CN110922587A - 一种纳米药物的制备方法及其在治疗骨肉瘤中的应用 - Google Patents
一种纳米药物的制备方法及其在治疗骨肉瘤中的应用 Download PDFInfo
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Abstract
本发明公开了一种纳米药物的制备方法及其在骨肉瘤治疗中的应用。本发明所合成的Cys‑8E材料生物相容性好,包载药物能力强。将该纳米载体包载Apatinib和GSK‑J4制成纳米药物(NPJ4+Apa)后可以靶向骨肉瘤的肿瘤部位,并且对于传统药物无法作用的骨肉瘤干细胞具有较佳的药物递送能力。该纳米药物NPJ4+Apa可以诱导骨肉瘤干细胞凋亡,显著提高Apatinib和GSK‑J4治疗效果。同时,纳米药物NPJ4+Apa可以阻止Apatinib和GSK‑J4作用于正常细胞,降低其毒副作用。本发明的纳米药物NPJ4+Apa具有靶向骨肉瘤干细胞和副作用小等优势,在骨肉瘤瘤临床领域具有良好的应用前景和广阔的发展空间。
Description
技术领域
本发明属于生物医药技术领域。更具体地,涉及一种纳米药物的制备方法及其在治疗骨肉瘤中的应用。
背景技术
骨肉瘤是最常见的原发性恶性骨肿瘤,约占全部骨肿瘤的15%,发病率约2~3/100万/年,而15岁~19岁青少年高达到8-11/100万/年。目前骨肉瘤的治疗以手术联合的系统化疗为主,但由于传统的化疗药物没有选择性,大部分药物集中于肿瘤外区域,使达到肿瘤的有效剂量较低,而且带来严重的毒副反应,并且,化疗药物多重耐药以及新型治疗方式尚未规范化,骨肉瘤的临床药物治疗受到限制。
如何提高化疗的有效率,减少肿瘤多耐药,减少骨肉瘤的复发和转移,是目前临床中对骨肉瘤治疗的研究重点。近来,很多肿瘤学的研究把重点放在了肿瘤干细胞的领域。肿瘤干细胞具有无限增值,自我更新和多向分化的能力,而且肿瘤干细胞多处于静止期,对化疗不敏感。经化疗之后,肿瘤体内干细胞比例明显提高,是产生化疗耐药性和肿瘤复发的主要原因。已有的研究表明骨肉瘤由多种不同功能的肿瘤细胞亚群构成,其中有一小部分骨肉瘤细胞具有肿瘤干细胞的特征,例如自我更新和多向分化能力,这些能力使骨肉瘤干细胞在骨肉瘤的增殖、侵袭、复发、转移和耐药中发挥着决定性的作用。骨肉瘤干细胞的发现为理解骨肉瘤的生物学特性提供了新的视野,但是截至目前,尚未有可以靶向骨肉瘤干细胞的治疗方案成功运用于临床治疗,所以找到一种可以有效杀伤肿瘤干细胞,减少肿瘤干细胞的比例的治疗手段,是提高治疗效果的重要途径。
近年来纳米技术已快速进入肿瘤治疗领域,以纳米材料作为载体进行的主动或被动靶向治疗,甚至基因治疗不仅可以减少化疗药物非特异性分布带来的毒副反应,而且还可以靶向肿瘤干细胞,抵御多药耐药性,提高药物抗癌的功效。其中,刺激响应性聚合物体系(包括温度,光,氧化还原,酸碱度响应)用于纳米载体的制备已经广泛的应用于生物医学领域,其中还原响应控释体系因其聚合物分子结构中带有特殊的还原敏感性官能团如二硫键等,能够响应于肿瘤微环境中偏高的谷胱甘肽浓度而被广泛的应用于抗癌药物的递送与肿瘤治疗中。
此外,聚酯高分子是一类重要的生物医用纳米材料,具有良好的生物相容性和优良的生物降解性,且具有无毒无害、廉价广泛等优点,在药物传递领域具有良好的应用前景和广阔的发展空间。直接缩聚法是传统合成聚酯高分子的主要方法之一,但直接缩聚法仍具有反应温度、压强、时间、及真空度等条件难以控制等缺点。因此,研究一种合成方法简洁、合成条件可控性好且合成产物具有一定优良性质的聚酯材料,是促进聚合物运用于肿瘤治疗的重要条件之一。
GSK-J4,是一种组蛋白去甲基酶抑制剂。现有技术认为GSK-J4通过抑制组蛋白H3第27位氨基酸的去甲基化酶UTX(又称KDM6A)和JMJD3(又称KDM6B)活性发挥作用,抑制胶质瘤和乳腺癌细胞的增殖。
GSK-J4的结构如下
阿帕替尼(Apatinib),又名艾坦,是目前被证实在晚期胃癌标准化疗失败后安全有效的口服药物。经大量的临床研究表明,通过抑制肿瘤组织新血管的生成,Apatinib能够显著延长晚期胃癌患者生存期。
Apatinib的结构如下
最新研究表明,Apatinib或GSK-J4具有抑制骨肉瘤肿瘤细胞生长的效应,但该药物组合物均呈疏水性,且无法靶向肿瘤干细胞,抗肿瘤效果存在一定的局限性。因此,研究开发一种生物相容性好,且具有靶向肿瘤干细胞的纳米药物在骨肉瘤治疗中具有重要意义。
发明内容
本发明要解决的技术问题是克服上述现有技术的缺陷和不足,提供了一种新型纳米药物,并实现了通过纳米沉淀法同时包载药物GSK-J4和Apatinib(NPJ4+Apa),制备具有GSH响应性的纳米双载药体系,并具有作为NPJ4+Apa纳米药物的应用前景。该NPJ4+Apa纳米药物可以实现对Apatinib和GSK-J4的高效负载,对肿瘤环境GSH、pH具有较强的敏感性,并且能够将药物有效递送到骨肉瘤干细胞中,Apatinib和GSK-J4可在干细胞中快速释放诱导其凋亡,为骨肉瘤的有效治疗开拓了一种新的途径。
本发明的第一个目的是提供一种新型聚酯Cys-8E。
本发明的第二个目的是提供上述新型聚酯Cys-8E的合成方法。
本发明的第三个目的是提供上述聚合物Cys-8E在药物递送方面的应用。
本发明的第四个目的是提供一种GSH响应型纳米双载药系统。
本发明的第五个目的是提供NPJ4+Apa纳米药物制备方法,即利用上述GSH响应型纳米双载药系统包载Apatinib和GSK-J4的制备方法。
本发明的第六个目的是提供上述纳米药物在治疗骨肉瘤中的应用。
本发明上述目的通过以下技术方案实现:
本发明提供了一种新型聚酯Cys-8E。该新型聚酯Cys-8E结构式如下所示:
所述的新型聚合物Cys-8E的制备方法指在缚酸剂的作用下,一定量的癸二酰氯滴入已经溶解有等摩尔的L-胱氨酸二甲酯二盐酸((H-Cys-OMe)2·2HCl)的有机混合溶液中。搅拌一定时间后,用冷乙醚沉淀数次,在惰性还原气氛下干燥,最终得到固体Cys-8E。Cys-8E聚合物单体L-胱氨酸二甲酯二盐酸和癸二酰氯的摩尔比为1:1。反应条件为室温,搅拌,反应时长为20min~5h。可用乙醚沉淀,在惰性还原气流中(如氮气,氩气等)干燥。分子量在1500~35000之间。
本发明首次将Apatinib和GSK-J4联合装载于该纳米材料中,并首次提供了纳米双载药系统NPJ4+Apa的制备方法。该载药系统抗肿瘤药效优于单纯药物联合,对骨肉瘤及骨肉瘤干细胞具有明显的抑制效果。
所述的用纳米沉淀法制备同时包载Apatinib和GSK-J4的纳米颗粒的方法,包括将Apatinib、GSK-J4和Cys-8E与稳定剂(如聚乙烯醇(PVA),二硬脂酰基磷脂酰乙醇胺-聚乙二醇(DSPE-PEG)类,磷脂分子等)通过一定比例溶解于与水互溶的有机溶剂(如二甲基亚砜,N,N-二甲基甲酰胺等),形成油相。然后将油相缓慢滴入水相中,获得粒径均一,稳定的纳米溶液。通过以上方法制备的纳米溶液经过DLS测量,粒径可控制在10-500nm左右。
在优选的方案中,制备空白的Cys-8E纳米颗粒时,将Cys-8E溶于DMSO中,形成油相1。稳定剂DSPE-PEG2000溶解于DMSO中,形成油相2。将1,2相油以相同体积混合,加入到水中。优选地,油相与水相体积之比为1:9。制备载药的Cys-8E纳米颗粒时,将Cys-8E溶于DMSO中形成油相1。将药物Apatinib和GSKJ4溶于油相1中。稳定剂DSPE-PEG2000溶解于DMSO中,形成油相2。取适量体积油相1,2充分混合,加入到水中。优选地,油相与水相体积之比为1:9。
在本发明的一些具体实施方案中,所述Apatinib和GSK-J4的摩尔比为2:1。
在本发明的一些具体实施方案中,所述骨肉瘤细胞为143B细胞和SJSA1细胞,所述骨肉瘤干细胞为143B细胞和SJSA1细胞在干性培养条件下形成的骨肉瘤干细胞瘤球。
与现有技术相比,本发明具有以下有益效果:
(1)本发明通过一步缩聚法,简单高效地合成了Cys-8E聚合物,并且聚合物中大量存在的二硫键使得体系具有GSH快速还原响应性。
(2)本发明用生物相容性良好,具有还原响应的聚酯高分子同时包载两种抗癌药物制备得到可控粒径的纳米粒,可通过肿瘤组织的高通透性及高保留性(EPR effect)蓄积在肿瘤组织中,从而实现被动靶向的作用。然后利用肿瘤组织高浓度的谷胱甘肽作用,使得纳米体系中的二硫键开始断裂,加速药物的释放,起到治疗癌症的作用,具有极高的临床应用价值。
本发明对药物的剂型不作限定,凡是药物领域接受的剂型均在本发明的保护范围之内。
附图说明
图1为本发明中合成聚酯材料Cys-8E的核磁氢谱图。
图2为本发明合成聚酯材料Cys-8E的红外吸收图谱。
图3A是本发明制备空白纳米粒和包载了Apatinib和GSKJ4的NPJ4+Apa纳米药物的动态光散射(DLS)图;图3B是本发明制备空白纳米粒和NPJ4+Apa纳米药物的透射电子显微镜(TEM)照片。
图4是本发明实施例中骨肉瘤细胞对纳米药物摄取的情况。图4A是骨肉瘤细胞系143B细胞和SJSA1细胞对NPs纳米粒的摄取能力;图4B骨肉瘤干细胞以及图4C是骨肉瘤干细胞在实验动物体内所成肿瘤对NPs纳米药物的摄取能力。
图5是本发明实施例中制备的NPJ4+Apa纳米药物对骨肉瘤细胞(图5A)和骨肉瘤干细胞(图5B)存活的作用。
图6是本发明实施例中制备的NPJ4+Apa纳米药物对骨肉瘤干细胞体内成瘤的抑制作用。6A是肿瘤大小对比图;6B是肿瘤生长曲线图。
具体实施方式
以下结合说明书附图和具体实施例来进一步说明本发明,但实施例并不对本发明做任何形式的限定。除非特别说明,本发明采用的试剂、方法和设备为本技术领域常规试剂、方法和设备。
在以下各实施案例中,溶液百分比浓度,除特别说明外,均为重量百分比浓度。
实施例1聚合物Cys-8E的制备
1、聚合物Cys-8E的制备,包括以下步骤:
以三乙胺作为缚酸剂,将10mmol癸二酰氯滴入已经溶解有等摩尔的L-胱氨酸二甲酯二盐酸((H-Cys-OMe)2·2HCl)的DMSO混合溶液中。搅拌20分钟后,用250ml冷乙醚沉淀三次,在氮气气氛下还原干燥,最终得到白色带黄色固体。由聚合物的核磁氢谱图分析可证明得到所需Cys-8E聚合物。从红外光谱图可看出二硫键的存在。
实施例2一种GSH响应型的空白纳米载药体系的制备
制备空白的Cys-8E纳米颗粒时,将Cys-8E溶于DMSO中,浓度为20mg/ml,形成油相1。稳定剂DSPE-PEG2000以4mg/ml的浓度溶解于DMSO中,形成油相2。将1,2相油以相同体积混合,加入到以2000r/m的速度搅拌的去离子水中。油相与水相体积之比为1:9。使用截留分子量为100,000Da的超滤管离心三次,去除游离有机溶液DMSO,最后用PBS重悬浮。DLS检测该载药纳米粒的粒径为70-90nm;TEM检测结果可知纳米粒呈均匀分散的球形结构。
实施例3一种GSH响应型的双载药Apatinib和GSKJ4纳米体系的制备
制备载药的Cys-8E纳米颗粒时,将Cys-8E溶于DMSO中形成油相1,浓度为20mg/ml。将药物Apatinib和GSKJ4以2:1的质量比溶于油相1中,药物浓度为9mg/ml。稳定剂DSPE-PEG2000溶解于DMSO中,浓度为4mg/ml,形成油相2。
取适量体积1,2相油充分混合,使DSPE-PEG2000为Cys-8E,Apatinib和GSKJ4总质量的20wt%左右,逐滴加入到以2000r/m的速度搅拌的去离子水中。油相与水相体积之比为1:9。使用截留分子量为100,000Da的超滤管离心三次,去除游离有机溶液DMSO,最后用PBS重悬浮。DLS检测该载药纳米粒的粒径为100-150nm;TEM图像可以观察到纳米粒呈均匀分散的球形结构。
实施例4聚合物Cys-8E的药物递送能力
用荧光物质香豆素6(1.3ug/ml)载入NPs获得NP香豆素6。
(1)将处于对数级增长期的143B(ATCC编号CRL-8303,人源,上皮样贴壁生长)和SJSA1细胞(ATCC编号CRL-2098,人源,上皮样贴壁生长),用胰酶消化,吹散成单细胞悬液,计数,接种到6孔培养板中。在培养箱中培养24h,待细胞贴壁后,分别加入单纯香豆素6溶液及NP香豆素6溶液,在37℃下共同孵育30分钟后,用4%多聚甲醛固定后采用DAPI染核。采用荧光显微镜及流式细胞仪记录荧光强度。
(2)将处于对数级增长期的143B和SJSA1细胞接种于低黏附96孔板,于37℃培养箱培养5天后,选取单个,紧凑且形态规则的肿瘤球(骨肉瘤干细胞)进行实验,分别加入单纯香豆素6溶液及NP香豆素6溶液,在37℃下共同孵育30分钟后,用4%多聚甲醛固定15分钟。采用荧光显微镜及流式细胞仪记录荧光强度。
(3)实验采用4周龄雌性裸鼠,购自南京大学模式动物研究所,体重在15~20g之间,在无特殊病原菌(SPF)条件下分笼饲养,12h交替光照,自由饮食。骨肉瘤干细胞(SJSA1来源)用5%胰蛋白消化酶消化,再用生理盐水洗涤细胞2次。洗涤完成后生理盐水重悬细胞,调整细胞浓度为107/ml,备皮下成瘤用。裸鼠随机分为三组,每组5只,分别编号,进行前腋皮下注射107/ml细胞悬液100mL。定期监测肿瘤大小,待肿瘤长至100mm3,在小动物活体成像观察之前0,1,24小时,分别通过小鼠尾静脉注射100mL生理盐水,100mL溶有10ug近红外染料(DiR)的生理盐水,以及等量的NPDiR。最后检测记录各组成像结果。
实验结果:
无论是骨肉瘤SJSA1和143B细胞系,还是骨肉瘤干细胞来源的肿瘤球及动物模型都显示细胞经纳米包裹作用后的荧光强度均明显增强(图4),表明Cys-8E纳米载体具有较佳的靶向骨肉瘤能力。
实施例5 NPJ4+Apa纳米药物对骨肉瘤干细胞增殖的影响比较。
GSK-J4和Apatinib按照不同浓度配置好后待用。
通过MTT实验的方法,检测不同浓度NPJ4+Apa纳米粒和GSK-J4+Apatinib游离药物对骨肉瘤细胞增殖及骨肉瘤干细胞形成肿瘤瘤球的影响。
(1)将处于指数级增长期的143B和SJSA1细胞用胰酶消化,吹散成单细胞悬液,计数,接种到96孔培养板中。在培养箱中培养24h,待细胞贴壁后,加入不同浓度的NPJ4+Apa纳米粒(以Apatinib浓度计算)和GSK-J4+Apatinib游离药物,在培养箱中培养48h后,每孔加入20μl MTT(5mg/mL),37℃避光孵育4h。然后将各个孔内液体弃去,加入150μL DMSO,震荡15min,使结晶物充分溶解,在酶标仪490nm波长下测定细胞光密度值。
(2)将处于对数级增长期的143B和SJSA1细胞接种于低黏附96孔板,于37℃培养箱培养5天后,选取单个,紧凑且形态规则的肿瘤球进行实验,分别加入DMSO,不同浓度的GSK-J4/Apatinib游离以及等量浓度的NPJ4+Apa纳米药物(以Apatinib浓度计算)。作用48小时后,采用显微镜下计数法测定肿瘤瘤球数量。
实验结果:
如图5所示,NPJ4+Apa纳米药物对骨肉瘤细胞系及骨肉瘤干细胞来源的肿瘤球细胞增殖的抑制作用明显优于GSK-J4/Apatinib游离药物。药物作用关系计算方法:生存率=(实验组数值-空白组数值)/(对照组数值-空白组数值)
实施例6 NPJ4+Apa纳米药物在动物模型对骨肉瘤干细胞的抑制作用。
将骨肉瘤细胞SJSA1细胞进行肿瘤瘤球培养获得骨肉瘤干细胞,培养5天后,用PBS制成1×107个/mL的单细胞悬液,皮下注射于雄性裸鼠左侧腋下位置处,每只0.2mL。每日观测小鼠状况,用游标卡尺测量肿瘤长径(a)和短径(b),根据公式V(mm3)=(a×b2)/2计算瘤体积。待肿瘤体积达到80~100mm3时,将动物随机分为6组,每组5只。分别为对照组PBS;纳米材料空白对照组NPs;Apatinib组6mg/kg;GSK-J4组3mg/kg;联用组Apatinib 6mg/kg+GSK-J4 3mg/kg以及6mg/kg NPJ4+Apa(以Apatinib浓度计算),隔日一次尾静脉,连续给药5次。24天后,颈部脱臼处死小鼠,将肿瘤剥离、称重,对比肿瘤生长大小。
实验结果:
结果显示NPJ4+Apa纳米药物对于骨肉瘤干细胞来源的肿瘤生长抑制效果明显好于其他实验组,表明NPJ4+Apa纳米药物在体内同样具有抑制骨肉瘤干细胞自我更新能力的效果。
上述实施例为本发明较佳的实施方式,但本发明的实施方式并不受上述实施例的限制,其他的任何未背离本发明的精神实质与原理下所作的改变、修饰、替代、组合、简化,均应为等效的置换方式,都包含在本发明的保护范围之内。
Claims (10)
2.权利要求1所述的聚合物Cys-8E的制备方法,其特征在于:在缚酸剂,优选为三乙胺的存在下,将癸二酰氯滴入溶解有L-胱氨酸二甲酯二盐酸((H-Cys-OMe)2·2HCl)的有机溶液,经乙醚沉淀数次,在惰性还原气氛下干燥,最终得到固体Cys-8E。
3.根据权利要求2所述的制备方法,其特征在于,L-胱氨酸二甲酯二盐酸和癸二酰氯的摩尔比为1:1。
4.根据权利要求2所述的制备方法,其特征在于,在氮气或氩气中干燥。
5.根据权利要求2~4任一所述的制备方法,其特征在于,癸二酰氯与L-胱氨酸二甲酯二盐酸((H-Cys-OMe)2·2HCl)在室温下搅拌反应20min~5h。
6.权利要求1所述聚合物Cys-8E用于制备药物传递载体的应用。
7.根据权利要求6所述的应用,其特征在于,所述药物为靶向肿瘤部位,优选是靶向骨肉瘤的肿瘤部位的药物,优选为Apatinib和/或GSK-J4。
8.一种GSH以及pH敏感型的纳米药物,其特征在于,以权利要求1所述的聚合物Cys-8E为药物载体。
9.根据权利要求8所述的药物,其特征在于,所述药物为靶向肿瘤部位,优选为靶向骨肉瘤的肿瘤部位的药物,所述药物优选为Apatinib和/或GSK-J4,更优选地,二者比例为1~10:1,进一步优选是2:1。
10.根据权利要求9所述的药物的制备方法,其特征在于包括以下步骤:先制备包含Apatinib、GSK-J4、Cys-8E和稳定剂的油相,所述的油相能够溶解于水,然后将油相缓慢加入水相中,获得纳米药物。
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