Background
Monomethyl Auristatin E (MMAE), as a synthetic derivative of dolastatin 10, a linear pentapeptide originally isolated from the extracts of the sea hare Dolabella auriculari. Monomethyl Auristatin E, as a synthetic derivative of dolastatin 10, a linear pentapeptide originally isolated from the extracts of the sea hare Dolabella auriculari. Monomethyl Auristatin E can inhibit tubulin polymerization, thus blocking mitosis.[1]
In vitro, Monomethyl Auristatin E and Monomethyl Auristatin E-phosphate shown the inhibition with IC50 of 2 and 48 nM, respectively, in PC-3 and C4-2B cell lines.[1] In vitro experiment it shown that 5 nM MMAE resulted in 50% of HCT-116 cells blocked in G2/M and 2 nM in PANC-1 cells.[2] MMAE shown the inhibition of cell growth with IC50 of 1.7 nM in HCT-116, 0.6 nM in PANC-1, and 5.6 nM in 779E cells, respectively.[2] In addition, MMAE also showed markedly polarized transport in both MDCK-WT and MDCK-MDR1 cells with ERs at 13.6 and 44.5, respectively, resulting ratio of ratios of 3.3. MMAE shown dose-dependent cytotoxicity in HepG2, Hep3B2, H226, N87 or OVCAR3 cells.[3]
In vivo, treatment with 30 mg/kg cAC10-vcMMAE in mice had no signs of toxicity.[4] In vivo efficacy test it shown that treatment with 6.5 mg/kg DD1-MMAE (the bivalent DARPin dimer) or DFc-MMAE (a DARPin-Fc) twice weekly did not cause any sequela in mice.[5] Moreover, nude mice were injected intravenously 2.5, 5, and 10 mg/kg hertuzumab-vcMMAE on day 0 resulted in obvious and sustained antitumor effects. [6]
Abawi A, et al. Monomethyl Auristatin E Grafted-Liposomes to Target Prostate Tumor Cell Lines. Int J Mol Sci. 2021 Apr 15;22(8):4103.
Buckel L, et al. Tumor radiosensitization by monomethyl auristatin E: mechanism of action and targeted delivery. Cancer Res. 2015 Apr 1;75(7):1376-1387.
Liu-Kreyche P, et al. Lysosomal P-gp-MDR1 Confers Drug Resistance of Brentuximab Vedotin and Its Cytotoxic Payload Monomethyl Auristatin E in Tumor Cells. Front Pharmacol. 2019 Jul 17;10:749.
Francisco JA, et al. cAC10-vcMMAE, an anti-CD30-monomethyl auristatin E conjugate with potent and selective antitumor activity. Blood. 2003 Aug 15;102(4):1458-65.
Karsten L, et al. Bivalent EGFR-Targeting DARPin-MMAE Conjugates. Int J Mol Sci. 2022 Feb 23;23(5):2468.
Li H, et al. An anti-HER2 antibody conjugated with monomethyl auristatin E is highly effective in HER2-positive human gastric cancer. Cancer Biol Ther. 2016 Apr 2;17(4):346-54.
参考文献:
Monomethyl Auristatin E (MMAE)，作为海兔毒素 10 的合成衍生物，海兔毒素 10 是一种线性五肽，最初是从海兔 Dolabella auriculari 的提取物中分离出来的。 Monomethyl Auristatin E，作为海兔毒素 10 的合成衍生物，海兔毒素 10 是一种线性五肽，最初是从海兔 Dolabella auriculari 的提取物中分离出来的。单甲基 Auristatin E 可以抑制微管蛋白聚合，从而阻断有丝分裂。[1]
在体外，Monomethyl Auristatin E 和 Monomethyl Auristatin E-phosphate 在 PC-3 和 C4-2B 细胞系中的 IC50 分别为 2 和 48 nM。[1]体外实验表明，5 nM MMAE 导致 50% 的 HCT-116 细胞在 G2/M 期受阻，2 nM 在 PANC-1 细胞中受阻。[2] MMAE 显示出抑制细胞生长的 IC50在 HCT-116 中为 1.7 nM，在 PANC-1 中为 0.6 nM，在 779E 细胞中为 5.6 nM。[2] 此外，MMAE 在 MDCK-WT 和 MDCK 中也表现出明显的极化转运-ER 分别为 13.6 和 44.5 的 MDR1 细胞，所得比率为 3.3。 MMAE 在 HepG2、Hep3B2、H226、N87 或 OVCAR3 细胞中表现出剂量依赖性细胞毒性。[3]
在体内，用 30 mg/kg cAC10-vcMMAE 处理小鼠没有毒性迹象。[4] 体内药效试验表明，用 6.5 mg/kg DD1-MMAE 处理（二价 DARPin 二聚体）或 DFc-MMAE（一种 DARPin-Fc）每周两次在小鼠体内未引起任何后遗症。[5] 此外，裸鼠静脉注射 2.5、5 和 10 mg/ kg hertuzumab-vcMMAE 在第 0 天产生明显和持续的抗肿瘤作用。 [6]
Abawi A 等人。 Monomethyl Auristatin E 移植脂质体靶向前列腺肿瘤细胞系。 Int J Mol Sci。 2021 年 4 月 15 日；22(8):4103。
Buckel L 等人。单甲基 auristatin E 的肿瘤放射增敏作用:作用机制和靶向递送。癌症研究。 2015 年 4 月 1 日；75(7):1376-1387。
Liu-Kreyche P 等人。溶酶体 P-gp-MDR1 赋予 Brentuximab Vedotin 及其在肿瘤细胞中的细胞毒性有效载荷单甲基奥瑞他汀 E 的耐药性。前药理学。 2019 年 7 月 17 日；10:749。
Francisco JA 等人。 cAC10-vcMMAE，一种抗 CD30-单甲基 auristatin E 偶联物，具有有效和选择性的抗肿瘤活性。血。 2003 年 8 月 15 日；102(4):1458-65。
Karsten L 等人。二价 EGFR 靶向 DARPin-MMAE 偶联物。 Int J Mol Sci。 2022 年 2 月 23 日；23(5):2468。
Li H, et al.与单甲基 auristatin E 偶联的抗 HER2 抗体对 HER2 阳性人胃癌非常有效。癌症生物学疗法。 2016 年 4 月 2 日；17(4):346-54。
Protocol
| Cell experiment [1]: |
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Cell lines
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MCF7-R1 cells
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Preparation Method
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100,000 MCF7-R1 cells were seeded into each well of a 12-well culture plate, allowed to adhere overnight, and treated with 10 nM Monomethyl Auristatin E (MMAE) or conjugates in the presence of 10 U/mL heparin for 72 h. Then the cells were harvested with a TrypLE Express solution, stained by Annexin V-FITC and propidium iodide, and analyzed by flow cytometry using a NovoCyte 2060R flow cytometer.
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Reaction Conditions
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10 nM; for 72 h
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Applications
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After 72 h of treatment of MCF7-R1 cells with 10 nM conjugates, the cells were mainly in the early stage of apoptosis.
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| Animal experiment [2]: |
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Animal models
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Mice
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Preparation Method
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The breast tumor models were prepared via subcutaneous injection of 1 × 106 4T1 cells. When the tumor volumes were approximately 100 mm3, mice were divided into three groups: (i) saline; (ii) Monomethyl Auristatin E (MMAE) (0.2 mg/kg); and (iii) FRRG-MMAE nanoparticles (equivalent dose of 0.2 mg/kg based on MMAE contents). The mice were treated once every three days, and tumor volumes were calculated as the smallest diameter 2 × largest diameter × 0.53. The mice with a tumor volume of 2000 mm3 or larger were counted as dead. The toxicity study of FRRG-MMAE nanoparticles was assessed via histology.
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Dosage form
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0.2 mg/kg
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Applications
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The results demonstrated that free MMAE-treated mice showed rapid tumor growth compared to FRRG-MMAE-treated mice during monitoring for 15 days.Finally, mice treated with free MMAE showed significant body weight loss owing to the severe toxicity; eventually, all the mice were dead within five days of treatment.These results show the significantly reduced MMAE-related toxicity in the FRRG-MMAE nanoparticle group.
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参考文献:
[1] Krzyscik MA, et al. Fibroblast Growth Factor 2 Conjugated with Monomethyl Auristatin E Inhibits Tumor Growth in a Mouse Model. Biomacromolecules. 2021 Oct 11;22(10):4169-4180.
[2] Cho H, et al. Tumor-Specific Monomethyl Auristatin E (MMAE) Prodrug Nanoparticles for Safe and Effective Chemotherapy. Pharmaceutics. 2022 Oct 7;14(10):2131.
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