CN114796521B - 一种特异性识别pd-l1的分子印迹纳米结构及其应用 - Google Patents

一种特异性识别pd-l1的分子印迹纳米结构及其应用 Download PDF

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CN114796521B
CN114796521B CN202110063443.5A CN202110063443A CN114796521B CN 114796521 B CN114796521 B CN 114796521B CN 202110063443 A CN202110063443 A CN 202110063443A CN 114796521 B CN114796521 B CN 114796521B
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钱若灿
周泽蕊
汪肖原
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East China University of Science and Technology
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Abstract

本发明提供一种特异性识别PD‑L1的分子印迹纳米结构及其应用，以硼酸功能化的等离子体金纳米粒子(GNPs)为核心，酶解PD‑L1的n–连接聚糖作为印迹模板，形成SiO2印迹层。本发明为提高免疫检查点治疗的疗效提供了一种有效的方法。分子印迹纳米结构可以靶向PD‑L1的n‑连接聚糖，从而抑制PD‑L1和PD‑1的结合，诱导T细胞免疫的重新激活。在此基础上，为了增强T细胞浸润，进一步将纳米细胞与唾液酸酶偶联以实现SA的降解。与天然PD‑L1抗体不同，印迹纳米粒子可以与PD‑L1表面n–连接聚糖结合，从而更有效地封锁PD‑L1。而且纳米抗体的体积比天然抗体大，进一步增强了阻断作用。

Description

一种特异性识别PD-L1的分子印迹纳米结构及其应用
技术领域
本发明涉及细胞活体成像和纳米材料技术领域，尤其涉及一种特异性识别PD-L1的分子印迹纳米结构及其应用。
背景技术
Southern在1975年首先提出了分子印迹的概念。他将琼脂糖凝胶电泳分离的DNA片段在凝胶中进行变性使其成为单链，然后将一张硝酸纤维素(nitrocellulose，NC)膜放在凝胶上，上面放上吸水纸巾，利用毛细管作用原理使凝胶中的DNA片段转移到NC膜上，使之成为固相化分子。载有DNA单链分子的NC膜就可以在杂交液与另一种带有标记的DNA或RNA分子(即探针)进行杂交，具有互补序列的RNA或DNA结合到存在于NC膜的DNA分子上，经放射自显影或其他检测技术就可以显现出杂交分子的区带。由于这种技术类似于用吸墨纸吸收纸张上的墨迹，因此称为"blotting"，译为"印迹技术"。
生物大分子印迹技术发展极为迅速，已广泛用于DNA、RNA、蛋白质的检测。通常人们将DNA印迹技术称为Southern blotting，将RNA印迹技术称为Northern blotting，将蛋白质印迹技术称为Western blotting，将不经凝胶的印迹技术称为斑点印迹(Dotblotting)。
程序性死亡1(PD-1)和程序性死亡配体1(PD-L1)的发现给临床癌症治疗带来了革命性的变化，因为PD-1/PD-L1免疫检查点封锁在抑制免疫T细胞中发挥了重要作用。通过阻断PD-1或PD-L1来激活T细胞免疫已成为一种有用的癌症治疗策略，而特异性靶向PD-1或PD-L1的抗体已被广泛用于不同癌症的治疗。
PD-L1(又称B7同源物1,B7-h1)自1999年首次被发现以来，被认为是PD-1的结合和功能伙伴，是人T细胞的抑制剂。以PD-L1为靶点的抗体，如atezolizumab、avelumab、durvalumab等，已广泛应用于多种肿瘤的治疗。然而，随着研究的深入，越来越多的证据表明，其抗体评估的PD-L1水平由于翻译后糖基化而不可靠。值得注意的是，PD-L1的n-连接糖基化可导致其抗原表位无法被常规PD-L1抗体识别。PD-L1上的n-连聚糖可通过特定酶进行剪切，而N聚糖是一种连接在蛋白质肽链中天冬酰胺残基侧链酰胺氮上的寡糖，此类寡糖通常均有一个核心的五糖和类似结构的外周糖链。一般n-连聚糖包含n-复合型，杂合型及高甘露糖型糖链。
因此，尽管免疫检查站阻断(immune checkpoint blockade,ICB)疗法在各种PD-L1阳性恶性肿瘤中具有持久的抗肿瘤作用，但由于肿瘤细胞表面PD-L1的n-链糖基化作用抑制了PD-L1抗体对PD-L1的识别，因此治疗效果有限。PD-L1和PD-L1抗体识别能力下降，给ICB治疗的应用带来了临床挑战，迫切需要开发更有效的PD-L1阻断策略，通过T细胞活化提高抗肿瘤效果。
发明内容
本发明的第一个目的在于，为了避免PD1/PD-L1结合引起肿瘤细胞的免疫逃逸，我们提出了一种特异性识别PD-L1的分子印迹纳米结构，它可以靶向PD-L1的n-连接聚糖，从而抑制PD-L1和PD-1的结合，诱导T细胞免疫的重新激活。
本发明的第二个目的在于，提供特异性识别PD-L1的分子印迹纳米结构在制备抗肿瘤药物中的应用。
为了实现上述目的，本发明提供了一种特异性识别PD-L1的分子印迹纳米结构，包括金纳米粒子核心和SiO2印迹层，以硼酸功能化的等离子体金纳米粒子(GNPs)为核心，酶解PD-L1的n–连接聚糖作为印迹模板，形成SiO2印迹层。
本发明实施例中优选用肽N-糖苷酶F(PNGase F)用于酶解PD-L1的n–连接聚糖，通过在n-聚糖的最内层GlcNAc和N-聚糖之间切开而释放出完整的双链高甘露糖和杂合型N-聚糖。
作为一个优选方案，所述SiO2印迹层还包括唾液酸酶，其可同时剪切PDL1周边细胞膜唾液酸。在SiO2印迹层基础上进一步将其与唾液酸酶结合，实现在其与PDL1特异性结合的同时降解唾液酸，提高了T细胞的肿瘤杀伤活性。
特异性识别PD-L1的分子印迹纳米结构合成步骤包括：
(1)合成金胶作为种子；
(2)利用金种合成纳米金；
(3)从PDL1中提取聚糖模板：蛋白粉末加入PNGase F，孵育，其用于对PDL1上的n-连接聚糖进行切断，再将n-连接聚糖从PDL1的糖蛋白中用Amicon Utra-0.5ultrafiltration catridge，离心获得n-聚糖模板；
(4)用纳米金合成能特异性识别PD-L1的包裹二氧化硅的纳米金：将氨基苯硼酸和纳米金放入摇床过夜，加入n-聚糖，通过硼酸和n-链糖之间的硼酸亲和作用，将n-聚糖模板固定在金纳米粒子表面。再加入无水乙醇持续搅拌，随后加入28％氨水，混合搅拌后加入TEOS，搅拌，使连有n-聚糖的金纳米粒子包裹上一层二氧化硅，离心，分散，从而得到具有n-聚糖印记模板的纳米结构。
(5)制备可同时识别PD-L1和剪切唾液酸的纳米金：将(4)中制备的包裹有二氧化硅壳层的纳米金上再修饰上唾液酸剪切酶，从而实现在分子印迹PDL1的同时对肿瘤细胞表面唾液酸的剪切。
为了实现上述第二个目的，本发明提供了特异性识别PD-L1的分子印迹纳米结构在制备抗肿瘤药物中的应用。
作为一个优选方案，所述抗肿瘤药物是指免疫检查点阻断治疗药物。癌症免疫治疗中的免疫检查点阻断治疗凭借着阻断免疫检查点，激活内源性抗肿瘤T细胞(开启机体天然屏障)，具有杀死癌细胞的优势，这类药物主要分为两类，一类是以PD1为代表的抑制剂，一类为激活剂。
本发明的优点在于，本发明为提高免疫检查点治疗的疗效提供了一种有效的方法。我们提出了一种分子印迹纳米结构，命名为“NanoNiche”，它可以靶向PD-L1的n-连接聚糖，从而抑制PD-L1和PD-1的结合，诱导T细胞免疫的重新激活。在此基础上，为了增强T细胞浸润，进一步将纳米细胞与唾液酸酶偶联以实现SA的降解。与天然PD-L1抗体不同，印迹纳米粒子可以与PD-L1表面n–连接聚糖结合，从而更有效地封锁PD-L1。而且纳米抗体的体积比天然抗体大，进一步增强了阻断作用。考虑到细胞表面蛋白质通常是糖基化的，基于分子印迹的纳米结构可以轻易地扩展到许多其他靶点。
附图说明
图1为通过具有靶向PD-L1的n-连接聚糖的印迹纳米结构阻断PD-L1而重新激活T细胞免疫工作原理图。
图2为孵育不同时间下T细胞对于肿瘤细胞的攻击程度以及唾液酸剪切效率。
具体实施方式
下面结合具体实施例，进一步阐述本发明。下述实施例中所使用的实验方法如无特殊说明，均为常规方法。下述实施例中所用的材料、试剂等，如无特殊说明，均可从商业途径得到。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。
实施例1.合成可同时检测细胞内野生型和变异p53蛋白的纳米囊泡
(1)根据已有文献，合成13nm金胶作为种子。将50mL HAuCl4(0.01％)溶液加入圆底烧瓶中加热至沸腾，然后快速加入5mL柠檬酸钠溶液(38.8mM)并且持续搅拌30分钟，直到溶液变成红色，得到的13nm金种被用来制备粒径在60nm左右的纳米金。
(2)利用金种合成60nm的纳米金。将1mL金种溶液与100μL NH2OH·HCl(0.2M)混合后用纯水稀释至25mL，之后将3.0mLHAuCl4(0.01％)缓慢逐滴加入上述混合溶液中，持续搅拌30分钟直到溶液变成暗红色。将得到的纳米金溶液离心，用纯水洗涤，于4℃条件下保存。
(3)从PDL1中提取聚糖模板。将蛋白粉末配制成0.25mg/mL。取400微升，将其煮沸15min，冷却至室温。再加入10U PNGase F，在37摄氏度下孵育24h，其用于对PDL1上的n-聚糖进行切断。再将n-聚糖从PDL1的糖蛋白中用Amicon Utra-0.5ultrafiltrationcatridge,在11000rpm下离心15min从而获得n-聚糖模板。
(4)用60nm的纳米金合成能特异性识别PD-L1的包裹二氧化硅的纳米金。将0.3mg的氨基苯硼酸和1mL纳米金在室温下放入摇床过夜，加入200微升n-聚糖摇床6h，通过硼酸和n-链糖之间的硼酸亲和作用，将n-聚糖模板固定在金纳米粒子表面。再加入1mL无水乙醇持续搅拌，随后加入0.035mL28％氨水，混合搅拌5min，后加入0.3mL 10mM TEOS，搅拌40min，使连有n-聚糖的金纳米粒子包裹上一层二氧化硅。最后7000rpm,10min离心，分散于0.5mL去离子水中，从而得到具有n-聚糖印记模板的纳米结构。
(5)制备可同时识别PD-L1和剪切唾液酸的纳米金。将(4)中制备的包裹有二氧化硅壳层的纳米金上再修饰上唾液酸剪切酶，从而实现在分子印迹PDL1的同时对肿瘤细胞表面唾液酸的剪切。
以上所述仅是本发明的优选实施方式，应当指出，对于本技术领域的普通技术人员，在不脱离本发明原理的前提下，还可以做出若干改进和润饰，这些改进和润饰也应视为本发明的保护范围。

Claims (4)

1.一种特异性识别PD-L1的分子印迹纳米结构，其特征在于，包括金纳米粒子核心和SiO2印迹层，以硼酸功能化的等离子体金纳米粒子为核心，酶解PD-L1的n–连接聚糖作为印迹模板，形成SiO2印迹层。
2.根据权利要求1所述的一种特异性识别PD-L1的分子印迹纳米结构，其特征在于，所述SiO2印迹层还包括唾液酸酶。
3.权利要求1或2所述的一种特异性识别PD-L1的分子印迹纳米结构在制备抗肿瘤药物中的应用。
4.根据权利要求3所述的应用，其特征在于，所述抗肿瘤药物是指免疫检查点阻断治疗药物。
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