Systemic Administration of siRNA with Anti-HB-EGF Antibody-Modified Lipid Nanoparticles for the Treatment of Triple-Negative Breast Cancer,Molecular Pharmaceutics

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Systemic Administration of siRNA with Anti-HB-EGF Antibody-Modified Lipid Nanoparticles for the Treatment of Triple-Negative Breast Cancer
Molecular Pharmaceutics ( IF 4.5 ) Pub Date : 2018-03-05 00:00:00 , DOI: 10.1021/acs.molpharmaceut.7b01055
Ayaka Okamoto _{1,

2} , Tomohiro Asai ₁ , Yusuke Hirai ₁ , Kosuke Shimizu _{1,

3} , Hiroyuki Koide ₁ , Tetsuo Minamino ₄ , Naoto Oku ₁

Affiliation

Triple-negative breast cancer is one of the intractable cancers that are not sensitive to treatment with existing molecular-targeted drugs. Recently, there has been much interest in RNA interference-mediated treatment of triple-negative breast cancer. In the present study, we have developed lipid nanoparticles encapsulating siRNA (LNP-siRNA) decorated with an Fab′ antibody against heparin-binding EGF-like growth factor (αHB-EGF LNP-siRNA). αHB-EGF LNP-siRNA targeting polo-like kinase 1 (PLK1) was prepared and evaluated for its anticancer effect using MDA-MB-231 human triple-negative breast cancer cells overexpressing HB-EGF on their cell surface. Biodistribution data of radioisotope-labeled LNP and fluorescence-labeled siRNA indicated that αHB-EGF LNP effectively delivered siRNA to tumor tissue in MDA-MB-231 carcinoma-bearing mice. Expression of PLK1 protein in the tumors was clearly suppressed after intravenous injection of αHB-EGF LNP-siPLK1. In addition, tumor growth was significantly inhibited by treatment with this formulation of siRNA and an antibody-modified carrier. These findings indicate that αHB-EGF LNP is a promising carrier for the treatment of HB-EGF-expressing cancers, including triple-negative breast cancer.

中文翻译：

siRNA 与抗 HB-EGF 抗体修饰脂质纳米颗粒的全身给药治疗三阴性乳腺癌

三阴性乳腺癌是对现有分子靶向药物治疗不敏感的难治性癌症之一。最近，人们对 RNA 干扰介导的三阴性乳腺癌治疗产生了浓厚的兴趣。在本研究中，我们开发了封装有 siRNA 的脂质纳米颗粒 (LNP-siRNA)，其修饰有针对肝素结合 EGF 样生长因子 (αHB-EGF LNP-siRNA) 的 Fab' 抗体。制备了靶向 polo 样激酶 1 (PLK1) 的 αHB-EGF LNP-siRNA，并使用细胞表面过表达 HB-EGF 的 MDA-MB-231 人三阴性乳腺癌细胞评估其抗癌效果。放射性同位素标记的 LNP 和荧光标记的 siRNA 的生物分布数据表明，αHB-EGF LNP 有效地将 siRNA 递送至 MDA-MB-231 荷瘤小鼠的肿瘤组织。静脉注射αHB-EGF LNP-siPLK1后，肿瘤中PLK1蛋白的表达明显受到抑制。此外，用这种 siRNA 制剂和抗体修饰载体进行治疗可显着抑制肿瘤生长。这些发现表明，αHB-EGF LNP 是治疗表达 HB-EGF 的癌症（包括三阴性乳腺癌）的有前途的载体。

更新日期：2018-03-05

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