CN116509876A - 一种负载皮质激素类药聚环糊精-单宁酸纳米粒子及其制备方法和应用 - Google Patents
一种负载皮质激素类药聚环糊精-单宁酸纳米粒子及其制备方法和应用 Download PDFInfo
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- CN116509876A CN116509876A CN202310443847.6A CN202310443847A CN116509876A CN 116509876 A CN116509876 A CN 116509876A CN 202310443847 A CN202310443847 A CN 202310443847A CN 116509876 A CN116509876 A CN 116509876A
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Abstract
本发明公开了一种负载皮质激素类药聚环糊精‑单宁酸纳米粒子及其制备方法和应用,属于生物功能材料技术领域。本发明所述的纳米粒子无生物毒性,在小鼠体内不引起体重减轻和组织损伤。本发明所提供的多酚主客体组装形成载药纳米粒子的方法无需使用有害化学试剂,具有成本低廉、操作简便、重现性好的优势。本发明制备多酚主客体载药纳米粒子与传统方法相比具有炎症靶向性,提供更强的药物使用效率,不易引起常规药物所导致的副作用,且具有ROS清除能力,有望用于口服药品治疗相关疾病。
Description
技术领域
本发明属于生物功能材料技术领域,涉及一种用于口服药物递送生物材料的制备方法和应用。
背景技术
炎症性肠病(IBD)是一种慢性的胃肠道炎症性疾病,影响了全球多达700万人,且复发率高和终身护理需求严重损害了他们的生活质量。IBD的病因和发病机制是多因素的,尚未完全明了,但普遍认为与粘膜免疫反应的失调、肠屏障功能的破坏和活性氧(ROS)水平的升高密切相关。
目前IBD的药物干预包括氨基水杨酸类、抗生素、皮质类固醇和免疫抑制剂,其目的是抑制炎症和诱导临床缓解。然而,这些药物的频繁和长期使用容易引起严重的副作用,如头痛、水肿、关节痛、糖尿病和骨质疏松。因此,迫切需要寻找治疗IBD的替代方法。
一种将药物靶向递送到炎症部位和清除ROS的能力结合起来的治疗策略,可能是治疗IBD比较有效的一种方法。这种策略可以通过将药物局限在炎症部位,避免暴露于健康或远处的组织,从而减少药物的副作用,并防止ROS引起的内皮功能障碍和组织损伤。因此,多种具有炎症靶向和ROS清除能力的新型生物材料已经被开发用于治疗IBD。这些生物材料的炎症靶向能力是通过不同的机制实现的,例如尺寸介导的靶向、与炎症性结肠上皮细胞的CD44蛋白的亲和作用、以及与带正电荷的炎症性结肠粘膜的静电作用。同时,ROS清除能力是通过抗氧化剂实现的,抗氧化剂可以分为两类:天然抗氧化剂,如含有超氧化物歧化酶(SOD)酶的脂质纳米颗粒或透明质酸-胆红素共轭纳米聚集体;合成抗氧化剂,如含有人工单原子催化剂(SAzymes)的活性材料或CeO2-偶联蒙脱土纳米颗粒。然而,这些策略仍然面临一些需要克服的挑战,如酶的易降解和高成本、使用有害化学试剂、制备材料的复杂和耗时过程,以及患者对灌肠或静脉注射给药方式的不依从。
发明内容
本发明的目的是提供一种负载皮质激素类药聚环糊精-单宁酸纳米粒子及其制备方法,利用该纳米粒子具有负电荷的特性将其靶向到带有正电荷的炎症部位,同时利用其中的多酚组分具有较强的ROS清除能力以抑制免疫反应,两者结合以解决现有技术中存在的问题。
本发明是通过以下技术方案实现的:
一种负载皮质激素类药聚环糊精-单宁酸纳米粒子,包括皮质激素类药、聚环糊精和单宁酸。首先,皮质激素类药通过主客体作用负载到聚环糊精中;然后单宁酸通过主客体作用将负载皮质激素类药的聚环糊精交联起来形成纳米粒子。所述的负载皮质激素类药聚环糊精-单宁酸纳米粒子具有较好的重复性和尺寸均一性,且带有一定的负电能靶向到带正电的炎症部位。
一种上述负载皮质激素类药聚环糊精-单宁酸纳米粒子的制备方法,具体包括以下步骤:
(1)聚环糊精的制备
将β-环糊精(βCD)和NaOH混合后溶于水中,再加入环氧氯丙烷,将反应液在30℃的条件下搅拌反应2h。再向体系中倒入足量的丙酮停止反应,将产物先用过量乙醇冲洗,再加入足量水进行溶解,并用HCl将产物的pH调至中性。然后将调至中性的产物用透析袋进行纯化,得到聚环糊精。
(2)负载皮质激素类药的聚环糊精的制备
将皮质激素类药加入到步骤(1)制得的聚环糊精水溶液中,孵育20~120min后,得到负载皮质激素类药的聚环糊精。
(3)负载皮质激素类药聚环糊精-单宁酸纳米粒子的制备
将单宁酸加入到步骤(2)制得的负载皮质激素类药的聚环糊精水溶液中,剧烈搅拌5~60s进行交联,得到负载皮质激素类药的聚环糊精-单宁酸纳米粒子。
进一步地,步骤(1)中,所述的βCD浓度为0.2~1g mL-1。
进一步地,步骤(1)中,所述的NaOH浓度为0.2~0.8g mL-1。
进一步地,步骤(2)中,所述皮质激素类药包括地塞米松磷酸钠、泼尼松龙磷酸钠和倍他米松磷酸钠。
进一步地,步骤(2)中,所述聚环糊精和皮质激素类药的体积比为4:1,聚环糊精和皮质激素类药的浓度均为10mg mL-1。
进一步地,步骤(2)中,所述皮质激素类药在环糊精中的孵育时间为30min。
进一步地,步骤(3)中,所述聚环糊精、皮质激素类药和单宁酸的体积比为4:1:5;单宁酸的浓度为4~20mg mL-1,优选8~12mg mL-1。
进一步地,步骤(3)中,单宁酸交联负载皮质激素类药的环糊精的时间为10s。
进一步地,所述负载皮质激素类药聚环糊精-单宁酸纳米粒子的直径范围为14~630nm,负载皮质激素类药聚环糊精-单宁酸纳米粒子的直径通过控制单宁酸的浓度而成。
一种负载皮质激素类药聚环糊精-单宁酸纳米粒子在口服药物递送中的应用。
本发明的有益效果:本发明所述的纳米粒子无生物毒性,在小鼠体内不引起体重减轻和组织损伤。本发明所提供的多酚主客体组装形成载药纳米粒子的方法无需使用有害化学试剂,具有成本低廉、操作简便、重现性好的优势。本发明制备多酚主客体载药纳米粒子与传统方法相比具有炎症靶向性,提供更强的药物使用效率,不易引起常规药物所导致的副作用,且具有ROS清除能力,有望用于口服药品治疗相关疾病。
附图说明
图1为负载地塞米松磷酸钠聚环糊精-单宁酸纳米粒子形成示意图。
图2为负载地塞米松磷酸钠聚环糊精-单宁酸纳米粒子溶液图片;其中(a)为溶液图片,(b)为纳米粒子溶液的丁达尔效应。
图3为聚环糊精/地塞米松磷酸钠/单宁酸质量比为4:1:6时形成的纳米粒子的电镜图片;其中(a)为透射电子显微镜图片,(b)为原子力显微镜图片,(c)为原子力显微镜高度线。
图4为负载地塞米松磷酸钠聚环糊精-单宁酸纳米粒子在小鼠体内的炎症靶向能力成像;其中(a)为荧光图片,(b)为荧光图片的定量统计数据。
图5为负载地塞米松磷酸钠聚环糊精-单宁酸纳米粒子的ROS清除能力,其中(a)为通过ABTS法测定,(b)为通过DPPH法测定。
图6为负载地塞米松磷酸钠聚环糊精-单宁酸纳米粒子治疗硫酸葡聚糖钠(DSS)诱导的结肠炎小鼠体重变化图。
图7为负载地塞米松磷酸钠聚环糊精-单宁酸纳米粒子治疗硫酸葡聚糖钠(DSS)诱导的结肠炎小鼠体内的炎症因子水平;其中(a)为白介素-6含量,(b)为干扰素-γ含量,(c)为肿瘤坏死因子-α水平。
图8为负载地塞米松磷酸钠聚环糊精-单宁酸纳米粒子治疗硫酸葡聚糖钠(DSS)诱导的结肠炎小鼠肠道组织损伤情况;其中(a)为组织切片图,(b)为组织学评分。
图9为负载泼尼松龙磷酸钠聚环糊精-单宁酸纳米粒子溶液图片;其中(a)为溶液图片,(b)为纳米粒子溶液的丁达尔效应。
图10为负载倍他米松磷酸钠聚环糊精-单宁酸纳米粒子溶液图片;其中(a)为溶液图片,(b)为纳米粒子溶液的丁达尔效应。
具体实施方式
以下,举出实施例来说明本发明的具体实施方式,但本发明的实施方式不受如下这些实施例的限制,可在不影响本发明所要达到的技术效果的范围内做出任意选择和变更。实施例和试验例中未注明具体条件者,按照常规条件或制造商建议的条件进行,所用试剂或仪器未注明生产厂商者,均为可以通过市购获得的常规产品。
实施例1
本实施例选用的纳米粒子为负载地塞米松磷酸钠聚环糊精和单宁酸形成的纳米粒子,制备过程包括以下步骤:
步骤1.制备聚环糊精
将15gβCD与7.8g NaOH溶解于24mL水中,再加入10.5mL的环氧氯丙烷,随后在30℃的条件下剧烈搅拌反应2h。通过向该反应液中倒入足量的丙酮停止反应,将产物先用过量乙醇冲洗,再加入足量水进行溶解,并用0.5mol L-1的HCl将产物的pH调至中性。将调至中性的产物用透析袋进行纯化,以去除产物中未反应的环氧氯丙烷以及低分子量交联产物。
步骤2.准备负载地塞米松磷酸钠的聚环糊精
将地塞米松磷酸钠(100μL,10mg mL-1)加入到步骤1制得的聚环糊精(400μL,10mgmL-1)水溶液中,孵育30min,得到负载地塞米松磷酸钠的聚环糊精。
步骤3.制备负载地塞米松磷酸钠的聚环糊精-单宁酸纳米粒子
将不同浓度的单宁酸(500μL,具体浓度见表1)加入步骤2制得的负载地塞米松磷酸钠的聚环糊精溶液中,剧烈搅拌10s,得到负载地塞米松磷酸钠的聚环糊精-单宁酸纳米粒子。
通过动态光散射仪对上述制备的纳米粒子进行测试,动态光散射数据展示出不同浓度的单宁酸制备的纳米粒子的粒径,参数如表1所示:
表1负载地塞米松磷酸钠的聚环糊精-单宁酸纳米粒子粒径与单宁酸浓度的关系
图1清晰地展示了负载地塞米松磷酸钠的聚环糊精-单宁酸纳米粒子形成的过程;图2所示的负载地塞米松磷酸钠的聚环糊精-单宁酸纳米粒子溶液具有明显的丁达尔效应图片;图3所示的聚环糊精/地塞米松磷酸钠/单宁酸质量比为4:1:6时形成的纳米粒子(PDT)的电镜图片,图片显示纳米粒子干态直径大小为15μm左右,形状为圆形,尺寸分布较为均一。
负载地塞米松磷酸钠的聚环糊精-单宁酸纳米粒子的功能测试,包括以下方面:
功能1.负载地塞米松磷酸钠的聚环糊精-单宁酸纳米粒子在小鼠体内的炎症靶向能力成像
将纳米粒子PDT通过灌胃投递到小鼠体内,12小时后通过小鼠成像系统观察取出的肠道的荧光强度。如图4所示,PDT在炎症小鼠肠道内的荧光强度显著高于正常小鼠肠道的荧光强度,表明了PDT在小鼠肠道的炎症靶向能力。
功能2.负载地塞米松磷酸钠的聚环糊精-单宁酸纳米粒子的ROS清除能力
负载地塞米松磷酸钠纳米粒子的ROS清除能力通过ABTS和DPPH试验进行了研究。ABTS试验按照总抗氧化能力试剂盒(ABTS法)的方案进行。DPPH试验如下:将不同浓度的纳米粒子悬浮液的10μL分别加入到190μL的DPPH溶液(乙醇,0.06mmol L-1)中,并用涡旋振荡器混合。孵育1h后,用多模式微孔板读数器测量混合物在517nm处的UV吸光度。如图5所示,ABTS和DPPH两种方法均表明纳米粒子具有较强的ROS清除能力。
功能3.负载地塞米松磷酸钠的聚环糊精-单宁酸纳米粒子治疗硫酸葡聚糖钠(DSS)诱导的结肠炎小鼠
将结肠炎小鼠随机分为四组(每组5只小鼠),分别在第3、5、7和9天用负载地塞米松磷酸钠纳米粒子通过口服灌胃进行四次治疗。如图6-8所示,纳米粒子治疗显著抑制了结肠炎小鼠体重的减轻,降低了结肠炎小鼠体内炎症因子水平,改善了肠道组织损伤情况。
实施例2
本实施例选用的纳米粒子为负载泼尼松龙磷酸钠的聚环糊精和单宁酸形成的纳米粒子,制备过程包括以下步骤:
步骤1.制备聚环糊精
方法同实施例1。
步骤2.准备负载泼尼松龙磷酸钠的聚环糊精
将泼尼松龙磷酸钠(100μL,10mg mL-1)加入到步骤1制得的聚环糊精(400μL,10mgmL-1)水溶液中,孵育30min,得到负载泼尼松龙磷酸钠的聚环糊精。
步骤3.制备负载泼尼松龙磷酸钠的聚环糊精-单宁酸纳米粒子
将单宁酸(500μL,12mg mL-1)加入步骤2制得的负载泼尼松龙磷酸钠的聚环糊精溶液中,剧烈搅拌10s,得到负载泼尼松龙磷酸钠的聚环糊精-单宁酸纳米粒子。如图9所示,负载泼尼松龙磷酸钠的聚环糊精-单宁酸纳米粒子具有明显的丁达尔效应。
实施例3
本实施例选用的纳米粒子为负载倍他米松磷酸钠的聚环糊精和单宁酸形成的纳米粒子,制备过程包括以下步骤:
步骤1.制备聚环糊精
方法同实施例1。
步骤2.准备负载倍他米松磷酸钠的聚环糊精
将倍他米松磷酸钠(100μL,10mg mL-1)加入到步骤1制得的聚环糊精(400μL,10mgmL-1)水溶液中,孵育30min,得到负载倍他米松磷酸钠的聚环糊精。
3.制备负载倍他米松磷酸钠的聚环糊精-单宁酸纳米粒子
将单宁酸(500μL,12mg mL-1)加入步骤2制得的负载倍他米松磷酸钠的聚环糊精溶液中,剧烈搅拌10s,得到负载倍他米松磷酸钠的聚环糊精-单宁酸纳米粒子。如图10所示,负载倍他米松磷酸钠的聚环糊精-单宁酸纳米粒子具有明显的丁达尔效应。
Claims (7)
1.一种负载皮质激素类药聚环糊精-单宁酸纳米粒子的制备方法,其特征在于,该方法包括以下步骤:
(1)聚环糊精的制备
将β-环糊精和NaOH混合后溶于水中,再加入环氧氯丙烷,将反应液在30℃的条件下搅拌反应2h;再倒入足量的丙酮停止反应,将产物先用过量乙醇冲洗,再加入水进行溶解,并用HCl将产物的pH调至中性;然后将调至中性的产物用透析袋进行纯化,得到聚环糊精;所述的β-环糊精的浓度为0.2~1g mL-1,所述的NaOH的浓度为0.2~0.8g mL-1;
(2)负载皮质激素类药的聚环糊精的制备
将皮质激素类药加入到步骤(1)制得的聚环糊精水溶液中,孵育20~120min后,得到负载皮质激素类药的聚环糊精;
(3)负载皮质激素类药聚环糊精-单宁酸纳米粒子的制备
将单宁酸加入到步骤(2)制得的负载皮质激素类药的聚环糊精水溶液中,剧烈搅拌5~60s进行交联,得到负载皮质激素类药的聚环糊精-单宁酸纳米粒子。
2.根据权利要求1所述的制备方法,其特征在于,步骤(2)中,所述的皮质激素类药包括地塞米松磷酸钠、泼尼松龙磷酸钠和倍他米松磷酸钠。
3.根据权利要求1或2所述的制备方法,其特征在于,步骤(2)中,所述聚环糊精和皮质激素类药的体积比为4:1,聚环糊精和皮质激素类药的浓度均为10mg mL-1。
4.根据权利要求1或2所述的制备方法,其特征在于,步骤(3)中,所述聚环糊精、皮质激素类药和单宁酸的体积比为4:1:5;单宁酸的浓度为4~20mg mL-1。
5.根据权利要求4所述的制备方法,其特征在于,步骤(3)中,单宁酸的浓度为8~12mgmL-1。
6.一种如权利要求1-5任一所述的制备方法制备得到的负载皮质激素类药聚环糊精-单宁酸纳米粒子,其特征在于,所述的负载皮质激素类药聚环糊精-单宁酸纳米粒子带负电,其直径范围为14~630nm。
7.一种如权利要求6所述的负载皮质激素类药聚环糊精-单宁酸纳米粒子在口服药物递送中的应用。
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