CN117503737A - 和厚朴酚在制备治疗脂肪肉瘤药物中的用途 - Google Patents
和厚朴酚在制备治疗脂肪肉瘤药物中的用途 Download PDFInfo
- Publication number
- CN117503737A CN117503737A CN202410018737.XA CN202410018737A CN117503737A CN 117503737 A CN117503737 A CN 117503737A CN 202410018737 A CN202410018737 A CN 202410018737A CN 117503737 A CN117503737 A CN 117503737A
- Authority
- CN
- China
- Prior art keywords
- liposarcoma
- honokiol
- use according
- capsule
- liposome
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 206010024627 liposarcoma Diseases 0.000 title claims abstract description 63
- BYTORXDZJWWIKR-UHFFFAOYSA-N Hinokiol Natural products CC(C)c1cc2CCC3C(C)(CO)C(O)CCC3(C)c2cc1O BYTORXDZJWWIKR-UHFFFAOYSA-N 0.000 title claims abstract description 50
- FVYXIJYOAGAUQK-UHFFFAOYSA-N honokiol Chemical compound C1=C(CC=C)C(O)=CC=C1C1=CC(CC=C)=CC=C1O FVYXIJYOAGAUQK-UHFFFAOYSA-N 0.000 title claims abstract description 50
- VVOAZFWZEDHOOU-UHFFFAOYSA-N honokiol Natural products OC1=CC=C(CC=C)C=C1C1=CC(CC=C)=CC=C1O VVOAZFWZEDHOOU-UHFFFAOYSA-N 0.000 title claims abstract description 50
- 239000003814 drug Substances 0.000 title claims abstract description 26
- 238000002360 preparation method Methods 0.000 title claims abstract description 12
- 229940079593 drug Drugs 0.000 title abstract description 20
- 239000002502 liposome Substances 0.000 claims description 24
- 206010073135 Dedifferentiated liposarcoma Diseases 0.000 claims description 8
- 239000002775 capsule Substances 0.000 claims description 8
- 239000000463 material Substances 0.000 claims description 3
- 230000035755 proliferation Effects 0.000 claims description 3
- 239000004480 active ingredient Substances 0.000 claims description 2
- 239000007902 hard capsule Substances 0.000 claims description 2
- 238000010255 intramuscular injection Methods 0.000 claims description 2
- 239000007927 intramuscular injection Substances 0.000 claims description 2
- 238000010253 intravenous injection Methods 0.000 claims description 2
- 201000010393 mixed liposarcoma Diseases 0.000 claims description 2
- 230000002685 pulmonary effect Effects 0.000 claims description 2
- 239000007901 soft capsule Substances 0.000 claims description 2
- 238000010254 subcutaneous injection Methods 0.000 claims description 2
- 239000007929 subcutaneous injection Substances 0.000 claims description 2
- 238000009472 formulation Methods 0.000 claims 6
- 239000000203 mixture Substances 0.000 claims 6
- 239000008176 lyophilized powder Substances 0.000 claims 4
- 230000000694 effects Effects 0.000 abstract description 6
- 231100000331 toxic Toxicity 0.000 abstract 1
- 230000002588 toxic effect Effects 0.000 abstract 1
- 210000004027 cell Anatomy 0.000 description 29
- 238000002347 injection Methods 0.000 description 20
- 239000007924 injection Substances 0.000 description 20
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 description 12
- 238000011282 treatment Methods 0.000 description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 11
- 238000000034 method Methods 0.000 description 9
- 230000005764 inhibitory process Effects 0.000 description 8
- 206010039491 Sarcoma Diseases 0.000 description 7
- 239000002609 medium Substances 0.000 description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- 238000004113 cell culture Methods 0.000 description 6
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 6
- 229960004679 doxorubicin Drugs 0.000 description 6
- 238000002474 experimental method Methods 0.000 description 6
- 238000002512 chemotherapy Methods 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- 239000006143 cell culture medium Substances 0.000 description 4
- 238000012054 celltiter-glo Methods 0.000 description 4
- 238000012258 culturing Methods 0.000 description 4
- 238000004108 freeze drying Methods 0.000 description 4
- 238000007710 freezing Methods 0.000 description 4
- 230000008014 freezing Effects 0.000 description 4
- 230000001394 metastastic effect Effects 0.000 description 4
- 206010061289 metastatic neoplasm Diseases 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- 238000001959 radiotherapy Methods 0.000 description 4
- 208000021712 Soft tissue sarcoma Diseases 0.000 description 3
- 239000002246 antineoplastic agent Substances 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 235000012000 cholesterol Nutrition 0.000 description 3
- 238000011161 development Methods 0.000 description 3
- 235000019441 ethanol Nutrition 0.000 description 3
- 239000001963 growth medium Substances 0.000 description 3
- 230000004083 survival effect Effects 0.000 description 3
- 208000024891 symptom Diseases 0.000 description 3
- 239000003826 tablet Substances 0.000 description 3
- 230000001225 therapeutic effect Effects 0.000 description 3
- JLPULHDHAOZNQI-ZTIMHPMXSA-N 1-hexadecanoyl-2-(9Z,12Z-octadecadienoyl)-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCC\C=C/C\C=C/CCCCC JLPULHDHAOZNQI-ZTIMHPMXSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- JZNWSCPGTDBMEW-UHFFFAOYSA-N Glycerophosphorylethanolamin Natural products NCCOP(O)(=O)OCC(O)CO JZNWSCPGTDBMEW-UHFFFAOYSA-N 0.000 description 2
- 206010027476 Metastases Diseases 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 2
- 239000002671 adjuvant Substances 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- 239000006285 cell suspension Substances 0.000 description 2
- 229940127089 cytotoxic agent Drugs 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- SDUQYLNIPVEERB-QPPQHZFASA-N gemcitabine Chemical compound O=C1N=C(N)C=CN1[C@H]1C(F)(F)[C@H](O)[C@@H](CO)O1 SDUQYLNIPVEERB-QPPQHZFASA-N 0.000 description 2
- 229960005277 gemcitabine Drugs 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 230000009401 metastasis Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 210000005036 nerve Anatomy 0.000 description 2
- 201000008968 osteosarcoma Diseases 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 150000008104 phosphatidylethanolamines Chemical class 0.000 description 2
- 238000007747 plating Methods 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 239000008213 purified water Substances 0.000 description 2
- 230000000306 recurrent effect Effects 0.000 description 2
- 238000002390 rotary evaporation Methods 0.000 description 2
- 239000008227 sterile water for injection Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- 206010065553 Bone marrow failure Diseases 0.000 description 1
- 208000031229 Cardiomyopathies Diseases 0.000 description 1
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 1
- XXPXYPLPSDPERN-UHFFFAOYSA-N Ecteinascidin 743 Natural products COc1cc2C(NCCc2cc1O)C(=O)OCC3N4C(O)C5Cc6cc(C)c(OC)c(O)c6C(C4C(S)c7c(OC(=O)C)c(C)c8OCOc8c37)N5C XXPXYPLPSDPERN-UHFFFAOYSA-N 0.000 description 1
- 208000034951 Genetic Translocation Diseases 0.000 description 1
- 239000003798 L01XE11 - Pazopanib Substances 0.000 description 1
- 241001673966 Magnolia officinalis Species 0.000 description 1
- ZDZOTLJHXYCWBA-VCVYQWHSSA-N N-debenzoyl-N-(tert-butoxycarbonyl)-10-deacetyltaxol Chemical compound O([C@H]1[C@H]2[C@@](C([C@H](O)C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C=4C=CC=CC=4)C[C@]1(O)C3(C)C)=O)(C)[C@@H](O)C[C@H]1OC[C@]12OC(=O)C)C(=O)C1=CC=CC=C1 ZDZOTLJHXYCWBA-VCVYQWHSSA-N 0.000 description 1
- 206010030113 Oedema Diseases 0.000 description 1
- 102000004142 Trypsin Human genes 0.000 description 1
- 108090000631 Trypsin Proteins 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000003712 anti-aging effect Effects 0.000 description 1
- 230000003627 anti-cholesterol Effects 0.000 description 1
- 230000001430 anti-depressive effect Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000000845 anti-microbial effect Effects 0.000 description 1
- 230000002785 anti-thrombosis Effects 0.000 description 1
- 230000000767 anti-ulcer Effects 0.000 description 1
- 239000003146 anticoagulant agent Substances 0.000 description 1
- 239000000935 antidepressant agent Substances 0.000 description 1
- 229940005513 antidepressants Drugs 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 239000002249 anxiolytic agent Substances 0.000 description 1
- 230000000949 anxiolytic effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 229940044683 chemotherapy drug Drugs 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 210000002808 connective tissue Anatomy 0.000 description 1
- 238000005138 cryopreservation Methods 0.000 description 1
- 231100000433 cytotoxic Toxicity 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- 238000007405 data analysis Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 230000029087 digestion Effects 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 229960003668 docetaxel Drugs 0.000 description 1
- 239000000890 drug combination Substances 0.000 description 1
- 230000009982 effect on human Effects 0.000 description 1
- UFNVPOGXISZXJD-XJPMSQCNSA-N eribulin Chemical compound C([C@H]1CC[C@@H]2O[C@@H]3[C@H]4O[C@H]5C[C@](O[C@H]4[C@H]2O1)(O[C@@H]53)CC[C@@H]1O[C@H](C(C1)=C)CC1)C(=O)C[C@@H]2[C@@H](OC)[C@@H](C[C@H](O)CN)O[C@H]2C[C@@H]2C(=C)[C@H](C)C[C@H]1O2 UFNVPOGXISZXJD-XJPMSQCNSA-N 0.000 description 1
- 229960003649 eribulin Drugs 0.000 description 1
- 238000013401 experimental design Methods 0.000 description 1
- 102000037865 fusion proteins Human genes 0.000 description 1
- 108020001507 fusion proteins Proteins 0.000 description 1
- 231100000086 high toxicity Toxicity 0.000 description 1
- -1 however Substances 0.000 description 1
- HOMGKSMUEGBAAB-UHFFFAOYSA-N ifosfamide Chemical compound ClCCNP1(=O)OCCCN1CCCl HOMGKSMUEGBAAB-UHFFFAOYSA-N 0.000 description 1
- 229960001101 ifosfamide Drugs 0.000 description 1
- 239000012729 immediate-release (IR) formulation Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 231100001252 long-term toxicity Toxicity 0.000 description 1
- 210000002901 mesenchymal stem cell Anatomy 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 210000000653 nervous system Anatomy 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 229960000639 pazopanib Drugs 0.000 description 1
- CUIHSIWYWATEQL-UHFFFAOYSA-N pazopanib Chemical compound C1=CC2=C(C)N(C)N=C2C=C1N(C)C(N=1)=CC=NC=1NC1=CC=C(C)C(S(N)(=O)=O)=C1 CUIHSIWYWATEQL-UHFFFAOYSA-N 0.000 description 1
- 238000010837 poor prognosis Methods 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000002271 resection Methods 0.000 description 1
- 210000000574 retroperitoneal space Anatomy 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 231100001251 short-term toxicity Toxicity 0.000 description 1
- 229940083466 soybean lecithin Drugs 0.000 description 1
- 239000008347 soybean phospholipid Substances 0.000 description 1
- 238000007619 statistical method Methods 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 230000001502 supplementing effect Effects 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 239000007939 sustained release tablet Substances 0.000 description 1
- 238000011521 systemic chemotherapy Methods 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 238000010257 thawing Methods 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- PKVRCIRHQMSYJX-AIFWHQITSA-N trabectedin Chemical compound C([C@@]1(C(OC2)=O)NCCC3=C1C=C(C(=C3)O)OC)S[C@@H]1C3=C(OC(C)=O)C(C)=C4OCOC4=C3[C@H]2N2[C@@H](O)[C@H](CC=3C4=C(O)C(OC)=C(C)C=3)N(C)[C@H]4[C@@H]21 PKVRCIRHQMSYJX-AIFWHQITSA-N 0.000 description 1
- 229960000977 trabectedin Drugs 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 238000011269 treatment regimen Methods 0.000 description 1
- 239000012588 trypsin Substances 0.000 description 1
- 208000025443 tumor of adipose tissue Diseases 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
Classifications
-
- 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
- A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
- A61K31/05—Phenols
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/127—Liposomes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Abstract
本发明属于医药领域,具体涉及和厚朴酚在制备治疗脂肪肉瘤药物中的用途。和厚朴酚能够有效抑制脂肪肉瘤细胞的生长,安全性良好;将和厚朴酚用于脂肪肉瘤的治疗,为脂肪肉瘤患者提供一种新选择,解决当下脂肪肉瘤药物疗效有限、毒副作用大的问题。
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脂肪肉瘤药物中的用途。
背景技术
肉瘤是一种起源于间叶组织(包括结缔组织和肌肉)的罕见恶性肿瘤,其整体的发病率约为5/10万[1, 2]。肉瘤具有高度异质性,可以分为软组织肉瘤(Soft tissue sarcoma,STS)和原发性骨肉瘤(Osteosarcoma, OS)两大类[3],其中,脂肪肉瘤(Liposarcomas, LPS)是一种起源于间充质干细胞有向脂肪组织分化倾向的恶性肿瘤,是一种成人中最常见的软组织肉瘤亚型[4],约占所有软组织肉瘤的20%[5, 6]。脂肪肉瘤可发生于任何存在脂肪的部位[7],其最常见的发生部位是四肢,其次是腹膜后。大多数的脂肪肉瘤患者没有明显症状,只有当肿瘤长大到足以对周围结构产生影响时才会出现症状,这些症状包括疼痛/触痛、水肿或因神经血管束受阻而导致的功能丧失等[8, 9]。
根据组织形态学等不同,脂肪肉瘤主要可分为四种亚型,分别是高分化的脂肪肉瘤(Well-differentiated LPS, WDLPS)、去分化的脂肪肉瘤(Dedifferentiated LPS,DDLPS)、黏液型脂肪肉瘤(Myxoid LPS, MLPS)和多形性的脂肪肉瘤(Pleomorphic LPS,PLPS)[6, 10, 11]。不同亚型具有不同的临床表现、治疗敏感性和潜在的生物学特性。其中,WDLPS和DDLPS共同构成了脂肪肉瘤的最大亚群[12],而且常常同时存在(WD/DDLPS)[13],WDLPS的转移率低且对放疗和化疗不敏感[14],DDLPS则更具侵袭性、转移性和致命性;MLPS约占LPS的30%[13],大多数MLPS会由于染色体易位而具有融合蛋白[15];而PLPS是一种核型复杂、预后特别差的亚型,只占脂肪肉瘤诊断的不到10%[13, 16]。
脂肪肉瘤的罕见性加上各种组织学亚型的临床表现各不相同,使得对这些肿瘤的认识变得复杂,并阻碍了有效疗法的开发[29]。手术切除是脂肪肉瘤的主要治疗方法,但腹膜后脂肪肉瘤或邻近重要神经或血管结构的脂肪肉瘤通常无法彻底切除且切除难度较大,可能会出现影响血管或神经系统等情况[17, 18],且易发生局部复发[21-25],为了解决这个问题,辅助化疗药物(如多柔比星)通常与手术同时用于复发或转移性脂肪肉瘤,但治疗效果也有限[13, 19, 20],在所有脂肪肉瘤患者中,约有30%的患者会在病程中发生远处转移[5],在发生远处转移的病例中,中位生存时间仅约为10-12个月[26, 27],对于复发或转移性脂肪肉瘤患者,其生存率较低且一直未得到有效提升[28]。另外对于高级别病变,可能需要更广泛而深入的手术切除、以及辅助放疗和/或化疗[8]。其中,放疗可能是手术的重要辅助手段,然而,辅助放疗的作用还存在争议,尚未达成明确共识[30]。此外,脂肪肉瘤的化疗也仍处于试验阶段,对化疗的治疗效果也尚无充分证实。其中,细胞毒性类抗肿瘤药物多柔比星一直是治疗转移性软组织肉瘤最常用的化疗药物,但在脂肪肉瘤中的总体缓解率仅为36%[20]。在四个不同的组织学亚型中,WDLPS对全身化疗缓解率较低[31],主要采用局部治疗,包括在临床可行的情况下进行多次切除和剥离手术;DDLPS对多柔比星的缓解率也较低,约为13%[5, 31],有研究显示DDLPS可对化疗药物和药物组合产生反应,包括多柔比星(或多柔比星联合异环磷酰胺)、吉西他滨(或吉西他滨联合多西他赛)、曲贝替丁、艾瑞布林和帕唑帕尼,然而,化疗药物的治疗效果通常较差,缓解率通常较低,缓解持续时间通常较短[32-34],且联用会导致严重的短期或长期毒性,包括心肌病和骨髓抑制[35];PLPS的化疗耐药性也很强,对多柔比星的缓解率仅为5%[5];而MLPS被认为是化疗较为敏感的亚组,缓解率为44-48%[14, 36, 37]。
因此,在脂肪肉瘤患者的治疗中,尚无良好的治疗策略,目前针对脂肪肉瘤患者的治疗方式较少,部分患者由于发生部位特殊导致手术切除难度大,且现有的各类治疗方式存在治疗效果不佳、毒性较大等局限性,故针对脂肪肉瘤亟需开发新的药物来提高患者的生存率。
发明内容
针对现有脂肪肉瘤治疗方面的不足, 本发明的目的在于提供和厚朴酚在制备治疗脂肪肉瘤药物中的用途。
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脂肪肉瘤药物中的用途。
本发明所述脂肪肉瘤包括但不限于高分化的脂肪肉瘤、去分化的脂肪肉瘤、黏液型脂肪肉瘤、多形性的脂肪肉瘤或混合型脂肪肉瘤。
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,所述和厚朴酚抑制脂肪肉瘤的细胞增殖。
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、透皮制剂中一种。
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。
优选地,所述片剂包括速释片剂或缓释片剂。
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人脂肪肉瘤细胞的生长,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脂肪肉瘤药物的用途,解决当下脂肪肉瘤药物不足比如治疗疗效有限、毒副性大等问题,为脂肪肉瘤患者提供一种新选择。
附图说明
图1是药物(A、B、C)在人脂肪肉瘤SW872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)。
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SW872细胞株,SW872是一种人脂肪肉瘤细胞,SW872细胞系所使用的培养基是一种含有10% FBS的DMEM培养基,将SW872细胞置于37℃、5% CO2的细胞培养箱中培养,2~3天后换液传代一次。
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)首先将15 mL细胞培养基添加至T75培养瓶中。
2)将培养瓶放置于37℃、5% CO2的细胞培养箱中平衡约15分钟,使得培养基平衡至适当pH值及温度。
3)将保存在液氮中的SW872细胞的冻存管取出,并将其置于37℃的水浴锅中快速解冻,操作过程中需保持轻柔,然后使用70%的乙醇擦拭SW872细胞冻存管消毒,接下来将冻存管转移至生物安全柜,在生物安全柜中打开。
4)将细胞冻存管中的SW872细胞悬液转移至无菌的15 mL离心管中,离心管需预先吸取10 mL细胞培养基,操作过程需轻柔小心,再以200×g转速离心5分钟。
5)离心结束后,将冻存管小心转移至生物安全柜,弃除上清液,并将SW872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培养箱中培养。
1.1.2细胞传代培养
每隔2~3天补充或更换新鲜培养基,传代时使用胰蛋白酶消化,再用含血清的培养基终止消化,离心后重悬SW872细胞沉淀,转移至装有新鲜培养基的培养瓶中,置于37℃、5%CO2培养箱中继续培养。
1.2细胞铺板
1)常规培养SW872细胞至数量达到实验所需的量时,收集SW872细胞并计数。
2)用培养基重悬SW872细胞至实验设计所需密度。
3)将SW872细胞悬液加入96孔细胞培养板,每孔体积为90 µL,SW872细胞的铺板密度为10000 cells/well。每个处理条件各做3个复孔。
4)将培养板置于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开始稀释,在96孔细胞培养板中按照1:3的稀释比例使用DMSO/无菌注射用水梯度稀释和厚朴酚、注射用空白脂质体和注射用和厚朴酚脂质体,共设置9个药物浓度。
2)将梯度浓度的药物加入至铺好细胞的96孔细胞培养板中,每孔添加体积为10 μl (终浓度分别为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SW872细胞培养板置于37℃,5% CO2培养箱中培养,药物的处理时间为3天。
1.4.CTG分析
1)3天后,把孵育后的96孔细胞培养板从培养箱中移出,在室温下平衡15分钟。
2)将Cell Titer-Glo试剂从-20℃取出,置于4℃冰箱过夜融化,使用前需平衡至室温。
3)在每个待检测孔里加入100 μL的Cell Titer-Glo试剂 (Cell Titer-Glo试剂与培养基比例为1:1)。
4)室温避光孵育20分钟,再使用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获得注射用空白脂质体、和厚朴酚和注射用和厚朴酚脂质体在人脂肪肉瘤SW872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脂肪肉瘤SW872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脂肪肉瘤SW872细胞的生长具有抑制作用,其最大抑制率均可达100%,其在SW872细胞中3天的IC50值分别为36.51μM和38.93 μM。
和厚朴酚、注射用和厚朴酚脂质体对人脂肪肉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脂肪肉瘤药物中的用途。
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。
参考文献:
[1]SBARAGLIA M, BELLAN E, DEI T A. The 2020 WHO Classification ofSoft Tissue Tumours: news and perspectives[J]. Pathologica, 2021,113(2): 70-84.
[2]GATTA G, van der ZWAN J M, CASALI P G, et al. Rare cancers arenot so rare: the rare cancer burden in Europe[J]. Eur J Cancer, 2011,47(17):2493-2511.
[3]SKUBITZ K M, D'ADAMO D R. Sarcoma[J]. Mayo Clin Proc, 2007,82(11): 1409-1432.
[4]LIVINGSTON J A, BUGANO D, BARBO A, et al. Role of chemotherapy indedifferentiated liposarcoma of the retroperitoneum: defining the benefit andchallenges of the standard[J]. Sci Rep, 2017,7(1): 11836.
[5]HARATI K, DAIGELER A, HIRSCH T, et al. Tumor-associatedfibroblasts promote the proliferation and decrease the doxorubicinsensitivity of liposarcoma cells[J]. Int J Mol Med, 2016,37(6): 1535-1541.
[6]CUI J, DEAN D, HORNICEK F J, et al. ATR inhibition sensitizesliposarcoma to doxorubicin by increasing DNA damage[J]. Am J Cancer Res,2022,12(4): 1577-1592.
[7]VIJAY A, RAM L. Retroperitoneal liposarcoma: a comprehensivereview[J]. Am J Clin Oncol, 2015,38(2): 213-219.
[8]ZAFAR R, WHEELER Y. Liposarcoma[J]. 2023.
[9]LIN Z C, CHANG X Z, HUANG X F, et al. Giant liposarcoma of theesophagus: A case report[J]. World J Gastroenterol, 2015,21(33): 9827-9832.
[10]SUAREZ-KELLY L P, BALDI G G, GRONCHI A. Pharmacotherapy forliposarcoma: current state of the art and emerging systemic treatments[J].Expert Opin Pharmacother, 2019,20(12): 1503-1515.
[11]SUN R, SHEN J K, CHOY E, et al. The emerging roles andtherapeutic potential of microRNAs (miRs) in liposarcoma[J]. Discov Med,2015,20(111): 311-324.
[12]THWAY K. Well-differentiated liposarcoma and dedifferentiatedliposarcoma: An updated review[J]. Semin Diagn Pathol, 2019,36(2): 112-121.
[13]LEE A, THWAY K, HUANG P H, et al. Clinical and Molecular Spectrumof Liposarcoma[J]. J Clin Oncol, 2018,36(2): 151-159.
[14]JONES R L, FISHER C, AL-MUDERIS O, et al. Differentialsensitivity of liposarcoma subtypes to chemotherapy[J]. Eur J Cancer, 2005,41(18): 2853-2860.
[15]CROZAT A, AMAN P, MANDAHL N, et al. Fusion of CHOP to a novelRNA-binding protein in human myxoid liposarcoma[J]. Nature, 1993,363(6430):640-644.
[16]WANG W, LI X, LIU P, et al. [Clinical value of fluorescence insitu hybridization with MDM2 and DDIT3 probe in diagnosis of liposarcoma][J].Beijing Da Xue Xue Bao Yi Xue Ban, 2023,55(2): 228-233.
[17]de VREEZE R S, de JONG D, NEDERLOF P M, et al. Added Value ofMolecular Biological Analysis in Diagnosis and Clinical Management ofLiposarcoma: A 30-Year Single-Institution Experience[J]. Ann Surg Oncol,2010,17(3): 686-693.
[18]MANKIN H J, HORNICEK F J. Diagnosis, classification, andmanagement of soft tissue sarcomas[J]. Cancer Control, 2005,12(1): 5-21.
[19]BILL K L, CASADEI L, PRUDNER B C, et al. Liposarcoma: moleculartargets and therapeutic implications[J]. Cell Mol Life Sci, 2016,73(19):3711-3718.
[20]Van GLABBEKE M, van OOSTEROM A T, OOSTERHUIS J W, et al.Prognostic factors for the outcome of chemotherapy in advanced soft tissuesarcoma: an analysis of 2,185 patients treated with anthracycline-containingfirst-line regimens--a European Organization for Research and Treatment ofCancer Soft Tissue and Bone Sarcoma Group Study[J]. J Clin Oncol, 1999,17(1):150-157.
[21]SINGER S, DEMETRI G D, BALDINI E H, et al. Management of soft-tissue sarcomas: an overview and update[J]. Lancet Oncol, 2000,1: 75-85.
[22]KAUSHAL A, CITRIN D. The role of radiation therapy in themanagement of sarcomas[J]. Surg Clin North Am, 2008,88(3): 629-646.
[23]STOJADINOVIC A, LEUNG D H, HOOS A, et al. Analysis of theprognostic significance of microscopic margins in 2,084 localized primaryadult soft tissue sarcomas[J]. Ann Surg, 2002,235(3): 424-434.
[24]LEWIS J J, LEUNG D, HESLIN M, et al. Association of localrecurrence with subsequent survival in extremity soft tissue sarcoma[J]. JClin Oncol, 1997,15(2): 646-652.
[25]DAIGELER A, ZMARSLY I, HIRSCH T, et al. Long-term outcome afterlocal recurrence of soft tissue sarcoma: a retrospective analysis of factorspredictive of survival in 135 patients with locally recurrent soft tissuesarcoma[J]. Br J Cancer, 2014,110(6): 1456-1464.
[26]BILLINGSLEY K G, BURT M E, JARA E, et al. Pulmonary metastasesfrom soft tissue sarcoma: analysis of patterns of diseases and postmetastasissurvival[J]. Ann Surg, 1999,229(5): 602-610, 610-612.
[27]GHADIMI M P, AL-ZAID T, MADEWELL J, et al. Diagnosis, management,and outcome of patients with dedifferentiated liposarcoma systemic metastasis[J]. Ann Surg Oncol, 2011,18(13): 3762-3770.
[28]SAPONARA M, STACCHIOTTI S, GRONCHI A. Pharmacological therapiesfor Liposarcoma[J]. Expert Rev Clin Pharmacol, 2017,10(4): 361-377.
[29]ZHOU M Y, BUI N Q, CHARVILLE G W, et al. Treatment of De-Differentiated Liposarcoma in the Era of Immunotherapy[J]. Int J Mol Sci,2023,24(11).
[30]DOWLI A, MATTAR A, MASHIMO H, et al. A pedunculated giantesophageal liposarcoma: a case report and literature review[J]. JGastrointest Surg, 2014,18(12): 2208-2213.
[31]ITALIANO A, TOULMONDE M, CIOFFI A, et al. Advanced well-differentiated/dedifferentiated liposarcomas: role of chemotherapy andsurvival[J]. Ann Oncol, 2012,23(6): 1601-1607.
[32]DEMETRI G D, SCHÖFFSKI P, GRIGNANI G, et al. Activity of Eribulinin Patients With Advanced Liposarcoma Demonstrated in a Subgroup AnalysisFrom a Randomized Phase III Study of Eribulin Versus Dacarbazine[J]. J ClinOncol, 2017,35(30): 3433-3439.
[33]DEMETRI G D, von MEHREN M, JONES R L, et al. Efficacy and Safetyof Trabectedin or Dacarbazine for Metastatic Liposarcoma or LeiomyosarcomaAfter Failure of Conventional Chemotherapy: Results of a Phase III RandomizedMulticenter Clinical Trial[J]. J Clin Oncol, 2016,34(8): 786-793.
[34]SCHÖFFSKI P, CHAWLA S, MAKI R G, et al. Eribulin versusdacarbazine in previously treated patients with advanced liposarcoma orleiomyosarcoma: a randomised, open-label, multicentre, phase 3 trial[J].Lancet, 2016,387(10028): 1629-1637.
[35]JUDSON I, VERWEIJ J, GELDERBLOM H, et al. Doxorubicin aloneversus intensified doxorubicin plus ifosfamide for first-line treatment ofadvanced or metastatic soft-tissue sarcoma: a randomised controlled phase 3trial[J]. Lancet Oncol, 2014,15(4): 415-423.
[36]ITALIANO A, GARBAY D, CIOFFI A, et al. Advanced pleomorphicliposarcomas: clinical outcome and impact of chemotherapy[J]. Ann Oncol,2012,23(8): 2205-2206.
[37]PATEL S R, BURGESS M A, PLAGER C, et al. Myxoid liposarcoma.Experience with chemotherapy[J]. Cancer, 1994,74(4): 1265-1269.
Claims (9)
1.和厚朴酚在制备治疗脂肪肉瘤药物中的用途。
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,所述和厚朴酚抑制脂肪肉瘤的细胞增殖。
5.根据权利要求1~3任意一项所述的用途,其特征在于,所述脂肪肉瘤包括高分化的脂肪肉瘤、去分化的脂肪肉瘤、黏液型脂肪肉瘤、多形性的脂肪肉瘤或混合型脂肪肉瘤。
6.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。
7.根据权利要求6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、透皮制剂中一种。
8.根据权利要求7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。
9.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。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202410018737.XA CN117503737B (zh) | 2024-01-05 | 2024-01-05 | 和厚朴酚在制备治疗脂肪肉瘤药物中的用途 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202410018737.XA CN117503737B (zh) | 2024-01-05 | 2024-01-05 | 和厚朴酚在制备治疗脂肪肉瘤药物中的用途 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN117503737A true CN117503737A (zh) | 2024-02-06 |
CN117503737B CN117503737B (zh) | 2024-04-16 |
Family
ID=89755363
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202410018737.XA Active CN117503737B (zh) | 2024-01-05 | 2024-01-05 | 和厚朴酚在制备治疗脂肪肉瘤药物中的用途 |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN117503737B (zh) |
Citations (15)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20050176658A1 (en) * | 2003-11-04 | 2005-08-11 | Warren Chow | Method of using protease inhibitors for the treatment of liposarcomas |
CN101223120A (zh) * | 2005-02-23 | 2008-07-16 | 杰克·L·阿比瑟 | 用于治疗增殖障碍的和厚朴酚衍生物 |
WO2008137420A1 (en) * | 2007-05-03 | 2008-11-13 | Emory University | Honokiol analogs and their use in treating cancers |
US20100137194A1 (en) * | 2007-04-16 | 2010-06-03 | The Regents Of The University Of Michigan | Plasminogen Activator Inhibitor-1 Inhibitors and Methods of Use Thereof to Modulate Lipid Metabolism |
CN106588580A (zh) * | 2016-11-23 | 2017-04-26 | 成都金瑞基业生物科技有限公司 | 从厚朴中制备高纯度厚朴酚的方法 |
BR102016026797A2 (pt) * | 2015-11-25 | 2017-05-30 | Beiersdorf Ag | preparação cosmética |
CN111514122A (zh) * | 2020-05-28 | 2020-08-11 | 青岛大学附属医院 | 双硫仑在制备治疗脂肪肉瘤药物中的应用 |
CN112076179A (zh) * | 2020-09-27 | 2020-12-15 | 成都金瑞基业生物科技有限公司 | 和厚朴酚的医药用途 |
CN112870367A (zh) * | 2019-11-29 | 2021-06-01 | 江苏恒瑞医药股份有限公司 | Ezh2抑制剂、cdk4/6抑制剂和mek抑制剂在制备治疗肿瘤药物中的用途 |
CN112870366A (zh) * | 2019-11-29 | 2021-06-01 | 江苏恒瑞医药股份有限公司 | Ezh2抑制剂在制备治疗肿瘤药物中的新用途 |
WO2022251539A2 (en) * | 2021-05-26 | 2022-12-01 | C4 Therapeutics, Inc. | Egfr degraders to treat cancer metastasis to the brain or cns |
CN115463118A (zh) * | 2022-09-29 | 2022-12-13 | 成都金瑞基业生物科技有限公司 | 和厚朴酚在制备治疗或预防毛细血管瘤的药物中的用途 |
CN115702891A (zh) * | 2021-08-12 | 2023-02-17 | 成都金瑞基业生物科技有限公司 | 和厚朴酚在制备用于治疗脑膜瘤的药物中的用途 |
CN116723839A (zh) * | 2020-10-14 | 2023-09-08 | C4医药公司 | 用于降解靶蛋白质的三环杂双官能化合物 |
CN116785267A (zh) * | 2022-01-29 | 2023-09-22 | 成都金瑞基业生物科技有限公司 | 和厚朴酚在治疗耐药实体瘤以及耐药实体瘤的脑转移瘤中的用途 |
-
2024
- 2024-01-05 CN CN202410018737.XA patent/CN117503737B/zh active Active
Patent Citations (16)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20050176658A1 (en) * | 2003-11-04 | 2005-08-11 | Warren Chow | Method of using protease inhibitors for the treatment of liposarcomas |
CN101223120A (zh) * | 2005-02-23 | 2008-07-16 | 杰克·L·阿比瑟 | 用于治疗增殖障碍的和厚朴酚衍生物 |
US20100137194A1 (en) * | 2007-04-16 | 2010-06-03 | The Regents Of The University Of Michigan | Plasminogen Activator Inhibitor-1 Inhibitors and Methods of Use Thereof to Modulate Lipid Metabolism |
WO2008137420A1 (en) * | 2007-05-03 | 2008-11-13 | Emory University | Honokiol analogs and their use in treating cancers |
CN101742991A (zh) * | 2007-05-03 | 2010-06-16 | 杰克·L·阿比瑟 | 和厚朴酚类似物及其在治疗癌症中的用途 |
BR102016026797A2 (pt) * | 2015-11-25 | 2017-05-30 | Beiersdorf Ag | preparação cosmética |
CN106588580A (zh) * | 2016-11-23 | 2017-04-26 | 成都金瑞基业生物科技有限公司 | 从厚朴中制备高纯度厚朴酚的方法 |
CN112870366A (zh) * | 2019-11-29 | 2021-06-01 | 江苏恒瑞医药股份有限公司 | Ezh2抑制剂在制备治疗肿瘤药物中的新用途 |
CN112870367A (zh) * | 2019-11-29 | 2021-06-01 | 江苏恒瑞医药股份有限公司 | Ezh2抑制剂、cdk4/6抑制剂和mek抑制剂在制备治疗肿瘤药物中的用途 |
CN111514122A (zh) * | 2020-05-28 | 2020-08-11 | 青岛大学附属医院 | 双硫仑在制备治疗脂肪肉瘤药物中的应用 |
CN112076179A (zh) * | 2020-09-27 | 2020-12-15 | 成都金瑞基业生物科技有限公司 | 和厚朴酚的医药用途 |
CN116723839A (zh) * | 2020-10-14 | 2023-09-08 | C4医药公司 | 用于降解靶蛋白质的三环杂双官能化合物 |
WO2022251539A2 (en) * | 2021-05-26 | 2022-12-01 | C4 Therapeutics, Inc. | Egfr degraders to treat cancer metastasis to the brain or cns |
CN115702891A (zh) * | 2021-08-12 | 2023-02-17 | 成都金瑞基业生物科技有限公司 | 和厚朴酚在制备用于治疗脑膜瘤的药物中的用途 |
CN116785267A (zh) * | 2022-01-29 | 2023-09-22 | 成都金瑞基业生物科技有限公司 | 和厚朴酚在治疗耐药实体瘤以及耐药实体瘤的脑转移瘤中的用途 |
CN115463118A (zh) * | 2022-09-29 | 2022-12-13 | 成都金瑞基业生物科技有限公司 | 和厚朴酚在制备治疗或预防毛细血管瘤的药物中的用途 |
Non-Patent Citations (8)
Title |
---|
DJXZYY: "我院首获国家自然科学基金项目资助", pages 3 - 5, Retrieved from the Internet <URL:http://www.cqdjzyy.com/page51?article_id=422> * |
ZHENG JIAXIN,等: "Characterization, pharmacokinetics, tissue distribution and antitumor activity of honokiol submicron lipid emulsions in tumor-burdened mice", PHARMAZIE, vol. 68, no. 1, 31 December 2013 (2013-12-31), pages 41 - 46 * |
刘丽;彭枫;: "和厚朴酚的抗肿瘤作用研究进展", 华西医学, no. 03, 30 September 2006 (2006-09-30), pages 629 - 630 * |
刘静,等: "和厚朴酚抗结直肠癌的网络药理学分析及实验验证", 湖北科技学院学报(医学版), vol. 37, no. 3, 15 June 2023 (2023-06-15), pages 190 - 195 * |
喻亚萍;郝丽荣;: "长五聚蛋白3因子在炎性相关疾病中的作用", 临床与病理杂志, no. 04, 28 April 2018 (2018-04-28), pages 183 - 187 * |
张再良: "中医古典临床精华", 30 September 2004, 中国协和医科大学出版社, pages: 100 * |
张文政;黄星星;陈碧;刘颖;冯娇;刘水平;张若男;项煜;段婷;张明明;陈夏颖;陈鹏;隋新兵;谢恬;: "中西医结合防治肿瘤耐药的研究进展", 科学通报, no. 18, pages 61 - 72 * |
王颖,等: "厚朴酚与和厚朴酚的药理作用及提取合成研究进展", 陕西理工大学学报(自然科学版), vol. 34, no. 2, 20 April 2018 (2018-04-20), pages 58 - 64 * |
Also Published As
Publication number | Publication date |
---|---|
CN117503737B (zh) | 2024-04-16 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN111575237B (zh) | 一种乳腺癌无支架类器官专用培养基及培养方法 | |
CN106974938B (zh) | 一种具有抗肝癌作用的骨髓间充质干细胞来源的外泌体及其药物制剂 | |
CN106943432B (zh) | 一种脐带间充质干细胞来源的外泌体及其在制备治疗肝癌药物中的应用 | |
CN117503737B (zh) | 和厚朴酚在制备治疗脂肪肉瘤药物中的用途 | |
CN113143913A (zh) | 一种桉烷型倍半萜类化合物在制备抗胰腺癌药物中的应用 | |
CN109529041B (zh) | 脾酪氨酸激酶作为肝内胆管细胞癌治疗靶点的应用 | |
CN113440519A (zh) | 霉酚酸及其衍生物在制备靶向治疗癌症药物中的应用 | |
Jiang et al. | Inhibitory effect of 5-Fluorouracil on the proliferation of human osteosarcoma cells in vitro | |
CN100558353C (zh) | 绿原酸在制备治疗小细胞肺癌的药物中的用途 | |
CN109731004B (zh) | 西维斯多在治疗结直肠癌方面的应用 | |
CN117462521B (zh) | 和厚朴酚在制备治疗脊索瘤药物中的用途 | |
CN109999023B (zh) | 卤化ⅱ型聚酮类抗生素在抑制乳腺癌细胞增殖中的应用 | |
CN111920813A (zh) | 6-乙氧基血根碱在制备抗肿瘤药物中的应用 | |
CN117503736A (zh) | 和厚朴酚在制备治疗卵黄囊瘤药物中的用途 | |
CN110393716A (zh) | 防己诺林碱在制备抑制肺癌转移的药物中的应用 | |
CN113908148B (zh) | 川陈皮素在制备抗胆管癌药物中的应用 | |
CN113181166B (zh) | 莪术烯醇在制备抗肺癌药物中的应用 | |
CN111840412B (zh) | 茶褐素在制备抗黑色素瘤药物中的应用 | |
CN113577053A (zh) | 木犀草素在制备靶向抑制卵巢癌干细胞的药物中的应用 | |
CN114796257B (zh) | 一种药物化合物在治疗实体瘤中的新用途 | |
CN113599396B (zh) | 天然化合物联合人间充质干细胞在制备治疗骨质疏松症药物中的应用 | |
Jin et al. | Inhibitory effect of M3 receptor antagonist 4-DAMP on melanoma proliferation of A375 cell line. | |
CN112877431B (zh) | snoRNA-U41在检测以及治疗胰腺癌中的用途 | |
CN113143935B (zh) | 豆甾醇在制备改善心肌肥厚的药物中的应用 | |
CN114903901A (zh) | 治疗肝内胆管细胞癌的药物 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
GR01 | Patent grant | ||
GR01 | Patent grant |