CN113648283A - 靶向抑制HIF-2α的载药微球制备方法、载药微球及应用 - Google Patents
靶向抑制HIF-2α的载药微球制备方法、载药微球及应用 Download PDFInfo
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Abstract
本发明提供一种靶向抑制HIF‑2α的载药微球制备方法用于制备载药微球。通过微球体系共载PT‑2385,形成PT‑2385有效缓释体系,降低PT‑2385毒副作用的同时,能够靶向抑制HIF‑2α的表达,提升其抗肿瘤作用。同时,PT‑2385和阿霉素共载微球能够在体内达到长期缓释的作用,从而发挥长效抗肿瘤作用。另外,使用乳化交联法制备PT‑2385和阿霉素共载的靶向抑制HIF‑2α的新型载药微球,利用戊二醛作为交联剂,盐酸作为催化剂,适用于微球的批量生产,可快速制备得到不同粒径范围的载药微球。本发明还提供载药微球及其应用。
Description
技术领域
本发明涉及微球制备技术领域,具体涉及一种靶向抑制HIF-2α的载药微球制备方法及载药微球。
背景技术
肝细胞癌(HCC)是全球范围内高发的恶性肿瘤,严重威胁人类生命健康。肝癌具有发病隐匿、恶性程度高且进展迅速等特点,这也导致75%以上的患者临床确诊时已处于中晚期,失去外科手术切除的最佳时机,往往只能选择放化疗以及介入治疗等姑息性疗法,临床应对策略极为有限。针对这部分中晚期肝癌患者,以经导管动脉化疗栓塞术(TACE)为基础的介入综合治疗展现出卓越的抗肿瘤疗效,并逐渐成为目前临床上中晚期肝癌的重要治疗手段。TACE主要是通过导管选择性或超选择性地插入到肿瘤供血靶动脉,注入适量的栓塞剂,阻断肿瘤血管,从而引起肿瘤组织的缺血坏死,将抗癌药物和栓塞剂混合进行栓塞即可起到化疗性栓塞作用。目前临床上常利用载药微球进行TACE治疗,其是将化疗药包载在微球中,并通过微球骨架的降解实现化疗药物的缓慢释放,降低了化疗药物的全身血药浓度,从而减少化疗药物不良反应的发生。然而,目前的载药微球仍存在治疗效能低的问题,其肿瘤客观反应率仅为44%,且短期复发率高达29%,极大地限制了TACE在临床上的广泛推广应用。因此,亟需基于现有的载药微球治疗体系,进一步提升其载药微球整体治疗效能。
TACE术后瘤内从核心坏死区域到边缘残留肿瘤组织可形成独特的梯度缺氧微环境,这是引起TACE抵抗,并促进肿瘤局部进展和远处转移的重要调控因素。已有大量的研究证实TACE术后的梯度缺氧微环境的主要效应因子是缺氧诱导因子(HIF),其是肿瘤缺氧微环境中的关键调控因子。
以往的研究更多的是关注HIF-1α在TACE预后中的作用,这很大原因是由于HIF-1α主要再栓塞的早期发挥作用。HIF-2α是HIF家族的亚型之一,以往的研究证实HIF-2α能够在长期持续缺氧状态下起关键作用,与肿瘤缺氧后期的局部进展、新生血管形成、远处转移和耐药等预后密切相关。TACE作为一个引起长期堵塞肿瘤供血动脉的疗法,HIF-2α是影响其预后的关键调控因子,但靶向抑制HIF-2α的新型载药微球仍未见报道。
发明内容
针对现有技术的不足之处,本发明的目的在于提供一种靶向抑制HIF-2α的载药微球制备方法、载药微球及应用。
本发明的技术方案概述如下:
一方面,本发明提供靶向抑制HIF-2α的载药微球制备方法,制备方法包括:
S1、将100质量份的PVA溶解于水中,形成PVA溶液;
S2、在PVA溶液中,加入1质量份的透明质酸,在60℃以下搅拌加热,溶解形成HA-PVA溶液;
S3、将0.2质量份的PT-2385和1质量份的阿霉素溶于HA-PVA溶液中,作为乳液水相;
S4、制备乳液油相;
S5、将步骤S3中的乳液水相与步骤S4中的乳液油相混合,搅拌得到W/O的乳剂;
S6、加入交联剂和催化剂,搅拌形成微球;
S7、洗涤及干燥后、称重,得到标准的载药微球。
进一步地,步骤S4包括:
在液态石蜡中加入油溶性表面活性剂,混合搅拌试纸充分溶解后,制备得到乳液油相。
进一步地,所述油溶性表面活性剂为Span-80,1质量份的阿霉素对应加入100μl的Span-80。
进一步地,1质量份的阿霉素对应4ml的液态石蜡。
进一步地,所述交联剂为戊二醛;其中,1质量份的阿霉素对应加入0.4ml的戊二醛。
进一步地,所述催化剂为盐酸;其中,1质量份的阿霉素对应加入30μl的盐酸。
进一步地,步骤S7中洗涤采用石油醚对固化后的微球洗涤至少三次。
进一步地,步骤S1中,将100质量份的PVA溶解于水中,加热至90-100℃至PVA完全溶解,冷却降温至25℃以下。
另一方面,本发明还提供一种载药微球,采用如上任一项所述的靶向抑制HIF-2α的载药微球制备方法制备的载药微球。
又一方面,本发明还提供如上任一项所述的靶向抑制HIF-2α的载药微球制备方法制备的载药微球在靶向抑制HIF-2α的应用。
相比现有技术,本发明的有益效果在于:本发明提供的靶向抑制HIF-2α的载药微球制备方法,通过微球体系共载PT-2385后,将形成PT-2385有效缓释体系,在降低PT-2385毒副作用的同时,使其在肿瘤靶区有效富集,能够靶向抑制HIF-2α的表达,提升其抗肿瘤作用。同时,PT-2385和阿霉素共载微球能够在体内达到长期缓释的作用,从而发挥长效抗肿瘤作用。另外,使用乳化交联法制备PT-2385和阿霉素共载的靶向抑制HIF-2α的新型载药微球,利用戊二醛作为交联剂,盐酸作为催化剂,只需按照一定的速度搅拌即可快速交联形成微球,适用于微球的批量生产,可快速制备得到不同粒径范围的载药微球。本发明创新性地将通过HIF-2α的抑制提升TACE疗效的思路引入到微球中,并将PT-2385引入到化疗栓塞治疗体系中,以往的研究更多的是关注HIF-1α在TACE预后中的作用,这很大原因是由于HIF-1α主要再栓塞的早期发挥作用,而HIF-2α是在缺氧中晚期发挥作用,这与TACE的治疗过程更加契合。
上述说明仅是本发明技术方案的概述,为了能够更清楚了解本发明的技术手段,并可依照说明书的内容予以实施,以下以本发明的较佳实施例并配合附图详细说明如后。本发明的具体实施方式由以下实施例及其附图详细给出。
附图说明
此处所说明的附图用来提供对本发明的进一步理解,构成本申请的一部分,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。在附图中:
图1为实施例三至实施例六的透射电镜图及粒径分布图;
图2为实施例四和实施例六中阿霉素的体外释放情况图;
图3为实施例五和实施例六中PT-2385的体外释放情况图;
图4为实施例四至实施例六中的体外抗肿瘤效果图;
图5为实施例三至实施例六与对照组的体外HIF-2α抑制能力。
具体实施方式
下面结合附图对本发明做进一步的详细说明,本发明的前述和其它目的、特征、方面和优点将变得更加明显,以令本领域技术人员参照说明书文字能够据以实施。
接下来,结合附图以及具体实施方式,对本发明做进一步描述,需要说明的是,在不相冲突的前提下,以下描述的各实施例之间或各技术特征之间可以任意组合形成新的实施例。应当理解,本文所使用的诸如“具有”、“包含”以及“包括”术语并不配出一个或多个其它元件或其组合的存在或添加。
本实施例提供一种靶向抑制HIF-2α的载药微球制备方法,制备方法包括:
S1、将100质量份的PVA溶解于水中,形成PVA溶液;其中,步骤S1中,将100质量份的PVA溶解于水中,加热至90-100℃至PVA完全溶解,冷却降温至25℃以下。
S2、在PVA溶液中,加入1质量份的透明质酸,在60℃以下搅拌加热,溶解形成HA-PVA溶液;
S3、将0.2质量份的PT-2385和1质量份的阿霉素溶于HA-PVA溶液中,作为乳液水相;
S4、制备乳液油相;具体地,步骤S4包括:在液态石蜡中加入油溶性表面活性剂,混合搅拌试纸充分溶解后,制备得到乳液油相。
S5、将步骤S3中的乳液水相与步骤S4中的乳液油相混合,搅拌得到W/O的乳剂;
S6、加入交联剂和催化剂,搅拌形成微球;
S7、洗涤及干燥后、称重,得到标准的载药微球。
步骤S4中的油溶性表面活性剂为Span-80,1质量份的阿霉素对应加入100μl的Span-80。
步骤S4中,1质量份的阿霉素对应4ml的液态石蜡。
步骤S6中的交联剂为戊二醛;其中,1质量份的阿霉素对应加入0.4ml的戊二醛。
步骤S6中的催化剂为盐酸;其中,1质量份的阿霉素对应加入30μl的盐酸。
步骤S7中洗涤采用石油醚对固化后的微球洗涤至少三次。
相应地,本发明还提供一种载药微球,采用如上任一项所述的靶向抑制HIF-2α的载药微球制备方法制备的载药微球。
相应地,本发明还提供如上任一项所述的靶向抑制HIF-2α的载药微球制备方法制备的载药微球在靶向抑制HIF-2α的应用。
具体实施例有:
实施例一:
PVA/HA微球的制备方法,以500mg的PVA和5mg的HA作为主要壁材,京尼平作为交联剂,采用乳化交联法制备PVA/HA微球,具体制备过程如下:
步骤1将500mg的PVA溶解于10mL蒸馏水中,加热至90-100℃至PVA完全溶解,冷却降温至25℃以下,形成PVA溶液;
步骤2在PVA溶液中加入5mg的HA,适当搅拌加热(60℃以下),溶解形成HA-PVA溶液作为乳液水相;
步骤3将500μL的Span80溶解在20mL液体石蜡中制备油相;
步骤4在50℃条件下,将乳液水相和油相混合,磁力搅拌1h形成油包水(W/O)乳剂;
步骤5在W/O乳剂中加入不同含量(1mL、2mL以及4mL)的交联剂京尼平。
通过肉眼及显微镜观察发现上述W/O乳剂在不同剂量的京尼平作用下并未成球,只成片状,表明京尼平的交联固化效率不适合本专利微球的制备。
实施例二:
PVA/HA微球的制备方法,以500mg的PVA和5mg的HA作为主要壁材,戊二醛作为交联剂,采用乳化交联法制备PVA/HA微球,具体制备过程如下:
步骤1将500mg的PVA溶解于10mL蒸馏水中,加热至90-100℃至PVA完全溶解,冷却降温至25℃以下,形成PVA溶液;
步骤2在PVA溶液中加入5mg的HA,适当搅拌加热(60℃以下),溶解形成HA-PVA溶液作为乳液水相;
步骤3将500μL的Span80溶解在20mL液体石蜡中制备油相;
步骤4在50℃条件下,将乳液水相和油相混合,磁力搅拌1h形成油包水(W/O)乳剂;
步骤5在W/O乳剂中加入1mL的交联剂戊二醛固化形成微球;
步骤6收集固化后的微球用石油醚洗涤三次,自然干燥。
利用显微镜观察微球形态,发现制得较柔软,易破碎,且交联反应时间久,表明微球的固化效果欠佳。
实施例三:
PVA/HA微球的制备方法(PVA/HA-MS),以500mg的PVA和5mg的HA作为主要壁材,戊二醛作为交联剂,并加入催化剂盐酸,采用乳化交联法制备PVA/HA微球,具体制备过程如下:
步骤1将500mg的PVA溶解于10mL蒸馏水中,加热至90-100℃至PVA完全溶解,冷却降温至25℃以下,形成PVA溶液;
步骤2在PVA溶液中加入5mg的HA,适当搅拌加热(60℃以下),溶解形成HA-PVA溶液作为乳液水相;
步骤3将500μL的Span80溶解在20mL液体石蜡中制备油相;
步骤4在50℃条件下,将乳液水相和油相混合,磁力搅拌快速形成油包水(W/O)乳剂;
步骤5在W/O乳剂中加入2mL的交联剂戊二醛以及150μL盐酸固化形成微球;
步骤6收集固化后的微球用石油醚洗涤三次,自然干燥。
利用透射电镜观察微球形态,如附图1所示,发现其形态成球形,较为规则,粒径测定结果显示其粒径范围为18.33±4.93μm。
实施例四:
载阿霉素的PVA/HA微球的制备方法(DOX-MS),以500mg的PVA和5mg的HA作为主要壁材,以5mg的阿霉素作为负载药物,戊二醛作为交联剂,并加入催化剂盐酸,采用乳化交联法制备载阿霉素的PVA/HA微球,具体制备过程如下:
步骤1将500mg的PVA溶解于10mL蒸馏水中,加热至90-100℃至PVA完全溶解,冷却降温至25℃以下,形成PVA溶液;
步骤2在PVA溶液中加入5mg的HA,适当搅拌加热(60℃以下),溶解形成HA-PVA溶液作为乳液水相;
步骤3在乳液水相中加入5mg的阿霉素,搅拌溶解;
步骤4将500μL的Span80溶解在20mL液体石蜡中制备油相;
步骤5在50℃条件下,将含有阿霉素的乳液水相和油相混合,磁力搅拌快速形成油包水(W/O)乳剂;
步骤6在W/O乳剂中加入2mL的交联剂戊二醛以及150μL盐酸固化形成微球;
步骤7收集固化后的微球用石油醚洗涤三次,自然干燥。
利用透射电镜观察微球形态,如附图1所示,发现其形态成球形,较为规则,粒径测定结果显示其粒径范围为20.67±3.87μm,阿霉素的载药量测定为87.4±2.95%。
实施例五:
载PT-2385的PVA/HA微球的制备方法(PT-MS),以500mg的PVA和5mg的HA作为主要壁材,以1mg的PT-2385作为负载药物,戊二醛作为交联剂,并加入催化剂盐酸,采用乳化交联法制备载PT-2385的PVA/HA微球,具体制备过程如下:
步骤1将500mg的PVA溶解于10mL蒸馏水中,加热至90-100℃至PVA完全溶解,冷却降温至25℃以下,形成PVA溶液;
步骤2在PVA溶液中加入5mg的HA,适当搅拌加热(60℃以下),溶解形成HA-PVA溶液作为乳液水相;
步骤3在乳液水相中加入1mg的PT-2385,搅拌溶解;
步骤4将500μL的Span80溶解在20mL液体石蜡中制备油相;
步骤5在50℃条件下,将含有PT-2385的乳液水相和油相混合,磁力搅拌快速形成油包水(W/O)乳剂;
步骤6在W/O乳剂中加入2mL的交联剂戊二醛以及150μL盐酸固化形成微球;
步骤7收集固化后的微球用石油醚洗涤三次,自然干燥。
利用透射电镜观察微球形态,如附图1所示,发现其形态成球形,较为规则,粒径测定结果显示其粒径范围为21.33±5.75μm,PT-2385的载药量测定为85.3±2.29%。
实施例六:
阿霉素和PT-2385共载的PVA/HA微球(PT/DOX-MS)的制备方法,以500mg的PVA和5mg的HA作为主要壁材,以1mg的PT-2385以及5mg的阿霉素作为负载药物,戊二醛作为交联剂,并加入催化剂盐酸,采用乳化交联法制备阿霉素和PT-2385共载的PVA/HA微球,具体制备过程如下:
步骤1将500mg的PVA溶解于10mL蒸馏水中,加热至90-100℃至PVA完全溶解,冷却降温至25℃以下,形成PVA溶液;
步骤2在PVA溶液中加入5mg的HA,适当搅拌加热(60℃以下),溶解形成HA-PVA溶液作为乳液水相;
步骤3在乳液水相中加入1mg的PT-2385和5mg的阿霉素,搅拌溶解;
步骤4将500μL的Span80溶解在20mL液体石蜡中制备油相;
步骤5在50℃条件下,将含有PT-2385和阿霉素的乳液水相和油相混合,磁力搅拌快速形成油包水(W/O)乳剂;
步骤6在W/O乳剂中加入2mL的交联剂戊二醛以及150μL盐酸固化形成微球;
步骤7收集固化后的微球用石油醚洗涤三次,自然干燥。
利用透射电镜观察微球形态,如附图1所示,发现其形态成球形,较为规则,粒径测定结果显示其粒径范围为19.67±4.59μm,PT-2385的载药量测定为83.7±3.07%,阿霉素的载药量测定为84.3±1.08%。
精密称取实施例4和实施例6中的DOX-MS以及PT/DOX-MS各10mg,置于含有10mL磷酸缓冲盐溶液的释放管中,37℃,100rpm恒温振荡。在预设的时间点取样,每次取10mL上清液并加入10mL新鲜释放介质。用紫外分光光度法测定样品中的阿霉素浓度,测得微球中阿霉素的体外释放情况。两种不同微球的阿霉素释放行为如附图2所示,阿霉素在PT/DOX-MS的释放速率在前10天比后20天更快,10天后逐渐进入平台期,而DOX-MS中阿霉素的释放速率呈上升趋势,10天后比PT/DOX-MS快。同时,研究结果显示DOX-MS中阿霉素的释放在30天时达到69.61±4.96%,而PT/DOX-MS中为61.17±3.22%,表明阿霉素在DOX-MS中均实现了有效的缓释,且共载体系对阿霉素的释放行为具有轻微影响。
精密称取实施例5和实施例6中的PT-MS以及PT/DOX-MS各10mg,置于含有10mL磷酸缓冲盐溶液的释放管中,37℃,100rpm恒温振荡。在预设的时间点取样,每次取10mL上清液并加入10mL新鲜释放介质。利用高效液相色谱法测定样品中的PT-2385浓度,测得微球中PT-2385的体外释放情况。两种不同微球的PT-2385释放行为如附图3所示,PT-2385在PT-MS中的释放速率比PT/DOX-MS快,PT-MS和PT/DOX-MS均在前10天释放60%以上,30天时释放80%以上。
利用LM3肝癌细胞进行不同微球的体外抗肿瘤效果评价,精密称取实施例4、实施例5和实施例6中的PT-MS、DOX-MS以及PT/DOX-MS各10mg。将LM3肝癌常规消化,以5×104个(1mL)/孔,接种于12孔Transwell细胞板,每孔体积约1mL。孵育过夜,在Transwell小室中分别加入10mg的实施例4、实施例5和实施例6中所制得的DOX-MS、PT-MS以及PT/DOX-MS,未加微球的细胞作为空白对照,每孔设置3个平行组。在缺氧条件下,微球和细胞共孵育24h之后,将浓度为5mg/ml的MTT以每孔200μL加入12孔板中,放入培养箱中继续培养4h。弃去上清液,每孔加入1mL二甲亚砜以溶解紫色的沉淀物甲瓒,放入水浴恒温振荡器中,振荡15min。从12孔板中,每孔吸取200μL,加入96孔板中,每孔重复2次。将96孔板放入酶标仪中,测定在波长570nm处各孔吸光度A值。以未装有微球的细胞作为对照,求出各组肿瘤细胞的细胞存活率。
细胞存活率(%)=(AT/AC)×100%
式中AT为实验组570nm处的吸光值,AC为空白对照组570nm处的吸光值。根据吸光度值计算各实验组细胞存活率。
由附图4可知,由于PT-2385的加入,显著提升了微球的抗肿瘤效能,PT-2385和阿霉素能够产生协同抗肿瘤作用。
利用蛋白质免疫印迹(Western Blot)检测不同载药微球对HIF-2α的靶向抑制能力。将LM3肝癌常规消化,以5×104个(1mL)/孔,接种于12孔Transwell细胞板,每孔体积约1mL。孵育过夜,在Transwell小室中分别加入10mg的实施例3、实施例4、实施例5和实施例6中所制得的PVA/HA-MS、DOX-MS、PT-MS以及PT/DOX-MS,未加微球的细胞作为空白对照,每孔设置3个平行组。在缺氧条件下,微球和细胞共孵育24h之后收集细胞,通过RIPA裂解缓冲液裂解,并辅以完全不含EDTA的蛋白酶抑制剂混合物、磷酸酶抑制剂混合物1和2提取总蛋白,通过蛋白检测试剂盒进一步定量。通过凝胶电泳分离并电转移到PVDF膜上,在室温下用含有1%Tween的Tris缓冲盐水中的5%脱脂奶粉进一步封闭1小时。随后,将膜洗涤并与抗HIF-2α抗体在4℃下过夜。过夜孵育后,将膜与物种匹配的过氧化物酶偶联的二抗一起孵育。最后,通过增强的化学发光检测特定的反应蛋白。由附图5可知,PT-MS和PT/DOX-MS能够显著抑制肿瘤细胞中HIF-2α的表达。
因此,本发明提供的靶向抑制HIF-2α的载药微球制备方法,通过微球体系共载PT-2385后,将形成PT-2385有效缓释体系,在降低PT-2385毒副作用的同时,使其在肿瘤靶区有效富集,能够靶向抑制HIF-2α的表达,提升其抗肿瘤作用。同时,PT-2385和阿霉素共载微球能够在体内达到长期缓释的作用,从而发挥长效抗肿瘤作用。另外,使用乳化交联法制备PT-2385和阿霉素共载的靶向抑制HIF-2α的新型载药微球,利用戊二醛作为交联剂,盐酸作为催化剂,只需按照一定的速度搅拌即可快速交联形成微球,适用于微球的批量生产,可快速制备得到不同粒径范围的载药微球。本发明创新性地将通过HIF-2α的抑制提升TACE疗效的思路引入到微球中,并将PT-2385引入到化疗栓塞治疗体系中,以往的研究更多的是关注HIF-1α在TACE预后中的作用,这很大原因是由于HIF-1α主要再栓塞的早期发挥作用,而HIF-2α是在缺氧中晚期发挥作用,这与TACE的治疗过程更加契合。
上述说明已经充分揭露了本发明的具体实施方式。需要指出的是,熟悉该领域的技术人员对本发明的具体实施方式所做的任何改动均不脱离本发明的权利要求书的范围。相应地,本发明的保护范围也并不仅仅局限于前述具体实施方式。
Claims (10)
1.靶向抑制HIF-2α的载药微球制备方法,其特征在于,制备方法包括:
S1、将100质量份的PVA溶解于水中,形成PVA溶液;
S2、在PVA溶液中,加入1质量份的透明质酸,在60℃以下搅拌加热,溶解形成HA-PVA溶液;
S3、将0.2质量份的PT-2385和1质量份的阿霉素溶于HA-PVA溶液中,作为乳液水相;
S4、制备乳液油相;
S5、将步骤S3中的乳液水相与步骤S4中的乳液油相混合,搅拌得到W/O的乳剂;
S6、加入交联剂和催化剂,搅拌形成微球;
S7、洗涤及干燥后、称重,得到标准的载药微球。
2.如权利要求1所述的靶向抑制HIF-2α的载药微球制备方法,其特征在于,步骤S4包括:
在液态石蜡中加入油溶性表面活性剂,混合搅拌试纸充分溶解后,制备得到乳液油相。
3.如权利要求2所述的靶向抑制HIF-2α的载药微球制备方法,其特征在于,所述油溶性表面活性剂为Span-80,1质量份的阿霉素对应加入100μl的Span-80。
4.如权利要求2所述的靶向抑制HIF-2α的载药微球制备方法,其特征在于,1质量份的阿霉素对应4ml的液态石蜡。
5.如权利要求1所述的靶向抑制HIF-2α的载药微球制备方法,其特征在于,所述交联剂为戊二醛;其中,1质量份的阿霉素对应加入0.4ml的戊二醛。
6.如权利要求1所述的靶向抑制HIF-2α的载药微球制备方法,其特征在于,所述催化剂为盐酸;其中,1质量份的阿霉素对应加入30μl的盐酸。
7.如权利要求1所述的靶向抑制HIF-2α的载药微球制备方法,其特征在于,步骤S7中洗涤采用石油醚对固化后的微球洗涤至少三次。
8.如权利要求1所述的靶向抑制HIF-2α的载药微球制备方法,其特征在于,步骤S1中,将100质量份的PVA溶解于水中,加热至90-100℃至PVA完全溶解,冷却降温至25℃以下。
9.一种载药微球,其特征在于:采用如权利要求1-8任一项所述的靶向抑制HIF-2α的载药微球制备方法制备的载药微球。
10.如权利要求1-8任一项所述的靶向抑制HIF-2α的载药微球制备方法制备的载药微球在靶向抑制HIF-2α的应用。
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