WO2023029141A1 - 奥替尼啶双盐酸盐在制备抗肿瘤药物中的应用 - Google Patents
奥替尼啶双盐酸盐在制备抗肿瘤药物中的应用 Download PDFInfo
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Definitions
- the invention belongs to the technical field of medicine, in particular to the application of octenidine dihydrochloride in the preparation of antitumor drugs.
- Nasopharyngeal carcinoma is a regional malignancy with an incidence rate of 0.4 cases per 100,000 people in the United States, while most new cases occur in countries of Central and Southeast Asia.
- the incidence of nasopharyngeal carcinoma has a certain racial and family genetic aggregation, for example: Bidayuans in Borneo and Naga people in northern India [1] .
- Nasopharyngeal carcinoma is a malignant tumor that occurs in the outermost epithelial layer of the nasopharyngeal cavity, above the oropharynx and hypopharynx, near the base of the skull.
- NPC neurodegenerative medicine
- Conventional treatments for NPC include radiotherapy or chemotherapy or a combination of both.
- radiotherapy techniques and surgical facilities hinder the effectiveness of treatment, resulting in local residual tumors, which in turn lead to tumor recurrence and greatly reduce the overall survival rate of patients.
- the molecular basis of the pathogenesis of NPC is still poorly understood.
- the nasopharynx is very close to the brain stem cell area, major blood vessels and nerves, surgical resection is usually the last option for patients with advanced tumors.
- Octenidine dihydrochloride Octenidine dihydrochloride, OCT, also known as Octenidine dihydrochloride, is an effective antiseptic compound for skin mucous membranes and wounds, and its structural formula is as shown in formula I:
- OCT has antibacterial and anti-inflammatory effects [3] , and can be used for wound infection and preoperative skin preparation. It has obvious inhibitory effect on Staphylococcus aureus. It works by interacting with the surface structure of bacteria, resulting Its cleavage and death [4] . OCT can also stimulate phagocytosis and growth factors, which is beneficial to wound healing [4] , but the role of OCT in tumor cells has not been reported yet.
- the purpose of the present invention is to overcome the shortcomings and deficiencies of the prior art, and to provide the application of octenidine dihydrochloride in the preparation of antitumor drugs.
- OCT octenidine dihydrochloride
- the tumor includes but not limited to nasopharyngeal carcinoma, esophageal squamous cell carcinoma, colorectal cancer and lung cancer; preferably nasopharyngeal carcinoma.
- the effective concentration of octenidine dihydrochloride is 0-5 ⁇ M (excluding 0); preferably 0.8-5 ⁇ M.
- the medicine contains one or more pharmaceutically acceptable carriers or auxiliary materials.
- the auxiliary material is at least one of slow release agent, excipient, filler, binder, wetting agent, disintegrant, absorption accelerator, surfactant and lubricant; preferably edible oil; more preferably for corn oil.
- the medicine can be further made into pharmaceutical preparations by conventional methods in the art; including oral administration pharmaceutical preparations, such as capsules, pills, tablets, oral liquids, granules and the like.
- octenidine dihydrochloride in the preparation of drugs for inhibiting the growth and/or proliferation of nasopharyngeal carcinoma cells.
- the nasopharyngeal carcinoma cells include at least one of nasopharyngeal carcinoma cells CNE-1 and SUNE-1.
- the present invention Compared with the prior art, the present invention has the following advantages and effects: the present invention combines in vitro and in vivo experiments to find that octenidine dihydrochloride has anti-inflammatory and bactericidal effects on the skin surface, and also has the ability to inhibit nasopharyngeal carcinoma cells. Therefore, it can be used in tumor therapy and provide a new drug source for adjuvant therapy of cancer.
- Fig. 1 is a diagram showing the influence of OCT on the proliferation of nasopharyngeal carcinoma cells; wherein, A is the influence of OCT on nasopharyngeal carcinoma cell CNE-1; B is the influence of OCT on nasopharyngeal carcinoma cell CNE-1.
- Figure 2 is a graph showing the effect of OCT on the apoptosis of nasopharyngeal carcinoma CNE-1 cells; where, A is the result of flow cytometry; B is the situation of cell apoptosis.
- Fig. 3 is a graph showing the influence of OCT on the tumorigenic ability of nasopharyngeal carcinoma cells in mice; wherein, A is a photo of the tumor; B is the volume of the tumor; C is the weight of the tumor.
- Figure 4 is a diagram of the detection results of serum aspartate aminotransferase and alanine aminotransferase in mice after OCT treatment of mice; wherein, A is the activity of serum aspartate aminotransferase; B is the activity of serum alanine aminotransferase.
- Fig. 5 is a graph showing the results of immunohistochemical detection of the heart, liver, lung and kidney tissues and tumors of the mice treated with OCT.
- the present invention will be further described in detail below in conjunction with examples, but the embodiments of the present invention are not limited thereto.
- the reagents, methods and equipment used in the present invention are conventional reagents, methods and equipment in the technical field.
- the test methods that do not indicate the specific experimental conditions in the following examples, usually follow the routine experimental conditions or the experimental conditions suggested by the manufacturer.
- the reagents and raw materials used in the present invention can be obtained commercially.
- Octenidine dihydrochloride (OCT) in the examples of the present invention was purchased from Targetmol (https://www.targetmol.com).
- Nasopharyngeal carcinoma cells CNE-1 and SUNE-1 in the examples of the present invention were purchased from the Cell Bank of the Chinese Academy of Sciences.
- nasopharyngeal carcinoma mouse model 6-week-old, NCG male mice (purchased from Nanjing Model Animal Research Center) were selected, and the nasopharyngeal carcinoma mouse model was constructed by subcutaneous injection, that is, cell suspension (nasopharyngeal carcinoma) Cancer cells CNE-1) were mixed with Matrigel (Corning Matrigel Matrix) at a volume ratio of 1:1, and each mouse was injected with 2x106 cells (the resuspended cells were injected subcutaneously into the mice with a micro-syringe with a 25G needle) . After subcutaneous injection, the tumor size reached 5x5mm for follow-up experiments.
- the experiment is divided into three groups: low-concentration drug treatment group (5 animals, injection volume is 3mg/kg); high-concentration drug treatment group (5 animals, injection volume is 6mg/kg); control group (5 animals, injection volume is 6mg/kg); conventional commercial corn oil equal volume to the treatment group).
- OCT treatment after subcutaneous injection, when the tumor size reaches 5 ⁇ 5mm, start to treat with OCT, and administer it by intragastric administration, that is, dissolve OCT in corn oil at a concentration of 3 mg/kg and 6 mg/kg Administration was administered once every two days, for a total of 10 administrations; the control group was administered an equal volume of corn oil in the same manner.
- the mouse was euthanized and the tumor was taken out for observation and measurement.
- the heart, liver, lung, and kidney were taken out and sent to a biological company (Hubei Biosi Biotechnology Co., Ltd. (Guangzhou)) for HE staining.
- the tumor also Sent to the biological company for immunohistochemical staining (Ki-67 staining).
- Figure 3 shows the results of subcutaneous tumor formation experiments in mice. After intragastric administration of OCT to mice, the growth of nasopharyngeal carcinoma cell CNE-1 can be significantly inhibited; the growth curve of tumor volume and Tumor quality statistics showed that subcutaneous tumor formation in nude mice was significantly inhibited by OCT, indicating that OCT can inhibit the growth of nasopharyngeal carcinoma cells;
- Figure 4 shows that there is no significant difference in the detection of serum aspartate aminotransferase and alanine aminotransferase between the two groups of mice;
- Figure 5 It is the detection result of pathological tissue slices of mice.
- mice The heart, liver, lung, and kidney tissues of the experimental mice were tested by immunohistochemistry, and it was found that there was no significant difference between the experimental group and the control group, which proved the safety of OCT as an anti-tumor drug.
- OCT can inhibit the growth of nasopharyngeal carcinoma cell xenografts in mice.
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Abstract
奥替尼啶双盐酸盐（OCT）在制备抗肿瘤药物中的应用。奥替尼啶双盐酸盐能够抑制鼻咽癌细胞的生长和增殖，能明显抑制裸鼠体内皮下成瘤，安全性好，可用于制备治疗鼻咽癌、食管鳞癌、结直肠癌或肺癌等肿瘤的药物。
Description
本发明属于医药技术领域，特别涉及奥替尼啶双盐酸盐在制备抗肿瘤药物中的应用。
鼻咽癌(Nasopharyngeal carcinoma,NPC)是一种地区性的恶性肿瘤，在美国的发病率为每100,000人有0.4例，而在大多数新病例出现在中东南亚国家。此外，鼻咽癌发病率具有一定的种族及家系遗传的聚集性，例如：婆罗洲的比达友人以及印度北部的纳加人
[1]。鼻咽癌是一种恶性肿瘤，发生在鼻咽腔的最外层上皮层里，位于口咽和下咽上方，靠近颅底。
NPC常规的治疗方法包括放疗或化疗或两者结合。在鼻咽癌高发地区，有限的放射治疗技术和手术设施阻碍了治疗的效果，导致由局部残留肿瘤，进而产生肿瘤复发，大大降低患者总生存率。更重要的是，目前人们对于NPC发病的分子基础仍然知之甚少，鉴于鼻咽部位与脑干细胞区、主要血管和神经非常接近，手术切除通常是肿瘤晚期患者最后的选择。NPC的早期无明显症状，而发病时的一些症状类似头痛、神经性面部疼痛、颈部肿块、鼻衄或鼻塞等容易和其他疾病混淆，导致误诊，造成延误治疗。目前用于晚期鼻咽癌病人的治疗药物有顺铂、5-FU、紫杉醇和吉西他滨等
[2]，虽然这些化疗药物在临床上能使病人有一定的获益，然而，仍需要开发高效、低毒的新型药物以提升抗肿瘤效果。
奥替尼啶二盐酸盐(Octenidine dihydrochloride,OCT)，又称奥替尼啶双盐酸盐，是用于皮肤粘膜和伤口的有效的防腐化合物，其结构式如式I所示：
据相关报道显示，OCT具有抗菌和消炎作用
[3]，可用于伤口感染以及术前 皮肤准备，它对金黄色葡萄球菌有明显的抑制作用，它通过与细菌表面结构相互作用而起作用，导致其裂解和死亡
[4]。OCT还会刺激吞噬作用和生长因子，有利于伤口愈合
[4]，但OCT在肿瘤细胞中的作用还未见相关报道。
发明内容
本发明的目的在于克服现有技术的缺点与不足，提供奥替尼啶双盐酸盐在制备抗肿瘤药物中的应用。
本发明的目的通过下述技术方案实现：
奥替尼啶双盐酸盐(OCT)在制备抗肿瘤药物中的应用。
所述的奥替尼啶双盐酸盐的结构式如式I所示：
所述的肿瘤包括不限于鼻咽癌、食管鳞癌、结直肠癌和肺癌等；优选为鼻咽癌。
所述的奥替尼啶双盐酸盐的有效浓度为0～5μM(不包括0)；优选为0.8～5μM。
所述药物含有一种或多种药学上可接受的载体或辅料。
所述的辅料为缓释剂、赋形剂、填充剂、粘合剂、湿润剂、崩解剂、吸收促进剂、表面活性剂和润滑剂中的至少一种；优选为食用油；更优选为玉米油。
所述的药物可以采用本领域的常规方法进一步制成药物制剂；包括口服给药的药物制剂，如胶囊、丸剂、片剂、口服液、颗粒剂等。
奥替尼啶双盐酸盐在制备抑制鼻咽癌细胞生长和/或增殖的药物中的应用。
所述的鼻咽癌细胞包括鼻咽癌细胞CNE-1和SUNE-1中的至少一种。
本发明相对于现有技术具有如下的优点及效果：本发明结合体外与体内实验，发现奥替尼啶双盐酸盐除了在皮肤表面具有抗炎杀菌作用外，还具有抑制鼻咽癌细胞的生长和增殖的作用，因此可将其用于肿瘤治疗方面，为癌症的辅助治疗提供一种新的药物来源。
图1是OCT对鼻咽癌细胞增殖的影响图；其中，A为OCT对鼻咽癌细胞CNE-1的影响；B为OCT对鼻咽癌细胞CNE-1的影响。
图2是OCT对鼻咽癌CNE-1细胞凋亡的影响图；其中，A为流式细胞检测结果；B为细胞凋亡情况。
图3是OCT对小鼠体内鼻咽癌细胞的成瘤能力的影响图；其中，A为肿瘤照片图；B为肿瘤体积；C为肿瘤重量。
图4是OCT处理小鼠后，小鼠的血清谷草转氨酶和谷丙转氨酶的检测结果图；其中，A为血清谷草转氨酶的活性情况；B为血清谷丙转氨酶的活性情况。
图5是OCT处理小鼠后，小鼠的心、肝、肺和肾组织以及肿瘤的免疫组化检测结果图。
下面结合实施例对本发明作进一步详细的描述，但本发明的实施方式不限于此。除非特别说明，本发明采用的试剂、方法和设备为本技术领域常规试剂、方法和设备。下列实施例中未注明具体实验条件的试验方法，通常按照常规实验条件或按照制造厂所建议的实验条件。除非特别说明，本发明所用试剂和原材料均可通过市售获得。
本发明实施例中的奥替尼啶双盐酸盐(OCT)购买自Targetmol公司(https://www.targetmol.com)。
本发明实施例中的鼻咽癌细胞CNE-1和SUNE-1购自中国科学院细胞库。
实施例1体外实验
(1)OCT对细胞增殖的影响检测：分别将细胞CNE-1和SUNE-1铺于96孔板，每个孔铺5000个细胞，培养在37℃、CO
2含量为5％的培养箱中，24h后用不同浓度的OCT(终浓度为0、0.2、0.4、0.8、1.6和3.2μM)处理，处理时间为24h，通过CCK-8细胞增殖检测试剂盒(Targetmol)检测细胞活性，研究不同浓度的OCT对鼻咽癌细胞增殖的影响。
(2)流式细胞术检测细胞凋亡：流式细胞仪检测前用OCT处理细胞CNE-1，即将CNE-1细胞铺于六孔板中进行培养，使其细胞数量24h后达到每孔的70％，然后用不同浓度的OCT(终浓度为0、0.4、0.8、1.6μM)处理CNE-1细胞，处理时间为24h，随后用AnnexinV-FITC细胞凋亡检测试剂盒(碧云天)进行处理， 处理方法按照其提供的说明书进行，然后用流式细胞仪进行检测，来研究不同浓度的OCT对鼻咽癌细胞凋亡的影响。
细胞水平的实验结果如图1和2所示：图1中，鼻咽癌的细胞活性随着OCT浓度的增加而降低；图2中，鼻咽癌CNE-1细胞的细胞凋亡水平随着OCT浓度的增加而升高。说明OCT可以抑制人鼻咽癌细胞的增殖并促进凋亡。
实施例2体内实验
(1)构建鼻咽癌小鼠模型：选取6周龄、NCG雄性小鼠(购于南京模式动物研究中心)，采用皮下注射的方式构建鼻咽癌小鼠模型，即将细胞悬液(鼻咽癌细胞CNE-1)与基质胶(Corning Matrigel Matrix)按体积比为1：1混合，每只小鼠注射2x10
6个细胞(用25G针头的微注射器取重悬细胞对小鼠进行皮下注射)。皮下注射后，肿瘤大小达到5x5mm进行后续实验。
(2)实验分为三组：低浓度药物处理组(5只，注射量为3mg/kg)；高浓度药物处理组(5只，注射量为6mg/kg)；对照组(5只，注射与处理组等体积的常规市售玉米油)。
(3)OCT处理：皮下注射后，肿瘤大小达到5×5mm时，开始用OCT进行处理，用灌胃的方式给药，即将OCT溶解于玉米油中，以3mg/kg和6mg/kg的浓度给药，每两天给药一次，共给药10次；对照组按同样的方式给予等体积的玉米油。3周后，将小鼠安乐死并将肿瘤取出进行观察和测量，同时将心、肝、肺、肾取出送由生物公司(湖北百奥斯生物科技有限公司(广州))做HE染色，肿瘤也送至该生物公司做免疫组化染色(Ki-67染色)。
结果如图3～5所示：图3显示小鼠体内皮下成瘤实验结果，对小鼠使用OCT灌胃处理后，能够明显抑制鼻咽癌细胞CNE-1的生长；肿瘤体积的生长曲线和肿瘤质量统计表明裸鼠体内皮下成瘤受到OCT的明显抑制，表明OCT可以抑制鼻咽癌细胞生长；图4显示两组小鼠的血清谷草转氨酶和谷丙转氨酶检测均无太大差异；图5是小鼠病理组织切片检测结果，将实验小鼠的心、肝、肺、肾组织进行免疫组化检测，发现实验组和对照组无明显差异，证明OCT作为抗肿瘤药物的使用的安全性。体内实验结果表明OCT可以抑制小鼠体内鼻咽癌细胞移植瘤的生长。
上述实施例为本发明较佳的实施方式，但本发明的实施方式并不受上述实施例的限制，其他的任何未背离本发明的精神实质与原理下所作的改变、修饰、替 代、组合、简化，均应为等效的置换方式，都包含在本发明的保护范围之内。
参考文献：
[1]Sun Z,Wang X,Wang J,Wang J,Liu X,Huang R,et al.Key radioresistance regulation models and marker genes identified by integrated transcriptome analysis in nasopharyngeal carcinoma.Cancer medicine.2021.
[2]Xing X,Zhou X,Yang Y,Li Y,Hu C,Shen C.The impact of body composition parameters on severe toxicities in patients with locoregionally advanced nasopharyngeal carcinoma undergoing neoadjuvant chemotherapy.Annals of translational medicine.2021；9:1180.
[3]Kramer A,Dissemond J,Kim S,Willy C,Mayer D,Papke R,et al.Consensus on Wound Antisepsis:Update 2018.Skin pharmacology and physiology.2018；31:28-58.
[4]Hubner NO,Siebert J,Kramer A.Octenidine dihydrochloride,a modern antiseptic for skin,mucous membranes and wounds.Skin pharmacology and physiology.2010；23:244-58.
Claims (10)
- 奥替尼啶双盐酸盐在制备抗肿瘤药物中的应用。
- 根据权利要求1所述的应用，其特征在于：所述的肿瘤为鼻咽癌、食管鳞癌、结直肠癌或肺癌。
- 根据权利要求2所述的应用，其特征在于：所述的肿瘤为鼻咽癌。
- 根据权利要求1所述的应用，其特征在于：所述的奥替尼啶双盐酸盐的有效浓度为0～5μM，不包括0。
- 根据权利要求4所述的应用，其特征在于：所述的奥替尼啶双盐酸盐的有效浓度为0.8～5μM。
- 根据权利要求1～5任一项所述的应用，其特征在于：所述药物含有一种或多种药学上可接受的载体或辅料；所述的辅料为缓释剂、赋形剂、填充剂、粘合剂、湿润剂、崩解剂、吸收促进剂、表面活性剂和润滑剂中的至少一种。
- 根据权利要求6所述的应用，其特征在于：所述的辅料为食用油。
- 根据权利要求7所述的应用，其特征在于：所述的辅料为玉米油。
- 根据权利要求6所述的应用，其特征在于：所述的药物进一步制成胶囊、丸剂、片剂、口服液或颗粒剂。
- 奥替尼啶双盐酸盐在制备抑制鼻咽癌细胞生长和/或增殖的药物中的应用。
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| CN111417730A (zh) * | 2017-11-20 | 2020-07-14 | 托雷莫治疗股份公司 | 诊断方法 |
| US20210130182A1 (en) * | 2019-11-01 | 2021-05-06 | Regina VERTELOVA | Nanoparticle composition and method of use and manufacture |
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| US20210130182A1 (en) * | 2019-11-01 | 2021-05-06 | Regina VERTELOVA | Nanoparticle composition and method of use and manufacture |
Non-Patent Citations (3)
| Title |
|---|
| LI, LIHONG ET AL.: "Virtual screening based identification of miltefosine and octenidine as inhibitors of heat shock protein 90,", NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY, vol. 394, 18 August 2021 (2021-08-18), XP037588377, DOI: 10.1007/s00210-021-02133-y * |
| N O HÜBNER, J SIEBERT, A KRAMER: "Octenidine Dihydrochloride, a Modern Antiseptic for Skin, Mucous Membranes and Wounds", SKIN PHARMACOLOGY AND PHYSIOLOGY, S. KARGER AG, BASEL, vol. 23, no. 5, 1 July 2010 (2010-07-01), Basel , pages 244 - 258, XP055018202, ISSN: 16605527, DOI: 10.1159/000314699 * |
| SOPATA, M.; CIUPINSKA, M.; GLOWACKA, A.; MUSZYNKI, Z.; TOMASZEWSKA, E.: "Effect of Octenisept antiseptic on bioburden of neoplastic ulcers in patients with advanced cancer,", JOURNAL OF WOUND CARE, MACMILLAN, LONDON, GB, vol. 17, no. 1, 31 January 2008 (2008-01-31), GB , pages 24 - 27, XP009543996, ISSN: 0969-0700 * |
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