CN111514293A - 近红外无重原子氟硼吡咯在光动力治疗转移瘤及上转换中的应用 - Google Patents
近红外无重原子氟硼吡咯在光动力治疗转移瘤及上转换中的应用 Download PDFInfo
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Abstract
近红外无重原子氟硼吡咯在光动力治疗转移瘤及上转换中的应用,其属于精细化工及生命医学领域。该类试剂母体结构及其纳米粒子具有极好的光动力治疗效果。将其纳米粒子与免疫药物联用,并用肿瘤动物模型验证了其突出的治疗转移肿瘤的效果。该类光敏分子合成简单、成本低廉,在长波长区具有很强的吸收能力,并具有超长的三重态寿命,较高的三重态量子产率。鉴于该类光敏分子优异的表现,该类分子有望成为临床上新一代光动力治疗试剂及转移肿瘤治疗试剂。此外,本发明还涉及不含重原子的纯有机上转换体系,由于使用的光敏分子具有很强的吸光能力,可将红光转化为极为明亮的黄色上转换发光,在生物领域有较大的应用潜力。
Description
技术领域
本发明涉及精细化工及生命医学领域中的一类氟硼吡咯类光动力治疗肿瘤/转移肿瘤试剂和上转换试剂。该类光敏分子可在极低剂量的试剂浓度(0.25μg/kg,远低于最低临床使用剂量0.1mg/kg)和较低光剂量(6J/cm2)下实现高效的光动力治疗效果和强的上转换发光,与免疫药物联用具有增强免疫治疗效果、协同治疗转移肿瘤的功能,可用于临床上普通肿瘤和转移肿瘤的光动力学治疗和免疫治疗。本发明涉及该类试剂母体结构及其纳米粒子的制备并作为光动力治疗试剂及上转换试剂。本发明特别涉及该类试剂纳米粒子与免疫药物联用,并用肿瘤动物模型验证了其突出的治疗转移肿瘤的效果。
背景技术
癌症是全世界死亡率较高的疾病之一。[1]传统的化疗、放疗等治疗癌症的方法,具有较强的毒副作用和有限的抑制肿瘤的能力,会对患者的神经和器官造成一定程度的损伤。因此,研究人员一直试图利用人体免疫系统来治疗癌症,期望产生长期缓解。然而,肿瘤细胞能够产生免疫抑制作用,通过多种机制逃避机体的免疫识别。其中最重要的机制之一是PD-L1(在多种肿瘤细胞表面过度表达)与PD-1(在 T细胞表面表达)之间的相互作用。多种针对这种相互作用的抑制剂已经在临床中表现出良好效果。[2]特别是经美国食品和药物管理局 (FDA)批准的检查点阻断抗体anti-PD-L1作为免疫治疗试剂已应用于临床癌症治疗。[3]anti-PD-L1可通过与PD-L1相互作用,从而抑制 PD-L1和PD-1之间的相互作用以释放T细胞。然而,这种检查点阻断免疫治疗仅对肿瘤细胞中有大量T细胞存在的患者有效,因此应答率较低(10%±40%)。[4]此外,由于普通细胞也存在PD-L1并能够发生和PD-1之间的相互作用,因此大量的使用anti-PD-L1将产生很强的自身免疫性疾病等副作用。因而提高anti-PD-L1的免疫治疗的疗效和应答率十分必要。增多T细胞含量有助于提高肿瘤对检查点阻断免疫治疗的敏感性和应答率。据报道光动力治疗(PDT)能够刺激肿瘤特异性抗原的释放,启动抗肿瘤免疫应答(增多T细胞含量),但 PDT本身免疫治疗效果不佳。[5]PDT联合检查点阻断免疫治疗有望提高anti-PD-L1的免疫治疗的疗效和应答率。[6]
目前临床或临床前使用的PDT试剂药物仍有其缺陷性,这限制了PDT在临床上的广泛应用。例如,已被批准用于临床的PDT试剂 ALA(PpIX的前体)在长波长区的摩尔消光系数极低(635nm处ε= 5000M-1cm-1),因此在临床上需使用较高的剂量(40mg/kg-200 mg/kg),这可能会造成一定的副作用,例如反酸、恶心呕吐、皮肤敏感等。[7]同样在临床上广泛使用的Photofrin(630nm处ε=1170 M-1cm-1),也需要使用很高的浓度,导致过长的体内循环代谢时间,致使病人长时间对光敏感,在结束PDT治疗后依然需要数周的避光,这对患者是一个巨大的心理挑战。[8]另一类临床或临床前使用的二氢卟吩、酞菁类化合物由于具有较大的刚性π共轭平面,极易形成ππ堆积,造成单线态氧产生能力急剧下降,具有低溶解性、易聚集、从体内清除缓慢、肝毒害性等缺陷。[9]因此,开发新型的、优良的、近红外区吸收的光动力治疗试剂有利于打破PDT领域的瓶颈。氟硼吡咯 (Bodipy)被称为“卟啉的姊妹”,有望成为新一代光动力试剂。Bodipy 母体结构无系间窜越能力,因而该类光敏剂往往依赖重原子。而现有的重原子光动力治疗试剂如溴代或碘代的氟硼吡咯化合物存在由于重原子引起的诸多缺陷,如重原子有一定的生理毒性,重原子效应会猝灭三重态,导致化合物三重态寿命明显缩短,尤其是在乏氧肿瘤中会大幅降低化合物敏化单线态氧的能力。无重原子的光敏分子化合物可以有效规避掉此类缺陷,具有低毒性、[10]长寿命三重态[11]以及适于乏氧肿瘤的治疗等优势。
三重态-三重态湮灭上转换(TTA-UC)通过将三重态光敏剂与合适的受体混合,通过使用低能量的光激发三重态光敏剂,经系间窜越、三重态能量转移、三重态-三重态湮灭等过程,发出上转换发光。由于上转换可将低能量长波长的光转化为高能量短波长的光,因此可用于控制生物体重要的生理活动,如使用光控制神经系统、控制基因表达、药物释放等。[12]由于长波长的光(如红光)的组织穿透性强,生物体常用的上转换体系多为长波长吸收的上转换体系(实现由近红外光到黄光或绿光的上转换)。这些上转换体系多为镧系金属离子掺杂的无机上转换纳米粒子(UCNPs),[13]然而这种镧系金属离子掺杂的无机上转换纳米粒子,上转换效率极低,上转换发光不强,需要较高功率的激发光。此外,这种无机上转换纳米粒子是否能排出体内、在体内的毒性和生物安全性还不清楚。[13-14]而新型的有机长波长上转换材料还比较少。[15]
[1]A.Jemal,F.Bray,M.M.Center,J.Ferlay,E.Ward and D.Forman,CA:A CancerJournal for Clinicians 2011,61,69-90.
[2]a)D.M.Pardoll,Nature Reviews Cancer 2012,12,252-264;b)A.J.L.ByGordon J.Freeman, Yoshiko Iwai,Karen Bourque,Tatyana Chernova,HiroyukiNishimura,Lori J.Fitz,Nelly Malenkovich, Taku Okazaki,Michael C.Byrne,HeidiF.Horton,Lynette Fouser,Laura Carter,Vincent Ling,Michael R. Bowman,BeatrizM.Carreno,Mary Collins,Clive R.Wood,and Tasuku Honjo,Journal of ExperimentalMedicine 2000,192,1027–1034;c)H.Dong,S.E.Strome,D.R.Salomao,H.Tamura,F.Hirano,D.B. Flies,P.C.Roche,J.Lu,G.Zhu,K.Tamada,V.A.Lennon,E.Celis andL.Chen,Nature Medicine 2002,8, 793-800.
[3]A.Swaika,W.A.Hammond and R.W.Joseph,Molecular Immunology 2015,67,4-17.
[4]L.Hu,Z.Cao,L.Ma,Z.Liu,G.Liao,J.Wang,S.Shen,D.Li and X.Yang,Biomaterials 2019,223, 119469.
[5]A.P.Castano,P.Mroz and M.R.Hamblin,Nature Reviews Cancer 2006,6,535-545.
[6]a)X.Duan,C.Chan,N.Guo,W.Han,R.R.Weichselbaum and W.Lin,Journal ofthe American Chemical Society 2016,138,16686-16695;b)C.He,X.Duan,N.Guo,C.Chan,C.Poon,R.R. Weichselbaum and W.Lin,Nature Communications 2016,7,12499.
[7]a)T.J.Dougherty,C.J.Gomer,B.W.Henderson,G.Jori,D.Kessel,M.Korbelik,J.Moan and Q. Peng,JNCI:Journal of the National Cancer Institute1998,90,889-905;b)D.Sarezky,A.R.Raquib,J.L. Dunaief and B.J.Kim,ClinOphthalmol 2016,10,1899-1903.
[8]D.E.J.G.J.Dolmans,D.Fukumura and R.K.Jain,Nature Reviews Cancer2003,3,380-387.
[9]J.Karges,U.Basu,O.Blacque,H.Chao and G.Gasser,Angewandte ChemieInternational Edition 2019,58,14334-14340.
[10]a)L.Jiao,F.Song,J.Cui and X.Peng,Chemical Communications 2018,54,9198-9201;b)Z.Wang, M.Ivanov,Y.Gao,L.Bussotti,P.Foggi,H.Zhang,N.Russo,B.Dick,J.Zhao,M.Di Donato,G.Mazzone, L.Luo and M.Fedin,Chemistry–A European Journal2020,26,1091-1102.
[11]Y.Hou,Q.Liu and J.Zhao,Chemical Communications 2020,56,1721-1724.
[12]a)J.Li,H.Duan and K.Pu,Advanced Materials 2019,31,1901607;b)Y.Ma,J.Bao,Y.Zhang,Z.Li, X.Zhou,C.Wan,L.Huang,Y.Zhao,G.Han and T.Xue,Cell 2019,177,243-255e215.
[13]W.Zheng,P.Huang,D.Tu,E.Ma,H.Zhu and X.Chen,Chemical SocietyReviews 2015,44, 1379-1415.
[14]a)A.Gnach,T.Lipinski,A.Bednarkiewicz,J.Rybka and J.A.Capobianco,Chemical Society Reviews 2015,44,1561-1584;b)Y.Sun,W.Feng,P.Yang,C.Huang andF.Li,Chemical Society Reviews 2015, 44,1509-1525.
[15]L.Huang,Y.Zhao,H.Zhang,K.Huang,J.Yang and G.Han,Angewandte ChemieInternational Edition 2017,56,14400-14404.
[16]Z.Zhou,J.Zhou,L.Gai,A.Yuan and Z.Shen,Chemical Communications2017,53,6621-6624.
[17]W.P.H.Francis Wilkinson,and Alberta B.Ross,Journal of Physicaland Chemical Reference Data 22,113(1993)1993,22,113-262.
发明内容
本发明所解决的技术问题:尽管光动力治疗是一种极具前景的治疗癌症的手段,但该技术在临床上的使用尚不普遍,被批准用于临床使用的光动力治疗试剂较少(多为卟啉类化合物),临床使用的PDT 试剂剂量较高,存在各种副作用、长时间对光敏感等缺陷。此外,转移肿瘤的治疗一直以来是治疗癌症的重点和难点,癌症的诊断和治疗依旧是目前人类的一个重要挑战。
为了在一定程度上解决上述技术问题,本发明所采用的技术方案是:本发明提供了一类新型、高效的无重原子氟硼吡咯类光敏分子 (BDP-helical)作为光动力试剂。
一方面,本发明涉及的新型光敏剂分子氟硼吡咯类化合物 (BDP-helical)产生三重态的能力来源于Bodipy(或其类似物)的π共轭平面扭曲,故包含该母体结构的有机分子均具有产生三重态进而杀死肿瘤细胞或上转换的能力。此类分子的母体结构特征为(式I):
其中,R和R1各自独立选自氢、芳/烷基;(R与R1分别采用氢或者芳/烷基时,仅是对母体结构的简单衍生,不影响母体结构的π共轭平面扭曲产生三重态,故R或R1采用其他基团时也不会破坏化合物分子通过系间窜越产生三重态的机理,取代后的结构仍然具有系间窜越的能力,能有效的释放单线态氧杀死肿瘤细胞或实现上转换发光。)
其中,所述烷基指仅由碳和氢原子组成的直链或支链烃基,不含不饱和度;直链烃基包括但不限于甲基,乙基,正丙基,正丁基,正戊基;而支链烃基包括但不限于异丙基,仲丁基,异丁基,叔丁基,异戊基,2-甲基丁基,3-甲基丁基;所述芳基采用苯基、萘基;烷基、芳基通过单键和母体结构相连;
其中,所述芳基或烷基中的氢可被亲水与吸/给电子基团或者肿瘤靶向基团取代,所述亲水与吸/给电子基团包含但不限于炔基、烯基、叠氮化物、烷氧基、硝基、卤素、氨基、羧基、羟基、氰基、烷基芳基、环烷基、芳烷基、芳氧基、酰胺基、脒基、亚胺基、碳酸盐、磺酸基、氨基甲酸酯基、酰基、羰基、杂环烷基、杂环芳基、杂环芳基烷基、卤代烷氧基、卤代烷基、酯基、醚基、巯基、二硫键、烷基硫基、芳基硫基、硫羰基、氧基、磷酸盐、膦酸脂、次膦酸脂、硅烷基、亚砜基、磺酰基、磺胺基、亚硫酰基、尿素、聚乙二醇、聚醚;所述肿瘤靶向基团包含但不限于葡萄糖、叶酸、乳糖酸、姜黄素、壳聚糖、透明质酸、磺胺嘧啶;所述壳聚糖是由N-乙酰-D-氨基葡萄糖单体通过β-l,4-糖苷键连接起来的直链状高分子化合物;
其中,R2和R3各自独立选自:F、H、烷基、环烷基、羟基、烯基、炔基、Cl、烷氧基、氰基、三氟甲基、异氰酸根及以上基团取代的苯基或萘基;
在其他方面,本发明提供合成上述式I化合物纳米粒子的制备方法。该方法包括如下步骤:制备合成PSMA-PEG-OA,然后将 BDP-helical与PSMA-PEG-OA溶解于四氢呋喃中,加入PBS缓冲溶液(pH=7.24)。混合液在40℃条件下搅拌2h。反应液冷却至室温后,使用去离子水渗析24h,然后在4℃条件下低温保存。
在其他方面,本发明提供了上述光敏分子在上转换试剂中的用途。根据光敏分子BDP-helical的三重态能级,选取苝酰二亚胺及其衍生物(PBI)作为上转换受体,其结构式(式Ⅱ)如下:
其中,R=C1-n烷基、碳环基、碳环烷基、芳基、芳烷基、杂环烷基或杂环芳基。
在其他方面,本发明还提供了上述光敏分子的纳米粒子在光动力治疗癌症的试剂中的用途。
在其他方面,本发明还提供了上述光敏分子的纳米粒子与免疫治疗(anti-PD-L1)协同治疗转移肿瘤中的用途。
本发明的有益效果是:
本发明使用具有长波长强吸光能力、长三重态寿命、适宜的敏化单线态氧能力且不含任何重原子的氟硼吡咯作为新一代的光动力治疗试剂,将光敏分子制备成纳米粒子输送至肿瘤细胞。一系列体外实验评估(单线态氧量子产率,细胞成像,细胞暗毒性和光毒性)和体内实验评估(老鼠肿瘤模型)表明,该类光动力治疗试剂可在低剂量 (0.25μg/kg,远低于最低临床使用剂量0.1mg/kg,Table 1)便实现了高效的光动力治疗效果。该光动力治疗试剂与免疫治疗相结合,可实现治疗转移肿瘤的效果。在目前与免疫治疗相结合使用的光动力治疗试剂例子中,本发明实现了使用最低的光敏剂浓度和最小的光剂量 (Table 2)。
Table 1.比较临床上用于治疗肿瘤的光动力治疗试剂和本文实施例中的 BDP-helix-NP
a最大吸收波长;b摩尔消光系数;c没有报道
Table 2.比较文献报道的用于与免疫治疗结合使用的光动力治疗试剂和本文实施例中的BDP-helix-NP
a本文;bBiomaterials,2019,223,119469;cACSNano,2019,13,10242;dAdv.Funct.Mater.,2019,29,1902440;e Biomaterials,2019,217,119309;f J.Am.Chem.Soc.,2016,138,16686;g Nat.Commun.,2016,7,12499;h Mol.Pharmaceutics,2019,16,33;iNanoscale,2018,10,16738;j J.Am.Chem.Soc.,2018,140,5670;k没有报道
该类不含重原子的氟硼吡咯染料分子由于其结构的特殊性而具有系间窜越的能力。该类不含重原子的光敏分子可作为新型的光动力治疗试剂,并通过细胞和小鼠癌症模型验证了其光动力治疗效果。此外,通过搭配合适的受体,该光敏分子还可作为上转换试剂,实现了长波长光到黄光的上转换。
本发明提供了一种全新的、高效的新一代光动力治疗试剂,其具有以下几个优点:1)化学结构简单,合成容易,成本低廉;2)在长波长区有很强的吸光能力(吸收波长600-700nm,最大吸收波长处摩尔消光系数ε=176000M-1cm-1),有良好的组织穿透性,并利于对光的利用;3)实现了明亮的上转换发光;4)使用极低的光敏剂浓度(0.25μg/kg,远低于最低临床使用剂量0.1mg/kg)和较低光剂量 (6J/cm2),即可实现良好的小鼠体内光动力治疗效果;5)与免疫治疗联用,大大增强了免疫治疗转移肿瘤的效果。在目前与免疫治疗相结合使用的光动力治疗试剂例子中,本发明实现了使用最低的光敏剂浓度和最小的光剂量。本发明将开创性的提供一种高效的、提高癌症患者存活率的新型抗癌试剂。
附图说明
图1是本发明实施例BDP-helix-NP的结构示意图和动态光散射测试结果图,其中,a为结构示意图,b为动态光散射测试结果,测试结果显示该纳米粒子的粒径分布约为30nm。
图2是实施例BDP-helix-NP的吸收光谱和发光光谱以及毒性试验结果。其中,a是本发明实施例BDP-helix-NP的吸收光谱和发光光谱,其吸收波长在500-700nm,发光波长在600-800nm,为长波长吸收和发光的光敏分子。b是本发明实施例BDP-helix-NP对CT26 肿瘤细胞的毒性试验结果。在LED光照条件下(656nm,光剂量:6 J/cm2),BDP-helix-NP的细胞毒性较强,可有效杀死肿瘤细胞;在无光照条件下,BDP-helix-NP的细胞暗毒性较小。c是代表性的传统的光动力试剂IRDye 700DX[5]对CT26肿瘤细胞的毒性试验结果。在 LED光照条件下(710nm,光剂量:6J/cm2),IRDye 700DX的细胞毒性较弱,光动力治疗效果相对较差。
图3是使用钙黄绿素AM和碘化丙啶PI分别对活细胞和死细胞进行染色的结果。在注射本发明实施例BDP-helix-NP并进行光照的条件下,可有效造成细胞的死亡。无光照或无BDP-helix-NP均不能有效杀死细胞。
图4是本发明实施例BDP-helix-NP与免疫治疗anti-PD-L1协同治疗转移肿瘤的示意图。
图5是本发明实施例老鼠的分组情况:老鼠被随机分成五组:第一组为仅光照;第二组为仅注射anti-PD-L1,第三组为仅注射 BDP-helix-NP,第四组为注射BDP-helix-NP并光照,第五组为注射 BDP-helix-NP和anti-PD-L1并光照。
图6是本发明实施例老鼠双侧模型中主肿瘤和转移肿瘤的肿瘤大小随时间的变化趋势。其中,a是本发明实施例老鼠双侧模型中的主肿瘤的肿瘤大小随时间的变化趋势,主肿瘤注射BDP-helix-NP并进行光照后,可观察到主肿瘤的生长速率明显受到光动力治疗的抑制;b是本发明实施例老鼠双侧模型中的转移肿瘤的肿瘤大小随时间的变化趋势,转移肿瘤并未注射BDP-helix-NP且无光照,转移肿瘤的生长速率受到(对主肿瘤的)光动力治疗和免疫治疗的联合抑制。注:在治疗的同时,老鼠被注射了anti-PD-L1。G代表组(group)。
图7是本发明实施例对老鼠的脾的免疫细胞的测试分析结果。a) B细胞的百分含量;b)T细胞的百分含量;c)CD45+细胞的百分含量; d)CD4+T细胞的百分含量;e)CD8+T细胞的百分含量。数据显著性***p<0.001,**p<0.01,*p<0.05。CD4+T细胞和CD8+T细胞的含量在第五组老鼠中显著增加,说明PDT协同免疫治疗抑制转移肿瘤增长的机理是通过增加T细胞的含量。
图8是本发明实施例对老鼠的主肿瘤和转移肿瘤的免疫细胞的测试分析结果。a)B细胞的百分含量;b)T细胞的百分含量;c)CD45+细胞的百分含量;d)CD4+T细胞的百分含量;e)CD8+T细胞的百分含量。数据显著性***p<0.001,**p<0.01,*p<0.05。
图9是本发明实施例对治疗15天后的老鼠的主肿瘤和转移肿瘤的组织进行苏木素伊红(H&E)染色的测试分析结果。第四、五组老鼠的主肿瘤有明显的坏死,说明主肿瘤的光动力治疗效果显著;第五组的转移肿瘤有明显的坏死,说明主肿瘤的光动力治疗能够协同免疫作用抑制转移肿瘤的生长。
图10是本发明实施例对治疗15天后的老鼠的各器官组织(心脏、肝、脾、肺、肾)进行苏木素伊红(H&E)染色的测试分析结果。各组织均正常,说明该光动力治疗试剂BDP-helix-NP具有较好的生物相容性。
图11是上转换体系的光谱图及上转换强度-功率密度关系图。其中:a是本发明实施例使用BDP-helix作为光敏剂,使用苝酰二亚胺 (PBI-0)作为受体,在除氧的二氯甲烷中将红光上转换为500-600nm 的黄光的光谱图。使用635nm连续激光器(250mW/cm2)激发. c[BDP-helix]=5.0×10-6M,c[PBI]=2.0×10-4M.b是该上转换体系的上转换强度-功率密度关系图。
具体实施方式
以R采用苯基、R1采用氢、R2和R3均采用F的结构BDP-helix 为例,基于实施例进一步详细说明本发明,但本发明并不限于这些实施例。本发明中使用的各种原料均可市售获得,或者可通过本领域技术人员公知的方法或现有技术中公开的方法由本领域公知的原料简单地制备得到。经测定,BDP-helix具有系间窜越的能力,三重态量子产率为52%,单线态氧量子产率为36%(在二氯甲烷溶剂中),能有效的敏化氧气产生单线态氧杀死肿瘤细胞。
[实施例1]BDP-helix的制备
(1)化合物的合成参考文献合成得到。[16]将2,6位含有碘原子的氟硼吡咯染料1(100mg,0.175mmol)与邻甲酰基苯硼酸酯2(80mg, 0.52mmol)混合,加入四丁基溴化铵(60mg,0.17mmol)作为相转移催化剂,在惰性气体保护下溶解于20mL四氢呋喃溶剂中,并加入四(三苯基膦)钯催化剂(0.017~0.035mmol)。加入6mL的2M 碳酸钠水溶液,80℃条件下加热反应1.5h(TLC监测反应进程,以避免产物变质)。反应结束后,将反应液冷却到室温,蒸去溶剂。然后加入二氯甲烷有机溶剂,使用饱和盐水洗涤(3×20mL),使用无水硫酸镁或无水硫酸钠干燥。柱层析(甲苯:石油醚=4:1)分离提纯得深紫色固体30mg,产率为35%。核磁和高分辨质谱表征数据:1H NMR(400MHz,CDCl3):δ=8.22(d,2H,J=8.0Hz),7.95(d,2H,J=8.0Hz),7.81(d,2H,J=8.0Hz),7.77(d,2H,J=8.0Hz),7.66-7.64 (m,3H),7.53-7.50(m,4H),7.45-7.42(m,2H),2.06ppm(s,6H). MALDI-HRMS理论值:496.1922,检测值:496.2011。
[实施例2]BDP-helix-NP的制备
(1)聚合物PSMA-PEG-OA的制备:将PSMA(160mg)和 PEG2000-NH2(200mg)溶解在30mL干燥的四氢呋喃溶剂中。氮气保护下70℃加热5h。将十八胺(26mg)溶解于5mL干燥的四氢呋喃中,30min内缓慢加入上述混合液中。继续70℃搅拌5h。反应结束后,反应液在4℃条件下低温保存。
(2)将0.5mg BDP-helix与30mg PSMA-PEG-OA溶解于2mL 四氢呋喃中,加入10mLPBS缓冲溶液(pH=7.24)。混合液在40℃条件下搅拌2h。反应液冷却至室温后,使用去离子水渗析24h,得到BDP-helix-NP(如图1中a所示)在4℃条件下低温保存。
图1中b是实施例BDP-helix-NP的动态光散射测试结果,测试结果显示该纳米粒子的粒径分布约为30nm。
[实施例3]BDP-helix-NP敏化单线态氧能力的测定及细胞毒性的测定
(1)敏化单线态氧能力:将105CT26肿瘤细胞培养在细胞培养皿中,培养12h后,加入BDP-helix-NP(100nM,2mL PBS缓冲液) 和单线态氧荧光探针(SOSG,5μM)的混合液,继续培养4h,使用656nm LED光源(20mW/cm2)光照5min后,用激光(λex=488 nm)检测SOSG荧光的变化。使用亚甲基蓝作为标准参比化合物(亚甲基蓝在水中的单线态氧量子产率为60%[17]),测得BDP-helix-NP 的单线态氧量子产率(ΦΔ)为21%。
(2)体外细胞毒性测定:将肿瘤细胞CT26细胞培养在96孔板上, 24h后分别添加BDP-helix-NP(0,6.25,12.5,25,50,100nM),并在 37℃和5%CO2下继续培养4小时。用656nm LED光源照射细胞 60min(5min,20mW cm–2)后,继续培养24h,将20μL 3-(4,5- 二甲基-2-噻唑基)-2,5-二苯基四唑溴(MTT溶液,5mg mL–1)溶在PBS缓冲液(pH 7.4)中,添加到每孔培养基里,继续培养4h后移除掉未反应的MTT,每孔加入150μL DMSO,30min后用Bio-Rad 酶标仪检测595nm波长处的光密度(OD值),由公式(细胞活力=实验组OD值/对照组OD值×100%)计算得到肿瘤细胞的存活率。在656nm光照下,BDP-helix-NP对CT26细胞表现出高的光毒性(半致死浓度IC50=11.5nM)。
图2中a是本发明实施例BDP-helix-NP的吸收光谱和发光光谱,其吸收波长在500-700nm,发光波长在600-800nm,为长波长吸收和发光的光敏分子。图2中b是本发明实施例BDP-helix-NP对CT26 肿瘤细胞的毒性试验结果。在LED光照条件下(656nm,光剂量:6 J/cm2),BDP-helix-NP的细胞毒性较强,可有效杀死肿瘤细胞;在无光照条件下,BDP-helix-NP的细胞暗毒性较小。图2中c是代表性的传统的光动力试剂IRDye 700DX[5]对CT26肿瘤细胞的毒性试验结果。在LED光照条件下(710nm,光剂量:6J/cm2),IRDye 700DX 的细胞毒性较弱,光动力治疗效果相对较差。
图3是使用钙黄绿素AM和碘化丙啶PI分别对活细胞和死细胞进行染色的结果。在注射本发明实施例BDP-helix-NP并进行光照的条件下,可有效造成细胞的死亡。无光照或无BDP-helix-NP均不能有效杀死细胞。
[实施例4]BDP-helix-NP与免疫治疗协同作用抑制转移肿瘤
(1)如图5所示,老鼠被随机分成五组:第一组为仅光照;第二组为仅注射anti-PD-L1,第三组为仅注射BDP-helix-NP,第四组为注射BDP-helix-NP并光照,第五组为注射BDP-helix-NP和anti-PD-L1 并光照。
(2)双肿瘤模型的建立:如图4所示,在老鼠两侧分别植入肿瘤细胞后,其中,右侧的肿瘤细胞在一周后原位注射BDP-helix-NP并使用656nm LED光源进行光照,称为主肿瘤。左侧肿瘤细胞模拟无法接受光动力治疗的转移肿瘤,不进行BDP-helix-NP的注射及光照,称为转移肿瘤。(3)十天后在腹腔注射免疫治疗药物anti-PD-L1,该 anti-PD-L1对主肿瘤和转移肿瘤均有一定的免疫作用,但效果相对不够明显。
(4)如图6中a所示,主肿瘤细胞原位注射BDP-helix-NP并使用656nm LED光源进行光照后(第四组),光动力治疗试剂 BDP-helix-NP高效产生单线态氧杀死附近的主肿瘤细胞,相比于未注射BDP-helix-NP(第一组)和未经光照(第三组)的肿瘤来说,具有明显的光动力治疗效果,显著抑制了主肿瘤的生长。如图6中b所示,转移肿瘤细胞虽未进行光动力治疗,但主肿瘤的光动力治疗显著增强了anti-PD-L1的免疫效果,促进T细胞的释放(第五组),相比于仅注射anti-PD-L1的对照组(第二组)和仅进行光动力治疗(第四组) 的肿瘤来说,具有明显的协同治疗转移肿瘤的效果,显著抑制了转移肿瘤的生长。
图7表明了本实施例对老鼠的脾的免疫细胞的测试分析结果。a) B细胞的百分含量;b)T细胞的百分含量;c)CD45+细胞的百分含量; d)CD4+T细胞的百分含量;e)CD8+T细胞的百分含量。数据显著性 ***p<0.001,**p<0.01,*p<0.05。CD4+T细胞和CD8+T细胞的含量在第五组老鼠中显著增加,说明PDT协同免疫治疗抑制转移肿瘤增长的机理是通过增加T细胞的含量。
图8为本发明实施例对老鼠的主肿瘤和转移肿瘤的免疫细胞的测试分析结果。a)B细胞的百分含量;b)T细胞的百分含量;c)CD45+细胞的百分含量;d)CD4+T细胞的百分含量;e)CD8+T细胞的百分含量。数据显著性***p<0.001,**p<0.01,*p<0.05。
图9示出了本发明实施例对治疗15天后的老鼠的主肿瘤和转移肿瘤的组织进行苏木素伊红(H&E)染色的测试分析结果。第四、五组老鼠的主肿瘤有明显的坏死,说明主肿瘤的光动力治疗效果显著;第五组的转移肿瘤有明显的坏死,说明主肿瘤的光动力治疗能够协同免疫作用抑制转移肿瘤的生长。
图10为本发明实施例对治疗15天后的老鼠的各器官组织(心脏、肝、脾、肺、肾)进行苏木素伊红(H&E)染色的测试分析结果。各组织均正常,说明该光动力治疗试剂BDP-helix-NP具有较好的生物相容性。
[实施例5]BDP-helix用于上转换
本实施例选用的上转换受体苝酰二亚胺(PBI-0)结构式为:
如图11中a所示,将BDP-helix和PBI-0在二氯甲烷溶剂中混合后通惰性气体氮气除掉体系内的氧气,其中,使用BDP-helix作为光敏剂,使用苝酰二亚胺(PBI-0)作为受体,在除氧的二氯甲烷中将红光上转换为500-600nm的黄光的光谱;使用635nm连续激光器(250mW/cm2)激发.c[BDP-helix]=5.0×10-6M,c[PBI]=2.0×10-4M。使用红光激发BDP-helix,BDP-helix经系间窜越到达三重态并经过三重态能量转移生成受体PBI-0的三重态,再经受体分子间的三重态湮灭的过程生成受体的单重态,最终发出受体的荧光。整个过程将低能量的红光转化为高能量的黄光,实现光的上转换,图11中b是该上转换体系的上转换强度-功率密度关系图,经测定,上转换量子产率为 0.8%。由于BDP-helix具有极高的摩尔消光系数,因此能够发出很强的上转换发光(η=ε×ΦUC=1296)。
Claims (9)
1.一种氟硼吡咯衍生物的应用,其特征在于:衍生物BDP-helical的结构通式为:
其中,R和R1各自独立选自氢、芳基、烷基;所述烷基指仅由碳和氢原子组成的直链或支链烃基,不含不饱和度;直链烃基包括但不限于甲基,乙基,正丙基,正丁基,正戊基;而支链烃基包括但不限于异丙基,仲丁基,异丁基,叔丁基,异戊基,2-甲基丁基,3-甲基丁基;所述芳基采用苯基、萘基;烷基、芳基通过单键和母体结构相连;
其中,所述芳基或烷基中的氢可被亲水与吸/给电子基团或者肿瘤靶向基团取代,所述亲水与吸/给电子基团包含但不限于炔基、烯基、叠氮化物、烷氧基、硝基、卤素、氨基、羧基、羟基、氰基、烷基芳基、环烷基、芳烷基、芳氧基、酰胺基、脒基、亚胺基、碳酸盐、磺酸基、氨基甲酸酯基、酰基、羰基、杂环烷基、杂环芳基、杂环芳基烷基、卤代烷氧基、卤代烷基、酯基、醚基、巯基、二硫键、烷基硫基、芳基硫基、硫羰基、氧基、磷酸盐、膦酸脂、次膦酸脂、硅烷基、亚砜基、磺酰基、磺胺基、亚硫酰基、尿素、聚乙二醇、聚醚;所述肿瘤靶向基团包含但不限于葡萄糖、叶酸、乳糖酸、姜黄素、壳聚糖、透明质酸、磺胺嘧啶;所述壳聚糖是由N-乙酰-D-氨基葡萄糖单体通过β-l, 4-糖苷键连接起来的直链状高分子化合物;
其中,R2和R3各自独立选自:F、H、烷基、环烷基、羟基、烯基、炔基、Cl、烷氧基、氰基、三氟甲基、异氰酸根及以上基团取代的苯基或萘基;
所述衍生物BDP-helical用于制备光动力学治疗和/或诊断癌症和/或感染症和/或杀菌的药物。
2.根据权利要求1所述的一种氟硼吡咯衍生物的应用,其特征在于:所述衍生物BDP-helical用于制备光动力学治疗协同免疫治疗肿瘤和/或转移肿瘤的药物。
3.根据权利要求1所述的一种氟硼吡咯衍生物的应用,其特征在于:所述衍生物BDP-helical用于制备上转换试剂。
4.根据权利要求3所述的一种氟硼吡咯衍生物的应用,其特征在于:所述衍生物BDP-helical用于制备上转换试剂;上转换的受体为苝酰亚胺及其衍生物。
5.根据权利要求1所述氟硼吡咯衍生物BDP-helical的纳米粒子的制备方法,包括以下步骤:
(1)聚合物PSMA-PEG-OA的制备:将PEG2000-NH2和生物可降解的两亲性聚合物溶解在干燥的四氢呋喃溶剂中,氮气保护下加热反应;将十八胺溶解于干燥的四氢呋喃中,继续加热反应;反应结束后,得到聚合物两亲性聚合物-PEG-OA;所述两亲性聚合物:PEG2000-NH2:十八胺的质量比为8:10:1.3;两亲性聚合物为PSMA、PLGA或PEG-PCL;
(2)将氟硼吡咯衍生物BDP-helical:PSMA-PEG-OA按质量比为1:60进行混合搅拌,反应液使用去离子水渗析,即得到纳米粒子。
6.根据权利要求5所述的一种氟硼吡咯衍生物纳米粒子的应用,其特征在于:所述氟硼吡咯衍生物BDP-helical的纳米粒子用于制备光动力学治疗和/或诊断癌症和/或感染症和/或杀菌的药物。
7.根据权利要求5所述的一种氟硼吡咯衍生物纳米粒子的应用,其特征在于:所述氟硼吡咯衍生物BDP-helical的纳米粒子用于制备光动力学治疗协同免疫治疗肿瘤和/或转移肿瘤的药物。
8.根据权利要求5所述的一种氟硼吡咯衍生物纳米粒子的应用,其特征在于:所述氟硼吡咯衍生物BDP-helical的纳米粒子应用于上转换试剂。
9.根据权利要求8所述的一种氟硼吡咯衍生物纳米粒子的应用,其特征在于:所述氟硼吡咯衍生物BDP-helical的纳米粒子应用于上转换试剂,上转换的受体为苝酰亚胺及其衍生物。
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Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN113206294A (zh) * | 2021-04-15 | 2021-08-03 | 宁波梅山保税港区锂泰企业管理合伙企业(有限合伙) | 一种磷酸酯及其制备方法和应用 |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20100239659A1 (en) * | 2007-07-19 | 2010-09-23 | Allexcel., Inc. | Self-assembling amphiphilic polymers as anti-cancer agents |
CN102444027A (zh) * | 2011-08-24 | 2012-05-09 | 翔瑞(泉州)纳米科技有限公司 | 一种负载纳米银核壳高分子微球抗菌织物及其制备方法 |
-
2020
- 2020-05-03 CN CN202010370823.9A patent/CN111514293A/zh active Pending
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20100239659A1 (en) * | 2007-07-19 | 2010-09-23 | Allexcel., Inc. | Self-assembling amphiphilic polymers as anti-cancer agents |
CN102444027A (zh) * | 2011-08-24 | 2012-05-09 | 翔瑞(泉州)纳米科技有限公司 | 一种负载纳米银核壳高分子微球抗菌织物及其制备方法 |
Non-Patent Citations (4)
Title |
---|
DEBNATH等: "Phase Transfer and Surface Functionalization of Hydrophobic Nanoparticle using Amphiphilic Poly(amino acid)", vol. 32, no. 11, pages 2798 - 2807 * |
KISELEVA, NATALIA等: "The Janus-faced chromophore: a donor-acceptor dyad with dual performance in photon up-conversion", vol. 54, no. 13, pages 1607 - 1610 * |
ZHOU, ZHIKUAN等: "Naphtho[b]-fused BODIPYs: one pot Suzuki-Miyaura-Knoevenagel synthesis and photophysical properties", vol. 53, no. 49, pages 6621 - 6624 * |
孟翔峰等: "《简明口腔生物材料研究》", vol. 1, 东南大学出版社, pages: 324 - 325 * |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN113206294A (zh) * | 2021-04-15 | 2021-08-03 | 宁波梅山保税港区锂泰企业管理合伙企业(有限合伙) | 一种磷酸酯及其制备方法和应用 |
CN113206294B (zh) * | 2021-04-15 | 2022-09-02 | 湖州永兴新能源有限公司 | 一种磷酸酯及其制备方法和应用 |
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