通过脂质纳米颗粒联合递送喜树碱和 MiR-145,用于肝细胞癌的核磁共振可视靶向治疗。

IF 11.4 1区 医学 Q1 ONCOLOGY
Jing Rong, Tongtong Liu, Xiujuan Yin, Min Shao, Kun Zhu, Bin Li, Shiqi Wang, Yujie Zhu, Saisai Zhang, Likang Yin, Qi Liu, Xiao Wang, Lei Zhang
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引用次数: 0

摘要

背景:喜树碱(CPT)是治疗肝细胞癌(HCC)的常用小剂量化疗药物之一,但由于严重的毒性和获得性耐药性,其临床应用受到限制。据报道,化疗与基因治疗相结合是一种有效的策略,既能对抗耐药性,又能使癌细胞对细胞毒性药物敏感。因此,我们假设将 CPT 与 miR-145 结合使用可协同抑制肿瘤增殖并增强抗肿瘤活性:方法:我们开发了乳糖酸(LA)修饰的脂质纳米颗粒(LNPs),在体外和体内将CPT和miR-145共同递送到表达asialoglycoprotein受体的HCC中。我们在体外使用 CCK8、Western 印迹、细胞凋亡和伤口划痕试验评估了 miR-145 和 CPT 的协同抗肿瘤作用,并进一步研究了协同抗肿瘤作用的机制。利用二乙基亚硝胺(DEN)+CCl4诱导的HCC小鼠模型评估了肿瘤抑制效果、安全性评价和MRI可视能力:结果:LA修饰改善了载体对HCC细胞和组织的靶向递送。在体外和体内,LA-CMGL 介导的 miR-145 和 CPT 联合给药比 LA-CPT-L 或 LA-miR-145-L 单独治疗对肿瘤的抑制更有效,而且在治疗期间几乎没有副作用。从机理上讲,miR-145 可能通过靶向 SUMO 特异性肽酶 1(SENP1)介导的己糖激酶(HK2)SUMOylation 和糖酵解途径诱导细胞凋亡,进而使癌细胞对 CPT 敏感。体外和体内试验证实,负载的 Gd-DOTA 是一种有效的 T1 加权造影剂,可用于无创肿瘤检测以及药物输送和生物分布的实时监测:LA-CMGL介导的miR-145和CPT联合给药对HCC具有协同治疗作用。结论:LA-CMGL介导的miR-145和CPT联合给药对HCC具有协同治疗作用,这种新型的磁共振可见主动靶向化疗基因联合给药系统为未来HCC治疗策略的发展提供了科学依据和有益的思路。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Co-delivery of camptothecin and MiR-145 by lipid nanoparticles for MRI-visible targeted therapy of hepatocellular carcinoma.

Background: Camptothecin (CPT) is one of the frequently used small chemotherapy drugs for treating hepatocellular carcinoma (HCC), but its clinical application is limited due to severe toxicities and acquired resistance. Combined chemo-gene therapy has been reported to be an effective strategy for counteracting drug resistance while sensitizing cancer cells to cytotoxic agents. Thus, we hypothesized that combining CPT with miR-145 could synergistically suppress tumor proliferation and enhance anti-tumor activity.

Methods: Lactobionic acid (LA) modified lipid nanoparticles (LNPs) were developed to co-deliver CPT and miR-145 into asialoglycoprotein receptors-expressing HCC in vitro and in vivo. We evaluated the synergetic antitumor effect of miR-145 and CPT using CCK8, Western blotting, apoptosis and wound scratch assay in vitro, and the mechanisms underlying the synergetic antitumor effects were further investigated. Tumor inhibitory efficacy, safety evaluation and MRI-visible ability were assessed using diethylnitrosamine (DEN) + CCl4-induced HCC mouse model.

Results: The LA modification improved the targeting delivery of cargos to HCC cells and tissues. The LA-CMGL-mediated co-delivery of miR-145 and CPT is more effective on tumor inhibitory than LA-CPT-L or LA-miR-145-L treatment alone, both in vitro and in vivo, with almost no side effects during the treatment period. Mechanistically, miR-145 likely induces apoptosis by targeting SUMO-specific peptidase 1 (SENP1)-mediated hexokinase (HK2) SUMOylation and glycolysis pathways and, in turn, sensitizing the cancer cells to CPT. In vitro and in vivo tests confirmed that the loaded Gd-DOTA served as an effective T1-weighted contrast agent for noninvasive tumor detection as well as real-time monitoring of drug delivery and biodistribution.

Conclusions: The LA-CMGL-mediated co-delivery of miR-145 and CPT displays a synergistic therapy against HCC. The novel MRI-visible, actively targeted chemo-gene co-delivery system for HCC therapy provides a scientific basis and a useful idea for the development of HCC treatment strategies in the future.

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来源期刊
CiteScore
18.20
自引率
1.80%
发文量
333
审稿时长
1 months
期刊介绍: The Journal of Experimental & Clinical Cancer Research is an esteemed peer-reviewed publication that focuses on cancer research, encompassing everything from fundamental discoveries to practical applications. We welcome submissions that showcase groundbreaking advancements in the field of cancer research, especially those that bridge the gap between laboratory findings and clinical implementation. Our goal is to foster a deeper understanding of cancer, improve prevention and detection strategies, facilitate accurate diagnosis, and enhance treatment options. We are particularly interested in manuscripts that shed light on the mechanisms behind the development and progression of cancer, including metastasis. Additionally, we encourage submissions that explore molecular alterations or biomarkers that can help predict the efficacy of different treatments or identify drug resistance. Translational research related to targeted therapies, personalized medicine, tumor immunotherapy, and innovative approaches applicable to clinical investigations are also of great interest to us. We provide a platform for the dissemination of large-scale molecular characterizations of human tumors and encourage researchers to share their insights, discoveries, and methodologies with the wider scientific community. By publishing high-quality research articles, reviews, and commentaries, the Journal of Experimental & Clinical Cancer Research strives to contribute to the continuous improvement of cancer care and make a meaningful impact on patients' lives.
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