Kumar Dulla Naveen, Chaudhuri Aiswarya, Dehari Deepa, Gamper Armin M, Kumar Dinesh, Agrawal Ashish Kumar
Department of Pharmaceutical Engineering and Technology, Indian Institute of Technology (BHU), Varanasi, 221005, Uttar Pradesh, India.
Department of Oncology, University of Alberta, Edmonton, AB, T6G 1Z2, Canada.
Drug Deliv Transl Res. 2025 Jan 7. doi: 10.1007/s13346-024-01785-6.
Cancer, particularly skin cancer, is a major cause of mortality worldwide, with melanoma being one of the most aggressive and challenging to treat types. Current therapeutic options, such as dacarbazine (DTIC), have limitations due to dose-related toxicities like liver toxicity. Therefore, there is a need for new and effective treatments for melanoma. Dihydroartemisinin (DHA), derived from artemisinin compounds known for their anti-malarial properties, has shown promise as an anti-cancer agent. However, the clinical use of DHA faces challenges such as low solubility and toxicity, which limit its therapeutic efficacy. To overcome these challenges, we developed an exosomal formulation of DHA to enhance its anti-cancer activity and reduce metastasis. Exosomes, biological vesicles, contain many biological macromolecules such as DNA, RNAs, and many other proteins, involved in intercellular communication, were isolated and loaded with DHA using the sonication method. The loaded exosomes were characterized for size (90-103 nm), polydispersity index (PDI: 0.119-0.123), and zeta potential (-23 to -28 mV). In vitro studies demonstrated the efficacy of DHA-loaded exosomes through cytotoxicity and apoptosis assays. The molecular mechanism of action was further elucidated using immunoblotting analysis, focusing on key proteins involved in apoptosis and metastasis regulation, including Bax, Bcl-2, survivin, and MMP-9. Furthermore, we observed a significant improvement in oral bioavailability (2.8-fold) with the exosomal formulation and enhanced in vivo anti-cancer activity of DHA. Notably, treatment with Exo-DHA resulted in strong enhancement of tumor growth suppression and reduced melanoma cell metastasis compared to free DHA.
癌症，尤其是皮肤癌，是全球主要的死亡原因之一，黑色素瘤是最难治疗且最具侵袭性的癌症类型之一。目前的治疗方法，如达卡巴嗪（DTIC），由于存在与剂量相关的毒性，如肝毒性，存在局限性。因此，需要新的、有效的黑色素瘤治疗方法。双氢青蒿素（DHA）源自以抗疟特性闻名的青蒿素化合物，已显示出作为抗癌剂的潜力。然而，DHA的临床应用面临着诸如低溶解度和毒性等挑战，这限制了其治疗效果。为了克服这些挑战，我们开发了一种DHA的外泌体剂型，以增强其抗癌活性并减少转移。外泌体是生物囊泡，含有许多生物大分子，如DNA、RNA和许多其他蛋白质，参与细胞间通讯，通过超声处理方法分离并装载DHA。对装载后的外泌体进行了大小（90 - 103纳米）、多分散指数（PDI：0.119 - 0.123）和zeta电位（-23至-28毫伏）的表征。体外研究通过细胞毒性和凋亡检测证明了装载DHA的外泌体的功效。使用免疫印迹分析进一步阐明了作用的分子机制，重点关注参与凋亡和转移调节的关键蛋白，包括Bax、Bcl - 2、survivin和MMP - 9。此外，我们观察到外泌体剂型使口服生物利用度显著提高（2.8倍），并增强了DHA的体内抗癌活性。值得注意的是，与游离DHA相比，用Exo - DHA治疗导致肿瘤生长抑制显著增强，黑色素瘤细胞转移减少。
