Department of Pharmacy, Fudan University Shanghai Cancer Center; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.
College of Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan, Shandong 250355, China.
ACS Appl Mater Interfaces. 2021 Sep 15;13(36):42411-42428. doi: 10.1021/acsami.1c10325. Epub 2021 Aug 31.
Malignant melanoma is considered the most aggressive skin carcinoma with invasive growth patterns. Triptolide (TPL) possesses various biological and pharmacological activities involved in cancer treatment. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) can induce cancer cell apoptosis by binding to DR5 highly expressed on cancer cells. Exosomes are natural nanomaterials with low immunogenicity, nontoxicity, and excellent biocompatibility and have been extensively used as emerging delivery vectors for diverse therapeutic cargos. Herein, a delivery system based on TRAIL-engineered exosomes (TRAIL-Exo) for loading TPL for targeted therapy against malignant melanoma is proposed and systematically investigated. Our results showed that TRAIL-Exo/TPL could improve tumor targetability, enhance cellular uptake, inhibit proliferation, invasion, and migration, and induce apoptosis of A375 cells through activating the extrinsic TRAIL pathway and the intrinsic mitochondrial pathway in vitro. Moreover, intravenous injection of TRAIL-Exo/TPL significantly suppressed tumor progression and reduced the toxicity of TPL in the melanoma nude mouse model. Together, our research presents a novel strategy for high-efficiency exosome-based drug-delivery nanocarriers and provides an alternative dimension for developing a promising approach with synergistic therapeutic efficacy and targeting capacity for melanoma treatment.
恶性黑色素瘤被认为是最具侵袭性的皮肤癌，具有侵袭性生长模式。雷公藤内酯（TPL）具有多种参与癌症治疗的生物学和药理学活性。肿瘤坏死因子相关凋亡诱导配体（TRAIL）可以通过与癌细胞上高表达的 DR5 结合诱导癌细胞凋亡。外泌体是具有低免疫原性、低毒性和优异生物相容性的天然纳米材料，已被广泛用作各种治疗有效载荷的新兴递送载体。本文提出并系统研究了一种基于 TRAIL 工程外泌体（TRAIL-Exo）的载药系统，用于负载 TPL 以靶向治疗恶性黑色素瘤。我们的结果表明，TRAIL-Exo/TPL 可以通过激活外源性 TRAIL 途径和内在线粒体途径，提高肿瘤靶向性，增强细胞摄取，抑制 A375 细胞的增殖、侵袭和迁移，并诱导其凋亡。此外，静脉注射 TRAIL-Exo/TPL 显著抑制了黑色素瘤裸鼠模型中的肿瘤进展，并降低了 TPL 的毒性。总之，本研究提出了一种高效基于外泌体的药物递送纳米载体的新策略，为开发具有协同治疗效果和靶向能力的治疗黑色素瘤的新方法提供了新的思路。
