CN117126388A - 一种胆盐修饰的两亲性生物材料Fmoc-PEG-GCA及其制备方法和用途 - Google Patents
一种胆盐修饰的两亲性生物材料Fmoc-PEG-GCA及其制备方法和用途 Download PDFInfo
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- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G65/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
- C08G65/02—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring
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Abstract
本发明涉及生物材料和药物制剂领域,公开了一种胆盐修饰的两亲性生物材料Fmoc‑PEG‑GCA及其制备方法和用途。该生物材料结构如式I所示,该生物材料可在水中自组装成为一种纳米胶束,该胶束可在Fmoc的π‑π相互作用下高效包载紫杉醇。PEG在该胶束中具有高密度特性,能够促进胶束在肠道粘液层中高效穿透,甘氨胆酸(GCA)在该胶束中作为一种靶头,能够靶向回肠末端过表达的ASBT转运体靶头,从而显著提高胶束在肠上皮细胞转运效率。该生物材料作为紫杉醇口服递送的药物载体,能够显著提高紫杉醇的口服生物利用度,具有较高的临床应用价值。
Description
技术领域
本发明涉及一种胆盐修饰的两亲性生物材料Fmoc-PEG-GCA及其制备方法,本发明还涉及该生物材料用于口服紫杉醇递送的用途,属生物材料和药物制剂领域。
背景技术
紫杉醇是目前较为常见的一线抗癌药物,广泛用于治疗乳腺癌、肺癌、结肠癌等。紫杉醇可以与微管蛋白结合并诱导其聚合,从而抑制肿瘤细胞的有丝分裂和肿瘤的增殖。目前,紫杉醇主要的临床用药方式为静脉注射,如已经上市的等。然而,静脉注射往往有许多缺点,如给药不便、感染风险增加、患者依从性差、以及其他一些不可避免的副作用等。口服紫杉醇作为一种非常有潜力的新剂型,近年来引起了越来越多研究者的关注。口服给药是最容易被患者接受的给药途径,具有给药方便、安全性好等优点。它可以快速推动新药的临床应用,大大提高患者的生活质量。
然而,口服紫杉醇的开发中仍有许多困难需要克服,如紫杉醇容易被复杂的胃肠道环境所破坏,紫杉醇容易被肠道和肝脏中细胞色素P450代谢,在肠道吸收时也很容易被外排而降低其吸收效率。并且,肠道粘液层和肠细胞屏障也是影响紫杉醇口服吸收的主要障碍。纳米载体可以显著改善紫杉醇在水中的溶解度和稳定性,与传统剂型(片剂、胶囊等)相比,纳米载体一直是进行口服紫杉醇递送的首选。理想的口服制剂应该足够稳定,可以保护紫杉醇免受胃肠道中的酶、酸、碱和盐离子的损害。此外,药物还应避免过快地从载体中渗漏,以防止药物吸收减少,减少药物对胃肠道的毒性。此外,成功的口服制剂需要有良好的穿过肠道上皮细胞的能力,并将肠道中的酶代谢降至最低。更重要的是,纳米载体首先应该具有较好的粘膜粘附性和穿透性,这是提高口腔肠道吸收的一个非常重要的因素。高密度聚乙二醇(PEG)修饰纳米颗粒可以避免肠道粘液层的阻碍,可以保证载体快速穿透粘液层。然而,聚乙二醇修饰纳米粒在肠上皮细胞吸收效率不佳,这限制了其对紫杉醇口服生物利用度的提高。为了解决这个问题,我们进一步将胆盐修饰在载体表面,胆盐可以与心尖钠依赖胆汁酸转运体(ASBT)结合,以主动靶向的方式增加纳米粒在肠道中的吸收,从而提高药物的生物利用度。
本发明设计并合成了一种新型的生物材料Fmoc-PEG-GCA,以该生物材料作为药物载体制备的胶束可以用于紫杉醇的口服递送。在该胶束纳米粒中,以9-芴甲氧羰基(Fmoc)为疏水区,以聚乙二醇为亲水区,甘氨胆酸(GCA)存在于载体表面。Fmoc可以通过π-π相互作用与PTX紧密结合,从而可以获得高稳定性、高载药量的药物载体。由于Fmoc是一种小分子化学基团,将其与聚乙二醇偶联制得的纳米载体可以保证高密度聚乙二醇组分的存在。高密度的聚乙二醇纳米胶束载体可以保证其良好的粘膜渗透性,基于Fmoc的π-π相互作用的的高载药量和稳定性可以保证纳米载体在复杂的胃肠道环境中的稳定性,胆盐的修饰可以提高纳米载体的肠上皮转运,多种作用协同从而提高PTX的口服生物利用度。
发明内容
本发明的目的主要是解决口服紫杉醇递送现存的技术难点,提供了一种可以用于紫杉醇口服递送的两亲性生物材料Fmoc-PEG-GCA。
本发明的第二个目的是提供了一种胆盐修饰的两亲性生物材料Fmoc-PEG-GCA的制备方法。
本发明的第三个目的是提供了一种胆盐修饰的两亲性生物材料Fmoc-PEG-GCA用于口服紫杉醇递送的用途。
为解决本发明的技术问题,本发明提供如下技术方案:
本发明技术方案的第一方面是提供了一种胆盐修饰的两亲性生物材料Fmoc-PEG-GCA,其结构可以式1表示:
本发明技术方案的第二方面是提供了一种胆盐修饰的两亲性生物材料Fmoc-PEG-GCA的制备方法,可以用如下步骤完成:
(1)在反应瓶中将双端氨基PEG和Fmoc-Lys(Boc)-OH溶解在DMF中,溶解完全后向反应液中加入4-二甲基氨基吡啶(DMAP),继续搅拌溶解。反应体系溶解后,继续加入DCC,在0~60℃反应12~24小时后,过滤反应液。其中所述的端氨基PEG与Fmoc-Lys(Boc)-OH的摩尔比为1:0.1~1:1.5,端氨基PEG与DMAP的摩尔比为1:0.1~1:1.5,端氨基PEG与DCC的摩尔比为1:1~1:5,端氨基PEG与DMF的重量比为1:10~1:50。
(2)在上述过滤后的反应液中继续加入甘氨胆酸,搅拌溶解后加入DCC,继续在0~60℃持续反应12~24小时,反应结束后将反应液过滤除去不溶性固体,滤液减压浓缩后采用重沉淀法处理2-5次。沉淀后的固体收集后用冷乙醇和叔丁基甲基醚分别洗涤2-5次,产品在40℃下真空干燥12-48小时后可得到胆盐修饰的生物材料Fmoc-PEG-GCA。其中所述的端氨基PEG与GCA的摩尔比为1:0.1~1:1.5,端氨基PEG与DCC的摩尔比为1:1~1:5。端氨基PEG与冷乙醇、叔丁基甲基醚的重量比为1:10~1:50。
在本发明中,所述的端氨基PEG的分子量为200~5000。优选为1000~3000。
在本发明中,所述的重沉淀法所用的溶剂为乙醚、石油醚、叔丁基甲基醚、正己烷、正庚烷。
本发明技术方案的第三方面是提供了一种胆盐修饰的两亲性生物材料Fmoc-PEG-GCA在口服紫杉醇递送中的用途。
有益技术效果
1)本发明提供的胆盐修饰的生物材料Fmoc-PEG-GCA具有良好的生物相容性,可以高效包载紫杉醇用于口服递送。
2)本发明提供的胆盐修饰的生物材料Fmoc-PEG-GCA制备方法简单快速,可用于工业化生产。
3)本发明提供的胆盐修饰的生物材料Fmoc-PEG-GCA制备的紫杉醇胶束具有较好的胃肠道稳定性,能够快速穿透肠道粘液层、较好跨越肠道上皮细胞,可以有效提高紫杉醇的口服生物利用度。
附图说明
图1:Fmoc-PEG-GCA的红外光谱图
图2:Fmoc-PEG-GCA核磁共振氢谱图
图3:PTX@Fmoc-PEG-GCA胶束的粒径图
图4:PTX@Fmoc-PEG-GCA胶束的zeta电位图
图5:PTX@Fmoc-PEG-GCA胶束对Caco-2细胞安全性结果图
图6:PTX@Fmoc-PEG-GCA胶束在人工胃液中的稳定性结果图
图7:PTX@Fmoc-PEG-GCA胶束在人工肠液中的稳定性结果图
图8:PTX@Fmoc-PEG-GCA胶束在体外类人小肠上皮细胞摄取效率及机制图
图9:PTX@Fmoc-PEG-GCA胶束在体外类人小肠上皮细胞的转运效率结果图
图10:PTX@Fmoc-PEG-GCA胶束在体外类人小肠上皮细胞的表观渗透系数结果图
具体实施方式
以下实施例旨在说明本发明而不是对本发明的进一步限定。下面参照实施例进一步详细阐述本发明,但本发明并不限于这些实施例以及使用的制备方法。而且,本领域技术人员根据本发明的描述可以对本发明进行等同替换、组合、改良或修饰,但这些都将包括在本发明的范围内。
实施例1:一种胆盐修饰的两亲性生物材料Fmoc-PEG-GCA的制备方法,包括如下步骤:
(1)在反应瓶中将1摩尔分子量为2000的双端氨基PEG和1摩尔Fmoc-Lys(Boc)-OH溶解在10毫升DMF中,溶解完全后向反应液中加入0.2摩尔4-二甲基氨基吡啶(DMAP),继续搅拌溶解。反应体系溶解后,继续加入1摩尔N,N’-二环己基碳二亚胺(DCC),在25℃反应12小时后,过滤反应液。
(2)在上述过滤后的反应液中继续加入1摩尔GCA,搅拌溶解后加入1摩尔DCC,继续在25℃持续反应12小时,反应结束后将反应液过滤除去不溶性固体,滤液减压浓缩后采用叔丁基甲基醚重沉淀法处理2次。沉淀后的固体收集后分别用20毫升冷乙醇和叔丁基甲基醚分洗涤2次,产品在40℃下真空干燥12小时后可得到胆盐修饰的生物材料Fmoc-PEG-GCA。
本实施例制备的一种胆盐修饰的两亲性生物材料Fmoc-PEG-GCA分别用核磁共振氢谱、红外光谱进行表征。其红外光谱图如图1所示,核磁共振氢谱图如图2所示,由此可确定该材料成功合成。
实施例2:一种包载紫杉醇的胆盐修饰的两亲性生物材料Fmoc-PEG-GCA胶束(PTX@Fmoc-PEG-GCA胶束)及不包载紫杉醇的Fmoc-PEG胶束(空白Fmoc-PEG胶束)的制备方法,包括以下步骤:
表1为PTX@Fmoc-PEG-GCA胶束的处方组成:
制备方法:将67.5mg PEG-Fmoc、7.5mg实施例1制备的Fmoc-PEG-GCA、10mg紫杉醇溶于1mL乙腈和无水乙醇混合(体积比1:1)的溶液中至完全溶解,经0.22μm滤膜除去不溶物后备用。将上述溶液在600rpm/min搅拌下缓慢滴加至装有10mL 5%葡萄糖溶液的100mL圆底烧瓶中,溶液由澄清透明逐渐变为澄清乳白色,滴加完毕后再搅拌10min后,采用旋转蒸发仪在较低的转速下室温下除去体系内的有机溶剂。待有机溶剂除净后,经4000rpm/min离心除去没有被包裹的紫杉醇后可得到PTX@Fmoc-PEG-GCA胶束。未包载紫杉醇的空白胶束采用同样的制备方法,在不加紫杉醇的条件下可得到空白Fmoc-PEG-GCA胶束。
本实施例制备的PTX@Fmoc-PEG-GCA胶束,分别采用动态光散射的方法,采用马尔文粒径仪分别测定其粒径和zeta电位,其中粒径为122.7nm,PDI为0.087,如图3所示;电位为-9.49mV,如图4所示;通过高效液相色谱法测定胶束的包封率和载药量,其中包封率为97.04%;载药量为15.86%。
实施例3:空白Fmoc-PEG-GCA胶束对人结直肠细胞Caco-2细胞安全性实验
将实施例2制备的空白Fmoc-PEG-GCA胶束用培养液稀释成预定浓度的溶液。每个浓度设6个复孔,并设对照组和调零组。将人结肠癌细胞Caco-2细胞以1×104个/孔的密度接种于96孔板中,继续培养24h后,介质以含有0.001,0.01,0.1,1,10,50μg/ml的空白胶束浓度的新鲜培养液替换,分别继续培养24h。每孔加入CCK-8试剂20μl。继续孵育1~4h,于450nm处测定吸收值,并以650nm为参考波长。计算细胞活力,公式如下:
细胞活力(%)=[(OD实验-OD调零)/(OD对照-OD调零)]×100
表2为空白Fmoc-PEG-GCA胶束对人结肠癌细胞Caco-2细胞的增殖抑制情况
图5与表2表明,空白Fmoc-PEG-GCA胶束在所测定的浓度范围内,Caco-2细胞的活力均在85%以上,表明材料本身对细胞毒性较小。说明本专利提供的空白Fmoc-PEG-GCA胶束在安全性方面存在优势。
实施例4:PTX@Fmoc-PEG-GCA胶束在人工胃、肠液稳定性实验
人工胃液的配制:取100ml pH 1.2的盐酸溶液,加入320mg胃蛋白酶,溶解即得。
人工肠液的配制:取100ml pH 6.8的缓冲溶液,加入1000mg胰蛋白酶,溶解即得。
分别取实施例2制备的1mL紫杉醇浓度为1mg/mL的PTX@Fmoc-PEG-GCA胶束与4ml人工胃液及人工肠液混合孵育,置于37℃,100rpm恒温震荡。其中,人工胃液组样品,在1h,2h时间点分别取300μL样品,人工肠液组样品,在1h,2h,4h,6h时间点分别取300μL样品。测定所取样品的粒径及粒径分布,考察样品在模拟人工胃液和肠液中的稳定性。
表3为PTX@Fmoc-PEG-GCA胶束在人工胃液中的不同时间点下的粒径
时间 | PTX@Fmoc-PEG-GCA胶束 |
0h | 135.97±2.60 |
1h | 143.62±5.51 |
2h | 143.63±11.15 |
表4为PTX@Fmoc-PEG-GCA胶束在人工肠液中的不同时间点下的粒径
图6、7与表3、4表明PTX@Fmoc-PEG-GCA胶束在人工胃液2h时稳定性良好,在人工肠液中粒径会呈现略微升高的趋势,但整体变化不大。说明本专利提供的口服紫杉醇系统在胃肠道稳定性良好,可以以相对完整的状态到达小肠吸收部位。
实施例5:香豆素6标记的Fmoc-PEG-GCA胶束(Cou-6@Fmoc-PEG-GCA胶束)的制备
按上述实施例2中Fmoc-PEG-GCA胶束制备方法,制备香豆素6标记的纳米粒。将67.5mg PEG-Fmoc、7.5mg实施例1制备的Fmoc-PEG-GCA、10mg紫杉醇、0.5mg香豆素6溶于1mL乙腈和无水乙醇以体积比1:1混合的溶液中至完全溶解,经0.22μm滤膜除去不溶物后备用。将上述溶液在600rpm/min搅拌下缓慢滴加至装有10mL 5%葡萄糖溶液的100mL圆底烧瓶中,溶液由澄清透明逐渐变为澄清乳白色,滴加完毕后再搅拌10min后,采用旋转蒸发仪在较低的转速下室温下除去体系内的有机溶剂。待有机溶剂除净后,经4000rpm/min离心除去没有被包裹的紫杉醇后可得到Cou-6@Fmoc-PEG-GCA胶束。
实施例6:人结肠癌Caco-2细胞transwell模型的建立
将人结肠癌Caco-2细胞以1×105个细胞接种于12孔Tranwell小室中,下室加入1.5ml培养基,于37℃、5%CO2培养箱中培养48h后,弃去培养基更换新鲜培养液,于37℃、5%CO2培养箱中继续培养。前一周每两天换液,一周后每天换液,培养21天后,即得体外类人小肠上皮细胞模型。
实施例7:Fmoc-PEG-GCA胶束在体外小肠上皮细胞模型上的摄取及机制研究
利用酶标仪定量考察Fmoc-PEG-GCA胶束在体外小肠上皮细胞上的摄取能力。摄取机制实验采用100μM牛黄胆酸钠,5mg/mL M-β-环糊精,10μg/mL氯丙嗪,100μg/mL阿米洛利作为摄取抑制剂,加入小室内置于培养箱中孵育1h后吸去抑制剂溶液,用PBS洗涤细胞单层3次后,向小室中加入500μL用Hank’s缓冲液稀释的实施例5制备的Cou-6@Fmoc-PEG-GCA胶束(Cou-6浓度:10μg/mL),继续孵育1h。给药结束后,加入冷PBS洗去制剂,各孔分别加入150μL RIPA裂解液在冰浴条件下对细胞进行裂解,置于摇床中裂解30min后,收集细胞裂解液,分别采用BCA试剂盒和酶标仪对细胞裂解液中的蛋白含量与Cou-6含量进行测定,每组设置3个复孔。细胞摄取结果(药物/蛋白:ng/μg)按照下述公式进行计算:细胞摄取效率=(Cou-6被摄取的总量(ng))/(所有蛋白的总质量(μg))
表5Cou-6@Fmoc-PEG-GCA胶束在体外模拟人小肠上皮细胞模型中的摄取效率
由图表5,图8可以看出,细胞单层经不同摄取抑制剂处理后,对于Fmoc-PEG-GCA胶束在体外模拟人小肠上皮细胞模型中的摄取效率的摄取能力均有所下降。单层细胞经阿米洛利、M-β-环糊精、牛黄胆酸钠预处理后,对药物的摄取效率分别下降24.19%、49.86%、50.01%、35.90%,证明网格蛋白和小窝蛋白介导的胞吞作用与ASBT介导的细胞内吞作用在Fmoc-PEG-GCA胶束的细胞摄取中占据重要作用。
实施例8:无胆酸修饰的包载紫杉醇的Fmoc-PEG胶束(PTX@Fmoc-PEG)的制备方法,包括以下步骤:
表6为Fmoc-PEG胶束的处方组成:
制备方法:将75mg PEG-Fmoc、10mg紫杉醇溶于1mL乙腈和无水乙醇混合的溶液(体积比1:1)中至完全溶解,经0.22μm滤膜除去不溶物后备用。将上述溶液在600rpm/min搅拌下缓慢滴加至装有10mL 5%葡萄糖溶液的100mL圆底烧瓶中,溶液由澄清透明逐渐变为澄清乳白色,滴加完毕后再搅拌10min后,采用旋转蒸发仪在较低的转速下室温下除去体系内的有机溶剂。待有机溶剂除净后,经4000rpm/min离心除去没有被包裹的紫杉醇后可得到包载紫杉醇的无胆酸修饰的PTX@Fmoc-PEG胶束。
实施例9:PTX@Fmoc-PEG-GCA胶束在体外小肠上皮细胞模型上的转运效率研究
利用液相色谱定量考察Fmoc-PEG-GCA胶束在体外小肠上皮细胞上的转运能力。实验室预先用37℃保温的Hank’s溶液冲洗小室和外室3遍,在小室中分别加入500μL用Hank’s溶液稀释的紫杉醇注射液(Taxol注射液)、实施例2制备的PTX@Fmoc-PEG-GCA胶束和实施例8制备的PTX@Fmoc-PEG胶束,继续置于37℃、5%CO2培养箱中进行转运试验。分别在30min、60min、90min、120min从外室取300μL下层接收液进行紫杉醇含量测定,并及时补充37℃预热的Hank’s溶液于外室。每组设定3个复孔。将取得的样品加入等体积乙腈涡旋混匀,超声10min后,12000rpm离心10min,收集上清液进高效液相色谱进行含量测定。
计算PTX@Fmoc-PEG-GCA胶束、PTX@Fmoc-PEG胶束、Taxol注射液三组在不同时间下的转运效率及表观渗透系数。表观渗透系数的计算公式为:Papp=dQ/dt×1/(A×C0)。其中dQ/dt为紫杉醇在单位时间内药物的转运量,A为小室膜的表面积,C0为Caco-2细胞顶侧(肠腔)的药物初始浓度。
表7为Fmoc-PEG-GCA胶束在体外模拟人小肠上皮细胞模型中的转运效率
时间 | Taxol注射液 | PTX@Fmoc-PEG胶束 | PTX@Fmoc-PEG-GCA胶束 |
30min | 0.78%±0.23 | 1.92%±0.92 | 2.19%±0.36 |
60min | 1.45%±0.55 | 4.97%±1.28 | 7.65%±1.63 |
90min | 2.93%±0.45 | 8.16%±0.18 | 12.68%±0.63 |
120min | 5.42%±0.50 | 10.14%±0.22 | 15.66%±0.76 |
表8为Fmoc-PEG-GCA胶束在体外模拟人小肠上皮细胞模型中的表观渗透系数。
Taxol注射液 | PTX@Fmoc-PEG胶束 | PTX@Fmoc-PEG-GCA胶束 | |
Papp | 3.18×10^-6±0.21 | 5.88×10^-6±0.12 | 11.27×10^-6±0.71 |
由表7-8,图9-10可以看出,PTX@Fmoc-PEG-GCA胶束在体外模拟小肠上皮细胞模型上转运120min时,转运效率可以达到15.66%,PTX@Fmoc-PEG胶束的转运效率为10.14%,Taxol注射液组的转运效率为5.42%。Fmoc-PEG-GCA胶束转运渗透系数为11.27×10^-6cm/s,PTX@Fmoc-PEG胶束的转运渗透系数为5.88×10^-6±0.12,Taxol注射液的转运渗透系数为3.18×10^-7cm/s。由此可见,本发明所构建的Fmoc-PEG-GCA胶束可以明显提高紫杉醇的肠道转运能力。
Claims (5)
1.一种胆盐修饰的两亲性生物材料Fmoc-PEG-GCA,其特征是用式I所示:
2.权利要求1所述的一种胆盐修饰的两亲性生物材料Fmoc-PEG-GCA的制备方法,其特征是包括如下步骤:
(1)在反应瓶中将双端氨基PEG和Fmoc-Lys(Boc)-OH溶解在N,N’-二甲基甲酰胺(DMF)中,溶解完全后向反应液中加入4-二甲基氨基吡啶(DMAP),继续搅拌溶解,反应体系溶解后,继续加入N,N’-二环己基碳二亚胺(DCC),在0~60℃反应12~24小时后,过滤反应液,其中所述的端氨基PEG与Fmoc-Lys(Boc)-OH的摩尔比为1:0.1~1:1.5,端氨基PEG与DMAP的摩尔比为1:0.1~1:1.5,端氨基PEG与DCC的摩尔比为1:1~1:5,端氨基PEG与DMF的重量比为1:10~1:50;
(2)在上述过滤后的反应液中继续加入甘氨胆酸,搅拌溶解后加入DCC,继续在0~60℃持续反应12~24小时,反应结束后将反应液过滤除去不溶性固体,滤液减压浓缩后采用重沉淀法处理2-5次,沉淀后的固体收集后用冷乙醇和叔丁基甲基醚分别洗涤2-5次,产品在40℃下真空干燥12-48小时后可得到胆盐修饰的生物材料Fmoc-PEG-GCA;其中所述的端氨基PEG与GCA的摩尔比为1:0.1~1:1.5,端氨基PEG与DCC的摩尔比为1:1~1:5,端氨基PEG与冷乙醇、叔丁基甲基醚的重量比为1:10~1:50。
3.根据权利要求2所述的的制备方法,其特征在于,所述的端氨基PEG的分子量为200~5000,优选为1000~3000。
4.根据权利要求2所述的制备方法,其特征在于,所述的重沉淀法所用的溶剂为乙醚、石油醚、叔丁基甲基醚、正己烷、正庚烷。
5.权利要求1所述的一种胆盐修饰的两亲性生物材料Fmoc-PEG-GCA在口服紫杉醇递送中的应用。
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