CN109395091A - 功能化介孔硅肿瘤靶向运输控释系统及其制备方法 - Google Patents
功能化介孔硅肿瘤靶向运输控释系统及其制备方法 Download PDFInfo
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Classifications
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- A—HUMAN NECESSITIES
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- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
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Abstract
本发明提供一种功能化介孔硅肿瘤靶向运输控释系统及其制备方法,本发明通过环糊精包覆介孔硅,并进一步包覆聚赖氨酸,进行氨基酰胺化处理,得到具有较高药物运载和控制释放的系统;其制备工艺包括对甲苯磺酰基‑β‑环糊精的制备、氮化环糊精的制备、S‑(2‑氨乙巯基)‑2‑巯基吡啶盐酸盐的合成、巯基功能化介孔硅纳米粒子的制备、双硫功能化介孔硅纳米粒子的制备、炔基功能化介孔硅纳米粒子的制备、载药介孔硅纳米粒子的制备、金刚烷胺封端的聚赖氨酸的制备、聚赖氨酸包裹修饰、氨基酰胺化修饰;最终实现药物的靶向富集和释放,药物利用率高。
Description
技术领域
本发明涉及药物控制释放领域,具体涉及一种功能化介孔硅肿瘤靶向运输控释系统及其制备方法的领域。
背景技术
近年来,随着对肿瘤微环境的研究,人们逐渐意识到肿瘤微环境是由肿瘤细胞与其周围环境所组成的高度异质性的、且随着肿瘤发展而不断进化的微小生态系统。相比于正常组织和体内循环的血液,肿瘤组织有更低的pH(pH≈6.8),核内体和细胞内溶酶体表现出更低的pH值(<5.4)和更高的浓度的GSH。所以pH和还原敏感型载体得到广泛的应用。
细胞膜是磷脂双分子层,这就意味着构建一个带负电或者不带电的载体可以降低正常细胞对载体的吞噬作用。电荷翻转技术可以让载体在正常血液循环中带负电,而到达肿瘤组织以后翻转为正电,促进了癌细胞对载体的吞噬,提高了载体的渗透能力,肿瘤微环境的低pH为这种电荷反转提供可能。肿瘤细胞中细胞质内的谷胱甘肽(GSH)的浓度(高达10mM)比细胞外的浓度(2mM)高很多,人们便利用可以被谷胱甘肽还原的二硫键为桥梁,与“阀门”连接起来构建成具有还原响应的智能药物控释系统,实现药物在到达靶向部位的“零释放”。
在目前被广泛研究的药物载体中,无机介孔硅纳米粒子(MSN)的载体系统具备优异的性能,MSN的诸多优点:良好的生物相容性、大的比表面积及孔隙体积可以装载大量药物、良好的表面改性能力使其具有修饰各种功能基团的潜力。这些特点赋予了MSN载体系统良好的应用前景:特别是其百纳米级的尺寸满足“被动靶向”的需求。
在目前癌症的治疗策略中,化疗仍然是一种最常用的手段之一。但常规的癌症化疗,在高毒性的药物作用于全身造成强烈毒副作用的同时,病灶的药效却随之大幅降低。事实上,强毒副作用与低化疗效果成为了癌症病人的主要死亡原因之一。
聚赖氨酸/环糊精/介孔硅药物载体在药物控释方面的研究取得了一定进展,同时也存在许多问题:(1)聚赖氨酸/环糊精/介孔硅药物载体体系的研究属于生物工程,该研究受客观条件,临床试验在短时间内很难进行,这些结果不能完全、真实的反应人体试验的情况,所以给评价载体体系带来了很多不准确性。(2)由于肿瘤微环境的复杂性,载药系统无法做到较好的靶向性。(3)由于载体运输过程中的一系列障碍,实际到达病灶部位的药物是非常微量的。
发明内容
本发明提供了一种功能化介孔硅肿瘤靶向运输控释系统及其制备方法,本发明通过环糊精包覆介孔硅,并进一步包覆聚赖氨酸,进行氨基酰胺化处理,得到具有较高药物运载和控制释放的系统,以氧化-还原敏感的双硫键连接MSN及环糊精癌细胞内释药,载体进入癌细胞后,在细胞内还原环境下双硫键断开,包覆在载体介孔硅表面的环糊精脱离,释放药物;将大分子的聚赖氨酸通过主客体作用和环糊精相连,从而将载体的表面裹上了带正电的氨基酸,可以减少介孔硅的团聚,增加分散性。最终实现药物的靶向富集和释放,药物利用率高。
为了达到上述技术效果,采用如下技术方案:
一种功能化介孔硅肿瘤靶向运输控释系统的制备方法,包括如下步骤:
S1:对甲苯磺酰基-β-环糊精的制备(β-CD-OTs)
称取β-CD溶解于NaOH溶液中,在冰水浴中搅拌直至环糊精完全溶解;称取对甲苯磺酰氯(TsCl),缓慢滴加入到β-CD溶液;在冰水浴中搅拌反应后,抽滤;取滤液,用HCl调节pH至7.5-10,将混合物在室温下继续搅拌反应,将反应物置于冰箱中过夜,次日抽滤,将滤渣用去离子水洗三次;将最终产物在20-80℃干燥,得到β-CD-OTs;
S2:氮化环糊精的制备(β-CD-N3)
称取β-CD-OTs溶于去离子水中,加热至60-90℃,然后加入叠氮化钠(NaN3),搅拌反应10-24小时;将反应物冷却至室温,将反应液逐渐滴加至丙酮中沉淀,抽滤得到白色固体产物;将固体在20-80℃下干燥1-3天,得到β-CD-N3;
S3:双硫功能化介孔硅纳米粒子的制备(MSN-SS-NH2)
将巯基功能化介孔硅纳米粒子(MSN-SH)分散在甲醇中,然后加入S-(2-氨乙巯基)-2-巯基吡啶盐酸盐,在室温下搅拌反应12-36h;反应结束后将产物离心,用甲醇和去离子水洗数次,真空干燥得到MSN-SS-NH2;
S4:炔基功能化介孔硅纳米粒子的制备(MSN-SS-alkyne)
称取MSN-SS-NH2分散在用无水硫酸镁干燥过的无水甲醇中,然后加入溴丙炔,在室温下搅拌12-36h;反应结束后将产物离心,用甲醇和去离子水洗数次,真空干燥得到MSN-SS-alkyne;
S5:载药介孔硅纳米粒子的制备(X@MSN-SS-CD)
称取MSN-SS-alkyne分散在缓冲溶液(pH 7.4)和无水甲醇的混合溶液中,超声分散均匀以后,再加入药物X,在室温下剧烈搅拌反应24h;然后加入β-CD-N3、CuSO4·5H2O以及抗坏血酸钠,在氮气保护下,室温下避光搅拌反应三天;反应结束后,将产物离心,用甲醇和去离子水洗数次,真空干燥,得到包载了药物的还原响应型介孔硅纳米粒子(X@MSN-SS-CD);
S6:金刚烷胺封端的聚赖氨酸的制备(Ad-PLL-NH2)
称取赖氨酸(H-Lys(z)-OH)于三口烧瓶中,加入重蒸的四氢呋喃(THF),通氮气保护。再称取三光气溶于重蒸的THF中,缓慢滴加至反应体系中,在50℃下剧烈搅拌反应4h,将反应生成的HCl气体经过干燥塔导出至NaOH溶液中和;反应结束后,将得到的粗产物用石油醚沉淀三次,经过真空干燥以后,得到白色粉末状的终产物N-苄氧羰基赖氨酸-N-羧基内酸酐zLL-NCA;
称取zLL-NCA溶解在重蒸的DMF中,称取金刚烷胺溶于重蒸的DMF中,迅速加入到烧瓶中;在氮气保护下,室温下反应30min后,再在40℃下反应72h,将得到的粗产物用乙醚沉淀三次后,真空干燥得到终产物金刚烷胺封端的N-苄氧羰基赖氨酸Ad-PzLL-NH2。
称取Ad-PzLL-NH2于单口烧瓶中,加入三氟乙酸,冰水浴中搅拌15min,使得固体完全溶解;然后加入含33%溴化氢的乙酸溶液,反应1h。反应结束后,将反应粗产物用无水乙醚沉淀得到,然后用适量水溶解之后移入透析袋(MWCO3500Da)中,用去离子水透析三天,频繁换水,将所得溶液冻干得到终产物金刚烷胺封端的聚赖氨酸Ad-PLL-NH2;
S7:聚赖氨酸包裹修饰(X@MSN-SS-CD-PLL)
称取DOX@MSN-SS-CD和Ad-PLL-NH2,分散在缓冲溶液中(pH 7.4),常温下搅拌反应两天,将产物离心,用去离子水清洗数次,真空干燥得到产物X@MSN-SS-CD-PLL;
S8:氨基酰胺化修饰(X@MSN-SS-CD-PLL-DMMA)
称取X@MSN-SS-CD-Ad-PLL与圆底烧瓶中,称取二甲基马来酸酐(DMMA)溶解于100mL pH为8.3的缓冲溶液中,将溶液倒入上述圆底烧瓶中,常温下搅拌。反应一段时间后,再次测量反应液的pH,用少量的NaOH溶液调节pH>8.0;继续搅拌反应,反应一天后,将产物离心,用去离子水清洗数次,冻干得到终产物X@MSN-SS-CD-PLL-DMMA。
作为优选技术方案,步骤S3中所述巯基功能化介孔硅纳米粒子的制备方法为:
称取NaOH和CTAB溶解在去离子水中,升温至80℃,保持50r/min搅拌30min,然后缓慢滴加TEOS,15min滴完,再加入3-巯基丙基三甲氧基硅烷(MPTMS),继续反应2h,反应结束后,将反应液离心得到白色固体产物,用甲醇和水洗数次后真空干燥得到包含模板的介孔硅粒子(CTAB@MSN-SH);
将上述得到的产物进行脱模板处理:将CTAB@MSN-SH溶解在混合溶液中,60℃下回流,将产物离心后用甲醇和去离子水洗数次,真空干燥产物,得到脱掉模板后的介孔硅粒子(MSN-SH)。
作为优选技术方案,所述混合溶剂为甲醇和浓盐酸体积比为80:8-10的混合溶剂。
作为优选技术方案,步骤S3中所述S-(2-氨乙巯基)-2-巯基吡啶盐酸盐的制备方法为:称取2,2-二硫二吡啶,溶解在甲醇和乙酸的混合溶液中;将半胱胺盐酸盐溶解到甲醇溶液中,将配得的溶液逐渐滴加到上述溶液中,滴加0.5h;反应48h后得到黄色溶液,在室温下旋干浓缩成黄色油状液体;再将得到的油状液体用甲醇溶解,逐渐滴加到乙醚中,沉淀;在-20℃中冷冻12h,抽滤,将滤渣再次用乙醚沉淀抽滤。将最终产物干燥,得到黄色粉末状产物。
作为优选技术方案,所述甲醇和乙酸的混合溶液中甲醇和乙酸的比例为20:0.5-1.0。
作为优选技术方案,步骤S1中所述β-CD与对甲苯磺酰氯的质量比为25:10-25;
作为优选技术方案,步骤S1中冰箱过夜温度为1-10℃;
作为优选技术方案,步骤S2中所述β-CD-OTs与叠氮化钠的质量比为10:2-4。
作为优选技术方案,步骤S3中MSN-SH与S-(2-氨乙巯基)-2-巯基吡啶盐酸盐的质量比为1:1;
作为优选技术方案,步骤S4中MSN-SS-NH2与溴丙炔的质量体积比为100mg:2-4ml。
作为优选技术方案,药物X为盐酸阿霉素(DOX·HCl);步骤S5中MSN-SS-alkyne:药物X:β-CD-N3:CuSO4·5H2O:作为优选技术方案,抗坏血酸钠质量比为:200:1-300:100-300:100-300:100-400;
作为优选技术方案,步骤S6中,赖氨酸与三光气的质量比为3:1-2,zLL-NCA与金刚烷胺的质量比为900:40-100,Ad-PzLL-NH2与含33%溴化氢的乙酸溶液的质量体积比为600mg:2-8mL。
作为优选技术方案,步骤S7中X@MSN-SS-CD与Ad-PLL-NH2的质量比为1:1,X@MSN-SS-CD-Ad-PLL与DMMA的质量比为1:2。
同时,本发明还提供了采用上述功能化介孔硅肿瘤靶向运输控释系统的制备方法制备得到的功能化介孔硅肿瘤靶向运输控释系统。
有益的技术效果:
(1)选用百纳米尺寸的介孔硅纳米粒子(MSN)具有优良生物相容性、较高比表面积与孔体积、可调的介孔尺寸、胶体稳定性以及功能化简易性等优越的结构性质,药物装载量高,以MSN为主体的多功能刺激响应型纳米载药系统具有很好的“被动靶向”的能力。
(2)细胞膜有一种高度调控的机制来控制化合物的吸收,这通常会阻碍大型或高极性分子的内部化,如缩氨酸、寡核苷酸和纳米粒子。聚赖氨酸是由赖氨酸组成的,可以帮助细胞对载体吞噬,可以使药物载体在正常的血液循环中起到“隐形”作用,可以使药物系统在癌组织部位“被动靶向”富集。载体到达癌组织后,在癌细胞外弱酸性环境(pH≈6.0)下马来酸酐断开,从而使载体带正电,促进细胞摄取。
(3)以氧化-还原敏感的双硫键连接MSN及环糊精癌细胞内释药,载体进入癌细胞后,在细胞内还原环境(因GSH作用)下双硫键断开,包覆在载体介孔硅表面的环糊精脱离。从而释放药物;在进入肿瘤细胞前,体内的氧化环境能保证双硫键的稳定,保证药物不会被提前释放。
(4)将大分子的聚赖氨酸通过主客体作用和环糊精相连,从而将载体的表面裹上了带正电的氨基酸,可以减少介孔硅的团聚,增加分散性。
附图说明
图1为介孔硅(MSN)的透射电镜(TEM)图;
图2为介孔硅(MSN)的XRD图;
图3为实施例1中各步骤产物的氮气吸附等温线;
图4为实施例1中各步骤产物的BJH孔径分布图;
图5为实施例1中各步骤产物的TG图;
图6为实施例1中各步骤产物的FT-IR图。
具体实施方式
为了使技术人员更加直观的了解本发明的技术方案,下面选择几个典型实施例进行介绍,这些实施例不构成对本发明保护范围的限制,今后任何不背离本发明基本构思的实施方案都在本发明保护范围内。
实施例1
1.对甲苯磺酰基-β-环糊精的制备(β-CD-OTs)
称取25gβ-CD溶解于300mL 0.4M的NaOH溶液中,在冰水浴中搅拌直至环糊精完全溶解。称取18g的对甲苯磺酰氯(TsCl),缓慢滴加入到β-CD溶液。在冰水浴中搅拌反应90min后,抽滤。取滤液,用HCl调节pH至8.5,将混合物在室温下继续搅拌反应2h,将反应物置于冰箱中(4℃)过夜,次日抽滤,将滤渣用去离子水洗三次。将最终产物在60℃干燥,得到β-CD-OTs。
2.氮化环糊精的制备(β-CD-N3)
称取10gβ-CD-OTs溶于100mL去离子水中,加热至80℃,然后加入2.54g的叠氮化钠(NaN3),搅拌反应18h。将反应物冷却至室温,将反应液逐渐滴加至800mL丙酮中沉淀,抽滤得到白色固体产物。将固体在60℃下干燥两天,得到β-CD-N3。
3.S-(2-氨乙巯基)-2-巯基吡啶盐酸盐的合成
称取4.41g 2,2-二硫二吡啶,溶解在20mL甲醇和0.8mL乙酸的混合溶液中;将1.14g的半胱胺盐酸盐溶解到10mL的甲醇溶液中,将配得的溶液逐渐滴加到上述溶液中,滴加0.5h。反应48h后得到黄色溶液,在室温下旋干浓缩成黄色油状液体。再将得到的油状液体用10mL甲醇溶解,逐渐滴加到200mL乙醚中,沉淀。在-20℃中冷冻12h,抽滤,将滤渣再次用乙醚沉淀抽滤。将最终产物干燥,得到黄色粉末状产物。
4.巯基功能化介孔硅纳米粒子的制备(MSN-SH)
称取2.8g NaOH和1g CTAB溶解在480mL去离子水中,升温至80℃,保持50r/min搅拌30min,然后缓慢滴加5mL TEOS,15min滴完,再加入0.97mL MPTMS,继续反应2h,反应结束后,将反应液离心得到白色固体产物,用甲醇和水洗数次后真空干燥得到包含模板的介孔硅粒子(CTAB@MSN-SH)。
将上述得到的产物进行脱模板处理。将1g CTAB@MSN-SH溶解在80mL甲醇和9mL浓盐酸的混合溶液中,60℃下回流24h,将产物离心后用甲醇和去离子水洗数次,真空干燥产物,得到脱掉模板后的介孔硅粒子(MSN-SH)。
5.双硫功能化介孔硅纳米粒子的制备(MSN-SS-NH2)
将200mg MSN-SH分散在45mL甲醇中,然后加入200mg S-(2-氨乙巯基)-2-巯基吡啶盐酸盐,在室温下搅拌反应24h。反应结束后将产物离心,用甲醇和去离子水洗数次,真空干燥得到MSN-SS-NH2。
6.炔基功能化介孔硅纳米粒子的制备(MSN-SS-alkyne)
称取100mg MSN-SS-NH2分散在20mL用无水硫酸镁干燥过的无水甲醇中,然后加入3mL溴丙炔,在室温下搅拌24h。反应结束后将产物离心,用甲醇和去离子水洗数次,真空干燥得到MSN-SS-alkyne。
7.阿霉素载药介孔硅纳米粒子的制备(DOX@MSN-SS-CD)
称取200mg MSN-SS-alkyne分散在20mL缓冲溶液(pH 7.4)和5mL无水甲醇的混合溶液中,超声分散均匀以后,再加入50mg的盐酸阿霉素(DOX·HCl),在室温下剧烈搅拌反应24h。然后加入200mg的β-CD-N3、200mg CuSO4·5H2O以及340mg抗坏血酸钠,在氮气保护下,室温下避光搅拌反应三天。反应结束后,将产物离心,用甲醇和去离子水洗数次,真空干燥,得到包载了阿霉素药物的还原响应型介孔硅纳米粒子(DOX@MSN-SS-CD)。
8.金刚烷胺封端的聚赖氨酸的制备(Ad-PLL-NH2)
称取3.1g H-Lys(z)-OH于三口烧瓶中,加入50mL重蒸的四氢呋喃(THF),通氮气保护。再称取1.7g三光气溶于10mL重蒸的THF中,缓慢滴加至反应体系中,在50℃下剧烈搅拌反应4h,将反应生成的HCl气体经过干燥塔导出至NaOH溶液中和。反应结束后,将得到的粗产物用石油醚沉淀三次,经过真空干燥以后,得到白色粉末状的终产物N-苄氧羰基赖氨酸-N-羧基内酸酐zLL-NCA。
称取900mg zLL-NCA溶解在15mL重蒸的DMF中,称取72mg金刚烷胺溶于5mL重蒸的DMF中,迅速加入到烧瓶中。在氮气保护下,室温下反应30min后,再在40℃下反应72h,将得到的粗产物用乙醚沉淀三次后,真空干燥得到终产物金刚烷胺封端的N-苄氧羰基赖氨酸Ad-PzLL-NH2。
称取600mg Ad-NH2-PzLL于单口烧瓶中,加入35mL的三氟乙酸,冰水浴中搅拌15min,使得固体完全溶解。然后加入4mL含33%溴化氢的乙酸溶液,反应1h。反应结束后,将反应粗产物用无水乙醚沉淀得到,然后用适量水溶解之后移入透析袋(MWCO 3500Da)中,用去离子水透析三天,频繁换水,将所得溶液冻干得到终产物金刚烷胺封端的聚赖氨酸Ad-PLL-NH2。
9.聚赖氨酸包裹修饰(DOX@MSN-SS-CD-PLL)
称取100mg DOX@MSN-SS-CD和100mg Ad-PLL,分散在60ml的缓冲溶液中(pH 7.4),常温下搅拌反应两天,将产物离心,用去离子水清洗数次,真空干燥得到产物DOX@MSN-SS-CD-PLL。
10.氨基酰胺化修饰(DOX@MSN-SS-CD-PLL-DMMA)
称取100mg DOX@MSN-SS-CD-PLL与圆底烧瓶中,称取200mg DMMA溶解于100mL pH为8.3的缓冲溶液中,将溶液倒入上述圆底烧瓶中,常温下搅拌。反应一段时间后,再次测量反应液的pH,用少量的NaOH溶液调节pH>8.0。继续搅拌反应,反应一天后,将产物离心,用去离子水清洗数次,冻干得到终产物DOX@MSN-SS-CD-PLL-DMMA。
实施例1中制备的原始的MSN的附图1的投射电镜图可以确定其分散性和粒径;
附图2的小角X射线衍射图谱可以看出,此MSN孔道呈六方型排列,具有三个特征小角衍射峰分别对应(100),(110)与(200)晶面的布拉格衍射峰。
而下表示出实施例1各步骤产物的BET、VP和BJH数据
实施例2
1.对甲苯磺酰基-β-环糊精的制备(β-CD-OTs)
称取25gβ-CD溶解于350mL 0.4M的NaOH溶液中,在冰水浴中搅拌直至环糊精完全溶解。称取20g的对甲苯磺酰氯(TsCl),缓慢滴加入到β-CD溶液。在冰水浴中搅拌反应90min后,抽滤。取滤液,用HCl调节pH至8.5,将混合物在室温下继续搅拌反应2h,将反应物置于冰箱中(4℃)过夜,次日抽滤,将滤渣用去离子水洗三次。将最终产物在60℃干燥,得到β-CD-OTs。
2.氮化环糊精的制备(β-CD-N3)
称取10gβ-CD-OTs溶于100mL去离子水中,加热至80℃,然后加入3.22g的叠氮化钠(NaN3),搅拌反应18h。将反应物冷却至室温,将反应液逐渐滴加至800mL丙酮中沉淀,抽滤得到白色固体产物。将固体在60℃下干燥两天,得到β-CD-N3。
3.S-(2-氨乙巯基)-2-巯基吡啶盐酸盐的合成
称取4.41g 2,2-二硫二吡啶,溶解在20mL甲醇和0.8mL乙酸的混合溶液中;将1.14g的半胱胺盐酸盐溶解到10mL的甲醇溶液中,将配得的溶液逐渐滴加到上述溶液中,滴加0.5h。反应48h后得到黄色溶液,在室温下旋干浓缩成黄色油状液体。再将得到的油状液体用10mL甲醇溶解,逐渐滴加到200mL乙醚中,沉淀。在-20℃中冷冻12h,抽滤,将滤渣再次用乙醚沉淀抽滤。将最终产物干燥,得到黄色粉末状产物。
4.巯基功能化介孔硅纳米粒子的制备(MSN-SH)
称取2.8g NaOH和1g CTAB溶解在480mL去离子水中,升温至80℃,保持50r/min搅拌30min,然后缓慢滴加5mL TEOS,15min滴完,再加入0.97mL MPTMS,继续反应2h,反应结束后,将反应液离心得到白色固体产物,用甲醇和水洗数次后真空干燥得到包含模板的介孔硅粒子(CTAB@MSN-SH)。
将上述得到的产物进行脱模板处理。将1g CTAB@MSN-SH溶解在80mL甲醇和9mL浓盐酸的混合溶液中,60℃下回流24h,将产物离心后用甲醇和去离子水洗数次,真空干燥产物,得到脱掉模板后的介孔硅粒子(MSN-SH)。
5.双硫功能化介孔硅纳米粒子的制备(MSN-SS-NH2)
将200mg MSN-SH分散在45mL甲醇中,然后加入200mg S-(2-氨乙巯基)-2-巯基吡啶盐酸盐,在室温下搅拌反应24h。反应结束后将产物离心,用甲醇和去离子水洗数次,真空干燥得到MSN-SS-NH2。
6.炔基功能化介孔硅纳米粒子的制备(MSN-SS-alkyne)
称取100mg MSN-SS-NH2分散在20mL用无水硫酸镁干燥过的无水甲醇中,然后加入3.5mL溴丙炔,在室温下搅拌24h。反应结束后将产物离心,用甲醇和去离子水洗数次,真空干燥得到MSN-SS-alkyne。
7.阿霉素载药介孔硅纳米粒子的制备(DOX@MSN-SS-CD)
称取200mg MSN-SS-alkyne分散在20mL缓冲溶液(pH 7.4)和5mL无水甲醇的混合溶液中,超声分散均匀以后,再加入80mg的盐酸阿霉素(DOX·HCl),在室温下剧烈搅拌反应24h。然后加入220mg的β-CD-N3、220mg CuSO4·5H2O以及330mg抗坏血酸钠,在氮气保护下,室温下避光搅拌反应三天。反应结束后,将产物离心,用甲醇和去离子水洗数次,真空干燥,得到包载了阿霉素药物的还原响应型介孔硅纳米粒子(DOX@MSN-SS-CD)。
8.金刚烷胺封端的聚赖氨酸的制备(Ad-PLL-NH2)
称取3.1g H-Lys(z)-OH于三口烧瓶中,加入50mL重蒸的四氢呋喃(THF),通氮气保护。再称取1.7g三光气溶于10mL重蒸的THF中,缓慢滴加至反应体系中,在50℃下剧烈搅拌反应4h,将反应生成的HCl气体经过干燥塔导出至NaOH溶液中和。反应结束后,将得到的粗产物用石油醚沉淀三次,经过真空干燥以后,得到白色粉末状的终产物N-苄氧羰基赖氨酸-N-羧基内酸酐zLL-NCA。
称取900mg zLL-NCA溶解在15mL重蒸的DMF中,称取72mg金刚烷胺溶于5mL重蒸的DMF中,迅速加入到烧瓶中。在氮气保护下,室温下反应30min后,再在40℃下反应72h,将得到的粗产物用乙醚沉淀三次后,真空干燥得到终产物金刚烷胺封端的N-苄氧羰基赖氨酸Ad-PzLL-NH2。
称取600mg Ad-NH2-PzLL于单口烧瓶中,加入35mL的三氟乙酸,冰水浴中搅拌15min,使得固体完全溶解。然后加入4mL含33%溴化氢的乙酸溶液,反应1h。反应结束后,将反应粗产物用无水乙醚沉淀得到,然后用适量水溶解之后移入透析袋(MWCO 3500Da)中,用去离子水透析三天,频繁换水,将所得溶液冻干得到终产物金刚烷胺封端的聚赖氨酸Ad-PLL-NH2。
9.聚赖氨酸包裹修饰(DOX@MSN-SS-CD-PLL)
称取100mg DOX@MSN-SS-CD和100mg Ad-PLL,分散在60ml的缓冲溶液中(pH 7.4),常温下搅拌反应两天,将产物离心,用去离子水清洗数次,真空干燥得到产物DOX@MSN-SS-CD-PLL。
10.氨基酰胺化修饰(DOX@MSN-SS-CD-PLL-DMMA)
称取100mg DOX@MSN-SS-CD-Ad-PLL与圆底烧瓶中,称取200mg DMMA溶解于100mLpH为8.3的缓冲溶液中,将溶液倒入上述圆底烧瓶中,常温下搅拌。反应一段时间后,再次测量反应液的pH,用少量的NaOH溶液调节pH>8.0。继续搅拌反应,反应一天后,将产物离心,用去离子水清洗数次,冻干得到终产物DOX@MSN-SS-CD-PLL-DMMA。
Claims (10)
1.一种功能化介孔硅肿瘤靶向运输控释系统的制备方法,其特征在于:包括如下步骤:
S1:对甲苯磺酰基-β-环糊精的制备(β-CD-OTs)
称取β-CD溶解于NaOH溶液中,在冰水浴中搅拌直至环糊精完全溶解;称取对甲苯磺酰氯(TsCl),缓慢滴加入到β-CD溶液;在冰水浴中搅拌反应后,抽滤;取滤液,用HCl调节pH至7.5-10,将混合物在室温下继续搅拌反应,将反应物置于冰箱中过夜,次日抽滤,将滤渣用去离子水洗三次;将最终产物在20-80℃干燥,得到β-CD-OTs;
S2:氮化环糊精的制备(β-CD-N3)
称取β-CD-OTs溶于去离子水中,加热至60-90℃,然后加入叠氮化钠(NaN3),搅拌反应10-24小时;将反应物冷却至室温,将反应液逐渐滴加至丙酮中沉淀,抽滤得到白色固体产物;将固体在20-80℃下干燥1-3天,得到β-CD-N3;
S3:双硫功能化介孔硅纳米粒子的制备(MSN-SS-NH2)
将巯基功能化介孔硅纳米粒子(MSN-SH)分散在甲醇中,然后加入S-(2-氨乙巯基)-2-巯基吡啶盐酸盐,在室温下搅拌反应12-36h;反应结束后将产物离心,用甲醇和去离子水洗数次,真空干燥得到MSN-SS-NH2;
S4:炔基功能化介孔硅纳米粒子的制备(MSN-SS-alkyne)
称取MSN-SS-NH2分散在用无水硫酸镁干燥过的无水甲醇中,然后加入溴丙炔,在室温下搅拌12-36h;反应结束后将产物离心,用甲醇和去离子水洗数次,真空干燥得到MSN-SS-alkyne;
S5:载药介孔硅纳米粒子的制备(X@MSN-SS-CD)
称取MSN-SS-alkyne分散在缓冲溶液(pH 7.4)和无水甲醇的混合溶液中,超声分散均匀以后,再加入药物X,在室温下剧烈搅拌反应24h;然后加入β-CD-N3、CuSO4·5H2O以及抗坏血酸钠,在氮气保护下,室温下避光搅拌反应三天;反应结束后,将产物离心,用甲醇和去离子水洗数次,真空干燥,得到包载了药物的还原响应型介孔硅纳米粒子(X@MSN-SS-CD);
S6:金刚烷胺封端的聚赖氨酸的制备(Ad-PLL-NH2)
称取赖氨酸(H-Lys(z)-OH)于三口烧瓶中,加入重蒸的四氢呋喃(THF),通氮气保护。再称取三光气溶于重蒸的THF中,缓慢滴加至反应体系中,在50℃下剧烈搅拌反应4h,将反应生成的HCl气体经过干燥塔导出至NaOH溶液中和;反应结束后,将得到的粗产物用石油醚沉淀三次,经过真空干燥以后,得到白色粉末状的终产物N-苄氧羰基赖氨酸-N-羧基内酸酐zLL-NCA;
称取zLL-NCA溶解在重蒸的DMF中,称取金刚烷胺溶于重蒸的DMF中,迅速加入到烧瓶中;在氮气保护下,室温下反应30min后,再在40℃下反应72h,将得到的粗产物用乙醚沉淀三次后,真空干燥得到终产物金刚烷胺封端的N-苄氧羰基赖氨酸Ad-PzLL-NH2。
称取Ad-PzLL-NH2于单口烧瓶中,加入三氟乙酸,冰水浴中搅拌15min,使得固体完全溶解;然后加入含33%溴化氢的乙酸溶液,反应1h。反应结束后,将反应粗产物用无水乙醚沉淀得到,然后用适量水溶解之后移入透析袋(MWCO 3500Da)中,用去离子水透析三天,频繁换水,将所得溶液冻干得到终产物金刚烷胺封端的聚赖氨酸Ad-PLL-NH2;
S7:聚赖氨酸包裹修饰(X@MSN-SS-CD-PLL)
称取X@MSN-SS-CD和Ad-PLL-NH2,分散在缓冲溶液中(pH 7.4),常温下搅拌反应两天,将产物离心,用去离子水清洗数次,真空干燥得到产物X@MSN-SS-CD-PLL;
S8:氨基酰胺化修饰(X@MSN-SS-CD-PLL-DMMA)
称取X@MSN-SS-CD-Ad-PLL与圆底烧瓶中,称取二甲基马来酸酐(DMMA)溶解于100mL pH为8.3的缓冲溶液中,将溶液倒入上述圆底烧瓶中,常温下搅拌。反应一段时间后,再次测量反应液的pH,用少量的NaOH溶液调节pH>8.0;继续搅拌反应,反应一天后,将产物离心,用去离子水清洗数次,冻干得到终产物X@MSN-SS-CD-PLL-DMMA。
2.根据权利要求1所述的功能化介孔硅肿瘤靶向运输控释系统的制备方法,其特征在于:步骤S3中所述巯基功能化介孔硅纳米粒子的制备方法为:
称取NaOH和CTAB溶解在去离子水中,升温至80℃,保持50r/min搅拌30min,然后缓慢滴加TEOS,15min滴完,再加入3-巯基丙基三甲氧基硅烷(MPTMS),继续反应2h,反应结束后,将反应液离心得到白色固体产物,用甲醇和水洗数次后真空干燥得到包含模板的介孔硅粒子(CTAB@MSN-SH);
将上述得到的产物进行脱模板处理:将CTAB@MSN-SH溶解在混合溶液中,60℃下回流,将产物离心后用甲醇和去离子水洗数次,真空干燥产物,得到脱掉模板后的介孔硅粒子(MSN-SH)。
3.根据权利要求2所述的功能化介孔硅肿瘤靶向运输控释系统的制备方法,其特征在于:所述混合溶剂为甲醇和浓盐酸体积比为80:8-10的混合溶剂。
4.根据权利要求1所述的功能化介孔硅肿瘤靶向运输控释系统的制备方法,其特征在于:步骤S3中所述S-(2-氨乙巯基)-2-巯基吡啶盐酸盐的制备方法为:称取2,2-二硫二吡啶,溶解在甲醇和乙酸的混合溶液中;将半胱胺盐酸盐溶解到甲醇溶液中,将配得的溶液逐渐滴加到上述溶液中,滴加0.5h;反应48h后得到黄色溶液,在室温下旋干浓缩成黄色油状液体;再将得到的油状液体用甲醇溶解,逐渐滴加到乙醚中,沉淀;在-20℃中冷冻12h,抽滤,将滤渣再次用乙醚沉淀抽滤。将最终产物干燥,得到黄色粉末状产物。
5.根据权利要求4所述的功能化介孔硅肿瘤靶向运输控释系统的制备方法,其特征在于:所述甲醇和乙酸的混合溶液中甲醇和乙酸的比例为20:0.5-1.0。
6.根据权利要求1所述的功能化介孔硅肿瘤靶向运输控释系统的制备方法,其特征在于:步骤S1中所述β-CD与对甲苯磺酰氯的质量比为25:10-25;冰箱过夜温度为1-10℃;步骤S2中所述β-CD-OTs与叠氮化钠的质量比为10:2-4。
7.根据权利要求1所述的功能化介孔硅肿瘤靶向运输控释系统的制备方法,其特征在于:步骤S3中MSN-SH与S-(2-氨乙巯基)-2-巯基吡啶盐酸盐的质量比为1:1;步骤S4中MSN-SS-NH2与溴丙炔的质量体积比为100mg:2-4ml。
8.根据权利要求1所述的功能化介孔硅肿瘤靶向运输控释系统的制备方法,其特征在于:所述药物X为盐酸阿霉素(DOX·HCl);步骤S5中MSN-SS-alkyne:药物X:β-CD-N3:CuSO4·5H2O:抗坏血酸钠质量比为:
200:1-300:100-300:100-300:100-400;步骤S6中,赖氨酸与三光气的质量比为3:1-2,zLL-NCA与金刚烷胺的质量比为900:40-100,Ad-PzLL-NH2与含33%溴化氢的乙酸溶液的质量体积比为600mg:2-8mL。
9.根据权利要求1所述的功能化介孔硅肿瘤靶向运输控释系统的制备方法,其特征在于:步骤S7中X@MSN-SS-CD与Ad-PLL-NH2的质量比为1:1,X@MSN-SS-CD-Ad-PLL与DMMA的质量比为1:2。
10.权利要求1-9中任一项功能化介孔硅肿瘤靶向运输控释系统的制备方法制备得到的功能化介孔硅肿瘤靶向运输控释系统。
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