负载甘草酸的工程化雷公藤红素脂质体增强乳腺癌的协同抗肿瘤疗效。

Engineered celastrol liposomes with glycyrrhizic acid augment synergistic antitumor efficacy in breast cancer.

作者信息

Zhang Wei, Li Jiping, Gao Xiuli, Liu Likun, Liang Hong, Yue Liling

机构信息

Office of Academic Research, Qiqihar Medical University, Qiqihar, China.

School of Public Health, Qiqihar Medical University, Qiqihar, China.

出版信息

Front Oncol. 2025 May 20;15:1602585. doi: 10.3389/fonc.2025.1602585. eCollection 2025.

DOI:10.3389/fonc.2025.1602585

PMID:40463872

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12129919/

Abstract

BACKGROUND/OBJECTIVES: Breast cancer treatment remains challenged by the non-specific distribution and systemic toxicity of conventional chemotherapeutics. Celastrol (CEL), a natural compound with antitumor efficacy, faces clinical limitations due to its toxicity and poor solubility. Glycyrrhizic acid (GA), known for tumor-suppressive and membrane-modifying properties, offers potential to enhance targeted drug delivery. This study aimed to develop GA-modified liposomes (GA/LIP-CEL) to synergistically improve CEL's therapeutic specificity and safety.

METHODS

GA/LIP-CEL nanoparticles were engineered via thin-film hydration, replacing cholesterol with GA. Physicochemical properties were characterized using TEM, DLS, and HPLC. evaluations included stability assays, cellular uptake (flow cytometry), cytotoxicity (MTT assay), mitochondrial membrane potential (JC-1 staining), apoptosis (Annexin V/PI), DNA damage (γ-H2AX immunofluorescence), and cell cycle analysis in BT549 breast cancer and MCF-10A normal cells.

RESULTS

GA/LIP-CEL exhibited uniform spherical morphology (122.48 ± 5.37 nm), high drug loading (87.75 ± 2.61%), sustained release (70.13% cumulative release at 24 h), and colloidal stability (negligible size variation over 14 days). Compared to LIP-CEL, GA/LIP-CEL reduced IC50 in BT549 cells while lowering cytotoxicity in MCF-10A cells. Compared with the LIP-CEL group, GA/LIP-CEL treatment demonstrated a statistically significant increase in apoptotic cell proportion (P < 0.05). Enhanced mitochondrial dysfunction (P < 0.05) and DNA (P < 0.05) damage were observed. GA modification improved cellular uptake potentially via regulating membrane fluidity and receptor-mediated endocytosis effects, and induced S-phase arrest (31.66 ± 1.70% cells).

CONCLUSIONS

GA/LIP-CEL combines GA's membrane-targeting capabilities with CEL's therapeutic effects, improving stability, specificity, and safety. This platform represents a novel strategy for precision drug delivery, addressing limitations of conventional systems through natural component integration. Further validation of performance and pharmacokinetics is warranted to advance clinical translation.

摘要

背景/目的：传统化疗药物的非特异性分布和全身毒性仍然是乳腺癌治疗面临的挑战。雷公藤红素（CEL）是一种具有抗肿瘤功效的天然化合物，由于其毒性和低溶解性而面临临床应用限制。甘草酸（GA）以其肿瘤抑制和膜修饰特性而闻名，具有增强靶向药物递送的潜力。本研究旨在开发GA修饰的脂质体（GA/LIP-CEL），以协同提高CEL的治疗特异性和安全性。

方法

通过薄膜水化法构建GA/LIP-CEL纳米粒，用GA替代胆固醇。使用透射电子显微镜（TEM）、动态光散射（DLS）和高效液相色谱（HPLC）对其理化性质进行表征。评估包括稳定性测定、细胞摄取（流式细胞术）、细胞毒性（MTT法）、线粒体膜电位（JC-1染色）、凋亡（Annexin V/PI）、DNA损伤（γ-H2AX免疫荧光）以及BT549乳腺癌细胞和MCF-10A正常细胞的细胞周期分析。

结果

GA/LIP-CEL呈现均匀的球形形态（122.48±5.37nm），载药量高（87.75±2.61%），缓释性能好（24小时累积释放率为70.13%），且具有胶体稳定性（14天内粒径变化可忽略不计）。与LIP-CEL相比，GA/LIP-CEL降低了BT549细胞的半数抑制浓度（IC50），同时降低了对MCF-10A细胞的细胞毒性。与LIP-CEL组相比，GA/LIP-CEL处理后凋亡细胞比例有统计学显著增加（P<0.05）。观察到线粒体功能障碍（P<0.05）和DNA损伤（P<0.05）增强。GA修饰可能通过调节膜流动性和受体介导的内吞作用提高细胞摄取，并诱导S期阻滞（31.66±1.70%的细胞）。