Modulating versatile pathways using a cleavable PEG shell and EGFR-targeted nanoparticles to deliver CRISPR-Cas9 and docetaxel for triple-negative breast cancer inhibition.

IF 6.9 3区 医学 Q1 CHEMISTRY, MEDICINAL Archives of Pharmacal Research Pub Date : 2024-11-01 DOI:10.1007/s12272-024-01514-0
Yu-Li Lo, Ci-Jheng Hong, Chen-Shen Wang, Ching-Ping Yang
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Abstract

Human antigen R (HuR), an RNA-binding protein, is implicated in regulating mRNA stability and translation in cancer, especially in triple-negative breast cancer (TNBC), a highly aggressive form. CRISPR/Cas9-mediated HuR knockout (HuR CRISPR) presents a promising genetic therapeutic approach, but it encounters transfection limitations. Docetaxel (DTX), an effective cytotoxic agent against metastatic breast cancer (BC), faces challenges related to vehicle-associated adverse events in DTX formulations. Therefore, we designed multifunctional nanoparticles with pH-sensitive PEG derivatives and targeting peptides to enable efficient HuR CRISPR and DTX delivery to human TNBC MDA-MB-231 cells and tumor-bearing mice. Our findings indicated that these nanoparticles displayed pH-responsive cytotoxicity, precise EGFR targeting, efficient tumor penetration, successful endosomal escape, and accurate nuclear and cytoplasmic localization. They also demonstrated the ability to spare normal cells and prevent hemolysis. Our study concurrently modulated multiple pathways, including EGFR, Wnt/β-catenin, MDR, and EMT, through the regulation of EGFR/PI3K/AKT, HuR/galectin-3/GSK-3β/β-catenin, and P-gp/MRPs/BCRP, as well as YAP1/TGF-β/ZEB1/Slug/MMPs. The combined treatment arrested the cell cycle at the G2 phase and inhibited EMT, effectively impeding tumor progression. Tissue distribution, biochemical assays, and histological staining revealed the enhanced safety profile of pH-responsive PEG- and peptide-modified nanoformulations in TNBC mice. The DTX-embedded and peptide-modified nanoparticles mitigated the side effects of DTX, enhanced cytotoxicity in TNBC MDA-MB-231 cells, and exhibited remarkable antitumor efficacy and safety in TNBC-bearing mice with HuR CRISPR deletion. Collectively, the combination therapy of DTX and CRISPR/Cas9 offers an effective platform for delivering antineoplastic agents and gene-editing systems to combat tumor resistance and progression in TNBC.

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利用可裂解 PEG 外壳和表皮生长因子受体靶向纳米颗粒调节多功能途径,输送 CRISPR-Cas9 和多西他赛以抑制三阴性乳腺癌。
人类抗原 R(HuR)是一种 RNA 结合蛋白,与调节癌症中 mRNA 的稳定性和翻译有关,尤其是在侵袭性极强的三阴性乳腺癌(TNBC)中。CRISPR/Cas9 介导的 HuR 基因敲除(HuR CRISPR)是一种很有前景的基因治疗方法,但它遇到了转染限制。多西他赛(Docetaxel,DTX)是治疗转移性乳腺癌(BC)的有效细胞毒药物,但其制剂面临着与载体相关的不良反应挑战。因此,我们设计了具有 pH 敏感性 PEG 衍生物和靶向肽的多功能纳米颗粒,以实现向人类 TNBC MDA-MB-231 细胞和肿瘤小鼠高效递送 HuR CRISPR 和 DTX。我们的研究结果表明,这些纳米颗粒具有 pH 值响应的细胞毒性、精确的表皮生长因子受体靶向性、高效的肿瘤穿透性、成功的内体逃逸以及准确的核和细胞质定位。它们还具有保护正常细胞和防止溶血的能力。我们的研究通过调节表皮生长因子受体/PI3K/AKT、HuR/galectin-3/GSK-3β/β-catenin、P-gp/MRPs/BCRP以及YAP1/TGF-β/ZEB1/Slug/MMPs,同时调节了多种通路,包括表皮生长因子受体、Wnt/β-catenin、MDR和EMT。联合治疗可将细胞周期阻滞在 G2 期并抑制 EMT,从而有效阻止肿瘤进展。组织分布、生化检测和组织学染色显示,pH响应型PEG和多肽修饰的纳米制剂在TNBC小鼠中的安全性得到了提高。包埋 DTX 和多肽修饰的纳米颗粒减轻了 DTX 的副作用,增强了对 TNBC MDA-MB-231 细胞的细胞毒性,并在 HuR CRISPR 缺失的 TNBC 小鼠中表现出显著的抗肿瘤疗效和安全性。总之,DTX 和 CRISPR/Cas9 的联合疗法为提供抗肿瘤药物和基因编辑系统提供了一个有效的平台,以对抗 TNBC 的肿瘤耐药性和进展。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
CiteScore
13.40
自引率
9.00%
发文量
48
审稿时长
3.3 months
期刊介绍: Archives of Pharmacal Research is the official journal of the Pharmaceutical Society of Korea and has been published since 1976. Archives of Pharmacal Research is an interdisciplinary journal devoted to the publication of original scientific research papers and reviews in the fields of drug discovery, drug development, and drug actions with a view to providing fundamental and novel information on drugs and drug candidates.
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