CN114668854A - 一种光活化的卟啉前药三元组装体、其制备方法及其应用 - Google Patents
一种光活化的卟啉前药三元组装体、其制备方法及其应用 Download PDFInfo
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Abstract
本发明提供了一种光活化的卟啉前药三元组装体,由主体和客体相互作用得到,所述主体为全甲基化β‑环糊精修饰的透明质酸,所述客体为卟啉前药,所述卟啉前药由单羧基苯基卟啉与光氧化活性官能团修饰的抗肿瘤药物分子通过共价连接得到。本申请还提供了光活化的卟啉前药三元组装体的制备方法和应用。本申请提供的卟啉前药三元组装体可以方便、有效的进行荧光成像,示踪肿瘤的治疗过程;由于其治疗效果好、可以极大的减小化疗药物带来的全身毒性、具有远程操作性和非侵入性,具有高效、灵敏的成像能力,该超分子组装体在癌症及肿瘤治疗和成像领域有潜在的应用价值。
Description
技术领域
本发明涉及癌症及肿瘤治疗技术领域,尤其涉及一种光活化的卟啉前药三元组装体、其制备方法及其应用。
背景技术
化疗是目前治疗癌症和肿瘤的主要方法之一,可以在一定程度上减轻患者的痛苦、延长生命。但是,由于常用的化疗药物水溶性差、缺乏靶向性,会给患者带来不可避免的全身毒性,往往在杀死肿瘤细胞的同时会杀死大量的正常细胞,导致人体免疫系统的严重损伤,因此不能从根本上治愈癌症。为了解决化疗药物的这些缺点,设计具有肿瘤细胞靶向性、具有刺激响应性的前药已经成为一种流行的策略。
前药设计的一个常见策略是利用体内肿瘤微环境的相关内源性刺激(如乏氧、弱酸性、过度表达的谷胱甘肽等)或体外的物理刺激(如热或光)。其中,活性氧(ROS)响应性前药,尤其是利用近红外光进行刺激的前药进行光动力疗法(PDT)具有明显的优势。由于近红外的光可以穿透皮肤,因此能够从体外进行定点刺激,使得该治疗策略具有无创和远程操纵的能力。当活性药物分子受到ROS的刺激而释放时,提供了化疗的效果;与此同时,产生的ROS可以进一步破坏细胞的正常生命活动,损伤细胞,提供光动力治疗的效果。因此,基于不同ROS刺激响应的基团来制备ROS反应性前药的方法显示在临床癌症及肿瘤的治疗中显示出巨大的潜力。
由于β-环糊精廉价易得、易于修饰、水溶性好、生物相容性好、具有较大的疏水性空腔可以特异性键合某一类分子,因此在生物医药领域被广泛研究,并且已经作为一部分药物的辅剂应用于临床。鉴于上述说明光动力治疗和β-环糊精的结合有望应用于癌症治疗方面。
发明内容
本发明解决的技术问题在于提供一种光活化的卟啉前药三元组装体,其可在癌症及肿瘤治疗和成像方面具有好的应用。
有鉴于此,本申请提供了一种光活化的卟啉前药三元组装体,由主体和客体相互作用得到,所述主体为全甲基化β-环糊精修饰的透明质酸,所述客体为卟啉前药,所述卟啉前药由单羧基苯基卟啉与光氧化活性官能团修饰的抗肿瘤药物分子通过共价连接得到。
优选的,所述卟啉前药三元组装体的直径为100~200nm。
优选的,所述全甲基化β-环糊精修饰的透明质酸由单-6-脱氧-氨基-全甲基化-β-环糊精与透明质酸钠通过酰胺缩合得到。
本申请还提供了所述的光活化的卟啉前药三元组装体的制备方法,包括:
将卟啉前药的水溶液和全甲基化β-环糊精修饰的透明质酸的水溶液混合,超声,得到光活化的卟啉前药三元组装体。
优选的,所述全甲基化β-环糊精修饰的透明质酸的制备方法具体为:
将1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐、N-羟基琥珀酰亚胺磺酸钠盐和透明质酸钠的磷酸缓冲液混合,得到初始反应液;
在所述初始反应液中加入单-6-去氧-6-氨基-全甲基化-β-环糊精的透明质酸钠的磷酸缓冲液,反应,得到全甲基化β-环糊精修饰的透明质酸。
优选的,所述卟啉前药的制备方法具体为:
将氨基丙烯酸酯键修饰的抗肿瘤药物分子与单羧基苯基卟啉在催化剂的作用下进行酯化反应,得到光氧化活性官能团修饰的抗肿瘤药物分子。
优选的,所述卟啉前药与所述全甲基化β-环糊精修饰的透明质酸的摩尔浓度比为1:2。
本申请还提供了所述的光活化的卟啉前药三元组装体或所述的制备方法所制备的光活化的卟啉前药三元组装体在制备癌症治疗药物上的应用。
优选的,所述药物的使用方法为采用660nm激光体外照射。
本申请提供了一种光活化的卟啉前药三元组装体,其构筑单元以全甲基化β-环糊精修饰的透明质酸(HA-PMeCD)为主体,以具有单线态氧响应性质的卟啉前药(TPP-CA4)为客体,通过主客体相互作用构筑超分子纳米粒子;在三元组装体中,1)卟啉前药(TPP-CA4)在受到660nm光的照射后,会产生大量单线态氧,破坏细胞的正常生理活动,造成细胞损伤,与此同时,该分子是一种对单线态氧敏感的结构,在受到单线态氧的攻击时,结构发生破坏,会释放出活性药物分子,带来化疗的治疗效果;2)全甲基化β-环糊精修饰的透明质酸保留了环糊精的疏水空腔,使其可以选择性的键合特定结构的分子;另一方面,由于癌细胞的表面具有过量的透明质酸受体,该超分子组装体可以靶向运输至肿瘤细胞的表面;3)卟啉前药(TPP-CA4)分子中的卟啉结构与全甲基化β-环糊精之间可以以1:2的比例可以形成结构紧密的主客体复合物,进一步自组装形成纳米粒子,该纳米粒子的直径约为100nm,使其在生物体内可以通过被动靶向作用,自发运输至肿瘤部位;4)由于卟啉前药(TPP-CA4)与全甲基化β-环糊精修饰的透明质酸(HA-PMeCD)之间强烈的主客体相互作用,大大减弱了卟啉分子之间的π-π堆积,使得卟啉在受到光刺激后的单线态氧产率大大提高并且荧光发射强度也随之增加,为高效的药物释放和生物成像奠定了基础;5)该组装体使用660nm的激光从体外进行照射,使得该治疗方案具有远程性和非侵入性,减少了对生物体的伤害。
因此,本申请提供的光活化的卟啉前药三元组装体可以有效的抑制肿瘤的侵袭,高效的治疗癌症,减小化疗药物带来的全身毒性,具有远程操作性和非侵入性,并且可以通过荧光成像有效的示踪肿瘤的治疗过程,在癌症及肿瘤治疗和成像领域具有广阔的应用前景。
附图说明
图1为全甲基化-β-环糊精修饰的透明质酸(HA-PMeCD)的合成路线;
图2为卟啉前药(TPP-CA4)的合成路线;
图4为卟啉前药(TPP-CA4)随光照时间的高效液相色谱谱图;
图7为与卟啉前药结构类似的参比分子在与全甲基化β-环糊精修饰的透明质酸形成组装体前后,在光照下产生单线态氧能力的差异示意图;
图8为不同样品处理后的细胞共聚焦成像以及细胞活力测试结果;
图9为不同样品处理后小鼠的活体成像、体重变化以及肿瘤体积的变化结果;
图10为不同样品处理后小鼠的心、肝、脾、肺、肾以及肿瘤组织的H&E染色结果;
图11为光活化的卟啉前药三元组装体治疗癌症示意图。
具体实施方式
为了进一步理解本发明,下面结合实施例对本发明优选实施方案进行描述,但是应当理解,这些描述只是为进一步说明本发明的特征和优点,而不是对本发明权利要求的限制。
本申请利用全甲基化β-环糊精修饰的透明质酸-卟啉前药组装体提供了一种简便的超分子策略,在增强抗肿瘤药物水溶性和稳定性、提高药物靶向性、具有极大增强的光动力治疗效果的同时可以用于荧光成像以示踪肿瘤的治疗过程,这为开发治疗癌症和肿瘤方面提供了有效的策略。本发明实施例公开了一种光活化的卟啉前药三元组装体,由主体和客体相互作用得到,所述主体为全甲基化β-环糊精修饰的透明质酸,所述客体为单羧基苯基卟啉与光氧化活性官能团修饰的抗肿瘤药物分子通过共价连接得到。
本申请提供了一种基于原位药物释放与光动力治疗的光活化的全甲基化β-环糊精修饰的透明质酸-卟啉前药三元超分子组装体,其构筑单元以全甲基化β-环糊精修饰的透明质酸(HA-PMeCD)为主体,以具有单线态氧响应性质的卟啉前药(TPP-CA4)为客体,通过主客体相互作用构筑超分子纳米粒子;其中,全甲基化-β-环糊精修饰的透明质酸(HA-PMeCD)由单-6-脱氧-6-胺基-全甲基化-β-环糊精与透明质酸钠通过酰胺缩合得到,卟啉前药(TPP-CA4)为单羧基苯基卟啉与光氧化活性官能团修饰的抗肿瘤药物分子Combretastatin A-4(CA4)通过共价连接得到。该纳米粒子构筑单元的结构如图10所示。
在本申请中,所述卟啉前药三元组装体的直径为100~200nm,在具体实施例中,所述卟啉前药三元组装体的直径为100nm。
本申请还提供了所述光活化的卟啉前药三元组装体的制备方法,包括:
将卟啉前药的水溶液和全甲基化β-环糊精修饰的透明质酸的水溶液混合,超声,得到光活化的卟啉前药三元组装体。
在上述过程中,所述羧基苯基卟啉与光氧化活性官能团修饰的抗肿瘤药物分子也称卟啉前药(TPP-CA4),其制备方法具体为:
将氨基丙烯酸酯键修饰的抗肿瘤药物分子与单羧基苯基卟啉在催化剂的作用下进行酯化反应,得到羧基苯基卟啉与光氧化活性官能团修饰的抗肿瘤药物分子。
在上述过程中,所述氨基丙烯酸酯键修饰的抗肿瘤药物Combretastatin A-4分子依照文献合成,所述催化剂可选自三氟乙酸、DCC+DMAP或DIPEA+PyBOP;在具体实施例中,所述催化剂选自三氟乙酸。
所述全甲基化β-环糊精修饰的透明质酸(HA-PMeCD)的制备方法具体为:
将1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐、N-羟基琥珀酰亚胺磺酸钠盐和透明质酸钠的磷酸缓冲液混合,得到初始反应液;
在所述初始反应液中加入单-6-去氧-6-氨基-全甲基化-β-环糊精的透明质酸钠的磷酸缓冲液,反应,得到全甲基化β-环糊精修饰的透明质酸。
在本申请提供的卟啉前药三元组装体中,所述卟啉前药和所述全甲基化β-环糊精修饰的透明质酸的摩尔浓度比为1:2。
本申请还提供了上述方案所述的光活化的卟啉前药三元组装体在制备癌症治疗药物上的应用。
本发明提供的卟啉前药三元组装体是基于全甲基化β-环糊精修饰的透明质酸(HA-PMeCD)和卟啉前药(TPP-CA4)之间的主客体相互作用构筑的。该组装体利用透明质酸与肿瘤细胞表面过量的透明质酸受体进行特异性结合,显示出靶向性肿瘤细胞的能力;同时该纳米粒子的直径约为100nm,使得该纳米粒子可以通过被动靶向作用在生物体内自发运输至肿瘤组织;卟啉与抗肿瘤药物分子Combretastatin A-4(CA4)通过单线态氧敏感的官能团(氨基丙烯酸酯键)相连,在受到单线态氧攻击时可以发生响应并断裂释放出活性药物分子;TPP-CA4通过与HA-PMeCD形成结合紧密的1:2的络合物来降低卟啉分子之间的π-π堆积作用,可以极大的提高其在光照后产生单线态氧的能力,为前药分子(TPP-CA4)可以迅速响应单线态氧,发生结构转变并且释放出药物分子奠定了基础。同时,使用660nm激光照射过程中产生的大量单线态氧可以破坏细胞的正常生理活动、损伤细胞,带来光动力治疗的效果。除此之外,由于卟啉强烈的荧光发射,使得该组装体可以方便、有效的进行荧光成像,示踪肿瘤的治疗过程。由于其治疗效果好、可以极大的减小化疗药物带来的全身毒性、具有远程操作性和非侵入性,具有高效、灵敏的成像能力,该超分子组装体在癌症及肿瘤治疗和成像领域有潜在的应用价值。
为了进一步理解本发明,下面结合实施例对本发明提供的光活化的卟啉前药三元组装体、其制备方法及其应用进行详细说明,本发明的保护范围不受以下实施例的限制。
实施例1一种基于原位药物释放与光动力治疗的光活化的全甲基化-β-环糊精修饰的透明质酸-卟啉前药三元超分子组装体的制备方法,步骤如下:
1)全甲基化β-环糊精修饰的透明质酸(HA-PMeCD)的合成
将1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(EDC)(0.875mmol,167.7mg),N-羟基琥珀酰亚胺磺酸钠盐(NHSS)(0.875mmol,190mg)加入到溶有100mg透明质酸钠(Mw=93,000)的30mL磷酸缓冲液(PBS,0.1M,pH=7.2)中,室温下搅拌0.5个小时。随后,向反应液中加入溶解于10mL PBS溶液中的120mg单-6-去氧-6-氨基-全甲基化-β-环糊精,然后室温下继续搅拌24小时。待反应结束后,用去离子水进行透析5天,纯化后通过冻干溶剂得到HA-PMeCD白色固体;如图1所示,图1为全甲基化β-环糊精修饰的透明质酸(HA-PMeCD)的合成路线图;
2)卟啉前药(TPP-CA4)的合成
依照文献合成氨基丙烯酸酯键修饰的抗肿瘤药物分子Combretastatin A-4(CA4)分子,将其(0.10mmol,48.4mg)与单羧基苯基卟啉(0.08mmol,52.7mg)和三氟乙酸(TFA)(20μL)溶于20mL超干二氯甲烷中,室温下搅拌2小时。随后,将溶剂旋干除去,剩余物溶于甲醇,然后通过HPLC进行纯化,通过冻干得到TPP-CA4红色固体;如图2所示,图2为卟啉前药(TPP-CA4)的合成路线图;
3)抑制肿瘤侵袭的化疗与光动力治疗的光激活靶向联合治疗的超分子组装体的制备
将卟啉前药(TPP-CA4)的溶液(0.2mM,10%DMSO,90%H2O)与全甲基化-β-环糊精修饰的透明质酸(HA-PMeCD)的水溶液(0.4mM)等体积混合,超声30分钟,得到超分子组装体置于4℃冰箱保存。
图3为超分子组装体的表征,图4为卟啉前药随光照时间的高效液相色谱谱图,图5为超分子组装体随光照时间的高效液相色谱谱图,图6为卟啉前药、超分子组装体和超分子组装体在在660nm光照60min后的光致发光谱图;由图3可知,卟啉前药(TPP-CA4)与全甲基化β-环糊精修饰的透明质酸(HA-PMeCD)在水中可以通过自组装形成纳米粒子,表面带负电荷,尺寸大约为100nm;由图4可知,单独存在卟啉前药(TPP-CA4)时,光照5h后才可以产生足够的单线态氧以完全释放出原药(CA4);由图5可知,超分子组装体存在时,光照15min即可完全释放出原药(CA4);由图6可知,随着超分子组装体的形成以及光照刺激,该体系的荧光强度不断增加至单独卟啉前药(TPP-CA4)的4倍。
图7为与卟啉前药结构类似的参比分子在与全甲基化β-环糊精修饰的透明质酸形成组装体前后,在光照下产生单线态氧能力的差异示意图;其中图7a和图7b分别为TPP-CA4和in DMSO/water(v:v)=1/100用650nm光照的紫外-可见光谱;[PMeCD]=2[TPP-COOCH3]=20μM,[ABDA]=50μM,由此可知,形成超分子组装体后,该体系在光照下产生单线态氧的速度大大提高;图7c为归一化后ABDA在380nm处的紫外-可见光谱,图7d为ABDA在TPP-CA4和溶液中的分解速率,(ABDA是活性氧指示剂),由此可知,形成组装体后,在光照下产生单线态氧的能力提高至单独卟啉前药(TPP-CA4)的57倍。
A549细胞与不同样品共孵育后,用650nm光照射5min,再次培养15min后的共聚焦荧光图像:(a)空白对照,(b)TPP-CA4,(c)([TPP-CA4]=20nm,[HA-PMeCD]=40nm)。分别用4′、6-二氨基-2-苯基吲哚(DAPI,蓝色)和微管蛋白追踪器(绿色)对细胞核和细胞骨架进行染色。TPP-CA4的荧光为红色。(d)TPP-CA4,(e)([TPP-CA4]=20nm,[HA-PMeCD]=40nm)DCFH-DA用于染色活性氧,绿色荧光。(f)TPP-CA4,光照射下或不照射5分钟后,再次培养15min的A549细胞存活率。结果如图8所示。
图8为A549细胞在(a)control,(b)TPP-CA4+650nm光照5min,(c)光照5min,的共聚焦成像结果。([TPP-CA4]=20nMand[HA-PMeCD]=40nM)。DAPI(4’,6-Diamidino-2-phenylindole)染色细胞核,蓝色荧光;tubulin tracker green染色微管,绿色荧光;TPP-CA4,红色荧光。A549细胞在(d)TPP-CA4+650nm光照5min,(e)光照5min,的共聚焦成像结果([TPP-CA4]=20nM and[HA-PMeCD]=40nM)。DCFH-DA用于染色活性氧,绿色荧光。图8中图(a)在空白对照组,细胞中的微管呈现舒展的丝状;(b)和(c)中,细胞的微管形态发生明显转变,呈现聚集的点状,证明有CA4原药释放出来,干扰了微管的正常生理活动;(d)和(e)对比,在相同光照强度和时间下,比单独给药TPP-CA4的实验组明显产生更多的活性氧;(f)细胞活性测试,证明该体系的治疗效果为在实验所用剂量下,黑暗条件下均无明显的细胞毒性。
图9中(a)各组小鼠治疗后不同时间的体重;(b)不同处理组小鼠的肿瘤大小随时间变化;(c)不同处理组小鼠的活体荧光图像;(d)不同处理组小鼠活体荧光成像的荧光强度;(e)实验结束时,各处理组小鼠的肿瘤的代表性照片(i,PBS;ii,TPP-CA4;iii,iv,和v,),[HA-PMeCD]=[PMeCD]=2[TPP-CA4]=0.2mM。图9(a)说明该体系对小鼠没有明显的全身性毒性,是一个生物友好的体系;图9(c)(d)说明荧光成像结果 与图6结果一致,证明有良好的荧光活体成像能力。图9(b)(e)和图9说明实验组可以完全抑制肿瘤的生长,有较好的肿瘤治疗效果;总体肿瘤治疗效果:
图10为图9中各组小鼠安乐死后,各处理组小鼠的肿瘤、心、肝、脾、肺、肾组织H&E染色(放大倍数100倍)。
以上实施例的说明只是用于帮助理解本发明的方法及其核心思想。应当指出,对于本技术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范围内。
对所公开的实施例的上述说明,使本领域专业技术人员能够实现或使用本发明。对这些实施例的多种修改对本领域的专业技术人员来说将是显而易见的,本文中所定义的一般原理可以在不脱离本发明的精神或范围的情况下,在其它实施例中实现。因此,本发明将不会被限制于本文所示的这些实施例,而是要符合与本文所公开的原理和新颖特点相一致的最宽的范围。
Claims (9)
1.一种光活化的卟啉前药三元组装体,由主体和客体相互作用得到,所述主体为全甲基化β-环糊精修饰的透明质酸,所述客体为卟啉前药,所述卟啉前药由单羧基苯基卟啉与光氧化活性官能团修饰的抗肿瘤药物分子通过共价连接得到。
2.根据权利要求1所述的卟啉前药三元组装体,其特征在于,所述卟啉前药三元组装体的直径为100~200nm。
3.根据权利要求1所述的卟啉前药三元组装体,其特征在于,所述全甲基化β-环糊精修饰的透明质酸由单-6-脱氧-氨基-全甲基化-β-环糊精与透明质酸钠通过酰胺缩合得到。
4.权利要求1所述的光活化的卟啉前药三元组装体的制备方法,包括:
将卟啉前药的水溶液和全甲基化β-环糊精修饰的透明质酸的水溶液混合,超声,得到光活化的卟啉前药三元组装体。
5.根据权利要求4所述的制备方法,其特征在于,所述全甲基化β-环糊精修饰的透明质酸的制备方法具体为:
将1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐、N-羟基琥珀酰亚胺磺酸钠盐和透明质酸钠的磷酸缓冲液混合,得到初始反应液;
在所述初始反应液中加入单-6-去氧-6-氨基-全甲基化-β-环糊精的透明质酸钠的磷酸缓冲液,反应,得到全甲基化β-环糊精修饰的透明质酸。
6.根据权利要求4所述的制备方法,其特征在于,所述卟啉前药的制备方法具体为:
将氨基丙烯酸酯键修饰的抗肿瘤药物分子与单羧基苯基卟啉在催化剂的作用下进行酯化反应,得到光氧化活性官能团修饰的抗肿瘤药物分子。
7.根据权利要求4所述的制备方法,其特征在于,所述卟啉前药与所述全甲基化β-环糊精修饰的透明质酸的摩尔浓度比为1:2。
8.权利要求1~3所述的光活化的卟啉前药三元组装体或权利要求4~7任一项所述的制备方法所制备的光活化的卟啉前药三元组装体在制备癌症治疗药物上的应用。
9.根据权利要求8所述的应用,其特征在于,所述药物的使用方法为采用660nm激光体外照射。
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