CN110950899B - 一种具有超高效无能垒转子用于光热疗法的光热试剂及其制备方法与应用 - Google Patents
一种具有超高效无能垒转子用于光热疗法的光热试剂及其制备方法与应用 Download PDFInfo
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Abstract
本发明公开了一种具有超高效无能垒转子用于光热疗法的光热试剂及其制备方法与应用,属于纳米材料领域。本发明基于氟化硼二吡咯(BODIPY)母体合成光热试剂,在meso‑位置(tfm‑BDP)引入‑CF3“无能垒”转子。tmf‑BDP在近红外激光照射(808nm)下,激发态的‑CF3自由旋转,从而导致将光能高效的转化为热能。重要的是,在将tmf‑BDP封装成聚合物纳米颗粒之后,仍然可以保持‑CF3的自由旋转。因此,tfm‑BDP NPs显示超高的光热转化效率为88.3%。在静脉注射tfm‑BDP NPs后,即使在安全强度(0.3Wcm‑2,808nm)的激光照射后,也能够诱导荷瘤小鼠的完全肿瘤消融。“无能垒转子”策略为抗癌治疗PPT药剂的进一步设计提供了新的平台。
Description
技术领域
本发明涉及一种具有超高效无能垒转子用于光热疗法的光热试剂及其制备方法与应用,属于纳米材料领域。
背景技术
光热疗法(PTT)是一种典型的光子触发治疗方式,它通过在可见或近红外(NIR)光下由光热试剂产生的局部高温杀死肿瘤细胞。在现有的光热试剂中,NIR吸收有机材料被认为是有前途的光热试剂,具有良好的生物相容性、潜在的生物降解性和较高的重现性。光热转换效率是光热试剂的一个关键因素,它直接决定光热治疗过程中的激发光强。高强度的激发光很容易对皮肤和组织造成损害。据知,到目前为止最高的有机材料光热试剂的最高光热转化效率为64.7%。然而,这个光热试剂在近红外激光(808nm)的照射强度为1.0W cm-2才能使肿瘤完全消退,远高于最大允许照射光强度(MPE)(808nm,0.33W cm-2)。因此,提高光热试剂的光热转化效率,降低激发光强度,进一步推动体内安全的光热治疗,是非常迫切的。
为了应对上述挑战,学者们致力于增强非辐射衰减,以提高光热转换效率。例如,黄和他的同事利用分子内光诱导电子转移(PET)机制报道了一种光热剂,这种机制能够淬灭荧光,从而提高光热转换效率。Bazan和他的同事通过在共轭的寡电解质核中引入给吸电子减小光学能隙,从而提高辐射衰变。唐和同事报告,通过增强的分子运动来调节暗态扭曲分子内电荷转移态,从而增强了光热效应。这些工作和努力确实为设计PTT开辟了新的途径。然而,PTT的效率还有待进一步提高,已报道的光热试剂所需的近红外激发光强度通常大于等于0.8W cm-2,这远高于皮肤和组织最大允许的激发光强度。例如,在808nm的连续照射下,皮肤的最大允许的激发光强度为0.33W cm-2。光热治疗中使用的不安全激光强度是临床过渡中最严重的障碍之一。因此,设计具有更高光热转换效率的PTT新材料是非常必要的。
发明内容
为解决上述问题,本发明提供了一种具有超高效无能垒转子用于光热疗法的纳米粒子(tfm-BDP)。在BODIPY的meso位置引入-CF3,-CF3作为转动基团。tfm-BDP在NIR(808nm)激光照射下,导致-CF3自由旋转,这种无能垒旋转使tfm-BDP在激发态到基态属于超高效非辐射跃迁,最大限度地将光能转化为热能。此外,-CF3会使分子骨架发生明显扭曲,从而抑制平行梯状π-π堆积(H-聚集)。因此,将tfm-BDP包封在聚合物纳米粒子中,无能垒旋转可以继续保持在聚集状态。tfm-BDP NPs具有超高效光热转换88.3%,能显著提高温度,即使用低强度激光照射(808nm,0.3W cm-2)也能使皮下肿瘤完全消融。这种“无能垒”转子的策略将为临床PTT应用提供一个有希望的平台。
本发明提供了一种具有超高效无能垒转子用于光热疗法的光热试剂,所述光热试剂结构如通式Ⅰ所示:
其中,R1为CX3,X为F、Cl、Br或I;R2为OH、-NH2或通式Ⅱ,n=1,2,3……n;R3为F或通式Ⅲ,n=1,2,3……n。
进一步地,所述光热试剂结构如通式Ⅰ所示:
其中,R1为CX3,X为F、Cl、Br或I;R2为OH、-NH2或通式Ⅱ,n=1-10;R3为F或通式Ⅲ,n=1-10。
本发明还提供了一种具有超高效无能垒转子用于光热疗法的光热试剂的制备方法,包括如下步骤:
(1)在N2保护下,将CX3COOH和2,4-二甲基吡咯溶于CH2Cl2中,向溶液中滴加PhSiCl3并不断搅拌;向所得溶液中滴加Et3N,继续搅拌;再滴加BF3·Et2O溶液,继续搅拌;用饱和食盐水冲洗所得的反应混合物,用CH2Cl2提取水溶液,保留CH2Cl2层;将所得溶液用MgSO4干燥、过滤,蒸发有机溶剂、真空干燥箱中干燥,利用硅胶柱层析进行纯化,得化合物2;
(2)将化合物2与化合物3、AcOH和哌啶混合后加入活化分子筛,用干燥的甲苯做溶剂,搅拌回流;反应液冷却到室温,用水淬灭反应;用CH2Cl2萃取,饱和食盐水冲洗,Na2SO4干燥,蒸发溶剂;经薄层色谱纯化,得用于光热疗法的光热试剂化合物4;
或者将化合物4滴加到盛有AlCl3的CH2Cl2溶液中,回流反应,然后加入化合物5室温反应,粗产物减压浓缩,用CH2Cl2洗脱的碱性氧化铝柱层析纯化,得到用于光热疗法的光热试剂化合物6;
进一步地,所述步骤(1)中CX3COOH:2,4-二甲基吡咯:PhSiCl3的摩尔比为1:2:1,搅拌时间为3-6h,搅拌温度为室温。
进一步地,所述步骤(1)中Et3N与2,4-二甲基吡咯的摩尔比为5:1,添加Et3N后室温搅拌10-20分钟;BF3·Et2O溶液与Et3N的摩尔比为1.5:1,添加BF3·Et2O溶液后室温搅拌10-12h。
进一步地,所述步骤(1)中进行硅胶柱层析使用的淋洗剂的体积比为CH2Cl2:正己烷=1:3。
进一步地,所述步骤(2)中化合物2与化合物3的摩尔比为1:5,AcOH和哌啶为催化量;搅拌回流的条件为80℃搅拌回流2-4小时;薄层色谱展开剂的体积比为CH2Cl2:正己烷=3:1。
进一步地,所述步骤(2)中化合物4:AlCl3:化合物5的摩尔比为1:5:5;回流反应的条件为40℃,搅拌回流5-8min;室温反应时间为20-25min;柱层析洗脱液的体积比为CH2Cl2:CH3OH=20:1。
本发明还提供了利用所述光热试剂制备得到的具有超高效无能垒转子用于光热疗法的纳米粒子,制备方法包括如下步骤:将权利要求1所述的光热试剂溶解在四氢呋喃中,在超声处理下将其加入含DSPE-PEG2000的水中,所得分散液超声处理,得胶体分散体;将胶体分散体进行透析,收集透析管中的溶液即为用于光热疗法的纳米粒子。
进一步地,所述四氢呋喃和DSPE-PEG2000的体积比为1:5,所得分散液超声处理30-40分钟,所用的水为超纯水;所述胶体分散体透析的具体步骤为:将胶体分散体在超纯水中透析2-4天,在透析过程中,每4-6小时更换超纯水,最后用生理盐水透析分散液,透析袋为再生纤维素透析袋3500,收集透析袋中的溶液。
本发明还提供了具有超高效无能垒转子用于光热疗法的光热试剂在制备抗肿瘤药物中的应用。
发明有益效果
本发明所述tfm-BDP纳米粒子在NIR(808nm)激光照射下,导致-CF3自由旋转,这种无能垒旋转使tfm-BDP纳米粒子在激发态到基态属于超高效非辐射跃迁,最大限度地将光能转化为热能。将tfm-BDP包封在聚合物纳米粒子中,无能垒旋转可以保持在聚集状态。tfm-BDP NPs具有超高效光热转换88.3%,能显著提高温度,即使用低强度激光照射(808nm,0.3W cm-2)也能使皮下肿瘤完全消融。
附图说明
图1为本发明实施例1中制备光热试剂的化学方程式。
图2(a)为tfm-BDP、m-BDP和H-BDP的分子结构;图2(b)和图2(c)为tfm-BDP、m-BDP和H-BDP三种光热试剂的吸收和发射光谱;图2(d)为tfm-BDP NPs的TEM图像;图2(e)为tfm-BDP NPs的动态光散射(DLS);图2(f)为tfm-BDP、m-BDP和H-BDP三种纳米粒子在水中的吸收光谱;图2(g)为不同浓度(5~50μM)tfm-BDP NPs在808nm激光照射(0.3W cm-2)下的光热转换;图2(h)为808nm激光照射(0.3W cm-2,5min)下tfm-BDP纳米粒子和水的光热像;图2(i)为在不同曝光强度(0.1~0.8W cm-2)的808nm激光照射下,tfm-BDP纳米粒子的光热转换;图2(j)为tfm-BDP NPs在五个加热-冷却过程中的光热稳定性研究;图2(k)为不同浓度tfm-BDPNPs的光声图像;图2(l)为PA信号强度与tfm-BDP NPs浓度的线性关系。
图3(a)为tfm-BDP NPs的HOMO和LUMO能级;图3(b)为tfm-BDP NPs沿转动基态和激发态的势能曲线;图3(c)和图3(d)为(tfm-BDP中BODIPY与-CF3之间的二面角)单分子和tfm-BDP NPs的典型二面角分布。
图4为分子动力学模拟得到的非晶态tfm-BDP NPs的快照。
图5(a)为HeLa、MCF-7和4T1细胞在不同浓度tfm-BDP NPs孵育在黑暗和NIR光(808nm,0.3wcm,2,5min)照射后的细胞存活率;图5(b)为用30μm tfm-BDP NPs培养细胞后进行NIR光(808nm,0.3W cm-2,5min)照射MCF-7细胞,流式细胞术对不同处理后MCF-7细胞的凋亡和坏死分析。
图6(a)为在小鼠静脉内(i.v.)注射tfm-BDP NPs后的肿瘤的光声(PA)图像;图6(b)为在小鼠静脉内(i.v.)注射tfm-BDP NPs后的肿瘤的光声(PA)信号强度;图6(c)在小鼠静脉注射tfm-BDP NPs或盐水注射8小时后并用808nm 0.3Wcm-2激光照射7分钟的4T1荷瘤小鼠的热红外(IR)图像;图6(d)为在小鼠静脉注射tfm-BDP NPs或盐水注射8小时后并用808nm 0.3Wcm-2激光照射7分钟的4T1荷瘤小鼠对应肿瘤的温度变化曲线;图6(e)为不同治疗后小鼠的肿瘤体积变化;图6(g)为不同治疗后小鼠的体重变化;图6(f)为治疗后第18天肿瘤的平均重量;图6(h)为肿瘤组织的(H&E)染色(标尺:100μm)。
图7为tfm-BDP、m-BDP和H-BDP在不同浓度甘油下的荧光发射(a为tfm-BDP、b为m-BDP;c为H-BDP)。
图8为在不同曝光强度(0.1~0.8W cm-2)的808nm激光照射下,tfm-BDP在DMF溶液中的光热转换。
具体实施方式
下述非限定性实施例可以使本领域的普通技术人员更全面地理解本发明,但不以任何方式限制本发明。
实施例1
如图1所示,本发明合成了一系列不同取代结构的光热试剂,具体步骤如下:
化合物1a的合成:3,5-二甲基吡咯醛(100mg,0.81mM)溶于干燥的CH2Cl2(15mL)中。在0℃氩气气氛下,将POCl3(124mg,0.81mM)缓慢加入上述溶液中。将反应溶液在0℃下搅拌1小时,然后在室温加入NEt3(750mg,7.4mm)搅拌4小时,然后加入BF3·Et2O(0.93ml,7.4mM)反应2小时后,在真空下蒸发溶剂,用EtOAc(200ml)萃取。然后用H2O(3×50ml)洗涤有机层,并用无水Na2SO4干燥。粗产物用硅胶柱色谱(己烷/EtOAc=5∶1)纯化,得到99mg(49%)的1a(红色晶体)。
化合物2a的合成:在N2保护,室温下,将CF3COOH(0.35mL)和2,4-二甲基吡咯1a(1.0mL)溶于20mLCH2Cl2中,向溶液中滴加PhSiCl3(0.75毫升)搅拌5个小时。滴加Et3N(1.5毫升),继续搅拌15分钟。滴加BF3·Et2O溶液(2.0毫升),保持搅拌12h。用饱和食盐水(2x100mL)冲洗反应混合物,用CH2Cl2提取水溶液。MgSO4干燥有机层、过滤和蒸发有机溶剂,将有机层混合干燥。产物通过硅胶柱层析纯化,淋洗剂(CH2Cl2/正己烷=1:3)。以得到纯净的2a(306.8毫克,20%)为暗红色固体.
化合物2a的核磁氢谱分析如下:1H NMR(400MHz,CDCl3):δ(ppm)6.15(s,2H),2.53(s,6H),2.29(s,6H).13C NMR(101MHz,CDCl3):δ(ppm)158.8,143.1,131.1,124.3,123.6,120.9,15.9,14.9.11B NMR(128MHz,CDCl3):δ(ppm)0.38(t,J=32Hz).19F NMR(376MHz,CDCl3):δ(ppm)-52.7(t,J=7.5Hz,3F),-146.1(q,J=31.9Hz,2F).
化合物3a的合成:在室温下,向2,4-二甲基吡咯(5.4mL,52.0mM)的CH2Cl2(20mL)溶液中滴加乙酰氯(8.7mL,121.4mm)。深红溶液加热回流1h,冷却后倒入正己烷(100ML),至旋转蒸发器浓缩、干燥。所得到的化合物无需进一步纯化即可使用。然后,加入CH2Cl2(240ML)溶液中,加入NEt3(20.9mL,150mM),室温下搅拌15min。在此基础上,滴加BF3·Et2O(27.8mL,225mm),室温下搅拌1h。得到深红溶液,用饱和Na2CO3溶液(4×100mL)洗涤,用Na2SO4干燥,浓缩。硅胶上柱层析纯化红色油性残渣,干燥得橙色荧光产物组分,从CH2Cl2/MeOH中重结晶生成红橙结晶固体。产率(4.924g,72%)。
光热试剂H-BDP的合成:4-二甲氨基苯甲醛,化合物1a(其中,化合物1a与4-二甲氨基苯甲醛的摩尔比为1:5),AcOH(0.10mL)和哌啶(0.10mL)添加少量活化分子筛,用干燥的甲苯做溶剂。80℃下搅拌回流3个小时。将该混合物冷却到室温,用水淬灭。CH2Cl2萃取,用饱和食盐水冲洗,经Na2SO4干燥,蒸发溶剂。经薄层色谱(CH2Cl2/正己烷=3:1)纯化。
光热试剂tfm-BDP的合成:仅将化合物1a替换成化合物2a,其余步骤及用量均不变。
光热试剂m-BDP的合成:仅将化合物1a替换成化合物3a,其余步骤及用量均不变。
光热试剂H-BDP、tfm-BDP和m-BDP的核磁氢谱分析如下:
tfm-BDP:1H NMR(500MHz,CD2Cl2):δ(ppm)7.65-7.43(m,3H),7.30(d,J=16.3Hz1H),6.92-6.65(m,3H),3.05(s,6H),2.35(s,3H).HRMS-MALDI(m/z):[M+H]+calcd forC32H33BF5N4:579.30018;found:579.2993.
m-BDP:1H NMR(500MHz,CDCl3)δ7.53(s,4H),6.71(s,4H),3.02(s,6H),2.47(s,3H),1.54(s,3H).HRMS-MALDI(m/z):[M+H]+calcd for C32H36BF2N4:525.3001;found:525.2993.
H-BDP:1H NMR(500MHz,CDCl3)δ7.53(s,4H),6.79(d,J=76.1Hz,3H),3.03(s,6H),2.29(s,3H).HRMS-MALDI(m/z):[M+H]+calcd for C31H34BF2N4:511.2845;found:511.2845.
通过核磁氢谱质谱的分析,均成功合成出了目标化合物。
纳米粒子制备:将光热试剂(H-BDP、M-BDP或TFM-BDP)溶解在THF(1mg,1mL)中,在超声处理(180W)下将其加入含DSPE-PEG2000(5mg,5mL)的Milli-Q水中。所得分散液在超声处理(180W)中进一步保持40分钟。此后,将胶体分散体在Milli-Q水中透析3天,以除去有机溶剂。在透析过程中,每6小时更换Milli-Q水,最后用生理盐水透析分散液,透析袋为再生纤维素透析袋3500,然后收集透析管中的溶液,溶液即为所需纳米粒子。
实施例2
对三种光热试剂的紫外-可见光谱进行测定,由图2(b)可知,光热试剂tfm-BDP在810nm处有一个主吸收峰。由于PTT在近红外区域的长吸收波长是体内应用的重要前提之一,因为与UV或可见光相比,NIR能激发PTT的光活性,使其深入组织,造成较少的组织损伤。NIR吸收是由于其固有组分包括-CF3电子受体和N,N-二甲基氨基电子供体所引起的强的电子捐赠和接受强度(D-A)所致。作为比较,光热试剂H-BDP和m-BDP的最大吸收波长在670~700nm,比tfm-BDP的吸收波长短得多,因为它们的结构缺乏D-A强度。
对三种光热试剂的光致发光(PL)进行测定。由图2(c)可知,光热试剂H-BDP和m-BDP变现出了强发射,而tfm-BDP几乎没有发射。tfm-BDP的非发射特性将通过非辐射途径消耗激发态的能量,从而产生高效的光热效应。
另外,测试了粘度对PL的影响,使用不同浓度的甘油(0-100%)(图7)。即使在100%甘油中,tfm-BDP的光致发光强度也几乎没有变化,这可能是由于-CF3分子在中间位置的“自由能垒”旋转所致。随着溶液粘度的增加,m-BDP的PL逐渐增强,这是因为-CH3的旋转受到抑制,从而减少了非辐射衰变,导致PL增强。因此,高效旋转的-CF3可以保证良好的光热效应。
以两亲性共聚物(DSPE-PEG2000)为包封基质,通过纳米粒子沉淀法将tfm-BDP、m-BDP和H-BDP制备成纳米粒子。在此过程中,疏水分子随机聚集在核内,亲水PEG链形成壳层,形成水溶性纳米粒子(NPs)。分别用透射电镜(TEM)和动态光散射(DLS)对tfm-BDP、m-BDP和H-BDP NPs的尺寸和形貌进行了表征,如图2(d)为纳米粒子tfm-BDP的透射电镜图,透射电镜显示,tfm-BDP纳米粒子呈球形,平均直径为90~110nm,纳米粒子m-BDP和H-BDP通过透射电镜同样显示其形状呈球形,平均直径为90~110nm。如图2(e)为纳米粒子tfm-BDP的动态光散射图(DLS),DLS数据表明,tfm-BDP的流体力学直径分别为141nm,同样的对纳米粒子m-BDP和H-BDP的流体力学直径进行测试,结果表示纳米粒子m-BDP和H-BDP的流体力学直径分别为142nm和150nm。TEM测量得到的较小尺寸可能是由于干燥TEM样品中水化层的收缩所致。众所周知,由于直径在10~200nm之间的纳米粒子可增强其的渗透性和滞留效应,在肿瘤部位积累。因此,这些平均直径为100nm的纳米粒子,适合于体内抗肿瘤治疗。
对纳米粒子tfm-BDP、m-BDP和H-BDP在水中的吸收值进行测试,得到的3中纳米粒子在水中能很好地分散,具有良好的溶解性。如图2(f)所示,纳米粒子tfm-BDP、m-BDP和H-BDP的吸收极大值分别为810nm、650nm和655nm。其中,纳米粒子m-BDP和H-BDP的吸收波长发生明显的蓝移,这可能是由于它们的平面结构导致H-聚集。而-CF3则可能导致分子骨架发生明显扭曲,从而抑制纳米粒子tfm-BDP的平行梯状π-π堆积,以避免形成H-聚集体。此外,纳米粒子tfm-BDP几乎没有荧光发射,这表明封装在DSPE-PEG2000 NPs激发态的能量消耗主要是通过非辐射路径来实现的。
本发明进行了纳米粒子H-BDP、m-BDP和tfm-BDP在水中的光热转换。如图2(g)所示,为不同浓度(5~50μM)tfm-BDP纳米粒子在808nm激光照射(0.3W cm-2)下的光热转换,结果表明,当浓度为50μM时,光热转换最高。如图2(h)为808nm激光照射(0.3W cm-2,5min)下tfm-BDP纳米粒子和水的光热像,以NIR光(808nm)0.3W cm-2的强度照射tfm-BDP纳米粒子5分钟,溶液温度从22℃增加到76℃。同样对纳米粒子m-BDP和H-BDP在808nm激光照射(0.3Wcm-2,5min)下的光热像进行测试并将3中纳米粒子进行对比,结果表明tfm-BDP NPs的温度升高(ΔT~54℃)比激光照射后的m-BDP NPs(ΔT~19℃)和H-BDP NPs(ΔT~16℃)(671nm,0.3Wcm-2,5min)有显著的温度升高,清楚地表明了tfm-BDP NPs的超高效光热效应。如图2(i)是在不同曝光强度(0.1~0.8W cm-2)的808nm激光照射下,tfm-BDP纳米粒子的光热转换,通过图2(g)和图2(i)可以看出,光热效应与tfm-BDP NPs浓度、激光强度和照射时间呈正相关,表明可以很好地控制光热效果。如图2(j)为tfm-BDP NPs在五个加热-冷却过程中的光热稳定性的研究,结果表明,即使在连续激光照射下进行了5次加热和冷却之后,tfm-BDP NPs也表现出优异的热稳定性和光稳定性。tfm-BDP NPs的光热转换效率(η)计算为88.3%,远远高于H-BDP(42%)和m-BDP(50%)NPs。事实上,tfm-BDP NPs的光热转换效率比先前报告的光热试剂包括有机分子、聚合物和无机材料都高。更重要的是,tfm-BDP NPs的升高温度和tfm-BDP在DMF溶液中的升高温度相近(图8)。这可能是通过有效分子旋转引发;说明-CF3即使在NPs内部也保持有效旋转。
如图2(k)为不同浓度tfm-BDP NPs在NIR光照射产生光声信号图,图2(l)为PA信号强度与tfm-BDP NPs浓度的线性关系。结果表明,随着tfm-BDP NPs浓度的提高,光声信号强度显著增加,范围从0μM到180μM,表现出良好的线性关系,因此,tfm-BDP NPs可用作光声造影剂指导辐照时间和位置,这有助于提高PTT的准确性。
实施例3
基于tfm-BDP NPs在NIR区域具有强吸收和超高的光热转换效率,本发明研究了B3LYP/631G(d,p)水平的基态(S0)和第一激发态(S1)的几何结构,以解密研究分子的不同构象(图3(a))。利用密度泛函理论(DFT)和时变密度泛函理论(TDDFT)计算研究了分子几何结构(基态和激发态几何优化后的原子标准取向)。与tfm-BDP NPs相比,tfm-BDP NPs的分子骨架明显扭曲,m-BDP NPs和H-BDP NPs呈现平面结构。tfm-BDP NPs的扭曲结构阻碍了分子间π–π相互作用,有利于-CF3分子内旋转。
通过DFT计算了在S0-S1跃迁中涉及的三个分子的分子轨道。这三个分子中的每一个都被证明是π–π*跃迁。在tfm-BDP的分子中,最高的被占据分子轨道(HOMO)主要在聚甲基亚胺链上,LUMO在BDP的核心和N,N-二甲基氨基之间均匀地扩散。HOMO能级增加,由于-CF3具有强吸电子的特性和非对称的扭转结构LUMO能级降低,导致HOMO-LUMO间隙的大大减小。结果,tfm-BDP NPs的HOMO-LUMO能隙为1.65eV,小于m-BDP NPs(1.911eV)和H-BDP NPs(1.835eV),这与实验中观察到的tfm-BDP NPs的红移一致。事实上,非辐射衰减速率常数总是服从能隙定律,随着HOMO-LUMO能隙的减小而呈指数增长。因此,小的HOMO-LOMO能隙促进了光热效应。
接下来,本发明研究了室温下激发态分子的失活过程。BODIPY上有很多C-C键参与旋转,应用高水平的DFT和TDDFT量子化学计算方法可以是三个分子S0态和Sl态随不同C-C键扭转角变化的势能曲线,其横坐标为相应的二面角,纵坐标是对应的能量。对3中纳米粒子分别沿转动研究基态和激发态的势能曲线,tfm-BDP纳米粒子沿转动基态和激发态的势能曲线如图3(b)所示,分别对纳米粒子H-BDP和m-BDP同样进行势能曲线的绘制,通过比较H-BDP、m-BDP和tfm-BDP的势能曲线,表明m-BDP和tfm-BDP的非辐射跃迁主要是由meso-取代物(-CH3和-CF3)在第一激发态的旋转失活的。对于tfm-BDP,-CF3旋转在基态和第一激发态之间的能隙(34.561kcal mol-1)在所有角度保持恒定,表明分子中-CF3是无能垒转动(图3(b))。然而,在m-BDP中基态和第一激发态之间的能隙大于40.876kcal mol-1。-CH3转动能垒为0.711kcal mol-1,表明-CH3在室温下不能自由旋转。m-BDP大的能隙和-CH3转动势能在一定程度上降低了非辐射效率。tfm-BDP的超高光热转换效率是由低能隙和-CF3的无能垒旋转引起的超高效非辐射过程的结果。
进一步研究了tfm-BDP NPs的光热行为。证明了tfm-BDP在不同状态下(包括溶液中的自由分子态和NPs内的聚集态)的微观动力学。以分子动力学模拟时间的演化为函数,记录了-CF3与BODIPY的中间位置之间的键二面角,并根据分子动力学模拟中的分子构象(图4),图4为分子动力学模拟得到的非晶态tfm-BDP NPs的快照相应地获得了该二面角的相应分布。发现单分子的二面角广泛分布在-180度和180度之间,表明其自由旋转运动。图3(c)和图3(d)为(tfm-BDP中BODIPY与-CF3之间的二面角)单分子和tfm-BDP NPs的典型二面角分布,tfm-BDP NPs的相应二面角也分布在-180至180度的整个范围内,这表明-CF3在tfm-BDP NPs中仍保持自由旋转。
实施例4
根据实施例2和实施例3得出的结论,利用光热特性最佳的tfm-BDP NPs介导光热治疗。
研究了肿瘤细胞对tfm-BDP NPs的摄取。在用于荧光追踪的组装过程中,将疏水性染料装载到NPS的核中。本发明验证了负载的染料是否通过在NPS透析后监测荧光而泄漏。在透析NPs分散体之后没有检测到荧光,这表明没有来自NPS的染料泄漏。装载染料的tfm-BDPNPs与MCF-7细胞在黑暗中孵育不同的时间。随后,用PBS将细胞彻底洗涤,并用Hoechst33342染色细胞核。共聚焦激光扫描显微镜(CLSM)在孵育后细胞质中显示出强烈的绿色荧光,表明被癌细胞有效摄取。通过MTT法检测tfm-BDP NPs对HeLa、MCF-7和4T1癌细胞的光毒性。在黑暗条件下评价了tfm-BDP NPs对三种癌细胞系的细胞毒性(图5(a)),图5(a)为HeLa、MCF-7和4T1细胞在不同浓度tfm-BDP NPs孵育在黑暗和NIR光(808nm,0.3wcm,2,5min)照射后的细胞存活率。结果表明,即使使用高浓度的tfm-BDP NPS,几乎没有观察到细胞毒性,这表明胶束具有良好的生物相容性。
相反,当用0.3Wcm-2 808nm激光照射5分钟时,随着tfm-BDP NPs浓度的增加,细胞活力明显下降,结果表明,NPs在细胞中的光热作用可以通过低强度NIR辐射有效地杀死癌细胞。为了直观地显示tfm-BDP NPs的光热治疗的有效性,使用钙黄绿素AM(绿色)和碘化丙锭(红色)染料进行活细胞染色。绿色荧光代表活细胞,红色表示死细胞。如预期的,tfm-BDPNPs在NIR激光照射(0.3W cm-2,5min)后诱导完全破坏MCF-7细胞。然而,在光照组和NPs组中,仅观察到绿色荧光,这表明tfm-BDP NPs在激光照射下有强烈的细胞毒性。
接下来研究了tfm-BDP NPs在高温下诱导的的细胞死亡途径。在用0.3Wcm- 2808nmNIR激光照射5分钟后,坏死细胞的百分比从7.9%(空白对照)显著增加到60.6%(图5(b)),图5(b)为用30μm tfm-BDP NPs培养细胞后进行NIR光(808nm,0.3W cm-2,5min)照射MCF-7细胞,流式细胞术对不同处理后MCF-7细胞的凋亡和坏死分析。结果表明,tfm-BDPNPs即使在低功率808nm(0.3Wcm-2)激光照射下,也能有效诱导肿瘤细胞死亡,有望在体内应用。
实施例5
采用4T1 BALB/c荷瘤小鼠测试了tfm-BDP NPs的体内光热治疗效果。图6(a)为在4T1 BALB/c荷瘤小鼠静脉内注射tfm-BDP NPs后的肿瘤的光声(PA)图像,图6(b)为图6(a)的PA信号强度(注射后0、2、4、8和24h的图像,图6(a)中虚线圆圈表示肿瘤)。为了获得光热治疗的最佳时间点,通过尾静脉静脉注射tfm-BDP NPs后纵向记录PAI图像。肿瘤部位PA信号随时间的增加而增加,在注射8h后达到最大。因此,tfm-BDP NPs具有显著的EPR效应,导致肿瘤组织中的有效蓄积。此外,PA信号的高对比度有望在PTT期间引导辐照时间和位置。在注射后24小时,PA信号大大降低,表明tfm-BDP NPs在治疗后可从体内消除。
基于tfm-BDP NPs在肿瘤聚集和PA成像能力,利用安全光剂量照射(0.3Wcm-2)研究了tfm-BDP NPs的抗肿瘤作用。体内光热图像显示,光照组仅随光照时间略有升高ΔT~4℃(图6(c)和图6(d)),图6(c)为在静脉注射tfm-BDP NPs或盐水注射后8小时后并用808nm0.3Wcm-2激光照射7分钟的4T1荷瘤小鼠的热红外(IR)图像。图6(d)为肿瘤的温度变化曲线。没有引起过热的问题说明用0.3Wcm-2 808nm激光照射,适合于体内光治疗。而tfm-BDP NPs加光照组肿瘤的温度升高较快,为25℃,表明tfm-BDP NPs在体内光热转换过程中表现出良好的光热性质。通过每隔一天监测治疗后18天的肿瘤体积来评估各组的光热治疗效果(图6(e)),图6(e)为不同治疗后小鼠的肿瘤体积。对照组、单纯tfm-BDP NPs组和光照组均不能抑制肿瘤生长,肿瘤体积平均增加8~12倍。结果表明,单一激光照射强度为0.3Wcm-2(808nm)和tfm-BDP NPs组对肿瘤治疗的作用不明显。然而,由于PTT的有效作用,tfm-BDPNPs光照组的肿瘤完全根除并且无复发(图6(e)和图6(f)),图6(f)为治疗后第18天肿瘤的平均重量。这些结果与体外光毒性实验结果一致,证实了tfm-BDP NPs在低强度激光照射下的PTT效果良好。组织学苏木精和伊红(H&E)对治疗后肿瘤组织染色图像显示NPs+Light组肿瘤组织严重坏死,而其他各组肿瘤细胞未受影响(图6(h)),图6(h)为肿瘤组织的(H&E)染色。标尺:100μm。结果表明,tfm-BDP NPs在低光剂量下具有良好的光热治疗性能。
tfm-BDP NPs在体内也表现出优越的生理安全性.对照组和实验组的所有小鼠体重都缓慢增加,表明治疗对小鼠没有全身毒性作用(图6(g)),图6(g)为不同治疗后小鼠体重变化。此外,还通过组织学分析评估了tfm-BDP NPs对处死小鼠心脏、肝、脾、肺、肾等主要器官的毒性。所有组的这些器官没有出现任何病理组织损伤/异常,明确地证实了tfm-BDPNPs具有良好的生物相容性。
综上,本发明制备了一种新的用于癌症治疗的光热试剂,其在现有光热试剂中表现出最高的光热转换效率(88.3%)。在BODIPY骨架的meso-位置引入-CF3转子,由于在其激发态中无能垒旋转,实现了高效的非辐射转换。因此使得tfm-BDP具有优异的光热效果。重要的是,在将tfm-BDP封装到聚合物NPs之后,仍可以保持-CF3自由旋转。tfm-BDP NPs的体外和体内实验都达到了优异的治疗效果。特别地,小鼠体内实验表明tfm-BDP NPs在肿瘤部位有效地累积,并且在安全NIR激光(0.3W cm-2,808nm)照射下肿瘤完全消融。因此,tfm-BDPNPs能够克服传统光热试剂在活体实验中由高强度激光引起的副作用。因此,‘无能垒转动’的策略为光热试剂的未来设计开辟了一个新平台,为光热试剂的临床应用开辟了前景。
上述实施例只是用于对本发明的举例和说明,而非意在将本发明限制于所描述的实施例范围内。此外本领域技术人员可以理解的是,本发明不局限于上述实施例,根据本发明的教导还可以做出更多种的变型和修改,这些变型和修改均落在本发明所要求保护的范围内。
Claims (7)
2.权利要求1所述的应用,其特征在于,通式Ⅰ所示的光热试剂的制备方法,包括如下步骤:
(1)在N2保护下,将CX3COOH和2,4-二甲基吡咯溶于CH2Cl2中,向溶液中滴加PhSiCl3并不断搅拌;向所得溶液中滴加Et3N,继续搅拌;再滴加BF3·Et2O溶液,继续搅拌;用饱和食盐水冲洗所得的反应混合物,用CH2Cl2提取水溶液,保留CH2Cl2层;将所得溶液用MgSO4干燥、过滤,蒸发有机溶剂、真空干燥箱中干燥,利用硅胶柱层析进行纯化,得化合物2;
(2)将化合物2与化合物3、AcOH和哌啶混合后加入活化分子筛,用干燥的甲苯做溶剂,搅拌回流;反应液冷却到室温,用水淬灭反应;用CH2Cl2萃取,饱和食盐水冲洗,Na2SO4干燥,蒸发溶剂;经薄层色谱纯化,得用于光热疗法的光热试剂化合物4;
3.根据权利要求2所述的应用,其特征在于,所述步骤(1)中CX3COOH:2,4-二甲基吡咯:PhSiCl3的摩尔比为1:2:1,搅拌时间为3-6h,搅拌温度为室温。
4.根据权利要求2所述的应用,其特征在于,所述步骤(1)中Et3N与2,4-二甲基吡咯的摩尔比为5:1,添加Et3N后室温搅拌10-20分钟;BF3·Et2O溶液与Et3N的摩尔比为1.5:1,添加BF3·Et2O溶液后室温搅拌10-12h。
5.根据权利要求2所述的应用,其特征在于,所述步骤(1)中进行硅胶柱层析使用的淋洗剂的体积比为CH2Cl2:正己烷=1:3。
6.根据权利要求2所述的应用,其特征在于,所述步骤(2)中化合物2与化合物3的摩尔比为1:5,AcOH和哌啶为催化量;搅拌回流的条件为80℃搅拌回流2-4小时;薄层色谱展开剂的体积比为CH2Cl2:正己烷=3:1。
7.根据权利要求1所述的应用,其特征在于,所述四氢呋喃和DSPE-PEG2000的体积比为1:5,所得分散液超声处理30-40分钟,所用的水为超纯水;胶体分散体透析的具体步骤为:将胶体分散体在超纯水中透析2-4天,在透析过程中,每4-6小时更换超纯水,最后用生理盐水透析分散液,透析袋为再生纤维素透析袋3500,收集透析袋中的溶液。
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