CN114887055B - 一种糖靶向具有mr/nir显像和光动力治疗功能的诊疗一体化制剂及其制备方法和应用 - Google Patents
一种糖靶向具有mr/nir显像和光动力治疗功能的诊疗一体化制剂及其制备方法和应用 Download PDFInfo
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Abstract
本发明公开了一种糖靶向具有MR/NIR显像和光动力治疗功能的诊疗一体化制剂及其制备方法和应用。将Pyro‑NHS和Amine‑Sia溶于N,N‑二甲基甲酰胺(DMF),然后加入三乙胺，室温搅拌反应，之后真空减压除去DMF，然后通过硅胶色谱柱纯化得到Pyro‑Sia；将Pyro‑Sia溶于DMF，然后加入水合醋酸钆，加热搅拌反应，反应后，真空减压除去DMF，然后通过硅胶色谱柱纯化得到GdPyro‑Sia。本发明所得的GdPyro‑Sia在制备核磁共振显像和荧光显像双模态显像及光动力治疗药物中具备良好的应用前景。
Description
技术领域
本发明属于医学诊疗一体化领域，具体涉及一种糖靶向具有MR/NIR显像和光动力治疗功能的诊疗一体化制剂及其制备方法和应用。
背景技术
恶性肿瘤是严重威胁人类健康的疾病，随着肿瘤发病率的升高，寻找新的治疗方式具有十分重要的临床意义。光动力疗法(PDT)是目前一种较为理想的治疗方式。
焦脱镁叶绿素-a(Pyropheophorbide a,Pyro)化学结构稳定，制备过程简单，具有优良的单线态氧产生能力，是一个有临床应用潜力的光敏剂分子。因为光敏剂产生的单线态氧只能在纳米距离内造成损伤，所以PDT过程中光敏剂的位置至关重要。研究者们发现破坏关系细胞器能够提高PDT效率。溶酶体作为重要细胞器，负责回收破旧的细胞大分子和受损细胞器，以及消化通过内吞，自噬和吞噬等作用进入细胞的外来异物，对于维持细胞稳态至关重要。因此，有效诱导细胞器内部产生活性氧会诱导细胞死亡。据报道，由于肿瘤的嗜糖性，9位修饰疏水官能团的唾液酸可以靶向肿瘤，并定位肿瘤细胞的溶酶体。
参考文献：
(1)Lin,B.；Wu,X.；Zhao,H.；Tian,Y.；Han,J.；Liu,J.；Han,S.,Redirectingimmunity via covalently incorporated immunogenic sialic acid on the tumorcell surface.Chem.Sci.2016,7,3737-3741.
(2)Wang,J.；Liu,Q.；Zhang,Y.；Shi,H.；Liu,H.；Guo,W.；Ma,Y.；Huang,W.；Hong,Z.,Folic Acid-Conjugated Pyropheophorbide a as the Photosensitizer Tested forIn Vivo Targeted Photodynamic Therapy.J.Pharm.Sci.2017,106,1482-1489.
基于如上背景，设计合成了一种唾液酸(Sialic acid,Sia)为靶向，螯合Gd3+的光敏剂(Pyro)进行核磁共振显像和荧光显像双模态显像及光动力治疗作用的分GdPyro-Sia。
发明内容
本发明的目的在于克服现有技术的不足，提供了一种糖靶向具有MR/NIR显像和光动力治疗功能的诊疗一体化制剂及其制备方法和应用。该肿瘤诊疗一体化制剂具有MR/NIR双模态成像及光动力治疗功能。
本发明的糖靶向具有MR/NIR显像和光动力治疗功能的诊疗一体化制剂的制备方法包括如下步骤：
本发明首先提供了一种糖靶向具有MR/NIR显像和光动力治疗功能的诊疗一体化制剂的制备方法，其包括如下步骤：
1)将Pyro-NHS和Amine-Sia溶于N,N-二甲基甲酰胺(DMF),然后加入三乙胺，室温搅拌反应，之后真空减压除去DMF，然后通过硅胶色谱柱纯化得到Pyro-Sia；
2)将Pyro-Sia溶于DMF，然后加入水合醋酸钆，加热搅拌反应，反应后，真空减压除去DMF，然后通过硅胶色谱柱纯化得到GdPyro-Sia。
作为本发明的优选方案，所述的Pyro-NHS和Amine-Sia的摩尔比为1：1-1：3。
作为本发明的优选方案，所述的Pyro-NHS与三乙胺的摩尔比为1：3。
作为本发明的优选方案，所述的步骤1)中，室温搅拌反应的时间为24h。
作为本发明的优选方案，步骤2)中，Pyro-Sia与水合醋酸钆的摩尔比为1:3。
作为本发明的优选方案，步骤2)中，加热搅拌反应的反应温度为50℃，反应时间为24h。
本发明还提供了一种上述方法制备得到的糖靶向具有MR/NIR显像和光动力治疗功能的诊疗一体化制剂。
本发明还提供了上述的糖靶向具有MR/NIR显像和光动力治疗功能的诊疗一体化制剂在制备核磁共振显像和荧光显像双模态显像及光动力治疗药物中的应用。
与现有技术相比，本发明所具有的有益效果有：
(1)将具有荧光的卟啉类光敏剂和具有核磁共振信号的钆离子结合，得到MR/NIR双模态显像剂，克服现有光敏剂依靠单纯的荧光显像空间分辨率低的问题。
(2)将MR/NIR双模态显像剂与唾液酸结合，可以实现荷瘤模型鼠中的HepG2肿瘤良好定位，荧光和核磁共振双模态显像清晰，可更好的指导光动力学治疗中的激光照射。
(3)该双模态显像剂兼具光敏性能，外源660nm激光照射可抑制荷瘤模型鼠中HepG2肿瘤生长。
附图说明
图1为Pyro-Sia和GdPyro-Sia的紫外吸收光谱；
图2为Pyro-Sia和GdPyro-Sia的荧光发射光谱
图3由左至右，分别为注射前、注射后0.5h、2h、4h、6h、12h的MR图；
图4由左至右分别是注射前、注射后2h、6h、12h、24h的NIR图。
图5为分组治疗第14天的情况。
具体实施方式
下面结合具体实施方式对本发明做进一步阐述和说明。所述实施例仅是本公开内容的示范且不圈定限制范围。本发明中各个实施方式的技术特征在没有相互冲突的前提下，均可进行相应组合。
一、材料制备及表征
GdPyro-Sia的合成路线：
将Pyro-NHS(76.0mg,0.12mmol)和Amine-Sia(31.0mg,0.1mmol)溶于1mL N,N-二甲基甲酰胺(DMF),然后加入三乙胺(30.5mg,0.3mmol)，室温搅拌6小时之后真空减压除去DMF，然后通过硅胶色谱柱纯化以产率72％得到60mg Pyro-Sia。
将Pyro-Sia(10.0mg,0.012mmol)溶于4mL DMF,然后加入水合醋酸钆(12.7mg,0.036mmol),加热50度搅拌24小时之后，真空减压除去DMF，然后通过硅胶色谱柱纯化得到GdPyro-Sia。
Pyro-Sia和GdPyro-Sia的紫外吸收和荧光发射光谱图如图1和2所示。从图中可见，与Pyro-Sia相比，GdPyro-Sia保留了紫外吸收和荧光发射能力。
二、GdPyro-Sia对HepG2皮下荷瘤小鼠模型MR显像
用6周大的雌性BALB/c裸小鼠构建HepG2皮下荷瘤模型。随后饲养一周待肿瘤大小约为v≈200mm3进行显像研究。对建立的HepG2皮下荷瘤模型小鼠进行MR显像，每只老鼠尾静脉注射200nmol GdPyro-Sia，于注射后0.5h、2h、4h、6h、12h行MR成像，如图3所示，肿瘤部位MR信号较注射前强，肿瘤显示清晰，至12h，肿瘤部位信号仍较注射前强。
三、GdPyro-Sia对HepG2皮下荷瘤小鼠模型NIR显像
HepG2皮下荷瘤模型小鼠的制备、显像条件同上。由图4所示，肿瘤部位荧光信号较注射前强，肿瘤显示清晰，至12h，肿瘤部位信号仍较注射前强。
四、GdPyro-Sia对HepG2皮下荷瘤小鼠模型PDT
HepG2皮下荷瘤模型小鼠的制备。当接种的皮下瘤体积达到约80-120mm3时，小鼠被随机分为4组，每组3只小鼠。(1)注射100μL PBS，(2)注射100μL GdPyro-Sia的PBS溶液(浓度为2mmol/L)组，(3)注射100μLPBS+Light(激光)，(4)注射100μL GdPyro-Sia的PBS溶液(浓度为2mmol/L)+Light(激光)。在注射后2小时，使用波长660nm，激光功率为300mW/cm2，照射肿瘤15分钟，继续饲养14天后观察肿瘤大小结果，如图5所示，在PBS组、GdPyro-Sia组和PBS+Light(激光)组肿瘤快速生长，而在GdPyro-Sia+Light组肿瘤体积得到明显抑制。
以上所述实施例仅表达了本发明的几种实施方式，其描述较为具体和详细，但并不能因此而理解为对本发明专利范围的限制。对于本领域的普通技术人员来说，在不脱离本发明构思的前提下，还可以做出若干变形和改进，这些都属于本发明的保护范围。
Claims (8)
1.一种具有MR/NIR显像和光动力治疗功能的诊疗一体化制剂的制备方法，其特征在于包括如下步骤：
1）将Pyro-NHS和Amine-Sia溶于N,N-二甲基甲酰胺（DMF）, 然后加入三乙胺，室温搅拌反应，之后真空减压除去DMF，然后通过硅胶色谱柱纯化得到Pyro-Sia；
2）将Pyro-Sia溶于DMF，然后加入水合醋酸钆， 加热搅拌反应，反应后，真空减压除去DMF，然后通过硅胶色谱柱纯化得到GdPyro-Sia；
所述Pyro为焦脱镁叶绿酸-a；所述Sia为唾液酸。
2.根据权利要求1所述的制备方法，其特征在于，所述的Pyro-NHS和Amine-Sia的摩尔比1：1-1：3。
3.根据权利要求1所述的制备方法，其特征在于，所述的Pyro-NHS与三乙胺的摩尔比为1：3。
4.根据权利要求1所述的制备方法，其特征在于，所述的步骤1）中，室温搅拌反应的时间为16 h。
5.根据权利要求1所述的制备方法，其特征在于，步骤2）中，Pyro-Sia与水合醋酸钆的摩尔比为1:3。
6.根据权利要求1所述的制备方法，其特征在于，步骤2）中，加热搅拌反应的反应温度为50℃，反应时间为24 h。
7.一种权利要求1-6任一项所述方法制备得到的具有MR/NIR显像和光动力治疗功能的诊疗一体化制剂。
8.权利要求7所述的具有MR/NIR显像和光动力治疗功能的诊疗一体化制剂在制备核磁共振显像和荧光显像双模态显像及光动力治疗药物中的应用。
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