CN117618412A - 用于破坏肿瘤细胞膜的脂肪酸及其复合物、制备方法和用途 - Google Patents
用于破坏肿瘤细胞膜的脂肪酸及其复合物、制备方法和用途 Download PDFInfo
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Abstract
本发明公开了用于破坏肿瘤细胞膜的脂肪酸及其复合物、制备方法和用途。通过增加肿瘤细胞膜的流动性破坏细胞膜结构,以及破坏细胞外基质成分,进而杀灭肿瘤细胞;所述复合物为脂肪酸通过物理和化学的方式偶联靶向细胞膜成分的分子,从而赋予脂肪酸复合物具有靶向破坏肿瘤细胞膜的特性。本发明是第一次有药物可以直接破坏肿瘤细胞膜,从而杀灭和抑制肿瘤细胞。其中脂肪酸及其衍生物起到破坏肿瘤细胞的作用,大分子抗体或者小分子靶向药物与脂肪酸及其衍生物的结合,可以起到靶向破坏肿瘤细胞的作用。
Description
技术领域
本发明涉及抗肿瘤药物领域,尤其涉及用于破坏肿瘤细胞膜的脂肪酸及其复合物、制备方法和用途。
背景技术
目前治疗恶性肿瘤的药物包括化疗药:化疗药物是一种治疗肿瘤的药物。化疗药物可杀灭肿瘤细胞。这些药物能作用在肿瘤细胞生长繁殖的不同环节上,可以破坏肿瘤细胞的DNA和RNA,从而抑制癌细胞的生长和分裂,抑制或杀死肿瘤细胞。化疗药物治疗是目前治疗肿瘤的主要手段之一。根据药物的来源和化学结构,分为烷化剂、抗代谢药、抗癌抗生素、植物类、激素类和杂类等。根据药物对细胞增殖动力学的影响的不同分为细胞周期特异性药物和细胞周期非特异性药物;肿瘤内科学50年来在药物研制中的发展都是集中在细胞毒性攻击性的药物。虽然继蒽环类(阿霉素、表阿霉素)、铂类(顺铂、卡铂)之后又有很多强有力的化疗药物如泰素、泰索帝、开普拓、草酸铂、健择等问世并在各个不同的癌肿发挥重要的作用,但其性质仍然属于不能分辨肿瘤细胞和正常细胞的药物,临床应用受到诸多因素的限制。临床使用的抗肿瘤化学治疗药物均有不同程度的毒副作用,有些严重的毒副反应是限制药物剂量或使用的直接原因。它们在杀伤肿瘤细胞的同时,又杀伤正常组织的细胞,尤其是杀伤人体中生长发育旺盛的血液、淋巴组织细胞等。而这些细胞与组织是人体重要的免疫防御系统,破坏了人体的免疫系统,癌症就可能迅速发展,造成严重后果。化疗的毒副反应分近毒性反应和远期毒性反应两种。毒性反应又分为局部反应(如局部组织坏死、栓塞性静脉炎等)和全身性反应(包括消化道、造血系统、免疫系统、皮肤和粘膜反应、神经系统、肝功能损害、心脏反应、肺毒性反应、肾功能障碍及其他反应等)。远期毒性反应主要是生殖功能障碍及致癌作用、致畸作用等。此外,化疗由于其毒副作用,有时还可出现并发症,常见的有感染、出血、穿孔、尿酸结晶等。
导致肿瘤发生的驱动基因种类繁多,不同类型的癌症所依赖的信号通路或关键蛋白情况各异,靶向药物可以针对不同肿瘤生存、生长所依赖的关键蛋白选择性杀伤肿瘤细胞或抑制其生长。针对不同癌症患者的肿瘤特征,选择适合的靶向药物进行治疗,可在一定程度上实现肿瘤的个体化治疗。靶向药物凭借其良好的安全有效性已成为目前抗肿瘤药物领域主要发展方向之一。主要包括小分子靶向药物和大分子单克隆抗体和的使用,靶向药物已成为国内精准医疗的首选药物之一。例如靶向EGFR的药物,如吉西他滨和厄洛替尼,可以直接作用于癌细胞膜上的EGFR受体,从而阻止癌细胞的生长和扩散。
小分子药物主要是指化学合成药物,通常分子量小于1000的有机化合物。小分子药物结构具有良好的空间分散性,其化学性质决定了其良好的成药性能和药物代谢动力学性质。这些特点就使得小分子药物在药物研发过程及其它药物领域中表现出巨大优势,小分子药物研发越来越受到市场的青睐。小分子药物通常是信号传导抑制剂,它能够特异性地阻断肿瘤生长、增殖过程中所必需的信号传导通路,从而达到治疗的目的。
分子靶向治疗之所以受到密切关注,并引起研究者不断探究的兴趣,是因为它以肿瘤细胞的特性改变为作用靶点,在发挥更强的抗肿瘤活性的同时,减少对正常细胞的毒副作用。这种有的放矢的治疗方法为肿瘤治疗指明了新的方向。根据药物的作用靶点和性质,可将主要分子靶向治疗的药物分为以下几类:小分子表皮生长因子受体(EGFR)酪氨酸激酶抑制剂,如吉非替尼(Gefitinib,Iressa,易瑞沙);埃罗替尼(Erlotinib,Tarceva);Bcr-Abl酪氨酸激酶抑制剂,如伊马替尼(Imatinib);IGFR-1激酶抑制剂,如NVP-AEW541;mTOR激酶抑制剂,如CCI-779;泛素-蛋白酶体抑制剂,如Bortezomib;抗EGFR的单抗,如西妥昔单抗(Cetuximab,Erbitux);抗HER-2的单抗,如赫赛汀(Trastuzumab,Herceptin);血管内皮生长因子受体抑制剂,如Bevacizumab(Avastin);抗CD20的单抗,如利妥昔单抗(Rituximab)。
目前的分子靶向治疗也面临着同样的问题。除了伊马替尼高度针对引起CML的Bcr-Abl基因改变从而疗效异常显著外,大部分靶向药物的有效率基本都在10%左右。其原因正是因为大多数实体肿瘤都是多靶点多环节的调控过程。仅以结肠癌为例,且不说众所周知的表皮细胞生长因子受体-1(EGFR-1)的调控,研究人员还发现很多其它因子,如HER-2受体表达,蛋白酶激活的受体-2,胰岛素样生长因子-1和相应受体表达,Src非受体酪氨酸激酶,血管内皮生长因子(VEGF)过表达,转化生长因子-α受体,NAG-1(一种转化生长因子-β超家族成员)表达,Fas(CD95,APO-1)受体(一种诱导细胞凋亡的跨膜细胞表面受体)和A3腺苷受体等。它们不是直接参与肿瘤的生长就是间接影响细胞周期或其它生物过程。应该认识到,细胞中信号转导机构是一个复合的、多因素交叉对话的蛋白网络系统。它能通过有效的联络将上游的发起性因子信息转化成下游的效应性结果。因此,只是看到单一因素的过表达就一定有肿瘤生长的功能性作用,显然是不全面的。同样,阻断一个受体就能阻断任何信息传导也是不客观的。
进入二十一世纪后的抗肿瘤药物研发战略是在继续深入发展细胞毒性药物的基础上同时逐渐引入分子靶向性药物的开发。迄今为止,很多靶向药物已经在临床起了极其重要甚至是奇迹般的作用。
而直接靶向细胞膜和细胞外基质的药物还不多,细胞膜的结构由磷脂双分子层构成,构成磷脂双分子层的主要成分是脂肪酸,甘油磷脂和鞘磷脂是细胞中膜结构的主要构成成分。细胞外基质成分包括胶原蛋白、弹性蛋白、纤维连接蛋白、糖蛋白、透明质酸、硫酸软骨素、粘连蛋白。
发明内容
本发明针对现有技术中化疗药物及抗体药物的局限性,提供一种通过改变细胞膜结构,改变细胞膜流动性进行肿瘤治疗的脂肪酸及脂肪酸复合物。
为实现上述目的,用于破坏肿瘤细胞膜和/或细胞外基质成分的脂肪酸及其复合物,其特征在于,通过增加肿瘤细胞膜的流动性破坏细胞膜结构,以及破坏细胞外基质成分,进而杀灭肿瘤细胞;
所述复合物为脂肪酸通过物理和化学的方式偶联靶向细胞膜成分的分子,从而赋予脂肪酸复合物具有靶向破坏肿瘤细胞膜的特性;
优选的,所述脂肪酸的碳链选自脂溶性直链和/或带有支链、环状结构的饱和和/或不饱和碳链;所述碳链为碳原子数为3-100的分子或者分子的残基;
更优选的,所述碳链选自饱和和/或不饱和脂肪烃、饱和和/或不饱和脂肪醇或氧代脂肪醇、饱和和/或不饱和脂肪酸、疏水性氨基酸、脂溶性维生素、类胡萝卜素、固醇及类固醇类脂质、脂肪酸甘油酯、磷脂、鞘磷脂、糖脂和/或表面活性剂形成的碳原子数为3-100的碳链或碳链的残基;所述复合物为疏水性或者水溶性;
所述脂肪酸及其复合物的剂型为脂质体、油性和/或水溶性溶液。
进一步,所述靶向细胞膜成分的分子是指靶向肿瘤细胞膜外部的结构和成分、结构域,靶向细胞膜镶嵌的蛋白结构域,以及靶向肿瘤细胞膜内结构域的分子;
优选的,所述靶向细胞膜成分的分子包括抗体、蛋白、多糖、核酸、多肽、寡肽、寡糖、寡聚核苷酸、单糖、维生素、核苷酸、小分子靶向药物。
进一步,所述抗体是指与肿瘤相关抗原结合的抗体,所述蛋白是指与肿瘤相关抗原结合的蛋白,所述多肽是指与肿瘤相关抗原结合的多肽以及重组多肽;
优选的,所述肿瘤相关抗原包括:GD2、CD3、CD25、CD19、CD20、CD30、CD38、CD147、TNF-α、CTLA-4、EGFR、HER2、Nectin-4、SLAMF7、TROP-2、VEGF、VEGFR、PD-1、PD-L1;
更优选的,所述抗体选自以下至少任何一种:与GD2结合的达妥昔单抗;与CD19结合的博纳吐单抗;与CD20结合的替伊莫单抗、利妥昔单抗、托西莫单抗、奥滨尤妥珠单抗、奥法木单抗;与CD30结合的本妥昔单抗;与CD38结合的达雷木单抗;与CD147结合的美妥昔单抗;与CD25结合的重组抗CD25人源化单抗;与CD3结合的抗人T细胞CD3鼠单抗;与TNF-α结合的重组人Ⅱ型肿瘤坏死因子受体-抗体融合蛋白、阿达木单抗;与CTLA-4结合的伊匹单抗;与EGFR结合的耐昔妥珠单抗、西妥昔单抗;与HER2结合的帕妥珠单抗、曲妥珠单抗;与Nectin-4结合的恩弗妥单抗;与SLAMF7结合的埃罗妥珠单抗;与TROP-2结合的赛妥珠单抗;与VEGF结合的贝伐珠单抗、CimaVax肺癌疫苗;与VEGFR结合的雷莫芦单抗;与PD-1结合的纳武利尤单抗、帕博利珠单抗、卡瑞利珠单抗、特瑞普利单抗、替雷利珠单抗、信迪利单抗;与PD-L1结合的度伐利优单抗、阿替利珠单抗;
所述多肽为Ra-V(deoxybouvardin)、KLA多肽、ALOS-4、奥曲肽;寡肽为cRGD、iRGD、RGD-4C、RGD-PEG和RGD-Arg;
所述多糖为透明质酸、肝素、甘露聚糖、海藻多糖;、单糖为葡萄糖、N-乙酰葡萄糖胺、半乳糖、果糖;、维生素为维生素D、维生素E、维生素C、维生素K、维生素B12、维生素A、维生素F;
所述小分子靶向药物选自以下至少任何一种:AKT抑制剂;ALK抑制剂;BCL-2抑制剂;BCR-ABL抑制剂;BRAF V600E抑制剂;BTK抑制剂;CDK4/6抑制剂;EGFR抑制剂;FGFR抑制剂;EZH2抑制剂;HEG2抑制剂;HDAC抑制剂;MEK抑制剂;MET抑制剂;mTOR抑制剂;NTRK抑制剂;PARP抑制剂;PDGFR抑制剂;PI3K抑制剂;蛋白酶体抑制剂;RET抑制剂;ROS1抑制剂;SMO抑制剂;Src/Ab1双重抑制剂;VEGFR抑制剂;
优选的,所述AKT抑制剂为卡帕塞替尼;所述ALK抑制剂为克唑替尼、色瑞替尼、艾乐替尼、布加替尼、劳拉替尼;所述BCL-2抑制剂为维奈妥拉;BCR-ABL抑制剂为伊马替尼、达沙替尼、尼洛替尼、普纳替尼;所述BRAF V600E抑制剂为维莫非尼、达拉非尼、康奈非尼;所述BTK抑制剂为伊鲁替尼、阿卡替尼、泽布替尼、奥布替尼;所述CDK4/6抑制剂为帕博西林、瑞博西林、玻玛西林;所述EGFR抑制剂为吉非替尼、厄洛替尼、埃克替尼、阿法替尼、达克替尼、奥希替尼、阿美替尼;所述FGFR抑制剂为厄达替尼、培米替尼、英非格拉替尼;所述EZH2抑制剂为他泽司他;所述HEG2抑制剂为拉帕替尼、来那替尼、吡咯替尼、图卡替尼;所述HDAC抑制剂为伏立诺他、罗米地辛、贝利司他、帕比司他、西达本胺、Mocetinostat;所述MEK抑制剂为曲美替尼、考比替尼、比美替尼、司美替尼;所述MET抑制剂为卡马替尼、特泊替尼、沃利替尼;所述mTOR抑制剂为西罗莫司、替西罗莫司、依维莫司、佐他莫司;所述NTRK抑制剂为恩曲替尼、拉罗替尼、艾乐替尼;所述PARP抑制剂为奥拉帕利、尼拉帕利、他拉唑帕利、鲁卡帕利;所述PDGFR抑制剂为阿伐普替尼、米哚妥林、尼达尼布、拉多替尼、瑞普替尼;所述PI3K抑制剂为阿培利司、艾代拉利司、厄布利塞;所述蛋白酶体抑制剂为硼替佐米、卡非佐米、伊沙佐米;所述RET抑制剂为普雷西替尼、塞尔帕替尼;所述ROS1抑制剂为恩曲替尼;所述SMO抑制剂为维莫德吉、索尼德吉、格拉吉布;所述Src/Ab1双重抑制剂为博舒替尼;所述VEGFR抑制剂为索拉非尼、舒尼替尼、帕唑帕尼、瑞戈非尼、凡德他尼、乐伐替尼、卡博替尼、阿昔替尼、特拉替尼、阿帕替尼、安罗替尼、呋喹替尼。
进一步,所述脂肪酸为具有一定水溶性的脂肪酸;
优选的,所述具有一定水溶性的脂肪酸是指分子中具有水溶性的极性基团如羟基、羧基、氨基、胺基、季铵基、胍基、巯基、磺酸基、磺酰氧基、磷酸基,且组成碳链的碳原子的数目为3-100;
所述水溶性分子选自蛋白质、多糖、核酸和人工合成的水溶性高聚物中的一种或二种以上的水溶性大分子或其残基;
和/或,选自多肽、寡肽、寡糖、寡核苷酸和人工合成的水溶性中等分子量的聚合物中的一种或二种以上的中等分子或其残基;
和/或,选自氨基酸、单糖、二糖、核苷酸、脱氧核苷酸和水溶性维生素中的一种或二种以上的水溶性小分子或其残基;
所述复合物中的脂肪酸为疏水性脂肪酸,通过物理或化学方法偶联靶向细胞膜成分的分子形成亲水性复合物。
本发明还提供所述用于破坏肿瘤细胞膜和/或细胞外基质成分的脂肪酸及其复合物中的复合物的制备方法,其特征在于,
脂肪酸在催化剂的作用下,酸性条件下先进行活化,然后与靶向细胞膜的成分的分子进行化学或者物理偶联得到脂肪酸复合物溶液;
优选的,将脂肪酸复合物溶液纯化得到脂肪酸复合物。
本发明还提供所述用于破坏肿瘤细胞膜和或细胞外基质成分的脂肪酸及其复合物用于制备治疗肿瘤药物的用途。
本发明以细胞膜靶点而设计了一组药物,通过药物插入到细胞膜内,增加肿瘤细胞膜的流动性,进一步破坏肿瘤细胞膜的结构。
目前还没有一种肿瘤药物,可以直接破坏肿瘤细胞膜起作用,对肿瘤细胞进行破坏。本发明是第一次有药物可以直接破坏肿瘤细胞膜,从而杀灭和抑制肿瘤细胞。其中脂肪酸及其衍生物起到破坏肿瘤细胞的作用,大分子抗体或者小分子靶向药物与脂肪酸及其衍生物的结合,可以起到靶向破坏肿瘤细胞的作用。
本发明所述的脂肪酸大部分是疏水性的,它发挥抗肿瘤的作用是通过增加肿瘤细胞膜流动性破坏细胞膜结构,以及破坏细胞外基质成分,进而杀灭肿瘤细胞。
本发明最后的复合物可以是疏水性也可以是水溶性的,区别是给药方式不同,如果是疏水性的复合物,可以介入或者直接注射的方式起到治疗效果;如果是水溶性的复合物,可以通过静脉给药。制备成水溶性,是为了增加给药途径,如果是疏水性的给药途径比较局限,只能直接注射或者介入给药。
附图说明
图1为实施例1制得的亚油酸-贝伐单抗的红外光谱图。
图2为实施例1制得的亚油酸-特瑞普利单抗的红外光谱图。
图3为实施例1制得的亚油酸-西妥昔单抗的红外光谱图。
图4为实施例1制得的花生酸-曲妥珠单抗的结合位点。
图5为实施例1制得的EPA-伊匹木单抗的结合位点。
图6为实施例1制得的亚油酸-卡瑞利珠单抗的结合位点。
图7为实施例1制得的亚油酸-贝伐单抗的结合位点。
图8为实施例1制得的亚油酸-西妥昔单抗的增加细胞膜流动性结果图。
图9为实施例1制得的软脂酸(正十六烷酸)-阿达木单抗的体外抑瘤结果图。
图10为实施例1制得的c-9-十六碳烯酸-利妥昔单抗的体外抑瘤结果图。
图11为实施例1制得的十六烷二酸-达妥昔单抗的体外抑瘤结果图。
图12为实施例1制得的硬脂酸(十八烷酸)-雷莫芦单抗的体外抑瘤结果图。
图13为实施例1制得的油酸(c-9-十八烯酸)-本妥昔单抗的体外抑瘤结果图。
图14为实施例1制得的亚油酸-帕妥珠单抗的体外抑瘤结果图。
图15为实施例1制得的亚麻酸-达雷木单抗的体外抑瘤结果图。
图16为实施例1制得的十八烷二酸-美妥昔单抗的体外抑瘤结果图。
图17为实施例1制得的花生酸-曲妥珠单抗的体外抑瘤结果图。
图18为实施例1制得的EPA-伊匹单抗的体外抑瘤结果图。
图19为实施例1制得的二十烷二酸-赛妥珠单抗的体外抑瘤结果图。
图20为实施例1制得的芥酸-恩弗妥单抗的体外抑瘤结果图。
图21为实施例1制得的DHA-博纳吐单抗的体外抑瘤结果图。
图22为实施例1制得的c-9-十六碳烯酸-埃罗妥珠单抗的体外抑瘤结果图。
图23为实施例1制得的硬脂酸(十八烷酸)-信迪利单抗的体外抑瘤结果图。
图24为实施例1制得的亚油酸(all cis-9,12-十八碳二烯酸)-卡瑞利珠单抗的体外抑瘤结果图。
图25为实施例1制得的亚麻酸(all cis-9,12,15-十八碳三烯酸)-特瑞普利单抗的体外抑瘤结果图。
图26为实施例1制得的EPA(all cis-5,8,11,14,17-二十碳五烯酸)-贝伐珠单抗的体外抑瘤结果图。
图27为实施例1制得的DHA(all cis-4,7,10,13,16,19-二十二碳六烯酸)-西妥昔单抗的体外抑瘤结果图。
图28为实施例1制得的二十烷二酸-阿替利珠单抗的体外抑瘤结果图。
图29为实施例1制得的EPA-贝伐珠单抗的体内抑瘤结果图。
图30为实施例2制得的油酸-索拉菲尼的红外光谱图。
图31为实施例2制得的二十二烷二酸-卡帕塞替尼的体外抑瘤结果图。
图32为实施例2制得的软脂酸(正十六烷酸)-克唑替尼的体外抑瘤结果图。
图33为实施例2制得的c-9-十六碳烯酸-维奈妥拉的体外抑瘤结果图。
图34为实施例2制得的十六烷二酸-维莫非尼的体外抑瘤结果图。
图35为实施例2制得的硬脂酸-阿卡替尼的体外抑瘤结果图。
图36为实施例2制得的油酸-拉帕替尼的体外抑瘤结果图。
图37为实施例2制得的亚油酸-吉非替尼的体外抑瘤结果图。
图38为实施例2制得的亚麻酸-曲美替尼的体外抑瘤结果图。
图39为实施例2制得的花生酸-西罗莫司的体外抑瘤结果图。
图40为实施例2制得的油酸-索拉非尼的体外抑瘤结果图。
图41为实施例2制得的十八烷二酸-奥拉帕利的体外抑瘤结果图。
图42为实施例2制得的花生酸(正二十烷酸)-阿培利司的体外抑瘤结果图。
图43为实施例2制得的油酸(c-9-十八烯酸)-索拉菲尼的体内抑瘤结果图。
图44为实施例3制得的二十二烷二酸-透明质酸的体外抑瘤结果图。
图45为实施例4制得的软脂酸(正十六烷酸)-果糖的体外抑瘤结果图。
图46为实施例4制得的十六烷二酸-葡萄糖的体外抑瘤结果图。
图47为实施例5制得的芥酸(c-13-二十二烯酸)-奥曲肽的体外抑瘤结果图。
图48为亚油酸和亚油酸脂质体破坏肿瘤不可溶性胶原的结果图。
图49为油酸和油酸脂质体破坏肿瘤弹力蛋白的结果图。
图50为花生酸和花生酸脂质体破坏肿瘤可溶性胶原的结果图。
图51为EPA和EPA脂质体破坏肿瘤透明质酸的结果图。
图52为DHA和DHA脂质体破坏肿瘤粘多糖的结果图。
图53为亚油酸-贝伐单抗、亚油酸-特瑞普利单抗复合物破坏肿瘤不可溶性胶原的结果图。
图54为亚油酸-贝伐单抗、亚油酸-特瑞普利单抗复合物破坏肿瘤弹力蛋白的结果图。
图55为亚油酸-贝伐单抗、亚油酸-特瑞普利单抗复合物破坏肿瘤可溶性胶原的结果图。
图56为亚油酸-贝伐单抗、亚油酸-特瑞普利单抗复合物破坏肿瘤透明质酸的结果图。
图57为亚油酸-贝伐单抗、亚油酸-特瑞普利单抗复合物破坏肿瘤粘多糖的结果图。
具体实施方式
下面详细描述本发明的实施例,所述实施例的示例在附图中示出,其中自始至终相同或类似的标号表示相同或类似的元件或具有相同或类似功能的元件。下面通过参考附图描述的实施例是示例性的,旨在用于解释本发明,而不能理解为对本发明的限制。实施例中未注明具体技术或条件者,按照本领域内的文献所描述的技术或条件或者按照产品说明书进行。所用试剂或仪器未注明生产厂商者,均为可以通过市购获得的常规产品。
实施例1:脂肪酸-单抗复合物的制备及其体内、体外抑瘤实验
1.1.脂肪酸-单抗复合物的制备
本实施例中脂肪酸与单抗药物摩尔比为24:1,催化剂与脂肪酸摩尔比为1:1,催化剂选用1-乙基-(3-二甲基氨基丙基)碳酰二亚胺(EDC),N-羟基磺基琥珀酰亚胺(sulfo-NHS)。反应过程如下:
精密称取脂肪酸0.36mmol,EDC 0.36mmol,sulfo-NHS 0.36mmol;加酸催化激活羧基以形成活化脂肪酸;冰浴下搅拌活化15min。量取单抗药物溶液(单抗0.015mmol),加入到搅拌中的活化脂肪酸中,冰浴下继续搅拌反应过夜,即可得到脂肪酸-单抗药物复合物溶液。将上述溶液用冰丙酮沉淀,再用乙醇洗去沉淀中未反应的脂肪酸,将沉淀透析至完全溶解,同时除去小分子杂质(采用截留分子量为7kDa的透析袋进行透析,每隔4h换一次水),之后在冷冻真空干燥机中进行梯度低温干燥(-80℃低温预冷冻24h并真空12h,-20℃抽真空12h,4℃继续抽真空24h以上至产物完全干燥),得到脂肪酸连接单抗药物的复合物(即脂肪酸-单抗复合物)。
按上述方法合成的脂肪酸单抗药物复合物可以是:正丁酸-阿达木单抗、富马酸(t-丁烯二酸)-利妥昔单抗、正己酸-达妥昔单抗、t-2-己烯酸-雷莫芦单抗、正辛酸-本妥昔单抗、t-2-辛烯酸-帕妥珠单抗、壬酸-达雷木单抗、十一酸-美妥昔单抗、十一烷二酸-曲妥珠单抗、十二烷二酸-伊匹单抗、十三烷酸-赛妥珠单抗、十三烷二酸-恩弗妥单抗、十五烷二酸-博纳吐单抗、c-9-十六碳烯酸-埃罗妥珠单抗、硬脂酸(十八烷酸)-信迪利单抗、亚油酸(all cis-9,12-十八碳二烯酸)-卡瑞利珠单抗、亚麻酸(all cis-9,12,15-十八碳三烯酸)-特瑞普利单抗、EPA(all cis-5,8,11,14,17-二十碳五烯酸)-贝伐珠单抗、DHA(allcis-4,7,10,13,16,19-二十二碳六烯酸)-西妥昔单抗、二十烷二酸-阿替利珠单抗、软脂酸(正十六烷酸)-阿达木单抗、c-9-十六碳烯酸-利妥昔单抗、十六烷二酸-达妥昔单抗、硬脂酸(十八烷酸)-雷莫芦单抗、油酸(c-9-十八烯酸)-本妥昔单抗、亚油酸-帕妥珠单抗、亚麻酸-达雷木单抗、十八烷二酸-美妥昔单抗、花生酸-曲妥珠单抗、EPA-伊匹单抗、二十烷二酸-赛妥珠单抗、芥酸-恩弗妥单抗、DHA-博纳吐单抗、亚油酸-贝伐单抗、亚油酸-特瑞普利单抗、亚油酸-西妥昔单抗。所制备的部分复合物红外光谱如图1-3所示。
1.2.脂肪酸与单抗药物的结合位点
通过Pubmed数据库、Chemdraw软件获得亚油酸、花生酸、EPA的3D结构,利用PDB数据库下载贝伐单抗、伊匹木单抗、曲妥珠单抗、卡瑞利珠单抗,结合PyMOL 2.4.0软件和AutoDock Tools 1.5.7软件对作用靶点和活性成分进行相关的常规处理及分子对接,发现花生酸与曲妥珠单抗的结合位点为氨基酸残基SER-134和PRO-133,EPA与伊匹木单抗的结合位点为氨基酸残基TRP-108、PRO-45、LEU-47和ASP-106,亚油酸与卡瑞普利单抗的结合位点为氨基酸残基TYR-208、LYS-160和GLY-162,亚油酸与贝伐单抗的结合位点为LEU-54、SER-56和TYR-49。实验结果见图4-7。
1.3.脂肪酸-单抗复合物改变细胞膜流动性实验
将SK-HEP-1细胞以较低密度种在四分共聚焦皿中。在细胞长到50%满时,在每孔加入3μl Laurdan荧光染料溶液(10μM),孵育5h。移去旧的培养基,用PBS将细胞清洗两遍,加入亚油酸-西妥昔单抗与细胞孵育1h,检测荧光信号前,移去旧的培养基,用PBS将细胞清洗两遍,加入新的培养基。每隔20s记录细胞膜荧光强度,并计算出细胞膜荧光恢复率,结果表明,亚油酸-西妥昔单抗增强了细胞膜的流动性。实验结果见图8。从图中可以看出在100s时经过亚油酸-西妥昔单抗处理后细胞膜流动性可恢复到60%,而对照组只能恢复到53%。
1.4.脂肪酸-单抗复合物体外抑瘤实验
将SK-HEP-1细胞接种到96孔板(5000细胞/孔),然后用脂肪酸-单抗复合物以不同浓度处理24h。用冷PBS冲洗细胞后,再用100μL MTT(0.5mg/mL)孵育4h,然后除去MTT溶液,加入100μL二甲基亚砜溶解甲醛晶体,用微板读卡器记录在570nm处的吸光度。细胞存活率=[(As-Ab)/(Ac-Ab)]×100%。其中,As:实验孔(含有细胞的培养基,MTT,药物)Ac:对照孔(含有细胞的培养基,MTT,没有加药)Ab:空白孔(不含细胞和药物的培养基,MTT)。所述结果见图9-28。从图9-28可以看出:当脂肪酸-单抗复合物浓度为0时,细胞活性为100%;随着脂肪酸-单抗复合物浓度升高,细胞活性逐渐下降。说明脂肪酸-单抗复合物可以有效的抑制肿瘤细胞生长。
1.5脂肪酸-单抗复合物体内抑瘤实验
将4*105的SK-HEP-1肿瘤细胞通过皮下注射到BALB/c裸鼠右腿上侧,等肿瘤体积达到100mm3左右时开展抑瘤实验。将裸鼠分为两组,每组3只,PBS组(生理盐水组)和EPA-贝伐珠单抗复合物组。每隔两天从尾静脉注射PBS和EPA-贝伐珠单抗复合物,每次的注射量为100μL,0.3mM,记录裸鼠的体重变化和测量裸鼠的肿瘤直径。裸鼠的肿瘤体积计算方式如下:长*宽*宽/2。
所述结果见图29。附图29说明了EPA-贝伐珠单抗复合物可以有效抑制体内肿瘤生长。
实施例2:脂肪酸-小分子药物复合物的制备及其体内、体外抑瘤实验
2.1.脂肪酸-小分子药物复合物的制备
2.1.1二十二烷二酸-卡帕塞替尼
二十二烷二酸0.1mmol,N,N'-二环己基碳二亚胺(DCC)0.12mmol,N-羟基丁二酰亚胺(NHS)0.12mmol,加入6mL DMF中,室温下搅拌反应12h。卡帕塞替尼0.1mmol溶于4mL DMF,加入到巴豆酸反应液中,室温下继续反应12h。反应液用50mL乙酸乙酯稀释,依次用20mL纯化水、20mL饱和食盐水洗涤,有机层用无水硫酸钠干燥后,真空旋蒸除去溶剂得粗品。粗品经硅胶柱层析纯化,甲醇/二氯甲烷体系梯度洗脱(2-6%甲醇)得二十二烷二酸-卡帕塞替尼复合物。
2.1.2软脂酸(正十六烷酸)-克唑替尼
软脂酸(正十六烷酸)0.1mmol,1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(EDCI)0.12mmol,N-羟基丁二酰亚胺(NHS)0.12mmol,加入6mL二氯甲烷(DCM)中,室温下搅拌反应12h。克唑替尼0.1mmol溶于4mL DCM,加入到反应液中,室温下继续反应12h。反应液旋转蒸发除去溶剂,粗品使用硅胶柱层析纯化,乙酸乙酯/己烷体系梯度洗脱(0–100%乙酸乙酯),合并收集液蒸除溶剂,即得软脂酸(正十六烷酸)-克唑替尼复合物。
2.1.3c-9-十六碳烯酸-维奈妥拉
c-9-十六碳烯酸0.1mmol,1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(EDCI)0.12mmol,N-羟基丁二酰亚胺(NHS)0.12mmol,加入6mL二氯甲烷(DCM)中,室温下搅拌反应12h。维奈妥拉0.1mmol溶于4mL DCM,加入到反应液中,室温下继续反应12h。反应液旋转蒸发除去溶剂,所得粗品使用硅胶柱层析纯化,甲醇/乙酸乙酯体系梯度洗脱(0–5%甲醇),合并收集液蒸除溶剂,即得c-9-十六碳烯酸-维奈妥拉复合物。
2.1.4十六烷二酸-维莫非尼
十六烷二酸0.1mmol,N,N'-二环己基碳二亚胺(DCC)0.12mmol,N-羟基丁二酰亚胺(NHS)0.12mmol,加入6mL DMF中,室温下搅拌反应12h。维莫非尼0.1mmol溶于4mL DMF,加入到十六烷二酸反应液中,室温下继续反应12h。反应结束后加入20mL纯化水稀释,用50mL乙酸乙酯进行萃取,有机层用20mL饱和食盐水洗涤2次,无水硫酸钠干燥后,真空旋蒸除去溶剂得粗品。粗品经硅胶柱层析纯化,二氯甲烷/5%甲醇体系洗脱,合并收集液,蒸除溶剂得十六烷二酸-维莫非尼复合物。
2.1.5硬脂酸-阿卡替尼
硬脂酸0.1mmol,1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(EDCI)0.12mmol,N-羟基丁二酰亚胺(NHS)0.12mmol,加入6mL二氯甲烷(DCM)中,室温下搅拌反应12h。阿卡替尼0.1mmol溶于4mL DCM,加入到反应液中,室温下继续反应12h。反应液旋转蒸发除去溶剂,所得粗品使用HPLC进行纯化,C-18反相柱,乙腈-水为流动相,合并收集液,真空干燥即得硬脂酸-阿卡替尼复合物。
2.1.6油酸-拉帕替尼
油酸0.1mmol,1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(EDCI)0.12mmol,N-羟基丁二酰亚胺(NHS)0.12mmol,加入6mL DMF中,室温下搅拌反应12h。拉帕替尼0.1mmol溶于4mL DMF,加入到反应液中,室温下继续反应12h。反应液用50mL乙酸乙酯稀释,依次用20mL饱和食盐水洗涤2次,有机层用无水硫酸钠干燥后,真空旋蒸除去溶剂得粗品。粗品经硅胶柱层析纯化,甲醇/乙酸乙酯体系洗脱(5%甲醇),合并收集液蒸除溶剂,即得油酸-拉帕替尼复合物。
2.1.7亚油酸-吉非替尼
亚油酸0.1mmol,1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(EDCI)0.12mmol,N-羟基丁二酰亚胺(NHS)0.12mmol,加入6mL DMF中,室温下搅拌反应12h。阿卡替尼0.1mmol溶于4mL DMF,加入到反应液中,室温下继续反应12h。反应液转移至50mL纯化水中,过滤收集沉淀,干燥得粗品。粗品经硅胶柱层析纯化,二氯甲烷/甲醇体系洗脱(二氯甲烷:甲醇=9:1),合并收集液,蒸除溶剂即得亚油酸-吉非替尼复合物。
2.1.8亚麻酸-曲美替尼
亚麻酸0.1mmol,1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(EDCI)0.12mmol,N-羟基丁二酰亚胺(NHS)0.12mmol,加入6mL DMF中,室温下搅拌反应12h。曲美替尼0.1mmol溶于4mL DMF,加入到反应液中,室温下继续反应12h。反应液中加入纯化水50mL,室温下缓慢搅拌1h,过滤收集沉淀,干燥得粗品。粗品加DMF1mL,油浴加热至130℃搅拌使溶解,滴加正丁醇/水混合溶液(正丁醇:水=3:2)1mL,130℃搅拌30min,停止加热,搅拌下继续滴加纯化水1mL,继续搅拌至恢复室温,过滤收集沉淀,干燥即得。
2.1.9花生酸-西罗莫司
花生酸0.2mmol,1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(EDCI)0.24mmol,加入6mL干燥DCM中,室温下搅拌反应6h。4-二甲氨基吡啶(DMAP)0.24mmol,曲美替尼0.1mmol溶于4mL DCM,加入到反应液中,室温下继续反应24h。反应液用饱和盐水20mL洗2次,无水硫酸钠干燥,旋蒸除去溶剂得粗品。粗品经硅胶柱层析纯化,二氯甲烷/甲醇体系洗脱(二氯甲烷:甲醇=9:1),合并收集液,蒸除溶剂即得花生酸-西罗莫司复合物。
2.1.10油酸(c-9-十八烯酸)-索拉菲尼
索拉非尼0.1mmol溶于5mL DMF中,加三乙胺0.3mmol,冰浴下搅拌,滴加油酰氯0.3mmol,滴加完成后室温下搅拌反应24h,反应液加乙酸乙酯20mL稀释,饱和盐水20mL洗2次,旋蒸除去溶剂。所得固体加入石油醚1mL,超声使分散,抽滤,沉淀用1mL石油醚洗2次,真空抽除溶剂,干燥即得油酸(c-9-十八烯酸)-索拉菲尼复合物。所制备的复合物红外光谱如图30所示。可以看出:在油酸-索拉菲尼复合物的吸收峰上可明显看出油酸和索拉菲尼的吸收峰。
2.1.11十八烷二酸-奥拉帕利
十八烷二酸0.1mmol,1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(EDCI)0.12mmol,N-羟基丁二酰亚胺(NHS)0.12mmol,加入6mL二氯甲烷(DCM)中,室温下搅拌反应12h。奥拉帕利0.1mmol溶于4mL DCM,加入到反应液中,室温下继续反应12h。反应液用20mL饱和盐水洗2次,无水硫酸钠干燥,旋转蒸发除去溶剂,得粗品。所得粗品使用硅胶柱层析纯化,二氯甲烷/甲醇体系洗脱,合并收集液蒸除溶剂,即得十八烷二酸-奥拉帕利复合物。
2.1.12花生酸(正二十烷酸)-阿培利司
花生酸0.1mmol,1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(EDCI)0.12mmol,N-羟基丁二酰亚胺(NHS)0.12mmol,加入6mL DMF中,室温下搅拌反应12h。阿培利司0.1mmol溶于4mL DMF,加入到反应液中,室温下继续反应12h。反应液中加入乙酸乙酯50mL稀释,20mL饱和盐水洗2次,无水硫酸钠干燥,旋蒸除去溶剂,干燥得粗品。粗品经硅胶柱层析纯化,二氯甲烷/甲醇体系梯度洗脱(甲醇0-6%),合并收集液,蒸除溶剂即得花生酸-阿培利司复合物。
2.2.脂肪酸-小分子复合物体外抑瘤实验
将N1S1细胞接种到96孔板(5000细胞/孔),然后用脂肪酸-小分子复合物以不同浓度处理24h。用冷PBS冲洗细胞后,用100μL MTT(0.5mg/mL)孵育4h,然后除去MTT溶液,加入100μL二甲基亚砜溶解甲醛晶体,用微板读卡器记录在570nm处的吸光度。细胞存活率=[(As-A b)/(A c-A b)]×1 0 0%。所述结果见图31-42。从图30-42可以看出:当脂肪酸-小分子复合物浓度为0时,细胞活性为100%;随着脂肪酸-小分子复合物浓度升高,细胞活性逐渐下降。说明脂肪酸-小分子复合物可以有效的抑制肿瘤细胞生长。(比如图32,随着软脂酸-克唑替尼复合物浓度升高,细胞活性逐渐下降。当浓度为0.3mM时,细胞活性为6.06%。)
2.3脂肪酸-小分子复合物体内抑瘤实验
将4*105的N1S1肿瘤细胞注射到SD大鼠肝脏位置,等肿瘤体积达到100mm3左右时开展抑瘤实验。将大鼠分为两组,每组3只。PBS组和油酸(c-9-十八烯酸)-索拉菲尼复合物组。通过肝动脉注射PBS(生理盐水组)和油酸(c-9-十八烯酸)-索拉菲尼复合物,记录大鼠的体重变化和测量大鼠的肿瘤直径。大鼠的肿瘤体积计算方式如下:长*宽*宽/2。所述结果见图43。附图43说明了油酸(c-9-十八烯酸)-索拉菲尼复合物可以有效抑制体内肿瘤生长。
实施例3:脂肪酸-多糖复合物制备及其体外抑瘤实验
3.1.二十二烷二酸-透明质酸的制备
按照脂肪酸羧基与透明质酸羟基的摩尔比为4:1~1:1,催化剂与脂肪酸羧基的摩尔比为10:1-1:1,催化剂可以是EDC,DCC,NHS,DMAP,HoBt及其衍生物类似物等的一种或几种。
具体本实施例中,精密称取二十二烷二酸0.001mmol,加入催化剂EDC 0.001mmol和DMAP 0.001mmol,加DMF 2ml溶解,室温下搅拌反应12h。精密称取透明质酸0.0025mmol(以分子量200k Da为例,以质量计算为20mg),溶解于5ml生理盐水中,加入NaOH溶液将pH调至中性,搅拌均匀,得到透明质酸溶液。将透明质酸溶液加入到脂肪酸反应液中,室温继续搅拌反应12h,反应结束后采用截留分子量为7kDa的透析袋进行透析以纯化反应得到的化合物,每隔4h换一次水(除去小分子化合物),透析24h。在冷冻真空干燥机中进行梯度低温干燥(-80℃低温预冷冻24h并真空12h,-20℃抽真空12h,4℃继续抽真空24h以上至产物完全干燥),得到二十二烷酸-透明质酸复合物。
3.2.二十二烷二酸-透明质酸体外抑瘤实验
将SK-HEP-1细胞接种到96孔板(5000细胞/孔),然后用二十二烷酸-透明质酸复合物以不同浓度处理24h。用冷PBS冲洗细胞后,用100μL MTT(0.5mg/mL)孵育4h,然后除去MTT溶液,加入100μL二甲基亚砜溶解甲醛晶体,用微板读卡器记录在570nm处的吸光度。细胞存活率=[(As-Ab)/(Ac-Ab)]×100%。
所述结果见图44。可以看出:0.3mM的二十二烷酸-透明质酸明显抑制了SK-HEP-1生长。
实施例4脂肪酸-单糖复合物制备及其体外抑瘤实验
4.1.脂肪酸-单糖复合物的制备
脂肪酸0.72mmol,加入作为催化剂的EDC 0.72mmol和DMAP 0.72mmol,冰浴下搅拌活化10min,得到活化后的脂肪酸;葡萄糖1.44mmol,溶于10ml去离子水中,加入到活化后的脂肪酸溶液中,用NaOH调节pH值7.0-7.4,室温下搅拌反应12h,得到反应从产物溶液,反应结束后进行层析纯化,将产物溶液加至Shephadex G10层析柱(Φ26mm×50cm),生理盐水洗脱,流速50ml/h,分步收集洗脱液,用苯酚硫酸法检测,合并第1个洗脱峰即为反应产物。
按上述方法合成软脂酸(正十六烷酸)-果糖、十六烷二酸-葡萄糖用于后续实验。
4.2.脂肪酸-单糖复合物体外抑瘤实验
将SK-HEP-1细胞接种到96孔板(5000细胞/孔),然后用脂肪酸-单糖以不同浓度处理24h。用冷PBS冲洗细胞后,用100μL MTT(0.5mg/mL)孵育4h,然后除去MTT溶液,加入100μL二甲基亚砜溶解甲醛晶体,用微板读卡器记录在570nm处的吸光度。细胞存活率=[(As-Ab)/(Ac-Ab)]×100%。
所述结果见图45-46。可以看出:脂肪酸-单糖复合物可有效抑制细胞生长。
实施例5脂肪酸-多肽制备及其体外抑瘤实验
5.1.芥酸(c-13-二十二烯酸)-奥曲肽的制备
奥曲肽系由八个氨基酸组成的合成多肽,为D-苯丙氨酰-L-半胱氨酰-L-苯丙氨酰-D-色氨酰-L-赖氨酰-L-苏氨酰-N-[(1R,2R)-2-羟基-1-(羟甲基)丙基]-L-半胱氨酰胺环(2→7)-二硫键醋酸盐。分子中的赖氨酸残基可以与芥酸的羧基以酰胺键结合。
精密称取芥酸0.1mmol,1-乙基-(3-二甲基氨基丙基)碳酰二亚胺(EDC),N-羟基琥珀酰亚胺(NHS)各0.12mmol,加DMF 2ml溶解,室温下搅拌反应12h;奥曲肽0.1mmol溶于纯化水20ml中,将奥曲肽溶液加入到芥酸反应液中,室温下继续搅拌反应12h,反应溶液采用截留分子量为100-500的透析袋进行透析以纯化反应得到的化合物,每隔4h换一次水,透析24h,冷冻干燥,即得芥酸-奥曲肽复合物用于后续实验。
5.2.芥酸(c-13-二十二烯酸)-奥曲肽体外抑瘤实验
将SK-HEP-1细胞接种到96孔板(5000细胞/孔),然后用脂肪酸-多肽以不同浓度处理24h。用冷PBS冲洗细胞后,用100μL MTT(0.5mg/mL)孵育4h,然后除去MTT溶液,加入100μL二甲基亚砜溶解甲醛晶体,用微板读卡器记录在570nm处的吸光度。细胞存活率=[(As-Ab)/(Ac-Ab)]×100%。
所述结果见图47。可以看出:芥酸(c-13-二十二烯酸)-奥曲肽可有效抑制肿瘤生长。
实施例6脂肪酸和脂肪酸脂质体破坏肿瘤细胞外基质成分
6.1.脂肪酸脂质体的制备
脂肪酸脂质体乳液10mL,20%(V/V)脂肪酸的制备:取油酸mL,单硬脂酸甘油酯0.1g,三辛酸甘油酯0.1g。Pluronic F-68 0.45g,卵磷脂0.15g,PBS 7mL。按配方称取/量取相应物料,置小烧杯中,60℃水浴加热并搅拌,使固体物料溶解并混合均匀,保温备用。按配方称取/量取相应物料,置小烧杯中,60℃水浴加热并搅拌,使固体物料溶解并混合均匀,保温备用。将水相缓缓加入到油相中,60℃水浴加热并搅拌15min,定容至10mL,搅拌5min使混合均匀,得初乳。将初乳进行超声乳化处理,功率500W,时间30min,得脂肪酸脂质体乳液。
6.2.脂肪酸和脂肪酸脂质体破坏肿瘤细胞外基质成分
将4*105的SK-HEP-1肿瘤细胞通过皮下注射到BALB/c裸鼠右腿上侧,等肿瘤体积达到100mm3左右时开展抑瘤实验。将裸鼠分为PBS组、亚油酸组、油酸组、花生酸组、EPA组、DHA组、亚油酸脂质体组、油酸脂质体组、花生酸脂质体组、EPA脂质体组和DHA脂质体组。每组3只鼠。每隔两天从尾静脉分别给每组注射PBS、亚油酸、油酸、花生酸、EPA、DHA、亚油酸脂质体、油酸脂质体、花生酸脂质体、EPA脂质体和DHA脂质体,每次的注射量为100μL,0.3mM。15天后处死裸鼠,取出瘤子50mg使用Biocolor Assays检测试剂盒检测细胞外基质成分(不可溶性胶原、弹力蛋白、可溶性胶原、透明质酸、粘多糖)。所述结果见图48-52。说明脂肪酸和脂肪酸脂质体可有效破坏肿瘤细胞外基质成分。
实施例7脂肪酸-单抗复合物破坏肿瘤细胞外基质成分
将4*105的SK-HEP-1肿瘤细胞通过皮下注射到BALB/c裸鼠右腿上侧,等肿瘤体积达到100mm3左右时开展抑瘤实验。将裸鼠分为三组,PBS组、亚油酸-贝伐单抗和亚油酸-特瑞普利单抗。每组3只鼠。每隔两天从尾静脉注射PBS、亚油酸-贝伐单抗、亚油酸-特瑞普利单抗复合物,每次的注射量为100μL,0.3mM。15天后处死裸鼠,取出瘤子50mg使用BiocolorAssays检测试剂盒检测细胞外基质成分(不可溶性胶原、弹力蛋白、可溶性胶原、透明质酸、粘多糖)。所述结果见图53-57。说明脂肪酸-单抗复合物可有效破坏肿瘤细胞外基质成分。
尽管上面已经示出和描述了本发明的实施例,可以理解的是,上述实施例是示例性的,不能理解为对本发明的限制,本领域的普通技术人员在不脱离本发明的原理和宗旨的情况下在本发明的范围内可以对上述实施例进行变化、修改、替换和变型。
Claims (6)
1.一种用于破坏肿瘤细胞膜和/或细胞外基质成分的脂肪酸及其复合物,其特征在于,通过增加肿瘤细胞膜的流动性破坏细胞膜结构,以及破坏细胞外基质成分,进而杀灭肿瘤细胞;
所述复合物为脂肪酸通过物理和化学的方式偶联靶向细胞膜成分的分子,从而赋予脂肪酸复合物具有靶向破坏肿瘤细胞膜的特性;
优选的,所述脂肪酸的碳链选自脂溶性直链和/或带有支链、环状结构的饱和和/或不饱和碳链;所述碳链为碳原子数为3-100的分子或者分子的残基;
更优选的,所述碳链选自饱和和/或不饱和脂肪烃、饱和和/或不饱和脂肪醇或氧代脂肪醇、饱和和/或不饱和脂肪酸、疏水性氨基酸、脂溶性维生素、类胡萝卜素、固醇及类固醇类脂质、脂肪酸甘油酯、磷脂、鞘磷脂、糖脂和/或表面活性剂形成的碳原子数为3-100的碳链或碳链的残基;所述复合物为疏水性或者水溶性;
所述脂肪酸及其复合物的剂型为脂质体、油性和/或水溶性溶液。
2.如权利要求1所述用于破坏肿瘤细胞膜和/或细胞外基质成分的脂肪酸及其复合物,其特征在于,所述靶向细胞膜成分的分子是指靶向肿瘤细胞膜外部的结构和成分、结构域,靶向细胞膜镶嵌的蛋白结构域,以及靶向肿瘤细胞膜内结构域的分子;
优选的,所述靶向细胞膜成分的分子包括抗体、蛋白、多糖、核酸、多肽、寡肽、寡糖、寡聚核苷酸、单糖、维生素、核苷酸、小分子靶向药物。
3.如权利要求2所述用于破坏肿瘤细胞膜和/或细胞外基质成分的脂肪酸及其复合物,其特征在于,所述抗体是指与肿瘤相关抗原结合的抗体,所述蛋白是指与肿瘤相关抗原结合的蛋白,所述多肽是指与肿瘤相关抗原结合的多肽以及重组多肽;
优选的,所述肿瘤相关抗原包括:GD2、CD3、CD25、CD19、CD20、CD30、CD38、CD147、TNF-α、CTLA-4、EGFR、HER2、Nectin-4、SLAMF7、TROP-2、VEGF、VEGFR、PD-1、PD-L1;
更优选的,所述抗体选自以下至少任何一种:与GD2结合的达妥昔单抗;与CD19结合的博纳吐单抗;与CD20结合的替伊莫单抗、利妥昔单抗、托西莫单抗、奥滨尤妥珠单抗、奥法木单抗;与CD30结合的本妥昔单抗;与CD38结合的达雷木单抗;与CD147结合的美妥昔单抗;与CD25结合的重组抗CD25人源化单抗;与CD3结合的抗人T细胞CD3鼠单抗;与TNF-α结合的重组人Ⅱ型肿瘤坏死因子受体-抗体融合蛋白、阿达木单抗;与CTLA-4结合的伊匹单抗;与EGFR结合的耐昔妥珠单抗、西妥昔单抗;与HER2结合的帕妥珠单抗、曲妥珠单抗;与Nectin-4结合的恩弗妥单抗;与SLAMF7结合的埃罗妥珠单抗;与TROP-2结合的赛妥珠单抗;与VEGF结合的贝伐珠单抗、CimaVax肺癌疫苗;与VEGFR结合的雷莫芦单抗;与PD-1结合的纳武利尤单抗、帕博利珠单抗、卡瑞利珠单抗、特瑞普利单抗、替雷利珠单抗、信迪利单抗;与PD-L1结合的度伐利优单抗、阿替利珠单抗;
所述多肽为Ra-V(deoxybouvardin)、KLA多肽、ALOS-4、奥曲肽;寡肽为cRGD、iRGD、RGD-4C、RGD-PEG和RGD-Arg;
所述多糖为透明质酸、肝素、甘露聚糖、海藻多糖;、单糖为葡萄糖、N-乙酰葡萄糖胺、半乳糖、果糖;、维生素为维生素D、维生素E、维生素C、维生素K、维生素B12、维生素A、维生素F;
所述小分子靶向药物选自以下至少任何一种:AKT抑制剂;ALK抑制剂;BCL-2抑制剂;BCR-ABL抑制剂;BRAF V600E抑制剂;BTK抑制剂;CDK4/6抑制剂;EGFR抑制剂;FGFR抑制剂;EZH2抑制剂;HEG2抑制剂;HDAC抑制剂;MEK抑制剂;MET抑制剂;mTOR抑制剂;NTRK抑制剂;PARP抑制剂;PDGFR抑制剂;PI3K抑制剂;蛋白酶体抑制剂;RET抑制剂;ROS1抑制剂;SMO抑制剂;Src/Ab1双重抑制剂;VEGFR抑制剂;
优选的,所述AKT抑制剂为卡帕塞替尼;所述ALK抑制剂为克唑替尼、色瑞替尼、艾乐替尼、布加替尼、劳拉替尼;所述BCL-2抑制剂为维奈妥拉;BCR-ABL抑制剂为伊马替尼、达沙替尼、尼洛替尼、普纳替尼;所述BRAF V600E抑制剂为维莫非尼、达拉非尼、康奈非尼;所述BTK抑制剂为伊鲁替尼、阿卡替尼、泽布替尼、奥布替尼;所述CDK4/6抑制剂为帕博西林、瑞博西林、玻玛西林;所述EGFR抑制剂为吉非替尼、厄洛替尼、埃克替尼、阿法替尼、达克替尼、奥希替尼、阿美替尼;所述FGFR抑制剂为厄达替尼、培米替尼、英非格拉替尼;所述EZH2抑制剂为他泽司他;所述HEG2抑制剂为拉帕替尼、来那替尼、吡咯替尼、图卡替尼;所述HDAC抑制剂为伏立诺他、罗米地辛、贝利司他、帕比司他、西达本胺、Mocetinostat;所述MEK抑制剂为曲美替尼、考比替尼、比美替尼、司美替尼;所述MET抑制剂为卡马替尼、特泊替尼、沃利替尼;所述mTOR抑制剂为西罗莫司、替西罗莫司、依维莫司、佐他莫司;所述NTRK抑制剂为恩曲替尼、拉罗替尼、艾乐替尼;所述PARP抑制剂为奥拉帕利、尼拉帕利、他拉唑帕利、鲁卡帕利;所述PDGFR抑制剂为阿伐普替尼、米哚妥林、尼达尼布、拉多替尼、瑞普替尼;所述PI3K抑制剂为阿培利司、艾代拉利司、厄布利塞;所述蛋白酶体抑制剂为硼替佐米、卡非佐米、伊沙佐米;所述RET抑制剂为普雷西替尼、塞尔帕替尼;所述ROS1抑制剂为恩曲替尼;所述SMO抑制剂为维莫德吉、索尼德吉、格拉吉布;所述Src/Ab1双重抑制剂为博舒替尼;所述VEGFR抑制剂为索拉非尼、舒尼替尼、帕唑帕尼、瑞戈非尼、凡德他尼、乐伐替尼、卡博替尼、阿昔替尼、特拉替尼、阿帕替尼、安罗替尼、呋喹替尼。
4.如权利要求2所述用于破坏肿瘤细胞膜和/或细胞外基质成分的脂肪酸及其复合物,其特征在于,
所述脂肪酸为具有一定水溶性的脂肪酸;
优选的,所述具有一定水溶性的脂肪酸是指分子中具有水溶性的极性基团如羟基、羧基、氨基、胺基、季铵基、胍基、巯基、磺酸基、磺酰氧基、磷酸基,且组成碳链的碳原子的数目为3-100;
所述水溶性分子选自蛋白质、多糖、核酸和人工合成的水溶性高聚物中的一种或二种以上的水溶性大分子或其残基;
和/或,选自多肽、寡肽、寡糖、寡核苷酸和人工合成的水溶性中等分子量的聚合物中的一种或二种以上的中等分子或其残基;
和/或,选自氨基酸、单糖、二糖、核苷酸、脱氧核苷酸和水溶性维生素中的一种或二种以上的水溶性小分子或其残基;
所述复合物中的脂肪酸为疏水性脂肪酸,通过物理或化学方法偶联靶向细胞膜成分的分子形成亲水性复合物。
5.一种权利要求1所述用于破坏肿瘤细胞膜和/或细胞外基质成分的脂肪酸及其复合物中的复合物的制备方法,其特征在于,
脂肪酸在催化剂的作用下,酸性条件下先进行活化,然后与靶向细胞膜的成分的分子进行化学或者物理偶联得到脂肪酸复合物溶液;
优选的,将脂肪酸复合物溶液纯化得到脂肪酸复合物。
6.一种权利要求1所述用于破坏肿瘤细胞膜和或细胞外基质成分的脂肪酸及其复合物用于制备治疗肿瘤药物的用途。
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