肿瘤细胞治疗研究
英文原题：Astragaloside IV and rapamycin co-loaded bone marrow mesenchymal stem cell-derived exosome nanocarriers for targeted modulation of the PI3K/Akt/mTOR pathway in hepatocellular carcinoma.
RAP@AST-IV/EXO NC 通过联合抑制 PI3K/Akt/mTOR 和诱导线粒体凋亡，代表了一种有前景且具有生物相容性的靶向 HCC 治疗策略。
肝细胞癌（HCC）仍是一种高度侵袭性的恶性肿瘤，由于耐药性、全身毒性以及肿瘤靶向药物递送受限，其治疗结局较差。本研究旨在开发一种双药负载的外泌体纳米载体，包载雷帕霉素（RAP）和黄芪甲苷IV（AST-IV）（RAP@AST-IV/EXO NC），以抑制PI3K/Akt/mTOR信号通路并增强HCC中的线粒体凋亡。
分离骨髓间充质干细胞来源的外泌体（BM-MSC-Exos），并通过超声辅助加载用于共递送 RAP 和 AST-IV。评估了其理化性质、载药量和释放行为。通过细胞活力、凋亡、ROS 生成、线粒体膜电位、迁移和 Western blot 实验评估体外疗效。在携带 HepG2 异种移植瘤的雄性 BALB/c 小鼠中评估体内治疗效果和安全性。
RAP@AST-IV/EXO NC 显示出良好的理化特性、持续药物释放、增强的细胞凋亡、增加的 ROS 生成、线粒体膜破坏以及抑制癌细胞迁移。RAP@AST-IV/EXO NC 显著降低细胞活力，并抑制磷酸化 PI3K、Akt 和 mTOR 表达，同时激活线粒体凋亡标志物。在体内，RAP@AST-IV/EXO NC 显著抑制肿瘤生长，且无明显全身毒性。
BACKGROUND: Hepatocellular carcinoma (HCC) remains a highly aggressive malignancy with poor therapeutic outcomes due to drug resistance, systemic toxicity, and limited tumor-targeted drug delivery. This study aimed to develop dual-drug-loaded exosome nanocarrier encapsulating rapamycin (RAP) and Astragaloside IV (AST-IV) (RAP@AST-IV/EXO NC) to inhibit PI3K/Akt/mTOR signaling and enhance mitochondrial apoptosis in HCC. METHODS: Bone marrow mesenchymal stem cell-derived exosomes (BM-MSC-Exos) were isolated and used for co-delivery of RAP and AST-IV via sonication-assisted loading. Physicochemical properties, drug loading, and release behavior were evaluated. In vitro efficacy was assessed through cell viability, apoptosis, ROS generation, mitochondrial membrane potential, migration, and Western blot assays. In vivo therapeutic efficacy and safety were evaluated in male BALB/c mice bearing HepG2 xenografts. RESULTS: RAP@AST-IV/EXO NC showed favorable physicochemical characteristics, sustained drug release, enhanced apoptosis, increased ROS generation, mitochondrial membrane disruption, and inhibition of cancer cell migration. The RAP@AST-IV/EXO NC significantly reduced cell viability and suppressed phosphorylated PI3K, Akt, and mTOR expression while activating mitochondrial apoptotic markers. In vivo , RAP@AST-IV/EXO NC markedly inhibited tumor growth without evident systemic toxicity. CONCLUSION: RAP@AST-IV/EXO NC represent a promising biocompatible strategy for targeted HCC therapy through combined PI3K/Akt/mTOR inhibition and mitochondrial apoptosis induction.
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