Aldoxorubicin
(Synonyms: INNO-206;Doxorubicin-EMCH;INNO 206) 目录号 : GC14858
Aldoxorubicin是阿霉素（DNA拓扑异构酶II抑制剂）的一种白蛋白结合前体，在酸性条件下从白蛋白中释放出来。
Cas No.:1361644-26-9
Sample solution is provided at 25 µL, 10mM.
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Aldoxorubicin, an albumin-binding prodrug of doxorubicin (DNA topoisomerase II inhibitor), is released from albumin under acidic conditions[1]. Topoisomerase II is an ATP-dependent enzyme that relieves supercoiling tension by introducing double-strand DNA breaks, playing a crucial role in DNA replication, transcription, and chromosome segregation[2]. Aldoxorubicin is widely used in the research of malignant tumors such as soft tissue sarcoma by inhibiting topoisomerase II[3].
In vitro, treatment of L2987 human lung cancer cells with Aldoxorubicin (100nM; 48h) significantly inhibited cell proliferation[4]. Treatment of multiple myeloma cell lines with Aldoxorubicin (0.27-2.16μM; 48h; PH=5 or 7) inhibited blood vessel formation and reduced multiple myeloma cell growth in a pHdependent fashion[5].
In vivo, Aldoxorubicin (2×24 mg/kg), administered weekly by intravenous injection for 45 days, induced complete tumor regression in a breast cancer 3366 xenograft mouse model, significantly inhibited tumor growth in ovarian cancer A2780 and small cell lung cancer H209 xenograft mouse models, and reduced primary tumor size and inhibited metastasis in a pancreatic cancer AsPC-1 orthotopic mouse model[6]. Combination of Aldoxorubicin（16mg/kg; i.v.; administered weekly for 5 weeks）with temozolomide（0.9mg/kg/day; orally）significantly inhibited tumor growth（with a tumor volume inhibition rate of approximately 90%）and prolonged survival（survival rate increased by 37.5% compared with the saline control group）in a U87 human glioblastoma xenograft mouse model, with no obvious drug-related adverse effects observed[7].
References:
[1] Rhee HK, Park HJ, Lee SK, Lee CO, Choo HY. Synthesis, cytotoxicity, and DNA topoisomerase II inhibitory activity of benzofuroquinolinediones. Bioorg Med Chem. 2007;15(4):1651-1658.
[2] Swan RL, Cowell IG, Austin CA. Mechanisms to Repair Stalled Topoisomerase II-DNA Covalent Complexes. Mol Pharmacol. 2022;101(1):24-32.
[3] Sachdev E, Sachdev D, Mita M. Aldoxorubicin for the treatment of soft tissue sarcoma. Expert Opin Investig Drugs. 2017;26(10):1175-1179.
[4] Cranmer LD. Spotlight on aldoxorubicin (INNO-206) and its potential in the treatment of soft tissue sarcomas: evidence to date. Onco Targets Ther. 2019;12:2047-2062.
[5] Sanchez E, Li M, Wang C, et al. Anti-myeloma effects of the novel anthracycline derivative INNO-206. Clin Cancer Res. 2012;18(14):3856-3867.
[6] Graeser R, Esser N, Unger H, et al. INNO-206, the (6-maleimidocaproyl hydrazone derivative of doxorubicin), shows superior antitumor efficacy compared to doxorubicin in different tumor xenograft models and in an orthotopic pancreas carcinoma model. Invest New Drugs. 2010;28(1):14-19.
[7] Da Ros M, Iorio AL, De Gregorio V, et al. Aldoxorubicin and Temozolomide combination in a xenograft mice model of human glioblastoma. Oncotarget. 2018;9(79):34935-34944.
Aldoxorubicin是阿霉素（DNA拓扑异构酶II抑制剂）的一种白蛋白结合前体，在酸性条件下从白蛋白中释放出来[1]。拓扑异构酶II是一种ATP依赖的酶，通过引入双链DNA断裂来解除超螺旋张力，在DNA复制、转录和染色体分离中发挥着关键作用[2]。Aldoxorubicin通过抑制拓扑异构酶II被广泛用于软组织肉瘤等恶性肿瘤的研究[3]。
体外实验中，用Aldoxorubicin（100nM；48h）处理L2987人肺癌细胞可显著抑制细胞增殖[4]。在pH值为5或7的条件下，用Aldoxorubicin（0.27-2.16μM；48h）处理多发性骨髓瘤细胞系可抑制血管形成，并以pH依赖的方式减少多发性骨髓瘤细胞的生长[5]。
体内实验中，Aldoxorubicin（2×24mg/kg；每周静脉注射一次；持续 45 天）在乳腺癌3366细胞系裸鼠移植瘤模型中诱导了肿瘤完全缓解，在卵巢癌A2780和小细胞肺癌H209细胞系裸鼠移植瘤模型中显著抑制了肿瘤生长，并在胰腺癌AsPC-1细胞系裸鼠原位移植瘤模型中缩小了原发肿瘤体积并抑制了转移[6]。Aldoxorubicin（16mg/kg；静脉注射；每周给药一次；持续5周）与替莫唑胺（0.9mg/kg/天；口服）联合使用，在U87人胶质母细胞瘤裸鼠移植瘤模型中显著抑制了肿瘤生长（肿瘤体积抑制率约为90%），并延长了生存时间（与生理盐水对照组相比生存率提高了37.5%），且未观察到明显的药物相关不良反应[7]。
| Cell experiment [1]: | |
Cell lines | human multiple myeloma cell lines RPMI8226 and U266 |
Preparation Method | The human multiple myeloma cell lines RPMI8226 and U266 were maintained in RPMI-1640 supplemented with 10% FBS, 2mmol/L L-glutamine, 100I/U/mL penicillin, 100mg/mL streptomycin, and essential amino acids in an atmosphere of 5% CO2 at 37°C. Cells were seeded at 1×105 cells/100mL/well in 96-well plates in RPMI-1640 media with FBS for 24 hours before treatment. Cells were cultured in the presence of Aldoxorubicin (0.27-2.16μM) for 48 hours. Next, cell viability was quantified using the CellTiter 96 AQueous Non-Radioactive Cell Proliferation Assay. Each well was treated with MTS for 1 to 4 hours, after which absorbance at 490nm was recorded using a 96-well plate reader. The quantity of formazan product as measured is directly proportional to the number of living cells. |
Reaction Conditions | 0.27-2.16μM; 48h |
Applications | Aldoxorubicin markedly reduced multiple myeloma cell growth. |
| Animal experiment [2]: | |
Animal models | Foxn1 nude male mice |
Preparation Method | Glioblastoma Multiforme tumors were induced in 80 Foxn1 nude male mice, 6 weeks-old, by implantation of 3×105 U87MG-luc cells in the right lobe of the brain. One week after tumor implantation, 64 animals were randomly assigned to four groups (16 mice/group) to be treated with different drugs, as follow: Group 1 (vehicle): weekly intravenous (IV) administration of physiologic solution, i.e., 7, 14, 21, 28, 35 days. Group 2: daily oral (OS) administration of temozolomide(TMZ) 0.9mg/kg, from day 7 to day 35. Group 3: weekly administration of Aldoxorubicin 16mg/kg, IV, i.e., 7, 14, 21, 28, 35 days. Group 4: TMZ-Aldoxorubicin combination for up five weeks. At the end of treatments (day 42, one week after the last injection), 32 animals were sacrified by CO2 inhalation; the remaining mice (8 animals/group) were observed for mortality until the 90th day of the study. BW measurements were carried out 2 times a week and BLI imaging acquisition were performed at day 0 (immediately after tumor implantation), at day 3 and then weekly until the end of the experiment (day 90). A BW loss ≥ 15% has been considered as sign of suffering, involving the mouse sacrifice. |
Dosage form | 16mg/kg; i.v.; administered weekly for 5 weeks |
Applications | Combination of Aldoxorubicin with temozolomide significantly inhibited tumor growth（with a tumor volume inhibition rate of approximately 90%）and prolonged survival（survival rate increased by 37.5% compared with the saline control group）in a U87 human glioblastoma xenograft mouse model. |
References: | |
| Cas No. | 1361644-26-9 | SDF | |
| 别名 | INNO-206;Doxorubicin-EMCH;INNO 206 | ||
| 化学名 | N-[(Z)-[1-[(2S,4S)-4-[(2R,4S,5S,6S)-4-amino-5-hydroxy-6-methyloxan-2-yl]oxy-2,5,12-trihydroxy-7-methoxy-6,11-dioxo-3,4-dihydro-1H-tetracen-2-yl]-2-hydroxyethylidene]amino]-6-(2,5-dioxopyrrol-1-yl)hexanamide | ||
| Canonical SMILES | [H][C@@]1(O[C@H]2C[C@@](/C(CO)=N/NC(CCCCCN3C(C=CC3=O)=O)=O)(O)CC(C2=C4O)=C(O)C5=C4C(C6=C(OC)C=CC=C6C5=O)=O)O[C@@H](C)[C@@H](O)[C@@H](N)C1 | ||
| 分子式 | C37H42N4O13 | 分子量 | 750.75 |
| 溶解度 | DMSO : 75 mg/mL (99.90 mM) | 储存条件 | -80°C, stored under nitrogen,unstable in solution, ready to use. |
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| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 1.332 mL | 6.66 mL | 13.32 mL |
| 5 mM | 266.4 μL | 1.332 mL | 2.664 mL |
| 10 mM | 133.2 μL | 666 μL | 1.332 mL |
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动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
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| % DMSO % % Tween 80 % saline | ||||||||||
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工作液浓度： mg/ml；
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2.
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