CN107445997B - 一种光化疗铂类前药及其制备方法、应用 - Google Patents
一种光化疗铂类前药及其制备方法、应用 Download PDFInfo
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Abstract
本发明公开了一种光化疗铂类前药,其结构式如(Ⅰ)所示,其中,R1为H、OC(CH2)mCOOH、OCNH(CH2)nOCOCH3CH=CH2或OCNH(CH2)kOCOCH3CH‑CH2R3中的一种,R2为OC(CH2)mCOOH、OCNH(CH2)nOCOCH3CH=CH2或OCNH(CH2)kOCOCH3CH‑CH2R3中的一种;R3为单体的聚合物结构,其为式(I)的化合物与2‑甲基丙烯酰氧乙基磷酸(酰)胆碱或甲基丙烯酸中一种或几种单体聚合的结构,m、n和k分别取0~10。本发明的光化疗铂类前药在光照的情况下,光降解释放出顺铂化疗药,且还释放产生的活性氧物种用于光动力治疗,本发明集光动力治疗和化疗于一体,协同治疗以提高整个癌症治疗的疗效。
Description
技术领域
本发明属于铂类抗癌药肿瘤治疗技术领域,涉及一种光化疗铂类前药及其制备方法、应用,其中特别涉及光化疗四价顺铂类前药。
背景技术
光动力是一种无创的医疗手段,近年来获得越来越多的关注,并且已经被应用于许多领域。然而,当前临床上使用光动力剂也会遇到一些限制,如不好的水溶性,弱的光稳定性,以及对癌细胞选择性不好等(Nat.Rev.Cancer.3(2003)380-387)。
传统的光动力治疗包括施加聚集在部分组织周围的光敏化合物,一种常用产生单线态氧的方法就是从基态三线态氧通过光激发转变成单线态氧。这是当前的光动力治疗的一种策略,然而这种过程需要氧气,但是肿瘤细胞经常是乏氧的。尽管许多光敏剂被开发用于组织的深层次穿透,但是治疗效果还是不尽如人意,原因是肿瘤乏氧,这是实体瘤的一个重要标记(N.Engl.J.Med.365(2011)537-547)。另一方面,这种治疗的主要缺点是伴随的副作用,特别是在治疗位点处。这些副作用通常包括治疗后炎症例如红斑、肿胀、水肿、烧伤、瘙痒、鳞片样脱皮、色素沉着过度和长时间刺激和过敏。因此,克服光动力在肿瘤乏氧区域的低效率以及副作用等缺点需亟待解决。
传统的化疗药,顺铂等一类二价铂类复合物,是一类具有抗癌活性的金属配合物,由B.Rosenborg等人在1965年首次发现可以抑制肿瘤细胞生长后,就广泛应用于癌症化学治疗,在化疗药物中占有重要的位置(Nature 1965,205,698.)。之后陆续又有卡铂,奥沙利铂等二价铂类复合物等抗癌药被批准上市。然而一般的铂类复合物口服无效,临床使用方法多为以静脉滴注的方式给药,静脉注射后,顺铂等在血浆中迅速消失,快速分布全身,尤其是在肝、肾、大小肠及皮肤中分布最多,因此毒副作用大,如引起肾毒性、骨髓抑制及胃肠道副作用等(Chem.Rev.2014,114,4470-4495)。同时,顺铂等铂类复合物在血液中的半衰期短,因而达到病灶部位的比例很低,药效较差。因此,药物输送以及对化疗药物的改性对于改善药物的缺点至关重要。另一方面,肿瘤乏氧又会导致对于化疗药物耐药性的增加,这一直是困扰传统化疗药的一个问题之一。
近年来,各国科学工作将目光投向可修饰的铂类药物—四价铂类复合物,相比于传统的二价铂类复合物,该类化合物由于具有六配位的结构,可以进行功能化的修饰,而且这类化合物的药物活性是可以开闭的,因此可以降低药物本身的副作用,目前已经有多个四价铂类复合物被推上临床实验,至今得到广泛的应用。
发明内容
本发明的第一目的是提供一种光化疗前药,该药物为四价顺铂类复合物,如通式(Ⅰ)所示的四价顺铂类复合物,其中,该四价顺铂类复合物在光照射下释放出活性氧物种,并且还原得到二价顺铂抗癌药,利用活性氧物种的光动力治疗与本身的二价顺铂化疗药相结合的一种肿瘤治疗方式,从而克服了传统二价铂类药物耐药性及在乏氧区域不敏感等问题。
本发明的第二目的是提供式(Ⅱ)、(Ⅲ)和(Ⅴ)所示的光化疗四价顺铂类前药的制备方法。
本发明的第三目的是提供上述光化疗前药在制备治疗抗肿瘤药物中的用途。
本发明的技术方案如下:
一种光化疗前药,所述的光化疗前药为四价铂类复合物,所述的四价铂类复合物在光照射下释放出活性氧物种,且还原得到二价铂类化疗药,活性氧物种的光动力治疗与二价铂类化疗药相结合协同治疗肿瘤。
优选为,光照射波长为200nm-1200nm;所述的活性氧物种为超氧自由基、氢氧自由基或过氧自由基中的一种或几种。
优选为,所述的四价铂类复合物为四价顺铂类前药,其结构式如(Ⅰ)所示:
其中,R1为H、OC(CH2)mCOOH、OCNH(CH2)nOCOCH3CH=CH2或OCNH(CH2)kOCOCH3CH-CH2R3中的一种,R2为OC(CH2)mCOOH、OCNH(CH2)nOCOCH3CH=CH2或OCNH(CH2)kOCOCH3CH-CH2R3中的一种;R3为单体的聚合物结构,其为式(I)的化合物与2-甲基丙烯酰氧乙基磷酸(酰)胆碱或甲基丙烯酸中一种或几种单体聚合的结构,m、n和k分别取0~10。
所述的四价顺铂类前药优选为,其结构式如(Ⅱ)或(Ⅲ)所示:
所述的四价顺铂类前药优选为,其结构式如(Ⅳ)所示:
所述的四价顺铂类前药优选为,其结构式如(Ⅴ)所示:
本发明还公开了一种式(Ⅱ)或(Ⅲ)所示的光化疗顺铂类前药的制备方法,包括以下步骤:
(1)在氮气保护下,分别取顺式-二氯二氨二羟基铂和甲基丙烯酸异氰基乙酯于反应瓶中,并加入4-二甲氨基吡啶稳、2,6-二叔丁基对甲酚和二甲基甲酰胺,在0~60℃下,避光反应12~100小时;
(2)反应完毕后,降至室温,然后用冷乙醚分离,得到如式(Ⅱ)或(Ⅲ)所示的化合物。
优选为,顺式-二氯二氨二羟基铂和甲基丙烯酸异氰基乙酯的摩尔比为1:1.0~10;甲基丙烯酸异氰基乙酯、4-二甲氨基吡啶和2,6-二叔丁基对甲酚的摩尔比为1:0.001~2:0.01~2。
本发明还公开了一种式(Ⅴ)所示的光化疗顺铂类前药的制备方法,其特征在于,包括以下步骤:
(1)将式(II)所示的光化疗顺铂类前药,与2-甲基丙烯酰氧乙基磷酸(酰)胆碱加入茄型反应瓶中,并加入偶氮二异丁腈或过氧化苯甲酰引发剂和二硫酯类或三硫酯类链转移剂和溶剂,经过三次冷冻-抽气-解冻过程,反应温度为30~80℃,反应时间为0.5~72小时;
(2)反应完毕后,通过透析的方式提纯,冻干,最后得到式(Ⅴ)所示的光化疗顺铂类前药。
优选为,式(II)所示的光化疗顺铂类前药与2-甲基丙烯酰氧乙基磷酸(酰)胆碱的摩尔比为1:100~100:1;引发剂与2-甲基丙烯酰氧乙基磷酸(酰)胆碱的摩尔比为1:1000~1:1;链转移剂与引发剂的摩尔比为0:1000~1000:1。
本发明还公开了上述的光化疗前药在制备治疗抗肿瘤药物中的用途。
与现有技术相比,本发明的有益效果如下:
一、本发明的光化疗顺铂类前药具有一药两用的功能,在光照的情况下,可还原得到顺铂抗癌药,而且释放的活性氧物种可进一步进行光动力治疗,因此,既提高了传统顺铂的抗癌效果,且又解决了对于顺铂多药耐药性等问题;
二、相比传统的单药顺铂,本发明的光化疗顺铂类前药具有形式多样性,化学键修饰成的药物输送体系,可提高在体内的循环时间。
当然,实施本发明的任一产品并不一定需要同时达到以上所述的所有优点。
附图说明
图1为实施例2顺式-二氯二胺二(2-((氧基羰基)氨基)甲基丙烯酸乙酯)CPM的反应方程式;
图2为实施例2顺式-二氯二胺二(2-((氧基羰基)氨基)甲基丙烯酸乙酯)CPM的1HNMR谱图;
图3为实施例4聚铂类聚合物polyCPM的反应方程式;
图4为CPM光照后与顺铂的高效液相色谱-质谱谱图;
图5为顺铂、CPM和polyCPM光照前后羟基自由基电子自旋共振检测谱图;
图6为顺铂、CPM和polyCPM光照前后单线态氧电子自旋共振检测谱图;
图7为顺铂、CPM和polyCPM光照前后对肿瘤细胞A549细胞系生长抑制作用的示意图;
图8为顺铂、CPM和polyCPM光照前后对肿瘤耐药细胞A549R细胞系生长抑制作用的示意图;
图9为顺铂、CPM和polyCPM的药代动力学示意图;
图10为顺铂、CPM和polyCPM光照前后对A549小鼠肿瘤生长抑制作用的示意图;
图11为顺铂、CPM和polyCPM光照前后对A549小鼠肿瘤生长抑制作用的照片;
图12为顺铂、CPM和polyCPM光照前后对耐顺铂A549小鼠肿瘤生长抑制作用的示意图;
图13为顺铂、CPM和polyCPM光照前后对耐顺铂A549R小鼠肿瘤生长抑制作用的照片。
具体实施方式
下面结合具体实施例,进一步阐述本发明。应该理解,这些实施例仅用于说明本发明,而不用于限定本发明的保护范围。在实际应用中本领域技术人员根据本发明做出的改进和调整,仍属于本发明的保护范围。
本发明的一种光化疗铂类前药,其在光照下发生的反应如下所示:
该光化疗顺铂类前药在光照射下释放出活性氧物种,且还原得到二价顺铂抗癌药,本发明利用活性氧物种的光动力治疗与本身的化疗药相结合的一种肿瘤治疗方式。
其中,所述的化疗药前体可选自顺铂;光动力可选自的波长为200nm-1200nm;所述的光动力照射时间可选自0-10小时;所述的光动力的照射装置可选自为激光或LED灯光;所述的光动力的功率可选自0-5w/cm2之间;所述的光动力释放的物质可选自超氧自由基、氢氧自由基或过氧自由基中的一种或几种。
实施例1
顺式-二氯二氨二羟基铂的制备:称取0.2g顺铂,加入带有10倍含量过氧化氢(30%w/v,7.0mL,6.0×103mol)的5mL水溶液,50℃下避光搅拌过夜,最后重结晶得到淡黄色固体,并用冷水,冷乙醚,冷乙醇各洗三次,真空烘干,得到0.0109g顺式-二氯二氨二羟基铂固体,待用。
实施例2
结构式如(Ⅱ)或(Ⅲ)所示化合物的制备:取0.5g顺式-二氯二氨二羟基铂加入到100ml的茄型反应瓶,然后依次加入35mg的催化剂4-二甲氨基吡啶和70mg的稳定剂2,6-二叔丁基对甲酚,随后加入5ml的无水二甲基甲酰胺,通氮气保护后,开启搅拌,最后加入0.682g的甲基丙烯酸异氰基乙酯,反应温度控制在30℃,避光反应48h。反应完毕后,降到室温,吸取反应液并滴入200mL的冷乙醚中,出现沉淀并静置2小时,随后离心收集沉淀物,烘干后得到白色固体,化合物的结构经元素分析、红外光谱分析、1H-NMR和质谱分析符合要求,经HPLC检测纯度为99.7%。
本实施例(Ⅱ)或(Ⅲ)所示化合物的合成路线,如图1所示;式(Ⅱ)所示的化合物1HNMR如图2所示,测试溶剂为DMSO,分别对各个吸收峰进行归属,并在谱图中标明,具体如下:δ(ppm from TMS),6.7-6.9(1H,HN),6.4-6.7(3H,NH3),6.0-6.1(1H,C=CH),5.6-5.7(1H,C=CH),3.9-4.1(2H,NHCH2),3.1-3.2(2H,CH2OC),1.8-1.9(3H,H3CCCH2)。
将顺式-二氯二胺2-((氧基羰基)氨基)甲基丙烯酸乙酯铂(Ⅱ)简称为CPM,溶解在水、生理盐水、缓冲溶液、组织培养液或体液中的一种,将其配成溶液,然后施加波长为300-400nm的激光,功率为0.2-1.0w/cm2,在激光的作用下,释放出活性氧物种和顺铂。
实施例3
结构式如(Ⅳ)所示化合物的制备:称取4.1g丁二酸酐和3.3g顺式-二氯二氨二羟基铂于反应茄瓶中,加入5mL的DMSO溶解,溶液加热到70℃,并且反应15小时连续搅拌,然后冷却到室温,过滤,冻干法去除DMSO,并重结晶得到顺式-二氯二胺二丁二酸铂(Ⅳ)。
将顺式-二氯二胺二丁二酸铂溶解在水、生理盐水、缓冲溶液、组织培养液或体液中的一种,将其配成溶液,然后施加波长为300-400nm的激光,功率为0.2-1.0w/cm2,在激光的作用下,释放出活性氧物种和顺铂
实施例4
利用实施例2合成的CPM与2-甲基丙烯酰氧乙基磷酸(酰)胆碱单体、甲基丙烯酸单体或苯乙烯等中的一种或多种单体,以共聚合的方式合成聚铂类聚合物Ⅴ,简称polyCPM。聚合方法可采用自由基聚合,可控自由基聚合,可逆加成断裂链转移聚合方式。
本实施例合成polyCPM的合成路线,如图3所示,具体合成步骤如下:取CPM与2-甲基丙烯酰氧乙基磷酸(酰)胆碱于茄型反应瓶中,并加入引发剂、链转移剂和溶剂,经过三次冷冻-抽气-解冻过程,反应温度为30~80℃之间,反应时间为0.5~72小时,最后提出得到聚铂类聚合物(Ⅴ)。
其中,CPM与2-甲基丙烯酰氧乙基磷酸(酰)胆碱的摩尔比为1:100~100:1;引发剂为偶氮二异丁腈或过氧化苯甲酰,但又不局限于此两种引发剂,引发剂与单体的摩尔量比为1:1000~1:1;链转移剂为二硫酯类或三硫酯类链转移剂,但又不局限于此两种链转移剂,链转移剂与引发剂的摩尔量比例范围为0:1000~1000:1;溶剂为水、甲醇、二甲基亚砜、二氯乙烷或N,N-二甲基甲酰胺等中的一种或两种混合配的单一溶剂或混合溶剂。
将聚铂类聚合物溶解在水、生理盐水、缓冲溶液、组织培养液或体液中的一种,将其配成溶液,然后施加波长为300-400nm的激光,功率为0.2-1.0w/cm2,在激光的作用下,释放出活性氧物种和顺铂。
实施例5
铂类复合物顺式-二氯二胺2-((氧基羰基)氨基)甲基丙烯酸乙酯铂CPM(Ⅱ)和聚铂类聚合物polyCPM(Ⅴ)在激光波长300-1000nm范围内,进行光降解产物的评价,其中激光采用395nm波长。
分别取10毫克的CPM和polyCPM溶解在二甲基亚砜中,分别光照10-60分钟,光照后的物质与顺铂分别用高效液相色谱-质谱(HPLC-MS)检测,如图4所示。与顺铂的谱图相比,CPM光照后在7.74分钟出现同样的洗出峰,对应的质谱结果为[顺铂+H]+,证实光照降解产生了顺铂。
为了评价CPM和polyCPM在光照情况下产生了活性氧物种,采用电子自旋共振检测羟基自由基和单线态氧。分别取10毫克的CPM和polyCPM溶解在二甲基亚砜中,加入带有测试羟基自由基的二甲基吡啶N-氧化物(DMPO)水溶液,光照5分钟后进行检测,如图5所示,只有光照的CPM和polyCPM有1:2:2:1的信号,说明CPM和polyCPM在光照的情况下产生了羟基自由基。
分别将10毫克的CPM和polyCPM溶解在二甲基亚砜中,加入带有测试羟基自由基的2,2,6,6-四甲基哌啶(TEMP)甲醇溶液中,光照5分钟后进行检测,如图6所示,只有光照的CPM和polyCPM有信号,说明CPM和polyCPM在光照的情况下产生单线态氧。
实施例6
本实施例2和实施例4制得的光化疗顺铂前药CPM和polyCPM用于癌细胞的抗恶性肿瘤实验。
将顺铂、实施例2和实施例4中制备得到的CPM和polyCPM光化疗顺铂前药分别用细胞培养液配制成浓度为0.5,1,2.5,5,10,20,30,40μmol/L的溶液,然后分别跟非小型细胞肺癌A549及其耐药细胞系A549R培养72小时,其中对于CPM和polyCPM进行光照处理10min,采用MTT方法进行细胞活性测试,结果如图7和图8所示。当CPM和polyCPM光照以后,显示很好的细胞杀死效果,而在耐药细胞的MTT结果显示这种光化疗顺铂前药具有逆转细胞耐药性的功能,说明该光化疗顺铂前药在治疗恶性肿瘤中具有潜在的应用。
通过上述检测方式,四价铂类复合物微CPM和polyCPM在光照的情况下,释放出顺铂化疗药物和活性氧物种可作为光动力治疗的一类光化疗顺铂前药。
此外,还将实施例2和实施例4中制备得到的CPM和polyCPM光化疗顺铂类前药与顺铂单药进行动物水平的药代动力学的对比,分别尾静脉注射10mg/kg顺铂/小鼠体重当量的药物,每隔一定时间进行取血,通过电感耦合等离子体-质谱(ICP-MS)手段测得血样中铂元素的含量,最终得到三种药物的药代动力学曲线,如图9所示。从图9可以观察到:该polyCPM具有在体内长循环的作用,循环半衰期达到12小时左右,而单药顺铂和CPM的循环时间就很短,在半小时内就被清除,说明把光化疗药物修饰成高分子的结果有利于体内长循环。
最后,还将实施例2和实施例4中制备得到的CPM和polyCPM光化疗顺铂前药与顺铂单药进行动物水平肿瘤治疗效果的对比,首先,预先在小鼠后腿右上部种上非小型细胞肺癌A549细胞系肿瘤,等瘤体积达到50mm3,把小鼠分为5组,依次为生理盐水+光照,顺铂+光照,CPM+光照,polyCPM,和polyCPM+光照,分别尾静脉注射4mg/kg顺铂/小鼠体重当量的药物,每2天一次,总共5次,第二次注射后然后12小时内光照,激光强度0-0.85w/cm2,光照10分钟,治疗21天,对小鼠肿瘤体积每两天称量一次并且拍照,结果如图10和图11所示,polyCPM作为光化疗顺铂前药具有优秀的抗肿瘤效果,有些小鼠的肿瘤最终消失,说明该光化疗顺铂前药在治疗恶性肿瘤中具有潜在的应用。
进一步的,以上述同样的方式处理耐顺铂A549R的肿瘤小鼠,得到了相同的结论,如图12和图13所示,polyCPM作为光化疗顺铂前药具有优秀的抗耐药肿瘤效果,有些小鼠的肿瘤最终消失,说明该光化疗顺铂前药在治疗恶性肿瘤中,尤其是在肿瘤耐药性上也具有潜在的应用。
以上公开的本发明优选实施例只是用于帮助阐述本发明。优选实施例并没有详尽叙述所有的细节,也不限制该发明仅为所述的具体实施方式。显然,根据本说明书的内容,可作很多的修改和变化。本说明书选取并具体描述这些实施例,是为了更好地解释本发明的原理和实际应用,从而使所属技术领域技术人员能很好地理解和利用本发明。本发明仅受权利要求书及其全部范围和等效物的限制。
Claims (4)
2.一种如权利要求1所述的光化疗铂类前药的制备方法,其特征在于,包括以下步骤:
(1)在氮气保护下,分别取顺式-二氯二氨二羟基铂和甲基丙烯酸异氰基乙酯于反应瓶中,并加入4-二甲氨基吡啶、2,6-二叔丁基对甲酚和二甲基甲酰胺,在0~60℃下,避光反应12~100小时;
(2)反应完毕后,降至室温,然后用冷乙醚分离,得到如式(Ⅱ)所示的化合物。
3.如权利要求2所述的光化疗铂类前药的制备方法,其特征在于,顺式-二氯二氨二羟基铂和甲基丙烯酸异氰基乙酯的摩尔比为1:1.0~10;甲基丙烯酸异氰基乙酯、4-二甲氨基吡啶和2,6-二叔丁基对甲酚的摩尔比为1:0.001~2:0.01~2。
4.权利要求1所述的光化疗铂类前药或权利要求2或3所述的制备方法制得的所述的光化疗铂类前药在制备治疗抗肿瘤药物中的用途。
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