CN113651872A - 一类基于两亲性多肽的自组装纳米光敏剂及其制备方法与应用 - Google Patents
一类基于两亲性多肽的自组装纳米光敏剂及其制备方法与应用 Download PDFInfo
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Abstract
本发明提供了一类基于两亲性多肽的自组装纳米光敏剂及其制备方法及应用。本发明基于一类具有热激活延迟荧光性质的荧光素衍生染料和短链多肽形成单体化合物,其通过特定条件下的自组装,制备成的纳米光敏剂。所制备的这种纳米光敏剂,在肿瘤微环境中可以智能解组装,获得荧光和光动力效果,在肿瘤光动力治疗等领域具备良好应用前景。
Description
技术领域
本发明涉及一类基于两亲性多肽的自组装纳米光敏剂及其制备方法与应用。该类自组装纳米光敏剂具有在特定条件下激活的特性,可以用于肿瘤细胞和组织光动力治疗,特定场合细菌感染光动力杀菌等。
背景技术
癌症已成为威胁人类生命和健康的主要疾病之一,如何有效治疗癌症是全世界一直关注的重要课题。传统的癌症治疗方案包括手术、放疗和化疗3种。然而,手术切除肿瘤往往伴随着较高的复发率,放射治疗受到辐射剂量以及损害正常组织的限制,而化疗极易诱发全身毒副作用。相比传统癌症治疗方法,光动力治疗(Photodynamic Therapy,PDT)是一种有效的治疗癌症的方法,其具有抗癌谱广、创伤小、毒副作用低和耐药性少等优点,逐步成为一种独具特点又效果明显的肿瘤治疗手段,具有广阔的应用前景。
光动力治疗过程依赖的是光敏剂分子在吸收特定波段光能量后,从基态经历一个短暂的单重激发态后经系间窜越(ISC)过程转变为存在期相对较长的三重激发态,三重激发态能量直接转移到三线态氧分子上,形成强细胞毒性的单线态氧分子1O2,可直接杀死癌细胞、造成脉管系统损伤或免疫系统响应而根除肿瘤细胞及组织。
目前用于光动力治疗的光敏剂品种比较单一,常见的一类为卟啉类化合物,为小分子有机光敏剂。但这类有机光敏剂普遍存在特定肿瘤位置的选择性富集差的问题,难以获得高效的光动力治疗效果。随着纳米技术的发展,纳米光敏剂展现出解决上述问题的潜能,可以实现在肿瘤组织位置的靶向富集。当前纳米光敏剂的纳米基质主要有脂质体、高分子和硅胶等。这些传统纳米基质制备的纳米光敏剂仍然有一些不足,例如这些基质材料可能带来细胞毒性,难以得到高的载药量,同时缺少诊疗一体化的功能。
利用自组装策略来设计纳米光敏剂,省却了纳米基质,可以大幅提升载药量,避免基质本身的毒性。随着多肽固相合成方法的成熟和普及,以多肽作为自组装基质,用作药物载体,在组织工程、基因治疗等生物医学领域得到广泛应用。其中两亲性多肽本身具有自组装特性,与光敏剂耦合,在光动力治疗领域有着良好的研究开发前景。
发明内容
本发明解决的技术难题是针对当前具有低毒性高载药量和诊疗一体化功能的光敏剂的不足,而提供了一类基于两亲性多肽的自组装纳米光敏剂及其制备方法与应用。
本发明的技术方案如下:
一类基于两亲性多肽的自组装纳米光敏剂,所述自组装纳米光敏剂是通过一个荧光素多肽衍生化合物作为单体自组装形成的,所述的荧光素多肽衍生化合物具有通式Ⅰ的结构:
其中:
R和R’分别独立选自H,R1,R2,R3,R4和R5;
基于以上技术方案,优选的,所述自组装纳米光敏剂可以在肿瘤微环境酸性条件下智能解组装,诱导出荧光和光动力效果,激活其光敏性能,用于光动力治疗,具有诊疗一体化的能力。特别是自组装单体化合物末端有两个氨基,形成的纳米光敏剂的表面具有氨基,在中性条件下纳米粒子带有较高的正向zeta电位,使得纳米粒子在水溶性中有较好的稳定性。另外,自组装单体只包含光敏剂和两亲性多肽两部分,制得纳米光敏剂具有较高(超过50%)的载药量,并且所用的光敏剂是荧光素衍生物,在以往的研究中发现生物毒性低,加上多肽具有好的生物相容性,制得的纳米光敏剂生物毒性也比较低。所制备的这种纳米光敏剂,在肿瘤微环境中可以智能解组装,获得荧光和光动力效果,在肿瘤光动力治疗等领域具备良好应用前景。
基于以上技术方案,优选的,所述自组装单体荧光素多肽衍生化合物I的制备方法,包括如下步骤:
将原料化合物Ⅱ、缩合剂、酰化反应催化剂和含有短肽链的树脂Ⅲ在有机溶剂中混合,在真空、氮气保护下25~30℃反应1~2h,得到化合物Ⅳ,之后加入树脂脱除剂(切割试剂),制得模型荧光素多肽衍生化合物Ⅰ;其中原料化合物Ⅱ、缩合剂、酰化反应催化剂和含有短肽链的树脂Ⅲ的摩尔比为1:2:4:1。反应式如下:
基于以上技术方案,优选的,所述缩合剂为2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(HATU)、1-羟基苯并三氮唑(HOBT)、苯并三氮唑-N,N,N',N'-四甲基脲六氟磷酸盐(HBTU)、二环己基碳二亚胺(DCC)、1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(EDCI)中的至少一种。
基于以上技术方案,优选的,所述酰化反应催化剂为N,N-二异丙基乙胺(DIEA)、4-二甲氨基吡啶(DMAP)中的至少一种。
基于以上技术方案,优选的,反应溶剂为无水DMF、DMSO、乙腈中的至少一种。
基于以上技术方案,优选的,所述树脂脱除剂为体积分数为95%CF3COOH、2.5%H2O、2.5%TES组成的混合物。
基于以上技术方案,优选的,所述原料化合物Ⅱ的制备方法,包括如下步骤:
以2,6-二甲基4-吡喃酮和丙二腈为原料,合成了中间体2,6-二甲基-4-吡喃亚基丙二腈;以对醛基苯甲酸和4-氯间苯二酚为原料合成了化合物DCF-1,以化合物DCF-1、三氟乙酸和乌洛托品为原料通过Duff反应合成了化合物DCF-2,以化合物DCF-2和配体X为原料通过Knoevenagel缩合反应合成了化合物Ⅱ;反应式如下:
其中配体X有以下几种:
R与R’分别独立选自R1、R2、R3、R4、R5;
本发明还提供上述自组装纳米光敏剂的制备方法,如下步骤:
将荧光素多肽衍生化合物I溶解于去离子水中,在超声波震荡条件下,使用碱性溶液调节pH到适当的值(7.0~12),并持续使用同样功率超声波震荡5~120min,得到浑浊液,在25~30℃稳定放置1~24h沉降得到自组装纳米光敏剂。
基于以上技术方案,优选的,荧光素多肽衍生化合物I与去离子水的比例为1mg:2mL。
基于以上技术方案,优选的,所述碱性溶液的浓度为0.01~1000mM。
基于以上技术方案,优选的,所述碱性溶液为NaOH溶液。
本发明的有益效果:
本发明利用两亲性多肽与小分子有机光敏剂耦合形成自组装单体,在特定条件下形成自组装纳米粒子。两亲性多肽具有生物兼容性好的优势,在组织工程和基因治疗领域都有着广泛应用。同时选取本课题组前期原创的一类具有热激活延迟荧光性质的化合物(荧光素衍生染料)作为有机光敏剂,这类延迟荧光化光敏剂,前期研究已经发现其有良好的诊疗一体化潜力。本发明将其与两亲性短链多肽进行耦合,合成一类自组装单体,进而在特定条件下自组装形成纳米光敏剂。制备的纳米光敏剂,因自组装获得超过50%的高载药量,光敏剂分子会发生聚集诱导淬灭效应(ACQ),导致荧光和光敏性能的自淬灭。但这种自淬灭效应使得设计激活性诊疗一体化的光敏剂成为可能。针对肿瘤微环境和溶酶体的微酸环境,设计可以酸性激活的自组装纳米光敏剂,将在肿瘤治疗和病原性感染疾病的治疗中发挥重要作用。
本发明的有益效果,除了在肿瘤光动治疗方面外,也在其他非肿瘤治疗有广阔的应用前景,例如耐药病菌的杀伤,病原菌的清除等。
附图说明
图1为实施例1合成的自组装单体模型化合物FL-L4K2的质谱图。
图2为实施例1合成的自组装单体模型化合物FL-L4K2的高效液相色谱(HPLC)图。
图3为实施例1合成的化合物FL-L4K2和FL在PBS(PH=7.4)中的归一化吸收光谱图。
图4为实施例1合成FLKNPs的动态光散射图和透射电镜图,其中动态光散射图中的插图为透射电镜图。
图5为实施例1合成的化合物FL-L4K2和FLKNPs在PBS(PH=7.4)中的发射光谱图。
图6为实施例1合成的FLKNPs在不同pH的PBS缓冲液(pH为5.0和7.4)中荧光强度随时间变化图。
图7为实施例1合成的化合物FL-L4K2和FLKNPs的三重态瞬态吸收图。
图8为实施例1合成的FL-L4K2和FLKNPs在水相环境中随光照时间变化单线态氧的产生情况图。
图9为实施例1合成的FLKNPs在细胞中的共聚焦成像。
图10为实施例1合成的FLKNPs在细胞中的单线态氧产生。
图11为实施例1合成的FLKNPs对细胞的毒性测试。
图12为实施例1合成的FLKNPs在MCF-7细胞中的细胞器定位图像。
图13为实施例1合成的FLKNPs对MCF-7细胞溶酶体破坏成像图。
具体实施方式
下述非限制性实施例可以使本领域的普通技术人员更全面地理解本发明,但不以任何方式限制本发明。任何熟悉本技术领域的技术人员在本发明披露的技术范围内,根据本发明的技术方案及其发明构思进行等同替换或改变均属于本发明保护范畴。
下述实施例中,如无特殊说明,所用试剂均可由常规方法制备或由商业途径购买。
以2,6-二甲基4-吡喃酮和丙二腈为原料,按照文献方法合成了中间体2,6-二甲基-4-吡喃亚基丙二腈。以对醛基苯甲酸和4-氯间苯二酚为原料合成了化合物DCF-1,以化合物DCF-1、三氟乙酸和乌洛托品为原料通过Duff反应合成了化合物DCF-2,以化合物DCF-2和2,6-二甲基-4-吡喃亚基丙二腈为原料通过Knoevenagel缩合反应合成了化合物FL(J.Am.Chem.Soc.2014,136,9590-9597)
实施例1
1、多肽片段L4K2的合成
使用传统Fmoc多肽固相合成方法,以CTC树脂(2-氯三苯甲基)为多肽合成的载体,Fmoc保护的氨基酸为原料合成了两亲性六肽L4K2,具体步骤如下:
(1)称取CTC树脂(0.75g,0.675mmol,1.0eq),Fmoc-Lys-OH(0.791g,1.6875mmol,2.5eq)于多肽固相合成管中,加入15ml干燥的二氯甲烷和0.25ml N,N-二异丙基乙胺(DIEA),在漩涡震荡器上以250次/分的频率震荡2h,再向其中加入1.5mL甲醇和0.25mlDIEA,继续震荡30min,使得树脂溶胀并与第一个赖氨酸通过酯键相连。
(2)将(1)步骤后多肽合成管中的溶液放出,分别用N,N-二甲基甲酰胺(DMF)、二氯甲烷、甲醇、DMF洗涤两次并抽干,然后加入15ml 20%哌啶的DMF溶液,震荡30min脱去氨基酸的α-N Fmoc保护基,结束后放出管中溶液并重复上述脱保护步骤,30min后用DMF洗涤六次。
(3)称取O-苯并三氮唑-N,N,N',N'-四甲基脲四氟硼酸酯(TBTU,0.305g,0.945mmol,1.4eq),1-羟基苯并三唑(HOBT,0.13g,0.945mmol,1.4eq),Fmoc-Lys-OH(0.791g,1.6875mmol,2.5eq)于固相合成管中,再加入15ml无水DMF和0.5ml N,N-二异丙基乙胺(0.25mL)。震荡1.5h后,放出合成管中液体,并用DMF洗涤六次。
(4)按照多肽片段的氨基酸顺序从羧基端开始重复(2),(3)步直到多肽片段完成。
2、自组装单体模型化合物FL-L4K2的合成
将化合物FL(213.92mg,0.28mmol,1.0eq.),HATU(212.93mg,0.56mmol,2.0eq.),DIEA(0.5mL)和上述制备的L4K2(262.27mg,0.28mmol,1.0eq.)溶于15mL DMF中,加入0.5mLDIEA,在漩涡震荡器上以250次/分的频震荡2h,放出溶液后用DMF洗涤,然后向固相合成管中加入8mL切割试剂(95%三氟乙酸,2.5%三异丙基硅烷,2.5%水),震荡2.5h后过滤,将滤液滴加至大量乙醚中(-20℃预冷1h),观察到有红色絮状沉淀生成,将混合物离心、乙醚洗涤并用氮气吹干后得到FL-L4K2。
3、纳米光敏剂的制备
将化合物FL-L4K2溶解于去离子水(化合物FL-L4K2与去离子水的比例为1mg:2mL)中,在35kHz超声波震荡中,使用NaOH溶液(浓度100mM)调节pH到8.0,并持续使用同样功率超声波震荡15min,得到的浑浊液,室温稳定放置12h沉降得到自组装纳米光敏剂FLKNPs。
实施例2
对实施例1制得的纳米光敏剂FLKNPs进行可激活荧光和光动力治疗效果的实验验证。下述实验中孵育细胞所用的FLKNPs孵育染色液是以先制备浓度为2mg/mLpH 7.4的PBS含染料(FLKNPs)母液,再用含10%胎牛血清的RPMI-1640培养基稀释得到所需浓度。
图1为实施例1合成的自组装单体模型化合物FL-L4K2的质谱图。图中化合物FL-L4K2的质荷比与目标产物相对分子质量相符。
图2为实施例1合成的自组装单体模型化合物FL-L4K2的高效液相色谱(HPLC)图,在与质谱联合下,所得化合物为单一组分的目标产物。
图3为实施例1合成的化合物FL-L4K2和FL在PBS缓冲液(pH=7.4)中的归一化吸收光谱图。通过紫外光谱测试发现连接六肽的FL-L4K2依然保持FL的光谱特性。
图4为实施例1合成FLKNPs的动态光散射图和透射电镜图,其中动态光散射图中的插图为透射电镜图。从动态光散射结果可以看出,FLKNPs的水合粒径约为153.5nm,PDI为0.183,而透射电镜图像可以看出,FLKNPs是尺寸约为130nm左右的球形颗粒。
图5为实施例1合成的化合物FL-L4K2和FLKNPs在PBS缓冲液(pH=7.4)中的发射光谱图。可以看出FLKNPs的形成导致FL-L4K2的荧光猝灭,这提供了通过刺激响应策略开启荧光的机会。
图6为实施例1合成的FLKNPs在不同pH的PBS缓冲液(pH为5.0和7.4)中荧光强度随时间变化图。实验结果可以看出,pH 5.0条件下的荧光强度随时间显著增强,但在pH 7.4下看不到明显的荧光变化。这个结果表明FLKNPs可以在酸性环境中分解。
图7为实施例1合成的化合物FL-L4K2和FLKNPs的三重态瞬态吸收图。(a,b)FL-L4K2(20μM)在乙醇中经除氧后的三重态瞬态吸收图,(c,d)FLKNPs(20μg/mL)在PBS缓冲液(pH=7.4)中经除氧后的三重态瞬态吸收图。激发波长为532nm,每3.5微秒测一次。(a)中曲线由下到上依次为从0微秒开始,每3.5微秒测一次,到31.5微秒结束,得出的曲线图。可以看出FL-L4K2单体具有三重激发态(τ=8.90)。但是对于FLKNPs,没有检测到明显的三重态信号。这些结果表明,FLKNPs中的PDT效应关闭。
图8为实施例1合成的化合物FL-L4K2和FLKNPs在水相环境中随光照时间变化单线态氧的产生情况图。ABDA(9,10-蒽基-双(亚甲基)二丙二酸)作为单线态氧指示剂。其中(a)在pH为7.4的PBS缓冲液中的FLKNPs(7.36μg/mL),(b)在pH为7.4的PBS缓冲液中的FL-L4K2(5μM),和(c)pH 5.0的PBS缓冲液中的FLKNPs(7.36μg/mL)。从图中可以看出,FL-L4K2可以产生单线态氧但FLKNPs不能,这意味着聚集诱导的猝灭(ACQ)效应不仅使FLKNPs荧光猝灭,而且使PDT效应消失。同时,酸处理的FLKNPs可以恢复ROS的生成能力。这表明当FLKNPs在酸性环境中分解时,PDT效应也可以从关闭切换为开启。
图9为实施例1合成的FLKNPs在MCF-7和COS-7细胞中的共聚焦成像。其中(a)先用2mg/mLpH7.4的PBS含染料母液用含10%胎牛血清的RPMI-1640培养基稀释得到的10μg/mLFLKNPs,孵育4小时的MCF-7细胞的激光共聚焦荧光图像,(b)用与a相同的方法处理COS-7细胞的激光共聚焦荧光图像。其中,1为荧光场图像,2为明场图像,3为明场与荧光场叠加图像。在癌细胞MCF-7中有荧光,而在COS-7细胞中无荧光,表明FLKNPs具有对肿瘤细胞的特异性响应能力,而对正常细胞无响应。
图10为实施例1合成的FLKNPs在MCF-7细胞中的单线态氧产生。其中(a)对照组:未经任何处理;(b)仅MCF-7细胞进行光照(30mW/cm2,10分钟);(c)MCF-7细胞仅用质量浓度为5μg/mL FLKNPs孵育4h;(d)MCF-7细胞与5μg/mLFLKNPs共孵育后进行光照(30mW/cm2,10分钟)以商业化的活性氧探针DCFH-DA为单线态氧指示剂检测纳米颗粒在细胞中产生活性氧的能力。其中,1为明场图像,2为荧光场图像,3为明场与荧光场叠加图像。如图所示,仅在与FLKNPs孵育并经过光处理的MCF-7细胞中才能观察到强烈的绿色荧光。这些结果清楚地证明了PDT作用可以在肿瘤细胞中被激活。
图11为实施例1合成的FLKNPs对细胞的毒性测试。不同浓度的FLKNPs在光照条件(30mW/cm2,10min)和非光照条件下对细胞的存活率影响。低暗毒性和强光毒性表明FLKNPs具有优异的PDT效果。
图12为实施例1合成的FLKNPs在MCF-7细胞中的细胞器定位图像。用10μg/mL的FLKNP对MCF-7细胞进行染色,继续培养4h,吸除含有纳米粒子的培养液,用PBS缓冲液(pH=7.4)轻轻吹洗3次,最后加入含有1μM Lysosome Green的RPMI-1640不完全培养基的溶液培养30min后进行共聚焦荧光成像。其中(a)为Lysosome Green在细胞中的荧光成像(λex=488nm;λem=505–525nm),(b)为FLKNPs在细胞中的荧光成像(λex=488nm;λem>590nm),(c)为图a和图b的叠加图像,(d)为皮尔森覆染系数。这些结果说明FLKNPs纳米颗粒的分解过程应该在溶酶体的酸性环境中发生,并伴有荧光和PDT效应“开启”。
图13为实施例1合成的FLKNPs对MCF-7细胞溶酶体破坏成像图。其中(a)空白对照组,仅加入吖啶橙试剂(5μM)的PBS缓冲液(pH=7.4)孵育MCF-7细胞30min;(b)吖啶橙试剂(5μM)的PBS缓冲液(pH=7.4)孵育MCF-7细胞30min后,光照(30mW/cm2,10分钟);(c)FLKNPs(10μg/mL)孵育MCF-7细胞4h后,再使用吖啶橙试剂(5μM)的PBS缓冲液(pH=7.4)孵育MCF-7细胞30min;(d)先将FLKNPs(10μg/mL)孵育MCF-7细胞4h后、再用吖啶橙试剂(5μM)的PBS缓冲液(pH=7.4)孵育MCF-7细胞30min后,然后进行光照(30mW/cm2,10分钟)。如图所示,红色荧光仅在具有FLKNPs并光照的细胞组中消失,这意味着溶酶体被PDT破坏。以上结果证实,FLKNPs可以通过内吞作用选择性进入肿瘤细胞,在溶酶体分解,激活荧光和PDT,并通过破坏溶酶体诱导细胞凋亡。
对于任何熟悉本领域的技术人员而言,在不脱离本发明技术方案范围情况下,都可利用上述揭示的技术内容对本发明技术方案作出许多可能的变动和修饰,或修改为等同变化的等效实施例。因此,凡是未脱离本发明技术方案的内容,依据本发明的技术实质对以上实施例所做的任何简单修改、等同变化及修饰,均应仍属于本发明技术方案保护的范围内。
Claims (10)
2.根据权利要求1所述的自组装纳米光敏剂,其特征在于,所述的纳米光敏剂可以在酸性条件下解组装。
3.根据权利要求1所述的自组装纳米光敏剂,其特征在于,所述的纳米光敏剂具有超过50%的载药量。
4.权利要求1-3中任意一项所述的自组装纳米光敏剂在肿瘤诊疗一体化、非肿瘤治疗中的应用。
6.根据权利要求5所述的自组装纳米光敏剂的制备方法,其特征在于,所述缩合剂为2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯、1-羟基苯并三氮唑、苯并三氮唑-N,N,N',N'-四甲基脲六氟磷酸盐、二环己基碳二亚胺、1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐中的至少一种。
7.根据权利要求5所述的自组装纳米光敏剂的制备方法,其特征在于,所述酰化反应催化剂为N,N-二异丙基乙胺、4-二甲氨基吡啶中的至少一种。
8.根据权利要求5所述的自组装纳米光敏剂的制备方法,其特征在于,反应溶剂为无水DMF、DMSO、乙腈中的至少一种;所述树脂脱除剂为体积分数为95%CF3COOH、2.5%H2O、2.5%TES组成的混合物。
9.权利要求1所述的自组装纳米光敏剂的制备方法,其特征在于,包括如下步骤:
将荧光素多肽衍生化合物I溶解于去离子水中,在超声波震荡条件下,使用碱性溶液调节pH到7.0~12,超声波震荡5~120min,得到浑浊液,在25~30℃放置1~24h沉降得到自组装纳米光敏剂。
10.根据权利要9所述的自组装纳米光敏剂的制备方法,其特征在于,所述碱性溶液的浓度为0.01~1000mM;所述碱性溶液为NaOH溶液。
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