Department of Bioscience and Biotechnology, Konkuk University, Seoul 143-701, Republic of Korea.
Department of Bioscience and Biotechnology, Konkuk University, Seoul 143-701, Republic of Korea.
Acta Biomater. 2022 Mar 15;141:354-363. doi: 10.1016/j.actbio.2022.01.005. Epub 2022 Jan 8.
In this study, combination therapy with the transforming growth factor-β receptor I (TGFβRI) kinase inhibitor SD-208 and a toll-like receptor (TLR)-7/8 agonist resiquimod (R848) was examined along with serum-derived exosomes (EXOs) as versatile carriers. SD-208-encapsulated EXOs (SD-208/EXOs) and R848-encapsulated EXOs (R848/EXOs) were successfully prepared with a size of 87 ± 8 nm and 51 ± 4 nm, respectively, which were stable in aqueous solution at pH 7.4. SD-208/EXOs and R848/EXOs reduced the migration of cancer cells (B16F10 and PC-3) and triggered the release of proinflammatory cytokines from stimulated macrophages and dendritic cells, respectively. The fluorescent dye-labeled EXOs showed significantly improved penetration through the PC-3/fibroblast co-culture spheroids and enhanced accumulation in the B16F10 mouse tumor model compared with the free fluorescent dye. In addition, the combination therapy of R848/EXOs (R848 dose of 0.36 mg/kg) and SD-208/EXOs (SD-208 dose of 0.75 mg/kg) reduced tumor growth and improved survival rate at low doses in the B16F10 tumor xenograft model. Taken together, the combination therapy using the TGFβRI kinase inhibitor and TLR 7/8 agonist with EXOs may serve as a promising strategy to treat melanoma and prostate cancer. STATEMENT OF SIGNIFICANCE: Owing to the prevalence of several non-responding cancers that resist treatment, it is necessary to identify a novel combined treatment strategy with biomaterials to maximize therapeutic efficacy and minimize the undesirable side effects. In this study, we aimed to examine the use of the TGFβRI kinase inhibitor SD-208 and the TLR7/8 agonist resiquimod (R848) encapsulated within serum-derived EXOs for their synergistic antitumor effects. We first demonstrated that combined treatment with SD-208 and R848 can be a convincing strategy to circumvent tumor growth in vivo using serum-derived exosomes as promising carriers. Therefore, we believe this manuscript would be of great interest to the biomaterial communities especially who are studying immunotherapy.
在这项研究中，我们考察了转化生长因子-β受体 I (TGFβRI) 激酶抑制剂 SD-208 与 Toll 样受体 (TLR)-7/8 激动剂瑞喹莫德 (R848) 的联合治疗，同时还研究了血清衍生的外泌体 (EXOs) 作为多功能载体的作用。成功制备了大小分别为 87±8nm 和 51±4nm 的 SD-208 包裹的 EXOs（SD-208/EXOs）和 R848 包裹的 EXOs（R848/EXOs），它们在 pH 7.4 的水性溶液中稳定。SD-208/EXOs 和 R848/EXOs 分别减少了癌细胞（B16F10 和 PC-3）的迁移，并触发了受刺激的巨噬细胞和树突状细胞释放促炎细胞因子。与游离荧光染料相比，荧光染料标记的 EXOs 显著提高了穿透 PC-3/成纤维细胞共培养球体的能力，并增强了在 B16F10 小鼠肿瘤模型中的积累。此外，在 B16F10 肿瘤异种移植模型中，低剂量的 R848/EXOs（R848 剂量为 0.36mg/kg）和 SD-208/EXOs（SD-208 剂量为 0.75mg/kg）联合治疗可减少肿瘤生长并提高存活率。综上所述，使用 TGFβRI 激酶抑制剂和 TLR 7/8 激动剂与 EXOs 的联合治疗可能成为治疗黑色素瘤和前列腺癌的一种很有前途的策略。
由于存在几种对治疗有抵抗力的非响应性癌症，因此有必要确定一种新的联合治疗策略，使用生物材料来最大限度地提高治疗效果并最小化不良副作用。在这项研究中，我们旨在研究转化生长因子-β受体 I (TGFβRI) 激酶抑制剂 SD-208 和 Toll 样受体 7/8 激动剂瑞喹莫德 (R848) 包封在血清衍生的 EXOs 中以发挥协同抗肿瘤作用。我们首先证明，使用血清衍生的外泌体作为有前途的载体，联合使用 SD-208 和 R848 可以是一种有说服力的策略，可以规避体内肿瘤的生长。因此，我们相信这篇论文将引起生物材料界的极大兴趣，特别是那些正在研究免疫疗法的人。
