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首页> 外文会议>World biomaterials congress >Multifunctional unimolecular micelles loaded with the anti-cancer drug aminoflavone for triple negative breast cancer therapy
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Multifunctional unimolecular micelles loaded with the anti-cancer drug aminoflavone for triple negative breast cancer therapy

机译：载有抗癌药氨基黄酮的多功能单分子胶束用于三阴性乳腺癌治疗

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Introduction: Breast cancer is the second leading cause of cancer-related deaths in American women. Triple-negative breast cancers (TNBCs)-which lack expression of estrogen receptor a, progesterone receptor, and human epidermal growth factor receptor 2-are particularly aggressive and correlated with decreased survival. While TNBCs make up 15 to 20% of all breast cancer cases, they account for a disproportionately large number of breast cancer deaths. Aminoflavone (AF, NSC 686288) has been examined in multiple clinical trials for TNBCs, but the majority of these trials have been terminated due to toxicity. To address this problem, we have developed a unique unimolecular micelle as an AF delivery system for targeted TNBC therapy. The unimolecular micelles were conjugated with GE11 peptide as an active-tumor targeting ligand that can specifically target the epithermal growth factor receptors (EGFR) overexpressed by the TNBC cells. In the current study, we assessed the antitumor effects of AF-loaded and GE11 -conjugated unimolecular micelles both in vitro and in vivo. poly(ethylene glycol)-OCH3/Cy5.5/GE11. The hydrophobic polylactide core was used to encapsulate AF through hydrophobic interaction, and the PEG shell was used to provide water solubility and reduce opsonization in vivo. GE11 peptide and Cy5.5 dye were selectively conjugated onto the distal ends of the PEG for active tumor-targeting and detection of the micelles at the cellular level, respectively. EGFR-overexpressing and AF-sensitive human MDA-MB-468 TNBC cells were treated with the micelles. The effect of the GE11 peptide on the cellular uptake of the micelles was studied by flow cytometry and confocal laser scanning microscopy. The effect of GE11 on the cytotoxicity of the micelles was determined using the MTT assay. The antitumor efficacy of AF-loaded and GE11-conjugated micelles was determined in MDA-MB-468 xenografts at an AF dosage of 7 mg/kg BW. Results: The unimolecular micelles were developed for targeted delivery of AF to TNBCs. The GE11-conjugated micelles exhibited a much higher cellular uptake than non-targeted micelles based on flow cytometry and CLSM analyses. The AF loaded in the targeted micelles had the strongest inhibitory effect on MDA-MB-468 TNBC cell proliferation. Moreover, the AF-loaded and GE11-conjugated unimolecular micelles demonstrated the best antitumor efficacy by remarkable regression of the TNBC tumors without significant weight loss. Conclusions: The GE11 -targeting ligands conjugated onto the surface of the micelles substantially increased the cellular uptake of the micelles in MDA-MB-468 TNBC cells and improved the cytotoxic effect of AF. This in vivo anticancer study demonstrates that AF-loaded and GE11 -conjugated unimolecular micelles have the best therapeutic effect.
机译：简介：乳腺癌是美国女性与癌症相关的死亡的第二大主要原因。缺乏雌激素受体a，孕激素受体和人类表皮生长因子受体2表达的三阴性乳腺癌（TNBCs）特别具有侵略性，并且与生存率降低相关。尽管TNBC占所有乳腺癌病例的15％至20％，但它们却占了乳腺癌死亡人数的不成比例。在针对TNBC的多项临床试验中已经检查了氨黄酮（AF，NSC 686288），但是由于毒性，这些试验中的大多数已经终止。为了解决这个问题，我们已经开发出独特的单分子胶束作为靶向TNBC治疗的AF递送系统。单分子胶束与GE11肽偶联，作为一种活性肿瘤靶向配体，可以特异性靶向TNBC细胞过度表达的超热生长因子受体（EGFR）。在当前的研究中，我们评估了在体外和体内，AF负载和GE11缀合的单分子胶束的抗肿瘤作用。聚（乙二醇）-OCH3 / Cy5.5 / GE11。疏水性聚丙交酯核心用于通过疏水性相互作用封装AF，而PEG壳用于提供水溶性并减少体内调理作用。将GE11肽和Cy5.5染料选择性地缀合到PEG的末端，分别在细胞水平上主动靶向肿瘤并检测胶束。用微团处理EGFR过表达和AF敏感的人MDA-MB-468 TNBC细胞。通过流式细胞术和共聚焦激光扫描显微镜研究了GE11肽对胶束细胞摄取的影响。使用MTT测定法确定GE11对胶束的细胞毒性的作用。在7 mg / kg BW的AF剂量下，在MDA-MB-468异种移植物中确定了AF负载和GE11缀合的胶束的抗肿瘤功效。结果：开发了单分子胶束，用于将AF定向递送至TNBC。基于流式细胞仪和CLSM分析，与非靶向胶束相比，缀合GE11的胶束具有更高的细胞摄取。靶向胶束中的AF对MDA-MB-468 TNBC细胞增殖具有最强的抑制作用。此外，通过TNBC肿瘤的显着消退而没有明显的体重减轻，AF加载的和GE11缀合的单分子胶束表现出最好的抗肿瘤功效。结论：缀合到胶束表面上的靶向GE11的配体显着增加了MDA-MB-468 TNBC细胞中胶束的细胞摄取，并改善了AF的细胞毒作用。这项体内抗癌研究表明，载有AF和GE11缀合的单分子胶束具有最佳的治疗效果。

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