国食品药品监督管理局(FDA)批准用于临床试验的可生物降解高分子聚合物,由乳酸和羟基乙酸随机聚合而成,具有生物相容性、生物可降解性等优点,常用于亲脂性药物的包载。4-羟甲基苯硼酸及其衍生物在富电子的过氧化氢环境中,缺电子的硼酸酯易于被催化分解,具有ROS响应性的特征,可与聚合物键合构建具有ROS响应性的载体材料。因此,采用4-羟甲基苯硼酸修饰PLGA合成HPA,用于包载AS和CQ,可制备具有ROS响应性的纳米制剂。此外,4-羟甲基苯硼酸和AS之间可通过形成氢键而提高AS的包载效率。
本发明提出利用HPA的ROS敏感性,构建包载AS和CQ的ROS敏感性纳米制剂。纳米制剂被结直肠癌细胞摄取后,AS作用于线粒体产生ROS,同时CQ抑制细胞自噬,导致胞内ROS水平不可逆性升高;而载体材料的ROS敏感键断裂又进一步促进了纳米制剂的分解使药物完全释放,进一步加速上述过程,从而诱导结直肠癌细胞凋亡坏死。而当纳米制剂被M2表型肿瘤相关巨噬细胞摄取后,AS和CQ共同调控肿瘤相关巨噬细胞M2表型向M1表型的极化,降低IL-10水平和提高IL-6水平,逆转肿瘤免疫抑制微环境,激活抗肿瘤免疫,发挥对结直肠癌的抑制作用。
本发明构建了共载青蒿琥酯和氯喹的ROS响应性纳米制剂(HPA/AS/CQ)。其中,乳化剂的选择及外水相的浓度直接影响纳米粒的质量。
本发明除4-羟甲基苯硼酸与PLGA反应比例及水相和有机相比例外所涉及的比例均为重量比。
当固定选择一种乳化剂时,外水相的浓度不同时,HPA/AS/CQ的平均粒径和药物包载效率也不同。结果见表1。
表1:外水相的浓度对纳米粒粒径和包封率的影响(n=3)
从表可以看出,随着外水相的浓度逐渐增大时,纳米粒粒径减小,AS和CQ的载药效率也发生了变化;当外水相的浓度为0.01~0.5%时,粒径最大,AS载药效率为4.96%,CQ载药效率大于50%,但是AS载药效率太低,不能发挥较强药理作用;当外水相的浓度为0.5~1.5%时,纳米粒粒径为56nm左右,AS载药效率略微升高,但CQ载药效率大幅度下降,总体载药效率较低;当外水相的浓度为1.5~5%时,纳米粒粒径最小。因此,外水相的浓度优选为1.5~5%。但是,AS载药效率为10%左右,CQ载药效率为20%左右,总体载药效率较低。因此,考虑更换乳化剂的选择。
当固定外水相的浓度优选为1.5~5%时,乳化剂的种类不同时,HPA/AS/CQ的平均粒径和药物包封率也不同。结果见表2。
表2:乳化剂的类型对纳米粒粒径和包封率的影响(n=3)
从表可以看出,当固定外水相的浓度优选为1.5~5%时,乳化剂的种类不同时,HPA/AS/CQ的平均粒径和载药效率也发生了变化;当乳化剂为SDS时,粒径小于50nm,AS载药效率为13%左右,CQ载药效率为26%左右,但是粒径太小,纳米粒稳定性差,且载药效率较低;当乳化剂为PVA时,纳米粒粒径为166nm左右,AS、CQ载药效率都有升高,但粒径略大;当乳化剂为Tween-80时,纳米粒粒径为136nm载药,AS载药效率为23%左右,CQ载药效率为34%左右。因此,综合考虑粒径和载药效率,选择Tween-80作为乳化剂,具有更好发挥治疗作用的潜力。
技术效果:与现有技术相比,本发明制备的共载青蒿琥酯和氯喹的纳米制剂,可通过4-羟甲基苯硼酸的羟基和青蒿琥酯的羧基形成氢键,显著提高药物的包封率;该纳米制剂对HCT116结直肠癌细胞和IL-4和IL-13诱导的M2型肿瘤相关巨噬细胞均有调节作用。一方面,显著上调结直肠癌细胞ROS水平和下调VEGF和HIF-1α水平,且由于载体材料的ROS响应性,使得ROS产生和药物释放形成正反馈,实现青蒿琥酯和氯喹的完全释放;另一方面,通过调节肿瘤相关巨噬细胞协同促进M2到M1表型极化,IL-10水平降低和IL-6水平增加,逆转免疫抑制肿瘤微环境,以激活抗肿瘤免疫,共同发挥对结直肠癌的抑制作用。为设计针对结直肠癌治疗的纳米制剂提供了一种有效的方法。
附图说明
图1是本发明的透射电子显微镜下HPA/AS/CQ的形态观察;
图2是本发明的HPA/AS/CQ对结直肠癌细胞的增殖抑制作用;
图3是本发明的HPA/AS/CQ体外对肿瘤相关巨噬细胞的极化作用;
图4是本发明的HPA/AS/CQ对小鼠结直肠癌肿瘤相关巨噬细胞的极化作用。
图5是本发明的HPA反应式和核磁图谱。
具体实施方式
下面将结合实施例对本发明作进一步说明,以便全面了解本发明。
以下实施例中所用HPA的合成方法如下:
①将300mgPLGA(30kDa,x:y=50:50,0.01mmol)、5.7mgEDCI(0.03mmol)、2.4mgDMAP(0.02mmol)溶解于2mL氯仿中,冰浴搅拌活化30min。
②将HPBA溶于DMSO中(20mg/mL),取0.31mL滴入①的反应液中,55℃下冷凝回流反应24h。
③反应结束后,将反应液转移至玻璃试管中,1200rpm离心5min,除去未反应的HPBA沉淀;取上清加入10mL石油醚中,振摇沉淀以得到产物,在产物中加入5mL无水乙醇,涡旋混合后弃掉上清除去催化剂,将产物用乙醇和石油醚分别洗两次,抽滤后空气吹干,得最终产物HPA,核磁图谱见图5。
实施例1
分别称取处方量AS1mg、CQ0.5mg和HPA20mg置于刻度试管中,加入适量二氯甲烷,超声使之完全溶解作为有机相;再称取Tween-80溶于蒸馏水中,涡旋超声使之完全溶解,制备成2%(w/v)的Tween-80溶液作为外水相;将有机相滴加进入外水相中,有机相:外水相=1:5(v/v),超声波细胞破碎仪超声(200W,5min,开3s,停3s)对混合物进行超声处理形成乳剂。旋转减压蒸发除去有机溶剂,得到的纳米粒加入超滤管(100kDa)中3500×g超滤10min,PBS洗涤除去未包载的药物,最后用PBS定容,过无菌过滤后(膜滤器孔径0.45μm)后得到HPA/AS/CQ纳米粒。
成品性状:本品为白色有乳光液体。
粒径测定:取本品适量用采用激光粒度分析仪测定粒径,平均粒径为124.19nm,多分散系数为0.270,Zeta电位为-13.48mV。
实施例2
分别称取处方量AS1mg、CQ1mg和HPA20mg置于刻度试管中,加入适量二氯甲烷,超声使之完全溶解作为有机相;再称取Tween-80溶于蒸馏水中,涡旋超声使之完全溶解,制备成1%(w/v)的Tween-80溶液作为外水相;将有机相滴加进入外水相中,有机相:外水相=1:5(v/v),超声波细胞破碎仪超声(200W,5min,开3s,停3s)对混合物进行超声处理形成乳剂。旋转减压蒸发除去有机溶剂,得到的纳米粒加入超滤管(100kDa)中3500×g超滤10min,PBS洗涤除去未包载的药物,最后用PBS定容,过无菌过滤后(膜滤器孔径0.45μm)后得到HPA/AS/CQ纳米粒。
成品性状:本品为白色有乳光液体。
粒径测定:取本品适量用采用激光粒度分析仪测定粒径,平均粒径为135.61nm,多分散系数为0.182,Zeta电位为-11.83mV。
实施例3
CCK-8法考察HPA/AS/CQ制剂对结直肠癌细胞的体外毒性,对实施实例2的产品进行体外肿瘤细胞增值抑制实验研究。
制剂组:HPA/AS/CQ组
对照组:AS组、CQ组、AS+CQ联用组
空白载体组:未载药脂质纳米粒(HPA)
实验方法
取对数生长期的HCT116细胞以1×104个/孔接种于96孔板中,完全培养基37℃培养12h,移去培养液,用PBS清洗两次。按照上述分组加入不同药物浓度的制剂,与细胞共孵育48h。每孔加入100μL无血清培养基(含10μLCCK-8),孵育1h。使用酶孔仪在450nm处测量每个孔的光密度(OD)。根据公式计算试验制剂的抑制率(%)。
抑制率(%)=1-(样本OD-空白对照OD)/(对照OD-空白对照OD)×100%
采用CalcuSyn2.0软件计算联用指数,当联用指数小于0.7是时,认为产生协同作用。
实验结果
结果表明,AS和CQ在摩尔比为1:1和1:2时,联用指数分别为0.426和0.681,表明AS和CQ的摩尔比在1:1和1:2之间具有对HCT116细胞的协同抑制作用。空白载体HPA对HCT116抑制率小于10%,基本没有生长抑制作用。AS在6μM时抑制率为49%,CQ在11μM时抑制率为50%,而AS+CQ联用组在AS(6μM)和CQ(11μM)时抑制率达到62%。载有相同药物浓度的HPA/AS/CQ对HCT116细胞抑制率为45%。因此,AS+CQ联用显著增强了对结直肠癌细胞的生长抑制作用,而共载AS和CQ的纳米制剂HPA/AS/CQ小幅降低了药物组合对HCT116细胞的增殖抑制作用。
实施例4
采用流式细胞术分别检测M2和M1型肿瘤相关巨噬细胞的标志物CD206和CD86,对实施实例2的产品进行体外肿瘤免疫调控实验研究。
制剂组:HPA/AS/CQ组
对照组:PBS溶液组、AS组、CQ组、AS+CQ联用组
空白载体组:未载药脂质纳米粒(HPA)
实验方法
RAW264.7细胞培养条件为含有青霉素(终浓度为100U/mL)、链霉素(终浓度为100μg/mL),10%FBS的M3培养基,加入IL-4和IL-13诱导为M2型肿瘤相关巨噬细胞。按照上述分组加入不同药物浓度的制剂,与细胞共孵育48h。将细胞加入PBS重悬,调整细胞密度至1×106/ml。加入1ml破膜液,300g4℃离心5min,弃掉破膜液后再加入100μl新鲜破膜液,同时加入CD206和CD86抗体,冰上避光孵育30min,加入PBS洗2次,每管加入400μl2%多聚甲醛,室温避光固定20min,离心弃固定液,并用PBS洗两遍,。最后加入150μlPBS重悬,上流式细胞仪检测。
实验结果
空白载体HPA对肿瘤相关巨噬细胞没有极化作用。AS和CQ能够分别将肿瘤相关巨噬细胞表面M2型标志物CD206的表达量降低至37%和39%,同时将M1型标志物CD86的表达量增加至15%和14%;而AS+CQ联用组可将肿瘤相关巨噬细胞表面M2型标志物CD206的表达量降低至14%,同时将M1型标志物CD86的表达量增加至30%,表明AS和CQ联用能够调控肿瘤相关巨噬细胞由M2向M1型转变。载有相同药物浓度的HPA/AS/CQ将肿瘤相关巨噬细胞表面M2型标志物CD206的表达量由49%降低至28%,同时将M1型标志物CD86的表达量由1%增加至18%,表明HPA/AS/CQ能够有效发挥AS和CQ药物组合对肿瘤相关巨噬细胞极化的协同作用。
实施例5
考察HPA/AS/CQ制剂对结直肠癌小鼠体内肿瘤相关巨噬细胞的极化作用,对实施实例2的产品进行体内肿瘤免疫调控实验研究。
制剂组:HPA/AS/CQ组
对照组:PBS溶液组、AS组、CQ组、AS+CQ联用组
空白载体组:未载药脂质纳米粒(HPA)
实验方法
将BALB/c小鼠适应性饲养一周,在无菌环境下使用小动物麻醉机麻醉,术中皮肤消毒,铺无菌洞单,取左侧腹部横切口,切开进腹。小鼠开腹后,将细胞(2×106个,100μL)注入盲肠浆膜下层。术后继续喂养,注射30天后随机分为6组,按相应分组方式给药,每隔1天尾静脉注射相同的药物,共给药7次,第60天处死。分离肠组织,匀浆后分离组织细胞,采用流式检测肿瘤组织中M1和M2型肿瘤相关巨噬细胞的比例。
实验结果
对结直肠癌小鼠体内肿瘤相关巨噬细胞的极化作用研究中,空白载体HPA对肿瘤相关巨噬细胞没有极化作用。AS和CQ能够分别将肿瘤相关巨噬细胞表面M2型标志物CD206的表达量降低至38%和39%,同时将M1型标志物CD86的表达量增加至3.9%和4.4%;而AS+CQ联用组将肿瘤相关巨噬细胞表面M2型标志物CD206的表达量降低至32%,同时将M1型标志物CD86的表达量增加至9%,表明AS和CQ联用能够在体内协同调控肿瘤相关巨噬细胞由M2向M1型转变。相同给药剂量下,HPA/AS/CQ将肿瘤相关巨噬细胞表面M2型标志物CD206的表达量降低至26%,同时将M1型标志物CD86的表达量增加至18%,表明HPA/AS/CQ在体内进一步提高了AS和CQ药物组合对肿瘤相关巨噬细胞极化的协同作用。
Claims (10)
1.一种共载青蒿琥酯和氯喹的响应性纳米制剂,其特征在于,所述纳米制剂主要是由4-羟甲基苯硼酸HPBA和PLGA合成的载体材料HPA与青蒿琥酯和氯喹组装而成;所述的载体材料HPA通过以下方法合成:
①将PLGA、EDCI和DMAP溶解于氯仿中,冰浴搅拌活化;其中PLGA、EDCI和DMAP的摩尔比为1:(2~3):(2~3);
②将HPBA溶于DMSO中,并滴入步骤①的反应液中,50-60℃下冷凝回流反应,4-羟甲基苯硼酸与PLGA反应的摩尔比为(1~4):(1~4);
③反应结束后,离心除去未反应的HPBA,取上清加入石油醚中,振摇沉淀以得到产物,在产物中加入无水乙醇,涡旋混合后弃掉上清除去催化剂,将产物用乙醇和石油醚洗涤,干燥,得最终产物HPA。
2.根据权利要求1所述的共载青蒿琥酯和氯喹的响应性纳米制剂,其特征在于,所述PLGA的分子量为5~50kDa,其乳酸:羟基乙酸的比例为75:25、50:50或25:75;所述PLGA选自上述比例中的一种或几种混合。
3.根据权利要求1所述的共载青蒿琥酯和氯喹的响应性纳米制剂,其特征在于,4-羟甲基苯硼酸与PLGA反应的摩尔比为(3~4):1。
4.根据权利要求1所述的共载青蒿琥酯和氯喹的响应性纳米制剂,其特征在于,所述青蒿琥酯和氯喹的重量比为(1~3):(1~3),优选(1~3):1。
7.根据权利要求5所述的共载青蒿琥酯和氯喹的响应性纳米制剂,其特征在于,乳化剂为吐温-80、司盘-80、聚乙烯醇PVA、十二烷基硫酸钠中的一种或几种材料混合,优选吐温-80、聚乙烯醇PVA。
8.权利要求1-7任一项所述的共载青蒿琥酯和氯喹的响应性纳米制剂的制备方法,其特征在于,包括如下步骤:
取HPA、青蒿琥酯和氯喹溶解于有机溶剂中作为有机相,取乳化剂溶解于蒸馏水中作为外水相,将有机相加入外水相中,超声处理形成乳剂,蒸发除去有机溶剂,离心除去未包载的药物,得到所述共载青蒿琥酯和氯喹的响应性纳米制剂。
9.根据权利要求8所述的制备方法,其特征在于外水相的浓度为1.5~5%;所述有机溶剂选自二氯甲烷,所述有机相:外水相体积比为1:(4-6)。
10.权利要求1-7任一项所述的共载青蒿琥酯和氯喹的响应性纳米制剂在制备治疗肿瘤的药物中的应用。
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