WO2022184091A1 - 透明质酸在用于制备预防或治疗铁死亡相关疾病的药物中的应用 - Google Patents

透明质酸在用于制备预防或治疗铁死亡相关疾病的药物中的应用 Download PDF

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WO2022184091A1
WO2022184091A1 PCT/CN2022/078780 CN2022078780W WO2022184091A1 WO 2022184091 A1 WO2022184091 A1 WO 2022184091A1 CN 2022078780 W CN2022078780 W CN 2022078780W WO 2022184091 A1 WO2022184091 A1 WO 2022184091A1
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hyaluronic acid
ferroptosis
injury
sodium hyaluronate
treatment
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PCT/CN2022/078780
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English (en)
French (fr)
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刘志强
袁增强
邢晓雯
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中国人民解放军军事科学院军事医学研究院
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Publication of WO2022184091A1 publication Critical patent/WO2022184091A1/zh
Priority to US18/460,637 priority Critical patent/US20230405041A1/en

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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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/726—Glycosaminoglycans, i.e. mucopolysaccharides
    • A61K31/728—Hyaluronic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia

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  • the invention relates to the field of biomedicine, in particular to the application of hyaluronic acid in the preparation of a medicine for preventing or treating ferroptosis-related diseases.
  • Ferroptosis is a new programmed cell death method discovered in 2012 that is different from apoptosis, necrosis and autophagy in terms of morphology, biochemistry and genetics. Because this process depends on the presence of iron ions, it is called ferroptosis.
  • the mechanism is that the balance between the generation and degradation of reactive oxygen species in intracellular lipids is out of balance, and cells undergo iron ion-dependent, oxidative, non-apoptotic programmed cell death.
  • Typical features are: mitochondria become smaller, the density of the bilayer membrane increases, and the cell membrane lipid reactive oxygen radicals increase.
  • ferroptosis plays an important role in the pathological development of various diseases, including traumatic brain injury, cerebral hemorrhage, hemochromatosis, liver/kidney/heart disease, etc. Therefore, antiferroptosis interventions have great potential value in the treatment of various diseases.
  • ferroptosis inhibitors in research are deferoxamine (DFO) and Ferrostatin-1 (Fer-1).
  • DFO deferoxamine
  • Ferrostatin-1 Fe-1
  • deferoxamine is an iron ion chelator, which is mainly used for the treatment of acute iron poisoning in clinical practice
  • Fer-1 is still a compound only used for experimental research.
  • the present invention discovers the anti-ferroptosis function of hyaluronic acid material for the first time, and it can play a synergistic effect with known ferroptosis inhibitors such as DFO.
  • the primary purpose of the present invention is to propose the application of hyaluronic acid, hyaluronic acid salt or hyaluronic acid derivatives in the preparation of medicaments for preventing or treating ferroptosis-related diseases.
  • the second purpose of the present invention is to propose the application of hyaluronic acid, hyaluronic acid salt or hyaluronic acid derivatives in the preparation of a drug for inhibiting ferroptosis.
  • the third object of the present invention is to provide a ferroptosis inhibitor.
  • the fourth object of the present invention is to provide a ferroptosis inhibitor composition.
  • the fifth object of the present invention is to provide a ferroptosis inhibitor adjuvant.
  • the present invention discloses the anti-ferroptosis function of hyaluronic acid for the first time, which is the first natural extracellular matrix material with anti-ferroptosis function discovered so far.
  • Hyaluronic acid is one of the natural extracellular matrix components. It exists in large quantities in the human body and is also widely used in clinical practice. It is easy to mass-produce, has low cost and good safety.
  • the new function of hyaluronic acid disclosed in the present invention has important value for the research and development of antiferroptosis related medical products.
  • hyaluronic acid is an ingredient that has been approved by the FDA/CFDA for clinical use, and is widely used in a variety of drugs (such as arthritis treatment drugs, eye drops, etc.), food additives, cosmetics and other fields, and has good safety.
  • the application of the present invention can directly exert an anti-ferroptosis effect, and can be used as a drug for the treatment of diseases involving ferroptosis such as nerve injury; it can also be used in conjunction with existing ferroptosis inhibitors, such as DFO, for the synergistic treatment of diseases involving ferroptosis. .
  • the present invention provides an anti-ferroptosis therapeutic drug and adjuvant with clinical prospect.
  • FIG. 1 shows the expression of ferroptosis regulatory gene SLC7A11 detected by RNA sequencing of brain injury tissue in the embodiment of the present invention
  • FIG. 2 shows the expression of hyaluronan synthase 2 (HAS2) detected by RNA sequencing of brain injury tissue in the embodiment of the present invention
  • Figure 3 is the correlation analysis between the expression of SLC7A11 in brain injury and the expression of HAS2 in the embodiment of the present invention
  • Figure 4 is the effect of sodium hyaluronate on ferroptosis of HT22 cells in the embodiment of the present invention (****P ⁇ 0.0001);
  • Figure 5 shows the effect of sodium hyaluronate on H 2 O 2 -induced HT22 cell necrosis model in the example of the present invention (****P ⁇ 0.0001);
  • Fig. 6 is the effect of sodium hyaluronate on the apoptosis model of HT22 cells induced by cyclosporine in the embodiment of the present invention (****P ⁇ 0.0001);
  • Figure 7 is the effect of the molecular weight of sodium hyaluronate on its anti-ferroptosis function in the example of the present invention (* means P ⁇ 0.05 compared with other molecular weights).
  • Figure 8 shows the effect of sodium hyaluronate concentration of 0.0125%-0.1% on its anti-ferroptosis function in the embodiment of the present invention (P ⁇ 0.05);
  • Figure 9 shows the effect of the concentration of sodium hyaluronate at a concentration of 0.1%-0.5% in the embodiment of the present invention on its anti-ferroptosis function (P ⁇ 0.05);
  • Figure 10 is the synergistic effect of sodium hyaluronate and DFO in anti-ferroptosis in the embodiment of the present invention.
  • Figure 11 shows the protective effect of sodium hyaluronate dressing and sodium hyaluronate/DFO dressing treatment on the integrity of the blood-brain barrier after brain injury in the embodiment of the present invention
  • Figure 12 is the inhibitory effect of sodium hyaluronate dressing and sodium hyaluronate/DFO dressing treatment on ferroptosis-related markers after brain injury in the embodiment of the present invention
  • Figure 13 In the embodiment of the present invention, the effects of sodium hyaluronate dressing and sodium hyaluronate/DFO dressing treatment on animal behavior after brain injury;
  • hyaluronic acid can be used in combination with existing ferroptosis inhibitors such as DFO to synergistically be used for the treatment of diseases involving ferroptosis such as brain (nerve) injury.
  • the embodiment of the present invention proposes an anti-ferroptosis function and a new use of hyaluronic acid.
  • Hyaluronic acid is one of the natural extracellular matrix components with good safety.
  • the embodiments of the present invention relate to the application of hyaluronic acid, hyaluronate or hyaluronic acid derivatives in the preparation of a medicament for preventing or treating ferroptosis-related diseases. It also relates to the use of hyaluronic acid or a salt or derivative thereof in the preparation of a medicament for inhibiting ferroptosis.
  • the new function of hyaluronic acid disclosed in the present invention has important value for the research and development of antiferroptosis related medical products.
  • hyaluronic acid is natural or synthetic.
  • the hyaluronic acid salt is preferably a soluble salt of hyaluronic acid, preferably a sodium salt of hyaluronic acid.
  • the number-average molecular weight of hyaluronic acid or its salt ranges from 700kD to 1500kD.
  • the derivatives of hyaluronic acid include compounds modified with hyaluronic acid as the basic structural unit, and the substituents can be selected from alkyl groups, alkoxy groups, hydroxyl groups, carboxyl groups, acyl groups, ester groups, and the like.
  • diseases caused by ferroptosis include brain injury, stroke, cerebral hemorrhage, ischemia-reperfusion injury, nerve injury, neurodegenerative diseases, hemochromatosis, liver disease caused by abnormal levels of ferroptosis-related factors, and renal failure , heart disease, iron metabolism-related diseases; injuries include traumatic injuries, radiation injuries.
  • ferroptosis One of the typical pathological features of the above diseases is ferroptosis, and there is no anti-ferroptosis product in current clinical treatment methods. Therefore, hyaluronic acid, which has an inhibitory function on ferroptosis, can be a potential drug for the treatment of these diseases.
  • Neurodegenerative diseases include Alzheimer's disease, Parkinson's disease, Huntington's disease, and motor deficits; nerve injury includes periventricular leukomalacia; ischemia-reperfusion injury includes myocardial ischemia-reperfusion injury, hepatic ischemia-reperfusion injury Injury or renal ischemia-reperfusion injury; iron metabolism-related diseases include atherosclerosis or diabetes.
  • the dosage form of the drug includes tablets, powders, granules, capsules, injections, sprays, films, suppositories, nasal drops or pills;
  • the administration mode of the drug includes intravenous injection, intraperitoneal injection, intramuscular injection, subcutaneous injection, oral administration, sublingual administration, nasal administration or transdermal administration.
  • Embodiments of the present invention also relate to a ferroptosis inhibitor, which contains at least one of hyaluronate and hyaluronic acid derivatives. Further, the ferroptosis inhibitor also includes pharmaceutically acceptable excipients.
  • the ferroptosis inhibitor of the present invention can directly exert an anti-ferroptosis effect, and can be used as a drug for the treatment of diseases involving ferroptosis such as nerve injury.
  • the embodiment of the present invention also relates to a ferroptosis inhibitor composition
  • the ferroptosis inhibitor composition contains hyaluronic acid or its salt or its derivative and other ferroptosis inhibitors, preferably, the other ferroptosis inhibitors are selected from Deferoxamine and/or Ferrostatin-1 are not limited thereto.
  • the ferroptosis inhibitor also includes pharmaceutically acceptable excipients.
  • the ferroptosis inhibitors of the present invention can also be used synergistically with existing ferroptosis inhibitors, such as DFO, for synergistic treatment of diseases involving ferroptosis.
  • the embodiment of the present invention also relates to a ferroptosis inhibitor adjuvant, which contains hyaluronic acid or a salt or a derivative thereof. Further, the ferroptosis inhibitor also includes pharmaceutically acceptable excipients.
  • the embodiments of the present invention also provide a method for inhibiting ferroptosis, which specifically comprises administering an effective amount of hyaluronic acid to a subject in need of treatment.
  • the embodiments of the present invention also provide a method for preventing or treating ferroptosis-related diseases, which specifically includes administering an effective amount of hyaluronic acid to a subject in need of treatment.
  • it includes the treatment of brain injury, stroke, cerebral hemorrhage, ischemia-reperfusion injury, nerve injury, neurodegenerative diseases, hemochromatosis, liver disease caused by abnormal levels of ferroptosis-related factors, renal failure, heart disease, iron metabolism Methods for related diseases; injuries include traumatic injuries, radiation injuries.
  • neurodegenerative diseases include Alzheimer's disease, Parkinson's disease, Huntington's disease, motor neurological deficit; nerve injury includes periventricular leukomalacia; ischemia-reperfusion injury includes myocardial ischemia-reperfusion injury, hepatic ischemia Reperfusion injury or renal ischemia-reperfusion injury; iron metabolism-related diseases include atherosclerosis or diabetes.
  • mice Male, 20-25 g, Beijing Weitong Lihua Experimental Animal Center
  • 1% sodium pentobarbital solution 50 mg/Kg body weight
  • a 1-2cm incision was made along the skin of the midline of the head, the skull was exposed, the musculature above the skull was removed, and a window of about 2 mm in diameter was opened in the left fronto-parietal region (2 mm left of the herringbone point, 3 mm anterior) using a cranial rotation to expose the cerebral cortex.
  • the shock wound was prepared at the above exposure window by a precisely controlled cortical impactor (WILKERSON, USA), the impact parameters were set as 3.5m/s speed, 1mm impact depth, 0.5s dwell time, the scalp was sutured, and the mice were awake. The rear was kept in a single cage.
  • WILKERSON precisely controlled cortical impactor
  • the ferroptosis model (treated for 12 hours) and the H 2 O 2 -induced necroptosis model (treated for 24 hours) were added to the culture medium by Erastin (Merck Chemical) in vitro. hours), staurosporine (Beijing Soleibao Technology Co., Ltd.) to induce apoptosis model (treatment for 48 hours); at the same time, the final concentration of 0.1% sodium hyaluronate (number average molecular weight) was added to the culture medium of different cell death models. 1500kD, Bloomage Bio).
  • Example 2 Optimized molecular weight and concentration of hyaluronic acid against ferroptosis
  • HT22 cells were seeded in a 48-well plate at 2 ⁇ 10 4 /well. The next day, the medium was changed and 50 ⁇ M Erastin was added to induce ferroptosis.
  • Set different groups add 0.1% concentration of sodium hyaluronate of different molecular weights to the culture medium containing Erastin respectively, after 12h treatment, add CCK8 solution to incubate for 2h, and measure the OD value with a microplate reader.
  • the protective effect of different molecular weight sodium hyaluronate on the viability of HT22 cells The results showed that sodium hyaluronate with a molecular weight of 730kD-1500kD had a good protective effect on cell viability.
  • the optimized molecular weight of sodium hyaluronate for antiferroptosis is 700kD-1500kD.
  • HT22 cells were seeded in a 48-well plate at 2 ⁇ 10 4 /well. The next day, the medium was changed and 20 ⁇ M Erastin was added to induce ferroptosis. Set up different groups, add 0.01%, 0.025%, 0.05%, 0.1% concentration of sodium hyaluronate (1500kD) to the Erastin-containing culture medium respectively. After 12 hours of treatment, add CCK8 solution and incubate for 1.5 hours. OD value.
  • HT22 cells were 2 ⁇ 10 4 /well was inoculated in a 48-well plate, the culture medium was replaced the next day, 50 ⁇ M Erastin was added to induce ferroptosis, and 0.1%, 0.2%, 0.3%, 0.4%, 0.5% were added to the Erastin-containing culture medium, respectively.
  • Example 3 Synergistic effect of antiferroptosis of hyaluronic acid and deferoxamine (DFO, Merck Chemicals)
  • HT22 cells were seeded in a 48-well plate at 2 ⁇ 10 4 /well.
  • the next day set different groups: normal culture group, 50 ⁇ M Erastin treatment group, 50 ⁇ M Erastin+0.1% sodium hyaluronate treatment group, 50 ⁇ M Erastin+20 ⁇ M DFO treatment group, 50 ⁇ M Erastin+0.1% sodium hyaluronate+20 ⁇ M DFO treatment Group.
  • CCK8 solution was added to incubate for 2 hours, and the OD value was measured by a microplate reader.
  • both simple sodium hyaluronate and DFO have anti-ferroptosis functions, and when they are used together, they have obvious synergistic effects. DFO significantly rescued cell ferroptosis and maintained cell viability at a level similar to that of normal cultured cells, which was significantly better than the protective effect of sodium hyaluronate alone and DFO alone.
  • Example 4 Application of the anti-ferroptosis function of hyaluronic acid in brain injury
  • mice Male, 20-25 g, Beijing Weitong Lihua Experimental Animal Center
  • 1% sodium pentobarbital solution 50 mg/Kg body weight
  • a 1-2 cm incision was made along the skin of the midline of the head to expose the skull, remove the muscle tissue above the skull, and use a cranial rotation to open a window of about 2 mm in diameter in the left fronto-parietal region (2 mm to the left of the herringbone point, 3 mm anterior) to expose the cerebral cortex.
  • the impact wound was prepared at the above-mentioned exposure window by a precisely controlled cortical impactor, and the impact parameters were set as the speed of 3.5 m/s, the impact depth of 1 mm, and the dwell time of 0.5 seconds.
  • Example 5 Antiferroptotic effect of hyaluronic acid on other tissue cells

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Abstract

透明质酸在用于制备预防或治疗铁死亡相关疾病的药物中的应用。透明质酸或其盐或其衍生物在用于制备抑制铁死亡的药物中的应用。

Description

透明质酸在用于制备预防或治疗铁死亡相关疾病的药物中的应用 技术领域
本发明涉及生物医药领域，尤其涉及透明质酸在用于制备预防或治疗铁死亡相关疾病的药物中的应用。
背景技术
细胞铁死亡(Ferroptosis)是2012年发现的一种在形态学、生物化学和遗传学等方面均不同于细胞凋亡、细胞坏死和自噬的新的程序性细胞死亡方式。因该过程依赖于铁离子的存在，故称铁死亡。其发生机制为：细胞内膜脂质活性氧生成与降解的平衡失调，细胞发生依赖于铁离子的、氧化性的、非凋亡的程序性细胞死亡。典型特征为：线粒体变小，双层膜密度增加，同时表现为细胞膜脂质活性氧自由基增多。
自被首次报道后，越来越多的研究发现，铁死亡在多种疾病的病理发展中均具有重要作用，包括创伤性脑损伤，脑出血，血色素沉着症、肝/肾/心脏疾病等。因此，抗铁死亡干预在多种疾病治疗中具有重大潜在价值。目前，研究中最常用的铁死亡抑制剂是去铁胺(DFO)和Ferrostatin-1(Fer-1)。其中，去铁胺是一种铁离子螯合剂，在临床上主要用于急性铁中毒的治疗；Fer-1仍是仅用于实验研究的化合物。目前，尚未有抗铁死亡功能的天然生物材料被发现。本发明首次发现了透明质酸材料的抗铁死亡功能，且其能够和DFO等已知的铁死亡抑制剂发挥协同作用。
鉴于此，特提出本发明。
发明内容
本发明的首要发明目的在于提出透明质酸、透明质酸盐或透明质酸衍生物在用于制备预防或治疗铁死亡相关疾病的药物中的应用。
本发明的第二发明目的在于提出透明质酸、透明质酸盐或透明质酸衍生物在用于制备抑制铁死亡的药物中的应用。
本发明的第三发明目的在于提出一种铁死亡抑制剂。
本发明的第四发明目的在于提出一种铁死亡抑制剂组合物。
本发明的第五发明目的在于提出一种铁死亡抑制剂佐剂。
本发明的技术方案至少具有以下技术效果：
本发明首次公开了透明质酸的抗铁死亡功能，这是目前被发现的第一个具有抗铁死亡功能的天然细胞外基质材料。透明质酸是天然细胞外基质成分之一，在人体中大量存在，也是临床广泛应用的材料，易于量产，成本低，安全性好。本发明公开的透明质酸这一新功能，对于抗铁死亡相关医疗产品的研发具有重要价值。
此外，透明质酸是已被FDA/CFDA批准进入临床的成分，在多种药品(如关节炎治疗药物、眼药等)、食品添加剂、化妆品等领域广泛使用，具有良好的安全性。
本发明的应用可直接发挥抗铁死亡作用，作为药物用于神经损伤等涉及铁死亡的疾病治疗；也可与现有铁死亡抑制剂协同使用，如DFO，用于涉及铁死亡疾病的协同治疗。本发明提供了一种具有临床前景的抗铁死亡治疗药物及佐剂。
附图说明
图1为本发明实施例中脑损伤组织RNA测序检测铁死亡调控基因SLC7A11的表达情况；
图2为本发明实施例中脑损伤组织RNA测序检测透明质酸合成酶2(HAS2)表达情况；
图3为本发明实施例中脑损伤SLC7A11表达与HAS2表达相关性分析；
图4为本发明实施例中透明质酸钠对HT22细胞铁死亡的影响(****P＜0.0001)；
图5为本发明实施例中透明质酸钠对H 2O 2诱导HT22细胞坏死模型的影响(****P＜0.0001)；
图6为本发明实施例中透明质酸钠对环孢菌素诱导HT22细胞凋亡模型的影响(****P＜0.0001)；
图7为本发明实施例中透明质酸钠分子量对其抗铁死亡功能的影响(*表示与其他分子量相比P＜0.05)。
图8为本发明实施例中0.0125％-0.1％浓度的透明质酸钠浓度对其抗铁死亡功能的影响(P＜0.05)；
图9为本发明实施例中0.1％-0.5％浓度的透明质酸钠浓度对其抗铁死亡功能的影响(P＜0.05)；
图10为本发明实施例中透明质酸钠与DFO在抗铁死亡中的协同作用；
图11为本发明实施例中透明质酸钠敷料及透明质酸钠/DFO敷料治疗对脑损伤后血脑屏障完整性的保护作用；
图12为本发明实施例中透明质酸钠敷料及透明质酸钠/DFO敷料治疗对脑损伤后铁死亡相关标志物的抑制作用；
图13本发明实施例中透明质酸钠敷料及透明质酸钠/DFO敷料治疗对脑损伤后动物行为能力的影响；
图14本发明实施例中透明质酸钠对肾细胞293T的抗铁死亡效应(*P＜0.05；**P＜0.01；***P＜0.001)；
图15本发明实施例中透明质酸钠对肺上皮细胞BEAS-2B的抗铁死亡效应(*P＜0.05；**P＜0.01)。
具体实施方式
为了更清楚地说明本发明实施例或现有技术中的技术方案，在下述说明 中，不同的“一实施例”或“实施例”指的不一定是同一实施例。不同实施例之间可以替换或者合并组合，对于本领域普通技术人员来讲，在不付出创造性劳动的前提下，还可以根据这些实施例获得其他的实施方式。
发明人经过长期而深入的研究，在对创伤脑组织的深度RNA测序中发现透明质酸与铁死亡的潜在关系，进一步通过体内外实验证明了透明质酸的抗铁死亡功能。同时还发现，透明质酸可以与现有的铁死亡抑制剂如DFO联合使用，协同用于脑(神经)损伤等涉及铁死亡的疾病治疗。
本发明实施例提出一种透明质酸的抗铁死亡功能及新用途。透明质酸是天然的细胞外基质成分之一，具有良好的安全性。本发明实施例涉及透明质酸、透明质酸盐或透明质酸衍生物在用于制备预防或治疗铁死亡相关疾病的药物中的应用。还涉及透明质酸或其盐或其衍生物在用于制备抑制铁死亡的药物中的应用。本发明公开的透明质酸这一新功能，对于抗铁死亡相关医疗产品的研发具有重要价值。
其中，透明质酸为天然的或人工合成的。
透明质酸盐优选透明质酸的可溶性盐，优选透明质酸的钠盐。
优选地，透明质酸或其盐的数均分子量范围为700kD～1500kD。
具体的，透明质酸的衍生物包括以透明质酸为基本结构单元进行取代基修饰的化合物，取代基可选自烷基、烷氧基、羟基、羧基、酰基、酯基等。
具体的，铁死亡引起的疾病包括脑损伤、脑卒中、脑出血、缺血再灌注损伤、神经损伤、神经退行性疾病、血色素沉着症、由铁死亡相关因子水平异常引起的肝脏疾病、肾衰竭、心脏病、铁代谢相关疾病；损伤包括创伤性损伤、辐射性损伤。上述疾病的典型病理特征之一是细胞铁死亡，而目前的临床治疗手段上尚没有抗铁死亡的产品，因此，对铁死亡具有抑制功能的透明质酸可以是治疗这些疾病的潜在药物。
神经退行性疾病包括阿兹海默症、帕金森症、亨廷顿病、运动神经衰退症；神经损伤包括脑室周围白质软化症；缺血再灌注损伤包括心肌缺血再灌 注损伤、肝缺血再灌注损伤或肾缺血再灌注损伤；铁代谢相关疾病包括动脉粥样硬化或糖尿病。
具体的，药物的剂型包括片剂、散剂、颗粒剂、胶囊剂、注射剂、喷雾剂、膜剂、栓剂、滴鼻剂或滴丸剂；
具体的，药物的给药方式包括静脉注射、腹腔注射、肌肉注射、皮下注射、口服给药、舌下给药、鼻腔给药或经皮给药。
本发明实施例还涉及一种铁死亡抑制剂，该铁死亡抑制剂含有透明质酸盐和透明质酸衍生物中的至少一种。进一步的，该铁死亡抑制剂还包含药学上可接受的辅料。本发明的铁死亡抑制剂可直接发挥抗铁死亡作用，作为药物用于神经损伤等涉及铁死亡的疾病治疗。
本发明实施例还涉及一种铁死亡抑制剂组合物，该铁死亡抑制剂组合物含有透明质酸或其盐或其衍生物和其他铁死亡抑制剂，优选的，其他铁死亡抑制剂选自去铁胺和/或Ferrostatin-1，并不限于此。进一步的，该铁死亡抑制剂还包含药学上可接受的辅料。本发明的铁死亡抑制剂也可与现有铁死亡抑制剂协同使用，如DFO，用于涉及铁死亡疾病的协同治疗。
本发明实施例还涉及一种铁死亡抑制剂佐剂，该铁死亡抑制剂佐剂中含有透明质酸或其盐或其衍生物。进一步的，该铁死亡抑制剂还包含药学上可接受的辅料。
本发明实施例还提出一种抑制铁死亡的方法，具体包括给予向需要处理的对象施用有效量的透明质酸。本发明实施例还提出一种预防或治疗铁死亡相关疾病的方法，具体包括给予向需要处理的对象施用有效量的透明质酸。具体包括治疗脑损伤、脑卒中、脑出血、缺血再灌注损伤、神经损伤、神经退行性疾病、血色素沉着症、由铁死亡相关因子水平异常引起的肝脏疾病、肾衰竭、心脏病、铁代谢相关疾病的方法；损伤包括创伤性损伤、辐射性损伤。其中，神经退行性疾病包括阿兹海默症、帕金森症、亨廷顿病、运动神经衰退症；神经损伤包括脑室周围白质软化症；缺血再灌注损伤包括心肌缺 血再灌注损伤、肝缺血再灌注损伤或肾缺血再灌注损伤；铁代谢相关疾病包括动脉粥样硬化或糖尿病。
在进一步描述本发明具体实施例之前，应理解，通过以下实施例对本发明作进一步详细描述，以便本领域的技术人员进一步理解本发明，但不对本发明构成任何限制。
实施例1：透明质酸抗铁死亡功能的发现与证明
(1)C57小鼠(雄性，20-25克，北京维通利华实验动物中心)，腹腔注射1％戊巴比妥钠溶液(50mg/Kg体重)，使用弯剪小心去除头盖骨上方毛发，沿头部中线皮肤剪开1-2cm切口，暴露头盖骨，清除头盖骨上方肌肉组织，使用颅转在左额顶骨区(人字点左2mm，前3mm处)开大约直径2mm窗口，暴露脑皮层。随后，通过精准控制的皮质冲击器(美国WILKERSON)在上述暴露窗口处进行冲击伤制备，设定冲击参数为3.5m/秒速度，冲击深度1mm，停留时间0.5秒，缝合头皮，待小鼠苏醒后单笼存放饲养。
(2)上述脑损伤模型，分别在损伤后12h、24h取材损伤区脑组织，并取材正常小鼠的对应脑区组织作为对照；
(3)脑组织取材后使用TRIZOL(Life technologies)裂解，-80℃冻存，干冰运输至美吉生物科技有限公司进行RNA测序；
(4)对测序数据进行分析，分析铁死亡、坏死、凋亡等不同细胞死亡方式标志物的表达情况，以及不同细胞外基质成分的表达情况，包括胶原、纤连蛋白、层连蛋白、透明质酸合成酶2(HAS2)的表达。
分析结果显示，HAS2与铁死亡标志物SLC7A11在脑损伤后表达模式高度相似，如图1和图2所示。
对HAS2和SLC7A11的表达通过线性回归分析(linear regression analysis)进行相关性分析，如图3所示。
结果显示，HAS2与SLC7A11具有显著相关性(P＝0.0057)，说明透明 质酸与铁死亡的发生具有密切关系。
(5)以神经细胞系HT22(来源于ATCC)为对象，体外分别在培养液中加入Erastin(默克化工)诱导铁死亡模型(处理12小时)、H 2O 2诱导坏死亡模型(处理24小时)、星孢菌素(北京索莱宝科技有限公司)诱导凋亡模型(处理48小时)；同时，在不同细胞死亡模型培养液中加入终浓度0.1％的透明质酸钠(数均分子量1500kD，华熙生物)。采用CCK8试剂盒(美国Bimake生物科技有限公司)检测细胞活力，分析透明质酸钠在铁死亡、坏死、凋亡条件下对HT22细胞的保护效应。
结果如图4～图6所示，透明质酸钠的加入显著抑制了不同浓度Erastin诱导的HT22铁死亡的发生。而对HT22细胞的坏死(图5所示)、凋亡(图6所示)没有影响。结果表明，透明质酸具有抗铁死亡功能。
实施例2：透明质酸抗铁死亡的优化分子量与浓度
(1)数均分子量40kD、170kD、470kD、730kD、1500kD、2300kD透明质酸钠来源于华熙生物科技股份有限公司，1000kD透明质酸钠来源于北京索莱宝科技有限公司；
(2)HT22细胞，以2×10 4/孔接种于48孔板。次日，更换培养液，添加50μM的Erastin诱导铁死亡。设定不同分组，在含Erastin的培养液中分别添加0.1％浓度的上述不同分子量的透明质酸钠，处理12h后，加入CCK8溶液孵育2h，酶标仪测定OD值。如图7所示，不同分子量透明质酸钠对HT22细胞活力的保护作用。结果显示，分子量730kD-1500kD的透明质酸钠对细胞活力具有较好的保护效应。据此，透明质酸钠抗铁死亡的优化分子量为700kD-1500kD。
(3)HT22细胞，以2×10 4/孔接种于48孔板。次日，更换培养液，添加20μM的Erastin诱导铁死亡。设定不同分组，在含Erastin的培养液中分别添加0.01％、0.025％、0.05％、0.1％浓度的透明质酸钠(1500kD)，处理 12h后，加入CCK8溶液孵育1.5h，酶标仪测定OD值。如图8所示，随着透明质酸钠浓度的升高，细胞活力增加，0.1％透明质酸钠具有最佳的抗体死亡效能；为了进一步确定透明质酸抗铁死亡浓度效应，将HT22细胞以2×10 4/孔接种于48孔板，次日更换培养液，添加50μM的Erastin诱导铁死亡，在含Erastin的培养液中分别添加0.1％、0.2％、0.3％、0.4％、0.5％浓度的透明质酸钠(1500kD)，孵育12h后，加入CCK8溶液孵育2h，酶标仪测定OD值。如图9所示，0.1％浓度的透明质酸钠处理组与更高浓度处理组相比，细胞活力没有明显差异，表明0.1％浓度已可以达到透明质酸钠最佳的抗铁死亡功能，浓度的进一步提高并不能进一步增加其抗铁死亡功能的。结果说明，透明质酸钠抗铁死亡的优化浓度为＞0.1％。
实施例3：透明质酸的抗铁死亡功能与去铁胺(DFO，默克化工)的协同作用
HT22细胞，以2×10 4/孔接种于48孔板。次日，设定不同分组：正常培养组、50μM Erastin处理组、50μM Erastin+0.1％透明质酸钠处理组、50μM Erastin+20μM DFO处理组、50μM Erastin+0.1％透明质酸钠+20μM DFO处理组。处理12h后，加入CCK8溶液孵育2h，酶标仪测定OD值。如图10所示，单纯透明质酸钠与DFO均具有抗铁死亡功能，在两者共同使用时具有明显的协同作用，在50μM Erastin诱导铁死亡细胞模型下，0.1％透明质酸钠+20μM DFO显著挽救了细胞铁死亡，使细胞活力保持在与正常培养细胞相似的水平，显著优于单纯的透明质酸钠与单纯DFO的保护效应。
实施例4：透明质酸的抗铁死亡功能在脑损伤中的应用
(1)C57小鼠(雄性，20～25克，北京维通利华实验动物中心)，腹腔注射1％戊巴比妥钠溶液(50mg/Kg体重)，使用弯剪小心去除头盖骨上方毛发，沿头部中线皮肤剪开1～2cm切口，暴露头盖骨，清除头盖骨上方肌肉组织， 使用颅转在左额顶骨区(人字点左2mm，前3mm处)开大约直径2mm窗口，暴露脑皮层。随后，通过精准控制的皮质冲击器在上述暴露窗口处进行冲击伤制备，设定冲击参数为3.5m/秒速度，冲击深度1mm，停留时间0.5秒。
(2)动物模型随机分为三种：不治疗组、透明质酸钠敷料治疗组、透明质酸钠/DFO联合治疗组。其中，不治疗组创伤后不做任何治疗，直接缝合头皮；透明质酸钠敷料治疗组，使用3％浓度的透明质酸钠凝胶(生理盐水配制，数均分子量1500kD)50μL涂于创面，随后缝合头皮；透明质酸钠/DFO联合治疗组，3％透明质酸凝胶中同时溶解1mM的DFO药物，50μL涂于创面，随后缝合头皮。
(3)治疗后12h，尾静脉注射2％伊文思蓝染液100μL，2h后取材大脑，观察不同治疗组血脑屏障破坏情况，如图11所示，未治疗组动物血脑屏障显著破坏，创伤区及周围观察到大量的伊文思蓝染色区域，且着色较深；透明质酸钠敷料治疗组，伊文思蓝着色区域明显减小，着色程度明显降低，表明透明质酸钠治疗对脑创伤血脑屏障具有明显的保护作用；透明质酸钠/DFO治疗组，结果与单纯透明质酸钠治疗组相似，表明了对血脑屏障的保护作用。
(4)治疗后24h，取材不同治疗组损伤区脑组织，并以未创伤的假手术组作为对照。常规方法提取组织蛋白，并通过Westrn Blotting检测铁死亡相关标志物的表达水平。如图12所示，与对照组相比，脑损伤后铁死亡相关SCL7A11、PTGS2、GPX4(抗体均来自Abcam)等在未治疗组显著升高。然而，透明质酸钠敷料及透明质酸钠/DFO复合敷料治疗组显著抑制，表明上述敷料显著抑制了脑损伤后的神经细胞铁死亡。
(5)治疗后3周，通过平衡木测试实验对动物行为能力进行评价。如图13所示，平衡木测试显示单纯透明质酸钠敷料治疗(P＜0.05)，以及透明质酸钠/DFO复合敷料治疗(P＜0.01)均显著改善了动物运动能力，表明脑功能得到明显保护。单纯的透明质酸钠敷料与透明质酸钠/DFO复合敷料相比，尽管 统计分析平衡木测试未显示显著性差异(P＝0.086)，但从结果以及P值(接近0.05)可以看出，透明质酸钠/DFO复合敷料使动物行为能力得到更好的改善，表明透明质酸钠与DFO发挥了协同作用。
实施例5：透明质酸对其他组织细胞的抗铁死亡效应
(1)分别以人胎肾细胞(293T)(来源于ATCC)、人肺上皮细胞(BEAS-2B)(来源于ATCC)为研究对象。上述细胞以2×1 04/孔的数量接种到48孔培养板中，DMEM+10％胎牛血清培养液正常培养；
(2)12小时后，细胞完全贴壁，一部分细胞样品采用不同浓度的铁死亡诱导剂RSL3(默克化工)诱导铁死亡；另一部分细胞样品给与同样浓度RSL3诱导铁死亡的同时，添加0.1％浓度透明质酸钠(分子量1500kD)进行保护。37℃，5％二氧化碳培养箱中处理12小时后，按试剂盒说明加入CCK8溶液孵育2h，测定OD值，比较细胞活力。如图14所示，对于肾细胞293T，在相同浓度RSL3条件下，透明质酸钠的加入显著减缓了细胞活力的下降，表明透明质酸钠减少了293T的铁死亡；如图15所示，对于肺上皮细胞BEAS-2B，在相同浓度RSL3条件下，透明质酸钠的加入显著减缓了细胞活力的下降，表明透明质酸钠减少了BEAS-2B的铁死亡。上述结果说明，透明质酸对于不同类型的组织细胞均具有抗铁死亡效应。
本申请虽然以较佳实施例公开如上，但并不是用来限定权利要求，任何本领域技术人员在不脱离本申请构思的前提下，都可以做出若干可能的变动和修改，因此本申请的保护范围应当以本申请权利要求所界定的范围为准。

Claims (15)

  1. 透明质酸、透明质酸盐或透明质酸衍生物在用于制备预防或治疗铁死亡相关疾病的药物中的应用；
    优选的，所述透明质酸为天然的或人工合成的。
  2. 透明质酸、透明质酸盐或透明质酸衍生物在用于制备抑制铁死亡的药物中的应用；
    优选的，所述透明质酸为天然的或人工合成的。
  3. 根据权利要求1所述的应用，其特征在于，所述铁死亡相关疾病包括创伤性脑损伤、脑卒中、脑出血、缺血再灌注损伤、神经损伤、神经退行性疾病、血色素沉着症、由铁死亡相关因子水平异常引起的肝脏疾病、肾衰竭、心脏病、铁代谢相关疾病；
    优选的，所述损伤包括创伤性损伤、辐射性损伤。
  4. 根据权利要求3所述的应用，其特征在于，
    所述神经退行性疾病包括阿兹海默症、帕金森症、亨廷顿病、运动神经衰退症；
    所述神经损伤包括脑室周围白质软化症；
    所述缺血再灌注损伤包括心肌缺血再灌注损伤、肝缺血再灌注损伤或肾缺血再灌注损伤；
    所述铁代谢相关疾病包括动脉粥样硬化或糖尿病。
  5. 根据权利要求1～4任一项所述的应用，其特征在于，所述透明质酸盐优选透明质酸的可溶性盐，优选透明质酸钠盐、透明质酸钾盐、透明质酸锌盐。
  6. 根据权利要求1～5任一项所述的应用，其特征在于，所述透明质酸或透明质酸盐的数均分子量范围为700kD～1500kD。
  7. 根据权利要求1～6所述的应用，其特征在于，所述透明质酸衍生物包括以透明质酸为基本结构单元进行取代基修饰的化合物。
  8. 根据权利要求1～7所述的应用，其特征在于，所述药物的剂型包括片剂、散剂、颗粒剂、胶囊剂、注射剂、喷雾剂、膜剂、栓剂、滴鼻剂或滴丸剂；
    和/或，所述药物的给药途径包括静脉注射、腹腔注射、肌肉注射、皮下注射、口服给药、舌下给药、鼻腔给药或经皮给药。
  9. 一种铁死亡抑制剂，其特征在于，含有透明质酸、透明质酸盐和透明质酸衍生物中的至少一种，优选的，还包含药学上可接受的辅料。
  10. 一种铁死亡抑制剂组合物，其特征在于，所述组合物含有透明质酸、透明质酸盐和透明质酸衍生物中的至少一种和其他铁死亡抑制剂，
    优选的，其他铁死亡抑制剂选自去铁胺和/或Ferrostatin-1；
    更优选的，还包含药学上可接受的辅料。
  11. 根据权利要求10所述的铁死亡抑制剂组合物，其特征在于，所述透明质酸或透明质酸盐的数均分子量范围为700kD～1500kD。
  12. 一种铁死亡抑制剂佐剂，其特征在于，所述铁死亡抑制剂佐剂中含有透明质酸、透明质酸盐和透明质酸衍生物中的至少一种，
    优选的，还包含药学上可接受的辅料。
  13. 根据权利要求12所述的铁死亡抑制剂佐剂，其特征在于，所述透明质酸或透明质酸盐的数均分子量范围为700kD～1500kD。
  14. 一种抑制铁死亡的方法，具体包括给予向需要处理的对象施用有效量的透明质酸、透明质酸盐或透明质酸衍生物。
  15. 根据权利要求14所述的方法，其特征在于，所述透明质酸或透明质酸盐的数均分子量范围为700kD～1500kD。
PCT/CN2022/078780 2021-03-04 2022-03-02 透明质酸在用于制备预防或治疗铁死亡相关疾病的药物中的应用 WO2022184091A1 (zh)

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