CN110787305B - 一种含聚集诱导发光基团的供体-受体类近红外ii区荧光分子的白蛋白纳米制剂 - Google Patents
一种含聚集诱导发光基团的供体-受体类近红外ii区荧光分子的白蛋白纳米制剂 Download PDFInfo
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Abstract
本发明属于药物制剂领域,涉及含聚集诱导发光基团的供体‑受体类近红外II区荧光分子的白蛋白纳米制剂,本发明采用乳化高压均质法将牛血清白蛋白、人血清白蛋白或重组人血清白蛋白与具有聚集诱导发光基团的供体‑受体类荧光分子制备得到纳米粒;所述白蛋白与类荧光分子结合,使分子内旋转受限,分子构象发生改变,改变了扭曲分子内电荷转移和聚集诱导发光效应,得到兼具良好荧光成像和光热转化性能的纳米制剂。该纳米制剂在近红外光的照射下发出近红外II区荧光,并将部分光能转化为热能,实现影像指导的癌症光热治疗,本白蛋白纳米制剂可制备用于近红外II区(NIR‑II,1000‑1700nm)荧光成像和光热治疗的药物,有助于达到肿瘤“诊疗一体化”的目的。
Description
技术领域
本发明属于药物制剂领域,具体涉及一种含聚集诱导发光基团的供体-受体类近红外II区荧光分子的白蛋白纳米制剂及其制备方法。
背景技术
现有技术公开了恶性肿瘤是威胁人类健康的头号杀手,因此,肿瘤的有效诊断和治疗显得尤为重要。目前,近红外II区(NIR-II,1000-1700nm)荧光成像技术日渐发展成为一种高效的肿瘤的诊断手段,与近红外I区(NIR-I,700-950nm)荧光成像相比,因其波长更长,具有极低的背景自发荧光和组织散射干扰,更深的组织渗透能力,以及更高的空间分辨率和对比度,受到越来越多的学者、医生和患者的关注。肿瘤的光热治疗(Photothermaltherapy,PTT)是把照射至肿瘤部位的光能转化为热能,使肿瘤局部温度升高进行杀伤肿瘤细胞的一种新的、有效的肿瘤治疗方法,实践证实,此治疗方法最显著特点是其的无创性或微创性,治疗过程产生的热量仅对照射区域的细胞产生作用,因此相比于传统的肿瘤治疗方法其副作用显著降低。
随着纳米技术的发展,越来越多的在NIR区有强烈吸收的纳米材料被研究和报道,其中包括无机材料,如金纳米材料、碳纳米材料、钯纳米片和硫化铜纳米材料等;有机材料,如有机近红外染料、卟啉脂质体和高分子聚合物等;相较于无机材料,有机材料具有生物相容性高,易于代谢,毒副作用低等优点,更易于临床转化。由于近红外光具有良好的组织渗透性,因此开发具有NIR-II区成像功能、高光热转换性能和光热稳定性、制备方法简单的新型有机小分子可视化光热治疗剂具有良好的临床应用前景,有望实现肿瘤的“诊疗一体化”。在国内外文献中,目前尚未检索到兼具NIR-II区荧光成像和光热治疗功能的有机小分子荧光探针。
研究表明,某些具有供体-受体结构的荧光分子的最大发射波长可大于1000nm;此类荧光分子在非极性溶剂中呈平面结构,以局域激发(Locally excited,LE)态为主,产生强烈的荧光,在极性溶剂中,主要表现为扭曲分子内电荷转移(Twisted intramolecularcharge transfer,TICT)现象,分子内旋转使分子内二面角增大,平面结构受损,使辐射跃迁减少,荧光强度大幅减弱;同时,非辐射跃迁增加,光热转化能力增强。由于机体内环境是以水为主要组成的极性介质,供体-受体类荧光分子进入体内,处于TICT态,表现为荧光强度大幅减弱。如果在供体-受体类荧光分子结构中引入聚集诱导发光基(Aggregation-induced emission,AIE),当荧光分子处在不良溶剂中时,荧光分子将会发生聚集,分子内旋转受限,TICT受到抑制,从而使荧光强度增强。简言之,TICT是一个荧光强度降低,光热转化能力增强的过程;AIE是一个荧光强度增加,光热转化能力降低的过程。
基于现有技术的现状及研究基础,本申请的发明人拟提供一种含聚集诱导发光基团的供体-受体类近红外II区荧光分子的白蛋白纳米制剂及其制备方法
发明内容
本发明的目的在于基于现有技术的现状及研究基础,提供一种含聚集诱导发光基团的供体-受体类近红外II区荧光分子的白蛋白纳米制剂及其制备方法。
本发明采用乳化高压均质法将牛血清白蛋白、人血清白蛋白或重组人血清白蛋白与具有聚集诱导发光基团的供体-受体类荧光分子制备得到纳米粒;所述白蛋白与类荧光分子结合,使分子内旋转受限,分子构象发生改变,改变了扭曲分子内电荷转移和聚集诱导发光效应,从而得到兼具良好荧光成像和光热转化性能的纳米制剂。该纳米制剂在近红外光的照射下发出近红外II区荧光,并将部分光能转化为热能,实现影像指导的癌症光热治疗。
进一步,本白蛋白纳米制剂可制备用于近红外II区(NIR-II,1000-1700nm)荧光成像和光热治疗的药物。
更具体的,本发明的含聚集诱导发光基团的供体-受体类近红外II区荧光分子的白蛋白纳米制剂,由含聚集诱导发光基团的供体-受体类近红外II区荧光分子和白蛋白组成;
所述的含聚集诱导发光基团的供体-受体类近红外II区荧光分子,其结构通式为:
其中,D:供体基团;A:受体基团;X,Y=S,Se或Te。
本发明中,所述的荧光分子与白蛋白的质量比为1∶1-1∶100,优选地,质量比为1∶6-1∶15,制剂的载药量为1%~10%,制剂的粒径为50-1000nm。
本发明中,所述的受体基团(A)为下式含硫、硒或碲芳香杂环化合物,
X,Y=S,Se或Te。
本发明中,所述的供体基团(D)为如下结构的具有聚集诱导发光效应的二苯胺、三苯胺、四苯乙烯、四苯基吡嗪及其衍生物,
其中,R1=苯基,噻吩基;R2,R3=氢,羟基,氨基,卤素,C1-C20烷基,杂烷基,环烷基,芳基,杂芳基;或,
其中,R1=苯基,噻吩基;R2,R3,R4=氢,羟基,氨基,卤素,C1-C20烷基,杂烷基,环烷基,芳基,杂芳基,或,
其中,R1=苯基,噻吩基;R2,R3,R4,R5=氢,羟基,氨基,卤素,C1-C20烷基,杂烷基,环烷基,芳基,杂芳基;或,
其中,R1,R2,R3=氢,羟基,氨基,卤素,C1-C20烷基,杂烷基,环烷基,芳基,杂芳基。
本发明中,所述的白蛋白选自人血清白蛋白、重组人血清白蛋白或牛血清白蛋白中的一种或几种的混合物。
本发明提供了所述的含聚集诱导发光基团的供体-受体类近红外II区荧光分子的白蛋白纳米制剂的制备方法,包括步骤:
(1)将白蛋白溶解于水中;
(2)将所述荧光分子溶解于甲醇、乙醇、丙二醇、氯仿、二氯甲烷、四氢呋喃或它们的混合溶剂中;
(3)将步骤(1)的水溶液与步骤(2)的有机溶液混合均匀,得到白色乳液;
(4)将步骤(3)得到的混合液高压均质,使粒径控制在50-1000nm;
(5)将步骤(4)得到的产物减压去除有机溶剂,制得白蛋白纳米制剂。
作为优选,上述制备方法还包括将步骤(5)所获得的纳米制剂溶液进行脱水的步骤;优选地,所述的脱水处理为冷冻干燥。
优选地,步骤(1)中所述的白蛋白水溶液浓度为0.5%-20%(w/v),优选为1%-2%(w/v)。
优选地,步骤(2)中的荧光分子与步骤(1)中的白蛋白的比例为1∶6-1∶15(w/w)。
优选地,步骤(2)中的有机溶剂与步骤(1)中的水的比例为1∶20-1∶50(v/v)。
优选地,步骤(2)中的有机溶剂由疏水性有机溶剂和亲水性有机溶剂混合而成;所述的疏水性有机溶剂是四氢呋喃、氯仿、二氯甲烷或两种或三种的混合溶剂;所述的亲水性有机溶剂可以为无水乙醇、甲醇或其混合溶剂;有机溶剂与步骤(1)中水溶液的比例为1∶20-1∶50(v/v)。
优选地,步骤(4)中所述的高压均质,压力范围为10000psi--20000psi,循环次数为10-20次。
本发明制备的纳米制剂与原荧光小分子进行了比较试验,结果显示,本纳米制剂水溶性得到极大提高,达到了兼具NIR-II区荧光成像和光热转化能力的要求;经小鼠体内实验显示,本发明的此类荧光探针白蛋白纳米制剂的肿瘤靶向效果良好,能够实现肿瘤部位累积,在808nm激光照射下,可以实现肿瘤原位灶和转移灶的清晰成像;进一步的NIR-II区荧光成像指导的肿瘤光热治疗实验结果显示,本纳米制剂在体内具有良好的光热转化能力,能够有效杀死肿瘤细胞。
本发明通过采用白蛋白作为载体,制备了具有AIE基团的供体-受体类荧光分子的白蛋白纳米制剂,其中,利用具有AIE基团的供体-受体类荧光分子与白蛋白结合时荧光分子内旋转受限,分子平面性发生变化的特性,改变荧光分子的TICT和AIE效应,从而得到满足可视化光热治疗要求的兼具荧光成像和光热转化性能的诊疗一体化制剂。
下面结合附图和实施例、对本发明作进一步描述。
附图说明
图1.BPBBT纳米粒的TEM图和粒径分布图。
图2显示,(a)BPBBT(10μM)和BPBBT纳米粒(10μM)在不同溶液中的荧光光谱;(b)BPBBT(10μM)和BPBBT纳米粒(10μM)溶液可见光照片和溶液在808nm激光照射(激光功率密度为0.1W/cm2)下NIR-II区荧光成像。
图3显示,BPBBT纳米粒的磷酸缓冲盐溶液(200μM)和BPBBT的5%THF溶液(200μM),在808nm激光照射下(激光功率密度为0.8W/cm2)的溶液温度,激光照射10分钟,然后移去激光自然冷却至室温。
图4为BPBBT纳米粒在荷CT26-Luc皮下瘤模型小鼠体内NIR-II区荧光成像,其中显示鼠静脉给药(20mg/kg)48小时内的可见光照片及在808nm激光照射下(激光功率密度为0.1W/cm2)的NIR-II区荧光成像,箭头指示肿瘤位置。
图5显示了荷CT26-Luc原位瘤模型小鼠给药(20mg/kg)后30小时处肿瘤部位的原位瘤(a)和转移瘤(b,c)的可见光照片和相应的NIR-II区荧光成像(808nm,激光功率密度为0.1W/cm2)。箭头指示原位瘤或转移瘤位置。
图6显示了荷CT26-Luc原位瘤模型小鼠光热治疗效果,其中,(a)小鼠静脉给药(20mg/kg)或磷酸缓冲盐溶液后30小时原位瘤和转移瘤接受光照时肿瘤部位温度变化曲线,其中,给BPBBT纳米粒组小鼠,对于3×3mm大小的原位瘤施以808nm激光照射(激光功率密度为5W/cm2);3×3mm大小的转移瘤1施以808nm激光照射(激光功率密度为6W/cm2);1×1mm大小的转移瘤2施以808nm激光照射(激光功率密度为20W/cm2),给磷酸缓冲盐溶液组小鼠,对于3×3mm大小的原位瘤施以808nm激光照射(激光功率密度为5W/cm2);另外选取3×3mm大小的盲肠区域1施以808nm激光照射(激光功率密度为6W/cm2);1×1mm大小的盲肠区域2施以808nm激光照射(激光功率密度为20W/cm2)作为相应对照;(b)NIR-II区影像指导的光热治疗组、传统光热治疗组(即非影像指导的光热治疗组)和磷酸缓冲盐溶液组小鼠的生物发光强度变化图,(n=5)(c)NIR-II区影像指导的光热治疗组、传统光热治疗组(即非影像指导的光热治疗组)和磷酸缓冲盐溶液组小鼠的生存曲线,ns:无显著性差异,(n=5)。
具体实施方式
实施例1
化合物1(BPBBT)是具有AIE基团的供体-受体类NIR-II荧光分子,
将人血清白蛋白溶解于水中,并混合均匀,使蛋白浓度为1.5%(w/v),称取30g1.5%白蛋白水溶液(w/v)于50ml烧杯中,准确称取30.0mg BPBBT溶解于有机溶剂(氯仿∶无水乙醇=15∶85)中,按照药物质量∶蛋白质量=1∶15,有机溶剂与蛋白水溶液中的水的比例为1∶44制备,高速搅拌,制备粗乳,得到白色乳液;将白色乳液在20000psi压力下均质,使粒径控制在50-200nm;利用旋转蒸发仪将获得的BPBBT白蛋白纳米粒溶液中的有机溶剂去除后,用0.22μm的无菌滤膜过滤,冷冻干燥,得到BPBBT纳米粒的冻干粉末,纳米制剂的粒径、聚合物分散系数(Polymer dispersion index,PDI)、载药量和包封率(如表1所示),以及形态(如图1所示);
表1
BPBBT经831nm激发,其发射波长在900nm-1400nm,为NIR-II区荧光。BPBBT在良性极性溶剂70%四氢呋喃(THF)中表现为荧光淬灭,在不良溶剂5%THF中表现为AIE现象,发出强烈荧光,将BPBBT制备成白蛋白纳米制剂,其在水中的荧光强度介于BPBBT在5%THF与BPBBT在70%THF之间,表明将BPBBT制备成白蛋白纳米制剂后可以调节BPBBT的荧光强度(如图2所示);
采用热电偶检测200μM的BPBBT纳米粒的磷酸缓冲盐溶液,在808nm激发光源(激光功率密度为0.8W/cm2)照射10分钟后的溶液温度,显示BPBBT纳米粒溶液的升高温度大于相同浓度BPBBT在5%THF中的升高温度,证实将BPBBT制备成白蛋白纳米制剂后可以调节BPBBT的光热转化效率(如图3所示);
采用BALB/c小鼠右腹侧部位注射CT26结肠癌细胞,构建结肠癌皮下瘤模型,利用此模型于肿瘤体积达到100mm3时,静脉注射BPBBT纳米粒(20mg/kg),分别在0,1,2,4,8,12,24,30,36和48小时处,进行NIR-II区荧光成像(如图4所示),结果证实具有良好的肿瘤成像效果;
采用CT26-Luc细胞株建立原位结肠癌模型,静脉注射BPBBT纳米粒(20mg/kg)30小时后,切开盲肠部位的皮肤及腹膜,暴露肠段,对原位灶和转移灶分别进行NIR-II区荧光成像,可以对肿瘤的原位灶以及大小约为0.5mm的转移灶清晰成像(如图5所示),在NIR-II区荧光成像下,采用光纤对肿瘤部位实施光热治疗,肿瘤部位温度可以达到51℃。治疗后30天内荷瘤小鼠肿瘤未复发(如图6所示),而未经NIR-II荧光成像下的光热治疗,小鼠在30天内全部复发死亡。
实施例2
化合物2(BTPBBT)是具有AIE基团的供体-受体类NIR-II荧光分子,
将人血清白蛋白溶解于水中,并混合均匀,使蛋白浓度为0.5%(w/v),称取30g0.5%白蛋白水溶液(w/v)于50ml烧杯中。准确称取30.0mg BTPBBT溶解于有机溶剂(二氯甲烷∶无水乙醇=15∶85)中,按照药物质量∶蛋白质量=1∶15,有机溶剂与蛋白水溶液中的水的比例为1∶30的比例制备,高速搅拌,制备粗乳,得到白色乳液;将白色乳液在20000psi压力下均质,使粒径控制在50-200nm;利用旋转蒸发仪将获得的BTPBBT白蛋白纳米粒(BTPBBT纳米粒)溶液中的有机溶剂去除后,用0.22μm的无菌滤膜过滤,冷冻干燥,得到BTPBBT纳米粒的白蛋白纳米粒的冻干粉末,纳米制剂的粒径、PDI、载药量和包封率(如表2所示),以及形态;
表2
BTPBBT经831nm激发,其发射波长在900nm-1400nm,为NIR-II区荧光。BTPBBT在良性极性溶剂70%THF中表现为荧光淬灭,在不良溶剂5%THF中表现为AIE现象,发出强烈荧光,将BTPBBT制备成白蛋白纳米制剂,其在水中的荧光强度介于BTPBBT在5%THF与BTPBBT在70%THF之间,表明将BTPBBT制备成白蛋白纳米制剂后可以调节BTPBBT的荧光强度;
采用热电偶检测200μM的BTPBBT纳米粒磷酸缓冲盐溶液(按照含BTPBBT的浓度计算),在808nm激发光源(激光功率密度为0.8W/cm2)照射10分钟后的溶液温度;显示现BTPBBT纳米粒溶液的升高温度大于相同浓度BTPBBT在5%THF中的升高温度,证实将BTPBBT制备成白蛋白纳米制剂后可以调节BTPBBT的光热转化效率;
采用CT26-Luc细胞株建立原位结肠癌模型,静脉注射BTPBBT纳米粒(20mg/kg)30小时后,切开盲肠部位的皮肤及腹膜,暴露肠段,对原位灶和转移灶分别进行NIR-II区荧光成像,可以对肿瘤的原位灶以及大小约为0.5mm的转移灶清晰成像,在NIR-II区荧光成像下,采用光纤对肿瘤部位实施光热治疗,肿瘤部位温度可以达到51℃,治疗后30天内荷瘤小鼠肿瘤未发现复发,而未经NIR-II荧光成像下的光热治疗,小鼠在30天内全部复发死亡。
实施例3
化合物3(TPABBT)是具有AIE基团的供体-受体类NIR-II荧光分子。
将人血清白蛋白溶解于水中,并混合均匀,使蛋白浓度为3.5%(w/v),称取30g3.5%白蛋白水溶液(w/v)于50ml烧杯中,准确称取30.0mg TPABBT溶解于有机溶剂(氯仿∶无水甲醇=20∶80)中,按照药物质量∶蛋白质量=1∶30,有机溶剂与蛋白水溶液中的水的比例为1∶88的比例制备,高速搅拌,制备粗乳,得到白色乳液;将白色乳液在20000psi压力下均质,使粒径控制在50-200nm;利用旋转蒸发仪将获得的TPABBT白蛋白纳米粒(TPABBT纳米粒)溶液中的有机溶剂去除后,用0.22μm的无菌滤膜过滤,冷冻干燥,得到TPABBT纳米粒的白蛋白纳米粒的冻干粉末,纳米制剂的粒径、PDI、载药量和包封率(表3),以及形态;
表3
TPABBT经831nm激发,其发射波长在900nm-1600nm,为NIR-II区荧光,TPABBT在良性极性溶剂70%THF中表现为荧光淬灭,在不良溶剂5%THF中表现为AIE现象,发出强烈荧光,将TPABBT制备成白蛋白纳米制剂,其在水中的荧光强度介于TPABBT在5%THF与TPABBT在70%THF之间,表明将TPABBT制备成白蛋白纳米制剂后可以调节TPABBT的荧光强度;
采用热电偶检测200μM的TPABBT纳米粒磷酸缓冲盐溶液(按照含TPABBT的浓度计算),在808nm激发光源(激光功率密度为0.8W/cm2)照射10分钟后溶液温度,发现TPABBT纳米粒溶液的升高温度大于相同浓度TPABBT在5%THF中的升高温度,证实将TPABBT制备成白蛋白纳米制剂后可以调节TPABBT的光热转化效率;
采用CT26-Luc细胞株建立原位结肠癌模型,静脉注射TPABBT纳米粒(20mg/kg)30小时后,切开盲肠部位的皮肤及腹膜,暴露肠段,对原位灶和转移灶分别进行NIR-II区荧光成像,可以对肿瘤的原位灶以及大小约为0.5mm的转移灶清晰成像,在NIR-II区荧光成像下,采用光纤对肿瘤部位实施光热治疗,肿瘤部位温度可以达到51℃,治疗后30天内荷瘤小鼠肿瘤未发现复发,而未经NIR-II荧光成像下的光热治疗,小鼠在30天内全部复发死亡。
实施例4
化合物4(TPBBT)是具有AIE基团的供体-受体类NIR-II荧光分子,
将人血清白蛋白溶解于水中,并混合均匀,使蛋白浓度为20%(w/v),称取30g20%白蛋白水溶液(w/v)于50ml烧杯中,准确称取30.0mgTPBBT溶解于有机溶剂(THF∶无水乙醇=10∶90)中,按照药物质量∶蛋白质量=1∶80,有机溶剂与蛋白水溶液中的水的比例为1∶75的比例制备,高速搅拌,制备粗乳,得到白色乳液;将白色乳液在20000psi压力下均质,使粒径控制在50-200nm;利用旋转蒸发仪将获得的TPBBT白蛋白纳米粒(TPBBT纳米粒)溶液中的有机溶剂去除后,用0.22μm的无菌滤膜过滤。冷冻干燥,得到TPBBT纳米粒的白蛋白纳米粒的冻干粉末,纳米制剂的粒径、PDI、载药量和包封率(表4),以及形态;
表4
TPBBT经831nm激发,其发射波长在900nm-1400nm,为NIR-II区荧光,TPBBT在良性极性溶剂70%THF中表现为荧光淬灭,在不良溶剂5%THF中表现为AIE现象,发出强烈荧光,将TPBBT制备成白蛋白纳米制剂,其在水中的荧光强度介于TPBBT在5%THF与TPBBT在70%THF之间,表明将TPBBT制备成白蛋白纳米制剂后可以调节TPBBT的荧光强度;
采用热电偶检测200μM的TPBBT纳米粒磷酸缓冲盐溶液(按照含TPBBT的浓度计算),在808nm激发光源(激光功率密度为0.8W/cm2)照射10分钟后溶液温度,显示TPBBT纳米粒溶液的升高温度大于相同浓度TPBBT在5%THF中的升高温度,证实将TPBBT制备成白蛋白纳米制剂后可以调节TPBBT的光热转化效率;
采用CT26-Luc细胞株建立原位结肠癌模型,静脉注射TPBBT纳米粒(20mg/kg)30小时后,切开盲肠部位的皮肤及腹膜,暴露肠段,对原位灶和转移灶分别进行NIR-II区荧光成像,可以对肿瘤的原位灶以及大小约为0.5mm的转移灶清晰成像,在NIR-II区荧光成像下,采用光纤对肿瘤部位实施光热治疗,肿瘤部位温度可以达到51℃,治疗后30天内荷瘤小鼠肿瘤未发现复发,被全部治愈,而未经NIR-II荧光成像下的光热治疗,小鼠在30天内全部复发死亡。
Claims (5)
2.按权利要求1所述的含聚集诱导发光基团的供体-受体类近红外II区荧光分子的白蛋白纳米制剂,其特征在于,所述的荧光分子与白蛋白的质量比为1∶1-1∶100,制剂的载药量为1%~10%,制剂的粒径为50-1000nm。
3.按权利要求1所述的含聚集诱导发光基团的供体-受体类近红外II区荧光分子的白蛋白纳米制剂,其特征在于,所述的白蛋白选自人血清白蛋白、重组人血清白蛋白或牛血清白蛋白中的一种或几种的混合物。
4.权利要求1所述的含聚集诱导发光基团的供体-受体类近红外II区荧光分子的白蛋白纳米制剂的制备方法,其特征在于,采用乳化高压均质法制备,其包括步骤:
(1)将白蛋白溶解于水中;
(2)将所述荧光分子溶解于甲醇、乙醇、丙二醇、氯仿、二氯甲烷、四氢呋喃或它们的混合溶剂中;
(3)将步骤(1)的水溶液与步骤(2)的有机溶液混合均匀;
(4)将步骤(3)得到的混合液高压均质;
(5)将步骤(4)得到的产物减压去除有机溶剂,制得白蛋白纳米制剂。
5.权利要求1所述的含聚集诱导发光基团的供体-受体类近红外II区荧光分子的白蛋白纳米制剂在制备用于体内近红外II区荧光成像和光热治疗药物中的用途。
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