背景:黑色素瘤是最恶性的皮肤肿瘤,用化疗的替代疗法很难治愈,生物治疗,和免疫疗法。我们先前的研究表明,雷公藤甲素(TP)对黑色素瘤表现出强大的杀肿瘤活性。然而,TP的临床潜力受到其低水溶性的困扰,半衰期短,和生物毒性。因此,开发一种理想的载体以有效地加载TP并实现对黑色素瘤的靶向递送是充分利用其抗肿瘤功效的前瞻性方法。
结果:我们应用了来自人脐带间充质基质细胞(hUCMSCs)的外泌体(Exo),并用环状肽对其进行了外源工程,精氨酸-甘氨酸-天冬氨酸(cRGD),封装TP以建立仿生靶向给药系统(cRGD-Exo/TP),实现协同作用和降低毒性。cRGD-Exo/TP的平均尺寸为157.34±6.21nm,具有10.76±1.21%的高载药量。体外抗肿瘤实验结果表明,所设计的Exo给药平台能被靶向细胞有效吸收,具有明显的抗增殖作用,反入侵,A375细胞通过caspase级联反应和线粒体途径以及细胞周期改变而具有促凋亡活性。此外,生物分布和药代动力学结果表明,cRGD-Exo/TP具有优异的肿瘤靶向性,延长了TP的半衰期。值得注意的是,cRGD-Exo/TP显着抑制荷瘤小鼠的肿瘤生长并延长生存时间,全身毒性可忽略不计。
结论:结果表明,功能化的Exo平台为恶性黑色素瘤的靶向治疗提供了有希望的策略。
BACKGROUND: Melanoma is the most malignant skin tumor and is difficult to cure with the alternative treatments of chemotherapy, biotherapy, and immunotherapy. Our previous study showed that triptolide (TP) exhibited powerful tumoricidal activity against melanoma. However, the clinical potential of TP is plagued by its poor aqueous solubility, short half-life, and biotoxicity. Therefore, developing an ideal vehicle to efficiently load TP and achieving targeted delivery to melanoma is a prospective approach for making full use of its antitumor efficacy.
RESULTS: We applied exosome (Exo) derived from human umbilical cord mesenchymal stromal cells (hUCMSCs) and engineered them exogenously with a cyclic peptide, arginine-glycine-aspartate (
cRGD), to encapsulate TP to establish a bionic-targeted drug delivery system (
cRGD-Exo/TP), achieving synergism and toxicity reduction. The average size of
cRGD-Exo/TP was 157.34 ± 6.21 nm, with a high drug loading of 10.76 ± 1.21%. The in vitro antitumor results showed that the designed Exo delivery platform could be effectively taken up by targeted cells and performed significantly in antiproliferation, anti-invasion, and proapoptotic activities in A375 cells via the caspase cascade and mitochondrial pathways and cell cycle alteration. Furthermore, the biodistribution and pharmacokinetics results demonstrated that
cRGD-Exo/TP possessed superior tumor targetability and prolonged the half-life of TP. Notably,
cRGD-Exo/TP significantly inhibited tumor growth and extended survival time with negligible systemic toxicity in tumor-bearing mice.
CONCLUSIONS: The results indicated that the functionalized Exo platform provides a promising strategy for targeted therapy of malignant melanoma.