CN115040494B - 一种人参皂苷修饰的共载多元复合物的多功能纳米囊泡及其制备方法和应用 - Google Patents
一种人参皂苷修饰的共载多元复合物的多功能纳米囊泡及其制备方法和应用 Download PDFInfo
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Abstract
本发明公开了一种人参皂苷修饰的共载多元复合物的多功能纳米囊泡及其制备方法和应用,所述多功能纳米囊泡是由外泌体载体外壳包载纳米形式的药物内核,进一步经人参皂苷修饰所形成的。本发明材料易得且低廉、制备条件温和、操作简单,设计并成功制备的人参皂苷修饰的多功能纳米囊泡,具有高度内源性、生物安全性及高载药性,能够实现病灶部位精准靶向并高效浓集。该纳米囊泡递送系统能够实现化学治疗、光动力治疗联合免疫治疗的“多模式联合治疗”,可用于脑肿瘤等脑部疾病的协同治疗。
Description
技术领域
本发明属于纳米制剂技术领域,具体涉及一种人参皂苷修饰的共载多元复合物的多功能纳米囊泡及其制备方法和应用法。
背景技术
脑胶质瘤是中枢神经系统(central nervous system,CNS)最常见的最具侵袭性的肿瘤之一,约占成人所有恶性脑肿瘤的50%,预后差,复发率高,死亡率高。目前胶质瘤的标准治疗方式是最大限度的手术切除联合放疗和化疗。但基于生理病理屏障及脑胶质瘤复杂免疫抑制微环境的阻碍,其总体预后仍然很差,长期生存率仍然很低。胶质瘤患者的治疗效果受到多种因素的影响:①血脑屏障(blood-brain barrier,BBB)、血脑肿瘤屏障(blood-brain tumor barrier,BBTB)等生理病理屏障阻碍成像剂、治疗剂等大分子在脑部的渗透和蓄积;②胶质瘤具有高度耐药性,阻碍替莫唑胺等一线化疗药物的临床药物疗效;③脑胶质瘤免疫抑制微环境导致化疗药物预后差甚至产生耐药性;④药物水溶性差、体内半衰期短以及非靶向毒性作用仍阻碍药物治疗效果。因此亟需开发高靶向性、高安全性的新型多功能药物递送平台。
了解胶质瘤微环境的复杂结构为探索干预免疫抑制肿瘤微环境(tumormicroenvironment,TME)的联合治疗以改善胶质瘤治疗提供了前所未有的机会。受胶质瘤细胞招募肿瘤相关巨噬细胞(tumor-associated macrophages,TAMs)进入胶质瘤微环境的作用启发,将TAM从肿瘤支持性M2表型重新编程为抗肿瘤M1表型以调节免疫抑制性TME提供了诱人的胶质瘤免疫治疗策略。人参皂苷是一组天然存在的化学物质,主要从人参根中提取获得,具有悠久人类使用历史。人参皂苷Rg3作为人参的主要活性成分,具有抗氧化、抗炎、抗衰老以及抗癌等多种药理活性,在临床上得到广泛应用。此外,人参皂苷Rg3通过诱导M2巨噬细胞极化为M1表型并加速炎症消退,对TME重塑具有显著的免疫调节作用。然而,由于其在血液和胃肠道中迅速降解,且不能到达实体瘤部位,其抗肿瘤临床应用受到极大限制。
三氧化二砷(arsenic trioxide,ATO)是传统中药砒霜的主要成分,经砒石升华而得,常温下为白色粉末,性酸,热,有大毒,入脾、肺、肝经。早在20世纪70年代,就被用于治疗急性早幼粒细胞白血病(acute promyelocytic leukemia,APL)并取得了良好效果,并于2000年被美国食品药品监督管理局(FDA)批准为治疗APL的一线药。近年来的研究表明,ATO可通过诱导肿瘤细胞凋亡、自噬及影响肿瘤血管生成等发挥抗肿瘤作用,有效抑制肝癌、乳腺癌等癌细胞在体外或体内实体瘤的生长。但是,作为水溶性药物,ATO经静脉注射进入血液循环后广泛分布于血液及各脏器,肾脏清除快速,抑制了其在肿瘤部位的积累,递送效率低。因此,迫切需要开发一种新的递送策略来增加ATO在脑胶质瘤部位的蓄积,并在保持高生物相容性的同时提高其治疗效果。
光动力疗法(photodynamic therapy,PDT)是一种侵袭性小、全身毒性低、无初始耐药性的治疗方式,已经得到了临床的认可,被认为是一种很有前途的肿瘤治疗方法。PDT的机制是用特定波长的光激发定位于肿瘤的无毒光敏剂,转移能量、质子或电子以产生活性氧(reactive oxygen species,ROS)。随后,产生的ROS氧化直接导致肿瘤细胞凋亡或坏死的必需细胞大分子,从而杀死肿瘤细胞。然而,作为一种依赖于氧气的治疗方式,由于大多数实体肿瘤的乏氧微环境,PDT显示出明显的限制。
目前,单一的癌症治疗方法在临床上往往导致疗效低下和长期耐药性。例如,紫杉醇(PTX)化疗在细胞微管上起作用以抑制增殖,而不是直接杀死癌细胞,其副作用和细胞转运体的耐药性限制了其应用。通过与其他治疗方法(如化疗、光热疗法、放射疗法、免疫疗法、基因疗法等)的结合,可以进一步增强其效果,但是如何进行结合,需要进一步研究。
发明内容
发明目的:针对上述技术问题,本发明目的是提供一种人参皂苷修饰的共载多元复合物的多功能纳米囊泡,另一目的是提供一种人参皂苷修饰的共载多元复合物的多功能纳米囊泡的制备工艺,将药物活性成分进行纳米化处理,同时对天然外泌体进行表面修饰,充分利用外泌体内部载体空间,同时发挥其精准靶向病灶部位的作用,实现化疗、光动力治疗、免疫治疗的多模式治疗。
技术方案:为了达到上述发明目的,本发明所采用的技术方案如下:
一种人参皂苷修饰的共载多元复合物的多功能纳米囊泡,所述多功能纳米囊泡是由细胞来源的外泌体载体外壳包载纳米形式的药物内核,进一步经过人参皂苷修饰所形成的。
优选的,所述人参皂苷选自人参皂苷Rh2、人参皂苷Rg3、人参皂苷Rg5中的一种或几种,但不局限于这几种;所述外泌体选自血液来源、巨噬细胞来源、干细胞来源、树突细胞来源、肿瘤细胞来源中的一种或几种,但不局限于这些来源。
优选的,所述纳米形式的药物内核为白蛋白与化疗药物和/或光敏剂/成像剂构成的多元复合物。
进一步优选的,所述白蛋白选自卵清蛋白、人血清白蛋白、牛血清白蛋白、α-乳清蛋白的一种或几种,但不局限于这些物质;所述化疗药物选自三氧化二砷、紫杉醇、阿霉素、姜黄素、顺铂中的一种或几种,但不局限于这些物质;所述光敏剂/成像剂选自二氢卟吩e6、吲哚菁绿、IR780中的一种或几种,但不局限于这些物质。
所述人参皂苷修饰的共载多元复合物的多功能纳米囊泡的粒径为100-150nm。
本发明还提供了所述的人参皂苷修饰的共载多元复合物的多功能纳米囊泡的制备方法,主要包括:纳米形式的药物内核的制备,外泌体的提取及分离,纳米形式的药物内核的荷载,人参皂苷的修饰。
所述的人参皂苷修饰的共载多元复合物的多功能纳米囊泡的制备方法,包括如下步骤:
(1)制备纳米形式的药物内核;
(2)提取分离获得外泌体;
(3)将步骤(1)所得纳米形式的药物内核与步骤(2)所得外泌体混合,超声或者挤出,制得共载多元复合物内核的纳米囊泡;
(4)将步骤(3)所得共载多元复合物内核的纳米囊泡与人参皂苷溶液共孵育;
(5)除去游离药物,即得。
优选的,步骤(1)中,所述纳米形式的药物内核的制备方法,包括如下步骤:将白蛋白与活化的光敏剂/成像剂混合,搅拌,用谷胱甘肽还原后,加入化疗药物,搅拌,除游离,即得;或将白蛋白与活化的光敏剂/成像剂混合,搅拌,除游离,即得;或将白蛋白用谷胱甘肽还原,加入化疗药物,搅拌,除游离,即得。
优选的,步骤(3)中,当固体质量为mg时,液体质量以mL计,所述纳米形式的药物内核1份,外泌体1~5份,所述超声时间为5-10min。
优选的,步骤(4)中,当固体质量为mg时,液体质量以mL计,所述共载多元复合物内核的纳米囊泡1份,所述人参皂苷1~5份,所述共孵育时间为1-2h。
本发明还提供了人参皂苷修饰的共载多元复合物的多功能纳米囊泡在制备肿瘤诊断试剂或脑部疾病诊断试剂中的应用。
本发明还提供了所述人参皂苷修饰的共载多元复合物的多功能纳米囊泡在制备抗肿瘤药物或治疗脑部疾病药物中的应用。
应用时,或加生理盐水、或磷酸盐缓冲液、或5%葡萄糖溶液溶解,以静脉注射、或肌肉注射、或口服给药,该多功能仿生纳米囊泡递送平台能够实现药物的精准靶向和高效浓集,多模式治疗策略可实现化学治疗、光动力治疗与免疫治疗协同治疗,显著提高治疗效果。该多功能纳米囊泡递送平台具有独特的载体空间,能够有效负载各类药物,具有安全性高、穿透力强、靶向性高的特点,可用于肿瘤位置、形态、大小的确定或者其他脑部疾病的诊断。
本发明提供的人参皂苷修饰的共载多元复合物的多功能纳米囊泡,其中人参皂苷修饰可通过与葡萄糖转运蛋白(glucose transporters,GLUT)结合有效跨越BBB和靶向脑胶质瘤,多元复合物药物内核可赋予“多模式诊疗一体化”的潜力,使治疗效果最大化。人参皂苷Rg3含有的葡萄糖残基是GLUT的底物,BBB及胶质瘤细胞过度表达GLUT。人参皂苷Rg3的葡糖基残基为GLUT提供了完美的配体,使人参皂苷修饰的共载多元复合物的多功能纳米囊泡能够有效跨越BBB并靶向脑胶质瘤。此外,人参皂苷修饰可促进其靶向TAM并诱导TAM由促肿瘤的M2表型极化为抗肿瘤的M1表型以调节免疫抑制的TME。
本发明通过化学键将白蛋白与化疗药物、光敏剂/成像剂进行连接,制备纳米形式的多元复合物内核,并将其包载入人参皂苷修饰的外泌体中。该多功能纳米囊泡显著提高药物的包封率和载药量的同时,能够解决药物溶解性差、半衰期短的弊端,降低给药剂量,从而降低药物毒副作用,提高安全性。其次,还可以通过包载光敏剂或成像剂,实现疾病诊断及治疗一体化。
本发明通过将细胞来源的外泌体表面功能化,制备人参皂苷修饰的共载多元复合物的多功能纳米囊泡。细胞来源外泌体的表面功能化可提高该递送系统跨越BBB的能力,此外可进一步增强药物在病灶部位有效渗透和蓄积,从而改善药物穿透性差、靶向性差的递送弊端。
本发明利用化学键将化疗药物、光敏剂与白蛋白连接在一起,通过外泌体包覆及表面修饰,可有效改善单一治疗模式的治疗局限性。其具备以下优势:
(1)高生物安全性:细胞来源的外泌体具有良好的生物相容性和高度内源性,纳米形式的药物内核经包覆后,显著降低免疫原性,提高生物安全性;
(2)精准靶向性:病灶组织细胞来源的外泌体赋予该递送系统归巢效应,进一步进行人参皂苷表面功能化修饰,通过“配体-受体”特异性结合方式,使该纳米囊泡递送平台具备极强的靶向性。人参皂苷Rg3可以通过结合BBB及胶质瘤细胞过度表达的GLUT介导跨BBB转运。利用这一特点,用人参皂苷Rg3进行修饰,可以增强该纳米囊泡递送系统跨越BBB的能力;
(3)载药模式多元化:化疗药物、光敏剂/成像剂、中药活性成分,可通过不同方式包载至外泌体。该多功能纳米囊泡可同时具备疾病诊断、疾病治疗、主动靶向性等功能;
(4)高药物负载能力:外泌体的天然空腔结构为纳米形式的药物内核的负载奠定基础,药物经包载,可显著提高包封率和载药量;
(5)高效药物递送能力:药物经外泌体包载,可解决药物溶解性差、半衰期短的递送问题,可实现病灶部位高效递送和靶位浓集;
(6)治疗模式多样性:化疗药物、光敏剂及中药活性成分的共递送,可实现多模式协同治疗,包括化学疗法、光动力疗法、免疫疗法。
有益效果:与现有技术相比,本发明具有以下优势:
(1)本发明采用化学键结合的方法直接将药物、光敏剂与白蛋白相连,条件温和、操作简单、成本低廉、可实现工业化生产;
(2)本发明提供的人参皂苷修饰的共载多元复合物的多功能纳米囊泡具有归巢效应,可与病灶组织及细胞上多种特异性受体结合,实现精准靶向效果;
(3)本发明提供的人参皂苷修饰的共载多元复合物的多功能纳米囊泡能够通过选择不同功能的药物(如化疗药物可实现化疗、光敏剂可实现光动力治疗/光热治疗、成像剂可实现病灶部位诊断、中药活性成分可实现免疫治疗等)与外泌体共递送,从而实现疾病诊断、疾病治疗等不同目的,为疾病的多模式治疗提供新的研究思路;
(4)本发明提供的靶向修饰共载多元复合物的多功能纳米囊泡实现了药物的高包封率和载药量,并对其进行靶向性修饰,显著提高药物的生物安全性和主动靶向性,并实现了药物在病变部位的精准递送和靶位浓集。
本发明提供的人参皂苷修饰的共载多元复合物的多功能纳米囊泡可用于治疗作用药物(包括化疗药物、中药活性成分、光敏剂等)及成像作用药物的高效递送,该多功能纳米囊泡递送平台具有高生物安全性、精准靶向性及高负载能力。载药模式多元化使其药物选择广泛,能够同时实现肿瘤诊断及肿瘤治疗,并具备多模式协同治疗潜力,能够较好的满足临床肿瘤治疗的需要。本发明为多功能仿生型纳米囊泡递送平台在肿瘤中的应用提供了新的研究案例,具有广阔的临床转化潜力。
附图说明
图1为实施例三1.2中人参皂苷修饰的共载多元复合物的多功能纳米囊泡的形态;
图2为实施例三1.3中人参皂苷修饰的共载多元复合物的多功能纳米囊泡的紫外-可见吸收光谱图;
图3为实施例三1.4中人参皂苷修饰的共载多元复合物的多功能纳米囊泡的蛋白质印记图;
图4为实施例三1.5中人参皂苷修饰的共载多元复合物的多功能纳米囊泡的细胞内共定位图;
图5为实施例三1.6中人参皂苷修饰的共载多元复合物的多功能纳米囊泡的细胞凋亡图;
图6为实施例三1.7中人参皂苷修饰的共载多元复合物的多功能纳米囊泡的体外BBB穿透性考察图;
图7为实施例三1.8中人参皂苷修饰的共载多元复合物的多功能纳米囊泡的体外TAM极化考察图。
具体实施方式
通过以下实施例进一步对本发明进行进一步阐述。这些实施例完全是例证性的,他们仅用来对本发明进行具体描述,不应当理解为对本发明的限制。下面结合附图及实施例对发明作进一步描述:
实施例一:制备载药三元复合物内核
将0.88mg二氢卟吩e6(Ce6)、0.28mg EDC、0.18mg NHS与200μL DMSO混合,室温下搅拌1h。加入至10mL含牛血清蛋白BSA(2mg/mL)的PBS缓冲液中,磁力搅拌过夜。将溶液在14800rpm下离心5min以去除可能的聚集物,然后用超滤管(截留分子量:10kDa)超滤3次以去除游离Ce6。将溶液用60mM GSH于37℃处理1h,破坏分子内二硫键并暴露游离巯基。加入1mL ATO溶液,并用NaOH调节pH至7-8之间,于室温搅拌2h。将所得的三元复合物内核ATO@Ce6于4℃透析(截留分子量:8-14kDa)24h,以去除过量的ATO和GSH和副产物GSSG。
实施例二:提取肿瘤细胞来源的外泌体
待GL261细胞长满培养瓶底80%左右时,使用不含FBS的DMEM培养基培养GL261细胞48h。收集细胞培养液,在4℃下以300×g离心10min以除去细胞,2,000×g离心10min以除去死细胞,10,000×g离心30min以除去细胞碎片,收集上清液,并用0.22μm滤膜过滤。使用100kDa超滤管以4500rpm超滤5min。将上清加入外泌体分离试剂,轻柔混匀,于4℃条件下静置2h。然后以12,000×g于4℃下离心20min以沉淀外泌体。将外泌体沉淀物100μL PBS重悬,于-80℃保存备用。
实施例三:制备人参皂苷修饰的共载多元复合物的多功能纳米囊泡及考察性质
1.1人参皂苷修饰的共载多元复合物的多功能纳米囊泡制备
取1mL ATO@Ce6,加入200μg外泌体,冰浴超声破碎5min(功率:195W)。结束后加入10μL人参皂苷Rg3溶液(浓度:20mM),置于恒温振荡器,37℃孵育1h促进外泌体膜闭合,得Rg3-Exo/ATO@Ce6。
取上述1.1制备的Rg3-Exo/ATO@Ce6,进行如下考察:
1.2Rg3-Exo/ATO@Ce6的形态
取Rg3-Exo/ATO@Ce6 10μL滴加于铜网上,在干燥环境中静置15min,使纳米囊泡附着于铜网膜表面。用干净的滤纸小心吸去残留液体,吸取10μL 2%磷钨酸溶液滴于铜网上染色5min,用干净的滤纸吸去多余染液,室温静置晾干,通过TEM观察形貌和大小。结果如图1所示,Rg3-Exo/ATO@Ce6保留了外泌体的磷脂膜结构,呈现较为规则的椭圆形。
1.3紫外-可见(UV-vis)光谱分析
通过UV-vis分光光度计扫描含相同Ce6浓度(2μg/mL)的Ce6、BSA-Ce6、ATO@Ce6、Exo/ATO@Ce6和Rg3-Exo/ATO@Ce6溶液,测定其在紫外、可见和近红外范围内的吸收光谱,以验证Ce6的成功负载。结果如图2所示,BSA-Ce6、ATO@Ce6、Exo/ATO@Ce6和Rg3-Exo/ATO@Ce6在404nm及660nm处有2个典型的特征峰,这与游离Ce6的紫外吸收峰一致,证明Ce6与BSA的成功结合,且包载入Rg3-Exo中后其紫外吸收特性仍然保持。
1.4蛋白质印记(Western blot)表征外泌体表面CD63、CD81蛋白表达
使用Western blot法表征外泌体和Rg3-Exo/ATO@Ce6表面CD63、CD81蛋白表达。将蛋白提取液与2/5体积的5×样品上样缓冲液混匀,100℃沸水煮5min使蛋白变性,样品冷却至室温,12,000×g离心5min,取上清上样,在样品两端加入Marker。以100V恒压进行电泳,待溴酚蓝指示剂移到电泳槽底部,停止电泳,小心取出凝胶。
剪与凝胶大小相近的PVDF膜,预先在甲醇中浸泡5min以活化,纯水漂洗后放入转膜液中备用。另取两片大小适宜的滤纸,浸湿在转膜缓冲液中。在阳极板中央依次逐层放置:浸湿的海绵—滤纸—PVDF膜—待转印的凝胶—滤纸—海绵,轻轻赶走膜和胶之间的气泡后夹紧,固定后放入电泳槽。电泳槽中加入转膜缓冲液,四周放冰袋保证低温。转膜恒流200mA,2h。
将转膜后的PVDF膜置于含5%脱脂奶粉的TBST封闭液中封闭2h。封闭结束后,加入2mL一抗溶液(含1%脱脂奶粉的TBST配制,1:1000稀释),4℃孵育过夜。次日用1×TBST缓冲液洗涤膜5~6次,每次于室温缓慢摇8~10min。将膜放入装有二抗溶液(1:5000稀释)的盒内,室温缓慢摇动2h。
孵育二抗后的PVDF膜用1×TBST缓冲液洗涤5~6次,每次于室温缓慢摇8~10min。取适量的ECL发光液(等体积A、B液均匀混合),将PVDF膜沥干洗液后,靠胶的一面朝下浸入发光液中,室温放置1~2min,放入凝胶成像仪成像并拍照。
结果如图3所示,Exo与Rg3-Exo均显示CD63和CD81的蛋白条带,表明经纳米囊泡制。
1.5Rg3-Exo/ATO@Ce6的细胞内共定位
使用DiI染料标记外泌体。取10μL浓度为10mM的DiI溶液添加到200μL Exos中,于37℃孵育2h。以实施例三1.1方法制备DiI-Rg3-Exo/ATO@Ce6。取对数生长期的GL261细胞以完全培养基重悬(5×104个/mL),接种于12孔板中,每孔1mL,置于37℃,5%CO2培养。待细胞贴壁后,吸弃培养基,分别加入无血清DMEM单培稀释的DiI-Rg3-Exo/ATO@Ce6,37℃培养。4h后吸去培养基,PBS洗涤细胞3次。用4%多聚甲醛溶液固定15min,然后再用PBS洗涤3次。用含抗DAPI的封片剂封片,置于共聚焦显微镜拍摄。结果如图4所示,GL261细胞中Ce6荧光与DiI荧光的高度重合证明了DiI-Rg3-Exo/ATO@Ce6的成功制备,同时也显示了该纳米囊泡可以被GL261细胞高效摄取。
1.6细胞凋亡考察
使用Annexin V-FITC/PI凋亡试剂盒进行细胞凋亡分析。将GL261细胞以3×105个细胞/mL的密度接种于12孔板中,过夜贴壁后吸去培养液,对照孔加入无血清DMEM培养基,给药孔分别加入ATO+Ce6、ATO@Ce6、Exo/ATO@Ce6和Rg3-Exo/ATO@Ce6。对于体外PDT,将GL261细胞与不同纳米粒孵育4h后,用635nm激光(120mW/cm2,1min)照射细胞,继续培养至24h。除去培养基,将细胞用PBS洗涤3次,0.25%胰蛋白酶消化,离心收集细胞沉淀,加入500μL结合缓冲液重悬细胞,过300目尼龙网,加入5μL Annexin V-FITC染液和10μL PI染液,轻轻混合均匀,室温避光孵育10min,置于流式管中,流式细胞仪上样检测。结果如图5所示,PBS对照组在几乎没有凋亡细胞,当分别用ATO+Ce6(L)、ATO@Ce6(L)、Exo/ATO@Ce6(L)、Rg3-Exo/ATO@Ce6和Rg3-Exo/ATO@Ce6(L)处理GL261细胞时,各组均表现出明显的细胞凋亡作用。Rg3-Exo/ATO@Ce6(L)处理显示出最强的诱导细胞凋亡的能力,细胞凋亡率为(45.5±3.0)%,显著高于ATO+Ce6(L)组的(29.6±1.6)%,可能原因是Rg3-Exo包载增加了GL261细胞对ATO和Ce6的摄取,同时PDT效应通过诱导ICD介导强烈的免疫激活,联合外泌体共同促进免疫反应。
1.7体外BBB穿透性考察
使用Transwell培养体系建立体外BBB模型。将bEnd.3细胞以5×104个/孔的密度接种于24孔Transwell培养板上室。使用细胞电阻仪测定并监控跨细胞电阻,当细胞单层跨细胞电阻达到200Ω·cm2时方可进行后续实验。对于构建成功的Transwell孔,分别加入含Ce6、ATO@Ce6、Exo/ATO@Ce6或Rg3-Exo/ATO@Ce6(Ce6浓度2μg/mL)的无血清培养基,于给药后0.5、1、2、4、6、8、12、24h在下室中吸取样品100μL,并及时补充等量新鲜介质。取样结束后,通过酶标仪测定样品中Ce6的荧光强度,并通过公式(1-1)计算纳米粒的透过率。
透过率(%)=跨细胞单层的纳米囊泡累积量/纳米囊泡初始量×100%(1-1)
结果如图6所示,Rg3-Exo/ATO@Ce6的转运率为(32.86±1.90)%,显著高于用游离Ce6、ATO@Ce6或Exo/ATO@Ce6处理的转运率,分别为(10.38±2.13)%、(26.39±0.71)%和(27.89±1.36)%,表明Rg3-Exo/ATO@Ce6可以更有效地穿过BBB。BBB过度表达GLUT,人参皂苷Rg3的亲水糖苷链中的葡萄糖残基是GLUT的底物,为GLUT提供了完美的配体,使Rg3-Exo/ATO@Ce6能够有效跨越BBB。
1.8体外TAM极化考察
在Transwell细胞培养板建立GL261细胞与M2巨噬细胞共培养模型,评估给药后M2表型巨噬细胞极化情况。将GL261细胞以1×105细胞/孔的密度接种于Transwell板上室,M2细胞以1×105细胞/孔的密度接种于下室。共培养12h后,将游离Ce6、Rg3、ATO@Ce6、Exo/ATO@Ce6或Rg3-Exo/ATO@Ce6(相当于Ce6 2μg/mL、Rg3 20μg/mL)添加到上室,培养24h,未经处理的巨噬细胞用作对照。对于体外PDT,将GL261细胞与不同纳米粒孵育4h后,用635nm激光(120mW/cm2,1min)照射细胞,继续培养至24h。收集TAM(包括M1和M2表型),用冷PBS洗涤三次,并与FITC-F4/80抗体、PE-CD206抗体、PE/Cy7-CD86抗体孵育,标记M2和M1细胞。随后,通过流式细胞术分析细胞。根据图7可知,Rg3-Exo/ATO@Ce6(L)给药组,M2型巨噬细胞显著减少,M1型巨噬细胞显著增多,表明人参皂苷Rg3修饰的纳米囊泡可有效促进促肿瘤的M2巨噬细胞极化为抗肿瘤的M1型。
Claims (7)
1.一种人参皂苷修饰的共载多元复合物的多功能纳米囊泡,其特征在于,所述多功能纳米囊泡是由外泌体载体外壳包载纳米形式的药物内核,进一步经人参皂苷修饰所形成的;所述人参皂苷选自人参皂苷Rh2、人参皂苷Rg3、人参皂苷Rg5中的一种或几种;所述外泌体选自血液来源、巨噬细胞来源、干细胞来源、树突细胞来源、肿瘤细胞来源中的一种或几种;所述纳米形式的药物内核为白蛋白与化疗药物和/或光敏剂/成像剂构成的多元复合物,所述白蛋白选自卵清蛋白、人血清白蛋白、牛血清白蛋白、α-乳清蛋白的一种或几种;所述化疗药物选自三氧化二砷、紫杉醇、阿霉素、姜黄素、顺铂中的一种或几种;所述光敏剂/成像剂选自二氢卟吩e6、吲哚菁绿、IR780中的一种或几种;所述人参皂苷修饰的共载多元复合物的多功能纳米囊泡的制备方法,包括以下步骤:
(1)制备纳米形式的药物内核;
(2)提取分离获得外泌体;
(3)将步骤(1)所得纳米形式的药物内核与步骤(2)所得外泌体混合,超声或挤出,制得共载多元复合物内核的纳米囊泡;
(4)将步骤(3)所得共载多元复合物内核的纳米囊泡与人参皂苷溶液共孵育;
(5)除去游离药物,即得。
2.权利要求1所述的人参皂苷修饰的共载多元复合物的多功能纳米囊泡的制备方法,其特征在于,包括如下步骤:
(1)制备纳米形式的药物内核;
(2)提取分离获得外泌体;
(3)将步骤(1)所得纳米形式的药物内核与步骤(2)所得外泌体混合,超声或挤出,制得共载多元复合物内核的纳米囊泡;
(4)将步骤(3)所得共载多元复合物内核的纳米囊泡与人参皂苷溶液共孵育;
(5)除去游离药物,即得。
3.根据权利要求2所述的靶向修饰共载多元复合物的多功能纳米囊泡的制备方法,其特征在于,步骤(1)中,所述纳米形式的药物内核的制备方法,包括如下步骤:将白蛋白与活化的光敏剂/成像剂混合,搅拌,用谷胱甘肽还原后,加入化疗药物,搅拌,除游离,即得;或将白蛋白与活化的光敏剂/成像剂混合,搅拌,除游离,即得;或将白蛋白用谷胱甘肽还原,加入化疗药物,搅拌,除游离,即得。
4.根据权利要求2所述的靶向修饰共载多元复合物的多功能纳米囊泡的制备方法,其特征在于,步骤(3)中,当固体质量为mg时,液体质量以mL计,所述纳米形式的药物内核1份,外泌体1~5份,所述超声时间为5-10min。
5.根据权利要求2所述的人参皂苷修饰的共载多元复合物的多功能纳米囊泡的制备方法,其特征在于,步骤(4)中,当固体质量为mg时,液体质量以mL计,所述共载多元复合物内核的纳米囊泡1份,所述人参皂苷1~5份,所述共孵育时间为1-2h。
6.权利要求1所述的人参皂苷修饰的共载多元复合物的多功能纳米囊泡在制备肿瘤诊断试剂或脑部疾病诊断试剂中的应用。
7.权利要求1所述的人参皂苷修饰的共载多元复合物的多功能纳米囊泡在制备抗肿瘤药物或治疗脑部疾病药物中的应用。
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Citations (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN105708847A (zh) * | 2016-02-02 | 2016-06-29 | 成都大学 | 人参皂苷多组分共载靶向纳米体系的制备方法及其应用 |
KR20180005546A (ko) * | 2016-07-06 | 2018-01-16 | 인천대학교 산학협력단 | 약물이 탑재된 엑소좀 또는 나노베지클을 이용한 약학적 조성물 |
CN112168973A (zh) * | 2019-07-05 | 2021-01-05 | 中国科学院苏州纳米技术与纳米仿生研究所 | 核酸适配体递送载体,其制备方法及其应用 |
CN112933113A (zh) * | 2021-02-24 | 2021-06-11 | 江南大学附属医院 | 一种免疫增强型外泌体水凝胶复合物及其制备方法和应用 |
CN113616811A (zh) * | 2021-08-18 | 2021-11-09 | 南京中医药大学 | 一种载脂蛋白修饰的融合型多功能纳米囊泡及其制备方法和应用 |
CN113908293A (zh) * | 2021-10-15 | 2022-01-11 | 南京中医药大学 | 一种靶向肽修饰的中药多组分“外泌体样”融合纳米粒及其制备方法和应用 |
CN114376986A (zh) * | 2022-02-25 | 2022-04-22 | 南京中医药大学 | 一种同源重组外泌体多药递送的仿生纳米粒及其制备方法和应用 |
CN114558146A (zh) * | 2022-03-01 | 2022-05-31 | 南京中医药大学 | 一种荷载中药自组装胶束的“免疫外泌体”纳米粒及其制备方法和应用 |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101485629B (zh) * | 2008-01-16 | 2013-01-23 | 沈阳药科大学 | 一种给药系统及其制备方法 |
KR101720851B1 (ko) * | 2015-01-29 | 2017-03-28 | 포항공과대학교 산학협력단 | 세포의 지질막에서 유래된 나노소포체 및 이의 용도 |
-
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- 2022-06-01 CN CN202210614250.9A patent/CN115040494B/zh active Active
Patent Citations (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN105708847A (zh) * | 2016-02-02 | 2016-06-29 | 成都大学 | 人参皂苷多组分共载靶向纳米体系的制备方法及其应用 |
KR20180005546A (ko) * | 2016-07-06 | 2018-01-16 | 인천대학교 산학협력단 | 약물이 탑재된 엑소좀 또는 나노베지클을 이용한 약학적 조성물 |
CN112168973A (zh) * | 2019-07-05 | 2021-01-05 | 中国科学院苏州纳米技术与纳米仿生研究所 | 核酸适配体递送载体,其制备方法及其应用 |
CN112933113A (zh) * | 2021-02-24 | 2021-06-11 | 江南大学附属医院 | 一种免疫增强型外泌体水凝胶复合物及其制备方法和应用 |
CN113616811A (zh) * | 2021-08-18 | 2021-11-09 | 南京中医药大学 | 一种载脂蛋白修饰的融合型多功能纳米囊泡及其制备方法和应用 |
CN113908293A (zh) * | 2021-10-15 | 2022-01-11 | 南京中医药大学 | 一种靶向肽修饰的中药多组分“外泌体样”融合纳米粒及其制备方法和应用 |
CN114376986A (zh) * | 2022-02-25 | 2022-04-22 | 南京中医药大学 | 一种同源重组外泌体多药递送的仿生纳米粒及其制备方法和应用 |
CN114558146A (zh) * | 2022-03-01 | 2022-05-31 | 南京中医药大学 | 一种荷载中药自组装胶束的“免疫外泌体”纳米粒及其制备方法和应用 |
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