CN113893344A - 一种可光控金属离子递送颗粒及其制备方法与应用 - Google Patents
一种可光控金属离子递送颗粒及其制备方法与应用 Download PDFInfo
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Abstract
Description
技术领域
本发明涉及生物医学材料技术领域,尤其涉及一种可光控金属离子递送颗粒及其制备方法与应用。
背景技术
恶性肿瘤已成为目前全民健康的重要威胁,每年发病人数和致死病例都在不断增加。然而,恶性肿瘤的治疗方法有限,容易产生耐药性,因此,亟待开发新的治疗方式。近年来,化学动力学治疗(CDT)作为一种新兴的肿瘤治疗方式,引起了广泛的关注。CDT利用铁、铜等金属离子催化肿瘤微环境中双氧水,产生高毒性的羟基自由基(·OH)以杀死肿瘤细胞。在众多金属离子中,亚铁离子(Fe2+)活性最高,但其反应需要在pH=2-4的强酸性条件下才能达到最大效率。亚铜离子(Cu+)在弱酸性和中性条件下的催化效率是相同条件下亚铁离子催化反应效率的160倍。相比于亚铁离子的递送策略,亚铜离子的抗肿瘤治疗具有更大的应用潜力。然而,Cu2+/Cu+(~0.16V)的氧化还原电位非常低,Cu+极容易被氧化成Cu2+而失去催化活性。特别是在水溶液中,Cu+会发生歧化反应,生成Cu2+和单质铜,不能稳定存在。而直接递送Cu2+用于CDT治疗则必须经过还原后才能产生芬顿催化活性,这个过程对于高还原水平的肿瘤会有一定的效果,但是对于低还原水平的肿瘤而言,Cu2+抗肿瘤的效果就非常有限。因此如何在活体水平高效递送高活性的Cu+实现肿瘤CDT效果是一个巨大挑战。
因此,现有技术还有待于改进和发展。
发明内容
鉴于上述现有技术的不足,本发明的目的在于提供一种可光控金属离子递送颗粒及其制备方法与应用,旨在解决亚铜离子用于肿瘤化学动力学治疗的稳定性较差的问题。
本发明第一方面,提供一种可光控金属离子递送颗粒,其包括有机小分子配体和通过配位作用结合在所述有机小分子配体上的金属离子,所述有机小分子配体的化学结构式为:其中R为甲基、乙基和苄基中的一种;所述金属离子为铜离子或亚铜离子。
可选地,所述可光控金属离子递送颗粒的水合粒径为100-200nm。
本发明第二方面,提供一种如上所述可光控金属离子递送颗粒的制备方法,其中,包括步骤:将有机小分子配体溶于有机相中,加入金属离子混匀,再加入两亲性聚乙二醇类化合物进行第一预定时间的超声处理,得到反应产物;
向所述反应产物中加入超纯水后进行第二预定时间的超声处理,之后依次进行旋转蒸发、过膜、超滤离心以及水洗处理,得到所述可光控金属离子递送颗粒。
可选地,所述有机相为二氯甲烷、氯仿和四氢呋喃中的一种或多种。
可选地,所述金属离子的加入质量为所述有机小分子配体质量的8-12倍。
可选地,所述第一预定时间为20-35s;所述第二预定时间为4-6min。
可选地,所述两亲性聚乙二醇类化合物为DSPE-PEG2000。
本发明第三方面,提供一种如上所述可光控金属离子递送颗粒在制备诊断和/或治疗肿瘤的药剂中的应用。
可选地,所述诊断肿瘤的药剂为荧光成像药剂或光声成像药剂。
可选地,所述治疗肿瘤的药剂为光动力学治疗和化学动力学联用药剂。
可选地,所述药剂的剂型为胶囊剂、片剂、口服制剂、注射剂、栓剂、喷雾剂或软膏剂。
附图说明
图1为本发明一种可光控金属离子递送颗粒的制备方法流程图。
图2a为结合亚铜离子的递送系统自组装形成纳米颗粒(LC1)的透射电镜图及对应的水合粒径图。
图2b为结合铜离子的递送系统自组装形成纳米颗粒(LC2)的透射电镜图及对应的水合粒径图。
图3a为离子递送系统结合亚铜离子自组装形成纳米颗粒前后的紫外吸收谱变化图。
图3b为离子递送系统结合铜离子自组装形成纳米颗粒前后的紫外吸收谱变化图。
图4为离子递送系统结合两种不同价态铜离子的X-射线光电子能谱图,其中a为结合亚铜离子的X-射线光电子能谱图;b为结合铜离子的X-射线光电子能谱图;c为两种纳米颗粒的X-射线光电子能谱局部放大的对比图。
图5为结合不同价态铜离子的递送系统的光动力效果评价图。
图6a为两种价态铜离子递送系统产生羟基自由基的效率图。
图6b为LC1在不同功率的660nm激光照射下产生羟基自由基的效率图。
图6c为不同浓度LC1产生羟基自由基的效率图。
图7为电子顺磁共振谱检测LC1、LC2产生的羟基自由基和单线态氧
图8为LC1、LC2分别与4T1细胞孵育后的细胞存活率变化图。
图9中a-b为LC1、LC2在荷瘤小鼠体内的荧光成像随时间变化过程图;图9中c-d为LC1、LC2在荷瘤小鼠体内的光声成像随时间变化过程图。
图10中a为LC1、LC2在4T1荷瘤小鼠模型上的治疗效果评价图;b为治疗结束后小鼠肿瘤重量统计图;c为小鼠各治疗组在治疗期间的体重变化图。
具体实施方式
本发明提供一种可光控金属离子递送颗粒及其制备方法与应用,为使本发明的目的、技术方案及效果更加清楚、明确,以下对本发明进一步详细说明。应当理解,此处所描述的具体实施例仅仅用以解释本发明,并不用于限定本发明。
研究发现,含氮有机配体与铜离子形成稳定配合物后可以保护其价态稳定,有望实现Cu+在递送过程中的稳定性。此外,肿瘤疗效监测常需要借助成像诊断来实现精准的诊疗一体化,鉴于有机分子结构多变,因此有望实现其多功能化。例如,将具有光学成像功能的花菁母体分子与三联吡啶配体结合,可以实现递送Fe2+的同时具有荧光和光声成像的能力。既利用了荧光成像的高灵敏性和选择性,又结合光声成像高分辨率和深度组织穿透,实现了肿瘤治疗的诊疗一体化。
基于此,本发明提供了一种可光控金属离子递送颗粒,其包括有机小分子配体和通过配位作用结合在所述有机小分子配体上的金属离子,所述有机小分子配体的化学结构式为:其中R为甲基、乙基和苄基中的一种;所述金属离子为铜离子或亚铜离子。
本实施例利用N,N-双吡啶甲基二胺基团与花菁母体分子结构结合,制得所述有机小分子配体,所述有机小分子配体上的N可与铜离子或亚铜离子通过配位作用结合在一起。具体来讲,所述有机小分子配体上的吡啶中的N以及连接两个吡啶的N可与所述铜离子或亚铜离子配位结合,其具体的结合方式如下所示:
本实施例中,所述有机小分子配体可以保持金属离子价态稳定,并通过纳米自组装技术将金属离子递送到肿瘤部位;此外,有机小分子配体还兼具光敏剂的功能,可以实现先光动力治疗再化学动力学治疗的目的,因此可实现肿瘤部位的精准光控释放离子,减少全身毒性;这种新型递送药物的方式为肿瘤协同治疗提供了新的策略。因此,本实施例提供的可光控金属离子递送颗粒可实现荧光/光声成像指导下的亚铜离子、铜离子精准递送和肿瘤治疗。
在一些实施方式中,所述可光控金属离子递送颗粒的水合粒径为100-200nm。
在一些实施方式中,还提供一种所述可光控金属离子递送颗粒的制备方法,如图1所示,其包括步骤:
S10、将有机小分子配体溶于有机相中,加入金属离子混匀,再加入两亲性聚乙二醇类化合物进行第一预定时间的超声处理,得到反应产物;
S20、向所述反应产物中加入超纯水后进行第二预定时间的超声处理,之后依次进行旋转蒸发、过膜、超滤离心以及水洗处理,得到所述可光控金属离子递送颗粒。
在本实施例中,所述有机相为易挥发有机溶剂,作为举例,所述有机相可以为二氯甲烷、氯仿和四氢呋喃中的一种或多种,但不限于此;所述两亲性聚乙二醇类化合物为DSPE-PEG2000,但不限于此。
在本实施例中,为保证所述金属离子均能够结合在所述有机小分子配体上,所述金属离子的加入质量为所述有机小分子配体质量的8-12倍。
在本实施例中,所述第一预定时间为20-35s;所述第二预定时间为4-6min。
在本实施例中,所述过膜处理所用的PES膜孔径为220μm,过膜处理后将反应产物转移至30kD的超滤管中进行离心处理,离心条件为3000-4000转/min,离心时间为15分钟,离心后进行水洗处理,最后将得到的可光控金属离子递送颗粒在4℃条件下避光保存。
本实施例提供的可光控金属离子递送颗粒的制备方法合成简单,合成条件不苛刻,操作方便,可以用于大规模生产。
在一些实施方式中,还提供一种上所述可光控金属离子递送颗粒的应用,将所述可光控金属离子递送颗粒用于制备诊断和/或治疗肿瘤的药剂。
本实施例中,所述诊断肿瘤的药剂为荧光成像药剂或光声成像药剂,但不限于此;所述治疗肿瘤的药剂为光动力学治疗和化学动力学联用药剂。本实施例中的有机小分子配体可以保持金属离子价态稳定,并通过纳米自组装技术将金属离子递送到肿瘤部位。此外,配体分子还兼具光敏剂的功能,可以实现先光动力治疗再化学动力学治疗的目的,因此可实现肿瘤部位的精准光控释放离子,减少全身毒性;这种新型递送药物的方式为肿瘤协同治疗提供了新的策略。
优选地,所述药剂的剂型为胶囊剂、片剂、口服制剂、注射剂、栓剂、喷雾剂或软膏剂。
下面通过具体的实施例对本发明的技术方案作进一步地说明。
实施例1:不同价态铜离子递送系统的纳米颗粒的制备
1mg配体分子溶于1mL二氯甲烷中,先加入100μL亚铜离子(20mM),超声混匀,再分别加入不同量的DSPE-PEG2000(10mg),超声30s后,将上述液体加入至5mL超纯水中,然后超声5min,旋转蒸发去除二氯甲烷,过220μm的PES膜,转移至30kD的超滤管中,离心3500转,15分钟,4℃。得到LC1,水洗两次后,4℃避光保存备用。
将亚铜离子换成等量的铜离子,后续操作步骤不变即可得到LC2,4℃避光保存备用。
图2a是所制备的结合亚铜离子递送系统形成的纳米颗粒(LC1)的透射电镜图和对应的水合粒径图;图2b是所制备的结合铜离子的离子递送系统形成的纳米颗粒(LC2)的透射电镜图和对应的水合粒径图;从图2a和图2b可以看出,所述纳米颗粒LC1和LC2均呈圆球形,其大小均一、分散均匀。
图3a显示的是有机小分子配体加入铜离子螯合前后和自组装前后的紫外吸收谱的变化,从图中可以看出,探针结合离子后发生红移,紫外吸收峰在710nm左右,自组装后紫外吸收蓝移至680nm;图3b显示的是有机小分子配体螯合铜离子后荧光信号下降,并在自组装后荧光强度进一步下降。
图4显示了LC1、LC2的X-射线光电子能谱,图4中a的拟合结果显示LC1中主要含有亚铜离子;图4中b的拟合结果显示LC2中主要含有铜离子;图4中c是其局部放大的对比图。
实施例2:不同价态铜离子递送系统的光动力效果评价
采用660nm激光器照射加入了DPBF后的纳米颗粒溶液,照射功率为0.2W/cm2,每次照射时长为10秒钟。
图5表示相同浓度(20μM)的LC1,LC2在同一光功率照射下的DPBF吸收变化图。DPBF可用于检测单线态氧(1O2),415nm处吸收值下降越快,表明产生的单线态氧越多。图5结果表明LC1比LC2能产生更强的光动力学效果。
实施例3:不同价态铜离子递送系统的化学动力学效果评价
分别对比不同浓度,不同光功率照射下不同价态铜离子递送系统的羟基自由基产生效果。具体条件如下:6mM的对苯二甲酸(TA)溶液中加入10μL 30%的过氧化氢溶液,然后分别加入LC1或LC2,各5μM,在不同光功率照射下,通过荧光分光光度计监测TA在315nm处荧光强度的变化。以及不同浓度的LC1在660nm激光0.2W/cm2功率照射时TA在315nm处荧光强度的变化;相同浓度时,不同激光功率的激光照射下TA在315nm处荧光强度的变化。
图6a表示不同价态铜离子递送系统在非光照、光照条件下产生羟基自由基的效率对比。结果显示只有LC1在经过激光照射后使得TA的荧光强度明显提高,而LC2几乎没有效果。这可能由于溶液环境中没有还原剂存在,导致铜离子无法被还原成亚铜离子,从而无法引发芬顿反应。图6b为相同激光照射条件下TA的荧光强度变化,结果表明,溶液中的亚铜离子浓度与芬顿反应效果成正比。图6c显示,对于固定浓度的LC1(5μM)在0.5W/cm2功率的660nm激光照射下,TA的荧光强度亦有增加,因此,铜离子递送纳米探针的CDT效果与浓度和激光剂量程依赖关系。
图7是不同价态铜离子递送系统的的电子顺磁共振谱,结果更加直接的证明,LC1在经过激光照射后产生了(a)单线态氧和(b)羟基自由基两种活性氧。
实施例4:不同价态铜离子递送系统的细胞水平的治疗效果评价
采用标准的MTT法,评价化学动力学/光动力治疗协同治疗作用对4T1细胞存活率的影响。小鼠乳腺癌细胞4T1细胞每孔5×103密度接种到96孔板中,并置于37℃、5%CO2条件下培育24h。接着,吸出96孔板中的旧培养基,分别加入含有0,2.5,5,10,20μM LC2或LC1的培养基溶液。继续培养24h后,然后吸出96孔板中的旧培养基,在每个孔中加入100μL含10%MTT的培养基溶液(0.5mg/mL),继续培养4h。吸出96孔板中的残余培养基,在每个孔中加入150μL DMSO溶液,轻轻摇晃后,在Synergy H1型酶标仪上检测每孔的OD值(检测波长为490nm),用如下公式计算细胞存活率。细胞存活率(cell viability)(%)=(样品的OD490值/空白OD490值)×100%。而光照组在加入含纳米颗粒的溶液后继续培养4小时后,用660nm激光器以0.2W/cm2的功率对每个孔光照5分钟,然后继续培养20小时,后续操作步骤与不照光组相同。
如图8是肿瘤细胞(4T1)对LC1、LC2的细胞存活率图。纳米颗粒的细胞暗毒性较低,但照光组在浓度达到10μM后,肿瘤细胞的存活率降低到20%以下,表明本发明的铜离子递送系统可以有效杀死肿瘤细胞,且在GSH含量低的细胞系中的递送铜离子的效果明显低于亚铜离子。
实施例5:评价不同价态铜离子递送系统在荷瘤小鼠体内的分布变化
构建小鼠的乳腺癌模型。购买雌性无胸腺裸鼠(六周,20-25g),在裸鼠右后腿皮下注射150万4T1肿瘤细胞。当肿瘤体积达80mm3时,将LC1或LC2按照5mg/kg的剂量通过尾静脉注射的方式注入小鼠体内,利用小动物荧光成像系统(IVIS Spectrum)和小动物光声成像系统(VisualSonics Vevo LAZR system),检测肿瘤区的荧光信号和光声信号随时间的变化。
如图9中a-b所示,纳米颗粒通过尾静脉注入荷瘤小鼠12h后,小鼠肿瘤的荧光强度达到最强。同时如图9中c-d所示,光声成像的信号强度也在纳米颗粒注入12h后达到峰值。成像结果表明两种不同价态铜离子递送系统均可以有效地富集到肿瘤部位。
实施例6:不同价态铜离子递送系统的活体水平治疗效果的评价
构建小鼠的乳腺癌模型。购买雌性无胸腺裸鼠(六周,20-25g),在裸鼠右后腿皮下注射150万4T1肿瘤细胞。当肿瘤体积达80mm3时,将荷瘤小鼠随机分为5组,分别为:(1)空白组;(2)LC2组;(3)LC1组;(4)LC2+激光组;(5)LC1+激光组。分别将LC1、LC2溶液按照5mg/kg的剂量通过尾静脉注射的方式注入小鼠体内,在注射12小时后对需要激光照射的组用660激光器0.2W/cm2的功率照射,每只20分钟。从给药时算起,每隔一天用游标卡尺测量肿瘤体积,并按照公式V=AB2/2计算肿瘤体积,其中A是肿瘤的长径,B是肿瘤的短径(mm)。每次测量结果均通过处理前的起始肿瘤体积归一化,并且观察每组老鼠的体重变化。实验结果见图10。
图10中a为不同治疗组肿瘤体积随时间的变化情况。LC1+激光组和LC2+激光组能够显著抑制肿瘤的生长,其中LC1更优于LC2的治疗效果。图10中b显示治疗结束后LC1组的肿瘤重量明显小于其他组,进一步表明在4T1小鼠模型中亚铜离子递送的策略明显优于铜离子。图10中c显示在治疗过程中小鼠体重没有明显变化,表明由于其光控释放特性,避免了全身毒性,铜离子递送系统有较好的生物安全性。
综上所述,本发明所述的可光控金属离子递送颗粒(铜离子递送系统)可实现不同价态铜离子递送的目的,通过本发明所述制备方法获得的可光控金属离子递送颗粒可实现荧光成像和光声成像指导的光动力学联合化学动力学肿瘤治疗。本发明提供的可光控金属离子递送颗粒可递送亚铜离子、铜离子,在肿瘤部位产生化学动力学治疗;有机小分子配体在近红外光照射下引发光动力治疗的同时释放了离子,诱发了后续化学动力学治疗,这两种治疗方式的联合可以有效抑制肿瘤生长,克服肿瘤耐药性等问题。
应当理解的是,本发明的应用不限于上述的举例,对本领域普通技术人员来说,可以根据上述说明加以改进或变换,所有这些改进和变换都应属于本发明所附权利要求的保护范围。
Claims (10)
2.根据权利要求1所述可光控金属离子递送颗粒,其特征在于,所述可光控金属离子递送颗粒的水合粒径为100-200nm。
3.一种如权利要求1-2任一所述可光控金属离子递送颗粒的制备方法,其特征在于,包括步骤:
将有机小分子配体溶于有机相中,加入金属离子混匀,再加入两亲性聚乙二醇类化合物进行第一预定时间的超声处理,得到反应产物;
向所述反应产物中加入超纯水后进行第二预定时间的超声处理,之后依次进行旋转蒸发、过膜、超滤离心以及水洗处理,得到所述可光控金属离子递送颗粒。
4.根据权利要求3所述可光控金属离子递送颗粒的制备方法,其特征在于,所述有机相为二氯甲烷、氯仿和四氢呋喃中的一种或多种。
5.根据权利要求3所述可光控金属离子递送颗粒的制备方法,其特征在于,所述金属离子的加入质量为所述有机小分子配体质量的8-12倍。
6.根据权利要求3所述可光控金属离子递送颗粒的制备方法,其特征在于,所述第一预定时间为20-35s;所述第二预定时间为4-6min。
7.根据权利要求3所述可光控金属离子递送颗粒的制备方法,其特征在于,所述两亲性聚乙二醇类化合物为DSPE-PEG2000。
8.一种如权利要求1-2任一所述可光控金属离子递送颗粒的应用,其特征在于,将所述可光控金属离子递送颗粒用于制备诊断和/或治疗肿瘤的药剂。
9.根据权利要求8所述可光控金属离子递送颗粒的应用,其特征在于,所述诊断肿瘤的药剂为荧光成像药剂或光声成像药剂。
10.根据权利要求8所述可光控金属离子递送颗粒的应用,其特征在于,所述治疗肿瘤的药剂为光动力学治疗和化学动力学联用药剂。
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CN110559302A (zh) * | 2019-08-14 | 2019-12-13 | 深圳大学 | 一种纳米诊疗剂及其制备方法与应用 |
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CN109020955A (zh) * | 2018-08-02 | 2018-12-18 | 深圳大学 | 一种分子探针、制备方法及其应用 |
CN110559302A (zh) * | 2019-08-14 | 2019-12-13 | 深圳大学 | 一种纳米诊疗剂及其制备方法与应用 |
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BAOJIN MA等: "Self-Assembled Copper−Amino Acid Nanoparticles for in Situ Glutathione "AND" H2O2 Sequentially Triggered Chemodynamic Therapy", 《J. AM. CHEM. SOC.》 * |
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