CN111072679B - 一种非周边季铵基修饰锌酞菁及其制备方法和应用 - Google Patents
一种非周边季铵基修饰锌酞菁及其制备方法和应用 Download PDFInfo
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Abstract
本发明公开了一种非周边季铵基修饰锌酞菁及其制备方法和应用,属于光动力药物或光敏剂制备领域。本发明提供的非周边季铵基修饰锌酞菁可做为光敏剂用于光动力治疗和光动力诊断,也可以用于光动力‑免疫协同疗法。其独特的结构使其与免疫检查点阻断剂联用,具有优异的协同抗肿瘤效应,在转移性肿瘤的治疗上具有显著的应用前景。
Description
技术领域
本发明属于光动力药物和光敏剂技术领域,具体涉及一种非周边季铵基修饰锌酞菁及其制备方法和应用。
背景技术
酞菁配合物是一类重要的功能材料,通过不同的结构修饰可以发展为不同用途的功能材料。在酞菁环上引入合适取代基和中心离子,便有可能开发为氧化催化剂、脱硫催化剂、非线性光学材料、光敏药物、液晶材料、光记录材料或光导材料,但是如何调控取代基和中心离子来获得目标功能化合物,却是需要创造性的工作。
酞菁配合物作为光敏剂在光动力治疗(Photodynamic Therapy, PDT)中的应用前景引人瞩目。所谓的光动力治疗(或称光动力疗法),实质上,是光敏剂(或称光敏药物)的光敏化反应在医学领域的应用。其作用过程是,先将光敏剂注入机体,过一段时间后(这段等待时间是让药物在靶体中相对富集),用特定波长的光照射靶体(对体腔内的目标可借助光纤等介入技术导入光源),富集在靶体中的光敏剂在光激发下,启发了一系列光物理光化学反应,产生活性氧,进而破坏靶体(例如癌细胞和癌组织)。
在一些发达国家,光动力治疗已成为治疗癌症的第四种常规方法。与传统的疗法,如外科手术、化疗、放射治疗相比,光动力学治疗最大的优点是可对癌组织进行选择性破坏而不必施行外科手术,且副作用小,因而备受瞩目。
同时,近年来的研究还表明,光动力疗法还可有效地治疗细菌感染、口腔疾病、黄斑变性眼病、动脉硬化、创伤感染以及皮肤病等非癌症疾病。光敏剂还可以用于光动力消毒,最主要的是用于水体、血液和血液衍生物的灭菌消毒。同时,利用光敏剂的荧光性质进行光动力诊断,也是光敏药物的一个重要用途。
光动力治疗的关键在于光敏剂,当前获准在临床上正式使用的光敏剂主要为血卟啉衍生物。在美国、加拿大、德国、日本等国,使用的是Photofrin(美国FDA于1995年正式批准Photofrin用于临床治疗癌症),它是从母牛血液中提取的并进行化学改性的血卟啉低聚物的混合物。血卟啉衍生物显示了一定的疗效,但也暴露了严重缺点:最大吸收波长(380-420nm)不在对人体组织透过率较佳的红光区(650-800nm),皮肤光毒性大,是混合物、组成不稳定等,因而临床应用受到限制,所以开发新一代光动力药物(光敏剂)是国际上的研究热点。
由于具有最大吸收波长位于易透过人体组织的红光区域和光敏化能力强等特点,酞菁配合物作为光敏剂的应用已引起重视。在各种酞菁配合物中,由于以下原因锌酞菁作为新型光敏剂的应用受到高度重视:(1)锌酞菁可以在周环引入亲水性基团,从而能更有效地阻止酞菁环聚集,保证酞菁光敏化能力的发挥;(2)锌的生物相容性较高、无暗毒性。我国福州大学研制的周边不对称四取代酞菁锌(ZnPcS2P2K2)显示了较高光动力活性,已进入II期临床试验。但是,ZnPcS2P2K2的合成路线复杂,制备成本高,有异构体。因此,迫切需要筛选新的光敏活性高、制备简便、成本低、无异构体的锌酞菁光敏剂。另外,目前临床试验的光敏剂(包括酞菁类光敏剂)对深部肿瘤和转移性肿瘤无效,也是当前需要重点克服的问题。
近年来,基于调动和唤醒人体免疫系统来消除癌细胞的癌症免疫治疗受到高度重视,特别是基于免疫检查点抑制剂的免疫治疗(又称免疫检查点阻断疗法,Immunecheckpoint blockade, ICB)取得突破性进展,相关的基础研究获得了2018年诺贝尔奖。目前,已有一种PD-L1抗体(anezolizumab)和两种PD-1抗体(nivolumab和pembrolizumab)被美国FDA批准用于治疗晚期黑色素瘤、非小细胞肺癌和膀胱癌等。其中,nivolumab也于2018年6月被中国国家食品药品监督总局(CFDA)批准用于治疗非小细胞肺癌。然而,由于免疫检查点阻断疗法依赖于高表达的PD-L1的肿瘤或者预先存在能够表达PD-1的浸润性T细胞,因此PD-1/PD-L1抗体在晚期实体瘤非选择性人群中有效率仅在20%左右,并且常伴有自身免疫过敏的副作用,且治疗费用昂贵。因此,如何扩大ICB的适用性是临床推广需要解决的主要挑战。
将光动力疗法(PDT)和免疫检查点阻断疗法(ICB)联用可有望克服PDT和ICB各自存在的问题,两者联用显示了潜在的优势:可望协同ICB激活人体的免疫系统起到抑制远端肿瘤生长和转移的作用,可使一些本来对ICB疗法不敏感的肿瘤类型变得敏感;同时还能降低免疫检查点阻断剂的用量,从而大幅度降低治疗费用和减轻免疫过敏副作用。
但是目前还缺乏有效的联用光敏剂,尚未见高效协同ICB的光敏剂获批进入临床应用。也未见酞菁光敏剂与PD-L1抗体联用的报道,特别是,能与ICB疗法联用获得高效协同抗肿瘤转移效应的光敏剂的结构特征尚未深入研究,因此开发能与ICB高效协同联用的酞菁光敏剂具有重要价值。
发明内容
本发明的目的在于提供一种非周边季铵基修饰锌酞菁及其制备方法和应用,制得的酞菁锌不但显示了高的光动力活性,更重要的是,能很好的协同免疫检查点阻断剂PD-L1起高效抗肿瘤效应。
为实现上述目的,本发明采用如下技术方案:
一种非周边季铵基修饰锌酞菁的结构式如下:
上式代表的是非周边单取代的锌酞菁配合物。锌酞菁或称酞菁锌,是中心离子为锌的酞菁配合物,酞菁,英文名称phthalocyanine,是四苯并四氮杂卟啉的简称。取代基位于酞菁环的α位,称为非周边位,取代基R选自以下基团:
制备如上所述的非周边季铵基修饰锌酞菁的方法包括以下步骤:
(1)以1-[4-(氨基乙基)苯氧基]锌酞菁和碘甲烷为反应物,二者的投料比是1mg的1-[4-(氨基乙基)苯氧基]锌酞菁需要50mg-200mg碘甲烷。
(2)以N,N-二甲基甲酰胺为溶剂, 1mg的1-[4-(氨基乙基)苯氧基]锌酞菁需要0.3-3mL的N,N-二甲基甲酰胺,在氮气的保护下,0℃-室温下反应5~50h ,通过溶剂清洗和柱层析分离去除过量的原料和杂质,得到非周边季铵基修饰锌酞菁(1-[4-(N,N,N-三甲基-2-氨基乙基)苯氧基]锌酞菁碘化物)。
上述的非周边季铵基修饰锌酞菁应用于制备光动力药物或光敏剂或光动力-免疫联用光敏剂。所述光敏剂,在生物医药领域可称为光敏药剂,或称光敏药物制剂,又称为光动力药剂。所制备的光动力药物或光敏剂可用于光动力治疗、光动力诊断或光动力消毒。所述的光动力治疗可以是恶性肿瘤的光动力治疗,或是良性肿瘤的光动力治疗,或是白血病的骨髓体外光动力净化治疗,或是非癌症疾病的光动力治疗。所述的非癌症疾病,可以是细菌感染,或是口腔疾病,或是黄斑变性眼病,或是动脉硬化,或是创伤感染,或是皮肤病,或是病毒感染。所述的光动力消毒可以是血液或血液衍生物的光动力灭菌净化,或是水的光动力灭菌消毒,或是医用或生活用器的光动力消毒。
制备光动力药物或光敏剂的方法是:用水,或水和其它物质的混合溶液,其中其它物质的质量分数不高于10%,作为溶剂,溶解非周边季铵基修饰锌酞菁,配制成含一定浓度的光敏药剂,锌酞菁的浓度不高于其饱和浓度;在制成的溶液中加入抗氧化剂、缓冲剂和等渗剂作为添加剂以保持光敏药剂的化学稳定性和生物相容性;所述的其它物质是蓖麻油衍生物(Cremophor EL)、二甲亚砜、乙醇、甘油、N,N-二甲基甲酰胺、聚乙二醇300-3000、环糊精、葡萄糖、吐温、聚乙二醇单硬脂酸酯中的一种或几种的混合物。
本发明的有益效果和突出优势在于:
(1)本发明提供的非周边季铵基修饰锌酞菁在水溶液中的最大吸收波长位于679nm处,且摩尔吸收系数大(达105数量级),其光谱性质不但大大优于第一代光敏剂,而且优于正在进行临床实验的其他酞菁配合物。例如,本发明提供的锌酞菁配合物的最大吸收波长相对于美国的Pc4红移了4 nm,即治疗光谱可以红移4 nm,治疗光的组织穿透能力得到进一步提高,这对于光动力治疗和光动力诊断是十分有利的。
(2)本发明提供的酞菁配合物结构明确、不存在位置异构体。本发明对酞菁母体结构的化学修饰,是通过在酞菁非周边位引入单取代基团来实现,因而目标化合物结构明确、不存在异构体,易于制备。
(3)本发明提供的非周边季铵基修饰锌酞菁含有季铵基团可使化合物具有优良的两亲性,具有良好的光动力抗癌活性。本发明提供的锌酞菁的对于人宫颈癌细胞Hela的光动力活性显著高于其他类似化合物,例如,周环四取代锌酞菁1,8(11),15(18),22(25)-四(6,8-二磺酸基-2-萘氧基)锌酞菁八钠盐。
(4)本发明提供的非周边季铵基修饰锌酞菁具有高效的协同免疫治疗抗远端肿瘤效应。例如,其与免疫检查点阻断剂PD-L1抗体联用,不仅可以彻底清除原位肿瘤,还能对远端肿瘤(未光照处理的肿瘤)起90%左右的抑制率,并能激活肿瘤免疫记忆,防止肿瘤的复发。通过大量的筛选试验发现,本发明提供的提供的非周边季铵基修饰锌酞菁联合免疫检查点阻断剂PD-L1抗体抑制远端肿瘤的能力,高于其他酞菁光敏剂,包括其前驱体1-[4-(氨基乙基)苯氧基]锌酞菁和其对应的四取代酞菁锌,也包括1,8(11),15(18),22(25)-四(6,8-二磺酸基-2-萘氧基)锌酞菁八钠盐、1-(6,8-二磺酸基-2-萘氧基)锌酞菁二钠盐、四磺酸基取代酞菁和单磺酸基取代酞菁等。
具体实施方式
为进一步公开而不是限制本发明,以下结合实例对本发明作进一步的详细说明。
实施例1
非周边季铵基修饰锌酞菁(1-[4-(N,N,N-三甲基-2-氨基乙基)苯氧基]锌酞菁碘化物),结构如下式所示:
称取1-[4-(氨基乙基)苯氧基]锌酞菁20 mg(28.5 μmol)和K2CO3(168.28 μmol)超声溶解于含10 ml无水DMF的单口圆底烧瓶中,降温至0℃后缓慢加入2000mg CH3I, 搅拌30 min后,室温下反应。TLC点板, 24 h后停止反应,旋干反应溶剂,用5 ml DMF溶解反应物并用0.22 μm的针头滤膜过滤除去不溶物。抽真空旋干溶剂,用1ml DMF溶解,过S-X1凝胶柱并用DMF作为洗脱剂,收集最前沿蓝绿色组分。抽真空旋干溶剂,用EA溶解后过100-200目数硅胶柱(洗脱剂为EA:DMF=100:1),除去最前沿黄色组分,再用EA:DMF=10:1收集蓝绿色带。抽真空旋干溶剂,再过S-X1凝胶柱(DMF为洗脱剂),收集蓝色组分。将蓝色组分于大量正己烷:DCM=2:1溶液中析出,45℃温度烘箱中烘干,得蓝绿色固体。称重9.8mg,产率为39.8%。产物在DMF 中的最大吸收峰位于 674 nm 处,在水溶液中的最大吸收波长位于679 nm处。
产物的结构表征数据如下:1H NMR (400 MHz, DMSO) δ 9.23 (d, J = 23.3 Hz,6H), 8.83 (s, 1H), 8.16 (s, 6H), 7.77 (d, J = 6.2 Hz, 1H), 7.44 (s, 2H), 7.37(s, 2H), 7.09 (s, 1H), 3.90 (s, 2H), 2.74 (s, 2H), 1.50 (s, 2H), 1.26 (s,4H), 0.84 (s, 3H). HRMS (ESI) m/z calcd for C43H32N9OZn [M-I]+: 754.2016;found: 754.2042. HPLC (674 nm): > 95%.。
实施例2
将实施例1的反应溶剂替换为6ml或60ml无水DMF,其他条件不变,也能获得目标产物。产物的结构表征数据如下:1H NMR (400 MHz, DMSO) δ 9.23 (d, J = 23.3 Hz, 6H),8.83 (s, 1H), 8.16 (s, 6H), 7.77 (d, J = 6.2 Hz, 1H), 7.44 (s, 2H), 7.37 (s,2H), 7.09 (s, 1H), 3.90 (s, 2H), 2.74 (s, 2H), 1.50 (s, 2H), 1.26 (s, 4H),0.84 (s, 3H). HRMS (ESI) m/z calcd for C43H32N9OZn [M-I]+: 754.2016; found:754.2042. HPLC (674 nm): > 95%.。
实施例3
将实施例1的2000mg CH3I,替换为1000mg CH3I或4000mg CH3I,其他条件不变,也能获得目标产物。产物的结构表征数据如下:1H NMR (400 MHz, DMSO) δ 9.23 (d, J =23.3 Hz, 6H), 8.83 (s, 1H), 8.16 (s, 6H), 7.77 (d, J = 6.2 Hz, 1H), 7.44 (s,2H), 7.37 (s, 2H), 7.09 (s, 1H), 3.90 (s, 2H), 2.74 (s, 2H), 1.50 (s, 2H),1.26 (s, 4H), 0.84 (s, 3H). HRMS (ESI) m/z calcd for C43H32N9OZn [M-I]+:754.2016; found: 754.2042. HPLC (674 nm): > 95%.。
实施例4
将实施例1的反应时间,改为5h或50 h,其他条件不变,也能获得目标产物。产物的结构表征数据如下:1H NMR (400 MHz, DMSO) δ 9.23 (d, J = 23.3 Hz, 6H), 8.83 (s,1H), 8.16 (s, 6H), 7.77 (d, J = 6.2 Hz, 1H), 7.44 (s, 2H), 7.37 (s, 2H), 7.09(s, 1H), 3.90 (s, 2H), 2.74 (s, 2H), 1.50 (s, 2H), 1.26 (s, 4H), 0.84 (s,3H). HRMS (ESI) m/z calcd for C43H32N9OZn [M-I]+: 754.2016; found: 754.2042.HPLC (674 nm): > 95%.。
实施例5
参照本发明人专利号为ZL201711099145.1的中国专利合成1-[4-(氨基乙基)苯氧基]锌酞菁(结构如下式所示)。
实施例6
其他酞菁化合物(结构如下所示)参照已经发表的论文合成(Bioorg. Med. Chem.Lett. 2015, 25: 2386-2389; Chem. Sci., 2018, 9: 2098-2104; Angew. Chem. Int.Ed. 2018, 57: 9885 -9890; J. Am. Chem. Soc. 2019, 141: 1366-1372;Theranostics 2019, 9,6412-6423.)。
实施例7
将实施例1制得的非周边季铵基修饰锌酞菁溶于1%蓖麻油衍生物(CremophorEL,wt%)水溶液中,制成0.1mM 的光敏药剂。测试它们对人宫颈癌细胞Hela的暗毒性和光动力活性。
将0.1mM或0.2mM的光敏药剂稀释到细胞培养液中,制成不同浓度的含锌酞菁配合物的细胞培养液。将癌细胞分别在含有不同浓度的锌酞菁配合物的培养液中培养2小时,染后弃培养液,用PBS清洗细胞后,加入新的培养液(不含锌酞菁配合物)。光照实验组,对细胞进行红光照射(所用激发光光源为波长大于600nm的红光,照射30分钟,照射光的功率为15mw·cm-2);不照光组,将细胞置于暗处30分钟。光照或不光照后,细胞的存活率采用MTT法考察。具体实验步骤参见《Bioorganic & Medicinal Chemistry Letters》, 2006, 16,2450-2453。
上述波长大于610nm的红光是通过500W的卤素灯连接隔热水槽加大于610nm的滤光片来提供的。
结果表明,当将非周边季铵基修饰锌酞菁溶液稀释到浓度为4 μM(即4x10-6 mol/L)时,若不进行光照,则对人宫颈癌细胞Hela没有杀伤和生长抑制作用,表明它们没有暗毒性;但如果进行红光照射,可100%杀伤癌细胞。通过考察非周边季铵基修饰锌酞菁的浓度和细胞存活率的量效关系,获得在光照条件下的半致死浓度(IC50,即杀死50%癌细胞所需的药物浓度),分别是0.9 μM(实施例1所述非周边季铵基修饰锌酞菁),较低的IC50值,说明本发明的非周边季铵基修饰锌酞菁具有较高的光动力活性。
将上述1%蓖麻油衍生物(Cremophor EL,wt%)水溶液换成1%蓖麻油衍生物(Cremophor EL,wt%)磷酸盐缓冲溶液(PBS)或0.5%蓖麻油衍生物(Cremophor EL,wt%)水溶液,也可得到同样的实验结果。
实施例8
建立黑色素瘤细胞B16-F10的双侧荷瘤小鼠模型(近端和远端)。近端是指PDT治疗时的光照侧,远端是无光照侧。利用小动物荧光成像仪和组织提取法,考察光敏剂的在荷瘤小鼠体内的分布代谢,并在较佳条件下进行PDT治疗。设立以下5组实验,每组5只:PBS对照组;anti-PD-L1抗体治疗组;单纯酞菁 (无光照)治疗组; 酞菁+光照治疗组,即PDT治疗组;酞菁+光照+ anti-PD -L1抗体治疗组,即联合治疗组。其中,anti-PD-L1抗体购自BioXcell公司。
联合治疗组、光动力治疗组和单纯光敏剂组每只小鼠尾静脉注射100 μL酞菁化合物(浓度200 μM,母液用0.5% CEL稀释)。联合治疗组、光动力治疗组在给药后8-12小时后用波长为685nm激光照射(照射功率为15 mW/cm2,照射时间为5 min)右侧肿瘤(即近端肿瘤)。联合治疗组于激光治疗后立即腹腔注射50 μg PD-L1抗体/只,抗体组同一时间腹腔注射50μg PD-L1抗体/只。在第一天和第四天分别治疗一次。
从第一次治疗开始隔日测量所有小鼠的体重及肿瘤体积,并根据公式肿瘤体积=肿瘤长度×宽度×高度×π/6计算肿瘤大小,连续观察14天,计算各实验组的抑瘤率。
实验结果表明,对PDT治疗组(酞菁+光照治疗组),实施例1中所述的非周边季铵基修饰锌酞菁、实施例5中所述的非周边胺基修饰锌酞菁、实施6所述的其他酞菁光敏剂对B16-F10荷瘤小鼠的近端肿瘤(有光照肿瘤)的抑瘤率分别为51%、69%和50-65%,而对远端肿瘤(没有光照肿瘤)几乎没有抑制作用(抑瘤率低于2.5%),说明单纯使用酞菁光动力治疗无法抑制肿瘤转移和转移瘤。另一方面,单纯PD-L1抗体治疗对于近端和远端肿瘤的抑制作用也十分有限,抑瘤率分别为12%和13%。尽管单独实施例1中所述锌酞菁的光动力抑制肿瘤效应并非特别突出,但是却展现出令人意外的、显著的协同PD-L1抗体抑制远端肿瘤的能力。实施例1中所述锌酞菁+光照+ anti-PD -L1抗体治疗组对B16-F10荷瘤小鼠的远端肿瘤(无光照肿瘤)的抑瘤率高达90%,显著高于实施例5-6中所述的酞菁光敏剂(同样条件下,联合anti-PD -L1抗体治疗对远端肿瘤的抑瘤率为40-70%)。
更为重要的是,实施例1所述的锌酞菁与PD-L1抗体联用治疗后的小鼠有免疫记忆效应,可有效预防肿瘤的复发。我们在实施例1所述锌酞菁与PD-L1抗体联用治疗结束后的第7天,于ICR小鼠左腹侧每只皮下注射1×106 个B16-F10细胞(每组5只),继续观察21天。研究发现,实施例1所述锌酞菁与PD-L1抗体联合治疗组中,五只小鼠中仅有一只小鼠再次长出肿瘤,即预防复发的有效率是80%。但是,其余对照组的小鼠均观察到有明显的黑色素瘤再生长,观察不到预防肿瘤复发的能力。可见,相对于其他酞菁光敏剂,实施例1所述酞菁介导的PDT与PD-L1抗体联用显著增强了免疫应答的持续时间,可以成功刺激宿主免疫系统,促进免疫记忆,抑制肿瘤复发。
以上所述仅为本发明的较佳实施例,凡依本发明申请专利范围所做的均等变化与修饰,皆应属本发明的涵盖范围。
Claims (6)
2.一种如权利要求1所述的非周边季铵基修饰锌酞菁的制备方法,其特征在于: 以1-[4-(氨基乙基)苯氧基]锌酞菁和碘甲烷为反应物,N,N-二甲基甲酰胺为溶剂,在氮气的保护下,0℃-室温下反应5~50h,再通过溶剂清洗和柱层析分离除杂,即得到1-[4-(N,N,N-三甲基-2-氨基乙基)苯氧基]锌酞菁碘化物。
3.根据权利要求2所述的制备方法,其特征在于:所述1-[4-(氨基乙基)苯氧基]锌酞菁与碘甲烷的质量比是1:50-200。
4.根据权利要求2所述的制备方法,其特征在于:所述1mg的1-[4-(氨基乙基)苯氧基]锌酞菁需要0.3-3mL的N,N-二甲基甲酰胺。
5.一种如权利要求1所述的非周边季铵基修饰锌酞菁在制备光动力药物或光敏剂中的应用。
6.根据权利要求5所述的应用,其特征在于:采用所述非周边季铵基修饰锌酞菁制备得到的光敏剂与免疫检查点阻断剂联用治疗肿瘤。
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