CN115487295A - 一种抗术后肿瘤复发的免疫辅助贴片及其制备方法 - Google Patents
一种抗术后肿瘤复发的免疫辅助贴片及其制备方法 Download PDFInfo
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Abstract
本发明公开了一种抗术后肿瘤复发的免疫辅助贴片及其制备方法。该贴片以亲水性壳聚糖为基质,免疫活性组分与基质溶解分散混合均匀后置于模具内凝固成型而成;所述免疫活性组分为免疫抗体和免疫佐剂。本发明制备的免疫辅助贴片,借助亲水性医用壳聚糖,静电吸附带正电且具备酸调控特性和抗肿瘤免疫佐剂特性的LDHs功能纳米材料,静电吸附携带丰富氨基且能够逆转肿瘤免疫抑制的治疗性抗体,最终组装成伤口生理条件下可解体的生物功能贴片。本发明具备应用安全、性能优异的特点,有望作为新型术后免疫辅助方案,推动肿瘤治愈并惠及患者,改善术后患者的长期生存率和生存质量。
Description
技术领域
本发明属于生物功能材料技术领域,具体涉及一种抗术后肿瘤复发的免疫辅助贴片及其制备方法。
背景技术
外科手术是多数实体肿瘤患者的主要治疗方案。根据2015年柳叶刀肿瘤委员会的统计,全球超过80%的癌症患者需要手术治疗;最新的“2018与2040”年度对比推测模型显示,截止到2040年,这一需求将继续增长52%。然而,仅依靠手术难以彻底清除体内癌细胞。术后的伤口自然愈合又会迫使周边进入免疫抑制状态。该状态容易激发残存癌细胞生长扩散,同时压制抗癌细胞(譬如,细胞毒性T淋巴细胞,自然杀手细胞以及抗原呈递细胞等)活性,致使患者五年内疾病复发转移情况严重。
自然状态的术后伤口微环境中,免疫系统会优先修复手术创伤。这种选择性行为迫使术后伤口快速聚集大量M2表型巨噬细胞(又称为M2-TAMs)。M2-TAMs属于免疫抑制型细胞,能够刺激血管再生,促进癌细胞对外迁移、侵袭或向血管内游走,从而压制机体抵御癌细胞功能,加速癌症发生和恶化蔓延。最近的研究发现,肿瘤酸性微环境对巨噬细胞M2表型极化负主要责任。中和手术伤口的微酸环境,被证实能够重塑创伤内巨噬细胞为免疫刺激型(M1-TAMs),攻击残存癌细胞,显著抑制肿瘤复发。
但不容忽视的是,除了免疫抑制性手术伤口,淋巴系统对促进残余癌细胞的存活、转移同样“功不可没”,现阶段的术后研究未曾重视此关键问题的解决。大量研究证实,相比于直接的血液转移,癌细胞更倾向于通过附近引流淋巴结进行远程侵袭。这是因为与血液环境不同,引流淋巴结内铁离子含量低且油脂类物质丰富,癌细胞能够在此相对安全的环境中适应性地提高抗氧化能力,武装自身对抗血液铁死亡。另外在发生转移前,癌细胞会优先借助周边引流淋巴管对淋巴结内抗肿瘤杀伤性T细胞、抗原呈递细胞等进行免疫抑制,确保自身安全进入并实现系统转移。
发明内容
鉴于手术难以彻底清除病患体内癌细胞,且术后伤口会抑制机体抗癌免疫反应,协同引流淋巴结促进残留癌细胞的增殖和转移,本发明提供一种免疫辅助贴片及其制备方法,该贴片可应用于术后伤口,响应创口微环境并缓慢可持续性释放免疫治疗组分。释放的免疫抗体和免疫佐剂利用高效协同作用,重塑手术伤口,抑制创伤引发的促癌效应;与此同时,两者凭借尺寸优势,借助肿瘤与引流淋巴结之间的网络连接,富集于引流淋巴结,充分激活内部丰富抗肿瘤免疫细胞,清除残留癌细胞,唤醒机体抗肿瘤长效免疫记忆,有效预防术后肿瘤复发。
所述的抗术后肿瘤复发的免疫辅助贴片以亲水性壳聚糖为基质,免疫活性组分与基质溶解分散混合均匀后置于模具内凝固成型而成;所述免疫活性组分为免疫抗体和免疫佐剂。
所述的亲水性壳聚糖为羧化壳聚糖、羧甲基壳聚糖、甲基丙烯酰化羧甲基壳聚糖中的一种或几种。
所述的免疫佐剂为水滑石,其粒径小于100nm。所述水滑石的层板中的二价金属离子为镁离子、钙离子、锰离子、镍离子、铜离子、锌离子中的一种或几种,三价金属离子为铁离子、铝离子、钴离子中的一种或几种,二价金属离子和三价金属离子的摩尔比为1-20:1。
所述的免疫抗体和免疫佐剂,与亲水性壳聚糖的摩尔比均为1-20:1。
所述凝固成型的具体条件为:4-60℃真空干燥1-24h。
所述免疫抗体为抗程序性死亡蛋白-1抗体、抗程序性死亡配体-1抗体、抗细胞毒性T淋巴细胞相关抗原4抗体、抗淋巴细胞激活基因3抗体、抗T细胞免疫球蛋白黏蛋白3抗体、抗CD47抗体、和抗NKG2A抗体中的一种或几种。
所述免疫佐剂的制备方法为:将二价金属硝酸盐和三价金属硝酸盐按摩尔比1-20:1配制混合金属盐溶液,然后将混合金属盐溶液与氢氧化钠水溶液快速混合沉淀成核,20-200℃晶化反应5min-24h,最后4,000-15,000rpm离心洗涤,沉淀分散于去离子水中即得。
所述二价金属硝酸盐和三价金属硝酸盐的摩尔数之和与氢氧化钠的摩尔比为1:1-100。
上述的免疫辅助贴片在制备抗术后肿瘤复发的免疫辅助贴片中的应用。
本发明制备的免疫辅助贴片,借助亲水性的医用壳聚糖,静电吸附带正电且具备酸调控特性和抗肿瘤免疫佐剂特性的LDHs功能纳米材料,静电吸附携带丰富氨基且能够逆转肿瘤免疫抑制的治疗性抗体,最终组装成伤口生理条件下可解体的生物功能贴片。原位植入贴片于术后伤口处,释放的免疫抗体可以进入肿瘤引流淋巴结,恢复免疫抑制型杀伤T细胞的功能;释放的LDHs免疫佐剂可以对伤口微酸条件进行调变,逆转肿瘤手术创伤从免疫抑制至免疫刺激状态,亦可游走于肿瘤引流淋巴结,辅助免疫抗体,增强抗肿瘤免疫效果。本发明的免疫辅助贴片的设计,旨在维护并提升病患自身抗癌免疫功能,引发强有力的长期抗癌效应,借助病患自身免疫激活对抗残余癌细胞,抑制肿瘤复发。本发明具备应用安全、性能优异的特点,有望作为新型术后免疫辅助方案,推动肿瘤治愈并惠及患者,改善术后患者的长期生存率和生存质量。
附图说明
图1:抗术后肿瘤复发的免疫辅助贴片结构示意图(a);小鼠模型中,贴片作用于肿瘤切除后伤口部位的示意图(b)。
图2:小鼠模型中,贴片作用位点,肿瘤引流淋巴结和对侧淋巴结位置示意图(a);贴片贴附于术后伤口后,不同时段的肿瘤引流淋巴结和对侧淋巴结内,贴片负载的免疫活性组分富集量(b)和富集荧光图(c)。
图3:贴片免疫辅助的第5天,伤口微环境内巨噬细胞的PD-1表达(a,d),CD206表达(b,e),以及CD80和CD86的共表达情况(c,f)。其中,Untreated组:肿瘤切除后,未进行任何后续治疗;CC组:肿瘤切除后,伤口处贴附纯壳聚糖基质;aPD-1@CC组:肿瘤切除后,伤口处贴附仅包含PD-1抗体活性组分的贴片;LDH@aPD-1@CC组:肿瘤切除后,伤口处贴附包含PD-1抗体和LDHs免疫佐剂活性组分的贴片。
图4:贴片免疫辅助的第5天和第30天,肿瘤引流淋巴结内肿瘤特异性杀伤T细胞水平(a,b),杀伤T细胞的增殖水平(c)和毒性蛋白表达水平(d)。其中,小鼠分组情况见图3说明。
图5:贴片免疫辅助的第30天,肿瘤引流淋巴结内谷胱甘肽(GSH,a),氧化性谷胱甘肽(GSSG,b)以及两者的比率(c);贴片免疫辅助的第5天和第30天,肿瘤引流淋巴结内调节型T细胞水平(d)。其中,小鼠分组情况见图3说明。
图6:贴片免疫辅助作用后,各组小鼠的肿瘤复发情况(a,b)和小鼠存活率(c)。其中,小鼠分组情况见图3说明。
图7:收集图6实验中未复发小鼠进行同类肿瘤细胞二次种植,判断小鼠的肿瘤特异性免疫效果(a,b)。其中,小鼠分组情况见图3说明。
具体实施方式
为确保本发明的目的、技术方案和技术独特性等更加清晰明了,发明人结合具体实施例对本发明内容进行详细阐述。所描述的实施例仅包含本发明的部分实施例,而非全部。基于本发明中的实施例,本领域普通技术人员在没有做出创造性劳动的前提下所得到的所有其它实施方式,都属于本发明所保护的范围。
实施例1
将4mmol硝酸镁和1mmol硝酸铁溶解于5ml去离子水中,得到混合盐溶液A。将溶液A快速倒入20ml的氢氧化钠水溶液中(含10mmol氢氧化钠),得到混合悬浮液B。室温下快速搅拌悬浮液B半小时后,得到浅棕色沉淀。用大量去离子水反复离心洗涤沉淀物,离心条件为5,000rpm,5min。将得到的沉淀分散于20ml去离子水中,得到浓度为15mg/ml的LDHs纳米粒子水溶液,即为免疫佐剂水溶液。测定获得的LDHs呈六方片结构,直径为20~40nm,所带电荷为30~38mV。
免疫辅助贴片制备:将商用羧酸化壳聚糖(CC)溶解于去离子水中,制备浓度为60mg/ml的CC水溶液。选取细胞实验所需的48孔板盖子为贴片制备模板。超声混匀200μl的免疫佐剂水溶液、50μg PD-1抗体和100μl的CC水溶液后,滴定于盖板孔内,40℃条件下真空干燥1h,得到直径为10mm的携带PD-1抗体和LDHs纳米粒子的贴片(LDH@aPD-1@CC),其最终形貌和所含组分如图1a所示。
对比例1
与实施例1中贴片制备方法相同,不添加免疫佐剂水溶液和PD-1,得到直径为10mm的圆形CC贴片。
对比例2
与实施例1中贴片制备方法相同,不添加免疫佐剂水溶液,得到直径为10mm的携带PD-1抗体的贴片(aPD-1@CC)。
应用例1
为建立原位乳腺癌模型,2×106个鼠源4T1乳腺癌细胞种植于BALB/c母系小鼠的右侧第四个乳房内。监测肿瘤生长情况,肿瘤体积计算方式为4/3π×(x/2)^2×(y/2),其中x为肿瘤长度,y为垂直于x的肿瘤宽度。若无特殊说明,肿瘤长度达到2cm的小鼠须被执行安乐死。
贴片作用手术执行于肿瘤生长至约500mm3时段。如图1b所示,麻醉小鼠后手术切除乳腺肿瘤,原位贴合实施例1中的LDH@aPD-1@CC贴片,免疫辅助贴片能够与术后伤口完美贴合。
实施例2
将荧光标记的多肽插入LDHs纳米粒子层间,能够实现LDHs标记,追踪贴片在小鼠机体解体后释放的LDHs去向。选取1mg携带荧光团Cyanine-5.5的多肽SPSYVYHQF,溶解于100μl的DMSO溶液中。将得到的荧光肽溶液分散于2ml实施例1制备的LDHs纳米粒子水溶液中,经过1h的搅拌反应,荧光肽能够插入LDHs层间,得到LDH-Cy5.5纳米粒子。反复离心(10,000rpm,5min)、洗涤后,分散所得颗粒于去离子水中,得到15mg/ml的LDH-Cy5.5纳米粒子水溶液。
如实施例1所示方法,替换LDH为LDH-Cy5.5,得到LDH-Cy5.5@aPD-1@CC贴片。
如应用例1所示方法,术后伤口原位贴合LDH-Cy5.5@aPD-1@CC贴片。贴片作用前和贴片作用后第1,2,4,8,12,24,36天,分别收取小鼠的右侧第四个肿瘤引流淋巴结和相应对侧淋巴结(图2a,每个时间点分别有4只小鼠)。消化处理后,用ICP-MS测定淋巴结内Fe含量。贴片作用后第一周,手术剖开小鼠,荧光成像监测第四个肿瘤引流淋巴结内LDHs富集情况。贴片作用后第五周,手术剖开小鼠,荧光成像监测位于第四个肿瘤引流淋巴结对侧的淋巴结内LDHs富集情况。结果如图2b和2c所示,贴片作用后第一周,贴片释放的活性组分在肿瘤引流淋巴结内富集。第五周后,部分活性组分游走进入远程对侧淋巴结。分析实施例3内实验结果,贴片释放的活性组分能够进入周边引流淋巴结。
应用例2
如应用例1所示方法手术切除肿瘤,同时留下1‰(w/w)的肿瘤于术后部位,用于模拟术后残余。将术后小鼠分为4组,每组5只。第一组术后不进行任何处理,标记为Untreated;第二组术后伤口贴合CC贴片;第三组术后伤口贴合aPD-1@CC贴片;第四组术后伤口贴合LDH@aPD-1@CC贴片。
术后第5天,收取各组小鼠术后区域组织,消化处理后得到单分散细胞。荧光抗体染色标记后,借助流式细胞仪分析术后伤口处巨噬细胞的表型分化情况。结果如图3a,3b,3d和3e所示,未经任何处理、或CC贴片处理的术后伤口,巨噬细胞(TAMs)显示高表达的PD-1和CD206。这两者属于典型的免疫抑制型M2-TAMs的特征。经aPD-1@CC贴片处理后,释放的PD-1抗体能够靶向M2-TAMs表面的PD-1,缓解其免疫抑制特性(即降低CD206表达)。经LDH@aPD-1@CC贴片治疗后,M2-TAMs表面的PD-1和CD206水平进一步显著下调。结合图3c和3f的结果,LDH@aPD-1@CC贴片致使TAMs表面CD80和CD86显著提升(这两者属于典型的免疫促进型M1-TAMs的特征),我们可以得出结论:LDH@aPD-1@CC贴片逆转了术后伤口的M2-TAMs变为M1-TAMs,重塑巨噬细胞发挥抗肿瘤功效。
应用例3
如应用例1所示方法手术切除肿瘤,同时留下1‰(w/w)的肿瘤于术后部位,用于模拟术后残余。将术后小鼠分为4组,每组10只。第一组术后不进行任何处理,标记为Untreated;第二组术后伤口贴合CC贴片;第三组术后伤口贴合aPD-1@CC贴片;第四组术后伤口贴合LDH@aPD-1@CC贴片。
术后第5天和第30天,分别在各组小鼠随机抽取5只,收集各自肿瘤引流淋巴结,消化处理后得到单分散细胞。荧光抗体染色标记后,借助流式细胞仪分析淋巴结内CD8T细胞刺激结果。如图4a和4b所示,在aPD-1@CC或LDH@aPD-1@CC贴片作用下,术后第5天,肿瘤特异性CD8+T细胞(SPSYVYHQF-pentamer+CD8+T)比例显著上升。且相比单纯的PD-1抗体治疗,LDHs免疫佐剂的加持进一步将肿瘤特异性CD8+T细胞的含量提升至原来的三倍。术后第30天,上述显著的提升特征消失,这是由于激活的肿瘤特异性CD8+T细胞能够在短时间内彻底清除机体残余癌细胞。清除结束后,这些功能细胞就会功成身退。这些推测能够通过测定CD8+T细胞的增殖(Ki67)以及毒性蛋白(GzmB)的表达水平得以证实。如图4c和4d所示,LDH@aPD-1@CC贴片作用下,对比术后第5天和第30天结果,CD8+T细胞在前者显示出更高的Ki67+和GzmB+水平。
应用例4
如应用例1所示方法手术切除肿瘤,同时留下1‰(w/w)的肿瘤于术后部位,用于模拟术后残余。将术后小鼠分为4组,每组15只。第一组术后不进行任何处理,标记为Untreated;第二组术后伤口贴合CC贴片;第三组术后伤口贴合aPD-1@CC贴片;第四组术后伤口贴合LDH@aPD-1@CC贴片。
术后第30天,分别在各组小鼠随机抽取5只,收集各自肿瘤引流淋巴结放置于冰上,低温保护并超声打散,借助谷胱甘肽(GSH)试剂盒测定淋巴结内GSH和GSSG(氧化性谷胱甘肽)水平。结果如图5a-5c所示,贴片内LDHs免疫佐剂的存在能够氧化部分GSH为GSSG,下调GSH/GSSG比率,提升淋巴结内氧化压。这种变化能够下调引流淋巴结内免疫抑制性调节T细胞(Foxp3+CD4+T)。
术后第5天和第30天,分别在各组小鼠随机抽取5只,收集各自肿瘤引流淋巴结,消化处理后得到单分散细胞。荧光抗体染色标记后,借助流式细胞仪分析淋巴结内Foxp3+CD4+T细胞水平。结果如图5d所示,相比于PD-1抗体对Foxp3+CD4+T细胞的温和作用,LDHs免疫佐剂显示出更强效的下调功能。
应用例5
如应用例1所示方法手术切除肿瘤,同时留下1‰(w/w)的肿瘤于术后部位,用于模拟术后残余。将术后小鼠分为4组,每组6只。第一组术后不进行任何处理,标记为Untreated;第二组术后伤口贴合CC贴片;第三组术后伤口贴合aPD-1@CC贴片;第四组术后伤口贴合LDH@aPD-1@CC贴片。
监测不同小组内小鼠的肿瘤复发情况。结果如图6所示,术后40天内,未经任何处理或CC贴片处理的小鼠肿瘤复发情况严重;PD-1抗体的作用能够抑制50%的小鼠复发;而LDH@aPD-1@CC贴片显示出最佳的术后抑制效果,6只小鼠中仅有1只复发,其余全部治愈。
应用例6
收集应用例5中的各组治愈/未复发小鼠进行二次肿瘤种植(第二组共1只,第三组共3只,第四组共5只),评估小鼠机体的肿瘤特异性免疫激活情况。与之前不同,2×106个鼠源4T1乳腺癌细胞种植于BALB/c母系小鼠的左侧第四个乳房内。监测肿瘤生长情况,肿瘤体积计算方式为4/3π×(x/2)^2×(y/2),其中x为肿瘤长度,y为垂直于x的肿瘤宽度。若无特殊说明,肿瘤长度达到2cm的小鼠须被执行安乐死。
监测不同小组内小鼠的肿瘤生长情况。结果如图7所示,肿瘤种植后80天内,仅有经LDH@aPD-1@CC贴片治疗的小鼠显示出顽强的肿瘤特异性免疫活性,60%的小鼠成功抵抗了机体的肿瘤细胞生长,实现肿瘤预防。结合实施例7的肿瘤复发抑制疗效,本发明贴片高效地显示出设计之初提议的术后肿瘤“防+治”目标。
最后需要补充说明的是,上述实施例仅用以说明本发明的技术方案,而非对本发明保护范围的限制。尽管参照较佳实施例对本发明作了详细地说明,本领域的普通技术人员应当理解,可以对本发明的技术方案进行修改或者等同替换,而不脱离本发明技术方案的实质和范围。
Claims (8)
1.一种免疫辅助贴片,其特征在于,该贴片以亲水性壳聚糖为基质,免疫活性组分与基质溶解分散混合均匀后置于模具内凝固成型而成;所述免疫活性组分为免疫抗体和免疫佐剂。
2.根据权利要求1所述的免疫辅助贴片,其特征在于,所述的亲水性壳聚糖为羧化壳聚糖、羧甲基壳聚糖、甲基丙烯酰化羧甲基壳聚糖中的一种或几种。
3.根据权利要求1所述的免疫辅助贴片,其特征在于,所述的免疫佐剂为水滑石,其粒径小于100nm。
4.根据权利要求1所述的免疫辅助贴片,其特征在于,所述的免疫抗体和免疫佐剂,与亲水性壳聚糖的摩尔比均为1-20:1。
5.根据权利要求1所述的免疫辅助贴片,其特征在于,所述凝固成型的具体条件为:4-60℃真空干燥1-24h。
6.根据权利要求1所述的免疫辅助贴片,其特征在于,所述免疫抗体为抗程序性死亡蛋白-1抗体、抗程序性死亡配体-1抗体、抗细胞毒性T淋巴细胞相关抗原4抗体、抗淋巴细胞激活基因3抗体、抗T细胞免疫球蛋白黏蛋白3抗体、抗CD47抗体、和抗NKG2A抗体中的一种或几种。
7.根据权利要求3所述的免疫辅助贴片,其特征在于,所述水滑石的层板中的二价金属离子为镁离子、钙离子、锰离子、镍离子、铜离子、锌离子中的一种或几种,三价金属离子为铁离子、铝离子、钴离子中的一种或几种,二价金属离子和三价金属离子的摩尔比为1-20:1。
8.根据权利要求1-7任一项所述的免疫辅助贴片作为抗术后肿瘤复发的免疫辅助贴片的应用。
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