CN115141214B - 具有多转子的近红外有机小分子bbtd-tp及其纳米粒子和应用 - Google Patents
具有多转子的近红外有机小分子bbtd-tp及其纳米粒子和应用 Download PDFInfo
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Abstract
Description
技术领域
本发明属于药物制剂领域,涉及一种具有多转子的近红外有机小分子BBTD-TP及其纳米粒子和应用。
背景技术
在过去的几十年里,随着技术的快速发展,出现了许多新的癌症治疗方法,如免疫治疗、基因治疗、光动力治疗和光热治疗等。其中,光热治疗是将光热转换效率较高的材料(光热试剂)注射到生物体内,光热试剂利用靶向性识别技术或实体瘤的高通透性和滞留效应特异性聚集在肿瘤部位,再使用激光对肿瘤部位进行照射后,将吸收的光能转换为热能。这种热可以充分增加肿瘤温度,导致不可逆的细胞损伤,具有效率高、治疗时间短、可控辐射和温度等优点。而且,在这个过程中可以同时进行生物成像,如光声成像和光热成像。在光声/光热成像的引导下进行光热治疗,可以实现只需一次注射和单次照射即可提供同步准确的肿瘤成像并消除肿瘤。
光热治疗中的光不同于普通的可见光,使用的是近红外光。与可见光相比,近红外光更深的组织穿透性和生物体低的荧光背景,与传统的X射线相比有具有更小的副作用。目前对红外光的研究,我们更倾向于使用近红外二区的光,NIR-II的光相对NIR-I来说发射波长更长,可显著降低生物组织内光子的散射、吸收,具有更高的时间和空间分辨率,更强的穿透力。
光热剂在黑暗条件下没有毒性,在光照条件下才会有毒性,与传统的化学治疗和放射治疗相比,具有良好的空间特异性和非侵入性,符合当下生物医学领域对治疗的要求。目前的近红外光光热试剂包括有机小分子材料,半导体聚合物纳米材料,碳纳米材料,金属纳米材料等,与无机和聚合材料相比,有机小分子材料通常具有更好的生物相容性,尤其是较高的身体清除率。
发明内容
本发明的第一个目的是针对现有技术的不足,提供一种具有多转子的近红外有机小分子BBTD-TP。
所述具有多转子的近红外有机小分子BBTD-TP,其化学结构式如下:
本发明的第二个目的是提供上述具有多转子的近红外有机小分子BBTD-TP的合成方法;其合成路线为:
所述合成方法为:
(1)将化合物1在氩气保护下溶于超干四氢呋喃溶液中,然后在避光条件下,于冰水浴中少量多次加入卤化剂;反应1.5~3小时,经后处理得到化合物2;
作为优选,所述化合物1、卤化剂的物质的量之比为1:5;
作为优选,所述卤化剂采用入N-溴代琥珀酰亚胺、液溴、溴酸钾、溴水、碘酸、卤素、N-氯代丁二酰亚胺中的一种或多种,更为优选为N-溴代琥珀酰亚胺;
(2)将化合物2、1-(4-苯硼酸频哪醇酯)-1,2,2-三苯乙烯、缚酸剂、催化剂溶于四氢呋喃与水的混合溶剂中,然后用液氮和氮气冻抽三次除氧,在氩气保护下75~80℃加热反应12~24小时;反应结束后,经后处理得到化合物BBTD-TP;
作为优选,所述化合物2、4-乙烯基苯硼酸、碳酸钾、催化剂的物质的量之比为1:6~8:8:0.04;
作为优选,所述催化剂采用四(三苯基膦)钯、醋酸钯、三苯基膦、1,1'-双二苯基膦二茂铁二氯化钯中的一种或多种,更为优选为四(三苯基膦)钯;
作为优选,所述缚酸剂采用碳酸钾、碳酸铯、三乙胺中的一种或多种,更为优选为碳酸钾;
作为优选,步骤(1)中,所述后处理的方法为:反应物去除四氢呋喃溶剂后,用二氯甲烷和水萃取,收集有机相,干燥过滤后得到粗产物,然后以石油醚与二氯甲烷体积比为5:1的混合液为洗脱剂,通过硅胶层析柱分离纯化得到化合物2。
作为优选,步骤(2)中,所述后处理的方法为:反应物用二氯甲烷和水萃取,收集有机相,干燥过滤后得到粗产物,然后以石油醚与二氯甲烷体积比为3:1的混合液为洗脱剂,通过硅胶层析柱分离纯化得到化合物BBTD-TP。
本发明的第三个目的是提供上述具有多转子的近红外有机小分子BBTD-TP的水溶性纳米粒子;其合成方法为:
将具有多转子的近红外有机小分子BBTD-TP溶解在有机溶剂中,在超声环境下缓慢滴加入含有两亲性的共聚物的水溶液中,搅拌一段时间后,处理得到纳米粒子BBTD-TPNPs。
所述聚两亲性合物采用DSPE-PEG2000、DSPE-PEG2000-OH、DSPE-PEG2000-COOH、DSPE-PEG2000-NH3的一种或多种。
具体是将BBTD-TP溶于四氢呋喃溶液得到BBTD-TP溶液;DSPE-PEG2000溶于水中得到DSPE-PEG2000溶液;在超声环境下,将BBTD-TP溶液缓慢滴加入DSPE-PEG2000溶液,室温下通风搅拌24小时;通过0.22μm水系过滤器后冷冻,在低温和低压的条件下浓缩成固体粉末。
所述化合物BBTD-TP和DSPE-PEG2000的质量比为1:5~10。
本发明的第四个目的是提供具有多转子的近红外有机小分子BBTD-TP的水溶性纳米粒子作为光热剂在生物成像和治疗上的应用。
本发明的有益效果是:
本发明通过平衡辐射衰变和非辐射衰变之间的能量衰变途径,设计合成具有多转子的近红外有机小分子BBTD-TP。
本发明提供具有多转子的近红外有机小分子BBTD-TP所制备得到的纳米粒子作为光热剂在生物成像和治疗上的应用。所述纳米粒子具有近红外二区吸收的能力、优秀的光热转换能力和荧光发射的能力。在体外实验中,表现出良好的生物相容性、强的光毒性。
附图说明
图1为实施例一中合成的化合物2的核磁共振氢谱谱图(氘代氯仿为溶剂);
图2为实施例一中合成的化合物2的核磁共振碳谱谱图(氘代氯仿为溶剂);
图3为实施例一中合成的化合物2的高分辨质谱谱图;
图4为实施例一中合成的化合物BBTD-TP的核磁共振氢谱谱图(氘代氯仿为溶剂);
图5为实施例一中合成的化合物BBTD-TP的核磁共振碳谱谱图(氘代氯仿为溶剂);
图6为实施例一中合成的化合物BBTD-TP的高分辨质谱谱图;
图7为所述纳米粒子的体外光热性能;其中(a)为不同强度激光下的BBTD-TP NPs水溶液条件下的温度变化图,(b)为不同浓度纳米粒子在激光照射下的温度变化图,(c)为不同强度激光下的BBTD-TP NPs水溶液的光热成像图,(d)为激光条件下的4次照射-冷却循环的温度变化。
图8为所述纳米粒子的体外光热治疗效果(B16F10细胞);其中(a)为与不同浓度的BBTD-TP NPs共孵育后细胞存活率,(b)为不同处理后不同细胞的活/死染色图像。
具体实施方式
如前所述,鉴于现有技术的不足,本案发明人经长期研究和大量实践,提出了本发明的技术方案,其主要是依据至少包括:(1)将四苯乙烯基团引入分子,获得红移的吸收和提高的光热转换效率;(2)通过两亲性的聚合物包裹所得分子得到的纳米粒子,以纳米粒子作为多功能纳米平台,通过合理的分子设计可以实现近红外二区的吸收、高效的光热转换效率、良好的荧光发射和优秀的光稳定性,并将其应用于生物肿瘤成像和治疗中。
为了使本发明的目的、技术方案及优点更加清楚明白,以下结合附图及实施例,对本发明进行进一步详细说明。应当理解,此处所描述的具体实施例仅仅用以解释本发明,并不用于限定本发明。此外,下面所描述的本发明各个实施方式中所涉及到的技术特征只要彼此之间未构成冲突就可以相互组合。
第一方面,提供具有多转子的近红外有机小分子BBTD-TP,其合成路线为:
(1)将化合物1在氩气保护下溶于超干四氢呋喃溶液中,然后在避光条件下,于冰水浴中少量多次加入卤化剂;反应1.5~3小时,经后处理得到化合物2;
所述化合物1、卤化剂的物质的量之比为1:5;
所述卤化剂采用入N-溴代琥珀酰亚胺、液溴、溴酸钾、溴水、碘酸、卤素、N-氯代丁二酰亚胺中的一种或多种。
(2)将化合物2、1-(4-苯硼酸频哪醇酯)-1,2,2-三苯乙烯、缚酸剂、催化剂溶于四氢呋喃与水的混合溶剂,然后用液氮和氮气冻抽三次除氧,在氩气保护下75~80℃加热反应12~24小时;反应结束后,经后处理得到化合物BBTD-TP;
所述化合物2、1-(4-苯硼酸频哪醇酯)-1,2,2-三苯乙烯、缚酸剂、催化剂的物质的量之比为1:6~8:8:0.04;
所述催化剂采用四(三苯基膦)钯、醋酸钯、三苯基膦、1,1'-双二苯基膦二茂铁二氯化钯中的一种或多种;
所述缚酸剂采用碳酸钾、碳酸铯、三乙胺中的一种或多种。
作为优选,步骤(1)中,所述后处理的方法为:反应物去除四氢呋喃溶剂后,用二氯甲烷和水萃取,收集有机相,干燥过滤后得到粗产物,然后以石油醚与二氯甲烷体积比为5:1的混合液为洗脱剂,通过硅胶层析柱分离纯化得到化合物2。
作为优选,步骤(2)中,所述后处理的方法为:反应物用二氯甲烷和水萃取,收集有机相,干燥过滤后得到粗产物,然后以石油醚与二氯甲烷体积比为3:1的混合液为洗脱剂,通过硅胶层析柱分离纯化得到化合物BBTD-TP。
第二方面,提供具有多转子的近红外有机小分子BBTD-TP的水溶性纳米粒子,其合成方法为:
将具有多转子的近红外有机小分子BBTD-TP溶解在有机溶剂中,在超声环境下缓慢滴加入含有两亲性的共聚物的水溶液中,搅拌一段时间后,处理得到纳米粒子BBTD-TPNPs。
以下结合若干较佳实施例对本发明的技术方案作进一步的解释说明,但其中的实验条件和设定参数不应视为对本发明基本技术方案的局限。并且本发明的保护范围不限于下述的实施例。
实施例一:制备具有多转子的近红外有机小分子BBTD-TP
步骤(1)——化合物2的制备:
化合物1(30mg,0.02mmol)在氩气氛围下加入25mL圆底烧瓶中,加入超干四氢呋喃(10mL)溶解。在冰水浴条件下分批缓慢加入N-溴代琥珀酰亚胺(17.6g,0.1mmol),在氩气氛围下0℃反应1.5小时。反应结束后,用旋转蒸发仪去除溶剂。用二氯甲烷和水进行萃取,收集有机相用MgSO4进行干燥,过滤后用旋转蒸发仪减压浓缩得到粗产物,通过硅胶层析柱分离纯化(石油醚/二氯甲烷,v/v,5:1)最终得到绿色固体(18mg,49.7%),熔点:80-82℃。
如图1-3所示:1HNMR(500MHz,CDCl3,298K)δ(ppm):8.86(s,2H),7.49(d,J=8.5Hz,4H),7.40(d,J=8.7Hz,8H),7.11(d,J=8.5Hz,4H),7.01(d,J=8.8Hz,8H),2.77(d,J=7.0Hz,4H),1.78(m,2H),1.29-1.20(m,80H),0.86(m,12H).13C NMR(126MHz,CDCl3,298K)δ(ppm):151.0,146.3,146.2,144.1,138.8,136.2,135.5,132.5,130.3,129.7,125.8,123.6,116.0,112.8,39.1,33.5,33.2,31.9,30.1,29.8,29.8,29.7,29.7,29.7,29.7,29.4,29.4,26.5,22.7,14.1.ESI-HRMS[2+H]+:calcd.for[C98H134Br4N6S4]+1829.5474,found 1829.5474.
步骤(2)——化合物BBTD-TP的制备:
将化合物2(144mg,0.0785mmol)、1-(4-苯硼酸频哪醇酯)-1,2,2-三苯乙烯(0.55mmol)、碳酸钾(87mg,0.628mmol)、四(三苯基膦)钯(3.6mg,0.0031mmol)置于50mL史莱克瓶中,加入四氢呋喃与水的混合溶剂溶解固体(四氢呋喃/水,v/v,3:2),然后用液氮和氮气冻抽3次来除去氧气。在氩气氛围的保护下75℃加热反应18小时。反应结束后,冷却至室温并用旋转蒸发仪减压浓缩。用二氯甲烷和水进行萃取,收集有机相用MgSO4进行干燥,过滤后用旋转蒸发仪减压浓缩得到粗产物,通过硅胶层析柱分离纯化(石油醚/二氯甲烷,v/v,3:1),最终得到绿色的固体(65mg,29.2%),熔点:M.P.147℃。
图4-6所示1HNMR(500MHz,CDCl3,298K)δ(ppm):8.89(s,2H),7.51(d,J=8.6Hz,12H),7.37(d,J=8.3Hz,8H),7.20(dd,J=8.5,7.8Hz,12H),7.15-7.04(m,68H),2.81(d,J=6.3Hz,4H),1.82(m,2H),1.32-1.17(m,80H),1.02-0.70(m,12H).13C NMR(126MHz,CDCl3,298K)δ(ppm):151.2,147.0,146.5,144.6,143.8,143.7,142.5,141.0,140.6,138.8,138.1,136.2,135.4,135.3,131.8,131.4,131.3,130.1,128.9,127.7,127.7,127.6,126.5,126.4,125.7,124.7,123.3,113.0,39.1,33.5,33.2,31.9,30.1,29.8,29.7,29.7,29.7,29.7,29.6,29.4,29.3,26.5,22.7,14.1.ESI-HRMS[BBTD-TP+H]+:calcd.for[C202H201N6S4]+2838.479,found 2838.4725.
实施例二:BBTD-TP的纳米粒子的制备
将0.5mgBBTD-TP溶于2mL四氢呋喃得到BBTD-TP溶液;5mgDSPE-PEG2000溶于10mL水中得到DSPE-PEG2000溶液;在超声环境下,将BBTD-TP溶液缓慢滴加入DSPE-PEG2000溶液,室温下通风搅拌24小时;通过0.22μm水系过滤器后冷冻,在低温和低压的条件下浓缩成固体粉末。
实施例四:所述纳米粒子的体外光热性能
将1mL实施例二纳米粒子溶液置于1.5mL离心管中,用激光照射不同浓度的纳米粒子水溶液,激光功率功率密度为1.0W/cm2,记录溶液的光热图像和温度。用不同功率激光照射同一浓度的纳米粒子水溶液(30μM),记录溶液的光热图像和温度。用激光照射纳米粒子水溶液(30μM),测量溶液在4个辐射冷却循环中的温度变化来检测光稳定性。
如图7所示:观察到溶液的温度升高与激光功率和浓度呈现正相关,且表现出良好的光稳定性。
实施例五:所述纳米粒子的体外光热治疗效果
采用MTT法评价实施例二纳米粒子的体外细胞毒性和光热效应。将B16F10细胞接种于96孔板(每孔104个细胞),孵育18h。然后在每孔中更换含不同浓度实施例二纳米粒子(0、0.1、0.2、0.4、0.8、1.0和2.0μM)的新鲜培养基。24h后,用激光(1.5W/cm2)照射细胞5min。稳定18h后,用MTT溶液(0.5mg/mL)替换培养基,每孔100μL。然后在暗室中再孵育4h。最后,去除MTT培养基,用DMSO(100μL)溶解形成的甲瓒晶体。使用酶标仪监测570nm处的吸光度。根据吸光度计算细胞活力。另外使用活死细胞染色直观证明纳米粒子的体外光热治疗效果,将B16F10细胞接种于24孔板(每孔104个细胞),孵育18h。然后用以下处理处理细胞:对照;对照+激光照射;仅纳米粒子;纳米粒子+激光照射。18h后,去除含有纳米粒子的培养基,用生理盐水洗涤细胞2次,用钙黄绿素/碘化丙啶染色30min。用生理盐水洗涤两次后,用倒置荧光显微镜对活细胞(绿色)和死细胞(红色)进行成像。
如图8所示:随着纳米粒子浓度的增加,在激光照射下,细胞存活率超过80%。经过纳米粒子处理且没有激光照射的情况下对细胞存活的影响可以忽略不计,这表明纳米粒子具有良好的生物相容性和优秀的细胞杀伤能力。
Claims (9)
3.根据权利要求2所述方法,其特征在于化合物1、N-溴代琥珀酰亚胺的物质的量之比为1:5;化合物2、1-(4-苯硼酸频哪醇酯)-1,2,2-三苯乙烯、K2CO3、Pd(PPh3)4的物质的量之比为1:(6~8):8:0.04。
4.根据权利要求2所述方法,其特征在于步骤(1)中,所述后处理的方法为:反应物去除四氢呋喃溶剂后,用二氯甲烷和水萃取,收集有机相,干燥过滤后得到粗产物,然后以石油醚与二氯甲烷体积比为5:1的混合液为洗脱剂,通过硅胶层析柱分离纯化得到化合物2。
5.根据权利要求2所述方法,其特征在于步骤(2)中,所述后处理的方法为:反应物用二氯甲烷和水萃取,收集有机相,干燥过滤后得到粗产物,然后以石油醚与二氯甲烷体积比为3:1的混合液为洗脱剂,通过硅胶层析柱分离纯化得到化合物BBTD-TP。
6.具有多转子的近红外有机小分子BBTD-TP的水溶性纳米粒子的合成方法,其特征在于所述方法具体是:
将权利要求1所述具有多转子的近红外有机小分子BBTD-TP溶解在有机溶剂中,在超声环境下缓慢滴加入含有两亲性的共聚物的水溶液中,搅拌一段时间后,处理得到纳米粒子BBTD-TP NPs;
所述聚两亲性合物采用DSPE-PEG2000、DSPE-PEG2000-OH、DSPE-PEG2000-COOH、DSPE-PEG2000-NH3的一种或多种。
7.根据权利要求6所述方法,其特征在于具体是将BBTD-TP溶于四氢呋喃溶液得到BBTD-TP溶液;DSPE-PEG2000溶于水中得到DSPE-PEG2000溶液;在超声环境下,将BBTD-TP溶液缓慢滴加入DSPE-PEG2000溶液,室温下通风搅拌24小时;通过0.22μm水系过滤器后冷冻,在低温和低压的条件下浓缩成固体粉末;
所述化合物BBTD-TP和DSPE-PEG2000的质量比为1:5~10。
8.一种水溶性纳米粒子,采用权利要求6或7所述方法合成。
9.权利要求8所述一种水溶性纳米粒子作为光热剂在治疗上的应用。
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