Purpose: Tumor metastasis and drug resistance have always been vital aspects to cancer mortality and prognosis. To compromise metastasis and drug resistance, a nanoparticle IPPD-PHF2 (IR780/PLGA-PEI(Dox)-PHF2) has been engineered to accomplish efficient targeted epigenotherapy forced by PHF2-induced MET (mesenchymal to epithelial transition).
Materials and Methods: IPPD-PHF2 nanoparticle was synthesized and characterized by several analytical techniques. The transfection efficiency of IPP-PHF2 (IR780/PLGA-PEI-PHF2) was compared with PP-PHF2 (PLGA-PEI-PHF2) in vitro by WB and in vivo by IHC, and the cytotoxicity of IPP was compared with Lipo2000 in vitro by CCK8 assay. The inhibition of cancer cell migration caused by PHF2-upregulation was tested by wound healing assay, and the enhanced chemotherapeutic sensitivity was detected by flow cytometry. Tumor-targeting property of IPPD-PHF2 was proved by fluorescent imaging in vivo with MDA-MB-231 tumor-bearing nude mice. Except for fluorescent imaging ability, considerable photoacoustic signals of IPPD-PHF2 at tumor sites were verified. The anti-tumor activity of IPPD-PHF2 was investigated using in vivo human breast cancer MDA-MB-231 cell models.
Results: Tumor-targeting nanoparticle IPPD-PHF2 had an average size of about 319.2 nm, a stable zeta potential at about 38 mV. The encapsulation efficiency of doxorubicin was around 39.28%, and the adsorption capacity of plasmids was about 64.804 μg/mg. Significant up-regulation of PHF2 induced MET and caused reduced migration as well as enhanced chemotherapeutic sensitivity. Either IPPD (IR780/PLGA-PEI(Dox)) or IPP-PHF2 (IR780/PLGA-PEI-PHF2) presented minor therapeutic effects, whereas IPPD-PHF2 specifically accumulated within tumors, showed extraordinary transfection efficiency specifically in tumor sites, acted as inhibitors of metastasis and proliferation, and presented good multimodality imaging potentials in vivo.
Conclusion: IPPD-PHF2 NPs is a promising tool to bring epigenotherapy into a more practical era, and the potential application of harm-free multimodality imaging guidance is of great value.

Keywords: targeted epigenotherapy, metastasis, drug resistance, multimodality imaging, breast cancer


中文翻译：

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基于肿瘤靶向纳米颗粒的表观基因转染抑制转移和放大化疗效果。

目的：肿瘤转移和耐药性一直是癌症死亡率和预后的重要方面。为了妥协转移和耐药性，纳米颗粒 IPPD-PHF2 (IR780/PLGA-PEI(Dox)-PHF2) 已被设计用于完成由 PHF2 诱导的 MET（间充质到上皮转化）强制的有效靶向表观基因治疗。
材料和方法：IPPD-PHF2 纳米颗粒是通过几种分析技术合成和表征的。IPP-PHF2（IR780/PLGA-PEI-PHF2）在体外WB和IHC体内比较IPP-PHF2（IR780/PLGA-PEI-PHF2）和PP-PHF2（PLGA-PEI-PHF2）的转染效率，体外比较IPP和Lipo2000的细胞毒性通过 CCK8 测定。通过伤口愈合试验检测了 PHF2 上调引起的癌细胞迁移的抑制作用，并通过流式细胞术检测了增强的化疗敏感性。IPPD-PHF2的肿瘤靶向特性通过MDA-MB-231荷瘤裸鼠体内荧光成像得到证实。除了荧光成像能力外，IPPD-PHF2 在肿瘤部位的大量光声信号也得到了验证。使用体内人乳腺癌 MDA-MB-231 细胞模型研究了 IPPD-PHF2 的抗肿瘤活性。
结果：肿瘤靶向纳米颗粒 IPPD-PHF2 的平均尺寸约为 319.2 nm，稳定的 zeta 电位约为 38 mV。阿霉素的包封率约为39.28%，质粒吸附量约为64.804 μg/mg。PHF2 的显着上调诱导 MET 并导致迁移减少以及化疗敏感性增强。IPPD (IR780/PLGA-PEI(Dox)) 或 IPP-PHF2 (IR780/PLGA-PEI-PHF2) 表现出轻微的治疗效果，而 IPPD-PHF2 在肿瘤内特异性积累，在肿瘤部位表现出非凡的转染效率，充当转移和增殖的抑制剂，并在体内表现出良好的多模态成像潜力。
结论：IPPD-PHF2 NPs是将表观基因治疗带入更实用时代的有前景的工具，无害多模态成像指导的潜在应用具有重要价值。

关键词：靶向表观基因治疗，转移，耐药性，多模态成像，乳腺癌