CN113347950A - 眼用透镜、药学组合物及其用途 - Google Patents
眼用透镜、药学组合物及其用途 Download PDFInfo
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- CN113347950A CN113347950A CN202080009649.3A CN202080009649A CN113347950A CN 113347950 A CN113347950 A CN 113347950A CN 202080009649 A CN202080009649 A CN 202080009649A CN 113347950 A CN113347950 A CN 113347950A
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Abstract
本发明内容是关于眼用透镜及药学组合物。本发明内容的眼用透镜的特征在于具有二氢硫辛酸涂覆的金纳米团簇吸附于其上。本发明内容的药学组合物包含二氢硫辛酸涂覆的金纳米团簇,以及一药学上可接受的赋形剂。依据本发明内容某些实施方式,该二氢硫辛酸涂覆的金纳米团簇可降低细胞内ROS的含量、促进组织修复,以及抑制病理性血管新生。据此,本发明内容也提供利用本发明隐形眼镜或药学组合物来治疗眼部病症的方法。
Description
相关申请的交叉引用
本申请主张2019年1月19日所提交的美国临时申请号62/794,563的优先权,该美国临时申请案在此通过引用而并入其全文。
技术领域
本发明内容是关于治疗疾病的领域。更具体来说,本发明内容是关于利用隐形眼镜或药学组合物来治疗眼部病症,其中该隐形眼镜具有二氢硫辛酸(dihydrolipoic acid,DHLA)涂覆的金纳米团簇吸附于其上,且该药学组合物包含DHLA涂覆的金纳米团簇。
背景技术
活性含氧物(reactive oxygen species,ROS)是衍生自分子氧的化学反应性自由基。示例性的ROS包含过氧化氢(hydrogen peroxide,H2O2)、超氧化物(superoxide,O2 -)、羟基(hydroxyl radical,·OH)、单态氧(singlet oxygen,1[O2])及α-氧(alpha-oxygen,α-O)。ROS为代谢过程的天然产物,在细胞信息传递及体内平衡中扮演着重要的角色。然而,已知过量的ROS会造成氧化压力,进而导致细胞损伤,以及最终的细胞死亡。
ROS与多种眼部病症的发生及/或进程相关,包含干眼症(dry eye)、结膜炎(conjunctivitis)、葡萄膜炎(uveitis)、角膜炎(keratitis)、视网膜炎(retinitis)、白内障(cataract)、屈光不正(refractive error)、青光眼(glaucoma)、视神经病变(opticneuropathy)、黄斑部病变(macular degeneration)、视网膜病变(retinopathy),以及色素性视网膜炎(retinitis pigmentosa)。不幸的是,即使近年来科学及研究相关领域投入大量资源,某些眼部病症至今仍无有效的治愈方法。
有鉴于此,相关领域亟需一种可减少眼部ROS含量的方法,据以有效治疗眼部病症。
发明内容
发明内容旨在提供本发明内容的简化摘要,以使阅读者对本发明内容具备基本的理解。此发明内容并非本发明内容的完整概述,且其用意并非在指出本发明实施例的重要/关键组件或界定本发明的范围。
本发明内容的第一方面是关于一种用以治疗眼部病症的眼用透镜。依据本发明内容的实施方式,该眼用透镜的特征在于具有DHLA涂覆的金纳米团簇吸附于其上。在结构上,该DHLA涂覆的金纳米团簇是由金纳米团簇及复数个涂覆于该金纳米团簇上的DHLA所组成,其中该金纳米团簇是由复数个金纳米粒子所形成。较佳地,该DHLA涂覆的金纳米团簇的粒径为0.1到20纳米。
依据本发明内容某些实施方式,是于15-50℃,将一隐形眼镜培养于一含有DHLA涂覆的金纳米团簇的溶液至少30分钟,其中DHLA涂覆的金纳米团簇于该溶液的浓度为1-100nM,且该溶液的pH值为7.5-9.0,据以制备眼用透镜。较佳地,在培养步骤前,于120-140℃以1.2-2.0大气压(atmosphere(atm);等于912-1,520毫米汞柱,或1.2×105-2×105Pa)预处理该含有DHLA涂覆的金纳米团簇的溶液10-60分钟。依据本发明内容某些实施例,该隐形眼镜是培养于含有10-50nM的DHLA涂覆的金纳米团簇的溶液。
本发明内容还提供一种用以治疗眼部病症的试剂盒。该试剂盒包含一含有1-100nM的DHLA涂覆金纳米团簇的溶液,以及一浸泡于该溶液的隐形眼镜。依据某些较佳的实施方式,该含有DHLA涂覆的金纳米团簇的溶液是于120-140℃以1.2-2.0大气压预处理10-60分钟。
本发明内容的另一方面是关于一种药学组合物,其包含一DHLA涂覆的金纳米团簇,以及一药学上可接受的赋形剂。较佳地,该DHLA涂覆的金纳米团簇是于120-140℃以1.2-2.0大气压预处理10-60分钟。
本发明内容还提供利用本发明任一方面或实施方式所阐述的眼用透镜或药学组合物来治疗一个体的眼部病症的方法。依据某些实施方式,该方法包含将本发明眼用透镜置于该个体的角膜上,以减缓或改善与眼部病症相关的征状。依据某些实施方式,该方法包含对该个体的眼睛投予一有效量的本发明药学组合物,以减缓或改善与眼部病症相关的征状。
适用于本发明眼用透镜及/或药学组合物治疗的眼部病症可以是任何与损伤、活性含氧物及/或血管新生相关的眼部病症;举例来说,眼部损伤(eye injury)、干眼症(dryeye)、结膜炎(conjunctivitis)、葡萄膜炎(uveitis)、角膜炎(keratitis)、视网膜炎(retinitis)、白内障(cataract)、屈光不正(refractive error)、青光眼(glaucoma)、视神经病变(optic neuropathy)、黄斑部病变(macular degeneration)、视网膜病变(retinopathy),或是色素性视网膜炎(retinitis pigmentosa)。
在本发明内容中,该个体为一哺乳动物;较佳为一人类。
在参阅下文实施方式后,本领域技术人员当可轻易了解本发明的基本精神及其他发明目的,以及本发明所采用的技术手段与实施方式。
附图说明
为让本发明的上述与其他目的、特征、优点与实施例能更明显易懂,附图的说明如下:
图1A是依据本发明内容实施例1所绘示的柱状图,用以阐述本发明DHLA涂覆的金纳米团簇的抗氧化活性,其中是利用流式细胞仪来检测经特定处理后,内皮祖细胞(endothelial progenitor cell,EPC)的荧光强度。
图1B是依据本发明内容实施例1所绘示的线性图,用以阐述本发明DHLA涂覆的金纳米团簇的抗氧化活性,其中是利用光谱仪来分析经特定浓度的DHLA涂覆的金纳米团簇处理后,照射或不照射蓝光的牛角膜上皮细胞(bovine cornea epithelial cell,BCE)于485纳米及539纳米的吸光值。
图2A是依据本发明内容实施例1所绘示的柱状图,用以阐述本发明DHLA涂覆的金纳米团簇的抗氧化活性,其中是将经灭菌或未灭菌预处理的DHLA涂覆的金纳米团簇投予至EPC,反应一小时,之后利用流式细胞仪检测EPC的荧光强度。TBHP:叔丁基过氧化氢(t-butyl hydroperoxide),作为正对照组。R:仅有隐形眼镜溶液。*,p<0.05;**,p<0.01;n=3。
图2B是依据本发明内容实施例1所绘示的线性图,用以阐述本发明DHLA涂覆的金纳米团簇的抗氧化活性,其中是利用光谱仪来分析投予特定浓度的灭菌处理的DHLA涂覆金纳米团簇后,照射或不照射蓝光的BCE于485纳米及539纳米的吸光值。
图2C是依据本发明内容实施例1所绘示的柱状图,用以阐述ROS含量的减少百分比(%),其中分别检测投予特定浓度的经灭菌处理或未灭菌处理的DHLA涂覆金纳米团簇后,BCE的ROS含量,藉以决定ROS含量的减少百分比。
图2D是依据本发明内容实施例1所绘示的柱状图,用以阐述经灭菌处理或未灭菌处理的DHLA涂覆金纳米团簇的ROS抑制比,其中对BCE投予1,000nM经灭菌处理或未灭菌处理的DHLA涂覆金纳米团簇后,照射蓝光10、20或30分钟。利用光谱仪检测BCE于485纳米及539纳米的吸光值,以决定经灭菌处理或未灭菌处理的DHLA涂覆金纳米团簇的ROS抑制活性。
图3是依据本发明内容实施例2所绘示的柱状图,用以阐述隐形眼镜上特定金纳米团簇的吸附量。
图4A及4B是依据本发明内容实施例2所绘示的柱状图,分别阐述经特定处理后细胞中GSH的表达量。缓冲液_0nM:仅有培养液;缓冲液_30nM:含有30nM DHLA涂覆的金纳米团簇的培养液;镜片_0nM:经培养液预处理的隐形眼镜;镜片_30nM:经含有30nM DHLA涂覆的金纳米团簇的培养液预处理的隐形眼镜。***,p<0.001。
图5A到5C是依据本发明内容实施例2所绘示的柱状图,分别阐述经特定处理后细胞中GSH的表达量。缓冲液_0nM:仅有培养液;缓冲液_30nM:含有30nM DHLA涂覆的金纳米团簇的培养液;镜片_0nM:经培养液预处理的隐形眼镜;镜片_30nM:经含有30nM DHLA涂覆的金纳米团簇的培养液预处理的隐形眼镜。*,p<0.05。
图6A及6B是依据本发明内容实施例3所阐述的创伤愈合试验照片。PBS处理:经磷酸盐缓冲液(phosphate-buffered saline,PBS)处理的细胞;R处理:经滴眼液处理的细胞;R+30F处理:经含有30nM DHLA涂覆金纳米团簇的滴眼液处理的细胞;R+50F处理:经含有50nM DHLA涂覆金纳米团簇的滴眼液处理的细胞;R+100F处理:经含有100nM DHLA涂覆金纳米团簇的滴眼液处理的细胞;R+200F处理:经含有200nM DHLA涂覆金纳米团簇的滴眼液处理的细胞。
图7A到7C是依据本发明内容实施例3所阐述的角膜创伤愈合照片。图7A:机械性刮伤模式。图7B:STZ诱发模式。图7C:氧气诱发视网膜病变(oxygen-induced retinopathy,OIR)模式。
具体实施方式
为了使本发明内容的叙述更加详尽与完备,下文针对了本发明的实施方式与具体实施例提出了说明性的描述;但这并非实施或运用本发明具体实施例的唯一形式。实施方式中涵盖了多个具体实施例的特征以及用以建构与操作这些具体实施例的方法步骤与其顺序。然而,也可利用其他具体实施例来达成相同或均等的功能与步骤顺序。
I.定义
为方便起见,本说明书、实施例及所附申请专利范围中所使用的特定专有名词集中在此。除非本说明书另有定义,否则此处所使用的科学与技术词汇的含义与本领域技术人员所理解与惯用的意义相同。并且,在和上下文不相冲突的情形下,当可理解本说明书所使用的单数名词涵盖该名词的复数型,而所使用的复数名词时也涵盖该名词的单数型。具体而言,在本说明书与申请专利范围中,单数形式“一”(a及an)包括复数参考值,但依据上下文而另有指示者除外。此外,在本说明书与申请专利范围中,“至少一”(at least one)与“一或多”(one or more)表述方式的意义相同,两者都代表包含了一、二、三或更多。
虽然用以界定本发明较广范围的数值范围与参数皆是约略的数值,此处已尽可能精确地呈现具体实施例中的相关数值。然而,任何数值本质上不可避免地含有因个别测试方法所致的标准偏差。在此处,“约”通常指实际数值在一特定数值或范围的正负10%、5%、1%或0.5%之内。或者是,“约”一词代表实际数值落在平均值的可接受标准误差之内,视本领域技术人员的考虑而定。除了实验例之外,或除非另有明确的说明,当可理解此处所用的所有范围、数量、数值与百分比(例如用以描述材料用量、时间长短、温度、操作条件、数量比例及其他相似者)均经过“约”的修饰。因此,除非另有相反的说明,本说明书与附随申请专利范围所公开的数值参数皆为约略的数值,且可视需求而更动。至少应将这些数值参数理解为所指出的有效位数与套用一般进位法所得到的数值。
在本发明内容中,“单体”(monomer)一词是指在聚合作用前包含一或多个可聚合的官能基团的分子,以及一聚合物的重复单元。更具体来说,“单体”(monomer)一词是指任何可进行聚合反应的分子,其可通过化学反应来相互连接,以形成一具有较高分子量的分子。一共聚物(copolymer)为包含二或多种不同单体的分子。
在本发明内容中,“交联剂”(crosslinking agent)一词是指可形成稳定共价键的化合物。更具体来说,“交联剂”(crosslinking agent)一词包含任何分子或原子,其可于交联聚合物的分子之间形成一或多个交联,以及/或是于交联聚合物的单一分子中二或多个原子之间形成一或多个交联。“交联”(crosslink)一词在本发明内容是指用以将聚合物链连接至另一聚合物链的共价键。
在本发明内容中,“眼内透镜”(intraocular lens)一词具有最广泛的定义。一般来说,“眼内透镜”(intraocular lens)一词是指一透镜,其可移植至一眼睛内部,据以取代眼睛的天然晶体,或是在移除或不移除天然晶体的情况下增强视力。角膜内透镜(intracorneal lens)及晶体透镜(phakic lens)为二种示例性的透镜,其可在不移除天然晶体的情况下植入个体的眼睛内部。
“隐形眼镜”(contact lens)一词为本领域技术人员所熟知的,是指包含用以矫正视力、美容目的及保护角膜(例如,不是以矫正视力为目的)等装置。隐形眼镜包含“硬式”(hard)隐形眼镜,举例来说,具有良好的生物兼容性,但透氧性较差的聚甲基丙烯酸甲酯(poly(methyl methacrylate),PMMA);“透气型”(gas-permeable)隐形眼镜,举例来说,具有良好的生物兼容性,且可通过聚合结构使氧气扩散的聚甲基丙烯酸硅酯(poly(siliconemethacrylate));以及“软式”(soft)隐形眼镜,举例来说,具有良好的生物兼容性,且可利用水相传递通过聚合结构使氧气扩散的聚甲基丙烯酸羟乙酯(poly(hydroxyethylmethacrylate))。示例性的用以制备隐形眼镜的材料包含,但不限于,聚甲基丙烯酸甲酯、聚硅氧丙烯酸酯(poly(silicone acrylate))、聚甲基丙烯酸硅酯、聚氟丙烯酸酯(poly(fluoroacrylate))、聚氟丙烯酸甲酯(poly(fluoromethacrylate))、聚氟硅丙烯酸酯(poly(flurosilicone eacrylate))、聚甲基丙烯酸酯(polymethacrylate)、聚丙烯酸酯(polyacrylate)、聚氨酯(polyurethane)、聚硅氨酯(poly(silicone urethane))、聚衣康酸酯(polyitaconate),以及其组合。可利用一或多种交联剂来交联这些聚合材料。隐形眼镜通常包含一凸面以及一与眼球接触的凹面。一般来说,不同种类的隐形眼镜为本领域技术人员所熟知的。
在本发明内容中,“药学上可接受的”(pharmaceutically acceptable)成分为适用于人类及/或动物而不会产生过度的有害副作用(如毒性、刺激及过敏反应),且具有一适当的效益/危害比的物质。
在本说明书中,“治疗”(treating或treatment)一词是指获得一期望的医药及/或生理功效;例如,推迟或抑制一眼部病症的发生或进程。该效果可以是预防性的,即完全或部分预防一眼部病症或其病征;及/或是治疗性的,即部分或完全治愈一眼部病症及/或其所造成的不适。“治疗”(treating或treatment)在本说明书包含预防、治疗或减缓一哺乳类动物(特别是人类)的眼部病症;该治疗包含:(1)预防、治疗或减缓一个体罹患一眼部病症,其中该个体为罹患该眼部病症的高风险族群,或是已罹患该眼部病症而尚未确诊断定;(2)抑制一眼部病症(例如,抑制其发生或进程);或是(3)减轻一眼部病症(例如,减轻与该病症相关的征状)。一般来说,“治疗”(treating或treatment)一词在本发明内容是指抑制或改善一眼部病症(举例来说,与ROS、血管新生或眼部损伤或伤害相关的病症,或是由ROS、血管新生或眼部损伤或伤害所造成的病症),以及/或是促进损伤或受损的眼部组织愈合。
“有效量”(effective amount)在此处是指一成份或药物的用量足以产生要求的疗效反应。有效量也指一种化合物或组合物,其治疗有益效果超越其毒性或有害影响。一药剂的有效量不必然可治愈一疾病或病症,而是可对一疾病或病症提供治疗功效,例如推迟、预防或抑制疾病或病症的发生,或是改善与疾病或病症相关的征症。可将有效量配制为一、二或多次投予形式,在特定时间内以一、二或多次投予方式投予至个体体内。具体的治疗有效量取决于多种因素,例如欲治疗的特定状况、个体的生理条件(如,个体重、年龄或性别)、接受治疗的个体类型、治疗持续时间、并行治疗(如果有的话)的本质以及所用的具体配方和化合物或其衍生物的结构。举例来说,可将有效量表示成药物的总重量(例如,公克、毫克或微克),或是药物重量相对于体重的比例,例如,每公斤体重多少毫克(mg/Kg)。或者是,有效量也可以医药组合物中活性成份(例如,本发明内容的DHLA涂覆的金纳米团簇)的浓度来表示,例如摩尔浓度(molar concentration)、重量浓度(mass concentration)、体积浓度(volume concentration)、重量摩尔浓度(molality)、摩尔分率(mole fraction)、重量分率(mass fraction)及混合比例(mixing ratio)。技术人员可依据动物模式的剂量来计算药物(例如,本发明内容的DHLA涂覆的金纳米团簇)的人体等效剂量(human equivalentdose,HED)。举例来说,技术人员可依据美国食品药物管理局(US Food and DrugAdministration,FDA)所公告的“估算成人健康志愿者在初始临床治疗测式的最大安全起始剂量”(Estimating the Maximum Safe Starting Dose in Initial Clinical Trialsfor Therapeutics in Adult Healthy Volunteers)来估算人体使用的最高安全剂量。
“个体”(subject)一词在本发明内容是指包含人类等可接受本发明眼用透镜或药学组合物治疗的哺乳动物。除非另有所指,否则“个体”(subject)一词在本发明内容同时意指男性及女性。
II.发明详细说明
(i)眼用透镜
本发明内容的第一方面是关于一种眼用透镜,其具有矫正视力及/或抗氧化的功效,可据以治疗与ROS相关的眼部病症,以及/或是保护眼睛避免受到氧化伤害。本发明内容还提供用以制备本发明眼用透镜的试剂盒及方法,以及利用本发明眼用透镜来治疗眼部病症(特别是与ROS相关及/或由ROS造成的眼部病症)的方法。
本发明眼用透镜的特征在于具有DHLA涂覆的金纳米团簇分散于其中以及/或是吸附于其上。本发明内容所使用的DHLA涂覆的金纳米团簇为本领域技术人员所熟知的,其制程(Lin et al.,2009,ACS Nano 3:395-401)也为本领域技术人员所熟知的;因此,在此不再进一步解释其制备过程。在结构上,各DHLA涂覆的金纳米团簇是由复数个金纳米粒子所形成的金纳米团簇,以及复数个涂覆于该金纳米团簇外层的DHLA所组成。在激发波长约为420纳米的条件下,本发明DHLA涂覆的金纳米团簇可发散出650纳米的荧光,其发散波长介于红光至近红光的范围。各金纳米团簇的粒径约为0.1到20纳米,较佳为1到15纳米,更佳为2到13纳米。以上所揭露的金纳米团簇的粒径为干燥状态下的金纳米团簇,然而,如果用于本发明内容的金纳米团簇是水溶性的或至少可分散于液体培养基和/或水中,将会更好;由于与周边溶剂分子(例如,水)耦合,因此金纳米团簇的流体动力学粒径(hydrodynamicsize)明显大于其干燥尺寸。于一实施例中,金纳米团簇的流体动力学粒径(hydrodynamicsize)约相当于0.1至30千耳顿(kDa)的聚乙二醇(polyethylene glycol,PEG)。
依据使用目的不同,本发明内容的眼用透镜可制备为眼内透镜的形式,或是隐形眼镜(例如,软式隐形眼镜、硬式隐形眼镜,以及透气型隐形眼镜)的形式。在制备过程中,是在15-50℃(例如,15℃、16℃、17℃、18℃、19℃、20℃、21℃、22℃、23℃、24℃、25℃、26℃、27℃、28℃、29℃、30℃、31℃、32℃、33℃、34℃、35℃、36℃、37℃、38℃、39℃、40℃、41℃、42℃、43℃、44℃、45℃、46℃、47℃、48℃、49℃或50℃),将本发明眼用透镜培养于一包含DHLA涂覆的金纳米团簇的溶液至少30分钟(举例来说,30、31、32、33、34、35、36、37、38、39、40、41、42、43、44、45、46、47、48、49、50、51、52、53、54、55、56、57、58、59或60分钟,或是更长的时间),其中该DHLA涂覆的金纳米团簇于该溶液的浓度为1-100nM,且该溶液的pH值为7.5-9.0(例如,pH 7.5、7.6、7.7、7.8、7.9、8.0、8.1、8.2、8.3、8.4、8.5、8.6、8.7、8.8、8.9或9.0),藉以使DHLA涂覆的金纳米团簇吸附在眼用透镜的表面及/或分散于眼用透镜的结构中。依据某些实施例,是在20-45℃将本发明眼用透镜培养于含有DHLA涂覆的金纳米团簇的溶液30分钟,其中该溶液的pH值为7.5-8.5。在一特定实施例中,是在20-40℃将本发明眼用透镜培养于含有DHLA涂覆的金纳米团簇的溶液30分钟,其中该溶液的pH值为8.0-8.5。
非必要地,该DHLA涂覆的金纳米团簇溶液是于120-140℃(例如,120℃、121℃、122℃、123℃、124℃、125℃、126℃、127℃、128℃、129℃、130℃、131℃、132℃、133℃、134℃、135℃、136℃、137℃、138℃、139℃或140℃),以1.2-2.0大气压(例如,1.2、1.3、1.4、1.5、1.6、1.7、1.8、1.9或2.0大气压)预处理10-60分钟(例如,10、15、20、25、30、35、40、45、50、55或60分钟)。较佳地,该DHLA涂覆的金纳米团簇溶液是于125-135℃,以1.2-1.8大气压预处理20-50分钟。更佳地,该DHLA涂覆的金纳米团簇溶液是于130-135℃,以1.2-1.5大气压预处理20-40分钟。依据一特定实施例,该DHLA涂覆的金纳米团簇溶液是于132℃,以1.5大气压预处理30分钟。
依据本发明内容某些实施例,相较于未预处理的DHLA涂覆的金纳米团簇溶液,经特定条件预处理的DHLA涂覆的金纳米团簇溶液具有较佳的吸附能力及抗氧化能力。可在20-40℃将眼用透镜培养于1-100nM的经预处理的DHLA涂覆金纳米团簇溶液30分钟,使抗氧化DHLA涂覆的金纳米团簇吸附于其表面及/或结构中;举例来说,培养于1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29、30、31、32、33、34、35、36、37、38、39、40、41、42、43、44、45、46、47、48、49、50、51、52、53、54、55、56、57、58、59、60、61、62、63、64、65、66、67、68、69、70、71、72、73、74、75、76、77、78、79、80、81、82、83、84、85、86、87、88、89、90、91、92、93、94、95、96、97、98、99或100nM预处理的DHLA涂覆金纳米团溶液。较佳地,将眼用透镜培养于10-50nM预处理的DHLA涂覆金纳米团簇溶液。依据一特定实施例,将眼用透镜培养于30nM预处理的DHLA涂覆金纳米团簇溶液后,该眼用透镜可对角膜细胞提供一抗蓝光照射的保护功效。
眼用透镜的结构为本领域技术人员所熟知。举例来说,眼用透镜可包含至少一单体,以及一用以聚合该至少一单体的交联剂。
眼用透镜的制备(例如,形状、结构、中心轴及厚度等)可随着使用目的不同而有所变异,且可通过所属技术领域惯常使用或已知的方法来进行制备。举例来说,可通过热聚合法或光聚合法来制备眼内透镜。在这些方法中,用以制备眼内透镜的单体可以是丙烯、酯类、硅氧烷、丙烯酰胺、酰亚胺、疏水性或亲水性丙烯酸、或其他生物兼容性材料。示例性的常用以制备眼内透镜的单体包含,但不限于,甲基丙烯酸甲酯(methyl methacrylate,MMA)、甲基丙烯酸丁酯(butyl methacrylate)、甲基丙烯酸羟乙酯(hydroxyethylmethacrylate,HEMA)、甲基丙烯酸环己酯(cyclohexyl methacrylate)、甲基丙烯酸甘油酯(glycerol methacrylate)、二甲基丙烯酰胺(dimethylacrylamide)、甲基丙烯酸(methacrylic acid)、2-丙烯酸苯氧乙酯(2-phenoxyethyl acrylate)、2-丙烯酸苯乙硫酯(2-phenylethylthio acrylate)、2-丙烯酸苯乙胺酯(2-phenylethylamino acrylate)、丙烯酸苯酯(phenyl acrylate)、丙烯酸芐酯(benzyl acrylate)、2-丙烯酸苯乙酯(2-phenylethyl acrylate)、3-丙烯酸苯丙酯(3-phenylpropyl acrylate)、3-丙烯酸苯氧丙酯(3-phenoxypropyl acrylate)、4-丙烯酸苯丁酯(4-phenylbutyl acrylate)、4-丙烯酸苯氧丁酯(4-phenoxybutyl acrylate)、4-丙烯酸甲基苯酯(4-methylphenyl acrylate)、4-丙烯酸甲基芐酯(4-methylbenzyl acrylate)、2-2-丙烯酸甲基苯乙酯(2-2-methylphenylethyl acrylate)、2-3-丙烯酸甲基苯乙酯(2-3-methylphenylethylacrylate)、2-4-丙烯酸甲基苯乙酯(2-4-methylphenylethyl acrylate)、N-乙烯吡咯烷酮(N-Vinyl pyrrolidone,NVP)、硅氧丙烯酸酯(silicone acrylate)、甲基丙烯酸硅酯(silicone methacrylate)、氟丙烯酸酯(fluoroacrylate)、氟丙烯酸甲酯(fluoromethacrylate)、氟硅丙烯酸酯(flurosilicone eacrylate)、甲基丙烯酸酯、丙烯酸酯(acrylate)、氨酯(urethane)、硅氨酯(silicone urethane)、衣康酸酯(itaconate)、三氟甲基丙烯酸酯(trifluoroethyl methacrylate)、甲基丙烯酸六氟异丙酯(hexafluoroisopropyl methacrylate)、全氟辛乙基氧丙烯甲基丙烯酸酯(perfluorooctylethyloxypropylene methacrylate)、乙烯醇(vinyl alcohol,VA)、醋酸乙烯酯(vinylacetate)、乙二醇(ethylene glycol)、丙二醇(propylene glycol)、全氟多醚(perfluoropolyether),以及其组合。以上列示的硅氧(silicone)成分是选自由具有单甲基丙烯酸酯末端的聚二甲基硅氧烷(monomethacrylate terminatedpolydimethylsiloxane)、双-3-丙烯酰氧基-2-羟丙氧基丙基聚二烷基硅氧烷(bis-3-acryloxy-2-hydroxypropyloxypropyl polydialkylsiloxane)、具有单-(3-甲基丙烯酰氧基-2-羟基丙氧基)丙基末端的聚二烷基硅氧烷(mono-(3-methacryloxy-2-hydroxypropyloxy)propyl terminated polydialkylsiloxane)、具有单丁基的聚二烷基硅氧烷(mono-butyl terminated polydialkylsiloxane),以及其组合所组成的群组。
可利用车床法(lathe method)或成型法(molding method)来制备隐形眼镜。示例性的用以制备隐形眼镜的单体包含,但不限于,N-乙烯基-N-甲基乙酰胺(N-vinyl-N-methyl acetamide,VMA)、N-乙烯吡咯烷酮(N-Vinyl pyrrolidone,NVP)、1,4-丁二醇乙烯基醚(1,4-butanediol vinyl ether,BVE)、乙二醇乙烯基醚(ethylene glycol vinylether,EGVE)、二乙二醇乙烯基醚(diethylene glycol vinyl ether,DEGVE)、1,4-环己烷二甲醇乙烯基醚(1,4-cyclohexanedimethanol vinyl ether,CHDMVE)、甲基丙烯酸甲酯(methyl methacrylate,MMA)、2-甲基丙烯酸羟丁酯(2-hydroxybutyl methacrylate,HOB)、甲基丙烯酸2-乙基己酯(2-ethylhexy methacrylate,EHMA)、甲基丙烯酸叔丁酯(tert-butyl methacrylate,tBMA)、N,N-二甲基丙烯酰胺(N,N-dimethylacrylamide,DMA)、甲基丙烯酸羟乙酯(hydroxyethyl methacrylate,HEMA)、乙氧乙基甲基丙烯酰胺(ethoxyethyl methacrylamide,EOEMA)、乙二醇甲基醚甲基丙烯酸酯(ethylene glycolmethyl ether methacrylate,EGMA)、甲基丙烯酸异冰片酯(isobornyl methacrylate,IBM)、甲基丙烯酸甘油酯(glyceryl methacrylate,PGMA)、硅氧丙烯酸酯、甲基丙烯酸硅酯、氟丙烯酸酯、氟丙烯酸甲酯、氟硅丙烯酸酯(flurosilicone eacrylate)、甲基丙烯酸酯、丙烯酸酯、氨酯、硅氨酯、衣康酸酯、乙烯醇,以及其组合。以上列示的硅氧成分是选自由具有单甲基丙烯酸酯末端的聚二甲基硅氧烷、双-3-丙烯酰氧基-2-羟丙氧基丙基聚二烷基硅氧烷、具有单-(3-甲基丙烯酰氧基-2-羟基丙氧基)丙基末端的聚二烷基硅氧烷、具有单丁基的聚二烷基硅氧烷,以及其组合所组成的群组。依据某些实施方式,单体是HEMA。
示例性的用以聚合化单体的交联剂包含,但不限于,聚乙二醇二丙烯酸酯(ethylene glycol diacrylate,EGDA)、1,6-己二醇二丙烯酸酯(1,6-hexanedioldiacrylate,HDODA)、乙烯(ethylene)、乙二醇(glycol)、二甲基丙烯酸酯(dimethacrylate)、二乙二醇二甲基丙烯酸酯(diethylene glycol dimethacrylate,DEGDMA)、三羟甲丙烷(trimethylolpropane,TMP)、三甲基丙烯酸酯(trimethacrylate,TA)、三羟甲丙烷三甲基丙烯酸酯(trimethylolpropane trimethacrylate,TMPTMA)、甲基丙烯酸烯丙酯(allyl methacrylate,AMA)、二乙烯苯(divinylbenzene,DVB)、新戊四醇四甲基丙烯酸酯(pentaerythritol tetramethacrylate,PETMA)、乙二醇二甲基丙烯酸酯(ethylene glycol dimethacrylate,EGDMA)、1,3-丙二醇二甲基丙烯酸酯(1,3-propanediol dimethacrylate)、1,6-己二醇二甲基丙烯酸酯(1,6-hexanedioldimethacrylate)、1,4-丁二醇二甲基丙烯酸酯(1,4-butanediol dimethacrylate)、1,4-丁二醇二丙烯酸酯(1,4-butanediol diacrylate)、丙烯酸烯丙酯(allyl acrylate),以及其组合。
当可想见,除了眼内透镜或隐形眼镜之外,本发明DHLA涂覆的金纳米团簇也可应用于眼镜镜片(spectacle lens);举例来说,涂覆或吸附于眼镜镜片的表面。
本发明内容的另一方面是关于用以制备本发明眼用透镜的试剂盒。本发明试剂盒包含一溶液,以及一浸泡于该溶液的隐形眼镜或眼内透镜,其中该溶液包含DHLA涂覆的金纳米团簇。一般来说,DHLA涂覆的金纳米团簇在溶液中的浓度为1-100nM,且溶液可以是任何适用于保存隐形眼镜或眼内透镜的溶液;举例来说,适用于本发明的溶液包含,但不限于,氯化钠、硼酸、硼酸钠、聚离胺酸(polylysine,PS)、多磷酸(polyphosphoric acid)、聚乙烯吡咯烷酮(polyvinylpyrrolidone,PVP)、乙二胺四醋酸(ethylenediaminetetraacetic acid,EDTA)、泊洛沙姆(poloxamer),以及/或是抗菌剂。
本发明内容还提供一种利用本发明眼用透镜来治疗一个体的眼部病症的方法。一般来说,适用以本发明眼用透镜治疗的眼部病症可以由损伤所造成,以及/或是与损伤相关;举例来说,由棒球、石头或其他坚硬物体造成眼睛、眼睑及眼睛周围的肌肉或骨骼损伤;由棍棒、手指、木片、金属碎屑、沙子或玻璃造成角膜受损;由肥皂、洗发精或其他化学试剂引发化学灼伤,造成眼内严重损伤;或是因蓝光、紫外光或X射线造成角膜及视网膜损伤。依据某些实施方式,眼部病症是由ROS或氧化压力所造成,以及/或是与ROS或氧化压力相关,进而损害脂质、蛋白质、醣类及核酸(例如,脱氧核糖核酸(deoxyribonucleic acid,DNA))而引起细胞死亡。依据某些实施方式,眼部病症是由损伤所造成及/或与损伤相关,其中该损伤导致角膜受损。依据替代性的实施方式,眼部病症是由血管新生所造成,以及/或是与血管新生相关;例如发生于视网膜脉络膜及/或角膜的眼部血管新生(ocularangiogenesis,OA),其会导致诸如老年性黄斑部病变(age-related maculardegeneration,AMD)、糖尿病视网膜病变(diabetic retinopathy)、视网膜动脉或静脉阻塞(retinal artery or vein occlusion)、早产儿视网膜病变(retinopathy ofprematurity,ROP)、新生血管性青光眼(neovascular glaucoma)及角膜新生血管(cornealneovascularization)等不同病症。示例性的适用以本发明眼用透镜治疗的眼部病症包含眼部损伤、干眼症、结膜炎、葡萄膜炎、角膜炎、视网膜炎、白内障、屈光不正、青光眼、视神经病变、黄斑部病变、视网膜病变,以及色素性视网膜炎。
在某些实施方式中,本发明内容的眼用透镜可用以治疗一个体的白内障或屈光不正,其中是将眼用透镜制备为眼内透镜的形式,其可移植至个体的眼内,以改善个体的视力,以及降低/消除个体眼内的氧化压力。
在替代性的实施方式中,本发明内容的眼用透镜是制备为隐形眼镜的形式,其可置于一有需要的个体的角膜上,以达到矫正视力及/或治疗(例如,抗氧化、抗血管新生,或促进组织修复)的功效。
(ii)药学组合物
本发明内容的另一方面是关于一种药学组合物,其包含本发明内容第(i)部分所述的DHLA涂覆的金纳米团簇,以及一药学上可接受的赋形剂。
非必要地,本发明药学组合物的DHLA涂覆的金纳米团簇是于120-140℃,以1.2-2.0大气压预处理10-60分钟,接着再与药学上可接受的赋形剂混合。
依据目的不同,DHLA涂覆的金纳米团簇的重量约占药学组合物总重的0.01%到99.9%。在某些实施方式中,DHLA涂覆的金纳米团簇的重量至少占药学组合物总重的0.1%。在某些实施方式中,DHLA涂覆的金纳米团簇的重量至少占药学组合物总重的5%。在某些实施方式中,DHLA涂覆的金纳米团簇的重量至少占药学组合物总重的10%。在其他实施方式中,DHLA涂覆的金纳米团簇的重量至少占药学组合物总重的25%。
适用于制备本发明药学组合物的药学上可接受的赋形剂可以是本领域技术人员所知道的任何眼科可接受的赋形剂;举例来说,眼用缓冲液(例如,磷酸二氢钠及磷酸氢二钠等磷酸盐缓冲液、硼酸及其盐类等硼酸缓冲液、柠檬酸及其盐类等柠檬酸缓冲液,或是其组合)、螯合剂(例如,依地酸二钠(disodium edetate)、依地酸三钠(trisodium edetate)、依地酸四钠(tetrasodium edetate),或其组合)、张力剂(例如,丙二醇(propyleneglycol)、二乙二醇(diethylene glycol)、三甘酸(triethylene glycol)、甘油、葡萄糖、甘露醇、氯化钾、氯化钠,或其组合)、黏稠剂或悬浮剂(例如,甲基纤维素、乙基纤维素、羟乙基纤维素、聚乙二醇、羧甲基纤维素、羟丙基甲基纤维素、交联型丙烯酸聚合物,或其组合)、pH改良剂(例如,无机酸、氢氧化钾、氢氧化钠、盐酸,或其组合),或是其组合。
非必要地,本发明内容的药学组合物可更包含一治疗药剂,其可用以预防、改善或减缓眼部病症的病征。举例来说,该治疗药剂可以是一抗发炎剂(例如,环孢素(cyclosporine)或皮质类固醇(corticosteroid))、一泪液刺激药物或人工泪液(例如,毛果芸香碱(pilocarpine)、西维美林(cevimeline)及羟丙基纤维素等类胆碱药(cholinergics))、一抗感染药剂(例如,抗真菌剂、抗菌剂或抗病毒剂)、一抗氧化剂(例如,叶黄素、玉米黄质、维生素A、维生素C、维生素E、ω-3脂肪酸、硒或锌)、一抗血管新生药剂(例如,血管内皮生长因子(vascular endothelial growth factor,VEGF)或其受体(VEGFR)的抑制剂,或是血小板衍生生长因子(platelet-derived growth factor,PDGF)或其受体(PDGFR)的抑制剂)。
本发明内容还提供一种利用本发明药学组合物来治疗一个体的眼部病症的方法。该方法包含对该个体的眼睛投予一有效量的本发明药学组合物,据以减缓或改善与眼部病症相关的病征。
如本发明内容第(i)部分所述,适用以本发明药学组合物治疗的眼部病症可以是由损伤、ROS或血管新生所造成,以及/或是与损伤、ROS或血管新生相关;举例来说,眼部损伤、干眼症、结膜炎、葡萄膜炎、角膜炎、视网膜炎、白内障、屈光不正、青光眼、视神经病变、黄斑部病变、视网膜病变,以及色素性视网膜炎。
一般来说,可利用本发明眼用透镜、药学组合物及/或方法治疗的个体是一哺乳动物;举例来说,一人类、大鼠、小鼠、兔子、猴子、黑猩猩、狗、猫、猪、马、山羊或绵羊。较佳地,该个体是一人类。
下文提出多个实验例来说明本发明的某些方式,以利本领域技术人员操作本发明,且不应将这些实验例视为对本发明范围的限制。可以确定技术人员在阅读了此处提出的说明后,可在不需过度解读的情形下,完整利用并实践本发明。此处所引用的所有公开文献,其全文皆视为本说明书的一部分。
实施例
材料及方法
制备DHLA涂覆的金纳米团簇
本发明的荧光金纳米团簇是以先前所述方法(参见Lin et al.,ACS Nano 20093:395-401)进行制备。简言之,经由单相反应(Single phase reaction)(参见Jana andPeng,J Am Chem Soc 2003 125:14280-14281)来合成6-纳米的与双十二烷基二甲基溴化铵(didodecyldimethylammonium)稳定结合的金纳米团簇(AuNP@DDAB),其组成结构如图1所示。再逐渐滴加入黄金前驱溶液(氯化金溶于双十二烷基二甲基溴化铵-甲苯溶液)使电浆吸收作用逐渐耗失,直至溶液转变成黄色透明状为止。接着,将先前制备的纳米团簇加入至还原态硫辛酸中以进行配位基置换;还原硫辛酸需新鲜制备,其是以硫辛酸与溴化四丁基铵(TBAB)摩尔比为4:1的比例混合。上述步骤生成深褐色纳米团簇凝块混合物,以紫外线灯照射(365纳米,30分钟)纳米团簇凝块使凝块凝集。去除上清液,加入甲醇至纳米团簇凝块以重新悬浮并分散纳米团簇凝块,接着加入氯仿沉淀去除游离的接口活性剂。此干燥的纳米团簇沉淀物可再次以硼酸缓冲液(pH 9)悬浮散开。接着进行超高速离心(110,000rpm)三次,去除多余的硫辛酸。为了收集金纳米团簇,加入PBS缓冲液至30千道耳顿分子量截断(MWCO)浓缩离心管,至纳米团簇透明溶液胶体稳定且不具电浆吸收波锋为止。该金纳米团簇的浓度,于波长420纳米下的吸光系数约为450,000M-1cm-1。
为了增加吸附能力及抗氧化功效,于132℃的1.5大气压下,对DHLA涂覆的金纳米团簇进行30分钟的灭菌处理。
抗氧化活性-抗霉素A(Antimycin A,AA)刺激
为评估本发明金纳米团簇对AA诱导的ROS的功效,将内皮祖细胞(endothelialprogenitor cell,EPC)种植于96孔盘(每孔洞2×104细胞)。24小时后,将40微升的DHLA涂覆的金纳米团簇加入EPC中(以细胞培养液稀释,最终浓度为7.5、15或25nM),接着放置于37℃培养16小时。以新鲜培养液置换培养液后,将AA(一种用以刺激ROS释放的粒线体离子载体(mitochondrial ionophore);最终浓度为50μM)加至EPC,并于37℃反应1小时。收集EPC,并以流式细胞仪分析细胞的荧光强度,其中细胞强度与细胞内ROS的含量成正比关系。
抗氧化活性-蓝光照射
于第一天将牛角膜上皮细胞(bovine cornea epithelial cell,BCE)种植于96孔盘(每孔洞2×104细胞)。24小时后,将40微升的DHLA涂覆的金纳米团簇加至BCE中(以细胞培养液稀释,最终浓度为0.2、2、5、10、20、40、80、160、250、500、1,000或2,000nM),之后于37℃培养16小时。移除细胞培养液后,将荧光探针2’,7’-二氯二氢荧光素二乙酸酯(2’,7’-dichlorodihydrofluorescein diacetate,DCF-DA)加至各孔洞。将BCE置于37℃反应1小时,之后于37℃投予蓝光照射(波长:460-465纳米)0、10、20或30分钟。以光谱仪测量细胞于485纳米及539纳米波长的吸光值。485纳米与539纳米的比值(即,485/539纳米)与细胞内ROS的含量成正比关系。
以下述公式计算ROS含量的减少百分比:
ROS的减少量(%)=[(经蓝光照射且投予灭菌处理的DHLA涂覆金纳米团簇的细胞中ROS含量)/(经蓝光照射的细胞中ROS含量)]-[(经蓝光照射且投予未经灭菌处理的DHLA涂覆金纳米团簇的细胞中ROS含量)/经蓝光照射的细胞中ROS含量)]。
决定DHLA涂覆的金纳米团簇的吸附能力
为决定DHLA涂覆的金纳米团簇的吸附能力,将隐形眼镜置于包含15nM、25nM或35nM的DHLA涂覆的金纳米团簇(有或无1.5大气压、132℃灭菌预处理30分钟)的溶液(pH8.0-8.5)中,于1大气压(正常大氧压力;约为760毫米汞柱,或1×105Pa)、20-40℃反应30分钟。将检体浸泡于20%(体积/体积)硝酸溶液。加入1毫升高纯度王水后,置于室温1天,使隐形眼镜释放出DHLA涂覆的金纳米团簇;接着加入9毫升的去离子水。利用感应耦合电浆质谱仪(inductively coupled plasma mass spectrometry,ICP-MS)分析混合液中DHLA涂覆的金纳米团簇的浓度。以1%(体积/体积)王水将10ppm(高纯度)Au标准溶液稀释至0.8ppb、4ppb及20ppb标准溶液,以建立一校正曲线。基于ICP-MS分析的浓度,利用校正曲线来决定DHLA涂覆的金纳米团簇的吸附能力。
侦测谷胱甘肽(glutathione,GSH)
本实验利用二种模式来分析具有DHLA涂覆的金纳米团簇吸附的隐形眼镜对角膜细胞的功效。在防御模式中,是将5×105BCE种植于隐形眼镜上。16小时后,将隐形眼镜浸泡于包含30nM的DHLA涂覆的金纳米团簇的溶液中,并同时投予蓝光照射24小时。在修复模式中,是将5×105BCE种植于隐形眼镜后,投予蓝光照射24小时,之后再浸泡于包含30nM的DHLA涂覆的金纳米团簇的溶液16小时。
利用荧光染剂来决定二种模式中谷胱甘肽的表达量。简单来说,移除培养液后,以100微升的PBS洗涤细胞。将100微升的预热的荧光染剂(稀释于PBS中)加至细胞,接着置于37℃培养30分钟。利用荧光显微镜来观察细胞影像,并侦测波长为404纳米及526纳米的荧光激发及发散值。
创伤愈合试验
利用创伤愈合试验来决定本发明DHLA涂覆的金纳米团簇的组织修复功效。简单来说,将兔子的角膜上皮细胞培养于培养盘。以PBS洗涤后,利用吸量管尖端在细胞盘中形成一道刮痕。将特定处理液(即,PBS,或是包含0、30、50、100或200nM的DHLA涂覆的金纳米团簇的巿售滴眼液)加至细胞。15分钟后,将培养液置换为包含1%胎牛血清(fetal bovineserum,FBS)的低血清培养液。于37℃培养24小时后,利用光学显微境拍摄细胞影像,并以软件计算刮痕区域的距离。
动物模式
本实验利用三种动物模式来评估本发明金纳米团簇对组织修复的活性。
在机械性刮伤模式中,将舒泰(zoletil;每公斤6毫克)与赛拉嗪(xylazine;每公斤3毫克)的混合物腹腔注射至8周大的C57BL/6母鼠体内,进行麻醉处理。将一滤纸(直径0.9毫米)浸泡于20%乙醇中后,放置于小鼠右眼角膜中间部位约1分钟,之后以PBS清洗小鼠眼部。其后透过解剖显微镜利用穿孔器在小鼠眼睛的整个角膜区域上形成一个圆形伤口(机械性括除直径约2毫米的角膜),在不触及角膜基质、轮部或结膜的情况下形成一机械性的角膜伤口。于损伤一天后,将50微升的本发明DHLA涂覆的金纳米团簇(稀释于PBS中,浓度为:200μM)加至小鼠的右眼。在对照组中,是将50微升的PBS加至小鼠的右眼。以局部荧光素来染色小鼠角膜以观察伤口愈合情形,并以数字相机拍摄照片。利用计算机协助的影像分析器由相片计算缺陷面积,并据以计算在每一时间点相较于初始伤口面积的残余上皮缺损百分比。
在链脲菌素(streptozotocin,STZ)诱发模式中,是将每公斤65毫克的STZ腹腔注射至Brown Norway(BN)公鼠体内,连续注射3天。在第四天时,将本发明DHLA涂覆的金纳米团簇新鲜溶于0.01M柠檬酸钠(浓度为200μM),并通过尾静脉注入经STZ处理的小鼠体内(每公斤2毫升)。对照组大鼠仅以尾静脉注射方式投予每公斤2毫升的0.01M柠檬酸钠。之后,进行上述机械性刮伤实验,并投予或不投予DHLA涂覆的金纳米团簇治疗,以分析其对创伤愈合的功效。
在氧气诱发视网膜病变(oxygen-induced retinopathy,OIR)的模式中,是于室内空气(氧气浓度为20.8%)将1,000微升的DHLA涂覆的金纳米团簇(稀释于PBS中,浓度为1μM)腹腔注射至C57BL/6新生小鼠(6天大)体内。将1,000微升的PBS腹腔注射至小鼠体内作为对照组。一天后,将小鼠放置于高氧(氧气浓度为75%)环境5天,之后再移回室内空气(氧气浓度为20.8%)。氧气浓度的改变会造成动物体内相对缺氧的生理状态,进而活化内皮细胞内氧气反应分子(例如缺氧诱导因子-1(hypoxia inducible factor-1,HIF-1)及VEGF)的表达。五天后,取出动物的眼球,并通过组织分析来决定新生血管的表现程度。
实施例1 DHLA涂覆的金纳米团簇的抗氧化活性
本实施例将检测本发明DHLA涂覆的金纳米团簇的抗氧化活性。如材料及方法所述,将EPC或BCE与DHLA涂覆的金纳米团簇共同培养,并投予AA刺激或蓝光照射。利用流式细胞仪或光谱仪来决定细胞内ROS的含量;图1A及1B分别阐述这些结果。
相较于对照组(仅投予AA),投予DHLA涂覆金纳米粒子(FANC)可剂量相关地降低ROS于EPC的胞内含量(图1A)。图1B进一步证实相较于对照组(即,培养于黑暗环境而未投予光照的BCE),蓝光照射会时间相关地增加BCE中ROS的含量,而投予DHLA涂覆金纳米粒子则可降低蓝光照射所刺激诱发的细胞内ROS含量。
如材料及方法所述,于132℃的1.5大气压下,对DHLA涂覆的金纳米团簇进行30分钟的灭菌处理,接着加入EPC或BCE以检测其抗氧化活性。如图2A所示,相较于未经灭菌处理的DHLA涂覆的金纳米团簇,经灭菌处理的DHLA涂覆的金纳米团簇具有较高的抗氧化活性。此外,相较于投予35nM的经灭菌处理的DHLA涂覆的金纳米团簇,投予15nM或25nM的经灭菌处理的DHLA涂覆的金纳米团簇后,细胞具有较低的ROS含量(图2A)。图2B的结果进一步确认本发明DHLA涂覆的金纳米团簇对细胞内ROS含量的抑制功效,其中不论在何种测试浓度下(即,由0.2到2,000nM的浓度),经灭菌处理的DHLA涂覆的金纳米团簇皆可抑制BCE中的ROS含量。相较于未经灭菌处理的DHLA涂覆的金纳米团簇,经灭菌处理的DHLA涂覆的金纳米团簇也在BCE中具有较佳的抗氧化活性,其中经灭菌处理的DHLA涂覆的金纳米团簇的ROS抑制活性约高于未经灭菌处理的DHLA涂覆的金纳米团簇的ROS抑制活性10-30%(图2C及2D)。
由图1及图2可知,本发明DHLA涂覆的金纳米团簇(特别是经灭菌处理的DHLA涂覆的金纳米团簇)可降低细胞内ROS的含量。
实施例2 DHLA涂覆的金纳米团簇可吸附于隐形眼镜
本实施例将评估本发明DHLA涂覆的金纳米团簇对隐形眼镜的吸附能力。图3的结果指出,于20-40℃培养30分钟后,不论在何种测试浓度下(即,15、25或35nM),本发明DHLA涂覆的金纳米团簇皆可有效吸附于隐形眼镜。值得注意的是,经灭菌处理的DHLA涂覆的金纳米团簇对隐形眼镜的吸附量高于未经灭菌处理的DHLA涂覆的金纳米团簇对隐形眼镜的吸附量。
已知蓝光照射会通过引发氧化压力而造成细胞死亡,进而降低细胞内GSH的表达量。因此,本实施例进一步检测经不同条件处理的角膜细胞中GSH的表达量,以评估本发明DHLA涂覆的金纳米团簇的抗氧化活性。图4A及4B结果指出,不论是包含30nM金纳米团簇的溶液(缓冲液_30nM,图4A),或是经30nM金纳米团簇预处理的隐形眼镜(镜片_30nM,图4B),皆可显著地增加防御模式中细胞内GSH的表达量。类似的结果也可见于修复模式,其中相较于对照组(即,缓冲液_0nM,图5A;镜片_0nM,图5B),投予包含30nM金纳米团簇的溶液(缓冲液_30nM,图5A),或是投予以30nM金纳米团簇预处理的隐形眼镜(镜片_30nM,图5B),皆可明显地增加GSH的表达量。图5C的结果进一步指出,本发明眼用透镜的保护功效至少可于蓝光照射后持续72小时。
这些结果证明具有本发明金纳米团簇吸附的隐形眼镜对角膜细胞可产生抗ROS伤害的保护功效。
实施例3 DHLA涂覆的金纳米团簇的治疗功效
为评估本发明金纳米团簇对角膜创伤愈合的功效,如材料及方法所述,于兔子角膜上皮细胞产生一割痕,并给予特定处理。表1及图6A的结果指出,于刮痕产生24小时后,经PBS处理的角膜细胞具有明显的创伤闭合;然而,眼睛滴液(R处理)会抑制细胞向创伤处移动。相较于眼睛滴液(R处理),投予金纳米团簇(即,R+30F、R+50F、R+100F或R+200F处理)会促进创伤处的闭合(表1及图6B)。这些结果指出,本发明DHLA涂覆的金纳米团簇可促进角膜的创伤愈合。
表1未愈合区域的百分比
处理 | 未愈合区域的百分比(%) |
对照组 | 24.22 |
R | 18.62 |
R+30F | 8.18 |
R+50F | 17.02 |
R+100F | 11.35 |
R+200F | 14.13 |
*对照组:刮痕产生0小时后;R:仅投予眼睛滴液;R+30F:含有30nM DHLA涂覆的金纳米团簇的眼睛滴液;R+50F:含有50nM DHLA涂覆的金纳米团簇的眼睛滴液;R+100F:含有100nM DHLA涂覆的金纳米团簇的眼睛滴液;R+200F:含有200nM DHLA涂覆的金纳米团簇的眼睛滴液。
**以未愈合区域的影像面积/总面积来计算未愈合区域的百分比。
进一步以动物模式(包含机械性刮伤模式、STZ诱发模式及OIR模式)来确认本发明DHLA涂覆的金纳米团簇对促进组织修复的功效。图7A-7C阐述这些动物模式的实验结果。在机械性刮伤模式中,投予金纳米团簇的小鼠的上皮损伤程度显著小于对照组(即,投予PBS的小鼠)(图7A)。依据定量分析结果,经PBS及DHLA涂覆的金纳米团簇治疗后,小鼠的组织修复百分比分别为15.02%及79.68%。类似的结果也可见于STZ诱发模式,其中相较于PBS治疗组,本发明DHLA涂覆的金纳米团簇具有较佳的再上皮化(re-epithelialization)功效(图7B)。在治疗48小时后,经PBS及金纳米团簇治疗的小鼠的修复百分比分别为4.85%及51.18%。在OIR模式中,相较于PBS对照组(图7C的小图(a)),投予本发明DHLA涂覆的金纳米团簇可显著降低小鼠视网膜的血管新生(图7C的小图(b))。
这些结果指出,本发明DHLA涂覆的金纳米团簇可有效促进角膜修复,并抑制病理性血管新生;因此,本发明DHLA涂覆的金纳米团簇可作为用以治疗不同眼部病症的潜力药剂。
总结上述,本发明内容提供了DHLA涂覆的金纳米团簇于治疗眼部病症的新颖用途。依据本发明内容的实施例,DHLA涂覆的金纳米团簇可用以减少细胞内ROS的含量、促进组织修复(例如,角膜修复),以及抑制异常的血管新生。依据使用目的的不同,可将DHLA涂覆的金纳米团簇制备为一眼用透镜或一药学组合物,以对有治疗需要的个体提供治疗效益。
虽然上文实施方式中揭露了本发明的具体实施例,然其并非用以限定本发明,本领域技术人员在不悖离本发明的原理与精神的情形下,当可对其进行各种变化与修饰,因此本发明的保护范围当以附随权利要求所界定者为准。
Claims (22)
1.一种用以治疗一个体的眼部病症的眼用透镜,其中,所述眼用透镜的特征在于具有二氢硫辛酸(dihydrolipoic acid,DHLA)涂覆的金纳米团簇吸附于其上,其中,所述DHLA涂覆的金纳米团簇是由金纳米团簇及复数个涂覆于所述金纳米团簇上的DHLA所组成,其中,所述金纳米团簇是由复数个金纳米粒子所形成。
2.如权利要求1所述的眼用透镜,其中,所述DHLA涂覆的金纳米团簇是于120-140℃以1.2-2.0大气压预处理10-60分钟。
3.如权利要求1所述的眼用透镜,其中,所述DHLA涂覆的金纳米团簇的粒径为0.1到20纳米。
4.一种用以制备如权利要求1所述的眼用透镜的方法,其中,所述方法包含于15-50℃将一隐形眼镜培养于一含有所述DHLA涂覆的金纳米团簇的溶液至少30分钟,其中,所述DHLA涂覆的金纳米团簇于所述溶液的浓度为1-100nM,且所述溶液的pH值为7.5-9.0。
5.如权利要求4所述的方法,其中,所述方法更包含在培养步骤前,于120-140℃以1.2-2.0大气压预处理所述含有所述DHLA涂覆的金纳米团簇的溶液10-60分钟。
6.如权利要求4所述的方法,其中,所述隐形眼镜是培养于含有10-50nM的所述DHLA涂覆的金纳米团簇的溶液。
7.如权利要求4所述的方法,其中,所述DHLA涂覆的金纳米团簇的粒径为0.1到20纳米。
8.一种用以治疗一个体的眼部病症的方法,其中,所述方法包含将如权利要求1所述的眼用透镜置于所述个体的角膜上。
9.如权利要求8所述的眼用透镜,其中,所述DHLA涂覆的金纳米团簇是于120-140℃以1.2-2.0大气压预处理10-60分钟。
10.如权利要求8所述的眼用透镜,其中,所述DHLA涂覆的金纳米团簇的粒径为0.1到20纳米。
11.如权利要求8所述的眼用透镜,其中,所述眼部病症是与损伤、活性含氧物及/或血管新生相关。
12.如权利要求11所述的眼用透镜,其中,所述眼部病症是眼部损伤、干眼症、结膜炎、葡萄膜炎、角膜炎、视网膜炎、白内障、屈光不正、青光眼、视神经病变、黄斑部病变、视网膜病变,或是色素性视网膜炎。
13.一种用以治疗眼部病症的试剂盒,其中,所述试剂盒包含:
一溶液,其包含1-100nM的DHLA涂覆的金纳米团簇,其中,所述DHLA涂覆的金纳米团簇是由金纳米团簇及复数个涂覆于所述金纳米团簇上的DHLA所组成,其中,所述金纳米团簇是由复数个金纳米粒子所形成;以及
一浸泡于所述溶液的隐形眼镜。
14.如权利要求13所述的试剂盒,其中,所述溶液是于120-140℃以1.2-2.0大气压预处理10-60分钟。
15.如权利要求13所述的试剂盒,其中,所述溶液包含10-50nM的所述DHLA涂覆的金纳米团簇。
16.如权利要求13所述的试剂盒,其中,所述DHLA涂覆的金纳米团簇的粒径为0.1到20纳米。
17.一种用以治疗一个体的眼部病症的药学组合物,其中,所述药学组合物包含二氢硫辛酸(dihydrolipoic acid,DHLA)涂覆的金纳米团簇,以及一药学上可接受的赋形剂,其中,所述DHLA涂覆的金纳米团簇是由金纳米团簇及复数个涂覆于所述金纳米团簇上的DHLA所组成,其中,所述金纳米团簇是由复数个金纳米粒子所形成,其中,所述DHLA涂覆的金纳米团簇的粒径为0.1到20纳米。
18.如权利要求17所述的药学组合物,其中,所述DHLA涂覆的金纳米团簇是于120-140℃以1.2-2.0大气压预处理10-60分钟。
19.一种用以治疗一个体的眼部病症的方法,其中,所述方法包含对所述个体的眼睛投予一有效量的如权利要求17所述的药学组合物。
20.如权利要求19所述的方法,其中,所述DHLA涂覆的金纳米团簇是于120-140℃以1.2-2.0大气压预处理10-60分钟。
21.如权利要求20所述的方法,其中,所述眼部病症是与损伤、活性含氧物及/或血管新生相关。
22.如权利要求21所述的方法,其中,所述眼部病症是眼部损伤、干眼症、结膜炎、葡萄膜炎、角膜炎、视网膜炎、白内障、屈光不正、青光眼、视神经病变、黄斑部病变、视网膜病变,或是色素性视网膜炎。
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Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1729026A (zh) * | 2002-12-19 | 2006-02-01 | 诺瓦提斯公司 | 在其上具有抗微生物涂层的医疗装置 |
WO2006123248A2 (en) * | 2005-04-18 | 2006-11-23 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Improved methods and devices for delivering a therapeutic product to the ocular sphere of a subject |
CN101102733A (zh) * | 2004-04-30 | 2008-01-09 | 阿勒根公司 | 含有大分子的持续释放眼内植入物及相关方法 |
US20130052270A1 (en) * | 2011-08-26 | 2013-02-28 | Chung Yuan Christian University | Use of Gold Nanoclusters in Ameliorating Oxidate Stress and/or Aging |
CN103565801A (zh) * | 2012-08-02 | 2014-02-12 | 陈井然 | 用于治疗眼底黄斑水肿的组合物及该组合物在治疗眼部疾病中的应用 |
CN105228633A (zh) * | 2013-01-28 | 2016-01-06 | 新天然替代品公司 | 用于由氧化应激和/或氧化还原失衡产生的病理状态的全身治疗的组合物 |
CN106215236A (zh) * | 2016-07-20 | 2016-12-14 | 国家纳米科学中心 | 一种金纳米棒区域修饰人工晶状体及其制备方法和用途 |
Family Cites Families (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2832637B1 (fr) * | 2001-06-07 | 2004-07-30 | Lefaix Marie Therese Droy | Utilisation d'un antioxydant pour la fabrication d'un medicament destine au traitement des affections oculaires de surface |
TWI413524B (zh) * | 2011-08-26 | 2013-11-01 | 財團法人台灣基督長老教會馬偕紀念社會事業基金會馬偕紀念醫院 | 以金奈米團簇來減緩氧化壓力和/或老化的方法、組合物及用途 |
CN106620893B (zh) * | 2015-07-23 | 2021-07-30 | 爱博诺德(北京)医疗科技股份有限公司 | 用于眼部疾病光治疗的材料 |
CN109718376B (zh) * | 2017-10-27 | 2022-01-25 | 晶硕光学股份有限公司 | 具有抗敏舒缓效果的眼用产品 |
-
2020
- 2020-01-17 US US17/423,115 patent/US20220062169A1/en active Pending
- 2020-01-17 TW TW109101714A patent/TWI760682B/zh active
- 2020-01-17 WO PCT/CN2020/072718 patent/WO2020147830A1/en active Application Filing
- 2020-01-17 CN CN202080009649.3A patent/CN113347950A/zh active Pending
Patent Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1729026A (zh) * | 2002-12-19 | 2006-02-01 | 诺瓦提斯公司 | 在其上具有抗微生物涂层的医疗装置 |
CN101102733A (zh) * | 2004-04-30 | 2008-01-09 | 阿勒根公司 | 含有大分子的持续释放眼内植入物及相关方法 |
WO2006123248A2 (en) * | 2005-04-18 | 2006-11-23 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Improved methods and devices for delivering a therapeutic product to the ocular sphere of a subject |
US20130052270A1 (en) * | 2011-08-26 | 2013-02-28 | Chung Yuan Christian University | Use of Gold Nanoclusters in Ameliorating Oxidate Stress and/or Aging |
CN103565801A (zh) * | 2012-08-02 | 2014-02-12 | 陈井然 | 用于治疗眼底黄斑水肿的组合物及该组合物在治疗眼部疾病中的应用 |
CN105228633A (zh) * | 2013-01-28 | 2016-01-06 | 新天然替代品公司 | 用于由氧化应激和/或氧化还原失衡产生的病理状态的全身治疗的组合物 |
CN106215236A (zh) * | 2016-07-20 | 2016-12-14 | 国家纳米科学中心 | 一种金纳米棒区域修饰人工晶状体及其制备方法和用途 |
Non-Patent Citations (4)
Title |
---|
F.A MAULVI.ET AL: "Development of antibacterial contact lenses containing metallic nanoparticles", 《ACTA BIOMATERIALIA》, pages 1 * |
F.A MAULVI.等: "《Effect of gold nanoparticles on timolol uptake and its release kinetics from contact lenses: In vitro and in vivo evaluation》", 《ACTA BIOMATERIALIA》, vol. 86, pages 350 - 362 * |
J TOURNEBIZE.ET AL: "Role of Gold Nanoparticles Capping Density on Stability and Surface Reactivity to Design Drug Delivery Platforms", 《ACS APPLIED MATERIALS & INTERFACES》, pages 2 * |
王晓良: "《应用分子药理学》", 31 December 2005 * |
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