CN114668781B - 胎盘素多因子组合物及其制备方法、应用 - Google Patents
胎盘素多因子组合物及其制备方法、应用 Download PDFInfo
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Abstract
本发明属于治疗呼吸道疾病制剂领域,提供了一种胎盘素多因子组合物及其制备方法、应用;制备方法包括将胎盘素、富血小板血浆、干细胞组分混合;胎盘素、富血小板血浆、干细胞组分的体积比为1‑3:1‑6:1‑4;富血小板血浆经过经过活化处理;干细胞组分包括干细胞和干细胞外泌体。应用为胎盘素多因子组合物在制备治疗肺部疾病药物中的应用。本发明特异性针对肺部疾病患者肺部炎症、细胞纤维化、肺功能损伤的致病因素,联合干细胞、富血小板血浆(PRP)和胎盘素,建立了治疗肺损伤三重修复机制;通过这一共同作用机制对肺部炎症反应,肺泡上皮细胞凋亡,肺血管和组织损伤具有明显有益的修复作用,并可能成为肺部疾病尤其是慢性阻塞性肺病的治疗新途径。
Description
技术领域
本发明属于治疗呼吸道疾病制剂领域,具体涉及一种胎盘素多因子组合物及其制备方法、应用。
背景技术
慢性阻塞性肺病(Chronic obstructive pulmonary disease,COPD)即慢阻肺,是临床呼吸内科的多发疾病,病程较长,最严重可导致慢性呼吸衰竭。COPD的患病率占40岁以上人群的13.7%,中国总患病人数约9990万。世界卫生组织资料表明,2020年COPD在全球疾病经济负担排名位于第5位。随着人口老龄化及环境污染等情况的加剧,COPD患病率将呈进一步的上升趋势。COPD使患者运动耐力下降,降低患者生活质量,严重威胁人类健康。研究显示,慢阻肺患者由于肺部接触有害颗粒或气体引发异常炎性反应,由慢性呼吸道炎症引发进行性肺细胞纤维化,因此,缓解肺部炎症和修复受损细胞都是治疗的关键。
慢性阻塞性肺病目前的药物治疗首选支气管舒张剂,其他如抗氧化剂和糖皮质激素等,其它治疗包括氧疗和康复训练主要是稳定肺实质可逆性改变以及提高呼吸功能,其治疗效果比较有限,手术治疗主要是提高生活质量、缓解临床症状。目前的治疗手段仅能缓解症状,如β受体激动剂、糖皮质激素,黏液溶解剂和抗胆碱药物等吸入性药物,仅仅用于减轻患者症状;不能从根本上病情的发展,因此亟需寻找一种能够有效缓解炎症,促进肺部组织修复和功能重建的方法,这具有极其重要的意义。
发明内容
基于以上理由,有必要提供一种可有效缓解炎症,促进肺部组织修复和重建的胎盘素多因子组合物及其制备方法。
本发明的第一个目的,在于提供一种胎盘素多因子组合物的制备方法。
一种胎盘素多因子组合物的制备方法,其特征在于,包括以下步骤:
将胎盘素、富血小板血浆、干细胞组分混合;
所述胎盘素、富血小板血浆、干细胞组分的体积比为1-3:1-6:1-4;
所述富血小板血浆经过经过活化处理;所述干细胞组分包括干细胞和干细胞外泌体。
特别地,干细胞的密度为0.5-1.5×105/mL,所述胎盘素的浓度为1-5wt%,所述干细胞外泌体的浓度为1-8wt%。
特别地,所述活化处理为选自以下活法方法:自凝血酶活化、促凝血酶原激酶活化、组织因子活化、CaCl2活化和超声波活化。
当活化处理为超声波活化时候,条件为:25-37℃、40-60Hz、15-30min。
特别地,干细胞组分来自以下干细胞中的至少一种:外周血干细胞、骨髓干细胞、脂肪干细胞和间充质干细胞。
特别地,所述富血小板血浆为自体血浆。
本发明的第二个目的,在于提供前述胎盘素多因子组合物。
本发明的第三个目的,在于提供前述胎盘素多因子组合物在制备治疗肺部疾病药物中的应用。
特别地,治疗肺部疾病药物的剂型为雾化剂。
所述肺部疾病为慢性阻塞性肺病。
所述肺部疾病包括但不限于肺部炎症、肺部纤维化、呼吸阻滞、低氧血症和呼吸衰竭中的至少一种。
本发明发现慢阻肺外,多种肺部疾病都源于炎症、细胞凋亡或损伤。作为一种辅助治疗,本发明也能应用于这些肺部疾病,或缓解某些症状。
间充质干细胞是一类初始未分化的成体干细胞,具有自我更新及多向分化潜能。本发明发现间充质干细胞治疗慢阻肺的机制有:①抑制炎症反应的发生:慢性阻塞性肺病是多种细胞及因子共同参与的慢性炎症反应性疾病,间充质干细胞能够通过旁分泌作用降低炎症因子的水平,减少炎症反应的发生。②细胞凋亡:间充质干细胞能够通过多种途径抑制细胞凋亡。③修复作用:间充质干细胞能够通过Wnt信号通路的激活,从而分化成肺泡及气道上皮细胞参与损伤的修复。为充分发挥间充质干细胞的作用。间充质干细胞可存在于多种组织器官,如脐带、胎盘、骨髓、脂肪、牙髓等,这些来源的间充质干细胞具有类似的性质和功能。
无论是自体还是异体干细胞都具有抗炎特性,理论上均可用于治疗肺部炎症,但从安全性考虑,以自体干细胞,或脐带干细胞等抗原性弱,已经有大量临床研究已证实其安全的为首选。
本发明的相关成分包括干细胞以及干细胞外泌体。外泌体是干细胞旁分泌的一个重要组成部分,是各种活体细胞释放到细胞外微环境的大小约为50-150nm的膜性囊泡,其所含有的细胞因子、脂质、蛋白、受体和mRNA等成分在细胞间信息通信中发挥着重要的作用。
富血小板血浆(platelet-rich plasma,PRP)是通过离心的方法从自体血中分离出的血小板浓缩物。PRP被激活后,其内蕴含多种生长因子和蛋白质,可诱导、调节细胞分裂、分化及增殖,激发炎症和损伤愈合的级联反应,加速组织的自然愈合过程。本发明发现自体富血小板血浆既可以减轻肺细胞损伤后肺组织的含水量,减少肺组织内TNF-α、IL-6、IL-1β等炎性细胞和炎性介质的含量,进而间接的促进肺上皮细胞的增殖与修复。另外,PRP能够通过激活PI3K-AKT-NFκB信号通路,降低间充质干细胞在恶劣环境条件下的凋亡,促进其旁分泌功能,提高其存活率及其再生和修复功能。
胎盘素,是由胎盘提取的具有免疫活性的小分子化合物的总称,又称“胎盘多肽”。中医理论认为,胎盘性干、咸、归肺、肾经。功能为补气、养血、益精,可用作滋补、养颜、强壮之功能,自古以来便作为治疗肺部损伤的药物成分之一。其功效主要有:增强细胞的免疫功能,维持遗传物质的稳定和抗体的正常生理功能,抗疲劳作用、抗衰老作用。胎盘多肽还能提高骨髓造血功能的活性,并能有效降低感染的发生率。
在慢阻肺患者中,其氧化和抗氧化系统失衡,肺部炎症反应使炎症细胞释放大量活性氧,使血管和组织受到损伤,加速肺气肿的形成。本发明发现胎盘素能够有效抑制机体的过氧化反应,清除自由基,降低氧化应激水平,从而促进肺部血管和组织的修复。
本发明特异性针对肺部疾病患者肺部炎症、细胞纤维化、肺功能损伤的致病因素,联合干细胞、富血小板血浆(PRP)和胎盘素,建立了一套治疗肺损伤三重修复机制,如图1所示。其效果比干细胞、富血小板血浆(PRP)和胎盘素任一单独使用的治疗效果更佳。
干细胞、富血小板血浆(PRP)和胎盘素三者共同作用提示,间充质干细胞可以在肺部聚集并分化为肺泡及气道上皮细胞参与肺损伤的修复。
PRP可能通过促进间充质干细胞的功能,共同分泌细胞因子,缓解肺部炎症,促进肺部血管重建、参与细胞损伤修复。胎盘素可以通过调节免疫,清除自由基,抑制过氧化反应减轻肺部血管和细胞的损害,减少肺组织纤维化。
本发明通过这一共同作用机制对肺部炎症反应,肺泡上皮细胞凋亡,肺血管和组织损伤具有明显有益的修复作用,并可能成为肺部疾病尤其是慢性阻塞性肺病的治疗新途径。
附图说明
附图用来提供对本发明的进一步理解,并且构成说明书的一部分,与本发明的实施例一起用于解释本发明,并不构成对本发明的限制。
图1是本发明的作用路径示意图。
具体实施方式
下面结合具体实施例,对本发明作进一步详细的阐述,下述实施例不用于限制本发明,仅用于说明本发明。以下实施例中所使用的实验方法如无特殊说明,实施例中未注明具体条件的实验方法,通常按照常规条件,下述实施例中所使用的材料、试剂等,如无特殊说明,均可从商业途径得到。
在具体实施例中,没有详细说明的步骤、材料选择、数值参数均为现有技术中的常规选择,或者任何现有公开的现有技术。如例如Sambrook等人,分子克隆:实验室手册(NewYork:ColdSpring Harbor Laboratory Press,1989)中所述的条件,或按照制造厂商所建议的条件。实施例中所用到的各种常用化学试剂,均为市售产品。
本发明所用的胎盘、干细胞人类胚胎相关组织等均为合法来源且符合医学伦理道德规范。
本发明中富血小板血浆的制备方法包括但不限于下述方法:
获取自体外周血,于1-5℃、150-250g/min离心10-20min,弃去红细胞层,然后2000-2800g/min离心10~20min,弃去血浆层,活化处理后再次2000-2800g/min离心10-20min,取上清采用1-20μm过滤器过滤。
本发明中胎盘素的制备方法包括但不限于下述方法:
(1)选用经过筛选的新鲜健康胎盘组织100mL;
(2)将胎盘组织充分清洗并切成小块,去除血管和粘膜组织,切碎后置于100mL,50mmoL/L乙酸-乙酸钠缓冲液(pH4.0)中匀浆;匀浆液置于4℃水浴中保温2.5小时,期间不时搅拌;恢复至室温后冷冻离心(4℃,6600r/min,30min),得到沉淀和约150mL上清;
(3)在4℃,向步骤(2)中的上清中缓慢滴加6倍于上清体积的乙醇(-20℃预冷),滴加过程中不断搅拌,冷冻离心(4℃,6600r/min,30min)后取上清;
(4)用旋转蒸发器将步骤(3)的上清蒸发,水浴温度40℃,得蛋黄色粘稠物,用12.0mL生理盐水溶解,离心(16000r/min,20min),取上清;
(5)向步骤(2)中的沉淀加入3-5倍重量去离子水,搅拌,调pH7.0-9.0,加入0.1%胰蛋白酶,水解6-8小时,冷冻离心(4℃,6600r/min,30min)后取上清,与步骤(4)中的上清混合,即为胎盘提取物粗制品;
(6)用0.2μm滤膜过滤步骤(5)中胎盘提取物粗制品,进一步用DE-52阴离子交换层析,层析柱(2.6X40cm)先用50mmol/L Tris-HCl缓冲液(pH6.5)平衡,上样后用同样的缓冲液进行洗脱,流速均为18mL/h;
(7)收集所有活性峰,经HPLC进一步纯化后,100ml生理盐水配制,即得胎盘提取物;用双缩脲法测定胎盘提取物中的蛋白质含量,调整浓度直至终浓度为10mg/ml。
本发明所用的干细胞及干细胞外泌体的制备方法包括但不限于以下方法:
(1)选用经过筛选的新鲜胎盘组织100mL;
(2)将胎盘组织充分清洗并切成小块,去除血管和粘膜组织,剪碎成5mm3;
(3)将组织碎片贴附于10cm无菌培养皿中,加入DMF12培养液,置于5%的二氧化碳培养箱中培养至细胞可传代,常规传至第3代,即为间充质干细胞;
(4)选取第3代有活性的间充质干细胞,常规培养至其生长密度为60%,然后用PBS溶液清洗后进行换液处理;其中,该步骤所述的常规培养是指使用DMF12培养基且于温度为37℃、培养体系含有5%的二氧化碳的条件下培养;该处所述的换液处理是指使用其他培养基进行培养前,需要对间充质干细胞进行清洗处理,避免原培养基混入新培养基中;常规处理使用的培养基为DMF12培养基,换液时采用的培养基为DMEM培养基;
(5)向换液后的细胞培养液中添加组合诱导试剂IL-1β、EGF,并且二者在细胞培养液中终浓度分别为1ng/mL、100ng/mL,预处理48h。
(6)培养完毕后收集间充质干细胞的培养基,将培养基上清用高效滤网过滤,去除细胞碎片,即可得到干细胞生物活性蛋白粗提液;
(7)将干细胞生物活性蛋白粗提液置于高效超滤袋中,纯化溶液选用5%PBS,低温处理24h,期间更换纯化溶液2次。本步骤可以有效去除粗提液中酚红指示剂、各类小分子盐、抗生素以及其它杂质;
(8)将高效超滤袋置于20%PEG6000中继续处理3h,即为纯化后的干细胞外泌体浓缩液。
实施例1
一种胎盘素多因子组合物的制备方法,包括以下步骤:
(1)自体活化PRP制备:志愿者签署知情同意书并抽取自体外周血,通过前述方法制备成自体活化PRP。
所采用的活法方法为超声活法,温度为37℃水浴,50hz,30min。
(2)干细胞及干细胞外泌体的制备:取新鲜胎盘组织100mL,按前述方法制备,选择第3代有活性的间充质干细胞。
(3)胎盘素的制备:选用经过筛选的新鲜健康胎盘组织100mL;按前述方法制备。
(4)胎盘素多因子组合物雾化剂的制备:
各组分无菌处理后按表1中的配方配成雾化剂备用。
实施例2
一种胎盘素多因子组合物的制备方法,包括以下步骤:
(1)自体活化PRP制备:志愿者签署知情同意书并抽取自体外周血,通过前述方法制备成自体活化PRP。
所采用的活法方法为超声活法,温度为30℃水浴,40hz,25min。
(2)干细胞及干细胞外泌体的制备:取新鲜胎盘组织100mL,按前述方法制备,选择第3代有活性的间充质干细胞。
(3)胎盘素的制备:选用经过筛选的新鲜健康胎盘组织100mL;按前述方法制备。
(4)胎盘素多因子组合物雾化剂的制备:
各组分无菌处理后按表1中的配方配成雾化剂备用。
实施例3
一种胎盘素多因子组合物的制备方法,包括以下步骤:
(1)自体活化PRP制备:志愿者签署知情同意书并抽取自体外周血,通过前述方法制备成自体活化PRP。
所采用的活法方法为超声活法,温度为25℃水浴,60hz,15min。
(2)干细胞及干细胞外泌体的制备:取新鲜胎盘组织100mL,按前述方法制备,选择第3代有活性的间充质干细胞。
(3)胎盘素的制备:选用经过筛选的新鲜健康胎盘组织100mL;按前述方法制备。
(4)胎盘素多因子组合物雾化剂的制备:
各组分无菌处理后按表1中的配方配成雾化剂备用。
实施例4
一种胎盘素多因子组合物的制备方法,包括以下步骤:
(1)自体活化PRP制备:志愿者签署知情同意书并抽取自体外周血,通过前述方法制备成自体活化PRP。
所采用的活法方法为凝血酶活化/促凝血酶原激酶活化。
(2)干细胞及干细胞外泌体的制备:取新鲜胎盘组织100mL,按前述方法制备,选择第3代有活性的间充质干细胞。
(3)胎盘素的制备:选用经过筛选的新鲜健康胎盘组织100mL;按前述方法制备。
(4)胎盘素多因子组合物雾化剂的制备:
各组分无菌处理后按表1中的配方配成雾化剂备用。
实施例5
一种胎盘素多因子组合物的制备方法,包括以下步骤:
(1)自体活化PRP制备:志愿者签署知情同意书并抽取自体外周血,通过前述方法制备成自体活化PRP。
所采用的活法方法为组织因子活化。
(2)干细胞及干细胞外泌体的制备:取新鲜胎盘组织100mL,按前述方法制备,选择第3代有活性的间充质干细胞。
(3)胎盘素的制备:选用经过筛选的新鲜健康胎盘组织100mL;按前述方法制备。
(4)胎盘素多因子组合物雾化剂的制备:
各组分无菌处理后按表1中的配方配成雾化剂备用。
实施例6
一种胎盘素多因子组合物的制备方法,包括以下步骤:
(1)自体活化PRP制备:志愿者签署知情同意书并抽取自体外周血,通过前述方法制备成自体活化PRP。
所采用的活法方法为CaCl2活化。
(2)干细胞及干细胞外泌体的制备:取新鲜胎盘组织100mL,按前述方法制备,选择第3代有活性的间充质干细胞。
(3)胎盘素的制备:选用经过筛选的新鲜健康胎盘组织100mL;按前述方法制备。
(4)胎盘素多因子组合物雾化剂的制备:
各组分无菌处理后按表1中的配方配成雾化剂备用。
表1
上述实施例所制备的雾化剂对难治性慢阻肺的治疗效果和安全性初步评估。
治疗效果
招募64名常规治疗效果不佳的慢阻肺患者作为志愿者,其中48位维持常规治疗不变,另辅助用本发明雾化吸入剂治疗;另有16位作为安慰剂效应对比组,64名志愿者均已签注双盲实验知情同意书。
雾化剂为15mL装,每日1支,10日为1疗程,采用雾化器局部吸入给药;或,安慰剂为15mL装,内容物为生理盐水,每日1支,10日为1疗程,采用雾化器局部吸入给药,2个疗程后,检测血气分析和血氧饱和度以及CRP,观察治疗效果,如表2所示:
表2治疗效果
根据表2可知,与常规治疗(治疗前)相比,实施例1-6的患者辅助多因子组合物雾化剂吸入治疗后,大部分患者动脉氧分压得到了有效改善,血氧饱和度明显提高。而对比例1、2(安慰剂组)的患者治疗效果不明显,具有统计显著性。
表明胎盘素、活化处理的富血小板血浆联合干细胞的多因子雾化剂能显著缓解慢阻肺患者临床上呼吸受阻、低氧血症等呼吸系统症状,改善肺功能,有效降低肺部炎症。
安全性评估
检测64名8组志愿者用力肺活量FVC和血氧饱和度以及炎症指标CRP,TNF-α,观察效果,如表3所示。
表3安全性评估
如表3所示,实施例和对比例均无可见副作用,与实施例相比,辅助多因子组合物雾化剂吸入治疗后,用力肺活量FVC得到了有效改善,血氧饱和度明显提高。表明多因子雾化剂能显著缓解慢阻肺患者临床上呼吸受阻、低氧等症状,能有效改善患者肺功能。治疗实施例炎症指标CRP,TNF-α均低于对照组,表明胎盘素、活化处理的富血小板血浆联合干细胞能有效缓解肺部炎症。可以理解,本发明的多因子雾化剂不仅可以作为慢阻肺的辅助治疗方法,还可以用于其它有上述症状的肺部疾病的辅助治疗。
上述详细说明是针对本发明其中之一可行实施例的具体说明,该实施例并非用以限制本发明的专利范围,凡未脱离本发干细胞和间充质干细胞。
明所为的等效实施或变更,均应包含于本发明技术方案的范围内。
Claims (2)
1.一种胎盘素多因子组合物,其特征在于,所述胎盘素多因子组合物通过以下制备方法制得:
将胎盘素、富血小板血浆、干细胞组分混合;
所述胎盘素、富血小板血浆、干细胞组分的体积比为1-3:1-6:1-4;
所述富血小板血浆经过经过活化处理;所述干细胞组分为干细胞和干细胞外泌体;
干细胞的密度为0.5-1.5×105/mL,所述胎盘素的浓度为1-5wt%,所述干细胞外泌体的浓度为1-8wt%;
所述活化处理为选自以下活法方法:
自凝血酶活化、促凝血酶原激酶活化、组织因子活化、CaCl2活化和超声波活化;
当活化处理为超声波活化时候,条件为:25-37℃、40-60Hz、15-30min;
所述干细胞组分来自间充质干细胞;
所述富血小板血浆为自体血浆。
2.权利要求1所述的胎盘素多因子组合物在制备治疗慢性阻塞性肺病药物中的应用。
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