CN111333819B - 一种化合物及其用途 - Google Patents
一种化合物及其用途 Download PDFInfo
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- CN111333819B CN111333819B CN202010039642.8A CN202010039642A CN111333819B CN 111333819 B CN111333819 B CN 111333819B CN 202010039642 A CN202010039642 A CN 202010039642A CN 111333819 B CN111333819 B CN 111333819B
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Abstract
本发明提供一种化合物或其异构体、药学上可接受的水合物或盐在制备成像制剂或光热治疗制剂中的用途。本发明制得的化合物较高的消光系数、较高的荧光量子产率以及较高的有效NIR‑II亮度，如制得的L1057NPs可有效地将吸收的光能量转换为热能，光热转换效率达38％，能有效消灭肿瘤细胞；L1057NPs可以实现超快高分辨NIR‑II荧光成像，可用于肿瘤、血管等相关疾病的诊断。
Description
技术领域
本发明属于荧光成像技术领域，尤其涉及一种化合物及其用途。
技术背景
自2009年美国斯坦福大学戴宏杰教授团队首次利用单壁碳纳米管(SWNTs)实现了近红外二区(NIR-II，1000nm-1700nm)荧光活体成像以来，NIR-II荧光活体成像技术引起了学术界及临床医生的广泛关注。尤其是近几年铟镓砷(InGaAs)荧光成像系统的普及，使得NIR-II荧光成像领域呈现出蓬勃发展之势。目前，用于NIR-II荧光成像的材料可分为无机材料和有机材料两大类。无机NIR-II材料主要包括单壁碳纳米管、量子点、稀土掺杂下转换纳米粒子等。由于它们的长期毒性仍不明了，限制了临床转化的可能性。有机NIR-II材料主要是基于小分子染料、具有给体-受体-给体(D-A-D)结构的小分子和共轭聚合物这三类材料。鉴于目前FDA批准的荧光材料都是有机材料，有机NIR-II荧光材料更具有临床应用潜力。
发明内容
荧光成像的信号强弱主要由探针的亮度所决定，而亮度与激发波长的消光系数和荧光量子产率成正比，然而目前文献中报道的有机NIR-II荧光材料普遍存在一个问题：有效NIR-II(发射波长>1000nm的光子)亮度较低。申请人研究发现这主要是由以下几个因素造成的：1)荧光量子产率较低；2)消光系数较低；3)只有一部分发射光谱位于NIR-II范围内。
本发明的目的在于提供一种共轭聚合物，该共轭聚合物制得的NIR-II荧光试剂具有较高的有效NIR-II亮度、较高的消光系数、优异的光稳定性。
具体的方案如下：
一种化合物，其特征在于，具有式(Ⅰ)所示通式或其异构体、药学上可接受的水合物或盐：
其中，
R1选自CmH2m+1、CmH2mX、(CH2CH2O)mCH3、(CH2CH2O)mCH2X、
R2选自CmH2m+1、CmH2mX、(CH2CH2O)mCH3、(CH2CH2O)mCH2X、
R3、R4选自CmH2m+1、CmH2mX、(CH2CH2O)mCH3、(CH2CH2O)mCH2X；
X选自卤素原子、N3、C≡CH、COOH、NH2、OH、SH、
W选自CmH2m+1、CmH2mX、(CH2CH2O)mCH3；
n为1-100中的整数，m为0-100中的整数。
本发明一具体实施方式，所述R1选自(C6H4)C6H13，所述R2选自(C6H4)OC6H13。
本发明还提供了一种如式(Ⅰ)所示通式的化合物或其异构体、药学上可接受的水合物或盐在制备成像制剂或光热治疗制剂中的用途，
其中，
R1选自CmH2m+1、CmH2mX、(CH2CH2O)mCH3、(CH2CH2O)mCH2X、
R2选自CmH2m+1、CmH2mX、(CH2CH2O)mCH3、(CH2CH2O)mCH2X、
R3、R4选自CmH2m+1、CmH2mX、(CH2CH2O)mCH3、(CH2CH2O)mCH2X；
X选自卤素原子、N3、C≡CH、COOH、NH2、OH、SH、
W选自CmH2m+1、CmH2mX、(CH2CH2O)mCH3；
n为1-100中的整数，m为0-100中的整数。
本发明一具体实施方式，所述成像制剂作为近红外二区成像的制剂。
本发明一具体实施方式，所述成像制剂用于全身成像。
本发明另一具体实施方式，所述全身成像选自脑血管成像、肿瘤成像。
一种组合物，该组合物包括选自式(Ⅰ)所示通式的化合物或其异构体、药学上可接受的水合物或盐，以及药学上可接受的载体，
其中，
R1选自CmH2m+1、CmH2mX、(CH2CH2O)mCH3、(CH2CH2O)mCH2X、
R2选自CmH2m+1、CmH2mX、(CH2CH2O)mCH3、(CH2CH2O)mCH2X、
R3、R4选自CmH2m+1、CmH2mX、(CH2CH2O)mCH3、(CH2CH2O)mCH2X；
X选自卤素原子、N3、C≡CH、COOH、NH2、OH、SH、
W选自CmH2m+1、CmH2mX、(CH2CH2O)mCH3；
n为1-100中的整数，m为0-100中的整数。
本发明一具体实施方式，所述载体选自两亲性聚合物。
本发明另一具体实施方式，所述两亲性聚合物选自包括脂质体、多肽或糖类。
本发明一具体实施方式，所述组合物用于作为成像制剂、光热治疗制剂。
本发明一具体实施方式，所述成像制剂作为心脑血管疾病诊断、手术导航用的药剂。
本发明一具体实施方式，所述疾病包括脑缺血、血栓、中风、动脉粥样硬化。
与现有技术相比，本发明的有益效果：
本发明制得的化合物较高的消光系数、较高的荧光量子产率以及较高的有效NIR-II亮度，如制得的L1057NPs可有效地将吸收的光能量转换为热能，光热转换效率达38％，能有效消灭肿瘤细胞；L1057NPs可以实现超快高分辨NIR-II荧光成像，可用于肿瘤、血管等相关疾病的诊断。
附图说明
图1 L1057NPs的制备示意图；
图2 P2NPs在水溶液中的吸收(a)和发射(b)光谱；
图3 L1057NPs的动态光散射数据和透射电镜照片(插图)，标尺：100nm；
图4 L1057NPs在水溶液中的吸收和发射光谱；
图5 L1057NPs在水中的质量消光系数的测定；
图6 L1057NPs的光热性能；
图7注射L1057NPs小鼠的血清生化指标；
图8注射L1057NPs小鼠的肝肾功能指标；
图9重要器官(心、肺、肝、脾、肾)的病理切片对比(H&E染色)；
图10裸鼠全身成像和脑血管成像；
图11实时的NIR-II荧光显微成像脑血管；
图12实时的NIR-II荧光显微成像脑血管；
图13 4T1荷瘤裸鼠NIR-II荧光肿瘤成像；
图14 L1057NPs对肿瘤的光热治疗效果。
具体实施方式
下面将对本发明的技术方案进行清楚、完整地描述，显然，所描述的实施例仅仅是本发明一部分实施例，而不是全部的实施例。基于本发明中的实施例，本领域普通技术人员在没有做出创造性劳动前提下所获得的所有其他实施例，都属于本发明保护的范围。
除非另有定义，本文所使用的所有的技术和科学术语与属于本发明的技术领域的技术人员通常理解的含义相同。本文中在本发明的说明书中所使用的术语只是为了描述具体的实施例的目的，不是旨在于限制本发明。本文所使用的术语“及/或”包括一个或多个相关的所列项目的任意的和所有的组合。
本申请中，若无特殊申明所选用的原料、辅料均可通过市售购买得到。
一、聚合物的合成示例：
所述聚合物具有式(Ⅰ)所示通式：
其中，
R1选自CmH2m+1、CmH2mX、(CH2CH2O)mCH3、(CH2CH2O)mCH2X、
R2选自CmH2m+1、CmH2mX、(CH2CH2O)mCH3、(CH2CH2O)mCH2X、
R3、R4选自CmH2m+1、CmH2mX、(CH2CH2O)mCH3、(CH2CH2O)mCH2X；
X选自卤素原子、N3、C≡CH、COOH、NH2、OH、SH、
W选自CmH2m+1、CmH2mX、(CH2CH2O)mCH3；
n为1-100中的整数，m为0-100中的整数。
研究发现上述(Ⅰ)所示通式的聚合物其异构体、药学上可接受的水合物或盐仍然具备较高的有效NIR-II亮度、较高的消光系数、优异的光稳定性。
以下仅以部分基团为例进行说明：
示例1：
先制备得到共轭聚合物，后期再通过纳米共沉淀法制备得到相应的组合物。
在50mL的Schlenk管内加入单体1(134.5mg，0.1mmol)，单体2(69.8mg，0.1mmol)，催化剂Pd2(dba)3(3mg，3.3μmol)和P(o-tolyl)3(3mg，9.8μmol)和溶剂甲苯(10mL)。反应混合物在氩气气氛保护下于100℃反应2h。随后停止反应、冷却，将产物在甲醇里面沉淀出来。然后将粗产物溶解在二氯甲烷(200mL)里，并依次用水萃取(100mL×3)、Na2SO4干燥、过滤。最后，将有机相浓缩至～10mL，并滴加至甲醇(100mL)，通过沉淀，过滤即可获得P1为棕色固体(104mg，产率：67％)。
1HNMR(CDCl3，400MHz，ppm)δ:9.52-7.50(m)，7.78-7.76(m)，7.63(br)，7.57-7.55(d)，7.33-7.28(m)，7.22-7.17(m)，7.11-7.03(m)，6.65(br)，3.95(br)，2.55(br)，1.85(br)，1.41-1.24(m)，0.98(m)，0.88-0.82(m)。
合成过程：
示例2：
先制备得到共轭聚合物，再通过化学修饰制备得到相应的化合物。
聚合物4的合成方法和示例1中的P1相似，但是聚合物4的侧链上含有叠氮(N3)官能团，可以和含有炔键的底物进行点击化学反应。
聚合物P2合成示例：在50mL的反应管内加入反应物，聚合物4(50mg)、带炔键的聚乙二醇2000(146mg)，催化剂硫酸铜(5mg)、抗坏血酸钠(5mg)，溶剂四氢呋喃(50mL)。氩气气氛下室温反应48h，然后用截留分子量为12000-14000的透析膜在水中透析，除去未反应的带炔键的聚乙二醇2000和催化剂，随后冻干即可获得为絮状固体的聚合物P2。
1HNMR(CDCl3,400MHz,ppm):9.52(br),7.78(br),7.65-7.57(br),7.32(br),7.11(br),7.06(m),6.64(br),3.95(br),3.45(br),3.15(br),2.54(br),2.01-1.86(m),1.28(m),0.86(m)。
合成过程：
如图2：
P2NPs在水溶液中的最大吸收峰位于950nm，最大发射峰位于1028nm。其在水溶液中的荧光量子产率为0.9％(以IR26在1，2-二氯乙烷中的荧光量子产率为0.5％作为参比)。
二、实验过程
1、L1057NPs制备
由于所得的共轭聚合物材料具有很强的亲脂性，不能够直接应用于生物环境。为此，采取纳米共沉淀法将共轭聚合物包覆在生物相容性优异的两亲性聚合物内，如脂质体、多肽、糖类等。
以DSPE-PEG2000为基质为例制备纳米粒子，图1为纳米粒子制备示意图。
首先，将P1(1mg)和基质DSPE-PEG2000(2mg)充分溶解在三氯甲烷/四氢呋喃(2mL，1/1)中；然后，快速注入10倍当量的超纯水中，在超声作用下形成稳定分散的纳米粒子。随后，在通风橱内搅拌24h除去有机溶剂；最后通过透析、过滤、浓缩、标定浓度后即可获得L1057NPs并储存在常温备用。
还可以对共轭聚合物进行化学修饰，如1中示例2，从而使其可直接应用于生物环境，化学修饰可参照现有关于克服亲脂性的相关技术。
2、L1057NPs的性能表征
(1)L1057NPs的形貌、尺寸及稳定性
利用粒径分析仪(NanoPlus-3)表征纳米粒子在水溶液中的粒径分布，利用低分辨透射电镜(1400PLUS)表征纳米粒子的形貌。L1057NPs的透射电镜图像显示其为平均直径约为51nm的球状结构，这与动态光散射的测量结果相匹配(图3a)。L1057NPs在室温储存条件下没有产生明显的沉淀，并且其动态光散射测试结果显示，在连续14天的测试过程中，其尺寸没有明显变化(图3b)，说明L1057NPs具有良好的胶体稳定性。
图3(a)L1057NPs的动态光散射数据和透射电镜照片(插图)，标尺：100nm；(b)L1057NPs在水中的稳定性测试，纳米粒子尺寸由动态光散射确定。
(2)L1057NPs的吸收和荧光性能
利用紫外-可见-近红外(UV-vis-NIR)分光光度计表征了L1057NPs的吸收光谱。如图4所示，L1057NPs在水中的吸收光谱在470nm和937nm处有两个吸收峰：前者可归属于聚合物的共轭主链引起的π-π*和n-π*跃迁，后者可归属于从给体单元到受体单元的分子内电荷转移(ICT)。由于其吸收光谱较宽，L1057NPs可以在很大的波长范围内激发。例如，当以氙灯为激发光源以808nm为激发波长是，其荧光光谱在1057nm处有一个很强的发射峰。并且几乎所有的发射光谱都落在NIR-II区域，这意味着几乎所有的发射光子都可以用于NIR-II荧光成像。以染料IR26(其在1，2-二氯乙烷中荧光量子产率为0.5％)为参照，L1057NPs的有效NIR-II荧光量子产率(发射波长>1000nm)为1.25％，优于许多目前文献报道的有机NIR-II探针(如IR-E1、CH1055和PBT)。
L1057NPs在水溶液中的质量消光系数
将共轭聚合物(1mg)在氯仿中(5mL)中充分溶解后，测试不同浓度的聚合物在氯仿中的吸收光谱(如图5a所示)。随后，以共轭聚合物的浓度为横坐标，以共轭聚合物在980nm处的吸光度为纵坐标，制备标准曲线并进行线性拟合，斜率即为质量消光系数(如图5b所示)。然后，测试一定浓度的L1057NPs(2mL)在水溶液中的吸收光谱(如图5d所示)。再后，将相同浓度的L1057NPs水溶液(2mL)冻干，经真空干燥箱充分干燥后，溶解于氯仿(2mL)，并测试其吸收光谱(图5c)。根据图5b中的获得的聚合物在980nm处的消光系数，可计算出2mL水溶液中共轭聚合物的真实含量。根据L1057NPs在水中的吸收，即可算出L1057NPs水溶液在980nm处的消光系数为18Lg-1cm-1。
(3)L1057NPs在水溶液中的光热性能
为了评估L1057NPs的光热性能，将不同浓度的L1057NPs溶液置于980nm激光下分别连续照射10分钟。数据表明，在980nm激光的照射下，L1057NPs溶液的温度随着照射时间、浓度和激光功率的增加而迅速升高(见图6a)。如图6b所示，L1057NPs在浓度为100μg/mL、980nm的激光(1W/cm2)连续照射10分钟后，从室温升至60.3℃。当激光功率密度分别为0.72、0.6和0.33W/cm2时，其最高温度可达到53.6℃、45.1℃和39.8℃。根据美国国家激光安全使用标准，980nm激光的最大允许辐射量(MPE)0.72W/cm2。当光强密度高于MPE时，将会对皮肤造成伤害。如图6c所示，当L1057NPs在功率密度为0.72W/cm2时，在980nm激光的照射下，温度可升至50℃以上，这意味着将可以有效杀死肿瘤细胞。这些数据表明，L1057NPs是一种有效的光热制剂。
图中，
(a)不同浓度的L1057NPs 980nm激光照射500s后的光热照片；
(b)不同浓度的L1057NPs在980nm激光(1W/cm2)持续照射500s的温度变化曲线；
(c)L1057NPs(100μg/mL)在不同激光功率(0.33W/cm2和0.72W/cm2)的980nm激光照射500s的温度变化曲线；
(d)L1057NPs(100μg/mL)在980nm激光(1W/cm2)多次开/关条件下的光热性能稳定性；
(e)L1057NPs在808nm激光(1W/cm2)照射900s内的升温曲线及关闭激光后的降温曲线；
(f)图(e)中的冷却时间与从冷却后获得的温度驱动力的负自然对数的关系；
(g)光热处理后4T1细胞的细胞存活率(980nm激光的激光功率为0.72W/cm2)，以及(h)相应的用FDA和PI染色的细胞的共焦荧光图像，标尺：100nm。
此外，L1057NPs具有良好的光热稳定(图6d)，并根据一个循环的升温/降温曲线(图6e，7f)，我们计算出L1057NPs的光热转换效率为38％，这说明L1057NPs可以非常有效地将吸收的光能量转换为热能。
L1057NPs优异的光热性能使其具有极大的光热治疗应用潜力。为此，通过MTT方法研究了L1057NPs对细胞的光热毒性。将不同浓度的L1057NPs与4T1细胞共同孵育后，980nm(0.72W/cm2)的激光照射10min，并以未经激光照射的细胞作为对照组。如图6所示，L1057NPs本身对细胞活性几乎没有影响。相比之下，在980nm激光(0.72W/cm2)照射10min后，4T1细胞表现出明显的浓度依赖性，半抑制浓度(IC50)为3.1μg/mL。此外，我们通过二乙酸荧光素(FDA)和碘化丙钠(PI)染色来区分活细胞(绿色)和死细胞(红色)，染色结果与MTT结果一致(图6h)。这些结果进一步证明，L1057NPs是一种有效的光热制剂。
(4)L1057NPs在体内的毒性表征
探针的生物安全性是实现活体应用的前提。为此，我们首先以MTT实验考察了L1057NPs对健康细胞(3T3、LO2和MEH细胞)的毒性。将不同浓度的L1057NPs与细胞孵育24h后，细胞生存率未见明显降低，表明L1057NPs对正常细胞的毒性非常低。随后，我们又通过尾部静脉注射将L1057NPs(200μL，1mg/mL)递送至小鼠体内，所使用剂量与成像和治疗的剂量相同。在测试期间(28天)，未观察到任何小鼠有病理或异常行为。血清生化(图7)及肝肾功能分析(图8)均在正常范围内，肝、肾未见可检测到的损伤。注射L1057NPs28天后处死小鼠，并对主要器官进行H&E染色。结果表明，我们没有观察到任何主要器官(心、肺、肝、脾和肾)有明显的器官损伤或炎症病变(图9)。这些结果表明，至少在我们所使用的剂量下，L1057NPs对健康小鼠没有明显的体内毒性，适合用于活体成像和治疗。
(5)L1057NPs用于NIR-II荧光全身成像及脑血管造影
图中：
(a)裸鼠静脉注射L1057NPs后在980nm激光激发下进行小鼠全身NIR-II荧光成像(功率：25mW/cm2，曝光时间：30ms)，标尺：5mm；
(b)代表性血管直径的高斯拟合图；
(c)脑血管的显微荧光成像图，标尺：200μm；
(d)代表性脑血管直径的高斯拟合图。
图10a为通过尾静脉注射L1057NPs后小鼠的全身血管成像。此图是以980nm的激光作为激发光源，以LP1200滤光片收集荧光信号获得的。注射L1057NPs后即刻就可以清晰的观察到小鼠全身的血管，并且可以非常清楚的观察到直径约为198μm的毛细血管(图10b)。重要的是，在本研究中，使用的功率超低仅25mW/cm2，曝光时间较短仅30ms，与目前文章中报道使用的激光功率和曝光时间要低得多。成像所需的低激发功率和短曝光时间可归因于L1057NPs的高亮度。这些结果表明，L1057NPs可以实现超快高分辨成像，可用于血管相关的疾病评估，包括但不限于脑缺血、血栓、中风、动脉粥样硬化等疾病。
为了进一步评估L1057NPs对微小血管的检测能力，我们使用显微成像技术对小鼠大脑进行了5倍放大血管网络成像(图10c)。得益于传统宽场荧光显微镜的高帧频和NIR-II荧光成像的深层组织穿透能力，在静脉注射L1057NPs后，即使直径约为5.6μm的血管都清晰可见(图10d)。
(6)L1057NPs用于不同深度NIR-II荧光活体脑血管造影
为了评估L1057NPs体内NIR-II荧光成像的最大成像深度，我们通过逐步调整焦平面，对不同深度的脑血管进行了放大25倍的NIR-II荧光成像。如图11a所示，我们可以清楚地观测到不同深度的大脑血管，深度可达900μm。此外，定量地分析了深度为300、600和800μm的血管成像，通过高斯拟合发现，即使在深度为800μm时直径仅为3.7μm的毛细血管依旧清晰可见(图11b)。
图中：
(a)不同深度脑血管的显微荧光成像图，标尺：200μm；激发波长为980nm，信号收集为LP1200nm的滤光片；
(b)不同深度(300、600和800μm)的脑血管直径的高斯拟合图。
为了比较808nm和980nm作为激发波长对成像深度的影响，我们通过调节InGaAs相机的参数将相同浓度的L1057NPs在深度为0μm处的荧光强度调至相同，其他实验参数保持不变。在808nm激光照射下，我们发现最大穿透深度也可达到900μm(图12a)。并且在深度为800μm时，通过高斯拟合可清新分别直径为3.09μm的毛细血管，与980nm作为激发波长所得结果相似。通过比较说明，利用808nm和980nm作为激发波长可获得相仿的成像深度。
图中：
(a)不同深度的脑血管的显微荧光成像，标尺：200μm。激发波长为808nm，信号收集为LP1200nm的滤光片；
(b)不同深度(300、600和800μm)的脑血管直径的高斯拟合图。
(7)L1057NPs用于NIR-II肿瘤荧光造影
图中：
(a)4T1乳腺癌裸鼠及(b)其在不同时间点肿瘤部位的NIR-II荧光成像(LP1200nm)。激发波长：980nm；功率：25mW/cm2；曝光时间：20ms；
(c)L1057NPs在不同时间点的肿瘤/正常组织比(T/NT)变化曲线；
(d)L1057NPs在重要器官富集的体外荧光照片及(e)归一化平均荧光强度。
全身成像和脑血管成像表明L1057NPs是一种明亮的NIR-II荧光成像造影剂。接下来，我们表征其精确实现肿瘤成像的能力，这对于精确指导治疗和最小化对周围健康组织的损伤至关重要。我们通过将4T1乳腺癌细胞皮下接种于小鼠右腹部，成功建立异种移植瘤4T1小鼠乳腺癌模型。当肿瘤大小约为100mm3时，通过尾静脉注射将L1057NPs(200μL，1mg/mL)注入小鼠体内，并采集不同时间点肿瘤位置的NIR-II荧光信号(图13a)。如图13b所示，随着时间的延长，肿瘤部位的NIR-II荧光信号逐渐增强，这是由于肿瘤的高通透性和滞留效应(EPR效应)促进了肿瘤内L1057NPs的积累。同时，肿瘤的边界也越来越清晰。在注射L1057NPs48h后，肿瘤部位的荧光信号减弱，主要是因为循环系统清除体内纳米粒子的结果。另外，随着时间的推移，肿瘤与正常组织(T/NT)的比值也越来越高。注射L1057NPs48h后，肿瘤/正常组织比(T/NT)达到～7(图13c)，说明L1057NPs可以作为NIR-II荧光探针用于肿瘤诊断。
NIR-II荧光成像实验后处死小鼠，并解剖其主要器官(如肝、脑、脾、肌肉、心脏、胃、肾、肠和肺)和肿瘤，进行NIR-II区荧光成像(图13d)。基于这些器官的NIR-II成像图片，我们可以清晰地观察到肿瘤表现出强烈的荧光，表明L1057NPs在肿瘤处富集明显(图13e)。此外，在其他器官中，L1057NPs主要分布于积聚于网状内皮系统，如肝脏和脾脏。
(8)L1057NPs用于光热治疗
由于L1057NPs具有优异的体外光热性能以及肿瘤成像能力，我们进一步将L1057NPs应用于肿瘤光热治疗。我们将4T1荷瘤小鼠随机分为PBS、L1057NPs、PBS+980nm激光、L1057NPs+980nm激光4组，每组实验小鼠5只。为了实现安全光热治疗，我们将980nm激光的激光功率设置为0.72W/cm2(对应于相应的MPE)。在光热治疗期间，利用红外热像仪来监测肿瘤位置的温度变化。如图14a所示，在L1057NPs+980nm激光组中，肿瘤部位的热像颜色由蓝色(低温)迅速变为白色(高温)。定量分析结果表明，肿瘤的温度从～34℃提升至～58℃(图14b)，并保持在此高温保持8min以上，所产生的光热效应足以杀死肿瘤细胞。而其他各组的温度均没有超过42℃，对肿瘤细胞的杀伤作用微乎其微。在进行光热治疗期间，各组小鼠体重均逐渐增加，及表明上述五种实验方案均未造成明显毒性，影响小鼠正常生理活动(图14c)。肿瘤体积每3天测量一次(图14d)，可以看出仅有L1057NPs+980nm激光组成功地抑制了肿瘤增长，具有良好的抗肿瘤效应，而其它组别抗肿瘤效果不明显。光热治疗实验结束以后处死小鼠，并对肿瘤进行切除、称重、拍照。实验结果表明，L1057NPs+980nm激光组对肿瘤的抑制作用最强，而其他各组对肿瘤的抑制作用不明显(图14e)，与活体观测结果一致。为了进一步确定光热治疗效果，我们对肿瘤切片进行H&E染色来分析细胞状态。仅有L1057NPs+980nm激光组细胞形态损伤最严重，其他组别肿瘤细胞形态规则，细胞核完整(图14f)。
图中：
(a)4T1荷瘤小鼠在980nm的(0.72W/cm2)激光照射下的光热图像，以及(b)相应的温度变化曲线；
(c)小鼠治疗后体重和(d)肿瘤体积的变化曲线；
(e)光热治疗后肿瘤质量柱状图和(f)肿瘤组织的H&E染色，标尺：100μm。
申请人进一步的考察了波长为650nm、780nm、808nm、915nm和1064nm的激光用于光热治疗，研究发现在这些波长下的激光可以有效杀死肿瘤细胞，说明在650-1064nm范围内都可有效地实施光热治疗。
以上所述仅为本发明的优选实施例而已，并不用于限制本发明，对于本领域的技术人员来说，本发明可以有各种更改和变化。凡在本发明的精神和原则之内，所作的任何修改、等同替换、改进等，均应包含在本发明的保护范围之内。
Claims (3)
1.一种如式(Ⅰ)所示通式的化合物或其异构体、药学上可接受的水合物或盐在制备成像制剂或光热治疗制剂中的用途，
其中，
R1选自CmH2m+1、CmH2mX、(CH2CH2O)mCH3、(CH2CH2O)mCH2X、
R2选自CmH2m+1、CmH2mX、(CH2CH2O)mCH3、(CH2CH2O)mCH2X、
R3、R4选自CmH2m+1、CmH2mX、(CH2CH2O)mCH3、(CH2CH2O)mCH2X；
X选自卤素原子、N3、C≡CH、COOH、NH2、OH、SH、
W选自CmH2m+1、CmH2mX、(CH2CH2O)mCH3；
n为1-100中的整数，m为0-100中的整数。
2.根据权利要求1所述用途，其特征在于：所述成像制剂作为近红外二区成像制剂。
3.根据权利要求1或2任一所述用途，其特征在于：所述成像制剂用于全身成像；所述全身成像选自脑血管成像、肿瘤成像。
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