Huang Xuan, Kuerban Kudelaidi, Fan Jajun, Pan Danjie, Chen Huaning, Liu Jiayang, Wang Songna, Ju Dianwen, Zhu Yi Zhun, Liu Jiyong, Ye Li
School of Pharmacy & Laboratory of Drug Discovery from Natural Resources and Industrialization, Macau University of Science and Technology, Macau SAR 999078, China.
Department of Biological Medicines & Shanghai Engineering Research Center of Immunotherapeutics, School of Pharmacy, Fudan University, Shanghai 201103, China.
Asian J Pharm Sci. 2025 Apr;20(2):101020. doi: 10.1016/j.ajps.2025.101020. Epub 2025 Jan 10.
Immunotherapy with interleukin-2 (IL-2) in treating cancers is subject to several limitations such as systemic side effects and reduced efficacy against tumors with low immune cell infiltration despite its promise. To address these challenges, IL-2-So-Lipo, a novel liposomal formulation combining IL-2 with sorafenib derivative, was developed as an anti-angiogenic drug that inhibits the growth of new blood vessels which play crucial roles in tumor growth. Sorafenib derivatives could target at melanoma-specific receptors, further enhancing liposomal specificity at the tumor site. Our results demonstrated that the prepared IL-2-So-Lipo significantly enhanced anti-tumor activity compared to IL-2 or sorafenib monotherapies, as well as their combination. In a B16F10 melanoma model, IL-2-So-Lipo was found to significantly inhibit tumor progression (tumor volume of 108.01 ± 62.99 mm) compared to the control group (tumor volume of 1,397.13 ± 75.55 mm), improving the therapeutic efficacy. This enhanced efficacy is attributed to the targeted delivery of IL-2 which promoted the infiltration and activation of cytotoxic T lymphocytes. Additionally, liposomal encapsulation of sorafenib derivatives enhanced its delivery efficiency, promoting tumor cell apoptosis and suppressing angiogenesis. Mechanistically, IL-2-So-Lipo could kill tumors by inducing a shift towards an anti-tumor immune response via facilitating the polarization of macrophages towards the M1 phenotype. Furthermore, IL-2-So-Lipo downregulated several key proteins in the MAPK signaling pathway, exerting a significant role in mediating tumor resistance to sorafenib. These findings underscore the potential of IL-2-So-Lipo as a promising strategy to improve the therapeutic efficacy of immunotherapy and targeted therapy in cancers. Moreover, the combination of IL-2 and sorafenib in a liposomal delivery system overcame the limitations of conventional IL-2 therapy, offering a synergistic approach to improve therapeutic outcomes for solid tumors.
尽管白细胞介素-2（IL-2）免疫疗法在治疗癌症方面前景广阔，但仍存在一些局限性，如全身副作用以及对免疫细胞浸润低的肿瘤疗效降低。为应对这些挑战，研发了一种将IL-2与索拉非尼衍生物结合的新型脂质体制剂IL-2-So-Lipo，作为一种抗血管生成药物，可抑制在肿瘤生长中起关键作用的新血管生长。索拉非尼衍生物可靶向黑色素瘤特异性受体，进一步增强脂质体在肿瘤部位的特异性。我们的结果表明，制备的IL-2-So-Lipo与IL-2或索拉非尼单药治疗及其联合治疗相比，显著增强了抗肿瘤活性。在B16F10黑色素瘤模型中，与对照组（肿瘤体积为1397.13±75.55mm）相比，发现IL-2-So-Lipo显著抑制肿瘤进展（肿瘤体积为108.01±62.99mm），提高了治疗效果。这种增强的疗效归因于IL-2的靶向递送，它促进了细胞毒性T淋巴细胞的浸润和激活。此外，索拉非尼衍生物的脂质体包封提高了其递送效率，促进肿瘤细胞凋亡并抑制血管生成。从机制上讲，IL-2-So-Lipo可通过促进巨噬细胞向M1表型极化，诱导向抗肿瘤免疫反应转变来杀死肿瘤。此外，IL-2-So-Lipo下调了MAPK信号通路中的几种关键蛋白，在介导肿瘤对索拉非尼的耐药性方面发挥了重要作用。这些发现强调了IL-2-So-Lipo作为一种有前景的策略，可提高癌症免疫疗法和靶向疗法治疗效果的潜力。此外，IL-2和索拉非尼在脂质体递送系统中的联合克服了传统IL-2疗法的局限性，为改善实体瘤治疗结果提供了一种协同方法。
