CN116370500A - G3-Se MSN在制备治疗急性胰腺炎的药物中的应用 - Google Patents
G3-Se MSN在制备治疗急性胰腺炎的药物中的应用 Download PDFInfo
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Abstract
本发明公开了G3‑Se MSN在制备治疗急性胰腺炎的药物中的应用，属于新药研发领域。本发明采用牛黄胆酸钠模型和L‑arginine模型两种病理表现不同的急性胰腺炎模型证明了G3‑Se MSN对急性胰腺炎有良好的治疗效果，且G3‑Se MSN对急性胰腺炎的治疗效果是通过清除cf DNA和降低氧化应激产生的。本发明为将G3‑Se MSN作为治疗急性胰腺炎的一种新型药物提供了依据。
Description
技术领域
本发明涉及G3-Se MSN在制备治疗急性胰腺炎的药物中的应用，属于新药研发领域。
背景技术
胰腺是机体消化系统中非常重要的脏器，其生理功能主要分为两部分，外分泌功能以及内分泌功能。外分泌功能是指胰腺分泌大量的消化酶，这些酶会参与到营养物质的消化和吸收过程中，保证身体正常代谢和生长的需要；内分泌功能是分泌多种激素的功能，最常见的是胰岛素和胰高血糖素。急性胰腺炎(acute pancreatitis,AP)是最常见的消化道重症疾病，由多种病因导致的胰酶在胰腺内被过度激活，而后引起胰腺组织自身消化、水肿、出血甚至坏死的炎症反应。
急性胰腺炎的发病率为0.05％～8％，致死率为10％～30％。现针对急性胰腺炎的治疗方法和手段主要包括液体治疗、镇痛疗法、营养支持治疗以及针对感染性胰腺坏死的疗法。其中非手术治疗疗效慢且治疗效果不佳，手术治疗创伤大且并发症多，使患者难以接受。这些治疗方式存在的弊端和局限性，使得急性胰腺炎的死亡率和复发率并没有得到很大改善，因此亟待开发新的药物用于治疗急性胰腺炎。
游离DNA(Circulating free DNA or Cell free DNA,cfDNA)作为炎症发生的潜在标志物，已受到越来越多的关注。已有证据表明，双链DNA可以通过细胞表面分子激活免疫细胞和如内皮细胞在内的其他细胞，引起促炎细胞因子反应。因此cf DNA和炎症之间存在着如下反馈关系：多种因素刺激下机体会发生炎症反应，然后导致cfDNA释放的增加和炎症的进一步发展。因此可将cf DNA作为治疗急性胰腺炎的靶点。氧化应激(OxidativeStress,OS)是指体内氧化与抗氧化作用失衡的一种状态，主要偏向氧化。OS会导致中性粒细胞炎性浸润，蛋白酶分泌增加，并产生大量氧化中间产物。在这一过程中，最主要的促氧物是活性氧(ROS)和活性氮(RNS)。现有大量研究表明，急性胰腺炎发生，氧化应激水平升高，ROS在急性胰腺炎的发病机制和发展中起着关键作用。由此，我们提出将ROS作为治疗急性胰腺炎的又一关键靶点。
因此，通过清除cf DNA和降低氧化应激两个途径治疗急性胰腺炎具有良好的学术价值和临床意义。
发明内容
二硒化物桥联介孔有机硅纳米颗粒(Se-Se MSN)是一种可生物降解的粒子，其能够响应微环境中过多的ROS，减轻氧化应激水平，我们的前期结果表明，其对胰腺炎具有较好的治疗作用。同时，大量研究证实，第3代核酸结合聚合物聚酰胺-胺型树枝状聚合物(3rdgeneration polyamidoamine dendrimer,PAMAM-G3，之后简称为G3)，可以通过外源性清除促炎核酸和核酸-蛋白复合物来防止靶免疫细胞中的TLR激活，从而调控炎症的发生和发展，且在多种炎症性疾病的治疗中取得了良好的效果。已有研究表明，在临床相关的严重脓毒症模型中，PAMAM-G3能够通过清除cfDNA降低脓毒症死亡率并改善多器官损伤。而且在我们的前期研究中发现，与健康人相比，急性胰腺炎患者血清中cf DNA的水平明显升高(图1)。因此，本研究将PAMAM-G3与Se-Se MSN结合(G3-Se MSN)用于急性胰腺炎治疗，为G3-SeMSN作为治疗急性胰腺炎的新型有效药物提供科学的实验依据。
具体方法如下：
本发明提供了G3-Se MSN在制备治疗急性胰腺炎的药物中的应用
进一步地，所述的G3-Se MSN为PAMAM-G3和Se-Se MSN的组合物，PAMAM-G3和Se-SeMSN产生协同作用。
进一步地，在G3-Se MSN中，PAMAM-G3与Se-Se MSN的质量配比为：1～1.5:1；优选为：2:1.5。
进一步地，将G3-Se MSN制备成单一化学成分的药物制剂。
进一步地，所述G3-Se MSN的给药剂量为：每周腹腔注射三次，剂量为10mg/kg。
进一步地，所述G3-Se MSN在制备缓解急性胰腺炎造成的胰腺组织损伤和坏死的药物中的应用。
进一步地，所述G3-Se MSN在制备清除cf DNA治疗急性胰腺炎药物中的应用。
进一步地，所述G3-Se MSN在制备下调胰腺组织中的MDA水平，并上调SOD水平，通过抗氧化治疗急性胰腺炎药物中的应用。
进一步地，上述技术方案中，所述急性胰腺炎模型运用了牛黄胆酸钠模型和L-arginine模型两种动物模型，分别模拟的是临床上的急性坏死性胰腺炎和出血坏死性胰腺炎。
进一步地，上述技术方案中，能够明显减轻急性胰腺炎造成的胰腺组织损伤和坏死，在治疗急性胰腺炎中的应用。
发明有益效果
本发明采用牛黄胆酸钠模型和L-arginine模型两种病理表现不同的急性胰腺炎模型证明了G3-Se MSN对急性胰腺炎有良好的治疗效果，且G3-Se MSN对急性胰腺炎的治疗效果是通过清除cf DNA和降低氧化应激产生的。本发明为将G3-Se MSN作为治疗急性胰腺炎的一种新型药物提供了依据。
附图说明
图1为健康人和急性胰腺炎患者血清中cf DNA的表达，*p<0.05。
图2A为G3-Se MSN对急性胰腺炎生存率的影响。
图2B为G3-Se MSN对急性胰腺炎生存时间的影响。
与Control组相比，####p<0.0001；与AP组相比，*p<0.05，**p<0.01，***p<0.005，****p<0.0001。
图3为G3-Se MSN对急性胰腺炎造成的胰腺组织损伤及坏死的影响(牛黄胆酸钠模型)。
A：胰腺组织H&E染色(400x)；B：胰腺组织水肿程度比较图；C：血清中淀粉酶表达；D：血清中脂肪酶表达。与Control组相比，####p<0.0001；与AP组相比，*p<0.05，**p<0.01，***p<0.005，****p<0.0001。
图4为G3-Se MSN对急性胰腺炎造成的胰腺组织损伤及坏死的影响(L-arginine模型)。
A：胰腺组织H&E染色(400x)；B：胰腺组织Masson染色(400x)；C：血清中淀粉酶表达；D：血清中脂肪酶表达。与Control组相比，####p<0.0001；与AP组相比，*p<0.05，**p<0.01，***p<0.005，****p<0.0001。
图5为G3-Se MSN对体内cf DNA和氧化应激水平的影响。
A：大鼠血清cf DNA的表达(牛黄胆酸钠模型)；B-C：胰腺组织中SOD、MDA的表达(牛黄胆酸钠模型)；D：大鼠血清cf DNA的表达(L-arginine模型)；E-F：胰腺组织中SOD、MDA的表达(L-arginine模型)。与Control组相比，####p<0.0001；与AP组相比，*p<0.05，**p<0.01，***p<0.005，****p<0.0001。
具体实施方式
下述非限定性实施例可以使本领域的普通技术人员更全面地理解本发明，但不以任何方式限制本发明。
实施例1
1、实验方案：
1)牛黄胆酸钠模型：63只SD大鼠(～250g)适应环境一周后，将其随机分为7组：空白组、模型组、G3-Se MSN组、Se-Se MSN组、G3组、G3-S MSN组、S-S MSN组(阴性对照组)。
G3-Se MSN组表示：PAMAM-G3与二硒化物桥联介孔有机硅纳米颗粒(Se-Se MSN)联合给药组，PAMAM-G3与Se-Se MSN结合的质量配比为：2：1.5。
Se-Se MSN组表示：二硒化物桥联介孔有机硅纳米颗粒(Se-Se MSN)单独给药组，其具备ROS响应能力，能使ROS降解，设立此单独给药组检测证明其自身具备的药物功能，为上述联合给药提供理论依据。
G3组表示：PAMAM-G3单独给药组，能清除体内的cf DNA，设立此单独给药组检测证明其自身的药物功能，为上述联合给药提供理论依据。
G3-S MSN组表示：PAMAM-G3与二硫化物桥联介孔有机硅纳米颗粒(S-S MSN)联合给药组，设立此实验组的目的是进一步证明以二硒化物桥联介孔有机硅纳米颗粒作为给药载体的优越性。PAMAM-G3与S-S MSN结合的质量配比为：2：1.5。
S-S MSN组(阴性对照组)表示：二硫化物桥联介孔有机硅纳米颗粒(S-S MSN)单独给药组，其不具备ROS响应能力，无抗氧化功能，只能作为单纯的纳米载体，故作为阴性对照组。
模型构建方法为：实验开始前对所有大鼠禁食12h，称体重，将大鼠麻醉，开腹找到它的胰胆管，用动脉夹将大鼠胆胰管最前端夹住，以0.1ml/min的速度将5％牛黄胆酸钠溶液(0.1ml/100g)逆行注射进入胆胰管中，并保持动脉夹封闭约2min。最后取下动脉夹，缝合，消毒。五组给药治疗组腹腔注射分别给予相应的药物(10mg/kg)，给药时间为造模后3h、12h、24h，共给药三次，同时对照组和模型组腹腔注射给予等量的生理盐水。48h小时后，将各组鼠安乐死，取血清和胰腺组织备用。根据大鼠的生存率和生存时间看药物的治疗效果；结合H&E染色判断胰腺组织损伤、坏死情况；通过胰腺组织的水肿程度判断胰腺组织受损程度；采用相应试剂盒检测大鼠血清淀粉酶、脂肪酶、cf DNA含量和氧化应激标志物等指标。
2)L-arginine模型：实验开始前对所有大鼠禁食12h。称量大鼠体重，计算所需L-arginine注射量，分组同上。将20％ L-arginine进行腹腔注射，给药时间及方式同上。诱导术后48h，对所有大鼠实施安乐死，收集大鼠血清和胰腺组织样本。结合H&E和Masson染色判断胰腺组织损伤、坏死情况；采用相应试剂盒检测大鼠血清淀粉酶、脂肪酶、cf DNA含量和氧化应激标志物等指标。
2、实验结果：
2.1G3-Se MSN对急性胰腺炎生存率和生存时间的影响
生存率可作为评价急性胰腺炎治疗效果的重要指标，于是我们比较了各治疗组对急性胰腺炎模型大鼠生存率和生存时间的影响。图2A-图2B结果表明AP组的24h生存率为22.22％，48h生存率为0，以及48h内的平均生存时间为22.11h，证明此急性胰腺炎模型构建成功且死亡率较高。治疗组与模型组相比，其中G3-Se MSN组较其他组显著提高了大鼠的生存率并延长了其48h内平均生存时间，而Se-Se MSN组，G3组，G3-S MSN组这三组对这两项指标仅有一定程度的改善，其治疗程度逐渐减弱，阴性对照组S-S MSN组较模型组未对大鼠的生存率和生存时间产生明显改善效果。
2.2G3-Se MSN对急性胰腺炎造成的胰腺组织损伤及坏死的影响
牛黄胆酸钠模型：H&E染色(图3中的A)结果表明，Control组胰腺组织紧密完整，几乎没有水肿和炎症现象。与Control组相比，AP组中大鼠胰腺组织出现明显损伤，腺泡细胞严重坏死并伴随炎症细胞大量浸润。而G3-Se MSN治疗后，与AP组相比，G3-Se MSN组的腺泡坏死和炎症浸润现象明显减少，且G3-Se MSN组较其他治疗组效果最好。Se-Se MSN组、G3组、G3-S MSN组三组较AP组均起到了一定的治疗效果，治疗效果依次减弱，S-S MSN组较模型组未产生明显的治疗效果。急性胰腺炎通常伴随胰腺组织水肿，胰腺含水量增加等症状。图3中的B结果表明，与Control组相比，AP组胰腺组织产生了明显水肿。与AP组相比，各治疗组治疗后胰腺水肿程度的改善与上述实验结果一致，以G3-Se MSN组治疗效果最好，显著减轻了急性胰腺炎造成的胰腺组织水肿。在临床上，淀粉酶和脂肪酶被作为查验胰腺炎的重要指标，关于急性胰腺炎的临床诊断，其中一个生化指标就是血淀粉酶和血脂肪酶的增高。采用相应的试剂盒对这两项指标进行了检测(图3中的C-D)，与Control组相比，AP组血清中淀粉酶与脂肪酶的水平显著升高。经过各组材料给药治疗后，这两项指标在前四组治疗组中均有不同程度的降低，其中以G3-Se MSN组效果最好，而S-S MSN组较模型组无明显变化。
L-arginine模型：H&E染色(图4中的A)结果与牛黄胆酸钠模型结果一致，Control组胰腺组织紧密完整。与Control组相比，AP-L组中大鼠胰腺组织的腺泡细胞严重坏死。经G3-Se MSN治疗后，与AP-L组相比，G3-Se MSN组的腺泡坏死和炎症浸润现象明显减少，且G3-Se MSN组较其他治疗组效果最好。马松染色(图4中的B)结果表明，Control组胰腺组织紧密完整，几乎没有蓝色纤维产生。与Control组相比，AP-L组中大鼠胰腺组织损伤明显，腺泡细胞严重坏死并伴随大量蓝色纤维产生，AP-L组纤维化严重。经过G3-Se MSN治疗后，与AP-L组相比，G3-Se MSN组的蓝色纤维明显减少，明显改善了胰腺组织的纤维化，且G3-SeMSN组较其他治疗组对胰腺组织纤维化的治疗效果最好。同样，也利用试剂盒对血淀粉酶和血脂肪酶进行检测(图4中的C-D)，与牛黄胆酸钠模型结果一致，G3-Se MSN治疗能最为显著的降低淀粉酶和脂肪酶的表达。
因此，G3-Se MSN能明显减轻急性胰腺炎造成的胰腺组织损伤，对急性胰腺炎具有良好的治疗作用。
2.3G3-Se MSN对体内cf DNA和氧化应激水平的影响
首先通过相应的试剂盒检测了两个模型大鼠血清中cf DNA的表达水平(图5中的A,D)，与Control组相比，其在AP和AP-L组中表达水平显著升高，两模型经过给药后，材料中含G3的治疗组即G3-Se MSN组、G3组、G3-S MSN组的cf DNA表达水平显著降低。由此表明，含G3的材料治疗可显著降低体内cf DNA的表达水平。又用相应的试剂盒检测了两组模型中大鼠胰腺组织中丙二醛和超氧化物歧化酶的表达水平(图5中的B-C,E-F)。丙二醛(MDA)是一种脂质过氧化产物，与Control组相比，其在AP和AP-L组中表达水平显著升高，经过给药后，两种模型的治疗结果一致，结果表明，材料中含Se-Se MSN的治疗组即G3-Se MSN组和Se-SeMSN组的MDA的表达水平显著降低。超氧化物歧化酶(SOD)是一种物理抗氧化酶，与Control组相比，其在AP和AP-L组中表达水平显著降低，经过给药后，材料中含Se-Se MSN的治疗组即G3-Se MSN组和Se-Se MSN组的SOD的表达水平显著升高。上述结果表明，经含Se-Se MSN的材料治疗可显著降低体内的氧化应激水平。
综上所述，G3-Se MSN能明显缓解急性胰腺炎导致的胰腺损伤和坏死，可有效治疗急性胰腺炎，G3-Se MSN对急性胰腺炎的治疗是通过清除cf DNA和降低氧化应激达到的。G3-Se MSN能作为治疗急性胰腺炎的优良候选药物。
上述实施例只是用于对本发明的举例和说明，而非意在将本发明限制于所描述的实施例范围内。此外本领域技术人员可以理解的是，本发明不局限于上述实施例，根据本发明的教导还可以做出更多种的变型和修改，这些变型和修改均落在本发明所要求保护的范围内。
Claims (9)
1.G3-Se MSN在制备治疗急性胰腺炎的药物中的应用。
2.根据权利要求1所述的应用，其特征在于：所述的G3-Se MSN为PAMAM-G3和Se-Se MSN的组合物，PAMAM-G3和Se-Se MSN产生协同作用。
3.根据权利要求2所述的应用，其特征在于：在G3-Se MSN中，PAMAM-G3与Se-Se MSN的质量配比为：1～1.5:1。
4.根据权利要求3所述的应用，其特征在于：在G3-Se MSN中，PAMAM-G3与Se-Se MSN的质量配比为：2:1.5。
5.根据权利要求1、2、3或4所述的应用，其特征在于：将G3-Se MSN制备成单一化学成分的药物制剂。
6.根据权利要求1、2、3或4所述的应用，其特征在于：所述G3-Se MSN的给药剂量为：每周腹腔注射三次，剂量为10mg/kg。
7.根据权利要求1、2、3或4所述的应用，其特征在于：所述G3-Se MSN在制备缓解急性胰腺炎造成的胰腺组织损伤和坏死的药物中的应用。
8.根据权利要求1、2、3或4所述的应用，其特征在于：所述G3-Se MSN在制备清除cf DNA治疗急性胰腺炎药物中的应用。
9.根据权利要求1、2、3或4所述的应用，其特征在于：所述G3-Se MSN在制备下调胰腺组织中的MDA水平，并上调SOD水平，通过抗氧化治疗急性胰腺炎药物中的应用。
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