CN115350153A - 一种紫檀芪纳米胶束制剂及其肝保护作用 - Google Patents
一种紫檀芪纳米胶束制剂及其肝保护作用 Download PDFInfo
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Abstract
本发明公开了一种紫檀芪纳米胶束制剂及其在肝保护方面的应用。所述方法以两亲性材料聚乙烯己内酰胺‑聚醋酸乙烯脂‑聚乙二醇接枝共聚物(Soluplus)和泊洛沙姆188联合作为药物载体，通过薄膜‑水化法包载疏水性药物紫檀芪，得到紫檀芪纳米胶束。紫檀芪在胶束中的浓度为1mg/ml～5mg/ml，Soluplus在胶束中的浓度为12mg/ml～60mg/ml，泊洛沙姆188在胶束中的浓度为5mg/ml～25mg/ml。制备得到的紫檀芪纳米胶束稳定性好，且具有较高的包封率，可减少用药量和毒性。动物实验表明，紫檀芪纳米胶束可降低对乙酰氨基酚(APAP)诱导的小鼠急性肝损伤，体现出紫檀芪纳米胶束在治疗药物性肝损伤方面的应用前景。
Description
技术领域
本发明涉及天然药物领域，具体是一种紫檀芪纳米胶束制剂，特别涉及该制剂具有显著提高疏水性药物紫檀芪的水溶性及其对小鼠的肝保护作用。
背景技术
在患者使用药物的过程中，由药物自身或其代谢产物等原因不可避免的药物性肝损伤(DILI)。DILI发病机制复杂，单一药物或者药物联合使用均可以诱发DILI，DILI时常伴有脂肪肝等其他肝病并发症，明显加重患者DILI，给患者治疗带来巨大困难。目前因为DILI临床表现不典型，实验室检验无特异性，用药后出现症状的时间差异性较大等原因，导致目前对于DILI的有效治疗药物极为稀少。对乙酰氨基酚(APAP)是常见的解热镇痛药物，但过量使用可导致急性肝损伤，是临床中常见的副作用。目前APAP诱导的急性肝损伤的发病机制尚不明确，普遍认为APAP诱导肝脏氧化应激稳态的破坏以及炎症反应可能是导致肝损伤的主要原因。并且目前尚没有安全有效的治疗手段，寻找一种治疗药物性肝损伤的药物成为迫切要求。
cGAS是一种核酸转移酶，可以识别胞质中的DNA，激活干扰素刺激蛋白STING，调控机体免疫应答。细胞核DNA损伤可激活cGAS-STING信号通路，进而活化激活炎症反应和免疫应答，对于调控机体炎性损伤具有重要作用。目前cGAS-STING信号通路在APAP诱导的肝损伤中的作用尚无研究。
紫檀芪(Pterostilene，Pt，CAS号537-42-8)是一种来源于紫檀、蓝莓、葡萄和花榈木等植物的有效成分。紫檀芪有抗癌、抗炎、抗氧化和镇痛剂的作用。大量研究表明紫檀芪在皮肤疾病的治疗和防护中有较好的作用，特别是在抗氧化等领域。最新的研究表明，紫檀芪具有显著的抗氧化、抗炎、清除自由基等广泛的药理学活性，特别是对于药物性的肝损伤具有保护作用，但是由于紫檀芪水溶性差，分子结构不稳定，半衰期短及其口服生物利用度差等限制了其在临床中的应用，所以有必要开发一种安全、经济、有效的紫檀芪药物制剂。
泊洛沙姆188自身水溶性良好，独特的疏水内核-亲水外壳结构使之具备两亲性且具有良好的表面活性和反向胶凝性质，在体毒性低，是疏水性药物理想的给药载体。
Soluplus是一种低毒性，高增溶能力的新型两亲性载体材料，可以被用来构建胶束体系以提高难溶性药物的溶解度和稳定性。Soluplus是一种具有高性能，低毒性和较好的生物相容性的药物载体。同时，泊洛沙姆188和Soluplus都具有较低的临界胶束浓度，这些共同特征都使得泊洛沙姆188和Soluplus在制备紫檀芪纳米胶束方面具有巨大潜力。
本发明的创新点在于紫檀芪自组装纳米胶束在预防治疗APAP诱导肝损伤中的应用。具体通过抑制DNA损伤-cGAS-STING信号通路发挥肝保护作用。本研究针对DNA损伤-cGAS-STING信号通路探索治疗预防APAP诱导的肝损伤药物具有极高的创新性。
发明内容
本发明的目的是提高疏水性药物的紫檀芪的水溶性，而制备出一种高稳定性高包封率高的紫檀芪纳米胶束制剂。
本发明还提供一种紫檀芪纳米胶束的制备方法，步骤如下：
(1)将
和泊洛沙姆188按比例混合溶解在乙醇中，在48℃下轻轻搅拌使其完全溶解，将紫檀芪加入到上述的乙溶液中继续搅拌，直到形成透明溶液；
(2)采用薄膜水化法，在48℃下旋干乙醇，形成一层薄膜；
(3)加入PBS，超声使薄膜充分溶解，此时溶液呈浑浊状态；
(4)室温放置过夜，即紫檀芪纳米胶束。
本发明具有以下优点：本发明的紫檀芪纳米胶束用于药物性肝损伤的保护安全无毒，药物与辅料形成胶束，提高了药物的溶解度和稳定性，相对于单纯的紫檀芪药物，大大提高了该药物的抗氧化性，且制备方法简单，制备工艺能量消耗少，不使用有毒试剂溶剂。
附图说明
图1为紫檀芪纳米胶束粒径
图2为紫檀芪纳米胶束对APAP诱导的肝损伤小鼠肝指数的影响
图3为紫檀芪纳米胶束对APAP诱导的肝损伤小鼠血清谷丙转氨酶/谷丙转氨酶含量变化的影响
图4为紫檀芪纳米胶对APAP诱导的肝损伤小鼠肝脏组织病理形态的影响
图5为紫檀芪纳米胶束对APAP诱导的肝损伤小鼠肝组织DNA损伤-cGAS-STING信号通路的影响
具体实施方式
下面结合具体实施案例对紫檀芪纳米胶束做进一步阐述，但本发明不限于此。
实施例1
紫檀芪自组装纳米胶束的制备
精确称取
300mg和泊洛沙姆188 125mg混合溶解在12.5ml乙醇中，在48℃下轻轻搅拌使其完全溶解，将25mg紫檀芪(Pt)加入到上述的乙溶液中继续搅拌，直到形成透明溶液；采用薄膜水化法，在48℃下旋干乙醇，形成一层薄膜；加入5ml PBS，超声使薄膜充分溶解，此时溶液呈浑浊状态；室温放置过夜，即得紫檀芪纳米胶束(Pt-MMs)。制备得到的紫檀芪纳米胶束粒径在81.38nm，包封率86.7％。
实施例2
APAP诱导小鼠肝损伤后肝指数变化情况
实验动物：昆明小鼠，雄性，8周龄，体重20-22g，SPF级。小鼠48只，随机分为8组，每组小鼠6只。分组如下：(1)对照组(Control)；(2)不造模Pt组：紫檀芪(25mg/kg)；(3)APAP模型组：APAP(400mg/kg)；(4)辅料组(MMs)：
(5)游离紫檀芪低剂量组(Pt-25mg/kg-APAP)：APAP(400mg/kg)+紫檀芪(25mg/kg)；(6)游离紫檀芪高剂量组(Pt-50mg/kg-APAP)APAP(400mg/kg)+紫檀芪(Pt-50mg/kg)；(7)紫檀芪纳米胶束低剂量组(Pt-MMs-25mg/kg-APAP)：APAP(400mg/kg)+紫檀芪纳米胶束(25mg/kg)；(8)紫檀芪纳米胶束高剂量组(Pt-MMs-50mg/kg-APAP)：APAP(400mg/kg)+紫檀芪纳米胶束(Pt-MMs-50mg/kg)。小鼠灌胃给药，每天给药一次，连续给药5天。最后一次给药后灌胃给予APAP(400mg/kg)，禁食16小时后称重取血，处死小鼠。取肝组织称重并进行病理学检测等。
小鼠脏指数计算：肝指数＝肝重量(g)/小鼠体重(g)。肝脏重量与小鼠处死前的体重变化情况如图2。结果显示APAP造模后，导致小鼠体重减轻，进而诱导了肝脏指数的升高。紫檀芪纳米胶束显著降低了APAP导致的肝指数的升高，证明紫檀芪纳米胶束具有肝保护作用。
实施例3
肝脏损伤后小鼠血清谷丙转氨酶(ALT)和谷草转氨酶(AST)含量变化
谷丙转氨酶(ALT)主要存在肝细胞中，整个肝脏内转氨酶含量约为血中含量的100倍。正常时，只要少量释放入血中，血清中其酶的活性即可明显升高。在药物中毒性肝细胞坏死时，ALT大量释放入血中，因此它是诊断病毒性肝炎、中毒性肝炎的重要指标。取小鼠血清，采用ALT和AST检测试剂盒分别检测各组别小鼠血清中ALT和AST的含量。
ALT和AST含量如图3，结果显示，APAP作用后显著诱导小鼠血清ALT和AST含量升高，证明APAP诱导了肝损伤。紫檀芪纳米胶束组可显著降低ALT和AST的含量，证明紫檀芪纳米胶束具有肝保护作用。
实施例4
小鼠处死后，将其肝组织取下，进行外观形态的拍照。将肝脏放置于于4％甲醛中保存，之后进行病理切片并进行HE染色。在图4中可以看出，APAP造模组肝脏可见明显炎症损伤。通过病理照片可以看出，APAP造模组肝脏组织出现空泡样病变，炎性浸润，应用紫檀芪纳米胶束组无明显损伤。
实施例5
免疫组化检测。取小鼠肝脏组织病理切片，经脱蜡水化后，用0.01M的枸橼酸缓冲液进行抗原修复。滴加正常山羊血清封闭液，室温20分钟。加入一抗(cGAS、STING和γH2X)室温孵育2小时，PBS洗涤后加入二抗室温孵育1小时。PBS洗涤三次后加入DAB显色液显色，自来水冲洗10分钟。苏木精复染2分钟，盐酸酒精分化并用自来水洗涤10分钟。切片经脱水、透明、封片后与显微镜下观察并拍照。
小鼠肝免疫组化结果如图5所示。APAP作用后，小鼠出现严重的急性肝损伤，γH2AX、cGAS、STING的表达急剧升高，证明了APAP诱导了小鼠肝组织DNA损伤和cGAS-STING通路活化。应用紫檀芪纳米胶束治疗后小鼠肝组织γH2AX、cGAS、STING的表达显著减少。证明紫檀芪纳米胶束可保护顺铂导致的小鼠肾组织DNA损伤和cGAS-STING通路的活化。可见紫檀芪纳米胶束通过cGAS-STING通路发挥对肾脏治疗作用。
以上实验结果证明紫檀芪纳米胶束可通过抑制DNA损伤-cGAS-STING信号通路发挥肝保护作用，并且紫檀芪纳米胶束的治疗效果由于游离的紫檀芪。本发明证实了紫檀芪纳米胶束在预防和治疗急性肝损伤领域具有广阔的应用前景。
Claims (6)
1.一种紫檀芪纳米胶束制剂，以
和泊洛沙姆188为药物辅料制备成紫檀芪纳米胶束制剂，其特征在于制备的纳米胶束稳定性好，具有较好的包封率，其特征在于还包括紫檀芪在胶束中的浓度为1mg/ml～5mg/ml，
在胶束中的浓度为12mg/ml～60mg/ml，泊洛沙姆188在胶束中的浓度为5mg/ml～25mg/ml。
2.如权利要求1所述的紫檀芪纳米胶束制备过程如下：
1)将Soluplus和泊洛沙姆188按比例混合溶解在乙醇中，在48℃下轻轻搅拌使其完全溶解，将紫檀芪加入到上述的乙溶液中继续搅拌，直到形成透明溶液；
2)采用薄膜水化法，在48℃下旋干乙醇，形成一层薄膜；
3)加入PBS，超声使薄膜充分溶解，此时溶液呈浑浊状态；
4)室温放置过夜，即紫檀芪纳米胶束。
3.如权利要求1所述的紫檀芪纳米胶束在制备治疗和(或)预防肝损伤药物中的用途，肝损伤为对乙酰氨基酚(APAP)诱导的小鼠急性肝损伤。
4.如权利要求1-3所述的紫檀芪纳米胶束在制备治疗和(或)预防肝损伤药物中的用途，其特征在于，紫檀芪纳米胶束可改善对乙酰氨基酚诱导的氧化应激反应。
5.如权利要求1-3所述的紫檀芪纳米胶束在制备治疗和(或)预防肝损伤药物中的用途，其特征在于，紫檀芪纳米胶束可改善对乙酰氨基酚诱导的DNA损伤。
6.如权利要求1-3所述的紫檀芪纳米胶束在制备治疗和(或)预防肝损伤药物中的用途，其特征在于，紫檀芪纳米胶束可改善对乙酰氨基酚诱导的cGAS-STING通路的活化。
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