CN113769110A - 一种光动力联合钙超载的纳米载体及其制备方法与应用 - Google Patents
一种光动力联合钙超载的纳米载体及其制备方法与应用 Download PDFInfo
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Abstract
本发明涉及一种光动力联合钙超载的纳米载体及其制备方法与应用,具体公开了一种靶向肿瘤细胞的抗肿瘤纳米载体,其特征在于,所述纳米载体包括过氧化钙颗粒,所述过氧化钙颗粒表面静电吸附有黑磷量子点,且吸附有黑磷量子点的过氧化钙颗粒被聚合物包裹形成纳米颗粒,所述聚合物上偶联有靶向肿瘤表面标志物的修饰物;所述修饰物选自靶向肿瘤表面标志物的抗体、叶酸、多肽、适配体。所述纳米载体可以促进高表达GPC3的肿瘤细胞凋亡或抑制其增殖,可以作为GPC3结合位点的生物纳米类药物,可用于制备预防和/或治疗肝癌药物。
Description
技术领域
本发明涉及生物技术和生物医药领域,具体涉及一种光动力联合钙超载的纳米载体及其制备方法与应用。
背景技术
1.1.肝癌
肝细胞癌(HCC)是全球常见的恶性肿瘤,超过53%的HCC患者来自中国。目前,HCC的主要治愈性治疗方法是手术切除,这也是肿瘤大小小于3厘米的早期HCC患者的首选。然而,目前的治疗效果仍不令人满意,部分原因是术后肿瘤复发。据报道,大约50%的患者可能会出现肿瘤复发,表现为治愈性肝切除术后2年内出现肝内或肝外转移。因此,探索HCC复发的分子机制对改善临床预后仍有重要意义。
到2017年,中国致死率排名第三和第五的分别为肺癌和肝癌[1],癌症攻克方面依然面临着严峻的形式。传统的手术切除并不能彻底清除病灶,这就为术后复发和预后不理想埋下了隐患。临床治疗多采用手术和化疗、放疗协同作用手段,但是当前的化学治疗方法由于其药物本身性质和身体内药物递送机制使得其对身体危害极大,常常会带来更加严重的副反应。放射治疗方法又由于其放射剂量难以控制,过小的计量达不到杀死肿瘤的效果,剂量过大又会对正常组织造成破坏,所以肿瘤一般治疗依然处于进退两难的境地。纳米医学的兴起,为肿瘤治疗带来一丝曙光,利用纳米尺寸所带来的独特效应使得治疗趋于精准化、个人化。
1.2.可以被靶向的肝癌标志物GPC3
通常需要选择具有特异性靶向某种肿瘤的靶标蛋白,该蛋白需满足的基本条件是在肿瘤细胞中过度表达,而在正常细胞中低表达甚至不表达,这样可以使得递送的精准程度提高同时减少了毒副作用。
Glypican-3(GPC3)是硫酸乙酰肝素蛋白聚糖家族的成员,基本结构由核心蛋白,硫酸乙酰肝素链(Heparan sulfate proteoglycan,HSPG)和糖基磷脂酰肌醇(Glycophosphatidylinositol,GPI)组成。GPC3通过GPI锚定到细胞膜表面并通过接收来自细胞表面的受体信号调节细胞形态,粘附,增殖、迁移、生存和分化[2]。有一些研究表明,GPC3参与肝癌的发生和发展并被发现即使在肝癌早期也高水平表达且调节许多细胞的生理和病理进程。相比之下,未检测到GPC3表达在健康成年人的肝脏中。GPC3参与了与各种配体和受体相互作用的过程,参与抑制和调节包括细胞粘附分子,基质成分,生长因子,酶和酶抑制剂。GPC3在大多数中胚层组织和器官中潜在的分子机制仍然未知,但其作为肝癌靶向的标志物具有巨大的发展潜力。
1.3.钙离子治疗策略
Ca2+调节的能力与细胞的增殖、死亡息息相关,而潜在的药理作用也为开发新的药物和治疗方法提供思路。钙离子在肿瘤中的应用应考虑到如下几点:1)Ca2+稳态控制各种细胞过程,包括与肿瘤发生有关的过程,例如增殖,凋亡,基因转录;2)Ca2+通道(channels),泵(pumps)和交换蛋白(exchangers)控制着复杂而严格Ca2+稳态调节。尽管这些特定的蛋白质都是负责增加或减少细胞内游离的Ca2+,但是这些通道,泵和交换蛋白的细胞分布和运输机制并不完全相同,这意味着这些蛋白的抑制剂或激活剂都可能是癌症治疗潜在的治疗剂;3)许多Ca2+通道,泵和交换蛋白是由药理学调节的,是可作为药物开发靶点的;4)一些癌症与特定的Ca2+通道或泵的上调或下调有关。例如,TRPM8在前列腺癌中上调,而SERCA3在结肠癌中下调。考虑到上述因素,目前针对肿瘤细胞内的钙离子可开发出不同的治疗策略,大体上有三种:针对Ca2+通道或泵设计拮抗/激动剂、切断钙离子参与的促肿瘤信号以及针对细胞内广泛存在的Ca2+采取耗竭或过载的策略[3]。其中,切断信号或利用拮抗剂或促进剂都可通过小分子药物或抗体得以实现,而这一过程的实现给予纳米递药载体以广阔的发展空间。而钙离子过载策略是其中较为好实现的手段。
1.4.光动力疗法
光动力治疗(PDT)是光热治疗之外另一个具有很大潜力的治疗方法,它具有低细胞毒性、轻微副反应、良好的选择性等优势。利用一定波长下的光激发光敏剂由基态转变为激发态,当其从激发态返回到基态的时会释放能量引发组织中的氧气转变成活性氧(ROS),包括单线态氧1O2和游离自由基等[4]。PDT作用需要三个关键因素:光敏剂、激发光和氧气,但是研究表明肿瘤多处于低氧微环境[5-7],为了克服这个困难现在主要有三种形式的解决方法:1)O2补充策略:可直接补充氧气为PDT提供原料;2)新型PDT模式:减少对氧气的依赖;
3)其他免疫治疗联合PDT治疗:低氧或无氧激活PDT模式[8]。
参考文献
1.Zhou M,Wang H,Zeng X,Yin P,Zhu J,Chen W,Li X,Wang L,Wang L,Liu Y etal:Mortality,morbidity,and risk factors in China and its provinces,1990–2017:a systematic analysis for the Global Burden of Disease Study 2017.The Lancet2019,394(10204):1145-1158.
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发明内容
为了克服现有技术的不足和缺点,本发明的首要目的在于提供一种靶向肿瘤细胞表面标志物的纳米载体,该纳米载体与高表达肿瘤表面标志物的肿瘤细胞有较高亲和力,能够通过与肿瘤表面标志物,尤其是GPC3结合后进入肿瘤细胞内发挥光动力与钙超载的联合治疗模式,且证明了该纳米载体在靶向抑制肝癌细胞增殖、促进肝癌细胞凋亡等方面起着重要的作用,其在肝癌靶向治疗方面具有巨大的应用价值。
本发明的另一目的在于提供上述靶向肿瘤细胞表面标志物高表达肿瘤细胞的肿瘤细胞表面标志物的单克隆抗体修饰的PEG包裹负载黑磷量子点的过氧化钙的纳米颗粒及其衍生物,该衍生物也能够与高表达肿瘤标志物的肿瘤细胞特异性结合。
本发明的再一目的在于提供上述纳米颗粒及其衍生物的应用。
为了实现上述任务,本发明采取如下的技术解决方案:
本发明一个方面提供了一种靶向肿瘤细胞的抗肿瘤纳米载体,所述纳米载体包括过氧化钙颗粒,所述过氧化钙颗粒表面静电吸附有黑磷量子点,且吸附有黑磷量子点的过氧化钙颗粒被聚合物包裹形成纳米颗粒,所述聚合物上偶联有靶向肿瘤表面标志物的修饰物。
进一步地,所述修饰物选自靶向肿瘤表面标志物的抗体、叶酸、多肽、适配体;更进一步地,靶向肿瘤表面标志物的抗体选自靶向肝癌标志物GPC3的抗体、抗CD133抗体、抗CD44抗体、抗PD-L1抗体、抗EGFR抗体、叶酸、多肽、适配体;
更进一步地,所述抗体为单克隆抗体。
进一步地,所述聚合物选自聚乙二醇、PLGA、壳聚糖、透明质酸或其他生物膜材料。
进一步地,靶向肿瘤表面标志物的抗体通过化学键与聚合物偶联。
进一步地,所述聚合物优选为聚乙二醇,所述聚乙二醇的分子量为4000-6000。
进一步地,所述抗肿瘤纳米载体的粒径为150-200nm,优选为160-180nm。
进一步地,所述抗肿瘤纳米载体上还负载抗肿瘤药物。
本发明另一个方面提供了一种光动力联合钙离子超载的抗肿瘤的药物,所述药物包含上述纳米载体以及至少一种药学上可接受的辅料。
进一步地,所述药物中还包含钙离子超载辅助佐剂,更进一步地,所述超载辅助佐剂与上述纳米载体分离放置。
进一步地,所述钙离子超载辅助佐剂选自ionomycin。
进一步地,所述药学上可接受的辅料为稀释剂、赋形剂、填充剂、粘合剂、湿润剂、崩解剂、吸收促进剂、吸附载体、表面活性剂或润滑剂中的至少一种。
进一步地,所述的药物可以进一步制成片剂、粒剂、胶囊、口服液或注射剂等多种形式,各种剂型的药物可以按照药学领域的常规方法制备。
本发明另一个方面提供了靶向肿瘤细胞的抗肿瘤纳米载体的制备方法,所述制备方法包括以下步骤:
1)分别制备黑磷量子点和过氧化钙;
2)将过氧化钙与黑磷量子点在溶液中混合负载,形成负载黑磷量子点的过氧化钙;
3)将聚合物溶液加入到负载黑磷量子点的过氧化钙中,混合后获得聚合物包括的负载黑磷量子点的过氧化钙的纳米颗粒;
4)通过化学偶联的方式在聚合物上偶联靶向肿瘤表面标志物的修饰物。
进一步地,所述步骤1)中黑磷量子点的制备方法为将黑磷纳米片超声处理,形成黑磷量子点。
进一步地,所述步骤1)中过氧化钙的制备方法为氢氧化钙在阳离子表面活性剂以及氧化剂的存在下反应,获得过氧化钙。所述阳离子表面活性剂选自十六烷基三甲基溴化铵;氧化剂选自过氧化氢。
本发明再一个方面提供了本发明所述的纳米载体或药物在制备治疗肿瘤的制剂中的用途。
进一步地,所述肿瘤选自肝癌、肺癌、直结肠癌、乳腺癌、宫颈癌、卵巢癌、前列腺癌、胆管癌、胰腺癌、白血病、非小细胞肺癌、头颈癌。
在一些具体实施例中,所述的肿瘤选自高表达GPC3的肿瘤,例如高表达GP3C3的肝癌。
本发明再一个方面提供了本发明所述的纳米载体制备促进高表达GPC3的肿瘤细胞凋亡或抑制其增殖的药物中的用途。
本发明再一个方面一种光动力联合钙离子超载治疗肿瘤的方法,所述方法包括将发明的纳米载体施用于受试者的步骤。
进一步地,还包括在近红外条件下照射,和或进一步施用钙离子超载辅助佐剂引发钙离子超载治疗的步骤。
本发明相对于现有技术具有如下的优点及效果:
(1)本发明提供了一种纳米载体,能够较好与GPC3或其他肿瘤表面标志物结合,并在细胞内产生独特的光动力结合钙超载疗法。
(2)本发明设计得到的纳米载体可以通过促进细胞进入凋亡信号通路抑制肝癌细胞增殖,促进结肝癌细胞发生凋亡,可以作为GPC3结合位点的生物纳米类药物,可用于制备预防和/或治疗肝癌药物
附图说明
图1为实施例1制备的BPQD@CaO2-PEG-GPC3Ab纳米载体的透射电镜图;
图2为实施例1制备的BPQD@CaO2-PEG-GPC3Ab纳米载体靶向肝癌细胞Huh7的共聚焦激光扫描结果;
图3为实施例1制备的BPQD@CaO2-PEG-GPC3Ab纳米载体抑制肝癌细胞Huh7的增殖作用;其中A为BPQD@CaO2-PEG-GPC3Ab纳米在不同的CaO2浓度下对肿瘤细胞活力的影响,B为BPQD@CaO2-PEG-GPC3Ab纳米在不同的PBQD浓度下对肿瘤细胞活力的影响;
图4为实施例1制备的BPQD@CaO2-PEG-GPC3Ab纳米载体促进Huh7发生凋亡。A:不同处理组流式细胞仪检测对照组细胞凋亡;B:细胞凋亡数据统计。
具体实施方式
为了使本发明的上述目的、特征和优点能够更加明显易懂,下面对本发明的具体实施方式做详细的说明,但不能理解为对本发明的可实施范围的限定。
为了更清楚地理解本发明,现参照下列实施例及附图进一步描述本发明。实施例仅用于解释而不以任何方式限制本发明。实施例中,各原始试剂材料均可商购获得,未注明具体条件的实验方法为所属领域熟知的常规方法和常规条件,或按照仪器制造商所建议的条件。
实施例1:BPQD@CaO2-PEG-GPC3Ab纳米载体的合成。
本实施例主要是为了合成形貌良好尺寸适宜的BPQD@CaO2-PEG-GPC3Ab纳米载体。具体如下:
1.制备黑磷量子点与过氧化钙
①将10mL水溶液分散的黑磷纳米片(BPNs)混合物(200μg/mL)超声处理12h(或可适当延长),并通过冰水浴将温度保持在5℃以下;
②超声处理的频率为20kHz,超声头工作5s,每个周期间隔5s。;
③然后将超声处理的混合物以13000rpm离心30min。;
④得到的黑磷量子点(BPQDs)初产物用超纯水洗涤三次,并保存在4℃下以便将来使用;
⑤将1.0g氢氧化钙(Ca(OH)2)添加到20mL超纯水中,然后超声处理5min;
⑥将15wt%的十六烷基三甲基溴化铵(CTAB)添加至所获得的水溶液中,并在室温(RT)和磁力搅拌下反应50min;
⑦之后,将体系转移至在冰水浴中,以较缓慢的搅拌速度持续反应,同时将10.58mL的30%H2 O2溶液逐滴滴加到混合物中;
⑧反应完成后,离心分离出淡黄色产物,并用超纯水洗涤3次。最后,将湿固体在60℃下干燥4h。所得产物为带正电的CaO2,于在4℃下储存。
2.制备功能化的过氧化钙基载药载体
①无靶向基团连接的纳米载体制备:将制备的CaO2(1.0,2.0,4.0mg)添加至所制备的BPQDs溶液中将混合物调节至50、100、200μg/mL进行10min超声处理,缓慢搅拌4h形成负载黑磷量子点的过氧化钙(BPQD@CaO2)混合物,然后将500μL PEG(H2N-PEG-NH2,15mg,MW5000,预溶于超纯水)溶液缓慢添加至BPQD@CaO2混合物中,并缓慢搅拌过夜,以达到进一步改性的目的。24小时后,将PEG包裹负载黑磷量子点的过氧化钙的纳米颗粒(BPQD@CaO2-PEG)以13000rpm离心,并用超纯水洗涤3次除去过量的PEG分子。
②靶向基团的化学连接:为了获得抗体偶联的纳米颗粒,将上述纳米颗粒表面的PEG的氨基末端通过1-乙基-3-(3-二甲基氨基丙基)碳二亚胺盐酸盐/N-羟基琥珀酰亚胺(EDC/NHS)催化方法与抗GPC3抗体的羧基反应。具体方法为首先将抗GPC3单克隆抗体GPC3Ab(0.568mg/mL,0.1mL)市售抗体,产品号cat.No.207080溶于0.1mL MES缓冲液I(0.1M,pH 6.1)中进行活化,所述MES缓冲液中包含10.23mg NHS和11.36mg EDC。在室温下摇动2h后,将所得溶液与BPQD@CaO2-PEG纳米颗粒(2.0mg)混合,分散在5.0mL MES缓冲液II(0.1M,pH 7.5,300mM NaCl)中进行抗体偶联。12小时后,通过离心收集抗GPC3单克隆抗体修饰的PEG包裹负载黑磷量子点的过氧化钙的纳米颗粒(BPQD@CaO2-PEG-GPC3Ab),并用超纯水洗涤3次。
上述BPQD@CaO2-PEG-GPC3Ab纳米载体的合成主要利用静电相互作用以及化学修饰EDC/NHS的方法,其中静电修饰利用正负电荷之间的吸引力使得黑磷量子点吸附于过氧化钙纳米颗粒之上;EDC/NHS化学共价键修饰的方法将单克隆抗体偶联在PEG上。
实施例2纳米递药载体的物化性质表征
通过FEI Tecnai G2透射电子显微镜对BPQDs和CaO2基纳米颗粒的形貌进行了表征;制样方法:样品用水分散至合理浓度后取小滴溶液滴加至铜网上干燥过夜。结果见图1。
实施例3BPQD@CaO2-PEG-GPC3Ab靶向肝癌细胞Huh7实验
在细胞靶向实验中,Fluo-4 AM用于检测荧光强度从而间接表现出钙含量。
①将适当密度的细胞接种在载玻片上,并在37℃,5%CO2下培养24h;
②然后,将基于CaO2的纳米颗粒添加到培养基中,再进行2h孵育;
③然后根据标准实验过程:去除培养基后用PBS洗涤三次;
④然后再用PFA固定15min,接着PBS洗去PFA后用DAPI对细胞染色5-10min,并通过共聚焦激光扫描显微镜(CLSM)测定荧光,见图2。实验结果显示本发明制备获得的BPQD@CaO2-PEG-GPC3Ab纳米载体能够靶向肿瘤细胞。
实施例4BPQD@CaO2-PEG-GPC3Ab可以显著抑制肝癌细胞Huh7的增殖
①将肝癌细胞Huh7以5×103个/孔接种于96孔细胞培养板中,每孔培养基体积为200μL,培养24h,然后饥饿过夜;
②加入不同测试样品并进行处理:(i)BPQDs;(ii)BPQDs+808nm NIR(10min,1.0W/cm2)照射;(iii)CaO2和ionomycin(5μM)后处理;(iv)CaO2-PEG-GPC3Ab;(v)BPQD@CaO2-PEG-GPC3Ab;(vi)BPQD@CaO2-PEG-GPC3Ab的808nm NIR照射(10min,1.0W/cm2);(vii)BPQD@CaO2-PEG-GPC3Ab和ionomycin(5μM)后处理;(viii)BPQD@CaO2-PEG-GPC3Ab经过808nm NIR(10min,1.0W/cm2)辐射ionomycin(5μM)进行处理,培养24小时,其中ionomycin为钙离子超载辅助佐剂用于进一步使肿瘤细胞内钙离子超载;
③除去旧培养基,每孔中添加每100μL含有10μL CCK-8溶液的新鲜培养基;
④孵育1h后,将96孔板在450nm处进行光密度(OD)测量,实验结果见图3,其中A为各样品中CaO2的浓度分别为5μg/mL、10μg/mL、20μg/mL和40μg/mL的结果,而B为各样品中BPQD浓度分别为5μg/mL、10μg/mL和20μg/mL的结果。实验结果显示,相对于BPQDs、BPQDs+NIR处理、CaO2和ionomycin后处理、CaO2-PEG-GPC3Ab处理,BPQD@CaO2-PEG-GPC3Ab显示了更好的抑制肝癌细胞Huh7的增殖的作用,同时增加ionomycin后处理以及NIR处理后显著降低了肿瘤细胞的存活率,甚至实现完全杀灭肿瘤细胞的效果。
实施例5BPQD@CaO2-PEG-GPC3Ab可以促进肝癌细胞Huh7的凋亡
①将肝癌细胞Huh7以5×105个/孔接种于6孔细胞培养板中,每孔培养基体积为1mL,培养24h,然后饥饿过夜;
②加入不同处理(i)BPQD@CaO2-PEG-GPC3Ab,ii)BPQD@CaO2-PEG-GPC3Ab+NIR照射,iii)BPQD@CaO2-PEG-GPC3Ab+ionomycin(5μM)和iv)BPQD@CaO2-PEG-GPC3Ab+NIR照射+ionomycin(5μM)分别培养24小时;
③先将上清收集到离心管中,再用不含EDTA的胰酶小心消化收集细胞培养液到离心管。500g左右离心5分钟,沉淀细胞;
④用预冷的PBS洗涤细胞两次,500g左右离心5分钟收集细胞;
⑤加入100μL预冷的1×AnnexinV Binding Buffer,重悬细胞;
⑥加入5μL AnnexinV-FITC和5μL PI,轻轻混匀,室温避光反应15分钟;
⑦加入400μL预冷的1×AnnexinV Binding Buffer,轻轻混匀,将样品至于冰上避光放置,1h内用流式细胞仪检测。分析检测结果。
实验结果见图4,通过流式细胞仪分析发现,随着作用浓度的升高,B P QD@C aO2-P EG-GPC 3A可以明显促进肝癌细胞Huh7发生凋亡。与对照组相比较有显著性差异,**P<0.01。
Claims (10)
1.一种靶向肿瘤细胞的抗肿瘤纳米载体,其特征在于,所述纳米载体包括过氧化钙颗粒,所述过氧化钙颗粒表面静电吸附有黑磷量子点,且吸附有黑磷量子点的过氧化钙颗粒被聚合物包裹形成纳米颗粒,所述聚合物上偶联有靶向肿瘤表面标志物的修饰物;
优选地,所述修饰物选自靶向肿瘤表面标志物的抗体、叶酸、多肽、适配体。
2.根据权利要求1所述的抗肿瘤纳米载体,其特征在于,所述聚合物选自聚乙二醇、PLGA、壳聚糖、透明质酸或其他生物膜材料;
优选地,所述聚合物为聚乙二醇,所述聚乙二醇的分子量为4000-6000。
3.根据权利要求1所述的抗肿瘤纳米载体,其特征在于,所述靶向肿瘤表面标志物的抗体选自靶向肝癌标志物GPC3的抗体、抗CD133抗体、抗CD44抗体、抗PD-L1抗体、抗EGFR抗体、叶酸、多肽、适配体。
4.根据权利要求1所述的抗肿瘤纳米载体,其特征在于,所述抗肿瘤纳米载体上还负载抗肿瘤药物。
5.一种光动力联合钙离子超载的抗肿瘤的药物,其特征在于,所述药物包含上述纳米载体以及至少一种药学上可接受的辅料;
优选地,所述药学上可接受的辅料为稀释剂、赋形剂、填充剂、粘合剂、湿润剂、崩解剂、吸收促进剂、吸附载体、表面活性剂或润滑剂中的至少一种;
优选地,所述的药物进一步制成片剂、粒剂、胶囊、口服液或注射剂。
6.根据权利要求5所述的光动力联合钙离子超载的抗肿瘤的药物,其特征在于,所述药物中还包含钙离子超载辅助佐剂;
优选地,所述超载辅助佐剂与上述纳米载体分离放置;
优选地,所述钙离子超载辅助佐剂选自ionomycin。
7.根据权利要求1-4任一项所述的靶向肿瘤细胞的抗肿瘤纳米载体的制备方法,所述制备方法包括以下步骤:
1)分别制备黑磷量子点和过氧化钙;
2)将过氧化钙与黑磷量子点在溶液中混合负载,形成负载黑磷量子点的过氧化钙;
3)将聚合物溶液加入到负载黑磷量子点的过氧化钙中,混合后获得聚合物包括的负载黑磷量子点的过氧化钙的纳米颗粒;
4)通过化学偶联的方式在聚合物上偶联靶向肿瘤表面标志物的修饰物。
8.权利要求1-4任一项所述的纳米载体或权利要求5-6任一项所述的药物在制备治疗肿瘤的制剂中的用途;
优选地,所述肿瘤选自肝癌、肺癌、直结肠癌、乳腺癌、宫颈癌、卵巢癌、前列腺癌、胆管癌、胰腺癌、白血病、非小细胞肺癌、头颈癌;
优选地,所述的肿瘤选自高表达GPC3的肿瘤,更优选为高表达GP3C3的肝癌。
9.权利要求1-4任一项所述的纳米载体或权利要求5-6任一项所述的药物在制备促进高表达GPC3的肿瘤细胞凋亡或抑制其增殖的药物中的用途。
10.一种光动力联合钙离子超载治疗肿瘤的方法,所述方法包括将权利要求1-4任一项所述的纳米载体或权利要求5-6任一项所述的药物施用于受试者的步骤;
优选地,还包括在近红外条件下照射,和或进一步施用钙离子超载辅助佐剂引发钙离子超载治疗的步骤。
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