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Liposomal formulation of HIF-1α inhibitor echinomycin eliminates established metastases of triple-negative breast cancer.
Nanomedicine: Nanotechnology, Biology and Medicine ( IF 5.4 ) Pub Date : 2020-07-30 , DOI: 10.1016/j.nano.2020.102278
Christopher M Bailey 1 , Yan Liu 2 , Gong Peng 3 , Huixia Zhang 4 , Miao He 4 , Duxin Sun 4 , Pan Zheng 5 , Yang Liu 5 , Yin Wang 2
Affiliation  

Hypoxia-inducible factor 1α (HIF-1α) is recognized as a prime molecular target for metastatic cancer. However, no specific HIF-1α inhibitor has been approved for clinical use. Here, we demonstrated that in vivo efficacy of echinomycin in solid tumors with HIF-1α overexpression is formulation-dependent. Compared to previously-used Cremophor-formulated echinomycin, which was toxic and ineffective in clinical trials, liposomal-echinomycin provides significantly more inhibition of primary tumor growth and only liposome-formulated echinomycin can eliminated established triple-negative breast cancer (TNBC) metastases, which is the leading cause of death from breast cancer as available therapies remain minimally effective at this stage. Pharmacodynamic analyses reveal liposomal-echinomycin more potently inhibits HIF-1α transcriptional activity in primary and metastasized TNBC cells in vivo, the latter of which are HIF-1α enriched. The data suggests that nanoliposomal-echinomycin can provide safe and effective therapeutic HIF-1α inhibition and could represent the most potent HIF-1α inhibitor in prospective trials for metastatic cancer.



中文翻译:

HIF-1α 抑制剂棘霉素的脂质体制剂消除了三阴性乳腺癌的既定转移。

缺氧诱导因子 1α (HIF-1α) 被认为是转移性癌症的主要分子靶点。然而,还没有特定的 HIF-1α 抑制剂被批准用于临床。在这里,我们证明了体内棘霉素在 HIF-1α 过表达的实体瘤中的疗效取决于制剂。与之前使用的在临床试验中有毒且无效的 Cremophor 配方棘霉素相比,脂质体棘霉素对原发肿瘤生长的抑制作用明显更强,并且只有脂质体配方棘霉素才能消除已建立的三阴性乳腺癌 (TNBC) 转移灶,后者是乳腺癌死亡的主要原因,因为在此阶段可用的疗法仍然有效。药效学分析显示脂质体棘霉素更有效地抑制体内原发性和转移性 TNBC 细胞的 HIF-1α 转录活性,后者富含 HIF-1α。数据表明,纳米脂质体-棘霉素可以提供安全有效的治疗性 HIF-1α 抑制,并且可以代表转移性癌症前瞻性试验中最有效的 HIF-1α 抑制剂。

更新日期:2020-07-30
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