CN111569068B - 一种有机无机杂化光敏剂及杂化纳米诊疗试剂的制备方法 - Google Patents

一种有机无机杂化光敏剂及杂化纳米诊疗试剂的制备方法 Download PDF

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CN111569068B
CN111569068B CN202010407057.9A CN202010407057A CN111569068B CN 111569068 B CN111569068 B CN 111569068B CN 202010407057 A CN202010407057 A CN 202010407057A CN 111569068 B CN111569068 B CN 111569068B
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汪联辉
顾冰冰
鲍碧清
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Abstract

本发明公开了一种有机无机杂化光敏剂及杂化纳米诊疗试剂的制备方法，将具有立体笼状结构的聚倍半硅氧烷和十二长烷基链引入到卟啉光敏剂中，通过共沉淀法将光敏剂掺杂入有机半导体纳米粒子中，利用有机半导体高消光系数的特点，作为光能量给体，聚倍半硅氧烷的三维笼状结构有效抑制光敏剂卟啉聚集的同时，还能减轻有机半导体聚集引起的荧光猝灭，同时聚倍半硅氧烷上的十二长烷基链具有增强纳米粒子稳定性的效果，得到的有机无机杂化纳米诊疗剂用于高性能荧光成像指导下的癌症光动力治疗。

Description

一种有机无机杂化光敏剂及杂化纳米诊疗试剂的制备方法
技术领域
本发明具体涉及一种有机无机杂化纳米诊疗试剂的制备方法，属于肿瘤诊断和生物医学技术领域。
背景技术
近年来光动力疗法(PDT)由于其无创性，更高的治疗效率和降低全身的毒性，已成为癌症治疗的重要方案之一。当前的光敏剂主要基于卟啉，二氢卟酚及其衍生物，但是这类光敏剂的水溶性差，并且由于其π-π堆积的刚性和疏水性结构的在水溶液中显示出不令人满意的光动力功效和荧光猝灭。另外大多数传统的光敏剂总是具有低吸收截面，这需要较高的光照射功率和高浓度水平的光敏剂。目前明亮的荧光发射和有效的单线态氧生成的结合在图像引导的光动力癌症治疗和光动力抗菌治疗中具有一定性能优越性，但是光动力涉及光敏剂的激发以及随后与氧的系统间交叉相互作用以产生单线态氧，这与荧光发射过程存在争议，且通常会导致量子产率大大降低。
半导体聚合物纳米粒子以其较大的吸收系数、良好的光稳定性和优异的生物相容性，近年来在生物传感、光学成像和光疗等领域引起了广泛的关注。特别是，光捕获和高效的能量传输特性使得它们可以作为光学天线来显著放大光敏剂中的单线态氧的产生。利用这些优点，近年来有机半导体纳米粒子被用于将光敏剂分子物理封装在聚合物基体中，以克服有机光敏剂的水溶性问题，并通过能量传递放大其单线态氧的生成。
然而，当光敏剂分子被包裹在纳米颗粒中时，它们往往会形成聚集体，使整体荧光猝灭，同时也降低了单线态氧的生成能力。另外，小的光敏剂分子容易从纳米粒子中被滤出，导致纳米结构不稳定、光动力效能降低、暗毒性等问题。
发明内容
本发明的目的在于克服现有技术中的不足，提供一种有机无机杂化光敏剂及杂化纳米诊疗试剂的制备方法，制备方法简单，将荧光成像与光动力治疗相结合，增强光敏剂的光动力性能。
为达到上述目的，本发明所采用的技术方案是：
第一方面，本发明公开了一种有机无机杂化光敏剂，结构式如下：
Figure BDA0002491730400000021
其中R结构式如下：
Figure BDA0002491730400000031
第二方面，本发明公开了一种有机无机杂化纳米诊疗试剂的制备方法，包括如下制备步骤：
步骤a：以卟啉为主体光敏剂，将具有立体笼状结构的聚倍半硅氧烷和十二长烷基链引入到卟啉光敏剂中，合成有机无机杂化光敏剂；
步骤b：选取与有机无机杂化光敏剂紫外吸收谱在500-600nm处有重叠的有机半导体材料，与步骤a中的有机无机杂化光敏剂混合，共沉淀方法制备纳米粒子。
结合第二方面，所述步骤a是通过点击反应合成有机无机杂化光敏剂。
结合第二方面，可选的，所述步骤b中有机半导体材料包括有机半导体材料PFBT，其吸收波长为480nm，发射波长为560nm，分子式如下：
Figure BDA0002491730400000032
其中，n为20-30。
第三方面，本发明公开了一种有机无机杂化纳米诊疗试剂，包括上述任一所述的纳米粒子。
第四方面，本发明公开了一种有机无机杂化纳米诊疗试剂的应用，将其应用于图像引导的癌症治疗。
与现有技术相比，本发明所达到的有益效果：
(1)立体笼状结构的聚倍半硅氧烷通过共价连接到卟啉分子上，可以隔离卟啉分子间的距离，增强光敏剂的单线态氧产率；
(2)聚倍半硅氧烷上的十二长烷基链能够增强纳米粒子的稳定性，同时减轻有机半导体聚集引起的荧光猝灭；
(3)强吸光性的有机半导体作为能量给体，显著增强了光敏剂的光动力性能，同时有机半导体作为荧光成像的载体。
附图说明
图1是本发明实施例一种有机无机杂化光敏剂的分子结构式；
图2是本发明实施例有机半导体材料PFBT的分子结构式；
图3是本发明实施例一种有机无机杂化光敏剂与有机半导体材料PFBT共沉淀形成纳米粒子的紫外光谱图；
图4是本发明实施例一种有机无机杂化光敏剂与有机半导体材料PFBT共沉淀形成纳米粒子的荧光光谱图；
图5是本发明实施例一种有机无机杂化光敏剂与有机半导体材料PFBT共沉淀形成纳米粒子的光动力数据图。
具体实施方式
下面结合附图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。
实施例1
将14.4mg的乙烯基修饰的POSS基卟啉杂化光敏剂，100mg的1-十二烷基硫醇，4mg的安息香双甲醚(DMPA)混合加入500mL的圆底烧瓶中，以干燥的CH2Cl2为溶剂，通氮气15分钟以上，确保整个反应体系在惰性气体氮气的保护下反应，随即使用365nm紫外灯照射60分钟，反应结束后将滤液萃取、干燥、浓缩，并进行色谱法纯化，最终得到一种有机无机杂化光敏剂，其分子结构式如图1所示。
实施例2
如图2所示为有机半导体材料PFBT的分子结构式，选用深圳睿迅光电材料科技有限公司市售的F8BT，产品编号P1213，CAS：210347-52-7，分子量>20000，PDI<3。将实施例1中合成的有机无机杂化光敏剂与有机半导体材料共沉淀形成诊疗试剂纳米粒子，其具体制备流程如下：
a.用四氢呋喃溶解有机无机杂化光敏剂到浓度为0.1mg/mL，避光待用；
b.用四氢呋喃溶解有机半导体材料PFBT，至溶解浓度为0.1mg/mL，避光待用；
c.取1mL步骤b中的PFBT溶液和0.2mL步骤a中的光敏剂溶液混合，添加四氢呋喃至溶液体积6mL，进行超声混合均匀，取2mL溶液在超声状态下快速加入到10mL超纯水中超声7分钟，旋蒸浓缩至2mL，用0.22μm的水相过滤头过滤，得到诊疗试剂纳米粒子，避光4℃保存待用。
实施例3
如图3、图4所示，分别为一种有机无机杂化光敏剂与有机半导体材料PFBT共沉淀形成纳米粒子的紫外光谱图和荧光光谱图，准确配置3mL的诊疗试剂纳米粒子，使用紫外分光光度计去测试其紫外光谱，发现其在340nm和480nm处有有机半导体材料的两个紫外吸收峰，于是诊疗试剂纳米粒子在480nm激发下，在500-600nm会有很强的荧光发射，图示可以表明诊疗试剂纳米粒子具有不错的荧光成像。
实施例4
检测诊疗试剂纳米粒子的光动力效果，首先准确配置3mL的诊疗试剂纳米粒子溶液，取50μL制备好的单线态氧指示剂ADMA加入到溶液中，混合均匀后使用白光(400-700nm)进行光照样品并且每间隔2分钟记录一下材料的紫外吸收峰。
如图5所示，为本发明实施例一种有机无机杂化光敏剂与有机半导体材料PFBT共沉淀形成纳米粒子的光动力数据图，可以看到随着光照时间的延长，ADMA的吸收越来越低，说明诊疗试剂纳米粒子产生的单线态氧增多，具有不错的光动力效果。
以上所述仅是本发明的优选实施方式，应当指出，对于本技术领域的普通技术人员来说，在不脱离本发明技术原理的前提下，还可以做出若干改进和变形，这些改进和变形也应视为本发明的保护范围。

Claims (6)

1.一种有机无机杂化光敏剂，结构式如下：
Figure 489797DEST_PATH_IMAGE001
，
其中R结构式如下：
Figure 88269DEST_PATH_IMAGE002
。
2.一种有机无机杂化纳米诊疗试剂的制备方法，其特征在于，包括如下制备步骤：
步骤a：以卟啉为主体光敏剂，将具有立体笼状结构的聚倍半硅氧烷和十二长烷基链引入到卟啉光敏剂中，合成权利要求1所述的有机无机杂化光敏剂；
步骤b：选取与有机无机杂化光敏剂紫外吸收谱在500-600 nm处有重叠的有机半导体材料，与步骤a中的有机无机杂化光敏剂混合，共沉淀方法制备纳米粒子。
3.根据权利要求2所述的一种有机无机杂化纳米诊疗试剂的制备方法，其特征在于，所述步骤a是通过点击反应合成有机无机杂化光敏剂。
4.根据权利要求2所述的一种有机无机杂化纳米诊疗试剂的制备方法，其特征在于，所述步骤b中有机半导体材料包括PFBT有机半导体材料，其吸收波长为480 nm，发射波长为560 nm，分子式如下：
Figure 105903DEST_PATH_IMAGE003
其中，n为20-30。
5.一种有机无机杂化纳米诊疗试剂，其特征在于，所述试剂包括权利要求2-4任一所述的纳米粒子。
6.如权利要求2-4任一项所述纳米粒子在制备应用于癌症治疗中图像引导的荧光成像的有机无机杂化纳米诊疗试剂中的应用。
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