CN104114188A - 降低自由基伤害的复合微胞载体医药组成物 - Google Patents

降低自由基伤害的复合微胞载体医药组成物 Download PDF

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CN104114188A
CN104114188A CN201280054773.7A CN201280054773A CN104114188A CN 104114188 A CN104114188 A CN 104114188A CN 201280054773 A CN201280054773 A CN 201280054773A CN 104114188 A CN104114188 A CN 104114188A
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陈嘉宏
王朝晖
林炯森
邱铁雄
陈静仪
廖碧虹
苏家琪
廖伟全
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Original Biomedicals Co Ltd
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Abstract

本发明提供一种降低自由基伤害的复合微胞载体医药组成物，该组成物包含：至少一种金属或其离子；至少一种药物或受载体保护及修饰的抗自由基氧化物；及药物载体。本发明的载体可保存药物或抗氧化物的活性，使其不易被环境或体液内的天然自由基降低效力，达到延长保护力的效果，可应用于减轻辐射伤害与化疗药物副作用。

Description

降低自由基伤害的复合微胞载体医药组成物
技术领域
本发明提供一种复合微胞载体医药组成物，尤指一种降低自由基伤害的复合微胞载体医药组合物。
背景技术
氨磷汀(Amifostine)，又名WR-2721，是WR-1065加上磷酸根的化合物，为保护抗氧化活性的衍生物，目前已经获得世界多国医药品法规机关核可作为预防放射线治疗的伤害以及治疗铂类化疗药品不良(副)作用的适应症。Amifostine可透过自然水解的方式，与生物体内的碱性磷酸酶(alkaline phosphatase)作用，将其磷酸根与WR-1065的键结断裂后，释放WR-1065作为细胞内抗自由基的成分，以降低细胞毒性。但是氨磷汀在人体内的分布半衰期小于1分钟，排除半衰期为8分钟，在静脉投药6分钟后仅剩10％的氨磷汀存在。未被排除的氨磷汀可迅速的转化为具有活性的硫醇代谢物WR1065(active free thiol metabolite)，而开始于体内作用。因此，临床使用建议氨磷汀的静脉投予在放射线治疗为前三分钟，在化学治疗为前15分钟投予，以避免药物失去活性。因此，使用氨磷汀最重要且须克服的问题即是半衰期过短，而造成的使用困难。
过去许多研究与文献尝试透过不同的药物剂型或是载体，将氨磷汀设计为缓慢释放或是可透过非静脉给予的方式给药，这些研究尽管能延长半衰期或是增加口服有效性，但是仍然无法有效地控制氨磷汀的体内释放以及提供器官选择性的分布效果，所以无法提供临床上更多不同适应症的治疗效益，像是预防核电厂辐射外泄时的辐射伤害等。
其他抗氧化物也可能因为难以保存活性，或是容易被身体代谢而无法提供较长时间的抗自由基保护力，所以难以应用在预防辐射伤害与降低化疗药物不良作用的效果。
发明内容
鉴于上述的发明背景中，为了符合产业上特别的需求，本发明利用前案(台湾案申请案号101128939)一种利用金属离子复合微胞技术包覆药物氨磷汀或其他抗氧化物，以应用于降低辐射伤害与化疗药物不良作用。复合微胞药物载体将达成下述的目的，如延长药物生物体内半衰期、保护药物活性、改变药物体内分布。本发明所应用金属离子复合微胞能延缓药物的释放速率及改变体内分布，达到降低辐射伤害与化疗药物副作用的效果。金属离子复合微胞可依需求设计不同的脂水溶性及粒径等，以达到特定体内器官分布及保护的作用。
复合微胞药物载体释放出的药物活性成分如氨磷汀,WR-1065或其他抗氧化物，可减少放射线或化学治疗药物产生的自由基对正常组织器官的伤害，达到降低毒性的效果。
本发明的目的即在提供一种降低自由基伤害的复合微胞载体医药组成物，该组成物包含：至少一种金属或其离子；至少一种药物或受载体保护及修饰的抗氧化物；及药物载体。
为达成前述发明目的，上述的金属离子核心选自下列族群中之一或其任意组合或其衍生物：铁(Fe)、铜(Cu)、镍(Ni)、铟(In)、钙(Ca)、钴(Co)、铬(Cr)、钆(Gd)、铝(Al)、锡(Sn)、锌(Zn)、钨(W)、钪(Sc)及钛(Ti)。
上述的药物载体选自下列族群中之一或其任意组合或其衍生物：聚乙二醇(poly(ethylene glycol))、聚天门冬氨酸(poly(aspartic acid))、聚麸胺酸(poly(glutamic acid))、聚赖氨酸(poly(lysine))、聚丙烯酸(poly(acrylic acid))、几丁聚醣(chitosan)、聚乙烯亚胺(poly(ethyleneimine))、聚甲基丙烯酸(poly(methacrylic acid))、透明质酸(hyaluronic acid)、胶原蛋白(collagen)、聚氮-异丙基丙烯酰胺(poly(N-isopropyl acrylamide))、直链淀粉(amylose)、纤维素(cellulose)、聚羟基丁酸酯(poly(hydroxybutyrate))、聚乳酸(poly(lactic acid))、聚琥珀酸丁酯(poly(butylenesuccinate))、聚己内酯(poly(caprolactone))、羧甲基纤维素(carboxymethylcellulose)、糊精(dextran)、环糊精(cyclodextrin)、聚乙二醇-聚麸胺酸嵌段共聚物(poly(ethylene glycol)-b-poly(glutamic acid))、磷脂质(phospholipid)。
上述的药物载体选自下列族群中之一或其任意组合：微脂体(liposome)，微胞或高分子微胞(micelle/polymeric micelle)及树枝状高分子(dendrimer)。
上述的复合微胞载体医药组成物可与金属键结或不键结，上述的药物选自下列族群中之一或其任意组合或其衍生物：氨磷汀(amifostine)、WR-1065、维生素C(ascorbic acid、Vitamin C),榖胱甘肽(glutathione)、退黑激素(melatonin)、生育酚(tocopherols)、生育三烯醇(tocotrienols、Vitamin E)、左旋肉碱(L-carnitine)、胡萝卜素(carotenes)、还原型泛醌(ubiquinol)、硫辛酸(lipoic acid)、多酚(polyphenols)、儿茶酚胺(catecholamine)、姜黄素(curcumin)、白藜芦醇(resveratrol)、白藜芦醇苷(piceid)、乙酰半胱氨酸(acetylcysteine)、四甲基呱啶氧化物(Tempo)、细辛脑(asarone)、氨基胍(aminoguanidine)、维生素Ｅ单糖苷(tocopherol monoglucoside)、甘草酸(glycyrrhizic acid)、表儿茶素(epicatechin)、类黄酮(flavonoid)、荭草素(Orientin)、维采宁(vicenin)、2-巯基丙酰基-甘氨酸(MPG(2-mercaptopropionyl glycine))及美司钠(Mesna(2-mercaptoethanesulfonic acid))。
一种用于降低自由基伤害之复合微胞载体医药组成物，该组成物包含：铁离子；氨磷汀；及药物载体，该载体为聚乙二醇-聚麸胺酸嵌段共聚物。
为达成前述发明目的，所述的药物可以做为还原剂，还原受氧化的生物分子，以恢复其功能；可依其抗氧化效果阻止自由基持续传递与攻击；可以减少辐射、紫外线、化疗药品、电磁场效应等所造成的自由基，达到保护自由基伤害与降低其毒性的效果。
附图说明
前面的概述，以及本发明在结合附图以下的详细描述，阅读时将更容易地理解。然而，应当理解，本发明并不局限于所示的较佳实施例。
图1：所示为根据本发明的实施例一形成的具有金属核心的复合微胞药物载体示意图。***P<0.001相较于UV组别具有显著差异、#P<0.05相较于API40X2小时组具有显著差异、▲▲▲P<0.001相较于FePA20X2小时组具有显著差异。
图2:所示为彗星试验(Comet Assay)影像图，分别有CON(负向控制组)、UV(正向控制组)、API40X(2小时)、API40X(30分钟)、FeP40X(2小时)、FePA20X(2小时)、FePA20X(30分钟)。
图3：所示为彗星试验(Comet Assay)DNA拖尾率(％)数据图，分别有CON(负向控制组)、UV(正向控制组)、API40X(2小时)、API40X(30分钟)、FeP40X(2小时)、FePA20X(2小时)、FePA20X(30分钟)。
具体实施方式
本发明以下面的实施例予以示范阐明，但本发明不受下述实施例所限制。
实施例一
金属核心复合微胞药物载体控释剂型配制
图1为具有金属核心的复合微胞药物载体示意图。中心为金属或金属离子120；中心金属或金属离子旁为抗氧化物或其他类似药物110；外围则为载体100。
活性物质
氨磷汀为抗氧化物，是WR-1065加上磷酸根保护抗氧化活性的衍生物，已经世界多国医药品法规机关核可作为预防放射线治疗伤害以及铂类化疗药品副作用的适应症。
复合微胞药物载体
提供原料，该原料包含15gγ-benzyl-L-glutamate，7.5gtriphosgene溶于150mL无水tetrahydrofuran(THF)于氮气环境下55℃搅拌反应至澄清溶液，浓缩后沉淀于400mL n-hexane，移除n-hexane后以300mL n-hexane/ethyl acetate(1/1)再结晶，过滤后可得单体N-carboxy-γ-benzyl-L-glutamate anhydride(BLG-NCA)；15g BLG-NCA与2.1gα-amino-ω-methoxy-poly(ethylene glycol)(PEG-NH2)溶解于43mL dimethyl sulfoxide(DMSO)，40℃搅拌反应72小时，完成后粗产物沉淀于215mL diethyl ether，移除diethyl ether后加入315mL ethanol与210mL1N NaOH25℃搅拌反应24小时，接着以35％HCl冰浴调整pH值至7.0，利用MWCO3500透析膜透析纯化，冷冻干燥后可得聚乙二醇-聚麸胺酸嵌段共聚物(PEG-b-PGA)。
提供原料，该原料包含206.44mg氨磷汀、825.50mg聚乙二醇-聚麸胺酸嵌段共聚物(PEG-b-PGA)与206.44mg氯化亚铁(FeCl2·4H2O)；将该原料置入41.288ml缓冲液HEPES[4-(2-hydroxyethyl)-1-piperazinee-thanesulfonic acid)]中，以25℃下、pH值为7.0、转速200rpm进行匀相扰动程序。
调配物FePA的调配比例PEG-b-PGA:FeCl2·4H2O:amifostine＝4:1:1(w:w:w，以重量作为比例)，较佳氨磷汀反应浓度:5mg/mL。藉此，该氨磷汀经由该亚铁离子(Fe2+)与该聚乙二醇-聚麸胺酸嵌段共聚物(PEG-b-PGA)藉由配位键直接进行自组装(self-assembly)反应。
调配物实例1(FePA)
金属核心复合微胞药物载体的抗氧化效果-体外试验
本实验利用UV照射细胞模拟受到辐射所造成的影响，并以慧星试验(Comet Assay)做为检测方法。慧星试验是一种快速、灵敏、简便的检验DNA损伤的方法，广泛的应用于DNA放射损伤，DNA交联的检测，药物的遗传毒性评估，细胞凋零鉴定等工作。
实验共分成八组，其中
API为氨磷汀1mg/mL；
FePA成分为氯化亚铁1mg/mL、PEG-b-PGA4mg/mL、氨磷汀1mg/mL；
FeP成分为氯化亚铁1mg/mL与PEG-b-PGA4mg/mL；
各施予1mL于各实验组。处理方式如下表一所示：
表一
名称 盘数 条件处理
CON 2 完全不处理,不照射UV
UV 2 直接照UV
API40x 2 照UV前30分钟加药
FePA20x 2 照UV前30分钟加药
API40x 2 照UV前两小时加药
FeP40x 2 照UV前两小时加药
FePA20x 2 照UV前两小时加药
CON：负向控制组(Negative Control)
UV：正向控制组(Positive Control)
如正向控制
40X：40倍稀释
20X：20倍稀释
将小鼠胚胎肝细胞(BNLCL.2)以3*105cell/mL的密度接种于35mm培养皿中，并培养至少20小时后再进行试验。移除上清液，个别依照时间先后加入控制组及实验组化合物浓度混合含血清的新鲜培养液。使用PBS稍加清洗，让培养皿照射UVB(100J·m-2UVB doses)UV后，加入2mL新鲜培养液，再于培养箱(incubator)(温度37℃/4％CO2)进行培养4小时。待药物作用，用胶棒轻轻的将细胞刮下，转移细胞液到离心管中，计算总细胞数，然后进行离心沉淀(1200rpm、5分钟)，用PBS(Ca2+，Mg2+free)清洗一次，加入PBS使其细胞数为1*105cell/mL。
将低熔点洋菜胶瓶盖转松置于95℃开水中隔水加热融化5分钟后，再置于37℃水域槽至少20分钟进行冷却。在37℃下结合细胞(1×105/ml)与熔融的低熔点洋菜胶以7μL：70μL进行混合，混合后并立即吸取60μL到CometSlideTM。将玻片(slides)平放并避光置于冰上10分钟。将玻片浸泡在预冷的裂解液(lysis solution)后，置放于4℃冰箱中30分钟。轻敲玻片上多余的缓冲液(buffer)后，将玻片浸泡于新鲜置备的碱性解螺旋溶液(Alkaline Unwinding Solution)后，于室温下、避光60分钟。在电泳槽上加入950mL预冷的碱性电泳溶液(Alkaline ElectrophoresisSolution)，再把玻片放上，盖上slide Tray Overlay，跑胶条件为21V、30分。轻轻地排除电泳液，然后浸泡于去离子水2次，每次5分钟。浸泡于70％乙醇5分钟。在排气柜(hood)中干燥样品15分钟，干燥会使细胞呈现单一的平面，便于观察，样品可于此阶段放于干燥剂下于室温下储存。将100μL稀释后的SYBR Green I加于干燥的胶体，在放于4℃冰箱5分钟。轻轻拍打移除多余的SYBR溶液,并使玻片避光，于室温下晾干后，透过萤光显微镜(fluorescence microscopy)进行影像拍摄I最大激发光与散射光分别为494nm/521nm.并调整萤光滤镜至足够光源)200X。
实验结果如图2、图3可知，无论是照射UV前30分钟或是前2小时给予FePA20X、API40X、FeP40X，相较于正向控制组(UV)，其拖尾％平均值皆有明显减少，且与正常无照射UV控制组(CON)无差异，由此可知给予FePA的确有明显保护细胞免于UV照射所造成的损伤，且其状态几乎与正常无照射UV的细胞相同。
其他活体辐射伤害或是化学治疗不良作用改善的实验结果
效力结果(Efficacy Result)
动物试验中，小鼠NMRI(每只20-30克)30天的急性辐射保护力试验，辐射控制组：于10分钟内接受1、4、8戈雷(Gy)剂量的放射线；标准治疗组：接受FDA许可上市的药物氨磷汀(6.25mg/kg)静脉注射后30分钟，10分钟内接受8Gy剂量的辐射。A-01即为FePA，调配比例PEG-b-PGA:FeCl2·4H2O:amifostine＝4:1:1(w:w:w)。A-01实验组：接受A-01试验药物37.5mg/kg(与标准治疗组有相同的氨磷汀药物含量)静脉注射后120分钟，10分钟内接受8Gy剂量的辐射。观察白血球第30天数目与存活率分析。
实验结果如下表二所示，A-01实验组中白血球数量可达3-4倍单纯接受辐射的控制组，显见本药物A-01具有至少两小时以上的造血系统保护力，能有效降低辐射导致易受感染的不良作用。且本试验中，投药于小鼠身上的A-01药物中氨磷汀为6.25mg/kg，换算为60kg的人体约为30mg的投药量即具有保护力(含PEG-b-PGA等的A01药物微胞载体共180mg)，相比原先氨磷汀经美国FDA核可预防头颈部癌症患者接受氨磷汀治疗时剂量为200mg/m2，且仅能于放射线治疗前三分钟左右给药，并且仅有唾腺保护具显著差异，换算60kg成人约需要氨磷汀药物为320mg(200mg/m2)，可见A-01的药物可以透过选择性蓄积与缓慢释放达到更优异的抗辐射疗效。
表二
(-表示该实验因放射线剂量不足以产生严重造血系统伤害故不投予药物；
--组因于其他急性毒性的大小鼠安全性试验均没出现任何副作用，于正常范围内故不呈现白血球数字。)
综上所述，本案所提供的一种利用金属离子复合微胞技术包覆药物氨磷汀或其他抗氧化物的方法，以应用于降低辐射伤害与化疗药物副作用确属创新，过去习知技术中并无有效的方式去控制氨磷汀的药物释放，以及提供体内器官选择性分布。上述多项功效实属充分符合新颖性及进步性的法定发明专利要件，爰依法提出申请，恳请贵局核准本件发明专利申请案，以励发明。

Claims (9)

1.一种降低自由基伤害的复合微胞载体医药组成物，其特征在于该组成物包含：
至少一种金属或其离子；
至少一种药物或受载体保护及修饰的抗氧化物；及
药物载体。
2.如权利要求1所述的复合微胞载体医药组成物，其特征在于其中上述的金属离子核心选自下列族群中之一者或其任意组合或其衍生物：铁(Fe)、铜(Cu)、镍(Ni)、铟(In)、钙(Ca)、钴(Co)、铬(Cr)、钆(Gd)、铝(Al)、锡(Sn)、锌(Zn)、钨(W)、钪(Sc)及钛(Ti)。
3.如权利要求1所述的复合微胞载体医药组成物，其特征在于其中上述的药物载体选自下列族群中之一或其任意组合或其衍生物：聚乙二醇(poly(ethylene glycol))、聚天门冬氨酸(poly(aspartic acid))、聚麸胺酸(poly(glutamic acid))、聚赖氨酸(poly(lysine))、聚丙烯酸(poly(acrylic acid))、几丁聚醣(chitosan)、聚乙烯亚胺(poly(ethyleneimine))、聚甲基丙烯酸(poly(methacrylic acid))、透明质酸(hyaluronic acid)、胶原蛋白(collagen)、聚氮-异丙基丙烯酰胺(poly(N-isopropyl acrylamide))、直链淀粉(amylose)、纤维素(cellulose)、聚羟基丁酸酯(poly(hydroxybutyrate))、聚乳酸(poly(lactic acid))、聚琥珀酸丁酯(poly(butylenesuccinate))、聚己内酯(poly(caprolactone))、羧甲基纤维素(carboxymethylcellulose)、糊精(dextran)、环糊精(cyclodextrin)、聚乙二醇-聚麸胺酸嵌段共聚物(poly(ethylene glycol)-b-poly(glutamic acid))、磷脂质(phospholipid)。
4.如权利要求1所述的复合微胞载体医药组成物，其特征在于其中上述的药物载体选自下列族群中之一或其任意组合：微脂体，微胞或高分子微胞及树枝状高分子。
5.如权利要求1所述的复合微胞载体医药组成物，其特征在于其更包含一或多样药物，该药物可与金属键结或不键结，其中上述的药物选自下列族群中之一或其任意组合或其衍生物：氨磷汀(amifostine)、WR-1065、维生素C(ascorbic acid、Vitamin C),谷胱甘肽(glutathione)、退黑激素(melatonin)、生育酚(tocopherols)、生育三烯醇(tocotrienols、Vitamin E)、左旋肉碱(L-carnitine)、胡萝卜素(carotenes)、还原型泛醌(ubiquinol)、硫辛酸(lipoic acid)、多酚(polyphenols)、儿茶酚胺(catecholamine)、姜黄素(curcumin)、白藜芦醇(resveratrol)、白藜芦醇苷(piceid)、乙酰半胱氨酸(acetylcysteine)、四甲基呱啶氧化物(Tempo)、细辛脑(asarone)、氨基胍(aminoguanidine),维生素Ｅ单糖苷(tocopherol monoglucoside)、甘草酸(glycyrrhizic acid)、表儿茶素(epicatechin)、类黄酮(flavonoid)、荭草素(Orientin)、维采宁(vicenin)、2-巯基丙酰基-甘氨酸(MPG(2-mercaptopropionyl glycine))及美司钠(Mesna(2-mercaptoethanesulfonic acid))。
6.如权利要求1至5中任一项所述的复合微胞载体医药组成物，其特征在于其中该药物可以做为还原剂，还原受氧化的生物分子，以恢复其功能。
7.如权利要求1至5中任一项所述的复合微胞载体医药组成物，其特征在于其中该药物可依其抗氧化效果阻止自由基持续传递与攻击。
8.如权利要求1至5中任一项所述的复合微胞载体医药组成物，其特征在于其中该药物可以减少辐射、紫外线、化疗药品、电磁场效应等所造成的自由基，达到保护自由基伤害与降低其毒性的效果。
9.一种降低自由基伤害的复合微胞载体医药组成物，其特征在于该组成物包含：
铁离子；氨磷汀；及药物载体，该载体为聚乙二醇-聚麸胺酸嵌段共聚物。
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CN106267223A (zh) * 2015-05-11 2017-01-04 华东理工大学 一种基于氧自由基的靶向功能材料及其应用
CN110200941A (zh) * 2019-06-24 2019-09-06 苏州大学 作用于小肠的辐射防护纳米药物及其制备方法
CN110200941B (zh) * 2019-06-24 2020-05-15 苏州大学 作用于小肠的辐射防护纳米药物及其制备方法

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