CN114249717A - 特异性靶向肿瘤的近红外荧光探针及其合成方法和应用 - Google Patents
特异性靶向肿瘤的近红外荧光探针及其合成方法和应用 Download PDFInfo
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Abstract
本发明公开了一种特异性靶向肿瘤的近红外荧光探针及其合成方法和应用，其为下式Ⅰ所示的化合物或其药学可接受的盐：
其中：X是连接分子，选自无、PEGn、甘氨酸（Gm），n=0‑10，m=0‑10，连接分子的一端为氨基，另一端为羧基；Y是在近红外（NIR）范围内具有荧光激发和发射光谱的染料分子,且式Ⅰ所示的化合物或其药学可接受的盐能够维持或增强染料分子Y的荧光。本发明的近红外荧光探针在正常组织内能迅速清除，而在肿瘤部位长时间滞留，从而能达到活体诊断的作用，具备一定的临床应用前景，应用于临床术中导航。
Description
技术领域
本发明属于特异性分子靶向诊断试剂技术领域，具体涉及近红外荧光染料、连接分子和小分子抑制剂拉帕替尼组成的诊断试剂复合物。
背景技术
目前，癌症是除心血管疾病外严重危害我国居民健康的罪魁祸首之一，严重危害着人类的健康。临床上对于肿瘤的治疗主要有外科手术切除、化疗药物、放疗药物等。其中手术切除是所有实体瘤的最佳疗法之一，有效的手术切除，能极大的延长患者的生存期。近年来各种先进仪器设备的出现，如核磁共振成像、超声成像、Spect/CT造影等，能精准的定位肿瘤，找出病灶所在部位，再进行针对性的治疗。近红外荧光成像，波段在650-900nm之间，具有良好的穿透力，抗干扰强，成本低，能在手术过程中使用，为外科医生提供更清晰的视野，从而能够更精确的切除肿瘤。
吲哚菁绿（ICG）是经FDA获批的近红外荧光染料，能与血浆蛋白结合，经EPR效应集聚到肿瘤部位，一般手术前一天以静脉给药，经一天代谢后，第二天进行手术，体内肝肠基本清除干净，从而不会对手术产生干扰，存在的问题就是需要提前一天给药，走肝肠代谢，不利于肝脏、肠肿瘤成像，ICG容易产生假阳性。为避免这种假阳性的发生，需具有开发出经肾脏代谢的特异性靶向的荧光探针，从而具有更普遍的应用前景。特异性靶向的荧光探针，给药后特异性积聚于肿瘤部位，在肿瘤中滞留时间较长，而正常组织能迅速清除，在外科医生手术过程中，能更好的进行手术切除。
拉帕替尼是一个已上市的抗肿瘤药物，属于酪氨酸激酶抑制剂，靶点为Her2，用于乳腺癌、结直肠癌治疗。拉帕替尼能特异性靶向肿瘤组织，激活通路进一步导致肿瘤细胞凋亡，起到肿瘤治疗作用，在开发具有肿瘤特异性的荧光探针过程中，具有肿瘤特异性杀伤作用的抗肿瘤药物具备一定的研究价值，可用于特异性荧光探针的开发，进一步扩大药物的应用价值，用于外科手术导航，切除肿瘤。
发明内容
为解决上述现有技术中存在的问题，本发明的目的是提供一种特异性靶向肿瘤的近红外荧光探针及其合成方法和应用。
为实现上述目的，本发明采用如下技术方案：
一种特异性靶向肿瘤的近红外荧光探针，其为下式Ⅰ所示的化合物或其药学可接受的盐：
其中：
X是连接分子，选自无、PEGn、甘氨酸（Gm），n=0-10，m=0-10，连接分子的一端为氨基，另一端为羧基；
Y是在近红外（NIR）范围内具有荧光激发和发射光谱的染料分子,且式Ⅰ所示的化合物或其药学可接受的盐能够维持或增强染料分子Y的荧光。
所述连接分子选自PEG4、PEG6、6-氨基己酸、甘氨酸（G3、G6）、PEG4-甘氨酸，结构式如下：
所述染料分子Y选自以下结构：
一种特异性靶向肿瘤的近红外荧光探针的合成方法，包括以下步骤：
步骤a，在2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯（HATU）、碱和极性溶剂的存在下混合拉帕替尼和X；
步骤b，将步骤a得到的产物滴到水中，萃取后浓缩，再加三氟乙酸脱BOC保护基，浓缩得到拉帕替尼-X中间体化合物；
步骤c，在2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯（HATU）、碱和极性溶剂的存在下混合拉帕替尼-X中间体化合物和染料分子Y；
步骤d，将步骤c得到的产物以制备液相纯化，得到目标化合物拉帕替尼-X-Y，即为所述近红外荧光探针。
所述步骤a和c中，极性溶剂为N,N-二甲基甲酰胺（DMF）、无水二甲基亚砜（DMSO）、N-甲基吡咯烷酮的一种或多种。
所述步骤a和c中，碱为三乙胺（TEA）、N,N-二异丙基乙胺(DIEA)的一种或多种。
所述的特异性靶向肿瘤的近红外荧光探针在制备肿瘤诊断试剂中应用。
所述的特异性靶向肿瘤的近红外荧光探针在制备肿瘤精准手术导航的活体荧光成像试剂中的应用。
所述肿瘤为肝癌、乳腺癌、肺癌、胰腺癌、结直肠癌的一种或多种。
有益效果：本发明提供的特异性肿瘤靶向的近红外荧光探针，能主动靶向到肿瘤部位，在正常组织中不集聚或短时间清除干净，从而不影响其临床应用。本发明的近红外荧光探针在正常组织内能迅速清除，而在肿瘤部位长时间滞留，从而能达到活体诊断的作用，具备一定的临床应用前景，应用于临床术中导航。
附图说明
图1为实施例制备的YQ-H-01等吸收光谱；
图2为实施例制备的YQ-H-01等荧光光谱；
图3为实施例制备的YQ-H-01等在结直肠癌HT29荷瘤鼠中的体内成像；
图4为实施例制备的YQ-H-06探针分别在胰腺癌PANC1、肝癌Hepg2、肺癌H460荷瘤鼠中的体内成像。
具体实施方式
下面结合实施例对本发明做更进一步的解释。
根据下述实施例，可以更好的理解本发明。然而，本领域的技术人员容易理解，实施例所描述的具体的物料配比、工艺条件及其结果仅用于说明本发明，而不应当也不会限制权利要求书中所详细描述的本发明。
实施例1：YQ-H-01的合成
拉帕替尼(5mg，1.0eq)、ICG-02（12mg，1.5eq）、2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯（HATU，13mg，4.0eq）、三乙胺（6ul，5.0eq），避光室温反应3小时，以HPLC监测反应，反应完全后，以制备液相纯化，目标馏分冻干后得绿色固体YQ-H-01（5mg，Y=38.9%），经质谱和核磁氢谱确证，m/z=，1H NMR (300 MHz, DMSO) δ 8.88 (dd, J = 15.1,10.5 Hz, 2H), 8.66 (t, J = 12.4 Hz, 2H), 8.24 (dd, J = 11.1, 6.4 Hz, 1H),8.01 (t, J = 2.8 Hz, 1H), 7.85-7.66 (m, 4H), 7.60-7.45 (m, 3H), 7.42-7.16 (m,7H), 6.52 (dt, J = 24.9, 7.5 Hz, 3H), 5.34 (s, 2H), 4.64 (s, 2H), 4.26 (d, J= 7.2 Hz, 4H), 3.39 (t, J = 8.0 Hz, 2H), 3.17 (s, 2H), 3.04 (d, J = 9.4 Hz,4H), 2.73-2.59 (m, 8H), 2.55 (s, 3H), 2.07-1.88 (m, 4H), 1.78-1.65 (m, 2H),1.58 (d, J = 7.6 Hz, 12H).
实施例2：YQ-H-03的合成
拉帕替尼(10mg，1.0eq)、6-Boc-氨基己酸（8 mg，2eq）、2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯（HATU，13mg，2.0eq）、三乙胺（7.2ul，3.0eq），室温反应1小时，TLC监测反应，待反应完全后，将反应液滴入水中，再以乙酸乙酯萃取，合并有机层浓缩后加三氟乙酸脱Boc，同样以TLC监测反应，反应完全后，将三氟乙酸蒸除后，纯化得连上6-氨基己酸的拉帕替尼，后续参照化合物YQ-H-01的合成，得目标化合物YQ-H-03，绿色固体，结构经质谱核磁氢谱确证，m/z=， 1H NMR (300 MHz, DMSO) δ 8.88 (dd, J = 15.1,10.5 Hz, 2H), 8.66 (t, J = 12.4 Hz, 2H), 8.24 (dd, J = 11.1, 6.4 Hz, 1H),8.01 (t, J = 2.8 Hz, 1H), 7.85-7.66 (m, 4H), 7.60-7.45 (m, 3H), 7.42-7.16 (m,7H), 6.52 (dt, J = 24.9, 7.5 Hz, 3H), 5.34 (s, 2H), 4.64 (s, 2H), 4.26 (d, J= 7.2 Hz, 4H), 3.39 (t, J = 8.0 Hz, 2H), 3.17 (s, 2H), 3.04 (d, J = 9.4 Hz,4H), 2.73-2.59 (m, 8H), 2.55 (s, 3H), 2.07-1.88 (m, 4H), 1.78-1.65 (m, 2H),1.58 (d, J = 7.6 Hz, 12H)。
实施例3：YQ-H-04的合成
合成方法参考YQ-H-03，结构经质谱和核磁氢谱确证，m/z=，1H NMR (300 MHz,DMSO) δ 8.96 (dd, J = 8.0, 4.8 Hz, 2H), 8.66 (d, J = 14.0 Hz, 2H), 8.36 (d, J= 8.9 Hz, 1H), 8.01 -7.88 (m, 3H), 7.75 (d, J = 1.2 Hz, 2H), 7.65 (ddd, J =9.6, 8.6, 1.9 Hz, 3H), 7.53-7.46 (m, 1H), 7.45-7.30 (m, 5H), 7.25-7.14 (m,2H), 6.64-6.43 (m, 3H), 5.32 (s, 2H), 4.72 (d, J = 23.4 Hz, 2H), 4.40-4.23(m, 4H), 3.61-3.53 (m, 2H), 3.51-3.41 (m, 12H), 3.41-3.30 (m, 4H), 3.19-3.12(m, 2H), 3.03 (d, J = 4.6 Hz, 2H), 2.97 (td, J = 6.6, 3.9 Hz, 2H), 2.76 (dd,J = 11.9, 5.0 Hz, 2H), 2.73-2.59 (m, 8H), 2.55 (s, 3H), 2.42-2.31 (m, 2H),2.10-1.91 (m, 4H), 1.80-1.71 (m, 2H), 1.65 (d, J = 2.0 Hz, 12H)。
实施例4：YQ-H-05的合成
合成方法参考YQ-H-03，结构经质谱和核磁氢谱确证，m/z=，1H NMR (300 MHz,DMSO) δ 8.95 (t, J = 2.6 Hz, 2H), 8.67 (d, J = 14.1 Hz, 2H), 8.37 (dd, J =12.4, 3.7 Hz, 1H), 7.99 (dd, J = 7.1, 3.6 Hz, 1H), 7.96-7.88 (m, 2H), 7.75(d, J = 1.0 Hz, 2H), 7.70-7.59 (m, 3H), 7.54-7.30 (m, 6H), 7.25-7.14 (m, 2H),6.66-6.42 (m, 3H), 5.32 (s, 2H), 4.73 (d, J = 23.7 Hz, 2H), 4.33 (s, 4H),3.59-3.54 (m, 2H), 3.51 – 3.41 (m, 20H), 3.36 (dd, J = 11.4, 5.8 Hz, 4H),3.19-3.11 (m, 2H), 3.03 (s, 2H), 2.98 (d, J = 6.8 Hz, 2H), 2.77 (dd, J =11.5, 5.5 Hz, 2H), 2.61 (dd, J = 18.9, 12.8 Hz, 8H), 2.52 (d, J = 1.6 Hz,3H), 2.36 (t, J = 6.9 Hz, 2H), 2.01 (dd, J = 13.8, 7.4 Hz, 4H), 1.76 (d, J =3.2 Hz, 2H), 1.68 (d, J = 10.9 Hz, 12H)。
实施例5：YQ-H-06的合成
合成方法参考YQ-H-03，结构经质谱和核磁氢谱确证，m/z=，1H NMR (300 MHz,DMSO) δ 8.95 (s, 2H), 8.68 (dd, J = 13.9, 6.0 Hz, 2H), 8.49-8.38 (m, 1H),8.32-8.11 (m, 4H), 7.90 (dd, J = 7.0, 2.9 Hz, 2H), 7.76 (s, 2H), 7.65 (dd, J= 12.0, 5.6 Hz, 3H), 7.52-7.44 (m, 1H), 7.44-7.30 (m, 5H), 7.21 (dd, J =11.5, 5.7 Hz, 2H), 6.71-6.42 (m, 3H), 5.32 (s, 2H), 4.78-4.63 (m, 2H), 4.32m, 4H), 4.16 (m, 2H), 3.48-3.25 (m, 6H), 3.17 (s, 2H), 3.09-2.99 (m, 4H),2.76-2.56 (m, 8H), 2.52 (s, 3H), 2.45 (m, 2H), 2.02 (m, 4H), 1.76 (m, 2H),1.72-1.55 (m, 12H)。
实施例6：YQ-H-07的合成
合成方法参考YQ-H-03，结构经质谱和核磁氢谱确证，m/z=，1H NMR (300 MHz,DMSO) δ 8.94 (s, 2H), 8.67 (d, J = 14.0 Hz, 2H), 8.51-7.99 (m, 8H), 7.90 (dd,J = 5.4, 2.8 Hz, 2H), 7.77 (s, 2H), 7.63 (d, J = 8.4 Hz, 3H), 7.53-7.29 (m,6H), 7.25-7.15 (m, 2H), 6.72-6.41 (m, 3H), 5.32 (s, 2H), 4.80-4.65 (m, 2H),4.38-4.20 (m, 6H), 3.71 (d, J = 4.9 Hz, 12H), 3.35 (p, J = 7.9 Hz, 2H), 3.03(s, 2H), 3.00-2.92 (m, 2H), 2.65 (dd, J = 13.6, 8.1 Hz, 8H), 2.55 (s, 3H),2.43 (dd, J = 8.7, 2.8 Hz, 2H), 2.11-1.94 (m, 4H), 1.84-1.73 (m, 2H), 1.66(s, 12H)。
实施例7：YQ-H-08的合成
合成方法参考YQ-H-03，结构经质谱和核磁氢谱确证，m/z=，1H NMR (300 MHz,DMSO) δ 8.94 (d, J = 3.5 Hz, 2H), 8.42 (dd, J = 28.0, 9.0 Hz, 1H), 8.22-8.02(m, 6H), 7.94-7.86 (m, 2H), 7.76 (dd, J = 13.8, 7.2 Hz, 2H), 7.68-7.56 (m,5H), 7.49 (td, J = 8.0, 6.1 Hz, 1H), 7.37 (dd, J = 12.7, 9.3 Hz, 5H), 7.20(dd, J = 9.0, 6.1 Hz, 4H), 7.01 (t, J = 7.3 Hz, 2H), 6.63 (dd, J = 43.4, 3.1Hz, 1H), 6.34 (d, J = 14.4 Hz, 2H), 5.32 (s, 2H), 4.73 (d, J = 15.3 Hz, 2H),4.21 (d, J = 33.3 Hz, 6H), 3.78-3.64 (m, 12H), 3.36 (dd, J = 12.9, 5.9 Hz,2H), 3.03 (s, 2H), 2.83-2.64 (m, 6H), 2.59 (t, J = 6.5 Hz, 4H), 2.55 (s, 3H),2.35 (dd, J = 13.1, 5.9 Hz, 2H), 2.05-1.91 (m, 4H), 1.91-1.80 (m, 2H), 1.22(d, J = 4.2 Hz, 12H)。
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来说，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。
实施例 8
在皮下瘤HT29荷瘤鼠模型中，分别尾静脉给药YQ-H（30nmol，注射用生理盐水100uL溶解）系列探针,小动物活体成像CCD分别拍摄不同时间点荧光成像，依次是0h（给药前），6h，12h，24h，48h，结果显示在HT29荷瘤鼠中，探针YQ-H-01/03具有一定肿瘤靶向作用的同时在肝脏等有较强的荧光信号，可能不利于后续探针开发；探针YQ-H-08，在靶向分子拉帕替尼和荧光染料之间引入芳香苯环结构，一定程度上增强了肿瘤摄取，同时也导致小鼠全身信号明显，可能是脂溶性增强导致探针体内代谢时间延长所致；探针YQ-H-04/06/07表现出更好的体内代谢特点，肝脏部位荧光信号显著减少，肿瘤部位荧光信号明显，以探针YQ-H-06肿瘤效果更优，具备后续开发的潜力。
在此基础上，本发明对探针YQ-H-06进行胰腺癌（PANC1）、肝癌（HepG2）、肺癌（H460）荷瘤鼠肿瘤靶向验证，发现探针YQ-H-06在这三种皮下瘤荷瘤鼠上同样具有较好的肿瘤靶向作用，需进一步研究开发，以期应用于临床手术导航。
Claims (9)
1.一种特异性靶向肿瘤的近红外荧光探针，其特征在于：其为下式Ⅰ所示的化合物或其药学可接受的盐：
其中：
X是连接分子，选自无、PEGn、甘氨酸Gm，n=0-10，m=0-10，连接分子的一端为氨基，另一端为羧基；
Y是在近红外范围内具有荧光激发和发射光谱的染料分子，且式Ⅰ所示的化合物或其药学可接受的盐能够维持或增强染料分子Y的荧光。
2.根据权利要求1所述的特异性靶向肿瘤的近红外荧光探针，其特征在于：所述连接分子选自PEG4、PEG6、6-氨基己酸、甘氨酸G3、甘氨酸G6、PEG4-甘氨酸，结构式如下：
3.根据权利要求1所述的特异性靶向肿瘤的近红外荧光探针，其特征在于：所述染料分子Y选自以下结构：
4.一种权利要求1-3任一所述的特异性靶向肿瘤的近红外荧光探针的合成方法，其特征在于：包括以下步骤：
步骤a，在2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯、碱和极性溶剂的存在下混合拉帕替尼和X；
步骤b，将步骤a得到的产物滴到水中，萃取后浓缩，再加三氟乙酸脱BOC保护基，浓缩得到拉帕替尼-X中间体化合物；
步骤c，在2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯、碱和极性溶剂的存在下混合拉帕替尼-X中间体化合物和染料分子Y；
步骤d，将步骤c得到的产物以制备液相纯化，得到目标化合物拉帕替尼-X-Y，即为所述近红外荧光探针。
5.根据权利要求4所述的特异性靶向肿瘤的近红外荧光探针的合成方法，其特征在于：所述步骤a和c中，极性溶剂为N,N-二甲基甲酰胺、无水二甲基亚砜、N-甲基吡咯烷酮的一种或多种。
6.根据权利要求4所述的特异性靶向肿瘤的近红外荧光探针的合成方法，其特征在于：所述步骤a和c中，碱为三乙胺、N,N-二异丙基乙胺(DIEA)的一种或多种。
7.权利要求1所述的特异性靶向肿瘤的近红外荧光探针在制备肿瘤诊断试剂中应用。
8.权利要求1所述的特异性靶向肿瘤的近红外荧光探针在制备肿瘤精准手术导航的活体荧光成像试剂中的应用。
9.根据权利要求8所述的应用，其特征在于：所述肿瘤为肝癌、乳腺癌、肺癌、胰腺癌、结直肠癌的一种或多种。
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Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2011528560A (ja) * | 2008-07-24 | 2011-11-24 | マックス−プランク−ゲゼルシャフト ツール フォーデルング デル ヴィッセンシャフテン エー．ヴェー． | 新規キナーゼ阻害剤足場の迅速なスクリーニングおよび同定のための蛍光標識またはスピン標識キナーゼ |
| CN101440282B (zh) * | 2008-12-18 | 2012-06-27 | 中国药科大学 | 近红外荧光分子探针及其合成方法和用途 |
| KR101980292B1 (ko) * | 2017-08-03 | 2019-05-20 | (주)바이오액츠 | 형광 화합물 및 이의 제조방법 |
| CN107670050B (zh) * | 2017-08-30 | 2019-06-07 | 重庆阿普格雷生物科技有限公司 | 基于pki-587的抗癌中间体和聚乙二醇偶联抗癌药物、及其制备方法和应用 |
| CN114249717B (zh) * | 2022-03-01 | 2022-05-13 | 南京诺源医疗器械有限公司 | 特异性靶向肿瘤的近红外荧光探针及其合成方法和应用 |
-
2022
- 2022-03-01 CN CN202210191870.6A patent/CN114249717B/zh active Active
- 2022-05-09 WO PCT/CN2022/091632 patent/WO2023165015A1/zh active Application Filing
- 2022-05-09 EP EP22754275.0A patent/EP4269407A4/en active Pending
Non-Patent Citations (1)
| Title |
|---|
| 王成会等: "增强型超分子荧光探针对拉帕替尼的识别及其在细胞成像中的应用", 《有机化学》 * |
Cited By (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2023165015A1 (zh) * | 2022-03-01 | 2023-09-07 | 南京诺源医疗器械有限公司 | 特异性靶向肿瘤的近红外荧光探针及其合成方法和应用 |
| CN117866043A (zh) * | 2023-06-08 | 2024-04-12 | 江西省肿瘤医院(江西省第二人民医院、江西省癌症中心) | 一种靶向多肽及其荧光造影剂和应用 |
| CN116731021A (zh) * | 2023-06-14 | 2023-09-12 | 河北医科大学 | 用于肿瘤靶向成像的荧光探针化合物及其合成方法和应用 |
| CN116621823A (zh) * | 2023-07-06 | 2023-08-22 | 南京诺源医疗器械有限公司 | 诊断转移淋巴结近红外荧光示踪剂、合成方法及应用 |
| CN116621823B (zh) * | 2023-07-06 | 2023-10-31 | 南京诺源医疗器械有限公司 | 诊断转移淋巴结近红外荧光示踪剂、合成方法及应用 |
| CN117567348A (zh) * | 2023-11-27 | 2024-02-20 | 大连理工大学宁波研究院 | 一种kiaa1363酶靶向近红外荧光染料及其制备方法与应用 |
| CN117586174A (zh) * | 2024-01-19 | 2024-02-23 | 中国药科大学 | 用于诊断结直肠癌的近红外荧光探针及其制法和应用 |
| CN117586174B (zh) * | 2024-01-19 | 2024-05-10 | 中国药科大学 | 用于诊断结直肠癌的近红外荧光探针及其制法和应用 |
| CN117800951A (zh) * | 2024-02-27 | 2024-04-02 | 南京诺源医疗器械有限公司 | 一种近红外荧光探针及其制备方法与应用 |
| CN117800951B (zh) * | 2024-02-27 | 2024-05-28 | 南京诺源医疗器械有限公司 | 一种近红外荧光探针及其制备方法与应用 |
| CN118480031A (zh) * | 2024-07-16 | 2024-08-13 | 南京诺源医疗器械有限公司 | 一种用于主动靶向表皮生长因子受体检测的近红外荧光探针及其制备方法与应用 |
| CN118652257A (zh) * | 2024-08-16 | 2024-09-17 | 南京诺源医疗器械有限公司 | 一种靶向近红外荧光化合物及其制备方法和应用 |
Also Published As
| Publication number | Publication date |
|---|---|
| EP4269407A1 (en) | 2023-11-01 |
| EP4269407A4 (en) | 2024-09-04 |
| CN114249717B (zh) | 2022-05-13 |
| WO2023165015A1 (zh) | 2023-09-07 |
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