CN112494663A - 一种新型多模态纳米诊疗试剂及其制备方法和应用 - Google Patents
一种新型多模态纳米诊疗试剂及其制备方法和应用 Download PDFInfo
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Abstract
本发明公开了一种新型多模态纳米诊疗试剂及其制备方法和应用，其中诊疗试剂包括以吡咯并吡咯二酮衍生物为主体，以含碘修饰的两亲性聚合物PEG‑PHEMA‑I为包覆材料的纳米颗粒；其制备方法包括：将吡咯并吡咯二酮衍生物和含碘修饰的两亲性聚合物PEG‑PHEMA‑I溶于四氢呋喃中获得混合溶液，将该混合溶液边超声边加入纯水中，然后用氮气进行鼓吹，直到四氢呋喃被除去。本发明提供的新型多模态纳米诊疗试剂，可实现PA/NIR‑II荧光/CT多模态成像指导下增强型光动力/光热联合治疗，能够显著提高治疗效果。
Description
技术领域
本发明属于生物医药工程技术领域，具体涉及一种新型多模态纳米诊疗试剂及其制备方法和应用。
背景技术
作为世界上发病率高、治愈率低的疾病之一，癌症一直威胁着公众的健康。然而，由于肿瘤的复杂性、多样性和异质性，依靠手术、放疗或化疗难以抑制肿瘤复发和转移，因此发展新型有效的诊疗试剂用于肿瘤的诊断治疗具有重要意义。
荧光成像由于具有非入侵性、实时、分辨率高等优点，被广泛应用于生物技术及生命科学领域。由于近红外二区(NIR-II，1000-1700nm)的波段发射波长较长，生物组织自身的光散射及自荧光较弱，因此极大地提高了成像效果，近年来逐渐受到了广泛的关注。相比于近红外一区荧光成像，NIR-II荧光成像具有优异的信噪比、时空分辨率及灵敏度，但是NIR-II荧光成像的穿透深度依然有限。另外光声(PA)成像作为一种非辐射、无损伤生物医学影像技术，其结合了光学成像和超声成像的特点，具有高对比度、高分辨率及生物组织高穿透性的优点，在实时医学成像领域有着巨大的应用前景，但PA灵敏度低且在一些组织成像应用依然有限。电子计算机断层扫描(CT)成像利用X线的衰减特性使人体的组织、器官产生不同的衰减射线投影，由探测器接受得到断层图像，再经过图像重建可以得到多方位成像图，具有穿度深度深、高空间分辨率等优点，但在软组织成像诊断能力有限。由于肿瘤部位的复杂性，单独应用一种成像方式很难实现肿瘤的精准成像诊断。
此外，虽然化学疗法仍然是治疗癌症的主要手段，但是不容忽视的对正常组织的毒副作用和肿瘤耐药性限制了其长远发展。因此，人们亟需开发能够减小药物毒副作用并增强疗效的新疗法。
发明内容
本发明的目的在于克服现有技术中的不足，提供一种新型多模态纳米诊疗试剂及其制备方法和应用，可实现PA/NIR-II荧光/CT多模态成像指导下增强型光动力/光热联合治疗，能够显著提高治疗效果。
本发明提供了如下的技术方案：
一种新型多模态纳米诊疗试剂，包括以吡咯并吡咯二酮衍生物为主体，以含碘修饰的两亲性聚合物PEG-PHEMA-I为包覆材料的纳米颗粒。
优选的，所述吡咯并吡咯二酮衍生物的结构式为：
优选的，所述PEG-PHEMA-I的结构式为：
一种新型多模态纳米诊疗试剂的制备方法，包括以下步骤：
将吡咯并吡咯二酮衍生物和含碘修饰的两亲性聚合物PEG-PHEMA-I溶于四氢呋喃中获得混合溶液；
将所述混合溶液边超声边加入纯水中，然后用氮气进行鼓吹，直到四氢呋喃被除去，获得以吡咯并吡咯二酮衍生物为主体、以PEG-PHEMA-I为包覆材料的纳米颗粒水溶液，即为新型多模态纳米诊疗试剂。
优选的，所述吡咯并吡咯二酮衍生物的制备方法，包括如下步骤：
将3,6-双(5-溴噻吩-2-基)-2,5-双(2-辛基十二烷基)吡咯并[3,4-C]吡咯-1,4(2H,5H)二酮和1,4-二乙炔基苯加入二异丙胺中；
在氮气氛围下加入催化剂四(三苯基膦)钯和碘化铜，加热搅拌，除去溶剂，乙醚沉降后得到吡咯并吡咯二酮衍生物。
优选的，所述3,6-双(5-溴噻吩-2-基)-2,5-双(2-辛基十二烷基)吡咯并[3,4-C]吡咯-1,4(2H,5H)二酮和1,4-二乙炔基苯的摩尔质量比为1:1。
优选的，所述四(三苯基膦)钯和碘化铜的摩尔质量比为1:1。
优选的，所述PEG-PHEMA-I的制备方法，包括如下步骤：
将2-溴代异丁酰氯溶于无水四氢呋喃中，缓慢加入到甲氧聚乙二醇的无水四氢呋喃中，40℃搅拌24h，过滤旋蒸，用饱和氯化钠溶液洗涤，乙醚沉降得到产物PEG-Br；
将PEG-Br、联二吡啶和溴化铜加入聚合管中，抽真空鼓氮气，随后滴加HEMA和甲醇，室温反应，透析得到产物PEG-PHEMA；
将PEG-PHEMA和2,3,5-三碘苯甲酸溶于四氢呋喃中，加入DMAP和DCC，室温下反应，过滤沉淀，乙醚沉降得到最终产物PEG-PHEMA-I。
优选的，所述PEG-Br、联二吡啶和溴化铜的质量比为500:20:7，所述PEG-PHEMA和2,3,5-三碘苯甲酸的质量比为3:11。
一种新型多模态纳米诊疗试剂的应用，用于PA/NIR-II荧光/CT多模态成像指导的肿瘤增强型光动力及光热联合治疗。
与现有技术相比，本发明的有益效果是：
本发明中的新型聚合物吡咯并吡咯二酮衍生物(DPPB)具有优良的PA成像、NIR-II荧光成像、光动力及光热转换性能，利用含碘修饰的两亲性聚合物PEG-PHEMA-I对DPPB进行包覆，制备获得具有良好水溶性、生物相容性的DPPB-I纳米颗粒；含碘聚合物PEG-PHEMA-I的引入使得DPPB-I纳米颗粒具有良好的CT成像性能及更加优异的光动力及光热效果，可实现PA/NIR-II荧光/CT多模态成像指导下增强型光动力/光热联合治疗，能够显著提高治疗效果，具有较好临床应用前景。
附图说明
图1为新型多模态纳米诊疗试剂构筑示意图；
图2为DPPB-I纳米粒子的紫外吸收谱图；
图3为DPPB-I纳米粒子的荧光发射图；
图4为DPPB-I纳米粒子DLS图；
图5为DPPB-I纳米粒子光声成像图；
图6为DPPB-I纳米粒子近红外二窗荧光成像图；
图7为DPPB-I纳米粒子CT成像图；
图8为一定浓度DPPB-I纳米粒子在不同功率光照下DPBF的414nm紫外吸收强度随时间变化图；
图9为一定浓度DPPB纳米粒子在不同功率光照下DPBF的414nm紫外吸收强度随时间变化图；
图10为不同浓度DPPB-I纳米粒子在同一功率光照下的光热变化图；
图11为不同浓度DPPB纳米粒子在同一功率光照下的光热变化图；
图12为DPPB-I纳米粒子光热循环图。
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。
一、仪器准备
本发明的实施例所使用的试剂皆为市购，所使用的仪器分别为：
(1)近红外二窗荧光成像仪：NIRvana 640-Princeton instrument；
(2)光声成像仪：Endra Nexus 128；
(3)红外热成像仪：TESTO869；
(4)激光器：MDL-IH-660-1.5W-PSU-II-LED。
二、新型多模态纳米诊疗试剂的制备
本实施例提供的新型多模态纳米诊疗试剂的制备方法，包括以下步骤：
1、吡咯并吡咯二酮衍生物(DPPB)的制备
将3,6-双(5-溴噻吩-2-基)-2,5-双(2-辛基十二烷基)吡咯并[3,4-C]吡咯-1,4(2H,5H)二酮(0.1mmol,121mg)和1,4-二乙炔基苯(0.1mmol,15mg)加入二异丙胺中，在氮气氛围下加入摩尔质量比为1:1的催化剂四(三苯基膦)钯和碘化铜，83℃加热搅拌24h，除去溶剂，乙醚沉降后得到新型有机聚合物荧光探针DPPB。合成路线为：
2、PEG-PHEMA-I的制备
(1)移取1mL 2-溴代异丁酰氯溶于10mL无水四氢呋喃中，缓慢加入到甲氧聚乙二醇(PEG)(1g、0.2mmol)的无水四氢呋喃(20ml)中，40℃搅拌24h，过滤旋蒸，用50mL的饱和氯化钠溶液洗涤，乙醚沉降得到产物PEG-Br；
(2)称取0.5g PEG-Br、20mg联二吡啶和7mg溴化铜加入聚合管中，抽真空鼓氮气，随后滴加0.25mL的HEMA和0.5mL的甲醇，室温反应3h，透析得到产物PEG-PHEMA；
(3)称取0.3gPEG-PHEMA和1.1g 2,3,5-三碘苯甲酸溶于50mL四氢呋喃中，最后加入DMAP和DCC，室温下反应40h，过滤沉淀，乙醚沉降得到最终产物PEG-PHEMA-I。PEG-PHEMA-I的结构式为：
3、新型多模态纳米诊疗试剂的制备
(1)称取1mg的DPPB和30mg的PEG-PHEMA-I溶于3ml四氢呋喃中获得混合溶液；
(2)将上述混合溶液缓慢加入10ml超纯水中，边超声边加入，继续超声2分钟，然后用氮气进行鼓吹除去四氢呋喃，最后用超滤管对溶液进行离心去除部分水，得到浓度为1mg/mL的DPPB-I纳米颗粒水溶液。
三、性能表征
如图1所示，DPPB-I纳米颗粒以DPPB为主体，以含碘修饰的两亲性聚合物PEG-PHEMA-I为包覆材料。其紫外吸收谱图如图2所示，可见该纳米颗粒具有优异的近红外一区吸收性能。荧光光谱图如图3所示，可见该纳米颗粒具有优异的近红外二区荧光发射性能。所得到的纳米粒子的大小如图4所示，可见该纳米颗粒大小为100nm左右，具有良好的肿瘤富集能力。
1、PA成像/NIR-II荧光成像/CT成像
(1)PA成像
配置DPPB-I纳米颗粒水溶液于小离心管中，然后用光声成像仪进行成像，如图5所示，结果表明该纳米颗粒具有优异的PA成像能力。
(2)NIR-II荧光成像
配制DPPB-I纳米颗粒水溶液于小离心管中，在近红外二窗荧光成像仪下，用波长为808nm的激光激发，得到近红外二窗荧光成像，如图6所示，结果表明该纳米颗粒具有优异的NIR-II荧光成像能力。
(3)CT成像
配置DPPB-I纳米颗粒水溶液于小离心管中，然后用断层扫描成像仪进行成像，如图7所示，结果表明该纳米颗粒具有优异的CT成像能力。
2、光动力/光热性能测试方法
(1)光动力性能的测试
为更好的研究DPPB-I纳米粒子光动力/光热性能，采用不含碘修饰的DPPB纳米粒子作为对照。
不含碘修饰的DPPB纳米粒子的制备方法如下：将1mg的DPPB与30mg的两亲性聚合物F127溶于3ml四氢呋喃中；将前述溶液缓慢加入10ml超纯水中，边超声边加入，继续超声2分钟，然后用氮气进行鼓吹除去四氢呋喃，最后用超滤管对溶液进行离心去除部分水，获得不含碘修饰的DPPB纳米粒子。
在比色皿中加入DPPB-I纳米粒子或DPPB纳米粒子水溶液(0.25mM,1mL)，再滴加入40μL浓度为1mM的DPBF的乙醇溶液，分别用光功率密度0.25W/cm2、0.5W/cm2及0.75W/m2的激光(660nm)间断照射，每次光照5s，并监测在DPBF特征峰414nm处的紫外吸收峰的变化，图8为一定浓度DPPB-I纳米粒子在不同功率光照下DPBF的414nm紫外吸收强度随时间变化图，图9为一定浓度DPPB纳米粒子在不同功率光照下DPBF的414nm紫外吸收强度随时间变化图。可见随着不断的光照DPBF在414nm处的吸收峰有明显降低，从而反映光照过程产生了单线态氧。另外在DPPB-I纳米粒子溶液中，DPBF在414nm处的吸收峰下降的幅度明显比DPPB纳米粒子大，表明DPPB-I纳米粒子具有更加优异的光动力性能。
(2)光热性能测试方法
在250μL的小离心管中分别加入200μL的去离子水和浓度分别为0.2mg/mL、0.4mg/mL、0.6mg/mL、0.8mg/mL和1mg/mL的DPPB-I纳米粒子或DPPB纳米粒子水溶液，并用激光(660nm，1W/cm2)照射，由红外温敏相机记录溶液温度随时间变化的趋势。图10为不同浓度DPPB-I纳米粒子在同一功率光照下的光热变化图；图11为不同浓度DPPB纳米粒子在同一功率光照下的光热变化图。可以看出，相比与DPPB纳米粒子，DPPB-I纳米粒子具有更好的光热性能。
最后，测试纳米粒子的光热循环稳定性，用光功率密度为1W/cm2的660nm激光照射浓度为1mg/mL的DPPB-I纳米粒子水溶液，当溶液温度上升到最大温度时关闭激光器，使溶液自然冷却，冷却到室温再继续光照，循环往复5次，得到光热循环图，如图12所示，结果表明该纳米粒子具有良好的光热稳定性。
四、新型多模态纳米诊疗试剂的应用。
本实施例提供的新型多模态纳米诊疗试剂，用于PA/NIR-II荧光/CT多模态成像指导的肿瘤增强型光动力及光热联合治疗，肿瘤多模式联合治疗能够产生协同或者增加效应，从而可以显著提高治疗效果，而且在一定程度上可以预防对正常组织的毒副作用及肿瘤耐药性，具有较好临床应用前景。
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 (10)
1.一种新型多模态纳米诊疗试剂，其特征在于，包括以吡咯并吡咯二酮衍生物为主体，以含碘修饰的两亲性聚合物PEG-PHEMA-I为包覆材料的纳米颗粒。
2.根据权利要求1所述的新型多模态纳米诊疗试剂，其特征在于，所述吡咯并吡咯二酮衍生物的结构式为：
3.根据权利要求1所述的新型多模态纳米诊疗试剂，其特征在于，所述PEG-PHEMA-I的结构式为：
4.一种新型多模态纳米诊疗试剂的制备方法，其特征在于，包括以下步骤：
将吡咯并吡咯二酮衍生物和含碘修饰的两亲性聚合物PEG-PHEMA-I溶于四氢呋喃中获得混合溶液；
将所述混合溶液边超声边加入纯水中，然后用氮气进行鼓吹，直到四氢呋喃被除去，获得以吡咯并吡咯二酮衍生物为主体、以PEG-PHEMA-I为包覆材料的纳米颗粒水溶液，即为新型多模态纳米诊疗试剂。
5.根据权利要求4所述的新型多模态纳米诊疗试剂的制备方法，其特征在于，所述吡咯并吡咯二酮衍生物的制备方法，包括如下步骤：
将3,6-双(5-溴噻吩-2-基)-2,5-双(2-辛基十二烷基)吡咯并[3,4-C]吡咯-1,4(2H,5H)二酮和1,4-二乙炔基苯加入二异丙胺中；
在氮气氛围下加入催化剂四(三苯基膦)钯和碘化铜，加热搅拌，除去溶剂，乙醚沉降后得到吡咯并吡咯二酮衍生物。
6.根据权利要求5所述的新型多模态纳米诊疗试剂的制备方法，其特征在于，所述3,6-双(5-溴噻吩-2-基)-2,5-双(2-辛基十二烷基)吡咯并[3,4-C]吡咯-1,4(2H,5H)二酮和1,4-二乙炔基苯的摩尔质量比为1:1。
7.根据权利要求5所述的新型多模态纳米诊疗试剂的制备方法，其特征在于，所述四(三苯基膦)钯和碘化铜的摩尔质量比为1:1。
8.根据权利要求4所述的新型多模态纳米诊疗试剂的制备方法，其特征在于，所述PEG-PHEMA-I的制备方法，包括如下步骤：
将2-溴代异丁酰氯溶于无水四氢呋喃中，缓慢加入到甲氧聚乙二醇的无水四氢呋喃中，40℃搅拌24h，过滤旋蒸，用饱和氯化钠溶液洗涤，乙醚沉降得到产物PEG-Br；
将PEG-Br、联二吡啶和溴化铜加入聚合管中，抽真空鼓氮气，随后滴加HEMA和甲醇，室温反应，透析得到产物PEG-PHEMA；
将PEG-PHEMA和2,3,5-三碘苯甲酸溶于四氢呋喃中，加入DMAP和DCC，室温下反应，过滤沉淀，乙醚沉降得到最终产物PEG-PHEMA-I。
9.根据权利要求8所述的新型多模态纳米诊疗试剂的制备方法，其特征在于，所述PEG-Br、联二吡啶和溴化铜的质量比为500:20:7，所述PEG-PHEMA和2,3,5-三碘苯甲酸的质量比为3:11。
10.一种新型多模态纳米诊疗试剂的应用，其特征在于，用于PA/NIR-II荧光/CT多模态成像指导的肿瘤增强型光动力及光热联合治疗。
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| CN113087877A (zh) * | 2021-04-06 | 2021-07-09 | 南京邮电大学 | 近红外二区荧光发射水溶性共轭聚合物纳米光疗试剂及其制备方法与应用 |
| CN114989174A (zh) * | 2022-06-02 | 2022-09-02 | 南京邮电大学 | 一种有机小分子nir-ii荧光染料、纳米颗粒及其制备方法与应用 |
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