CN114870014B - 一种多功能抗肿瘤高分子药物及其制备方法和用途 - Google Patents

一种多功能抗肿瘤高分子药物及其制备方法和用途 Download PDF

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CN114870014B
CN114870014B CN202210538970.1A CN202210538970A CN114870014B CN 114870014 B CN114870014 B CN 114870014B CN 202210538970 A CN202210538970 A CN 202210538970A CN 114870014 B CN114870014 B CN 114870014B
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孙鹏飞
杜鑫龙
何坤
蒋欣悦
范曲立
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Nanjing University of Posts and Telecommunications
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Abstract

本发明公开了一种多功能抗肿瘤高分子药物及其制备方法和用途。高分子药物由水溶性刷状结构共轭高分子在水溶液中组装而成。该水溶性刷状结构共轭高分子以聚苯并噻二唑‑芴为共轭主链、酰胺‑胺型树枝状分子为侧链，且高分子表面修饰有一氧化碳供体CORM‑401和聚乙二醇。本发明的高分子药物可以在近红外光照射下产生Ⅰ和Ⅱ型光动力，实现对肿瘤的光动力治疗。在近红外光照射下，该高分子药物还可以释放一氧化碳，实现对肿瘤的气体治疗。此外，在近红外光激发下该高分子药物还可以产生近红外二区荧光，实现对肿瘤的光学成像。

Description

一种多功能抗肿瘤高分子药物及其制备方法和用途
技术领域
本发明属于高分子药物诊疗制剂技术领域，具体涉及一种多功能抗肿瘤高分子药物及其制备方法和用途，旨在提高肿瘤高分子药物的水溶性、光动力治疗效果和近红外二区荧光能力，同时具备光激发的气体治疗肿瘤效果。
背景技术
肿瘤是影响人类健康的第一大重要疾病，目前肿瘤的治疗方法主要为化学药物和放射治疗，然而这两种传统的治疗方法对人体存在极大的副作用。近二十年来，科学家发展了多种抗肿瘤新技术，如光动力治疗、光热治疗和基于一氧化碳或一氧化氮等的气体治疗，同时多种治疗方法联合协同治疗也成为目前癌症治疗研究的重点。其中基于光动力治疗和一氧化碳气体的联合治疗最为吸引大家的关注。在此联合治疗中，在光照条件下可以同步产生光动力和释放一氧化碳。然而，目前的光动力治疗高分子大多只具备Ⅱ型光动力的特征，严重限制了乏氧肿瘤的治疗效果。
近红外二区荧光成像技术具有优异的成像分辨率、高的信噪比和穿透深度高等特点，从而受到科研和医疗工作者的广泛关注。有机高分子的近红外二区荧光成像材料具备更为优异的生物安全性和可修饰性而成为最具发展潜力的一种造影剂。但是，目前报道的高分子近红外二区荧光造影剂大多只具备光热治疗特征。大多不能在近红外光激发下产生满意的Ⅰ和Ⅱ型光动力特性。因此，新型高分子抗肿瘤药物制剂需要具备优异的近红外二区荧光成像特性、在近红外光激发下可以产生Ⅰ和Ⅱ型光动力治疗，并且能够负载有丰富的一氧化碳供体实现一氧化碳的气体治疗。
发明内容
发明目的：本发明的目的在于提供一种多功能高分子抗肿瘤药物及其制备方法和用途，以解决现有技术中近红外二区荧光成像高分子材料没有Ⅰ和Ⅱ型光动力治疗效果、一氧化碳供体负载效率低的问题。
技术方案：为解决上述技术问题，本发明采用的技术方案为：
一种高分子药物，由一种水溶性刷状结构共轭高分子在水溶液中组装而成，所述水溶性刷状结构共轭高分子以聚苯并噻二唑-芴(PBF)为共轭主链、酰胺-胺型树枝状分子为侧链，且高分子表面修饰有一氧化碳供体CORM-401和聚乙二醇。
进一步地，所述水溶性刷状结构共轭高分子的结构式如下：
Figure BDA0003649712180000031
其中，共轭高分子主链的重复单元数n为5-10，高分子表面聚乙二醇分子量为2000、5000或10000克/摩尔，CORM-401含量重量比为1％-5％。
进一步地，所述高分子药物中，水溶性刷状结构共轭高分子的浓度为0.5毫克～5毫克/毫升。
进一步地，所述水溶性刷状结构共轭高分子根据以下步骤制备：
将PBF-AM3、聚乙二醇和CORM-401溶于EDC和NHS中得到混合物，通过鼓泡脱氧后，混合物在50℃下搅拌48小时，之后旋转蒸发除去EDC和NHS，然后将产品溶于THF，透析后冻干得到。
本发明还提供了前述的高分子药物的制备方法，包括：在搅拌条件下将所述水溶性刷状结构共轭高分子的有机溶液加入水中，通过自组装形成高分子药物。
进一步地，制备过程中，将所述水溶性刷状结构共轭高分子先溶于极性有机溶剂，所述有机溶剂为二甲基亚砜和N,N-二甲基甲酰胺中的一种或两种。
本发明还提拱了前述的高分子药物作为Ⅰ和Ⅱ型光动力治疗剂、一氧化碳气体治疗剂的应用。
进一步地，当所述高分子药物作为光动力治疗剂时，所用激光的波长范围在600-808纳米之间。
本发明还提拱了前述的高分子药物作为近红外二区荧光成像造影剂的应用。
本发明还提拱了前述的高分子药物在制备治疗肿瘤疾病的药物中的应用。
有益效果：1.本发明的高分子药物制备方法简单，由一种水溶性刷型结构共轭高分子通过自组装而成；2、本发明的高分子药物具有良好的水溶性和生物相容性，在近红外光源照射下可实现红外二区荧光成像介导的Ⅰ和Ⅱ光动力/一氧化碳气体协同治疗，使高分子药物多功能化；3、本发明的高分子药物中通过共价键负载一氧化碳供体CORM-401，该供体对光动力产生的自由基比较敏感，使得该高分子药物可在近红外光照射下同步产生Ⅰ和Ⅱ型光动力和一氧化碳气体，实现抗肿瘤治疗；4、本发明的高分子药物除了用作治疗剂外，还可进行红外二区荧光成像，为肿瘤治疗过程的实时诊断提供指导；5、本发明的高分子药物在600-808纳米波长的近红外光源照射下可产生Ⅰ和Ⅱ光动力治疗效果，比现在报道的激发波长更宽、更长。
附图说明
图1为本发明实施例1制备的高分子药物的透射电镜照片；
图2为本发明实施例1制备的高分子药物的动态光散射测得的流体力学粒径图；
图3为本发明实施例1制备的高分子药物在660纳米光源下产生一氧化碳气泡的实物图；
图4为本发明实施例1制备的高分子药物在660纳米光源照射下产生Ⅰ光动力的曲线图；
图5为本发明实施例1制备的高分子药物在660纳米光源照射下产生Ⅱ光动力的曲线图；
图6为本发明实施例1制备的高分子药物的发射光谱图；
图7为本发明实施例2制备的高分子药物在808纳米光源照射下产生Ⅰ光动力的曲线图；
图8为本发明实施例2制备的高分子药物在808纳米光源照射下产生Ⅱ光动力的曲线图；
图9为本发明实施例2制备的高分子药物在740纳米光源照射下产生Ⅰ光动力的曲线图；
图10为本发明实施例2制备的高分子药物在740纳米光源照射下产生Ⅱ光动力的曲线图；
图11为本发明实施例2制备的高分子药物对4T1肿瘤小鼠模型的近红外二区成像图；
图12为本发明实施例1制备的高分子药物在660纳米光源照射下产生一氧化碳的曲线图；
图13为本发明实施例2制备的高分子药物在660纳米光源照射下在细胞内产生一氧化碳的照片；
图14为本发明实施例1制备的高分子药物在660纳米光源照射下对细胞治疗的MTT表征图。
具体实施方式
下面结合具体实施例对本发明作进一步描述。以下实施例仅用于更加清楚地说明本发明的技术方案，而不能以此来限制本发明的保护范围。
本发明实施例提供了一种高分子药物，由一种水溶性刷状结构共轭高分子在水溶液中组装而成。其中，水溶性刷状结构共轭高分子制备如下：
1、PBF-AM3的合成
合成路线为：
Figure BDA0003649712180000061
Figure BDA0003649712180000071
具体合成过程如下：
(i)PBF-Br的合成
将BBT(35.2mg，0.1mmol)、TF(123.5mg，0.1mmol)、Pd2(dba)3(三(二亚苄基丙酮)二钯)(1.0mg，0.0032mmol)，P(o-Tol)3(三-o-甲苯基膦)(4.0mg，0.0044mmol)和无水甲苯(4.0mL)加入到10mL的聚合瓶中，鼓泡除氧后在100℃和氮气保护下搅拌24h。结束反应后，冷却至室温，用甲醇沉降得到墨绿色固体68.5mg，产率约为78.1％。
(ii)PBF-N3的合成
将PBF-Br(87.7mg，0.1mmol)和NaN3(15.6mg，0.1mmol)加入到10mL的圆底烧瓶中，然后加入5.0mL DMF并加热到50℃搅拌12h。结束反应后，冷却至室温，用甲醇沉降得到黑绿色固体63.1mg，产率约为80.3％。
(iii)PBF-AM2.5的合成
将PBF-N3(78.6mg，0.1mmol)、PAMAM2.5(285.7mg，0.2mmol)、TBTA(212.2mg，0.4mmol)和CuTc(噻吩-2-甲酸铜(I))(76.3mg，0.4mmol)加入到25mL的圆底烧瓶中，然后加入THF(15.0mL)，鼓泡除氧后在室温下搅拌12h。反应结束后，用Da＝3500透析袋透析，透析72h后冻干，得棕红色固体。
(iv)PBF-AM3的合成
将PBF-AM2.5(364.3mg，0.1mmol)和N-叔丁氧羰基-1,3-丙二胺(278.7mg，1.6mmol)加入到25mL的圆底烧瓶中，然后加入10.0mL甲醇，鼓泡除氧后在50℃下搅拌48h。反应结束后，旋蒸，除掉有机溶剂，得粗产物。
(v)将粗产物用二氯甲烷(DCM)(5.0mL)溶解后，加入三氟乙酸(TFA)脱保护，室温搅拌48h。反应结束后，旋蒸，然后将产物用THF(10.0mL)溶解，并用Da＝3500透析袋透析，透析72h后冻干，得棕红色固体。
2、水溶性刷状结构共轭高分子(PBF-g-CO/PEG)的合成
合成路线为：
Figure BDA0003649712180000091
具体合成过程如下：
该合成过程仅以聚乙二醇2000分子量为例说明：
将PBF-AM3(10毫克，0.3毫摩尔)、聚乙二醇(28毫克，0.12毫摩尔)和CORM-401(4毫克，12毫摩尔)加入到25毫升的圆底烧瓶中，然后加入EDC(1-乙基-(3-二甲基氨基丙基)碳酰二亚胺)(4.6毫克)和NHS(N-羟基琥珀酰亚胺)(2.76毫克)。通过鼓泡脱氧后，混合物在50℃下搅拌48小时，之后旋转蒸发除去EDC和NHS，然后将产品溶于THF(10毫升)，用Da＝3500透析袋透析，透析后冻干72小时，得到棕色固体。
调整上述步骤中共轭高分子聚苯并噻二唑-芴(PBF)主链嵌段重复单元数，即可得到共轭高分子主链的重复单元数n为5-10的水溶性刷状结构共轭高分子。调整上述步骤中的聚乙二醇的分子量，即可得到不同聚乙二醇修饰的水溶性刷型结构共轭高分子。调整上述步骤中的一氧化碳供体CORM-401的投料比，即可得到不同CORM-401含量的水溶性刷型结构共轭高分子。
实施例1:
将聚乙二醇分子量为5000、CORM-401含量为1％的水溶性刷型结构共轭高分子溶解于二甲基亚砜中20毫克/毫升，在搅拌条件下将5.0毫升水溶性刷型结构共轭高分子的二甲基亚砜溶液加到5.0毫升水中，透析一天后调节水溶液浓度为5毫克/毫升，便得到高分子药物。
图1为本实施例所得高分子药物的透射电镜照片，由图1可以看到在该配比下得到粒径在150至170纳米范围的高分子药物颗粒。
图2为本实施例所得高分子药物的动态光散射测得的流体力学粒径，所得结果与透射电镜结果相符合。
图3为本实施例所得高分子药物在660纳米光源下产生一氧化碳气泡的实物图，可在比色皿壁上明显观察到许多微小一氧化碳气泡。
图4和图5分别为本实施例所得高分子药物在660纳米光源照射下产生Ⅰ光动力和Ⅱ光动力的曲线。可以看出，本实施例制备的高分子药物可以在660纳米的近红外光照射下产生Ⅰ和Ⅱ型光动力，其可以作为对肿瘤的Ⅰ和Ⅱ型光动力治疗剂。
图6为本实施例所得高分子药物的发射光谱图，可以看出，发射峰在1000纳米以上，具有明显的二窗荧光发射。
图12为本发明实施例1制备的高分子药物在660纳米光源照射下产生一氧化碳的曲线图，在光源照射下释放的CO诱导的羰基化反应使得COP-1探针产生了明亮的荧光。
图14为本发明实施例1制备的高分子药物在660纳米光源照射下对细胞治疗的MTT表征，在光源照射下高分子纳米药物同时通过Ⅰ和Ⅱ型光动力治疗和一氧化碳治疗对4T1肿瘤细胞产生治疗，可以看出，随着高分子药物浓度的增加，肿瘤细胞生存率明显下降。
实施例2:
将聚乙二醇分子量为2000、CORM-401含量为5％的水溶性刷型结构共轭高分子溶解于二甲基亚砜中10毫克/毫升，在搅拌条件下将5.0毫升水溶性刷型结构共轭高分子的二甲基亚砜加到10.0毫升中，透析一天后调节水溶液浓度为2毫克/毫升，便得到高分子药物。
图7和图8分别为本实施例所得高分子药物在808纳米光源照射下产生Ⅰ光动力和Ⅱ光动力的曲线。由图中可以看出，本实施例制备的高分子药物可以在808纳米的近红外光照射下产生Ⅰ和Ⅱ型光动力。
图9和图10分别为本实施例所得高分子药物在740纳米光源照射下产生Ⅰ光动力和Ⅱ光动力的曲线。由图中可以看出，本实施例制备的高分子药物在740纳米的近红外光照射下同样可以产生Ⅰ和Ⅱ型光动力。
图11为本实施例所得高分子药物对4T1肿瘤小鼠模型的近红外二区成像图，尾静脉注射200微升，用近红外二区成像仪观察其小鼠肿瘤位置的信号强度变化图。可以看出，随着时间的延长，肿瘤的成像越来越明显，在24小时到达最大值，随后随时间的延长信号强度开始减弱。
图13为本实施例制备的高分子药物在660纳米光源照射下在细胞内产生一氧化碳照片。在光源照射8分钟后，在4T1细胞中检测到微弱的绿色荧光，证明有CO气体被释放，随着光照时间增加到15分钟，CO释放增多，细胞内出现明亮的绿色荧光。
由上述实施例可以看出，本发明的高分子药物可以作为近红外二区荧光成像造影剂、Ⅰ和Ⅱ型光动力治疗光敏剂和一氧化碳气体治疗的药物供体。本发明的高分子药物可以在近红外光照射下产生Ⅰ和Ⅱ型光动力，实现对肿瘤的光动力治疗，在近红外光照射下该高分子药物还可以释放一氧化碳，实现对肿瘤的气体治疗。此外，在近红外光激发下该高分子药物还可以产生近红外二区荧光，实现对肿瘤的光学成像，为肿瘤治疗过程的实时诊断提供指导。
以上已以较佳实施例公布了本发明，然其并非用以限制本发明，凡采取等同替换或等效变换的方案所获得的技术方案，均落在本发明的保护范围内。

Claims (9)

1.一种高分子药物，其特征在于，由一种水溶性刷状结构共轭高分子在水溶液中组装而成，所述水溶性刷状结构共轭高分子以聚苯并噻二唑-芴为共轭主链、酰胺-胺型树枝状分子为侧链，且高分子表面修饰有一氧化碳供体CORM-401和聚乙二醇；
所述水溶性刷状结构共轭高分子的结构式如下：
Figure FDA0004216102080000011
其中，共轭高分子主链的重复单元数n为5-10，高分子表面聚乙二醇分子量为2000、5000或10000克/摩尔，CORM-401含量重量比为1％-5％。
2.根据权利要求1所述的高分子药物，其特征在于，所述水溶性刷状结构共轭高分子的浓度为0.5毫克～5毫克/毫升。
3.根据权利要求1所述的高分子药物，其特征在于，所述水溶性刷状结构共轭高分子根据以下步骤制备：
将PBF-AM3、聚乙二醇和CORM-401溶于EDC和NHS中得到混合物，通过鼓泡脱氧后，混合物在50℃下搅拌48小时，之后旋转蒸发除去EDC和NHS，然后将产品溶于THF，透析后冻干得到。
4.如权利要求1-3任一项所述的高分子药物的制备方法，其特征在于，包括：在搅拌条件下将所述水溶性刷状结构共轭高分子的有机溶液加入水中，通过自组装形成高分子药物。
5.根据权利要求4所述的高分子药物的制备方法，其特征在于，制备过程中，将所述水溶性刷状结构共轭高分子先溶于极性有机溶剂，所述有机溶剂为二甲基亚砜和N,N-二甲基甲酰胺中的一种或两种。
6.如权利要求1-3任一项所述的高分子药物在制备Ⅰ和Ⅱ型光动力治疗剂、一氧化碳气体治疗剂的药物中的应用。
7.根据权利要求6所述的应用，其特征在于，当所述高分子药物作为光动力治疗剂时，所用激光的波长范围在600-808纳米之间。
8.如权利要求1-3任一项所述的高分子药物在制备近红外二区荧光成像造影剂的药物中的应用。
9.如权利要求1-3任一项所述的高分子药物在制备治疗肿瘤疾病的药物中的应用。
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