CN117442552B - 一种淋巴结内t细胞区靶向纳米粒及其水凝胶 - Google Patents
一种淋巴结内t细胞区靶向纳米粒及其水凝胶 Download PDFInfo
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Abstract
本发明属于生物与医药领域、mRNA递送和药物制剂技术领域,具体涉及一种淋巴结内T细胞区靶向纳米粒及其水凝胶。一种纳米粒MC‑Lip,包括空白纳米粒和CC趋化因子受体7 mRNA。一种水凝胶,包括空白水凝胶,树突状细胞招募因子,肿瘤抗原诱导剂和树突状细胞重编程剂,所述树突状细胞招募因子为粒细胞‑巨噬细胞集落刺激因子,所述肿瘤抗原诱导剂为活性成分为光动力药物Ce6的脂质体,所述树突状细胞重编程剂为纳米粒MC‑Lip。并进一步指明了纳米粒MC‑Lip及其水凝胶在淋巴结T区药物递送中的应用以及在制备抗肿瘤免疫药物中的应用。
Description
技术领域
本发明属于生物与医药领域、mRNA递送和药物制剂技术领域,具体涉及一种淋巴结内T细胞区靶向纳米粒及其水凝胶。
背景技术
公开该背景技术部分的信息仅仅旨在增加对本发明的总体背景的理解,而不必然被视为承认或以任何形式暗示该信息构成已经成为本领域一般技术人员所公知的现有技术。
免疫疗法已成为人类对抗肿瘤的新希望,正在引发一场深刻的医学革命。基于T细胞的免疫疗法是抗肿瘤免疫治疗的主流。有效活化T细胞是提高抗肿瘤免疫疗效的关键。然而,T细胞在体内分布不均匀,主要分布在淋巴结的皮层旁,难以通过传统的给药系统实现足够的免疫活性药物蓄积和有效的T细胞活化。
有效的淋巴结内部T细胞区药物蓄积需要实现以下条件:①药物/粒子经过给药后实现淋巴结趋向性蓄积,通过输入淋巴管实现在淋巴结囊下窦外部的足量蓄积,这要求药物/粒子要>20 KDa或10-100 nm. ②药物/粒子需要穿过囊下窦屏障,这要求药物/粒子需<70 KDa才能穿过囊下窦屏障进入淋巴结皮质区域。③药物/粒子需穿过皮质区的导管才可能到达淋巴结T细胞区域,这要求药物/粒子需<70 KDa或3-5 nm。因此,复杂的生理屏障和严格的粒径要求限制了基于淋巴结T细胞药物递送应用。
尽管目前多数研究聚焦于通过调控纳米递送系统的物理化学性质以期实现更多的淋巴结蓄积进而调控免疫疗效,但是很少有研究探索基于淋巴结内部免疫细胞药物的精准递送。2020年《Nature Nanotechnology》杂志报道,通过借助于可编程可降解的化学键的断裂来克服淋巴和淋巴结内运输障碍,实现淋巴结内部药物递送,但是这对药物的结构和性质提出了严格的要求,需要具备相应官能团实现和载体的化学键连接。开发具备普适性的淋巴结T区域药物递送系统将会填补当前淋巴结内部T细胞区药物递送的空白。通过开发普适性的淋巴结T区域药物递送系统,可以实现免疫活性药物等的淋巴结T细胞精准递送及提高免疫治疗疗效,降低患者免疫毒副作用,促进免疫疗法进展。
发明内容
鉴于传统纳米药物递送系统在淋巴结T细胞区递送中的层层屏障,受T细胞启动反应过程启发,我们发现抗原递呈细胞如树突状细胞(DC细胞)是一种天然的能够实现淋巴结T细胞区药物递送的“载体”。DC细胞的淋巴结迁移受到CC趋化因子受体 7(CCR7)/ CC趋化因子配体21(CCL21)轴的调控。具体而言,CCR7+DC细胞在淋巴管末端分泌的CCL21的趋化作用下,进入输入淋巴管,随后被动运输至囊下窦。在囊下窦部位,CCL21被囊下窦部位淋巴内皮细胞分泌的非典型趋化因子受体4(ACKR4)清除,形成向淋巴结内T细胞区方向的CCL21梯度,使CCR7+DCs有效迁移到淋巴结内的T细胞区。传统的疫苗或其他手段能够一定程度促进DC成熟,上调CCR7表达,从而实现淋巴结T细胞区递送,但仅通过诱导DC成熟其CCR7的表达是有限的。利用CCR7 mRNA编辑DC细胞将会有效保障CCR7在DC细胞上的表达,进而保证T细胞区域精准递送。
因此,开发了一种淋巴结内T细胞区靶向纳米粒及其水凝胶,来实现体内编辑DC细胞的药物递送。制备共载DC细胞招募因子粒细胞-巨噬细胞集落刺激因子(GM-CSF)、甘露糖(Mannose,Man)修饰的DC靶向重编辑纳米粒Man-CCR7 mRNA-Liposome(MC-Lip)和肿瘤抗原诱导剂Ce6-Liposome(Ce6-Lip)的水凝胶,瘤周注射后可以在GM-CSF的作用下实现DC的招募,然后MC-Lip可以靶向DC细胞并将其编辑为CCR7+DC细胞,同时Ce6-Lip能够在激光照射下促进肿瘤抗原产生,一定程度诱导DC细胞上CCR7的表达并促进CCR7+DC细胞的抗原递呈。所获得的携带抗原信息的CCR7+DC细胞可以实现淋巴结T细胞区精准递送和T细胞启动,提高抗肿瘤治疗效果。
本发明第一方面,提供一种纳米粒MC-Lip,包括空白纳米粒和CC趋化因子受体 7mRNA(CCR7 mRNA),所述空白纳米粒包含(2,3-二油氧基丙基)三甲基氯化铵(DOTAP),二油酰磷脂酰乙醇胺(DOPE)二硬脂酰基磷脂酰乙醇胺-聚乙二醇2000(DSPE-PEG2000)和二硬脂酰基磷脂酰乙醇胺-聚乙二醇2000-甘露糖(DSPE-PEG2000-Man)。
进一步的,DOTAP,DOPE,DSPE-PEG2000和DSPE-PEG2000-Man质量比为15:4:0.63:1.62。CCR7 mRNA和DOTAP的质量比为1:8。能够实现有效将DC细胞编辑为CCR7+DC细胞并确保其向淋巴结T细胞区的递送。
本发明另一方面,提供一种纳米粒MC-Lip的制备方法,称取DOTAP、DOPE、DSPE-PEG2000和DSPE-PEG2000-Man溶于乙醇,旋转蒸发,除去有机溶剂,形成脂质薄膜后,水化,用脂质体挤出仪挤压,获得空白纳米粒M-Lip,将空白纳米粒M-Lip和CCR7 mRNA混匀,孵育,获得MC-Lip。
本发明另一方面,提供一种纳米粒MC-Lip在淋巴结T区药物递送中的应用。
本发明另一方面,提供一种水凝胶,所述水凝胶包括空白水凝胶,树突状细胞招募因子,肿瘤抗原诱导剂和树突状细胞重编程剂。进一步的,所述树突状细胞招募因子为粒细胞-巨噬细胞集落刺激因子(GM-CSF),所述肿瘤抗原诱导剂为活性成分为光动力药物Ce6的脂质体(脂质体Ce6-Lip),所述树突状细胞重编程剂为纳米粒MC-Lip。
进一步的,所述光动力药物Ce6的脂质体包括大豆卵磷脂、胆固醇和光动力药物Ce6。更进一步的脂质体Ce6-Lip中大豆磷脂、胆固醇和光动力药物Ce6的质量比为15:1.875:1,能够在激光照射下有效杀伤肿瘤细胞并启动免疫原性细胞死亡效应,确保肿瘤抗原的产生。
进一步的,所述水凝胶中,CCR7 mRNA、Ce6、GM-CSF的质量比为10:60:1,能够达到有效招募DC,编辑DC以及促进肿瘤抗原向淋巴结T区递送。
进一步的,所述空白水凝胶为低分子壳聚糖(50,000-190,000 Da)-聚氧乙烯聚氧丙烯醚聚合物。
本发明另一方面,提供一种水凝胶的制备方法,步骤如下:
1)称取大豆卵磷脂、胆固醇、光动力药物Ce6,溶于乙醇和二氯甲烷混合溶液中,旋转蒸发,除去有机溶剂,形成脂质薄膜后,水化,用脂质体挤出仪挤压,获得Ce6-Lip;
2)称取DOTAP、DOPE、DSPE-PEG2000和DSPE-PEG2000-Man溶于乙醇,旋转蒸发,除去有机溶剂,形成脂质薄膜后,水化,用脂质体挤出仪挤压,获得空白纳米粒M-Lip,将空白纳米粒M-Lip和CCR7 mRNA混匀,孵育,获得MC-Lip。
3)将步骤1)中的Ce6-Lip、步骤2)中的MC-Lip和GM-CSF溶液溶解到低分子壳聚糖-聚氧乙烯聚氧丙烯醚聚合物中,获得水凝胶MC+Ce6-Lip+GM-CSF-gel(MC+Ce6-Lip+GC-gel)。
本发明另一方面,提供一种水凝胶在制备淋巴结T细胞区域的药物递送中的应用。
本发明另一方面,提供一种水凝胶在制备抗肿瘤免疫药物中的应用。
与现有技术相比,本发明的有益效果是:
(1)本发明制备的水凝胶,可以实现体内编辑DC细胞。体内招募DC,诱导抗原产生并编辑DC为携带抗原信息的CCR7+DC,获得的携带抗原信息的CCR7+DC细胞实现淋巴结T细胞区精准递送和T细胞启动,以提高抗肿瘤治疗效果。
(2)本发明显著提高了光动力治疗在黑色素瘤上的疗效;生理盐水组在第9天肿瘤体积即接近2000 mm3,MC-Lip-gel和Ce6-Lip-gel组在第15天肿瘤体积才接近2000 mm3,与生理盐水组相比显著抑制肿瘤生长,将抗原诱导剂和DC细胞编辑剂以及DC细胞招募因子共装载于凝胶中后,MC+Ce6-Lip+GC-gel能显著抑制肿瘤体积。
(3)本发明中的所选用的材料均为生物相容性,包括低分子壳聚糖-聚氧乙烯聚氧丙烯醚聚合物,大豆卵磷脂,胆固醇、DOTAP、DOPE、DSPE-PEG2000等。所选用的脂质浓度,脂质比例以及制备工艺是经过筛选后的最优工艺。
(4)本发明的制备得到的纳米粒粒径适宜(100~200 nm),工艺稳定,简单可行,易于工业化生产。
附图说明
构成本发明的一部分的说明书附图用来提供对本发明的进一步理解,本发明的示意性实施例及其说明用于解释本发明,并不构成对本发明的不当限定。
图1:M-Lip和Ce6-Lip的粒径、电位和电镜图;
图2:MC+Ce6-Lip+GC-gel的扫描电镜结果;
图3:流式细胞术表征Ce6-Lip在激光照射下释放抗原促进DC细胞成熟的能力;
图4:BMDC上CCR7表达;
图5:MC-Lip处理后DC2.4细胞对CCL21的趋化能力;
图6:瘤体积生长曲线。
具体实施方式
应该指出,以下详细说明都是例示性的,旨在对本发明提供进一步的说明。除非另有指明,本文使用的所有技术和科学术语具有与本发明所属技术领域的普通技术人员通常理解的相同含义。
需要注意的是,这里所使用的术语仅是为了描述具体实施方式,而非意图限制根据本发明的示例性实施方式。如在这里所使用的,除非上下文另外明确指出,否则单数形式也意图包括复数形式,此外,还应当理解的是,当在本说明书中使用术语“包含”和/或“包括”时,其指明存在特征、步骤、操作、器件、组件和/或它们的组合。
为了使得本领域技术人员能够更加清楚地了解本发明的技术方案,以下将结合具体的实施例与对比例详细说明本发明的技术方案。
实施例:
一、水凝胶的制备与表征
一种包载DC细胞招募因子,肿瘤抗原诱导剂和DC细胞重编程剂的水凝胶。DC细胞招募因子为GM-CSF,肿瘤抗原诱导剂为以大豆卵磷脂和胆固醇为载体的空白脂质体和光动力药物Ce6。DC细胞重编辑剂为二硬脂酰基磷脂酰乙醇胺-聚乙二醇-甘露糖 DSPE-PEG2000-Man和DSPE-PEG2000修饰的以DOTAP、DOPE为载体的空白纳米粒和CCR7 mRNA。凝胶材料为低分子壳聚糖-聚氧乙烯聚氧丙烯醚聚合物。
二、Ce6-Lip的制备方法如下:
将30 mg大豆卵磷脂、3.75 mg胆固醇、2 mg Ce6,加入2 ml的乙醇和二氯甲烷混合溶液中,在室温下,搅拌形成澄清溶液,在40-50℃下,使用旋转蒸发器除去有机溶剂,成膜,加入2 ml 0.9%NaCl(生理盐水),在50-60℃下,水化30 min,通过200 nm和100 nm的脂质体挤出仪6次。所述的空白脂质体中包括磷脂,胆固醇。磷脂、胆固醇的质量比例为8:1。
三、MC-Lip的制备方法如下:
将15 mg DOTAP、4 mg DOPE,0.63 mg DSPE-PEG2000和1.62 mg DSPE-PEG2000-Man加入1 ml的乙醇溶液中,在室温下,搅拌形成澄清溶液,在40-50℃下,使用旋转蒸发器除去有机溶剂,成膜,加入2 ml 0.9%NaCl(生理盐水),在50-60℃下,水化30 min,通过200 nm和100 nm的脂质体挤出仪6次。随后将空白纳米粒M-Lip和CCR7 mRNA在涡旋条件下混匀,室温孵育30 min,即可获得MC-Lip。所述的空白纳米粒中包括DOTAP,DOPE和DSPE-PEG2000和DSPE-PEG2000-Man。所述的磷脂为DOTAP和DOPE。
四、MC+Ce6-Lip+GC-gel的制备方法如下:
将MC-Lip、Ce6-Lip和GM-CSF溶液混合溶解低分子壳聚糖-聚氧乙烯聚氧丙烯醚聚合物材料,低分子壳聚糖-聚氧乙烯聚氧丙烯醚聚合物最终浓度为50 mg/ml。GM-CSF能够招募DC细胞,以实现对DC细胞的编辑。Ce6-Lip在激光照射下能够诱导肿瘤细胞抗原产生。MC-Lip能够靶向DC细胞并将其编辑为CCR7表达的DC细胞。
Ce6-Lip和MC-Lip采用薄膜分散法制备。Ce6-Lip采用大豆卵磷脂和胆固醇为材料制备,按照前述方法称取脂质和药物,并将其溶解在乙醇和二氯甲烷混合溶液中,在50℃下旋转蒸发30分钟,除去有机溶剂,形成薄的脂质膜。然后在60℃下在PBS(10 mM,pH 7.4,焦碳酸二乙酯(DEPC)水配制)中进行水合,并通过200 nm和100 nm的脂质体挤出机6次以控制颗粒大小。M-Lip采用DOTAP、DOPE、DSPE-PEG2000和DSPE-PEG2000-Man为材料制备,按照前述方法称取脂质,并将其溶解在乙醇中,在50℃下旋转蒸发30分钟,除去有机溶剂,形成薄的脂质膜。然后在60℃下在PBS(10 mM,pH 7.4,DEPC水配制)中进行水合,并通过200 nm和100nm的脂质体挤出机6次以控制颗粒大小。将获得的M-Lip和mRNA在涡旋条件下混匀,室温孵育30 min,即可获得MC-Lip。用DLS测定Ce6-Lip和M-Lip的粒径和电位,透射电镜表征Ce6-Lip和M-Lip的表面形态。
Ce6-Lip的粒径电位分别为120±2.75 nm, -8±0.63 mV。M-Lip的粒径电位分别为127±1.31 nm, 30±0.35 mV,具备装载mRNA的能力。Ce6-Lip和MC-Lip形态圆整(图1)。
将Ce6-Lip、MC-Lip和GM-CSF装载于凝胶材料中,冻干。对凝胶形态进行SEM扫描。结果显示,凝胶的孔径大于20 μm,且明显发现凝胶材料上附着纳米粒,证明Ce6-Lip、MC-Lip 和GM-CSF可以均匀分散在凝胶材料中(图2)。
五、Ce6-Lip的抗原诱导能力评价
用Transwell系统检测DC细胞成熟能力。将1×106BMDC细胞(600 μL)接种于24孔板,培养过夜。将1×105B16F10细胞(200 μL)接种于Transwell上腔,培养过夜。将不同的配方加入B16F10细胞中,培养4 h。Control+Laser、Ce6+Laser和Ce6-Lip +Laser组用660 nm激光(0.15 W/cm2, 5 min)照射。将上腔转移至BMDC板共培养24 h,收集BMDC细胞,用抗小鼠CD11c抗体、抗小鼠CCR7抗体和抗小鼠CD80抗体染色,流式细胞术分析。结果显示Ce6-Lip在激光照射下能够促进DC细胞成熟,并一定程度上诱导CCR7的表达,为CCR7+DC细胞向淋巴结T区递送足量抗原提供了保障(图3)。
六、MC-Lip编辑DC细胞CCR7表达能力
CCR7抗体染色后用流式细胞术检测CCR7转染情况。为了评估CCR7的表达,将小鼠骨髓来源树突状细胞(BMDCs)分为2组:PBS、MC-Lip。将1×106BMDCs接种于24孔板中培养过夜。然后,每孔加入不同配方的RPMI 1640培养基(不含胎牛血清),孵育4 h。PBS洗涤后,每孔加入新鲜的RPMI 1640培养基,转染24 h。最后,收集BMDCs,用CCR7抗体染色,进行流式细胞术检测。结果显示MC-Lip组CCR7表达量显著高于PBS组,可以编辑DC细胞为CCR7+DC细胞,CCR7+DC细胞能够在体内CCL21的趋化功能下通过淋巴管向淋巴结T区递送,为淋巴结T区精准递送提供了关键载体(图4)。
七、Transwell表征CCR7+DC细胞对CCL21的趋化能力
Transwell系统(8 μm)用于评估CCR7+DC的迁移能力。用PBS、MC-Lip转染DC2.4细胞。有效转染后,收集PBS、MC-Lip组的DC2.4细胞,通过Transwell系统将转染后的DC2.4细胞(200 μL)5×104加入上腔。取含有100 ng/mL CCL21的600 μL DMEM培养基移液至下腔。孵育24 h后,收集上腔,0.1%结晶紫溶液染色10 min。最后,染色后的DC2.4细胞清洗3次,在ECLIPSE Ni-E显微镜(Nikon, USA)下成像。结果显示MC-Lip转染后的DC细胞能够有效的响应CCL21实现迁移,进一步证明CCR7+DC细胞能够响应体内CCL21梯度,进而实现淋巴结T区精准递送(图5)。
八、MC+Ce6-Lip+GC-gel抗肿瘤疗效研究
将皮下携带肿瘤的小鼠(8×105个B16F10细胞)随机分为4组(6只小鼠/组)。NS、MC-Lip-gel、Ce6-Lip-gel和MC+Ce6-Lip+GC-gel。当肿瘤长到约80 mm3时,对小鼠进行瘤周注射,Ce6-Lip-gel和MC+Ce6-Lip+GC-gel组进行激光照射处理(660 nm,0.15 W/cm2,5min)。每两天记录肿瘤大小。当肿瘤体积为2000 mm3或16天后,绘制瘤体积曲线。结果显示MC-Lip-gel、Ce6-Lip-gel相比于NS瘤体积生长缓慢,而MC+Ce6-Lip+GC-gel具有最强的抑瘤效果(图6)。
以上所述仅为本发明的优选实施例而已,并不用于限制本发明,对于本领域的技术人员来说,本发明可以有各种更改和变化。凡在本发明的精神和原则之内,所作的任何修改、等同替换、改进等,均应包含在本发明的保护范围之内。
Claims (8)
1.一种水凝胶,其特征是,包括空白水凝胶、树突状细胞招募因子、肿瘤抗原诱导剂和树突状细胞重编程剂;所述树突状细胞招募因子为粒细胞-巨噬细胞集落刺激因子,所述肿瘤抗原诱导剂为活性成分为光动力药物Ce6的脂质体,所述树突状细胞重编程剂为纳米粒MC-Lip;所述纳米粒MC-Lip,包括空白纳米粒和CC趋化因子受体 7 mRNA,所述空白纳米粒包含(2,3-二油氧基丙基)三甲基氯化铵、二油酰磷脂酰乙醇胺、二硬脂酰基磷脂酰乙醇胺-聚乙二醇2000和二硬脂酰基磷脂酰乙醇胺-聚乙二醇2000-甘露糖。
2.如权利要求1所述的水凝胶,其特征是,CC趋化因子受体 7 mRNA和(2,3-二油氧基丙基)三甲基氯化铵的质量比为1:8。
3.如权利要求1所述的水凝胶,其特征是,所述的纳米粒MC-Lip的制备方法,步骤是:
称取(2,3-二油氧基丙基)三甲基氯化铵、二油酰磷脂酰乙醇胺、二硬脂酰基磷脂酰乙醇胺-聚乙二醇2000和二硬脂酰基磷脂酰乙醇胺-聚乙二醇2000-甘露糖溶于乙醇,旋转蒸发,除去有机溶剂,形成脂质薄膜后,水化,用脂质体挤出仪挤压,获得空白纳米粒M-Lip,将空白纳米粒M-Lip和CC趋化因子受体 7 mRNA混匀,孵育,获得MC-Lip。
4.如权利要求1所述的水凝胶,其特征是,所述光动力药物Ce6的脂质体包括大豆卵磷脂、胆固醇和光动力药物Ce6。
5.如权利要求1所述的水凝胶,其特征是,CC趋化因子受体 7 mRNA、光动力药物Ce6、粒细胞-巨噬细胞集落刺激因子的质量比为10:60:1。
6.如权利要求1所述的水凝胶制备方法,其特征是,步骤如下:
1)称取大豆卵磷脂、胆固醇、光动力药物Ce6,溶于乙醇和二氯甲烷混合溶液中,旋转蒸发,除去有机溶剂,形成脂质薄膜后,水化,用脂质体挤出仪挤压,获得光动力药物Ce6的脂质体;
2)称取(2,3-二油氧基丙基)三甲基氯化铵、二油酰磷脂酰乙醇胺、二硬脂酰基磷脂酰乙醇胺-聚乙二醇2000和二硬脂酰基磷脂酰乙醇胺-聚乙二醇2000-甘露糖溶于乙醇,旋转蒸发,除去有机溶剂,形成脂质薄膜后,水化,用脂质体挤出仪挤压,获得空白纳米粒M-Lip,将空白纳米粒M-Lip和CC趋化因子受体 7 mRNA混匀,孵育,获得MC-Lip;
3)将步骤1)中的光动力药物Ce6的脂质体、步骤2)中的MC-Lip和粒细胞-巨噬细胞集落刺激因子溶液溶解到低分子壳聚糖-聚氧乙烯聚氧丙烯醚聚合物中,获得水凝胶。
7.如权利要求1所述的水凝胶在制备淋巴结T细胞区域的药物递送系统中的应用。
8.如权利要求1所述的水凝胶在制备抗肿瘤免疫药物中的应用。
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