CN116999578A - 一种基于胆红素衍生物的用于诊断及治疗的超声波造影剂 - Google Patents
一种基于胆红素衍生物的用于诊断及治疗的超声波造影剂 Download PDFInfo
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- CN116999578A CN116999578A CN202311006588.7A CN202311006588A CN116999578A CN 116999578 A CN116999578 A CN 116999578A CN 202311006588 A CN202311006588 A CN 202311006588A CN 116999578 A CN116999578 A CN 116999578A
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Abstract
本发明涉及一种基于胆红素衍生物的用于诊断及治疗的超声波造影剂。本发明的含有胆红素衍生物的微细粒子,其对活性氧类(reactive oxygen species,ROS)敏感地反应,并且与疏水性药物结合,可以有效地将包括氧化铁纳米粒子在内的金属进行螯合。因此本发明的微细粒子,不仅可以用于超声波诊断的造影剂,而且还可以用于磁共振影像诊断的造影剂及基于疏水性药物或者铂金类药物的传递载体。
Description
技术领域
本专利申请对于2018年2月5日向韩国专利厅提交的韩国专利申请第10-2018-0014160号申请主张优先权,并且将该专利申请的公开内容作为参照并入本说明书中。
本发明涉及一种基于胆红素衍生物的用于诊断及治疗的超声波造影剂。
背景技术
超声波(ultrasound)是指具有大于人类的可听音域即20000Hz频率的声波,利用这一超声波将在体内的各种器官、骨头、肌肉组织和血液等各种边界通过声波的扩散、反射、吸收及散射来生成的信号差异用影像来体现的称为超声波影像(ultrasonography)。用于医疗诊断的超声波影像装置,其作为目前最广泛使用的诊断技术之一,移动性和接近性突出的同时,相较于磁共振成像(magnetic resonance imaging,MRI)和计算机断层摄影(Computed tomography,CT)等技术,最为安全且快,而且成本低效率高的诊断技术。不过,由于与MRI、CT和PET的技术相比影像质量低,因此为了改善影像质量正在开发各种超声波造影剂。
超声波造影剂,其为微米气泡(micro bubble)或纳米气泡(nano bubble)的形态,在其中心有疏水性的气态核心(gas core),并且该气态核心被由蛋白质、(磷)脂质或高分子等组成的壳(shell)围绕。当气体状态的超声波造影剂的气泡进入液体状态的血液并且暴露于超声波时,发生共振现象并且产生超声波散射,而且影像信号得到增强从而能够获得更清晰的影像。但是,为了增强所希望的位置上的影像,造影剂的气泡不得在气体和液体的界面处受温度或压力变化而破裂。因此,要求围绕超声波造影剂的壳的构成物质应当对气泡赋予结构上的稳定性,而且对人体免疫***的影响要小。例如亲水性分子,由于其在到达所需目标位置之前被人体的免疫***处理的可能性高,因此对与超声波造影剂的核心部(core)形成接触面的物质的研究,主要是围绕疏水性分子进行的。
最近,正在尝试着从利用超声波诊断疾病的领域中摆脱出来,以非侵入性的方法来治疗疾病的研究。尤其是,已经开发了以下方法:将超声波聚焦在一处以使人体组织的温度加热(tissue heating)到超过体温的温度,从而诱导细胞坏死,或者在短时间内暴露在高温(ablative therapy),从而去除组织。另外,进一步地,正在开发将超声波造影剂利用为药物载体以同时进行诊断和治疗的造影剂粒子。
[现有技术文献]
[专利文献]
韩国授权专利第10-1681299号
发明内容
[解决的技术问题]
本发明人为了开发可以利用超声波同时进行诊断和治疗的新的超声波造影剂粒子进行了坚持不懈地努力。在这一过程中,确认了通过将亲水性分子引入胆红素中制备的两亲性胆红素衍生物,可以用于以疏水性气体为核心的超声波造影剂粒子的壳,其对活性氧类(reactive oxygen species,ROS)敏感地反应,并且可以有效地将包括氧化铁纳米粒子在内的金属进行负载或者螯合,从而得以完成本发明。
因此,本发明的目的是提供一种微细粒子,包括:核心(core)部,在其内部含有疏水性气体;以及壳(shell)层,围绕所述核心部的表面并包含胆红素衍生物。
本发明的另一个目的是提供一种包含所述微细粒子的超声波造影剂。
本发明的另一个目的是提供一种患者诊断性成像的方法,包括:将包含所述微细粒子的有效量的超声波造影剂注入于患者的步骤;以及将所述患者的身体部位或身体组织进行成像的步骤。
本发明的另一个目的是提供一种患者治疗性成像的方法,包括:将包含所述微细粒子的有效量的超声波造影剂注入于患者的步骤;以及将所述患者的身体部位或身体组织的病变进行治疗的步骤。
本发明的另一个目的是提供一种所述微细粒子的制备方法。
[技术方案]
根据本发明的一个样态,本发明提供一种微细粒子,包括:核心(core)部,其内部含有疏水性气体(gas);以及壳(shell)层,围绕所述核心部的表面并包含胆红素衍生物。
本发明的“微细粒子”具有气泡(泡沫,bubble)结构,该气泡结构包括:在其内部含有疏水性气体的核心部和围绕所述核心部的表面的壳层。因此,本发明的微细粒子与“微细泡沫”或“微细气泡”是同义词。另外,本发明的“微细粒子”具有1nm-100μm的粒子大小。因此,可以将“微细粒子”同术语“纳米气泡(nano bubble)”或“微米气泡(micro bubble)”混用。
另外,本发明的微细粒子可以用于增强超声波影像信号的造影剂。超声波造影剂是将在注入于人体的纳米或微米大小的气泡界面上产生的超声波信号的差异用于诊断上。超声波造影剂通常是由蛋白质、脂质或高分子等构成的薄膜(壳,shell)包裹气态核心(core)的结构。
超声波造影剂的气态核心,因气体状态的分子的特性,对表面张力及外部压力的变化敏感。因此,超声波造影剂在血液中的稳定性,相较于固体状态的造影剂,液体状态的造影剂的稳定性低。因此,为了使超声波造影剂在血液中保持稳定状态,应当将在血液中具有低溶解度的疏水性气体用作造影剂的气态核心。此外,构成造影剂壳层的物质应当对其赋予结构上的稳定性,以使其不会因气体和液体之间的界面上受温度或压力变化而破裂,并且对人体免疫***的影响要小。
也就是说,本发明的微细粒子是构成包含胆红素衍生物的壳层的物质,其技术特征在于使用胆红素衍生物。因此,在本领域中可以使用的任何疏水性气体都可以用作本发明的微细粒子的疏水性气体。
根据本发明的一个实施例,所述疏水性气体可以选自例如由空气、氮气、氦气、氩气、二氧化碳、六氟化硫(sulfur hexfluoride,SF 6)和C1至C10的全氟碳(perfluorocarbon,PFC)组成的组中,但不限于此。所述C1至C10的全氟碳(perfluorocarbon)有全氟丁烷(perfluorobutane)、全氟戊烷(perfluoropentane)、八氟丙烷和十氟戊烷(decafluoropentane)等。
根据本发明的一个实施例,本发明的所述胆红素衍生物是亲水性分子共价结合于胆红素而制成。所述胆红素衍生物是由疏水性的胆红素与亲水性分子共价结合从而具有两亲性。
在本说明书中,术语“亲水性(hydrophilicity)”是主要在极性物质中出现的倾向,是指对水具有较强的亲和力且溶于水的性质。例如,亲水性高分子化合物易溶于水,在涂覆有亲水性物质的固体表面上,当滴入水滴时,接触角为90°以下。
在本说明书中,术语“疏水性(hydrophobicity)”是在非极性物质中出现的倾向,是指从水分子中排除并聚集的性质。当疏水性物质在亲水性液体中时,疏水性物质之间的疏水性结合得到增加,使得疏水性物质聚集。在涂覆有疏水性高分子化合物的固体表面上,当滴入水滴时,接触角为90°以上。
根据本发明的一个具体的实施例,所述亲水性分子(化合物)可以选自由葡聚糖(dextran)、羧葡聚糖(carbodextran)、多聚糖(polysaccharide)、环状糊精(cyclodextran)、普鲁兰多糖(pluronic)、纤维素(cellulose)、淀粉(starch)、糖原(glycogen)、碳水化合物(carbohydrate)、单糖类(monosaccharide)、双糖类(bisaccharide)和寡糖类(oligosaccharide)、多肽(polypeptide)、多磷酸肌酸(polyphosphagen)、聚丙交酯(polylactide)、聚(乳酸-羟基乙酸共聚物)(poly(lactic-co-glycolic acid))、聚己内酯(polycaprolactone)、聚酐(polyanhydride)、聚马来酸(polymaleic acid)以及聚马来酸的衍生物、聚氰基丙烯酸烷酯(polyalkylcyanoacrylate)、聚羟基丁酸酯(polyhydroxybutylate)、聚碳酸酯(polycarbonate)、聚原酸酯(polyorthoester)、聚乙二醇(polyethyleneglycol,PEG)、甲氧基聚乙二醇(methoxy polyethyleneglycol,mPEG)、聚丙二醇、聚乙烯亚胺(polyethylenimine)、多聚-L-赖氨酸(poly-L-lysine)、聚乙交酯(polyglycolide)、聚甲基丙烯酸甲酯(polymetacrylate)、聚乙烯吡咯烷酮(polyvinylpyrrolidone)、聚(丙烯酸酯)(poly[acrylate])、聚(丙烯酰胺)(poly[acrylamide])、聚(乙烯基酯)(poly[vinylester])、聚(乙烯醇)(poly[vinyl alcohol])、聚苯乙烯(polystryene)、多氧化物(polyoxide)、聚电解质(polyelectrolyte)、聚(1-硝基丙烯)(poly[1-nitropropylene])、聚(N-乙烯基吡咯烷酮)(poly[N-vinyl pyrrolidone])、聚(乙烯胺)(poly[vinylamine])、聚(甲基丙烯酸β-羟乙酯)(Poly[beta-hydroxyethylmethacrylate])、聚环氧乙烷(Polyethyleneoxide)、聚(环氧乙烷-环氧丙烷)(Poly[ethylene oxide-bpropyleneoxide])、聚赖氨酸(Polylysine)组成的组中,在本领域中能够使用的任何亲水性分子均予以使用。
本发明的所述亲水性分子与胆红素的羧基共价结合以形成亲水性/两亲性的胆红素衍生物(参照Amphiphiles:Molecular Assembly and Applications(ACS SymposiumSeries)1st Edition by Ramanathan Nagarajan及Various Self-Assembly Behaviorsof Amphiphilic Molecules in Ionic Liquids By Bin Dong and Yanan Gao,DOI:10.5772/59095)。以亲水性分子共价结合形态的胆红素具有两亲性。因此,不仅可溶于水溶性溶剂中,而且由于通过自发地自组装(self-assembled)来形成粒子,因此均可适用于疏水性制剂和亲水性制剂。如本发明的实施例中所确认的一样,本发明人通过使用作为亲水性化合物聚乙二醇(polyethyleneglycol,PEG)在羧酸盐中形成酰胺键的简单反应来制备了聚乙二醇化胆红素(PEG-BR,Pegylated bilirubin)。
根据本发明的另一个具体实施例,所述亲水性分子(化合物)是聚乙二醇或其衍生物。所述聚乙二醇衍生物可列举,甲氧基PEG(methoxy polyethylene glycol)、PEG丙酸丁二酰亚胺(succinimide of PEG propionic acid)、PEG丁二酸丁二酰亚胺(succinimideof PEG butanoic acid)、分叉的PEG-HNS(branched PEG-NHS)、聚乙二醇琥珀酸亚胺酯(PEG succinimidyl succinate)、羧甲基化聚乙二醇琥珀酰亚胺(succinimide ofcarboxymethylated PEG)、PEG苯并***碳酸酯(benzotriazole carbonate of PEG)、PEG-缩水甘油醚(PEG-glycidyl ether)、PEG-聚氧羰基咪唑(PEGoxycarbonylimidazole)、PEG硝基苯碳酸盐(PEG nitrophenyl carbonates)、PEG醛(PEGaldehyde)、PEG琥珀酰亚胺羧甲基酯(PEG succinimidyl carboxymethyl ester)和PEG琥珀酰亚胺酯(PEG succinimidylester)等。
根据本发明的一个实施例,所述聚乙二醇的平均分子量为200Da至20000Da。
在本发明中可以使用的亲水性分子的另一个具体实施例有,由两个以上(例如2-50个)氨基酸组成的多肽原。所述氨基酸不仅包括天然氨基酸,还包括非天然氨基酸。亲水性氨基酸有,谷氨酰胺、氨基琥珀酸、谷氨酸、苏氨酸、天冬酰胺、精氨酸、丝氨酸等,而疏水性氨基酸有,苯丙氨酸、色氨酸、异亮氨酸、亮氨酸、脯氨酸、蛋氨酸、缬氨酸和丙氨酸等。非编码的亲水性氨基酸例如有,Cit和hCys等。本领域技术人员可以基于所述信息和本领域已公开的肽合成技术,可以容易地合成亲水性多肽,并将其用于制备胆红素纳米粒子上。
所述亲水性分子的范围不仅包括上述提到的化合物,而且还包括它们的衍生物。更具体地,所述亲水性分子可以是具有胺基,或者是被改变,以具有胺基。此时,对于本领域技术人员而言显而易见的是,本发明的胆红素的羧基可以很容易地通过酰胺键与所述亲水性分子的胺基共价结合。
根据本发明的另一个实施例,本发明的微细粒子还包括:选自由Cu、Ga、Rb、Zr、Y、Tc、In、Ti、Gd、Mn、Fe、Au、Pt、Zn、Na、K、Mg、Ca、Sr和镧系金属组成的组中的金属离子或金属化合物。
根据本发明的另一个实施例,本发明的微细粒子还包括:选自由顺铂(cisplatin)、卡铂((carboplatin)、奥沙利铂(oxaliplatin)、奈达铂(nedaplatin)和庚铂(Heptaplatin)组成的组中的铂金类抗癌剂。
根据本发明的另一个实施例,本发明的微细粒子还包括:超顺磁性氧化铁纳米粒子(superparamagnetic iron oxide nanoparticle,SPION)。如本发明的一个实施例中所示,本发明的微细粒子(微细气泡)可以有效地负载氧化铁纳米(SPION)粒子,并且通过磁体可以容易地提取。
所述的在本发明的微细粒子中补充包括的金属离子、金属化合物、铂金类抗癌剂、超顺磁性氧化铁纳米粒子等分别对可用作超声波造影剂的微细粒子赋予附加的功能性。
根据本发明的另一个样态,本发明提供一种包含上述的本发明的微细粒子的超声波造影剂。
在本发明中,超声造影剂可用于腹部超声波、泌尿生殖***超声波、***超声波、肌肉骨骼超声波、甲状腺超声波、心脏超声波、经颅超声波(Transcranial ultrasound)、血管内超声波(Intra-Vascular Ultrasound,IVUS)和多普勒超声波(Doppler sonography)等在本领域中使用的所有的超声波检查。此外,还可以通过并用超声波来应用于所有的检查,例如内窥镜超声波(Endoscopic Ultrasound,EUS)和支气管内超声波(Endo-BronchialUltrasound,EBUS)。
尤其是,根据本发明的一个实施例的包含氧化铁纳米粒子(SPION)的微细粒子,其通过氧化铁的超顺磁性而具有磁共振(MR)敏感性,因此不仅用作超声波造影剂,而且还可以兼用于通过磁共振(magnetic resonance,MR)影像的诊断。
另外,根据本发明的具体的实施例,所述超声波造影剂进而还可以用于通过磁共振-引导聚焦超声波(MR-guided focused ultrasound,MRgFUS)的治疗上。
本发明的通过所述磁共振-引导聚焦超声波的治疗是通过由磁共振影像(magnetic resonance image,MRI)和超声波(ulstrasound,US)结合的设备来实施的治疗方法。该治疗方法主要用于治疗子宫肌瘤。该治疗方法是一种非侵袭性疗法,可以通过磁共振影像从三个维度上准确定位子宫肌瘤,并且利用大规模集成超声波来进行完全消融(ablation),从而无需通过手术的方式切除患病的部位(肌瘤组织)。
根据本发明的另一个实施例,本发明的包含微细粒子的超声波造影剂也可以以药物传递载体来使用。
可以通过超声波造影剂所独有的真空现象(cavitation)来短暂性瓦解待传递药物的组织的血管内皮细胞的结合,从而可以渗透到更深的组织内部,因此可用于传递抗癌剂及抗炎剂的传递载体。
具体地,由于本发明的微细粒子包含疏水性胆红素,因此可以通过疏水性相互作用与具有疏水性的药物进行结合。具有疏水性的药物例如有,紫杉醇(paclitaxel)、多西他赛(docetaxel)和喜树碱系抗癌剂,但不限于此。对于本领域技术人员显而易见的是,本领域中使用的疏水性药物,例如抗癌剂、抗炎剂和消炎剂等,不受限制得能够与本发明的微细粒子结合,从而可以传递药物。
另外,本发明的微细粒子包含与金属形成配位键的胆红素。因此,本发明的微细粒子容易得与上述的Cu、Ga、Rb、Zr、Y、Tc、In、Ti、Gd、Mn、Fe、Au、Pt、Zn、Na、K、Mg、Ca、Sr和镧系金属的离子以及它们的金属化合物,还有顺铂(cisplatin)、卡铂((carboplatin)、奥沙利铂(oxaliplatin)、奈达铂(nedaplatin)、和庚铂(Heptaplatin)等铂金类抗癌剂结合。
在本发明中,由胆红素衍生物与所述金属离子、金属化合物或铂金类抗癌剂形成的配位键,是在金属离子与胆红素衍生物的羧基、吡咯或内酰胺基之间形成。
在本发明的一个实施例中,本发明的微细粒子还包括疏水性药物即蒽环霉素类抗癌剂、紫杉烷(taxane)类抗癌剂或喜树碱(camptothecin)类抗癌剂。
在本发明中所述蒽环霉素类抗癌剂有,例如柔红霉素、亚德里亚霉素、表阿霉素、伊达比星、吉西他滨、米托葸醌、吡柔比星和戊柔比星等,但不限于此。
另外,在本发明中所述紫杉烷类抗癌剂有,例如紫杉醇(paclitaxel)、多西他赛(docetaxel)和卡巴他赛(cabazitaxel)等,但不限于此。
另外,由于本发明的微细粒子包含既是天然抗酸化剂又是对活性氧类(reactiveoxygen species,ROS)类敏感的物质胆红素,其在产生非正常水平的活性氧的癌和炎症等部位中消除活性氧,因此具有抗炎活性。本发明的包含微细粒子的胆红素衍生物,如韩国专利申请第10-2014-0190881号中所公开的一样,具有胆红素衍生物本身的抗癌作用和抑制血管新生的作用。因此,本发明的微细粒子可以用作治疗癌症或血管新生疾病的药物组合物。
可以适用本发明的微细粒子的炎症疾病可以列举,炎症性肠道疾病(inflammatory bowel disease)、过敏性皮炎、浮肿、皮炎、过敏、哮喘、结膜炎、牙周炎、鼻炎、中耳炎、粥样硬化症、咽喉炎、扁桃体炎、肺炎、胃溃疡、胃炎、克罗恩病、大肠炎、痔疮、痛风、间质性脊椎炎、风湿热、狼疮、纤维肌痛(fibromyalgia)、牛皮癣关节炎、骨关节炎、类风湿性关节炎、肩周炎、腱炎、肌肉炎症、肝炎、膀胱炎、肾炎、干燥综合症和多发性硬化症等,但不限于此。
本发明的微细粒子还可以适用于超声波血栓溶解术(Sonothrombolysis)中,超声波血栓溶解术是对中风或心肌梗塞等缺血性疾病直接将超声波射入血栓以溶解从而进行治疗的手术。进一步地,由于被称为胆红素的壳起到消除活性氧的作用,因此也可以适用于预防性治疗缺血-再灌注损伤(ischemic-reperfusion injury)上,缺血-再灌注损伤是指在急性或慢性低氧供应的周边缺血组织中在再灌注后突然产生的损伤,因此可以实现与现有的超声波造影剂区别适用。
根据本发明的另一个样态,本发明提供一种患者的诊断性影像方法(method ofdiagnostic imaging of a patient),包括:向患者注入有效量的本发明的包含微细粒子的超声波造影剂的步骤;以及将所述患者的身体部位或组织进行成像的步骤。
根据本发明的另一个样态,本发明提供一种患者的治疗性影像方法(method ofdiagnostic imaging of a patient),包括:向患者注入有效量的本发明的包含微细粒子的超声波造影剂的步骤;以及对所述患者的身体部位或组织的病变进行治疗的步骤。
所述诊断性影像是指通过使用造影剂来增强患者的身体部位(body part)或组织的影像的对比度以提供诊断所需的信息的成像技术。
治疗性影像包括使用造影剂治疗患者疾病的方法,所述造影剂是指能够在体内和/或体外发挥生物学作用或者能够发挥生物学作用的造影剂。治疗性影像是一个包括上述的磁共振-引导聚焦超声波治疗和通过药物封入的药物传递的概念。
在本说明书中使用的术语,“注入”或“进行注入”是指通过将用于诊断或治疗的有效量的本发明造影剂直接给受试者(个体或患者)注入,从而在受试者体内形成相同量的造影剂。
所述组合物的“治疗性有效量”是指足以向待注入组合物的受试体提供治疗性或者预防性作用的含量,这里包括“预防性有效量”的含义。
所述组合物的“诊断性有效量”是指为提供增强对比度效果的足够的组合物的含量,从而向待注入组合物的受试体提供诊断所需的信息。
另外,在本说明书中使用的术语“受试体”包括但不限于人、小鼠、大鼠、豚鼠、狗、猫、马、牛、猪、猴子、黑猩猩、狒狒(baboon)或恒河猴。具体地,本发明的受试体是人。
由于本发明的所述诊断性影像方法和治疗性影像方法是包括注入本发明的一个样态的微细粒子或者包含微细粒子的超声波造影剂的步骤的方法,因此为了避免本说明书的过度复杂性,将省略对重复内容的说明。
根据本发明的另一个样态,本发明提供一种包括以下步骤的微细粒子的制备方法。
(a)通过将包含亲水性分子结合于胆红素的胆红素衍生物的纳米粒子溶解在水性溶剂中来制备胆红素衍生物纳米粒子溶液的步骤;
(b)通过将胆红素衍生物纳米粒子溶液与含有气体的油相溶液混合并对其进行超声波处理,从而使气体截留在内部而形成核心部,并且所述核心部的表面被胆红素衍生物纳米粒子包围以形成壳层来制备微细粒子的步骤。
本发明的所述微细粒子的制备方法在图1中通过图形方式进行了说明。在下面按步骤详细说明本发明的微细粒子的制备方法。
步骤(a):通过将包含亲水性分子结合于胆红素的胆红素衍生物的纳米粒子溶解
在水性溶剂中来制备胆红素衍生物纳米粒子溶液的步骤
本步骤是制备胆红素与亲水性分子结合的亲水性或两亲性的胆红素衍生物,由此制备包含胆红素衍生物的纳米粒子溶剂。
所述胆红素与亲水性分子的结合,具体地,使用EDC(1-乙基-3-(3-二甲基氨丙基)碳二亚胺)(1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide)活化胆红素的羧基,并诱导通过酰胺键来与具有胺基的亲水性分子的共价结合。所述与胆红素结合的亲水性分子是如上述的亲水性分子,其具有胺基,或者是被改变,以具有胺基。
具体地,首先将胆红素溶解在有机溶剂(例如二甲基亚砜,DMSO)中,然后添加EDC以活化胆红素中存在的羧基,并在常温下反应5-30分钟。此后,添加在末端具有胺基的亲水性分子(例如聚乙二醇)并反应一段时间以合成结合了亲水性分子的胆红素衍生物。之后,通过硅胶柱将具有通过羧基和胺基之间的反应形成的酰胺键的胆红素衍生物从附属物中分离并提纯。
将通过上述方式制备的胆红素衍生物溶解在有机溶剂(例如,氯仿)中,然后在氮气气氛下或真空状态下进行干燥以形成膜层。之后,将水性溶剂例如磷酸缓冲溶液、去离子水添加至所述膜层上,并进行超声波处理以制备包含胆红素衍生物的纳米粒子溶液。
所述胆红素衍生物纳米粒子是胆红素衍生物在水性溶剂中通过自组装(self-assembled)形成的纳米粒子,可以是以下形态:在胆红素衍生物中,疏水性的胆红素部分位于胆红素衍生物的内部,而与胆红素共轭的亲水性分子部分则与水性溶剂的界面接触的胶束(micelle)形态。关于制备所述胆红素纳米粒子液体的内容已经公之于众。关于这一部分的内容,韩国专利申请第10-2014-0190881号的所有内容在本说明书中作为参照并入本文。
步骤(b):通过将胆红素衍生物纳米粒子溶液与含有气体的油相溶液混合并对其
进行超声波处理,从而使气体截留在内部而形成核心部,并且所述核心部的表面被胆红素
衍生物纳米粒子包围以形成壳层来制备微细粒子的步骤
本步骤是通过将疏水性气体(例如,全氟碳)与胆红素衍生物纳米粒子溶液混合并将疏水性气体封入于胆红素衍生物纳米粒子的疏水性核心中来制备微细粒子的步骤。
将预先制备的胆红素衍生物(聚乙二醇化胆红素,Pegylated bilirubin)溶解在去离子水中,并将油相(oil phase)的疏水性气体(例如,全氟戊烷)滴入至胆红素纳米粒子溶液中,然后进行一定时间的超声波处理(sonication)。通过所述过程,制备将疏水性气体用作核心并且由胆红素衍生物形成壳的乳液(emulsion)形态的纳米-或微米-气泡***(图1)。
根据本发明的一个实施例,代替所述(b)步骤,在胆红素衍生物纳米粒子溶液中,将含有疏水性气体;及选自由Cu、Ga、Rb、Zr、Y、Tc、In、Ti、Gd、Mn、Fe、Au、Pt、Zn、Na、K、Mg、Ca、Sr和镧系金属组成的组中的金属离子或金属化合物的油相溶剂进行混合,并对其进行超声波处理,从而可以制备还包含金属离子或金属化合物的微细粒子。
根据本发明的另一个实施例,代替所述(b)步骤,在胆红素衍生物纳米粒子溶液中,将含有疏水性气体;及选自由顺铂(cisplatin)、卡铂((carboplatin)、奥沙利铂(oxaliplatin)、奈达铂(nedaplatin)和庚铂(Heptaplatin)组成的组中的铂金类抗癌剂的油相溶剂进行混合,并对其进行超声波处理,从而可以制备还包含铂金类抗癌剂的微细粒子。
根据本发明的另一个实施例,代替所述(b)步骤,在胆红素衍生物纳米粒子溶液中,将含有疏水性气体;及蒽环霉素类抗癌剂、紫杉烷(taxane)类抗癌剂或喜树碱(camptothecin)类抗癌剂的油相溶剂进行混合,并对其进行超声波处理,从而可以制备还包含蒽环霉素类抗癌剂或紫杉烷类抗癌剂的微细粒子。
根据本发明的另一个实施例,代替所述(b)步骤,在胆红素衍生物纳米粒子溶液中,将含有疏水性气体;及超顺磁性氧化铁纳米粒子(SPION:superparamagnetic ironoxide nanoparticle)的油相溶剂进行混合,并对其进行超声波处理,从而可以制备还包含超顺磁性氧化铁纳米粒子的微细粒子。
本发明的所述微细粒子的制备方法,其构成成分与所述的微细粒子相同,因此对形成核心部的气体的种类、与胆红素衍生物配对的亲水性分子的种类等重复的部分,为了避免使本说明书过度复杂,将省略此部分的说明。
[发明的效果]
本发明提供一种微细粒子、其制备方法以及包含微细粒子的超声波造影剂,微细粒子,包括:核心(core)部,在其内部含有疏水性气体;以及壳(shell)层,围绕所述核心部的表面并包含胆红素衍生物。
本发明的含有胆红素衍生物的微细粒子,其对活性氧类(reactive oxygenspecies,ROS)敏感地反应,从而消除活性氧。另外,本发明的微细粒子与疏水性药物结合,可以有效地将包括氧化铁纳米粒子在内的金属进行螯合。因此本发明的微细粒子,不仅可以用于超声波诊断的造影剂,而且还可以用于磁共振影像诊断的造影剂及基于疏水性药物或者铂金类药物的传递载体。
附图说明
图1是以图形方式对涂覆有聚乙二醇化胆红素的超声波造影剂的制备方法进行说明的图;
图2是将涂覆有本发明的聚乙二醇化胆红素的超声波造影剂制备后进行拍摄的照片;
图3示出了在涂覆有聚乙二醇化胆红素的超声波造影剂中,根据全氟戊烷的不同体积浓度(PFP分别为0、2.5、5、10%v/v)的开始测量时点(t=0分钟)的代表性幻影成像图;
图4是根据涂覆有聚乙二醇化胆红素的超声波造影剂的全氟戊烷(PFP)的不同体积浓度(PFP分别为0、2.5、5、10%v/v),将幻影成像的变化按时间呈现的图;
图5是根据涂覆有聚乙二醇化胆红素的超声波造影剂的全氟戊烷(PFP)体积浓度(PFP分别为0、2.5、5、10%v/v),将幻影成像的标准化超声波强度按时间呈现的图;
图6是通过透射电子显微镜来观察涂覆有聚乙二醇化胆红素的超声波造影剂的影像图,所测量的造影剂气泡的大小为2-4μm;
图7是在光学显微镜下观察的涂覆有聚乙二醇化胆红素的超声波造影剂(白箭头)的影像(A)和为计算每体积的造影剂粒子的数量而分配在血细胞计数器网格上的影像(B)图;
图8是示出活性氧类处理后的涂覆有聚乙二醇化胆红素的超声波造影剂的流体动力型粒度逐渐增加[红色(●)、①绿色(■)→②蓝色(▲)]的图;
图9是用图形来说明涂覆有负载氧化铁纳米粒子的聚乙二醇化胆红素的超声波造影剂的图;
图10的(A)是示出负载氧化铁纳米粒子的聚乙二醇化胆红素附着于磁体的位置(箭头)的图,图10(B)是通过透射电子显微镜观察涂覆有负载氧化铁纳米粒子的聚乙二醇化胆红素的超声波造影剂((iron oxide nanoparticle-loaded PEGylated bilirubincoated US contrast agents)的影像。
具体实施方式
下面,将通过实施例对本发明进行更加详细地说明。这些实施例仅仅是用于更具体地说明本发明,因此,对于本领域技术人员而言显而易见的是,根据本发明的宗旨,本发明的范围不受这些实施例的限制。
实施例1:本发明的基于聚乙二醇化胆红素的超声波造影剂的制备
1-1.胆红素衍生物(聚乙二醇化胆红素,Pegylated bilirubin)的制备
本发明人在制备基于胆红素的超声波造影剂之前,制备了将亲水性分子与胆红素结合的胆红素两亲性衍生物。作为亲水性分子,使用了聚乙二醇(polyethyleneglycol)。
具体地,首先将胆红素溶解在二甲基亚砜(dimethylsulfoxide,DMSO)中,然后添加EDC(1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide)适当量以活化胆红素中存在的羧基,从而诱导所希望的反应,并在常温下反应10分钟。此后,添加在末端具有胺基的聚乙二醇并反应一段时间以合成了由胆红素的羧基和聚乙二醇的胺类通过酰胺键共价结合的胆红素衍生物(Pegylated bilirubin)。之后,通过硅胶柱将所述制备的最终的胆红素衍生物从附属物中分离并提纯。
1-2.制备以聚乙二醇化胆红素涂层的超声波造影剂
基于本发明的胆红素的回声阴影性微细粒子(echogenic nanoparticle,ormicroparticle)是通过简单的水包油(oil-in-water,O/W)乳化方法制备的。通过将已在所述实施例1-1中事先制备的胆红素衍生物(Pegylated bilirubin)溶解在去离子水中来制备胆红素微细粒子溶液(1.2mg/2ml),并将其转移至配备有探针型超声波粉碎机的冰浴中。作为构成气泡核心的疏水性气体,使用了全氟戊烷(perfluoropentane,PFP)。将以油相(oil phase)形式存在的全氟戊烷,以各种体积比(PFP,2.5、5、10%v/v)滴入至胆红素微细粒子溶液(水相,water phase)中,然后以30%的功率进行超声波处理(sonication)90秒。通过所述过程,制备了将以乳液形态的疏水性气体全氟戊烷(perfluoropentane,PFP)用作核心并且由胆红素衍生物形成壳的乳液(emulsion)形态的纳米-或微米-气泡***(图1)。
将以油相形式存在的全氟戊烷以各种体积比和滴加到胆红素微粒溶液(水相,water phase)中。超声波处理进行90秒。结果,制备了纳米或微米气泡***,其中以乳液形式的疏水性气体(全氟戊烷)为核心,并且由胆红素衍生物来形成壳的纳米-或者微米-气泡***(图1和图2)。
实施例2:本发明的基于聚乙二醇化胆红素的超声波造影剂的幻影成像
超声波幻影成像是使用配备有用于小鼠的超声波设备探针即RMV 706探针的Vevo770(High-Resolution Micro-Imaging System,Visualsonics,Toronto,Canada)而获得。本发明人为了模拟用于超声波影像的体内条件,使用了琼脂糖-凝胶体模,琼脂糖-凝胶体模是通过将500μL单位的微量离心管包埋于3%(w/v)的琼脂糖凝胶中而制造。
首先,分别将使用全氟戊烷(perfluoropentane,PFP)作为疏水性气态核心的本发明的基于聚乙二醇化胆红素的造影剂样品(PFP 0、2.5、5、10%v/v)300μL放入琼脂糖-凝胶体模中,并通过40MHz超声波获得了影像。在180分钟的时间内测量每个样品(PFP分别为0、2.5、5、10%v/v)的超声波强度变化,作为标准化过程,将从样品的超声波强度中减去(subtraction)水对照组的超声波强度。在图3至图5中示出了根据气态核心体积比对聚乙二醇化胆红素溶液中的随时间的回声阴影特点的检测结果。
图3示出了在涂覆有聚乙二醇化胆红素的超声波造影剂中,根据全氟戊烷的不同体积浓度(PFP分别为0、2.5、5、10%v/v)的开始测量时点(t=0分钟)的代表性幻影成像图,图4是根据涂覆有聚乙二醇化胆红素的超声波造影剂的全氟戊烷(PFP)的不同体积浓度(PFP分别为0、2.5、5、10%v/v),将幻影成像的变化按时间呈现的图。如图3和图4所示,回声阴影最高的样品是PFP 5.0%(v/v)测试组。
图5是根据涂覆有聚乙二醇化胆红素的超声波造影剂的全氟戊烷(PFP)体积浓度(PFP分别为0、2.5、5、10%v/v),将幻影成像的标准化超声波强度按时间呈现的图。基于聚乙二醇化胆红素的超声波造影剂的回声信号的原位半衰期约为45分钟。
根据上述结果确认了,将本发明的包括聚乙二醇化胆红素在内的与亲水性分子结合的胆红素衍生物,稳定地发挥其作为围绕疏水性气态核心的壳的作用,并且通过幻影成像增强超声波影像效果。因此,根据本发明制备的基于胆红素衍生物的微细气泡可作为超声波造影剂使用。
实施例3:本发明的基于聚乙二醇化胆红素的超声波造影剂的特征
3-1.显微镜形态学
微细粒子的显微镜形态学是通过乙酸双氧铀(uranium acetate)的负染色法(with negative staining)和透射电子显微镜法(Tecnai G2 F30,Eindhoven,Netherlands)(图6)及盖玻片下的光学显微镜(图7)来观察的。
图6是通过透射电子显微镜(TEM,transmission electron microscopy)来观察基于聚乙二醇化胆红素的超声波造影剂的图。图6示出构成本发明的超声波造影剂的微米大小的气泡粒子。图7是通过光学显微镜来观察的基于聚乙二醇化胆红素的超声波造影剂。
另外,为了计算造影剂的每体积包含的气泡数量,将本发明的基于聚乙二醇化胆红素的造影剂放入血细胞计数器网格上,以此进行了数量计算(图7的(B))。通过计算确认了,本发明的每1毫升(ml)的造影剂包含约2.0x109个气泡。
3-2.基于聚乙二醇化胆红素的超声波造影剂对活性氧(ROS)的活性
本发明的基于聚乙二醇化胆红素的超声波造影剂包括天然抗氧化剂即胆红素。本发明人使用Nanosizer ZS 90(Malvern Instruments,Ltd.,Malvern,UK)来测量了在活性氧类(ROS;H 2O 2)处理之前和之后的本发明的造影剂的微细气泡的流体动力型粒度分布(hydrodynamic size distribution),以确认本发明的超声波造影剂对活性氧(reactiveoxygen species,ROS)类的反应性。其结果,在图8中示出。如图8所示,本发明的超声波造影剂与活性氧类(H 2O 2)进行反应,从而使气泡的流体动力型大小增加。
胆红素是人体内的天然抗氧化剂。当胆红素与富含活性氧类的患病的部位的活性氧类发生反应时,胆红素就会变成胆绿素(biliverdin)。其结果是,胆红素衍生物之间,以及胆红素衍生物与气体核心(core)之间的疏水性相互作用被减弱,从而破坏造影剂气泡的两亲性的胆红素衍生物-涂层壳。最终,产生超声波影像的对比度与在疏水性气态核心的瞬间聚集状态(conglomeration)后逐渐增大成比例地增强的现象(图8)。
因此,本发明的包括聚乙二醇化胆红素在内的,与亲水性分子结合的胆红素衍生物可以增强富含活性氧类的患病的部位的超声波影像,并且由于其固有的抗氧化特性而对患病的部位起到抗氧化效果。因此,含有本发明的胆红素衍生物的微细粒子不仅可以用于通过超声波的诊断上,还可以有效地用于通过超声波的治疗上。
实施例4:基于负载氧化铁纳米粒子的聚乙二醇化胆红素的超声波造影剂的制备
负载氧化铁纳米粒子(iron oxide nanoparticle)是通过改变上述实施例1的制备方法来实施的。制备水包油(oil-in-water,O/W)层时,将分散在己烷(hexane)中的氧化铁纳米粒子与以油相(oil phase)存在的全氟戊烷(PFP)同时滴入。然后,将通过上面所述的方法进行超声波处理来获得的乳液,在昏暗的光线(dim light)下搅拌6个小时以蒸发己烷,然后以5000rpm进行离心分离,以去除絮凝物。并对上层液体进行分液后,使用稀土磁体(rare earth magnet)提取负载氧化铁纳米粒子的聚乙二醇化胆红素微细气泡(ironoxide nanoparticles-loaded PEGylated bilirubin microbubble)(图9和图10)。
图9是用图形来说明涂覆有负载氧化铁纳米粒子的聚乙二醇化胆红素的超声波造影剂的图。如图9所示,本发明的超声波造影剂,其与亲水性聚合物结合的胆红素的亲水性部分(亲水性分子)面向水相(water-phase),疏水性部分(胆红素)则与疏水性气体(PFP)核心直接接触,从而形成壳。在这里,氧化铁纳米粒子与胆红素结合后其反应是,涂覆在氧化铁纳米粒子上的油酸(oleic acid)层被脱落,取而代之的是,胆红素的羧基通过螯合反应与氧化铁纳米粒子结合。或者,15nm尺寸的氧化铁纳米粒子通过氧化铁纳米粒子与疏水性气体核心之间的疏水性结合来负载在具有更大体积的疏水性气体核心上。
图10的(A)是使用磁体提取负载氧化铁纳米粒子的聚乙二醇化胆红素造影剂的结果图,示出了含有氧化铁纳米粒子的造影剂附着于磁体(红色箭头)。图10(B)是通过透射电子显微镜观察涂覆有负载氧化铁纳米粒子的聚乙二醇化胆红素的超声波造影剂的影像。图10(B)的箭头是指本发明的基于聚乙二醇化胆红素的超声波造影剂的微细气泡上的氧化铁纳米粒子。氧化铁纳米粒子的尺寸相当于约15nm。
通过以上结果确认了,本发明的基于与亲水性分子结合的胆红素衍生物的超声波造影剂可以负载包括氧化铁纳米粒子在内的磁共振敏感性金属粒子。因此,本发明的基于胆红素衍生物的超声波造影剂不仅可以用作超声波造影剂,而且非常有效地作为磁共振-引导聚焦超声波(MR-guided focused ultrasound,MRgFUS)的造影剂来使用。
进一步地,利用胆红素金属粒子的螯合特性,如果在本发明的超声波造影剂上负载基于铂金粒子的抗癌剂而不是氧化铁纳米粒子,那么还可以将超声波造影剂用作传递抗癌剂的载体。特别是,磁共振-引导聚焦超声波(MRgFUS)是一种可以短暂性增强血-脑屏障(blood-brain barrier,BBB)可透性的新技术。使用磁共振-引导聚焦超声波,能够将治疗剂传递到中枢神经***中,并且能够提高脑肿瘤的治疗效率。因此,本发明的超声波造影剂***可以作为同时执行超声波造影剂、磁共振敏感性造影剂和抗氧化剂/抗癌剂的传递载体三种作用的平台技术来有效地应用。
Claims (19)
1.一种微细粒子的制备方法,包括以下步骤:
(a)通过将包含亲水性分子结合于胆红素的胆红素衍生物的纳米粒子溶解在水性溶剂中来制备胆红素衍生物纳米粒子溶液的步骤;以及
(b)通过将所述胆红素衍生物纳米粒子溶液与含有疏水性气体的油相溶液混合并对其进行超声波处理,以制备微细粒子的步骤;
其中,所述微细粒子包括:
核心(core)部,所述疏水性气体被截留在核心部的内部;以及
壳(shell)层,所述胆红素衍生物纳米粒子包围所述核心部的表面以形成壳层;
其中,所述微细粒子是所述胆红素位于内部,所述亲水性分子与所述水性溶剂的界面接触的胶束(micelle)形态;
其中,所述微细粒子具有2-4μm的粒子大小。
2.根据权利要求1所述的微细粒子的制备方法,其特征在于,
所述气体选自由空气、氮气、氦气、氩气、二氧化碳、六氟化硫(sulfur hexfluoride,SF6)和C1至C10的全氟碳(perfluorocarbon)组成的组中。
3.根据权利要求1所述的微细粒子的制备方法,其特征在于,
所述亲水性分子选自由葡聚糖(dextran)、羧葡聚糖(carbodextran)、环状糊精(cyclodextran)、普鲁兰多糖(pluronic)、纤维素(cellulose)、淀粉(starch)、糖原(glycogen)、单糖类(monosaccharide)、二糖类(bisaccharide)和寡糖类(oligosaccharide)、多肽(polypeptide)、多磷酸肌酸(polyphosphagen)、聚丙交酯(polylactide)、聚(乳酸-羟基乙酸共聚物)(poly(lactic-co-glycolic acid))、聚己内酯(polycaprolactone)、聚酐(polyanhydride)、聚马来酸(polymaleic acid)以及聚马来酸的衍生物、聚氰基丙烯酸烷酯(polyalkylcyanoacrylate)、聚羟基丁酸酯(polyhydroxybutylate)、聚碳酸酯(polycarbonate)、聚原酸酯(polyorthoester)、聚乙二醇(polyethyleneglycol,PEG)、甲氧基聚乙二醇(methoxy polyethyleneglycol,mPEG)、聚丙二醇、聚乙烯亚胺(polyethylenimine)、多聚-L-赖氨酸(poly-L-lysine)、聚乙交酯(polyglycolide)、聚甲基丙烯酸甲酯(polymetacrylate)、聚乙烯吡咯烷酮(polyvinylpyrrolidone)、聚(丙烯酸酯)(poly[acrylate])、聚(丙烯酰胺)(poly[acrylamide])、聚(乙烯基酯)(poly[vinylester])、聚(乙烯醇)(poly[vinyl alcohol])、聚苯乙烯(polystryene)、多氧化物(polyoxide)、聚电解质(polyelectrolyte)、聚(1-硝基丙烯)(poly[1-nitropropylene])、聚(N-乙烯基吡咯烷酮)(poly[N-vinylpyrrolidone])、聚(乙烯胺)(poly[vinyl amine])、聚(甲基丙烯酸β-羟乙酯)(Poly[beta-hydroxyethylmethacrylate])、聚环氧乙烷(Polyethyleneoxide)、聚(环氧乙烷-环氧丙烷)(Poly[ethylene oxide-bpropyleneoxide])、聚赖氨酸(Polylysine)组成的组中。
4.根据权利要求1所述的微细粒子的制备方法,其特征在于,还包括:
选自由Cu、Ga、Rb、Zr、Y、Tc、In、Ti、Gd、Mn、Fe、Au、Pt、Zn、Na、K、Mg、Ca、Sr和镧系金属组成的组中的金属离子或金属化合物。
5.根据权利要求1所述的微细粒子的制备方法,其特征在于,还包括:
选自由顺铂(cisplatin)、卡铂((carboplatin)、奥沙利铂(oxaliplatin)、奈达铂(nedaplatin)和庚铂(Heptaplatin)组成的组中的铂金类抗癌剂。
6.根据权利要求1所述的微细粒子的制备方法,其特征在于,还包括:
蒽环霉素类抗癌剂、紫杉烷(taxane)类抗癌剂或喜树碱(camptothecin)类抗癌剂。
7.根据权利要求6所述的微细粒子的制备方法,其特征在于,
所述蒽环霉素类抗癌剂选自由柔红霉素、亚德里亚霉素、表阿霉素、伊达比星、吉西他滨、米托葸醌、吡柔比星和戊柔比星组成的组中。
8.根据权利要求6所述的微细粒子的制备方法,其特征在于,
所述紫杉烷类抗癌剂选自由紫杉醇(paclitaxel)、多西他赛(docetaxel)和卡巴他赛(cabazitaxel)组成的组中。
9.根据权利要求1所述的微细粒子的制备方法,其特征在于,还包括:
超顺磁性氧化铁纳米粒子(SPION:superparamagnetic iron oxide
nanoparticle)。
10.根据权利要求1所述的微细粒子的制备方法,其特征在于,
所述(b)步骤,在所述胆红素衍生物纳米粒子溶液中,将含有所述疏水性气体;及选自由Cu、Ga、Rb、Zr、Y、Tc、In、Ti、Gd、Mn、Fe、Au、Pt、Zn、Na、K、Mg、Ca、Sr和镧系金属组成的组中的金属离子或金属化合物的油相溶剂进行混合,并对其进行超声波处理。
11.根据权利要求1所述的微细粒子的制备方法,其特征在于,
所述(b)步骤,在所述胆红素衍生物纳米粒子溶液中,将含有所述疏水性气体;及选自由顺铂(cisplatin)、卡铂((carboplatin)、奥沙利铂(oxaliplatin)、奈达铂(nedaplatin)和庚铂(Heptaplatin)组成的组中的铂金类抗癌剂的油相溶剂进行混合,并对其进行超声波处理。
12.根据权利要求1所述的微细粒子的制备方法,其特征在于,
所述(b)步骤,在所述胆红素衍生物纳米粒子溶液中,将含有所述疏水性气体;及蒽环霉素类抗癌剂、紫杉烷(taxane)类抗癌剂或喜树碱(camptothecin)类抗癌剂的油相溶剂进行混合,并对其进行超声波处理。
13.根据权利要求12所述的微细粒子的制备方法,其特征在于,
所述蒽环霉素类抗癌剂选自由柔红霉素(daunorubicin)、亚德里亚霉素(doxorubicin)、表阿霉素(epirubicin)、伊达比星(idarubicin)、匹杉琼(pixantrone)、米托葸醌(mitoxantrone)和戊柔比星组成的组中。
14.根据权利要求12所述的微细粒子的制备方法,其特征在于,
所述紫杉烷类抗癌剂选自由紫杉醇(paclitaxel)、多西他赛(docetaxel)和卡巴他赛(cabazitaxel)组成的组中。
15.根据权利要求1所述的微细粒子的制备方法,其特征在于,
所述(b)步骤,在所述胆红素衍生物纳米粒子溶液中,将含有所述疏水性气体;及超顺磁性氧化铁纳米粒子(SPION:superparamagnetic iron oxide nanoparticle)的油相溶液进行混合,并对其进行超声波处理。
16.一种包括权利要求1至权利要求15中的任何一项所述的制备方法所制备的微细粒子的超声波造影剂。
17.根据权利要求16所述的超声波造影剂,其特征在于,
所述超声波造影剂兼用于通过磁共振(magnetic resonance,MR)影像的诊断。
18.根据权利要求17所述的超声波造影剂,其特征在于,
所述超声波造影剂用于磁共振-引导聚焦超声波(MR-guided focused ultraso und,MRgFUS)上。
19.根据权利要求16所述的超声波造影剂,其特征在于,
所述超声波造影剂兼用于药物传递载体。
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US20180147773A1 (en) | 2015-06-03 | 2018-05-31 | Sabic Global Technologies B.V. | Material extrusion additive manufacturing of polyimide precursor |
WO2016199430A1 (ja) | 2015-06-10 | 2016-12-15 | 学校法人帝京大学 | セラノスティクス用のバブル製剤(tb)及びその使用方法 |
KR101779283B1 (ko) * | 2016-01-14 | 2017-09-26 | 연세대학교 산학협력단 | Tl 및 T2 이중 기능의 자기공명영상 조영제 |
KR102254093B1 (ko) * | 2017-05-12 | 2021-05-20 | 주식회사 빌릭스 | 빌리루빈 유도체 및 금속을 포함하는 입자 |
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JP2021514941A (ja) | 2021-06-17 |
US11571486B2 (en) | 2023-02-07 |
WO2019151827A1 (ko) | 2019-08-08 |
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