CN117503736A - 和厚朴酚在制备治疗卵黄囊瘤药物中的用途 - Google Patents
和厚朴酚在制备治疗卵黄囊瘤药物中的用途 Download PDFInfo
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Abstract
本发明属于医药领域，具体涉及和厚朴酚在制备治疗卵黄囊瘤药物中的用途。和厚朴酚能够有效抑制卵黄囊瘤细胞的生长，安全性及耐受性良好，将和厚朴酚用于卵黄囊瘤的治疗，解决当下卵黄囊瘤治疗疗效有限、毒性大、易耐药的问题，为临床上卵黄囊瘤的综合治疗提供了一种新选择。
Description
技术领域
本发明属于医药领域，具体涉及和厚朴酚的医药用途，更具体地，本发明涉及和厚朴酚在制备治疗卵黄囊瘤药物中的用途。
背景技术
卵黄囊瘤(Yolk sac tumor, YST)又称内胚窦瘤(Endodermal sinus tumor,EST)，因其在组织学上与原始卵黄囊的间质相似而得名[1]。卵黄囊瘤是一种罕见的恶性原始生殖细胞肿瘤，生殖细胞肿瘤通常发生在性腺内，即睾丸和卵巢，但有时也会发生在性腺外，被称为性腺外生殖细胞肿瘤[2]。性腺外卵黄囊瘤发生较为少见，仅有约24%的病例起源于性腺外部位[3, 4]，常见的性腺外部位是头颈部，占所有良性和恶性生殖细胞肿瘤的5%[5]，其余性腺外部位还包括骶尾部、阴道、前列腺、胃、肝脏等[6-8]。当肿瘤生长到一定大小时，根据肿瘤部位的不同，会出现不同的临床表现，多为疼痛或肿块，通常没有特异性[9]。
卵黄囊瘤常见于儿童，且卵黄囊瘤也是儿童中最常见的睾丸肿瘤，它约占儿童中生殖细胞肿瘤的30%，其中位诊断年龄为18个月。通常，儿童患的是纯卵黄囊瘤，预后良好。而在成人中，卵黄囊瘤通常表现为混合性生殖细胞肿瘤[10, 11]，即卵黄囊肿瘤与其他类型的生殖细胞肿瘤(如畸胎瘤和胚胎癌)合并出现[12, 13]。除睾丸外，卵黄囊瘤常起源于卵巢，是恶性卵巢生殖细胞肿瘤中第二常见的肿瘤，约占所有恶性卵巢生殖细胞肿瘤的20-25%，在确诊时，大多数病例仅限于单侧卵巢[14, 15]。卵巢卵黄囊瘤好发于年轻女性或青春期少女，40%的患者在青春期前确诊，确诊的中位年龄为19岁[16]。其中，约60%的卵巢卵黄囊肿瘤是纯卵黄囊瘤，40%的卵巢卵黄囊肿瘤伴有混合性生殖细胞肿瘤[17, 18]。
大多数(90%)卵黄囊瘤患者会出现甲胎蛋白(AFP)表达增加，该标志物的升高有助于卵黄囊瘤的诊断[19, 20]，且在治疗期间，可持续监测血清甲胎蛋白变化以评估疗效，若血清甲胎蛋白水平再次升高则提示肿瘤可能发生复发或耐药[9, 21, 22]。此外，在组织病理学上，卵黄囊瘤的诊断性特征是出现席勒-杜瓦尔(Schiller-Duval)小体，这是一种典型的组织学发现，是一种小的肾小球样结构[23, 24]，但并不总是可见。在卵黄囊瘤患者的预后中，疾病分期和患者年龄是关键的因素，年龄较大的患者预后通常较差，容易发生转移，疾病的第III/IV期比第I/II期预后更差[14]，卵黄囊肿瘤I-II期的存活率为60-100%，III-IV期为50-75%[16]。目前治疗卵黄囊肿瘤的方法主要是手术和化疗，然而由于卵黄囊瘤发病率低且恶性程度高，与之相关的预后因素尚不明确，其标准治疗方法也尚未确立[25, 26]，另外放疗对卵黄囊瘤的疗效不佳[3, 27, 28]。卵黄囊瘤理想的治疗策略是完全切除肿瘤，同时进行术后辅助化疗[29, 30]。卵黄囊瘤的手术后辅助化疗的治疗模式显著提高了卵黄囊瘤患者的生存率，长春新碱、放线菌素D、环磷酰胺、博来霉素和顺铂已被用于治疗卵黄囊瘤患者，并取得了良好的效果[31, 32]。且博来霉素、依托泊苷和顺铂(BEP)方案在治疗卵黄囊瘤方面取得了重大进展[33]，有研究称BEP化疗方案是卵黄囊瘤患者的最佳选择[19]，根据临床情况，术后应进行2-4个周期的BEP方案的治疗[34]，卵黄囊瘤患者在BEP化疗方案后，病情治愈率高达80-90%[8, 29, 35]，接受BEP化疗方案的早期卵黄囊瘤患者的总体5年生存率为94%[34]。然而，BEP等化疗方案伴有毒性，包括肺纤维化、高血压、永久性听力损失、慢性肾病以及白血病等继发性癌症的增加，虽然大多数患者可通过手术和化疗治愈，但也有一部分患者因化疗耐药、复发或不能耐受化疗的副作用而导致临床疗效不佳[14, 36-38]。
此外，发生于性腺外的卵黄囊瘤一般发现较晚，卵黄囊瘤包膜常常不完整，肿瘤实体易发生碎裂，且因其特殊的内胚窦样结构，术中易大量出血，导致手术无法根治[7, 39]。卵黄囊瘤的非手术方法，主要包括化疗和放疗，适用于手术无法切除肿瘤的辅助治疗，其他针对卵黄囊瘤的非手术治疗方法，如免疫检查点阻断治疗，目前的研究还很少，虽然有研究显示在卵黄囊瘤组织中发现了高水平的CTLA-4[28]，但到目前为止，免疫检查点抑制剂(如pembrolizumab)在卵黄囊瘤相关临床试验中的疗效相当有限[40]，且通常将卵黄囊瘤纳入生殖细胞肿瘤的研究，免疫检查点阻断治疗卵黄囊瘤的效力尚未得到证实[28]。因此，针对卵黄囊瘤治疗存在的治疗效果有限、治疗方式缺乏，现有治疗方式毒性较大、耐药等问题，急需开发治疗卵黄囊瘤的药物，来打破现有的治疗瓶颈，为卵黄囊瘤患者提供更有效、毒性更小和具有良好安全性的治疗方案。
发明内容
针对现有卵黄囊瘤治疗方面的不足， 本发明的目的在于提供和厚朴酚在制备治疗卵黄囊瘤药物中的用途。
和厚朴酚，英文名为Honokiol，化学名为3',5-二-2-丙烯基-1,1'-联苯-2,4'-二酚，结构式如下式（I）所示：
。
和厚朴酚是从厚朴Magnolia officinalisRehd. et Wils.的皮中提取分离出来的一种具有广泛生物活性的小分子化合物，其主要生物活性包括抗炎、抗微生物、抗溃疡、抗氧化、抗焦虑、抗抑郁、抗血栓、抗衰老和降低胆固醇等。
申请人致力于从事和厚朴酚药物开发，在长期大量的实验研究中，发明人意外发现了和厚朴酚的新用途，即和厚朴酚在制备治疗卵黄囊瘤药物中的用途。
本发明所述卵黄囊瘤包括但不限于颅内卵黄囊瘤、性腺卵黄囊瘤或颅外性腺外卵黄囊瘤。
优选地，所述性腺卵黄囊瘤为睾丸卵黄囊瘤或卵巢卵黄囊瘤。
优选地，所述和厚朴酚被制备成和厚朴酚脂质体。
优选地，所述和厚朴酚脂质体为注射用和厚朴酚脂质体。注射用和厚朴酚脂质体经临床试验表明其安全性及耐受性良好（WO2023016519A1）。
优选地，所述和厚朴酚抑制卵黄囊瘤的细胞增殖。
优选地，所述药物是以有效量的和厚朴酚为活性成分，加入药学上可接受的辅料或辅助性成分制备而成的制剂。
优选地，所述制剂包括冻干粉制剂、片剂、胶囊剂或者透皮制剂。
更优选地，所述冻干粉制剂包括注射冻干粉制剂或口服冻干粉制剂。
更优选地，所述片剂包括速释片剂或缓释片剂。
更优选地，所述胶囊剂包括硬胶囊、软胶囊、缓释胶囊或肠溶胶囊。
优选地，所述药物通过如下途径给药:静脉注射、肌内注射、皮下注射、口服给药、眼部给药、肺部给药、经皮给药或鼻腔给药。
本发明的有益效果如下：
和厚朴酚能够有效抑制卵黄囊瘤细胞的生长，且注射用和厚朴酚脂质体经临床试验表明其安全性及耐受性良好，本发明提供了和厚朴酚在制备治疗卵黄囊瘤药物的用途，尤其是和厚朴酚在制备治疗睾丸卵黄囊瘤药物的用途，解决了当下卵黄囊瘤药物治疗疗效有限、毒性大、易耐药问题，为临床上卵黄囊瘤的综合治疗提供了一种新选择。
附图说明
图1是药物（A、B、C）在人卵黄囊瘤NCR-G1细胞中3天的IC50拟合曲线图，其中A为Liposome(注射用空白脂质体)，B为Honokiol(和厚朴酚)，C为Honokiol-liposome(注射用和厚朴酚脂质体)。
具体实施方式
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。此外应理解，在阅读了本发明讲授的内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。
实施例涉及的细胞系及药物：
所用的细胞系为NCR-G1，这是一种人睾丸卵黄囊瘤细胞。NCR-G1细胞系所使用的培养基是一种含有血清的G-031101培养基，将其放置于37℃、5% CO2的细胞孵箱中培养，每2~3天换液传代一次。
使用药物为Liposome (注射用空白脂质体)、Honokiol (和厚朴酚，纯度≥99%)和Honokiol-liposome (注射用和厚朴酚脂质体)。注射用和厚朴酚脂质体来源于成都金瑞基业生物科技有限公司，或者可根据以下方法制备获得：取和厚朴酚50mg，大豆磷脂500mg，胆固醇200mg，培化磷脂酰乙醇胺200mg，溶于无水乙醇50mL中，完全溶解后注入到纯化水300mL中，搅拌，旋转蒸发除去乙醇，加入蔗糖800mg作为冻干赋形剂，冷冻干燥。注射用空白脂质体来源于成都金瑞基业生物科技有限公司，或者可根据以下方法制备获得：取大豆磷脂500mg，胆固醇200mg，培化磷脂酰乙醇胺200mg，溶于无水乙醇50mL中，完全溶解后注入到纯化水300mL中，搅拌，旋转蒸发除去乙醇，加入蔗糖800mg作为冻干赋形剂，冷冻干燥。
实施例涉及的材料和设备如下表1：
表1
实施例1
1.实验方法：
1.1细胞培养
1.1.1细胞复苏
（1）添加15 mL细胞的培养基于T75培养瓶中。
（2）将细胞培养瓶置于37℃、5% CO2细胞培养箱中平衡15分钟左右，以使培养基平衡至适当的pH值及温度。
（3）从液氮中取出保存有NCR-G1细胞的冻存管，在37℃的水浴中轻柔的、快速的解冻，然后使用70%乙醇擦拭NCR-G1细胞冻存管消毒，接下来在生物安全柜中打开。
（4）将冻存管中的NCR-G1细胞悬液小心地转移到装有10 mL培养基的无菌15 mL离心管中，转速200×g离心5分钟。
（5）弃除上清液，并将NCR-G1细胞重悬在1 mL新鲜细胞培养基中，然后转移到含有预热细胞培养基的T75培养瓶中，置于37℃、5% CO2细胞培养箱中培养。
1.1.2细胞传代培养
每2~3天补充或更换新鲜的培养基，传代时使用胰蛋白酶消化，再用含有血清的细胞培养基终止消化，离心后重悬NCR-G1细胞沉淀，转移至装有新鲜细胞培养基的培养瓶中，置于37℃、5% CO2培养箱中继续培养。
1.2细胞铺板
（1）NCR-G1细胞常规培养至数量达到实验所需量时，收集NCR-G1细胞并进行计数。
（2）用培养基重悬NCR-G1细胞至实验设计所需的密度。
（3）将NCR-G1细胞悬液加入96孔细胞培养板，每孔体积为90 µL，NCR-G1细胞的铺板密度为15000 cells/well。每个处理条件各做3个复孔。
（4）将96孔细胞培养板置于37℃，5% CO2培养箱中培养过夜。
1.3.药物处理细胞
（1）将药物从3600 μM开始进行稀释，在96孔细胞培养板中以1:3的稀释比例使用DMSO/无菌注射用水梯度稀释和厚朴酚、注射用空白脂质体及注射用和厚朴酚脂质体，共设9个药物浓度。
（2）将梯度浓度的药物加入铺好细胞的96孔细胞培养板中，每孔添加10 μl (终浓度为0.05 μM、0.16 μM、0.49 μM、1.48 μM、4.44 μM、13.33 μM、40 μM、120 μM和360 μM)。
（3）将96孔细胞培养板置于37℃，5% CO2细胞培养箱中培养，药物处理的时间为3天。
1.4.CTG分析
（1）3天后，将孵育后的96孔细胞培养板从细胞培养箱中移出，在室温下平衡15分钟。
（2）Cell Titer-Glo试剂从-20℃取出，置于4℃冰箱过夜融化，使用前需要平衡至室温。
（3）在每个待检测孔里加入100 μL的Cell Titer-Glo试剂 (Cell Titer-Glo试剂和培养基的比例为1:1)。
（4）室温避光孵育20分钟，接下来使用Envision进行数值读取。
1.5.统计分析
使用GraphPad Prism 8计算半数抑制浓度 (IC50)，利用非线性拟合公式得到IC50：
Y=100/(1+10^((LogIC50-X)*HillSlope))
其中，X：剂量浓度的对数；Y：抑制率；HillSlope：斜率因子。
抑制率(%)=100×[1-(测试孔读值-低读值) / (高读值-低读值)]
其中，低读值孔：空白对照孔，没有细胞，仅有培养基；高读值孔：对照孔，细胞与含有0.1% DMSO或无菌注射用水的培养基。
2.实验结果
按照以上步骤进行实验和数据分析得到注射用空白脂质体、和厚朴酚和注射用和厚朴酚脂质体在人卵黄囊瘤NCR-G1细胞中3天的IC50拟合曲线图 (图1)。
使用CTG分析方法对注射用空白脂质体、和厚朴酚和注射用和厚朴酚脂质体在人卵黄囊瘤NCR-G1细胞系中的增殖抑制作用进行了评估，根据三组数据的平均值计算得出IC50和最大抑制率详见表2。
图1和表2中的数据为3组数据的平均值计算所得。
表2 最大抑制率及IC50（3天）
由图1和表2可知：和厚朴酚和注射用和厚朴酚脂质体对人卵黄囊瘤NCR-G1细胞的生长具有抑制作用，二者的最大抑制率均可达100%，其3天的IC50值分别为34.56μM和38.92μM。
和厚朴酚、注射用和厚朴酚脂质体对人卵黄囊瘤均具有明显抑制作用，且注射用和厚朴酚脂质体经临床试验表明其安全性及耐受性良好（专利WO2023016519A1），本发明提供了和厚朴酚在制备治疗卵黄囊瘤药物的用途，尤其是和厚朴酚在制备治疗睾丸卵黄囊瘤药物的用途。
以上所述的仅是本发明的优选实施方式，应当指出，对于本领域的普通技术人员来说，在不脱离本发明创造构思的前提下，还可以做出若干变形和改进，这些都属于本发明的保护范围。
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Claims (10)
1.和厚朴酚在制备治疗卵黄囊瘤药物中的用途。
2.根据权利要求1所述的用途，其特征在于，所述和厚朴酚被制备成和厚朴酚脂质体。
3.根据权利要求2所述的用途，其特征在于，所述和厚朴酚脂质体为注射用和厚朴酚脂质体。
4.根据权利要求1~3任意一项所述的用途，其特征在于，所述和厚朴酚抑制卵黄囊瘤的细胞增殖。
5.根据权利要求1~3任意一项所述的用途，其特征在于，所述卵黄囊瘤为颅内卵黄囊瘤、性腺卵黄囊瘤或颅外性腺外卵黄囊瘤。
6.根据权利要求5所述的用途，其特征在于，所述性腺卵黄囊瘤为睾丸卵黄囊瘤或卵巢卵黄囊瘤。
7.根据权利要求1所述的用途，其特征在于，所述药物是以有效量的和厚朴酚为活性成分，加入药学上可接受的辅料或辅助性成分制备而成的制剂。
8.根据权利要求7所述的用途，其特征在于，所述制剂包括冻干粉制剂、片剂、胶囊剂或者透皮制剂。
9.根据权利要求8所述的用途，其特征在于，所述冻干粉制剂包括注射冻干粉制剂或口服冻干粉制剂；片剂包括速释片剂或缓释片剂；胶囊剂包括硬胶囊、软胶囊、缓释胶囊或肠溶胶囊。
10.根据权利要求1所述的用途，其特征在于，所述药物通过如下途径给药:静脉注射、肌内注射、皮下注射、口服给药、眼部给药、肺部给药、经皮给药或鼻腔给药。
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