CN109602703A - 一种复合双亲肽纳米胶束及其制备方法和应用 - Google Patents
一种复合双亲肽纳米胶束及其制备方法和应用 Download PDFInfo
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Abstract
本发明公开了一种复合双亲肽纳米胶束及其制备方法和应用,具体是一种新型靶向整合素αvβ3的复合双亲肽纳米胶束,及其在乳腺癌荧光成像、光动力治疗与光热治疗中的应用。基于靶向复合双亲肽纳米胶束良好的生物相容性、包载物质的荧光成像、光动力治疗与光热治疗功能,有望在体内标记与示踪、生物医学影像和肿瘤的早期诊断与治疗等领域得到广泛应用,在生命健康与个性化医疗等方面产生良好的经济与社会效益。
Description
技术领域
本发明涉及一种新型双亲肽自组装胶束和制备工艺,及其特异性靶向黑色素瘤、子宫颈癌整合素αvβ3的荧光成像和作为潜在光动力与声动力治疗剂的生物医学应用。
背景技术
黑色素瘤是临床上较为常见的皮肤黏膜和色素膜恶性肿瘤,也是发病率增长最快的恶性肿瘤之一,年增长率为3%-5%。虽然黑色素瘤在我国发病率较低,但近年来成倍增长,每年新发病例约2万例。皮肤黑色素瘤的病因目前唯一的证据是与过度接受紫外线照射相关,但亚洲(包括我国)和非洲地区黑色素瘤患者的原发病灶多位于足跟、手掌、指趾和甲下等接触紫外线极少的地方,其病因仍不明确。近年来随着黑色素瘤的分子生物学特征、临床组织学特征和基因变异之间关系的研究不断深入,发现特定类型与特定的基因变异相关。现在黑色素瘤的诊断主要靠典型的临床表现和查体体征,病理检查是确诊及分期的金标准,免疫组织化学染色是鉴别黑色素瘤的主要辅助手段。S-100、HMB-45和波形蛋白是诊断黑色素瘤的较特异指标。黑色素瘤的治疗主要通过外科治疗、术后辅助治疗、放疗以及全身治疗。
另外,对于子宫颈癌,在世界范围内,每年发病510000例,死亡288000例,是仅次于乳腺癌发病率而居第二位,近3/4的病例发生在发展中国家。老年、经济状况差及不参加子宫颈癌涂片筛查的部分患者可进展并死于肿瘤。大约80%子宫颈癌组织学为鳞癌,15%为腺癌,尽管都认为腺癌预后不好,但目前无资料证明在治疗方法上与其他宫颈癌有何不同。子宫颈涂片检查是发现早期子宫颈癌最重要的方法,怀疑有浸润前病变的患者可行阴道镜、宫颈管诊刮术(ECC)等检查,怀疑膀胱或直肠病灶者,须经膀胱镜或直肠镜检查活检,并有组织学证实,IB1期或以上建议行盆腹腔CT或MRI检查,从而确定临床分期,对制定后续治疗意义重大,而子宫颈癌的治疗主要靠手术治疗,还有放疗和化疗。
因此,黑色素瘤和子宫颈癌已经成为严重危害我国人民健康的疾病之一,如何早期发现并有效的治疗成为当前研究的重点。
荧光成像在生物检测和医学影像等领域广泛应用,是一种常见的光学成像技术,样品具有极高的穿透性、灵敏度和选择性等优势,但传统的有机染料同时存在一些致命缺陷,如性质不稳定,容易被光漂白,不能长期使用等。因此,如何克服荧光染料在使用中的缺陷成为当前研究的重点。
双亲肽具有类似天然磷脂分子的两亲特性、丰富的分子结构、独特新颖的组装体结构以及特殊的生物学功能,是多肽自组装研究的热点领域。两亲性多肽分子结构具有类似于表面活性剂的疏水链段和亲水端,在疏水性链段间的疏水性作用力和亲水性多肽链段间的氢键协同驱动下,多肽分子能够自组装形成规整有序的纳米/微米结构。
双亲肽所具有的脂肪族疏水尾通过疏水作用形成疏水性内核,可包裹疏水性材料,亲水头具有精氨酸-甘氨酸-天冬氨酸(RGD)三肽序列,能特异性识别肿瘤细胞中高表达的整合素αvβ3。多肽作为天然的优良组装分子,具有特殊的生物活性和良好的生物相容性,能够赋予材料独特的生物学功能,易于合成和化学修饰也是多肽分子的突出优势。同时,双亲肽对PH高敏感,当PH值小于4时,自组装成球性纳米胶束的双亲肽会发生降解形成单个多肽序列。细胞经过吞饮与受体内吞作用摄取复合双亲肽纳米胶束进入细胞后,酸性环境的溶酶体视之为异物从而使之解体,复合双亲肽纳米胶束对PH高敏感性有利于胶束内所包裹的活性物质在细胞内的释放。
随着纳米技术的不断发展,将纳米技术与高灵敏度的荧光分子相结合,发展制备包载荧光分子的分子影像探针,将为克服上述问题提供新的策略。近年来双亲肽纳米胶束以其毒性低、生物兼容性好、特殊生物活性等优点日益受到关注。研究发现,荧光小分子经过双亲肽纳米胶束包载后其荧光稳定性和结构稳定性都会有明显的提升。当荧光双亲肽纳米探针表面RGD多肽配体特异性作用于病变区域高表达的配体时,可通过所包裹的荧光探针来突出显示病变部位,从而提高诊断的准确性与敏感性,这种靶向造影剂成为现今研究领域的热点。整合素αVβ3是肿瘤组织最常用的靶标之一,它由αV亚基(CD51,150000)和β3亚基(CD61,105000)组成,其中α链的胞膜外区能特异性识别含精氨酸-甘氨酸-天冬氨酸(RGD)序列的多肽,介导整合素与细胞外基质的黏附。整合素αVβ3在正常组织器官及成熟血管内皮细胞中不表达或低表达,在多种肿瘤(包括肺癌、成胶质细胞瘤、乳腺癌、黑色素瘤、子宫颈癌、骨肉瘤等)细胞表面和新生血管内皮细胞中有高表达,在肿瘤的新生血管生成、侵袭和转移过程中起重要作用。特异性标记的外源性RGD多肽进入体内后可与整合素αVβ3位点高选择性结合,从而RGD多肽可以作为一种特异性配体靶向组织,并通过各种影像学方法进行示踪。
此外,光热治疗是利用具有较高光热转换效率的材料,将其注射入活体内部,利用靶向性识别技术聚集在病灶附近,并在外部光源(一般是近红外光)的照射下将光致热效应杀死癌细胞的一种治疗方法。这种方法具有高效率、低痛苦、副作用小、作用时间短等优点,并且治愈效果明显,用于光热治疗的材料无毒无害,因此在肿瘤治疗方面具有非常广阔的应用前景。
同时,光动力治疗剂是一种光敏剂,将其注射入活体内部,利用靶向性识别技术聚集在黑色素瘤、子宫颈癌附近,在特定波长激光的照射下受到激发,激发态的光敏剂又把能量传递给周围的氧,生成活性很强的单态氧,单态氧和相邻的生物大分子发生氧化反应,产生细胞毒性作用,进而导致癌细胞受损甚至死亡的一种治疗方法。这种方法能够选择性地杀伤局部原发和复发的肿瘤细胞,对健康组织基本没有损害或损害较小,毒副反应少,对年老体弱,不能手术或需静脉化疗的患者尤为适宜,尤其是对那些用传统治疗方法无效或危险的晚期肿瘤患者有着良好的转化应用前景。
发明内容
本发明的目的是为了克服常用荧光物质孟加拉玫瑰红(单独使用)快速消除、肿瘤部位累积差等缺点,以及为了实现双亲肽纳米胶束的多功能应用(如生物成像、药物释放、肿瘤治疗等),而提供一种具有靶向整合素αvβ3的复合双亲肽纳米胶束。
本发明的另一个目的是提供一种具有靶向整合素αvβ3的复合双亲肽纳米胶束的制备工艺。
本发明的另一个目的是提供具有靶向整合素αvβ3的复合双亲肽纳米胶束在黑色素瘤和子宫颈癌新生血管荧光成像的应用。
本发明的另一个目的提供基于具有靶向整合素αvβ3的复合双亲肽纳米胶束的光动力治疗剂。
本发明的另一个目的是提供基于具有靶向整合素αvβ3的复合双亲肽纳米胶束声动力治疗剂。
为实现本发明的第一个目的,本发明的技术方案是:
以表面具有黑色素瘤、子宫颈癌靶向整合素αvβ3的双亲肽为构建基质,包载组分为荧光物质孟加拉玫瑰红,表面具有特异性靶向多肽分子。
进一步设置是所述具有靶向整合素αvβ3的复合双亲肽纳米胶束的直径为10-50纳米,电位为0-40毫伏。
优选的,靶向基团为含有精氨酸-甘氨酸-天冬氨酸三肽序列的C18-GRRRRRRRRGDS(C18GR7RGDS)双亲肽。
实现本发明的第二个发明目的是技术方案包括以下步骤:
a.取双亲肽C18GR7RGDS溶解于超纯水,制备浓度为10克/毫升的溶液;
b.取孟加拉玫瑰红溶解于超纯水,制备浓度为2克/毫升的溶液;
c.将上述双亲肽溶液与孟加拉玫瑰红溶液按体积比2:1-1:1充分混合,避光放置于超声波
清洗仪中,仪器参数设置为:温度10-30摄氏度、时间10-40分钟、功率5-35千赫兹,
得到复合双亲肽纳米胶束产物;
d.将上述复合双亲肽纳米胶束转移至截留分子量500-1500道尔顿的透析袋,透析48-72小
时即得具有靶向整合素αvβ3的复合双亲肽纳米胶束。
所述步骤c温度25摄氏度、时间20~40分钟、功率28千赫兹。
所述步骤d透析袋为截留分子量1000道尔顿。
实现本发明的第三个发明目的技术方案是一种靶向复合纳米荧光探针,其为具有靶向整合素αvβ3的复合双亲肽纳米胶束,并用于黑色素瘤和子宫颈癌新生血管荧光成像。
实现本发明的第四个发明目的,用于光动力治疗的治疗剂,其为所述的具有靶向整合素αvβ3的复合双亲肽纳米胶束。
实现本发明的第五个发明目的,用于光热治疗的治疗剂,其为所述的具有靶向整合素αvβ3的复合双亲肽纳米胶束。
本发明的有益效果是:本发明所述具有靶向整合素αvβ3的复合双亲肽纳米胶束及选择性构建方法对发展新型生物探针、拓展荧光造影剂的制备工艺、提高荧光探针的生物利用率、实现肿瘤新生血管的早期分子诊断、光动力治疗与光热治疗具有重要意义。
本发明得到复合双亲肽纳米胶束,其通用工艺与结构(如图1)所示。纳米材料的稳定性以及孟加拉玫瑰红的搭载率变化图(如图2)。如图2所示材料稳定性好,在30天内粒径没有很大的变化,都在10-40纳米之间,纳米级别的物质更易通过细胞膜进入细胞;孟加拉玫瑰红的搭载率随着孟加拉玫瑰红质量的增加,趋于饱和状态。制成的靶向复合双亲肽纳米胶束具有良好的生物相容性和安全性(如图3)。复合双亲肽纳米胶束在黑色素瘤和子宫颈癌细胞中有良好的声动力效应(如图4),并且复合双亲肽纳米胶束具有良好的光动力效应和生动力效应(如图5)。
将此发明所涉及的靶向黑色素瘤和子宫颈癌整合素αVβ3的复合双亲肽作为荧光成像、光动力及光热治疗材料,不仅可以丰富黑色素瘤和子宫颈癌无创(或微创)治疗方案,而且对于开发新型肿瘤诊疗模式、减小目前临床治疗的副作用、降低对于正常组织伤害、提高癌症诊疗效率与精准性具有重要意义,同时对于促进所述双亲肽作为新型黑色素瘤和子宫颈癌靶向诊疗的临床转化具有重要的实用价值。
下面结合说明书附图和具体实施方式对本发明做进一步介绍。
附图说明
图1为本发明所涉及的靶向复合双亲肽纳米胶束的通用结构与工艺;
图2为新型靶向复合双亲肽纳米胶束荧光探针的纳米材料稳定性(图2A)和孟加拉玫瑰红搭载率(图2B)图;
图3为新型靶向复合双亲肽纳米胶束荧光探针分别在黑色素瘤细胞(B16)(图3A)、子宫颈癌细胞(Hela)(图3B)、成纤维细胞(L929)(图3C)细胞毒性效果图;
图4为靶向复合双亲肽纳米胶束分别应用于黑色素瘤细胞(B16)(图4A)和子宫颈癌细胞(Hela)(图4C)的光声效应效果图;以及靶向复合双亲肽纳米胶束分别应用于黑色素瘤细胞(B16)(图4B)和子宫颈癌细胞(Hela)(图4D)的不同时间下的光声效应效果图;
图5为靶向复合双亲肽纳米胶束在不同时间下及不同浓度下的光热效应和光声效应效果图;(图5A)PARN在US或Laser下不同时间段(1,3,5min)的ROS;(图5B)PARN和RB在US作用下不同RB浓度(0,2,4,6,8,10μg/ml)的ROS;(图5C)PARN和RB在Laser作用下不同RB浓度(0,2,4,6,8,10μg/ml)的ROS。
具体实施方式
下面通过实施例对本发明进行具体的描述,只用于对本发明进行进一步说明,不能理解为对本发明保护范围的限定,该领域的技术工程师可根据上述发明的内容对本发明作出一些非本质的改进和调整。
本发明所采用的制备原料均为商品获得。
实施例1:取2毫升双亲肽序列C18GR7RGDS溶液(宁波康贝生化有限公司,型号:817870,批号:17040701))(10毫克/毫升)和1毫升亚甲基蓝溶液(2毫克/毫升)混匀,将混合溶液避光放置于超声波清洗仪,条件设置为25摄氏度、30分钟、28千赫兹。超纯水清洗截留分子量为1000道尔顿透析袋,随后将该混合溶液转移至透析袋,放入盛有超纯水透析液的烧杯并使之浮于透析液中,该透析液体积为2000毫升,PH值为7.4,放入磁子置于磁力搅拌仪上,室温下转速为120转,透析2小时时发现透析液颜色变蓝,透析袋中混合溶液变透明,继续透析至48小时,紫外分光光度计测量透析袋溶液,未发现亚甲基蓝的特征性吸收峰,说明亚甲基蓝未包裹进双亲肽纳米胶束。这也说明,用本发明合成的双亲肽序列很难包裹亚甲基蓝而形最终的产物。
实施例2:取2毫升双亲肽C18GR7RGDS溶液(10毫克/毫升)和1毫升姜黄素(2毫克/毫升,溶于醋酸)混匀,将混合溶液避光放置于超声波清洗仪,条件设置为25摄氏度、30分钟、28千赫兹。超纯水清洗截留分子量为1000道尔顿透析袋,随后将该混合溶液转移至透析袋,放入盛有超纯水透析液的烧杯并使之浮于透析液中,该透析液体积为2000毫升,PH值为7.4,放入磁子置于磁力搅拌仪上,室温下转速为120转,透析3小时时发现透析袋内出现黄色沉淀析出,随着透析时间增加,黄色沉淀物也逐渐增加,混合液中通过透析袋进入纯水,姜黄素不溶于水便析出。这也说明,本发明的双亲肽序列不能很好的包裹姜黄素。
实施例3:取2毫升双亲肽C18GR7RGDS溶液(宁波康贝生化有限公司,型号:817870,批号:17040701)(10毫克/毫升)和1毫升孟加拉玫瑰红溶液(2毫克/毫升,)混匀,将混合溶液避光放置于超声波清洗仪,条件设置为25摄氏度、30分钟、28千赫兹。超纯水清洗截留分子量为1000道尔顿透析袋,随后将该混合溶液转移至透析袋,放入盛有超纯水透析液的烧杯并使之浮于透析液中,该透析液体积为2000毫升,PH值为7.4,放入磁子置于磁力搅拌仪上,室温下转速为120转,每4小时更换一次透析水,透析48小时,即得荧光双亲肽自组装纳米胶束。经过测试,发现绝大部分的孟加拉玫瑰红被成功包裹进本发明的多肽序列里;形成了自组装纳米胶束。
用纳米粒度仪测量粒径,并每隔两天再测一次粒径,发现复合双亲肽稳定性好,且正电荷有利于细胞的摄取。(如图2)
用紫外分光光度计测量OD值,计算搭载率,发现随着孟加拉玫瑰红浓度的增加,复合双亲肽纳米胶束的搭载率趋于稳定。(如图2)
黑色素瘤和子宫颈癌(αvβ3阳性)细胞,以及成纤维细胞分别铺于96孔板,每孔1×104个细胞,37摄氏度孵育48小时,细胞长满后,分别加入用培养基配置的不同浓度复合双亲肽纳米胶束(按照本实施例子合成的)与相应浓度孟加拉玫瑰红(对照),培养24小时后吸出培养基,CCK8法处理后用酶标仪于450纳米处检测细胞存活率。如(图3)所示,随着孟加拉玫瑰红浓度增加,复合双亲肽纳米胶束对细胞的杀伤作用明显高于纯孟加拉玫瑰红的作用,且复合双亲肽纳米胶束对正常细胞如成纤维细胞毒性也较弱,在20微克每毫升的浓度下,成纤维细胞的细胞存活率达到了80%以上,说明复合双亲肽纳米胶束有良好的生物相容性,也将用这个浓度作为后续实验的最适浓度。
实施例4:取3毫升双亲肽C18GR7RGDS溶液(10毫克/毫升)和2毫升孟加拉玫瑰红溶液(2毫克/毫升)混匀,将混合溶液避光放置于超声波清洗仪,条件设置为25摄氏度、40分钟、28千赫兹。超纯水清洗截留分子量为1000道尔顿透析袋,随后将该混合溶液转移至透析袋,放入盛有超纯水透析液的烧杯并使之浮于透析液中,该透析液体积为2000毫升,PH值为7.4,放入磁子置于磁力搅拌仪上,室温下转速为120转,每4小时更换一次透析水,将透析60小时,即得荧光双亲肽自组装纳米胶束。
黑色素瘤和子宫颈癌(αvβ3阳性)细胞分别铺于96孔板,每孔1×104个细胞,37摄氏度孵育48小时,细胞长满后,分别加入20微克每毫升的复合双亲肽纳米胶束(按照本实施例子合成的)与相应浓度孟加拉玫瑰红(对照),培养4小时后吸出培养基,用超声或激光处理不同时间,继续培养至24小时,CCK8法处理后用酶标仪于450纳米处检测细胞存活率。如(图4)所示,随着时间增加,复合双亲肽纳米胶束对细胞的杀伤作用增加,所以,选取了3分钟作为后续实验的最适治疗时间。
另外,黑色素瘤和子宫颈癌(αvβ3阳性)细胞分别铺于96孔板,每孔1×104个细胞,37摄氏度孵育48小时,细胞长满后,分别加入20微克每毫升的复合双亲肽纳米胶束(按照本实施例子合成的)与相应浓度孟加拉玫瑰红(对照),培养4小时后吸出培养基,用超声或激光处理3分钟,继续培养至24小时,CCK8法处理后用酶标仪于450纳米处检测细胞存活率。如(图4)所示,说明复合双亲肽纳米胶束对黑色素瘤细胞和子宫颈癌细胞的光声效应和光热效应。
实施例5:取1毫升双亲肽C18GR7RGDS溶液(10毫克/毫升)和1毫升孟加拉玫瑰红溶液(2毫克/毫升)混匀,将混合溶液避光放置于超声波清洗仪,条件设置为25摄氏度、20分钟、28千赫兹。超纯水清洗截留分子量为1000道尔顿透析袋,随后将该混合溶液转移至透析袋,放入盛有超纯水透析液的烧杯并使之浮于透析液中,该透析液体积为2000毫升,PH值为7.4,放入磁子置于磁力搅拌仪上,室温下转速为120转,透析72小时,即得荧光双亲肽自组装纳米胶束。
配置20微克每毫升复合双亲肽纳米胶束与相应浓度的孟加拉玫瑰红2毫升,每组均加入20微升DPBF(1,3-二苯基异苯并呋喃),紫外可见光分光光度计548纳米处测OD值,然后用能量为1.5瓦每平方厘米的808纳米激光分别照射0,1,3,5分钟,或者1瓦每平方厘米的超声作用0,1,3,5分钟,紫外可见分光光度计548纳米下测量OD值。结果(图5)所示,随着时间的增加,复合纳米胶束的OD值下降,并选择3分钟作为后续实验的最适治疗时间。
配置不同浓度复合双亲肽纳米胶束与相应浓度的孟加拉玫瑰红2毫升,每组均加入20微升DPBF(1,3-二苯基异苯并呋喃),紫外可见光分光光度计548纳米处测OD值,然后用能量为1.5瓦每平方厘米的808纳米激光照射3钟,或者1瓦每平方厘米的超声作用3分钟,紫外可见分光光度计548纳米下测量OD值。结果(图5)所示,因DPBF(1,3-二苯基异苯并呋喃)被氧化后其在548纳米处的吸收峰会降低,可用来量化光照后或者超声后光敏剂或声敏剂产生的活性氧ROS,从而可知复合纳米胶束产生的活性氧较多。
本发明应用了具体实施例对本发明的原理及实施方式进行了阐述,以上实施例的说明只是用于帮助理解本发明的方法及其中心思想。应当指出,对于本领域的普通技术人员来说,在不脱离本发明原理的前提下,还可以对本发明进行若干改进和修饰,这些改进和修饰也落入本发明权利要求的保护。
Claims (9)
1.一种复合双亲肽纳米胶束,其特征在于:以表面具有黑色素瘤、子宫颈癌靶向整合素αvβ3的双亲肽为构建基质,包载组分为荧光物质孟加拉玫瑰红。
2.根据权利要求1所述的复合双亲肽纳米胶束,其特征在于:靶向基团为含有精氨酸-甘氨酸-天冬氨酸三肽序列的C18-GRRRRRRRRGDS双亲肽。
3.根据权利要求1所述的复合双亲肽纳米胶束,其特征在于:所述复合双亲肽纳米胶束的直径为10-40纳米,电位为0-40毫伏。
4.一种权利要求1-3任意一项权利要求所述的复合双亲肽纳米胶束的制备方法,其特征在于,包括以下步骤:
a.取双亲肽C18GR7RGDS溶解于超纯水,制备浓度为10克/毫升的溶液;
b.取孟加拉玫瑰红溶解于超纯水,制备浓度为2克/毫升的溶液;
c.将上述双亲肽溶液与孟加拉玫瑰红溶液按体积比2:1-1:1充分混合,避光放置于超声波清洗仪中,仪器参数设置为:温度10-30摄氏度、时间10-40分钟、功率5-35千赫兹,得到复合双亲肽纳米胶束产物;
d.将上述复合双亲肽纳米胶束转移至截留分子量500-1500道尔顿的透析袋,透析48-72小时即得具有靶向整合素αvβ3的复合双亲肽纳米胶束。
5.根据权利要求4所述的复合双亲肽纳米胶束的制备方法,其特征在于,所述步骤c温度25摄氏度、时间20~40分钟、功率28千赫兹。
6.根据权利要求4所述的复合双亲肽纳米胶束的制备方法,其特征在于,所述步骤d透析袋为截留分子量1000道尔顿。
7.一种如权利要求1-3任意一项权利要求所述的复合双亲肽纳米胶束在黑色素瘤、子宫颈癌荧光成像中的应用。
8.一种如权利要求1-3任意一项权利要求所述的复合双亲肽纳米胶束在制备黑色素瘤、子宫颈癌光热治疗剂和光声治疗剂中的应用。
9.一种如权利要求1-3任意一项权利要求所述的复合双亲肽纳米胶束在制备黑色素瘤、子宫颈癌光动力治疗剂和声动力治疗剂中的应用。
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