Aminoflavone-loaded EGFR-targeted unimolecular micelle nanoparticles exhibit anti-cancer effects in triple negative breast cancer.
Aminoflavone-loaded EGFR-targeted unimolecular micelle nanoparticles exhibit anti-cancer effects in triple negative breast cancer.
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DOI：
10.1016/j.biomaterials.2016.05.041
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发表时间：
2016-09
期刊：
影响因子：
14
通讯作者：
Xu, Wei
中科院分区：
文献类型：
--
作者：
Brinkman, Ashley M.;Chen, Guojun;Wang, Yidan;Hedman, Curtis J.;Sherer, Nathan M.;Havighurst, Thomas C.;Gong, Shaoqin;Xu, Wei
关键词：
三阴性乳腺癌（TNBC）是一种侵袭性乳腺癌亚型，目前尚无可用的靶向治疗。TNBC病例对乳腺癌相关死亡率的贡献不成比例，因此迫切需要新的有效治疗方法。我们之前已经证明，美国国家癌症研究所（NCI）的研究药物氨基甲酮（AF）在TNBC细胞中表现出强烈的生长抑制作用。然而，体内肺毒性导致AF的几项人体临床试验的撤回或终止。在此，我们报告了AF纳米制剂的体内疗效，其增强了TNBC中AF的治疗指数。我们设计了一种独特的单分子胶束纳米颗粒（NP），负载AF并与GE 11偶联，GE 11是一种靶向表皮生长因子受体（EGFR）的12个氨基酸肽，因为在TNBC肿瘤中经常观察到EGFR扩增。这些单分子胶束具有优异的稳定性，并优先释放药物的有效载荷在内涵体pH值水平，而不是血液pH值水平。GE 11靶向肽的使用导致TNBC细胞中增强的细胞摄取和强的生长抑制作用。此外，AF-负载的、GE 11-缺乏的、GE 11-缀合的与用AF-负载的、缺乏GE 11-的治疗相比，（靶向的）单分子胶束NP显著抑制异种移植模型中的原位TNBC肿瘤生长。（非靶向的）单分子胶束NP或游离AF。有趣的是，用负载AF的动物，靶向NP在不同治疗组中具有最高的AF血浆和肿瘤水平，但未表现出血浆天冬氨酸转氨酶（AST）升高活动水平或处死时可观察到的组织损伤。总之，这些结果突出了AF负载的EGFR靶向单分子胶束NP作为EGFR过表达的TNBC的有效治疗选择。
Triple negative breast cancer (TNBC) is an aggressive subtype of breast cancer for which there is no available targeted therapy. TNBC cases contribute disproportionately to breast cancer-related mortality, thus the need for novel and effective therapeutic methods is urgent. We have previously shown that a National Cancer Institute (NCI) investigational drug aminoflavone (AF) exhibits strong growth inhibitory effects in TNBC cells. However, in vivo pulmonary toxicity resulted in withdrawal or termination of several human clinical trials for AF. Herein we report the in vivo efficacy of a nanoformulation of AF that enhances the therapeutic index of AF in TNBC. We engineered a unique unimolecular micelle nanoparticle (NP) loaded with AF and conjugated with GE11, a 12 amino acid peptide targeting epidermal growth factor receptor (EGFR), since EGFR amplification is frequently observed in TNBC tumors. These unimolecular micelles possessed excellent stability and preferentially released drug payload at endosomal pH levels rather than blood pH levels. Use of the GE11 targeting peptide resulted in enhanced cellular uptake and strong growth inhibitory effects in TNBC cells. Further, AF-loadedloaded, GE11-lacking, GE11-conjugated (targeted) unimolecular micelle NPs significantly inhibit orthotopic TNBC tumor growth in a xenograft model, compared to treatment with AF-loaded, GE11-lacking (non-targeted) unimolecular micelle NPs or free AF. Interestingly, the animals treated with AF-loaded, targeted NPs had the highest plasma and tumor level of AF among different treatment groups yet exhibited no increase in plasma aspartate aminotransferase (AST) activity level or observable tissue damage at the time of sacrifice. Together, these results highlight AF-loaded, EGFR-targeted unimolecular micelle NPs as an effective therapeutic option for EGFR-overexpressing TNBC.
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作者：
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