CN114958722A - 一种结直肠靶向载药外泌体及应用和治疗结直肠疾病的药物 - Google Patents
一种结直肠靶向载药外泌体及应用和治疗结直肠疾病的药物 Download PDFInfo
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- CN114958722A CN114958722A CN202210707540.8A CN202210707540A CN114958722A CN 114958722 A CN114958722 A CN 114958722A CN 202210707540 A CN202210707540 A CN 202210707540A CN 114958722 A CN114958722 A CN 114958722A
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Abstract
本发明公开了一种结直肠靶向载药外泌体及应用和治疗结直肠疾病的药物；所述结直肠靶向载药外泌体由用于治疗结直肠疾病的药物导入到具有结直肠组织靶向性的外泌体中获得，所述具有结直肠组织靶向性的外泌体来源于肺部位的细胞；结直肠疾病治疗药物包含上述结直肠靶向载药外泌体。与现有技术相比，本发明使用肺部位的细胞分泌的外泌体不需要作任何修饰就可以在结直肠富集，用肺部位的细胞来源的外泌体，解决了外泌体产量的问题，具有很好的应用前景；而且用肺部位的细胞来源的外泌体可以装载不同药物或活性分子，通过靶向结直肠组织给药，提高结直肠疾病的治疗效果，降低药物毒副反应。
Description
技术领域
本发明属于生物医学领域，涉及一种结直肠靶向载药外泌体及应用和治疗结直肠疾病的药物。
背景技术
结肠和直肠是消化系统的一部分，二者组成一个肌肉长管，称为大肠。起源于结肠的癌症称为结肠癌，而起源于直肠的癌症称为直肠癌。二者也可以称之为结直肠癌。结肠直肠癌是胃肠道中常见的恶性肿瘤，是世界的第四大肿瘤类型，每年导致50万的患者死亡。早期症状不明显，随着癌肿的增大而表现排便习惯改变、便血、腹泻、腹泻与便秘交替、局部腹痛等症状，晚期则表现贫血、体重减轻等全身症状。其发病率和病死率在消化系统恶性肿瘤中仅次于胃癌、食管癌和原发性肝癌。
近50年来，尽管外科技术有迅猛发展，但大肠癌的手术治愈率、5年生存率始终徘徊在50％左右，治疗失败原因主要为局部复发率较高，故提高大肠癌的治疗效果必须考虑综合治疗。除了手术治疗的方法外，近年来也上市了一些针对于结直肠癌症治疗的药物。结直肠肿瘤的靶向药物治疗，按照作用机制分为三大类：第一种作用于肿瘤细胞生长信号通路，通过阻断肿瘤细胞生长信号，抑制肿瘤细胞的增殖。代表药物：西妥昔单抗、帕尼单抗。第二种作用于肿瘤生长的微环境(肿瘤血管生成)，通过阻断肿瘤细胞的血液供应，阻断其营养供应，达到“饿死肿瘤”目标。代表药物：贝伐珠单抗、瑞戈非尼。第三种作用于患者免疫细胞 (T细胞)，通过使免疫细胞持续活化，增强免疫细胞对肿瘤的识别和杀伤作用。代表药物：抗PD-1单抗(Pembrolizumab)。这些药物虽然在一定层度上延长了患者的寿命，但因为其靶向能力较弱都具有明显的毒副作用。
良好的靶向药物，可以携带药物进入病兆部位，而正常组织和器官不富集药物。这样可以提高药物在病灶部位的有效浓度，进而提高疗效，同时也可以降低药物在正常组织和器官的浓度进而降低药物的副作用。虽然近年来靶向治疗得到医学药学领域的大力关注，有文献指出采用靶向基团(例如癌细胞表面特异性的受体结合的配体)与载药体系结合，可以增加药物的靶向作用，但是临床应用显示这样的靶向作用效果甚微。目前一直没有理想的药物靶向给药体系，这是癌症治疗方面亟待解决的重大科学难题。
近年来，外泌体的出现有望解决这一问题。研究发现外泌体是身体各个组织和细胞间信息传递的载体。它可以在身体进行远距离的信息传递。且外泌体可以自由跨越细胞膜是一个理想的载药体系。
化疗药物具有良好的抗肿瘤活性，但由于其较差的靶向性导致化疗药物具有极大的毒副作用。例如：奥沙利铂(Oxaliplatin)和五氟尿嘧啶等。奥沙利铂为第3代铂类抗癌药，为二氨环己烷的铂类化合物，即以1，2-二氨环己烷基团代替顺铂的氨基。与其他铂类药作用相同，即均以DNA为靶作用部位，铂原子与 DNA形成交叉联结，拮抗其复制和转录。
因此，制备一种高效的结直肠靶向外泌体载药体系对结直肠部相关疾病进行治疗是亟需的。
发明内容
本发明的目的是要解决现有技术中存在的不足，提供一种结直肠靶向性外泌体及应用和治疗结直肠相关疾病的药物，通过靶向结直肠组织给药，提高结直肠疾病的治疗效果，降低药物毒副反应。
为达到上述目的，本发明是按照以下技术方案实施的：
本发明第一方面提供了一种结直肠组织靶向性外泌体，所述靶向外泌体来源于肺部位的细胞。
术语“外泌体”是一种囊泡，其从细胞向细胞外分泌，或具有由存在于细胞内的脂质双分子层构成的膜结构。外泌体的直径约为30-1000nm，外泌体在多泡体与细胞膜融合时从细胞中释放出来，或直接从细胞膜中释放出来。已知外泌体发挥运输细胞内的生物分子蛋白、生物活性脂质和RNA(miRNA)的作用，以实现其在介导凝固、细胞间通讯和细胞免疫方面的功能性作用。
上述外泌体的概念包括微泡。已知外泌体的标记蛋白有CD63、CD81、 TSG101等，除此之外，已知的还有细胞表面受体(如：EGFR)，信号传导相关分子、细胞粘附相关蛋白、MSC相关抗原、热休克蛋白、囊泡形成相关Alix等蛋白。
在一些实施方案中，外泌体直径为约30到约500、直径为约30到约300、直径为约30到约250、直径为约30到约220、直径为约40到约175、约50到约150、约30到约150或约30到约120nm。
进一步，所述细胞选自正常细胞或其衍生株、癌细胞。
进一步，所述细胞来源于人或非人类哺乳动物。
进一步，所述非人类哺乳动物包括非人灵长类动物、啮齿动物、牛、猪、羊、犬、兔、猫、马。
进一步，所述啮齿动物包括小鼠、大鼠、仓鼠、豚鼠。
进一步，所述灵长类动物包括猴、猩猩、狒狒、猿。
在本发明中，所述肺部位的细胞是指来源于肺的细胞或者干细胞诱导分化的肺细胞。所述干细胞包括多能干细胞、胚胎干细胞。在本发明中，所述多能干细胞选自诱导多能干细胞。
诱导多能干细胞是通过诱导一种或多种干细胞特异性基因的表达而产生的非多能细胞(通常是成熟体细胞)的人工衍生干细胞。这样的干细胞特异性基因包括但不限于八聚体转录因子家族，即Oct-3/4；Sox基因家族，即Sox1，Sox2， Sox3，Sox15和Sox 18；Klf基因家族，即Klf1，Klf2，Klf4和Klf5；Myc基因家族，即c-myc和L-myc；Nanog基因家族，即OCT4，NANOG和REX1。
进一步，所述肺部位的细胞包括胚肺成纤维细胞、胚肺细胞、肺成纤维细胞、胚肺二倍体细胞、肺细胞、肺泡上皮细胞、支气管上皮细胞、肺癌细胞、诱导多能干细胞诱导的肺细胞。
进一步，所述胚肺成纤维细胞包括但不限于HFL-1、HELF、IMR-90，胚肺细胞包括但不限于MRC-5、WI-38、HLF，肺成纤维细胞包括但不限于HEL-2、 HEL-1、CCL-153，胚肺二倍体细胞包括但不限于HLF-02，肺细胞包括但不限于V79，肺泡上皮细胞包括但不限于HPAEpic、SJPL、ATII、AEC、AECII，支气管上皮细胞包括但不限于NHBEC、HBE、HBEC3-KT、16HBE、BEAS-2B、BEP2D、NHBE、MBEC、BBEC、4MBr-5，肺癌细胞包括但不限于LLC1、A549、SK-MES-1、 NCL-H460、H1299、MSTO-211H、HCL-H1299。
在本发明中，肺部位的细胞也可以进行基因修饰或改造或诱导以使其对结直肠组织具有靶向性，包括但不限于基因改造、基因修饰、基因过表达或删除、分子修饰等；肺部位的细胞分泌的外泌体也可以进行表面修饰或改造以使其对结直肠组织具有靶向性，包括但不限于表面蛋白修饰、表面蛋白改造、表面小分子修饰等。
本发明第二方面提供了一种本发明第一方面所述的靶向性外泌体的制备方法，包括以下步骤：
培养细胞，获取细胞培养液；
离心，取上清液；
二次离心，取上清液；
再次离心，缓冲液重悬沉淀获得靶向性外泌体。
进一步，步骤2)离心条件为2000g离心10min。
进一步，步骤3)离心条件为10000g离心30min。
进一步，步骤4)离心条件为100000g离心2h。
进一步，步骤4)所述的缓冲液为PBS。
本发明第三方面提供了一种药物组合物，所述药物组合物包括本发明第一方面所述的靶向外泌体；和治疗剂/预防剂。
进一步，所述治疗剂或预防剂包括小分子化学药物、肽类或蛋白质药物、抗体、酶、细胞因子、激素、抗生素、疫苗和/或核酸类药物。所述治疗剂或预防剂可以是任何常规药物，只要其能起到治疗结直肠部位的疾病即可。
进一步，所述核酸类药物包括质粒DNA、mRNA、microRNA、小干扰RNA、 shRNA、有义RNA、反义寡核苷酸、适配体。
进一步，所述小分子化学药物包括盐酸吉西他滨、顺铂、吉西他滨、紫杉醇、卡铂、依托泊苷、长春新碱、氟尿嘧啶、奥沙利铂、伊立替康、卡培他滨、苏尼替尼、替西罗莫司、帕唑帕尼、阿西替尼、索拉非尼、卡博替尼、依维莫司、乐伐替尼。
进一步，所述小分子化学药物包括氟尿嘧啶、奥沙利铂、伊立替康、卡培他滨。
进一步，所述小分子化学药物选自奥沙利铂。
进一步，所述抗生素包括丝裂霉素、阿霉素。
进一步，所述疫苗包括卡介苗。
进一步，所述治疗剂/预防剂用于治疗或预防结直肠疾病。
在本发明中，结直肠疾病是指任何发生于结直肠(结肠或直肠)部位或与结直肠(结肠或直肠)相关的疾病。
进一步，所述结直肠疾病包括结直肠炎、结直肠息肉、结直肠癌、结直肠类癌。在本发明中，结直肠疾病包括结肠和/或直肠部位的疾病。
进一步，所述结直肠疾病选自结直肠癌。
进一步，所述药物组合物通过将治疗剂或预防剂导入到靶向性外泌体中获得。
进一步，所述药物组合物还包括药学上可接受的载体。
术语“药学上可接受的”是指载体一般在化学上和/或物理上与构成调配物的其它成分相容，且在生理上与其接受者相容。
用于本发明的药物组合物中的药学上可接受的载体可包括但不限于例如药学上可接受的液体、凝胶或固体载剂、水性媒剂(例如氯化钠注射液、林格氏注射液、等渗葡萄糖注射液、无菌水注射液或林格氏葡萄糖和乳酸盐注射液)、非水性媒剂(例如植物来源的非挥发性油、棉籽油、玉米油、芝麻油或花生油)、抗微生物剂、等渗剂(如氯化钠或右旋糖)、缓冲液(如磷酸盐或柠檬酸盐缓冲液)、抗氧化剂(如硫酸氢钠)、悬浮/分散剂(如羧甲基纤维素钠、羟丙基甲基纤维素或聚乙烯吡咯烷酮)、螯合剂(如EDTA(乙二胺四乙酸)或EGTA(乙二醇四乙酸))、乳化剂(如聚山梨醇酯80(Tween 80))、稀释剂、佐剂、赋形剂、或无毒辅助物质、所属领域中已知的其它组分，或其各种组合。适合的组分可包括例如填充剂、结合剂、崩解剂、缓冲剂、防腐剂、润滑剂、调味剂、增稠剂、着色剂或乳化剂。
本发明的药物组合物可以分别根据通常的方法剂型化为散剂、颗粒剂、片剂、胶囊剂、悬浮液、乳液、糖浆、喷剂等口服剂型、外用剂、栓剂及灭菌注射溶液的形态来使用。上述药物组合物所包含的载体、赋形剂及稀释剂可以为乳糖、葡萄糖、蔗糖、山梨糖醇、甘露醇、木糖醇、赤藓糖醇、麦芽糖醇、淀粉、阿拉伯胶、海藻酸盐、明胶、磷酸钙、硅酸钙、纤维素、甲基纤维素、微晶纤维素、聚乙烯吡咯烷酮、水、羟基苯甲酸甲酯、羟基苯甲酸丙酯、滑石、硬脂酸镁及矿物油等。制剂化时可以使用通常使用的填充剂、增量剂、结合剂、湿润剂、崩解剂、表面活性剂等稀释剂或赋形剂来制备。用于口服给药的固体制剂包括片剂、丸剂、散剂、颗粒剂、胶囊剂等，这些固体制剂通过在本发明的药物组合物中混合一种以上的赋形剂，例如淀粉、碳酸钙、蔗糖或者乳糖、明胶等来制备。并且，除单纯的赋形剂以外，还使用如硬脂酸镁、滑石的润滑剂。用于口服的液体制剂有悬浮剂、内服液剂、乳剂、糖浆剂等，除广泛使用的作为单纯稀释剂的水、液体石蜡以外，还可以包括多种赋形剂，例如湿润剂、甜味剂、芳香剂、保存剂等。用于胃肠外给药的制剂包括灭菌的水溶液、非水性溶剂、悬浮剂、油剂、冷冻干燥制剂、栓剂。非水性溶剂、悬浮剂可以使用丙二醇、乙二醇、如橄榄油的植物油、如油酸乙酯的可注射酯类等。栓剂的基剂可以使用witepsol、聚乙二醇、吐温 (tween)61、可可脂、肉实树酯、甘油明胶等。
本发明的药物组合物能够以多种途径向鼠、家畜、人类等哺乳动物给药。可以预测给药的所有方式，包括但不限于口腔、静脉内、肌内、动脉内、骨髓内、鞘内、心脏内、透皮、皮下、腹腔内、鼻腔内、肠道、局部、舌下或直肠。优选为口服或非口服给药。本申请中使用的术语“非口服”包括皮下、皮内、静脉内、肌内、关节内、滑膜囊内、胸骨内、鞘内、病灶内及颅骨内注射或输注技术。
依据本发明的药物组合物，可以作为单独的治疗剂给药，或与其他治疗剂并用给药，也与传统治疗剂依次或同时给药，且可单次或多次给药。综合考虑以上因素，重要的是应以最小的量达到最大的效果且无副作用，这对本领域技术人员来说是很容易确定的。
本发明的药物组合物可通过任意装置给药以使活性物质递送至靶细胞。优选的给药方式及制剂为注射剂。注射剂可利用生理盐水、林格尔氏液、汉克氏(Hank) 液或无菌水溶液等的水性溶剂、橄榄油等的植物油、油酸乙酯等的高级脂肪酸酯及乙醇、苯甲醇、丙二醇、聚乙二醇或甘油等的非水溶剂等来配制，为了黏膜渗透，可使用适合于所要通过的屏障的本领域公知的非侵入型制剂，还可包括如抗坏血酸、亚硫酸氢钠、丁基羟基茴香醚(BHA)、生育酚、乙二胺四乙酸(EDTA) 等的用于防止变质的稳定剂、乳化剂、用于调节pH值的缓冲剂、苯基硝酸汞、硫柳汞、苯扎氯铵、苯酚、甲酚、苯甲醇等的用于抑制微生物生长的保鲜剂等的药学上可接受的载体。
本发明的药物组合物的剂量根据治疗对象的年龄、性别、体重、所要治疗的特定疾病或者病理状态、疾病或者病理状态的严重程度、给药途径以及处方人员的判断不同。基于上述因素的剂量的确定在本发明所属技术领域的普通技术人员的水平范围内。
“治疗”可以指治疗性处理和预防性或防止性措施，其中目的是预防或减缓 (减轻)靶向性病理状况或疾病。需要治疗的受试者包括已经患有病症的受试者，以及有患有疾病的倾向的受试者，或需要预防疾病的受试者。治疗益处可以指症状或所治疗的潜在疾病的根除或改善。此外，通过根除或改善与潜在疾病相关的一种或多种生理症状使得在受试者中观察到改善，尽管受试者仍然可以受潜在疾病的折磨可以实现治疗益处。预防效果可包括延迟、预防或消除疾病或病况的出现，延迟或消除疾病或病况的症状的发作，减缓、停止或逆转疾病或病况的进展，或其任何组合。对于预防性益处，处于发生特定疾病的风险中的受试者或报告疾病的一种或多种生理症状的受试者可以进行治疗，即使不能进行对该疾病的诊断。
本发明第四方面提供了一种组合物，所述组合物包括本发明第一方面所述的靶向性外泌体，和检测标记。
进一步，所述检测标记包括荧光蛋白、生物素、酶、标签、放射性核素、发光标记或可以通过NMR或ESR光谱法检测的化合物。
根据本发明的标记被定义为可以使用试验检测的任何部分。报道分子的非限制性实例包含酶、放射性标记、半抗原、荧光标记、磷光分子、化学发光分子、发色团、光亲和分子、有色颗粒或配体，如生物素。本发明所采用的标记还包含标签，例如His标签、Flag标签等。标记包含生物素，所述生物素是抗生物素蛋白的底物。
标记缀合物适合用作诊断剂。诊断剂通常分为两类，一类用于体外诊断，并且另一类用于体内诊断方案，通常称为“定向成像”。许多合适的成像剂在本领域中是已知的。所使用的成像部分可以是顺磁离子、放射性同位素、荧光染料、 NMR可检测物质和X光成像剂。
在顺磁离子的情况下，可以通过举例提及离子，如铬(III)、锰(II)、铁(III)、铁(II)，钴(II)、镍(II)、铜(II)、钕(III)、钐(III)、镱(III)、钆(III)、钒(II)、铽(III)、镝(III)、钬(III)和/或铒(III)，其中钆是特别优选的。适用于其它上下文的离子，如X光成像，包含但不限于镧(III)、金(III)、铅(II)，并且尤其是铋(III)。
在用于治疗和/或诊断应用的放射性同位素的情况下，可提及砹211、14碳、51铬、36氯、57钴、58钴、铜67、152Eu、镓67、3氢、碘123、碘125、碘131、铟111、59铁、32磷、铼186、铼188、75硒、35硫、锝99m和/或钇90。125I适用于某些实施例，而锝99m和/或铟111由于其能量低且适于长距离检测而特别适用。放射性标记的肽和多肽可以根据本领域众所周知的方法产生。例如，肽和多肽可以通过与碘化钠和/或碘化钾以及化学氧化剂(如次氯酸钠)或酶氧化剂(如乳过氧化物酶)接触而碘化。可以通过配体交换过程用锝99m标记肽，例如通过用亚锡溶液还原高锝酸盐，将还原的锝螯合到葡聚糖凝胶柱上，并且将肽应用于此柱。可替代地，可以使用直接标记技术，例如通过温育高锝酸盐、还原剂如SNCl2、缓冲溶液如邻苯二甲酸钠钾溶液和肽。通常用于将作为金属离子存在的放射性同位素与肽结合的中间官能团是二亚乙基三胺五乙酸(DTPA)或乙二胺四乙酸(EDTA)。
荧光标记包含Alexa 350、Alexa 430、AMCA、BODIPY 630/650、BODIPY 650/665、BODIPY-FL、BODIPY-R6G、BODIPY-TMR、BODIPY-TRX、级联蓝色、Cy3、Cy5,6-FAM、荧光素异硫氰酸盐、HEX、6-Joe、俄勒冈绿488、俄勒冈绿500、俄勒冈绿514、太平洋蓝、REG、罗丹明绿、罗丹明红、造影剂 (Renographin)、ROX、TAMRA、PKH67、PKH26、TET、四甲基罗丹明，和/或得克萨斯州红。
当涉及体外诊断，与第二结合配体和/或酶(酶标签)连接，所述酶在与显色底物接触时将产生有色产物。合适的酶的实例包含尿素酶、碱性磷酸酶、(辣根)过氧化氢酶或葡萄糖氧化酶。合适的二次结合配体是生物素和抗生物素蛋白以及链霉亲和素化合物。此类标签的使用对于本领域技术人员是熟知的。
本发明第五方面提供了载药结直肠组织靶向性外泌体的制备方法，包括：
将用于治疗结直肠疾病的药物和本发明第一方面所述的靶向性的外泌体放入电转杯中进行电转，将电转产物离心去除游离的药物，得到纯化后靶向载药外泌体。
进一步，电转使用的电压选自50-300V。
进一步，电转使用的电压为250V。
在本发明的具体实施方式中，载药结直肠组织靶向性外泌体的制备方法如下：
1)取结直肠靶向性外泌体与奥沙利铂混合，加入电转缓冲液，转移至电转杯中；
2)对结直肠靶向外泌体及盐酸吉西他滨进行电转；
3)将电转产物于100000g离心力下超速离心120min，收集上清。
作为本发明可选择的实施方式，电转采用本领域常规的波形，包括但不限于指数波、方形波。
在本发明的可实施方式中，电转缓冲液选自本领域常规的电转缓冲液，包括但不限于PBS、DMEM、Cytomix、Tris-HCl。
本发明第六方面提供了本发明第一方面所述的靶向性外泌体在靶向结直肠组织中的应用。在本发明中，靶向性外泌体可以作为递送载体或者示踪或检测物质靶向结直肠组织。
本发明第七方面提供了本发明第一方面所述的靶向性外泌体或本发明第三方面所述的药物组合物在制备治疗结直肠疾病的药物中的应用。
进一步，所述结直肠疾病包括结直肠炎、结直肠息肉、结直肠癌、结直肠类癌。
进一步，所述结直肠疾病选自结直肠癌。
本发明第八方面提供了本发明第一方面所述的靶向性外泌体或本发明第四方面所述的组合物在制备检测结直肠疾病的产品中的应用。
进一步，所述结直肠疾病包括结直肠炎、结直肠息肉、结直肠癌、结直肠类癌。
进一步，所述结直肠疾病选自结直肠癌。
在本发明中，“结直肠组织靶向”、“结直肠靶向”、“靶向结直肠组织”、“靶向结直肠”可互换使用
本发明的优点和有益效果：
本发明使用的组织靶向外泌体不需要作任何修饰就可以在相应组织富集，靶向性外泌体的细胞来源简单，解决了外泌体产量的问题，具有很好的应用前景；肺部位的细胞来源的外泌体可以装载不同药物或活性分子，通过靶向结直肠组织给药，提高结直肠疾病的治疗效果，降低药物毒副反应。
附图说明
图1是人胚肺成纤维细胞HFL-1分泌的外泌体标志性蛋白检测图；
图2是人胚肺成纤维细胞HFL-1分泌的外泌体粒径分布检测图；
图3是不同细胞来源的外泌体在不同组织中的分布图；其中，3A是HFL-1细胞； 3B是A549细胞；3C是AECII细胞；3D是16HBE细胞；3E是猪肺细胞；
图4是载有用于治疗结直肠疾病的药物奥沙利铂的结直肠靶向性外泌体抗肿瘤活性体外检测图；
图5是载有用于治疗结直肠疾病的药物奥沙利铂的结直肠靶向性外泌体抗肿瘤活性体内检测图。
具体实施方式
为使本发明的目的、技术方案及优点更加清楚明白，以下结合实施例，对本发明进行进一步的详细说明。此处所描述的具体实施例仅用于解释本发明，并不用于限定发明。
实施例1靶向外泌体的制备及检测
收集人胚肺成纤维细胞HFL-1、人肺癌细胞A549、人肺泡上皮细胞AECII、人支气管/肺上皮细胞16HBE、猪肺细胞进行细胞培养。
取各细胞的细胞培养液(各细胞培养液均为无外泌体血清和DMEM或 RPMI1640培养基进行培养的)在2000g离心力下离心10min，取上清液；再在 10000g离心力下离心30min，取上清液，弃去细胞碎片及沉淀物；将离心后的细胞培养液在100000g(g为重力加速度)离心力下离心2h，沉淀用无菌PBS重悬收集，4℃短期保存，即得靶向外泌体。提取分离所得的靶向外泌体表面标记蛋白及粒径分布如图1、图2所示。
其中，猪肺细胞培养液的制备方法如下：
将新生猪用氯胺酮(18mg/kg)麻醉后，在无菌状态下剖腹取出脏器，用含抗生素的D-Hank's清洗3次去除血液并仔细去除肉眼可见的结缔组织和淋巴组织。然后将肺组织剪成0.5-1mm3大小组织碎片，再用D-Hank's液清洗3次后，置入50ml锥形瓶中，加入新鲜配制的浓度为0.5-1mg/mL的V型胶原酶，37℃水浴中震荡消化10min，加入40ml冷D-Hamk’s液，4℃终止消化，震荡锥形瓶待较大组织块沉淀后将上清液移入50ml离心管中，加入8ml小牛血清，混匀后再低速离心(800r/min),得到沉淀细胞待培养。残余组织块沉淀物中再加入 D-Hank's液充分震荡后吸取上清液离心。该过程重复2-3次将第一次消化能分离的细胞尽量分离出来，避免进入第二次消化过程。将分离的细胞加入20％小牛血清、青霉素100U/mL、谷氨酰胺100mg/L增补的RPMI1640液培养。次日更换培养基，以后隔日换一次培养基。第5天换无外泌体血清培养基，第7天收集细胞培养液。
对细胞分泌的外泌体表达量进行测定，BCA法检测细胞分泌的外泌体蛋白含量，结果显示，肺胚成纤维细胞HFL-1分泌的外泌体蛋白浓度为2.73μg/μL。
实施例2外泌体的靶向检测
取实施例1制备的外泌体，用PKH67或PKH26染色，对肺部位的细胞分泌的外泌体在体内的分布进行示踪，雄性C57bl/6小鼠(4-6周)购买于北京华阜康生物科技股份有限公司，所有小鼠均培育于SPF级设施。具体步骤如下：
取100μg的外泌体，与1μL PKH67或PKH26 4℃避光孵育过夜，在 100000g(g为重力加速度)离心力下离心2h，弃掉上清，用PBS清洗两次后，无菌PBS重悬肾细胞分泌的外泌体，经尾静脉注射入C57bl/6小鼠体内；24h后，麻醉小鼠，取小鼠的心脏，肝脏，脾脏，肺脏，肾脏、胃和结直肠做冰冻切片， Hoechst33342染细胞核后，观察外泌体在小鼠各个器官的生物分布。
结果如图3显示：来自肺部位的细胞HFL-1、A549、AECII、16HBE、猪肺细胞分泌的外泌体在结直肠组织中出现明显富集(图3A-3E)，靶向效率可高达65％-90％。其中，靶向效率的计算方法为取视野内100个细胞，65-90个细胞中会有外泌体摄入，而其他组织摄入外泌体总和为10-35个/100个细胞。
实施例3靶向载药外泌体的制备
将用于治疗疾病的药物导入到相应靶向外泌体制备靶向治疗药物，靶向载药外泌体包括：
1)取150μg结直肠靶向性外泌体与奥沙利铂混合，电转缓冲液可以为PBS、 DMEM、Cytomix、Tris-HCl，本实施例中选用PBS将其补足至150μL，转移至不同规格(0.2cm、0.4cm)电转杯中。采用不同波形(指数波、方形波)，使用不同的电压(50-300V)分别对结直肠靶向性外泌体及奥沙利铂进行电转；
2)将电转产物于100000g离心力下超速离心120min，收集上清测载药量。
3)结果：对于奥沙利铂，150μg结直肠靶向外泌体与奥沙利铂在250V的电压下进行电转，效率最高，可达34.3％。结果显示：奥沙利铂成功载入了外泌体中。
实施例4靶向载药外泌体的治疗效果检测
本实施例进一步通过体内外实验检测实施例3中制备的载有用于治疗疾病的药物的靶向外泌体对疾病的治疗作用，体内实验使用的Balb/c nude小鼠(4-6 周)购买于北京华阜康生物科技股份有限公司，所有小鼠均培育于SPF级设施。
具体步骤如下：
1、体外实验：
将结直肠癌细胞HCT-116细胞铺于96孔板中，每孔5×103个细胞，分别加入结直肠靶向性外泌体(对照组)、载有结直肠肿瘤治疗药物奥沙利铂的结直肠靶向性外泌体，MTT检测载有结直肠肿瘤治疗药物奥沙利铂的结直肠靶向性外泌体对结肠癌细胞的杀伤作用。
结果如图4所示，载有结直肠肿瘤治疗药物的结直肠靶向性外泌体相较于单纯的结直肠靶向性外泌体可以有效的杀伤肿瘤细胞。
2、体内实验：
在体内实验中，建立结直肠癌模型，将5×106个HCT-116细胞注射至Balb/c nude小鼠皮下，待其生长到约100mm3时，尾静脉注射载有结直肠肿瘤治疗药物奥沙利铂的结直肠靶向性外泌体，每3天注射一次，共注射4次，随后隔天测量肿瘤体积，肿瘤体积＝1/2×a×b2。a代表长径，b代表短径。
结果如图5所示，载有肿瘤治疗药物的靶向外泌体较等剂量的游离抗肿瘤药物组可显著降低小鼠的肿瘤大小。
对于本领域技术人员而言，显然本发明实施例不限于上述示范性实施例的细节，而且在不背离本发明实施例的精神或基本特征的情况下，能够以其他的具体形式实现本发明实施例。因此，无论从哪一点来看，均应将实施例看作是示范性的，而且是非限制性的，本发明实施例的范围由所附权利要求而不是上述说明限定，因此旨在将落在权利要求的等同要件的含义和范围内的所有变化囊括在本发明实施例内。
此外，应当理解，虽然本说明书按照实施方式加以描述，但并非每个实施方式仅包含一个独立的技术方案，说明书的这种叙述方式仅仅是为清楚起见，本领域技术人员应当将说明书作为一个整体，各实施例中的技术方案也可以经适当组合，形成本领域技术人员可以理解的其他实施方式。
Claims (10)
1.一种结直肠组织靶向性外泌体，其特征在于，所述靶向外泌体来源于肺部位的细胞；
优选地，所述细胞选自正常细胞或其衍生株、癌细胞；
优选地，所述细胞来源于人或非人类哺乳动物；
优选地，所述非人类哺乳动物包括非人灵长类动物、啮齿动物、牛、猪、羊、犬、兔、猫、马；
优选地，所述啮齿动物包括小鼠、大鼠、仓鼠、豚鼠。
2.根据权利要求1所述的靶向性外泌体，其特征在于，所述肺部位的细胞包括胚肺成纤维细胞、胚肺细胞、肺成纤维细胞、胚肺二倍体细胞、肺细胞、肺泡上皮细胞、支气管上皮细胞、肺癌细胞、诱导多能干细胞诱导的肺细胞；
优选地，所述胚肺成纤维细胞包括HFL-1、HELF、IMR-90，胚肺细胞包括MRC-5、WI-38、HLF，肺成纤维细胞包括HEL-2、HEL-1、CCL-153，胚肺二倍体细胞包括HLF-02，肺细胞包括V79，肺泡上皮细胞包括HPAEpic、SJPL、ATII、AEC、AECII，支气管上皮细胞包括NHBEC、HBE、HBEC3-KT、16HBE、BEAS-2B、BEP2D、NHBE、MBEC、BBEC、4MBr-5，肺癌细胞包括LLC1、A549、SK-MES-1、NCL-H460、H1299、MSTO-211H、HCL-H1299。
3.权利要求1或2所述的靶向性外泌体的制备方法，其特征在于，包括以下步骤：
1)培养细胞，获取细胞培养液；
2)离心，取上清液；
3)二次离心，取上清液；
4)再次离心，缓冲液重悬沉淀获得靶向性外泌体；
优选地，其特征在于，步骤2)离心条件为2000g离心10min；
优选地，步骤3)离心条件为10000g离心30min；
优选地，步骤4)离心条件为100000g离心2h；
优选地，步骤4)所述的缓冲液为PBS。
4.一种药物组合物，其特征在于，所述药物组合物包括权利要求1或2所述的靶向性外泌体；和治疗剂/预防剂。
优选地，所述治疗剂或预防剂包括小分子化学药物、肽类或蛋白质药物、抗体、酶、细胞因子、激素、抗生素、疫苗和/或核酸类药物；
优选地，所述核酸类药物包括质粒DNA、mRNA、microRNA、小干扰RNA、shRNA、有义RNA、反义寡核苷酸、适配体；
优选地，所述小分子化学药物包括盐酸吉西他滨、顺铂、吉西他滨、紫杉醇、卡铂、依托泊苷、长春新碱、氟尿嘧啶、奥沙利铂、伊立替康、卡培他滨、苏尼替尼、替西罗莫司、帕唑帕尼、阿西替尼、索拉非尼、卡博替尼、依维莫司、乐伐替尼；
优选地，所述小分子化学药物包括氟尿嘧啶、奥沙利铂、伊立替康、卡培他滨；
优选地，所述小分子化学药物选自奥沙利铂；
优选地，所述抗体包括贝伐珠单抗、西妥昔单抗、帕尼单抗、尼妥珠单抗、曲妥珠单抗、帕妥珠单抗；
优选地，所述抗生素包括丝裂霉素、阿霉素；
优选地，所述疫苗包括卡介苗；
优选地，所述治疗剂/预防剂用于治疗或预防结直肠疾病；
优选地，所述结直肠疾病包括结直肠炎、结直肠息肉、结直肠癌、结直肠类癌；
优选地，所述结直肠疾病选自结直肠癌。
5.根据权利要求4所述的药物组合物，其特征在于，所述药物组合物通过将治疗剂或预防剂导入到靶向性外泌体中获得；
优选地，所述药物组合物还包括药学上可接受的载体。
6.一种组合物，其特征在于，所述组合物包括权利要求1或2所述的靶向性外泌体，和检测标记；
优选地，所述检测标记包括荧光蛋白、生物素、酶、标签、放射性核素、发光标记或可以通过NMR或ESR光谱法检测的化合物。
7.载药结直肠组织靶向性外泌体的制备方法，其特征在于，包括：
将用于治疗结直肠疾病的药物和权利要求1或2所述的靶向性的外泌体放入电转杯中进行电转，将电转产物离心去除游离的药物，得到纯化后靶向载药外泌体；
优选地，电转使用的电压选自50-300V；
优选地，电转使用的电压为250V。
8.权利要求1或2所述的靶向性外泌体在靶向结直肠组织中的应用。
9.权利要求1或2所述的靶向性外泌体或权利要求4-5任一项所述的药物组合物在制备治疗结直肠疾病的药物中的应用；
优选地，所述结直肠疾病包括结直肠炎、结直肠息肉、结直肠癌、结直肠类癌；
优选地，所述结直肠疾病选自结直肠癌。
10.权利要求1或2所述的靶向性外泌体或权利要求6所述的组合物在制备检测结直肠疾病的产品中的应用；
优选地，所述结直肠疾病包括结直肠炎、结直肠息肉、结直肠癌、结直肠类癌；
优选地，所述结直肠疾病选自结直肠癌。
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| CN114958722B (zh) | 2023-09-26 |
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