Cytidinyl/Cationic Lipid Encapsulating Insulin-Like Growth Factor 1 Receptor siRNA for Hepatocellular Carcinoma Therapy.

IF 4.5 2区 医学 Q2 MEDICINE, RESEARCH & EXPERIMENTAL
Molecular Pharmaceutics Pub Date : 2025-06-02 Epub Date: 2025-04-27 DOI:10.1021/acs.molpharmaceut.4c01318
Yang Pu, Quanxin Wang, Yufei Pan, Xixian Wang, Zhu Guan, Yuejie Zhu, Zhenjun Yang
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引用次数: 0

Abstract

Hepatocellular carcinoma (HCC) is the most prevalent form of invasive liver cancer, representing over 90% of all liver cancer cases. Currently, there is a lack of targeted therapy for HCC. Insulin-like growth factor 1 receptor (IGF1R) is abnormally expressed in HCC, leading to the malignant proliferation and contributing to the antiapoptosis mechanisms in tumor cells. In this study, small interfering RNAs targeting IGF1R mRNA (siIGF1Rs) have been designed. Additionally, a full 2'-F/2'-OMe modification with partial phosphorothioation was applied to improve the biological properties of these siIGF1Rs. Based on previous research, stable lipid complexes with uniform particle sizes were constructed using cytidinyl lipid DNCA/cationic lipid CLD (Mix) supplemented with DSPE-PEG (siIGF1R/Mix/PEG). The complexes were formed through hydrogen-bonding, π-π stacking, and electrostatic interactions. The siIGF1R/Mix/PEG complex entered the cytoplasm and nucleus of HCC cells, reduced IGF1R mRNA and pre-mRNA levels by over 95% and 50% respectively, further arrested the cell cycle in the S phase, and promoted cell apoptosis. Importantly, siIGF1R/Mix/PEG (0.8 mg/kg, i.v.) selectively accumulated in the tumor, significantly inhibiting tumor growth by 91.31% compared to the naked siRNA group, with slower release and a more prolonged effect.

胞苷基/阳离子脂质包封胰岛素样生长因子1受体siRNA用于肝癌治疗。
肝细胞癌(HCC)是侵袭性肝癌中最常见的形式,占所有肝癌病例的90%以上。目前,缺乏针对HCC的靶向治疗。胰岛素样生长因子1受体(IGF1R)在HCC中异常表达,导致肿瘤细胞恶性增殖,并参与肿瘤细胞的抗凋亡机制。本研究设计了靶向IGF1R mRNA的小干扰rna (siIGF1Rs)。此外,采用2'-F/2'-OMe部分磷酸化修饰来改善这些siIGF1Rs的生物学特性。在前人研究的基础上,采用胞苷基脂质DNCA/阳离子脂质CLD (Mix)外加DSPE-PEG (siIGF1R/Mix/PEG)构建粒径均匀的稳定脂质复合物。配合物是通过氢键、π-π堆叠和静电相互作用形成的。siIGF1R/Mix/PEG复合物进入HCC细胞的细胞质和细胞核,使IGF1R mRNA和pre-mRNA水平分别降低95%和50%以上,进一步阻滞细胞周期于S期,促进细胞凋亡。重要的是,siIGF1R/Mix/PEG (0.8 mg/kg,静脉注射)选择性地在肿瘤中积累,与裸siRNA组相比,显著抑制肿瘤生长91.31%,释放更慢,作用时间更长。
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来源期刊
Molecular Pharmaceutics
Molecular Pharmaceutics 医学-药学
CiteScore
8.00
自引率
6.10%
发文量
391
审稿时长
2 months
期刊介绍: Molecular Pharmaceutics publishes the results of original research that contributes significantly to the molecular mechanistic understanding of drug delivery and drug delivery systems. The journal encourages contributions describing research at the interface of drug discovery and drug development. Scientific areas within the scope of the journal include physical and pharmaceutical chemistry, biochemistry and biophysics, molecular and cellular biology, and polymer and materials science as they relate to drug and drug delivery system efficacy. Mechanistic Drug Delivery and Drug Targeting research on modulating activity and efficacy of a drug or drug product is within the scope of Molecular Pharmaceutics. Theoretical and experimental peer-reviewed research articles, communications, reviews, and perspectives are welcomed.
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