Biomedical Polymers Laboratory, College of Chemistry, Chemical Engineering and Materials Science, and State Key Laboratory of Radiation Medicine and Protection, Soochow University, Suzhou 215123, PR China; College of Pharmaceutical Sciences, Soochow University, Suzhou 215123, PR China.
Laboratory of Bone Tissue Engineering, Beijing Laboratory of Biomedical Materials, Beijing Research Institute of Traumatology and Orthopaedics, Beijing Jishuitan Hospital, Beijing 100035, PR China.
J Control Release. 2022 Oct;350:460-470. doi: 10.1016/j.jconrel.2022.08.048. Epub 2022 Aug 31.
Osteosarcoma (OS) is a rare but frequently lethal bone malignancy in children and adolescents. The adjuvant chemotherapy with doxorubicin (Dox) and cisplatin remains a mainstream clinical practice though it affords only limited clinical benefits due to low tumor deposition, dose-limiting toxicity and high rate of relapse/metastasis. Here, taking advantage of high IL-11Rα expression in the OS patients, we installed IL-11Rα specific peptide (sequence: cyclic CGRRAGGSC) onto redox-responsive polymersomes encapsulating Dox (IL11-PDox) to boost the specificity and anti-OS efficacy of chemotherapy. Of note, IL-11Rα peptide at a density of 20% greatly augmented the internalization, apoptotic activity, and migration inhibition of Dox in IL-11Rα-overexpressing 143B OS cells. The active targeting effect of IL11-PDox was supported in orthotopic and relapsed 143B OS models, as shown by striking repression of tumor growth and lung metastasis, and substantial survival benefits over free Dox control. We further verified that IL11-PDox could effectively inhibit patient-derived OS xenografts. IL-11Rα-targeted nanodelivery of chemotherapeutics provides a potential therapeutic strategy for advanced osteosarcoma.
骨肉瘤（OS）是儿童和青少年中一种罕见但经常致命的骨恶性肿瘤。尽管多柔比星（Dox）和顺铂联合辅助化疗提供的临床获益有限，但由于肿瘤沉积低、剂量限制毒性和高复发/转移率，它仍然是一种主流的临床实践。在这里，我们利用骨肉瘤患者中高表达的白细胞介素 11 受体 α（IL-11Rα），将 IL-11Rα 特异性肽（序列：环状 CGRRAGGSC）安装到包载 Dox 的氧化还原响应聚合物囊（IL11-PDox）上，以提高化疗的特异性和抗骨肉瘤疗效。值得注意的是，IL-11Rα 肽的密度为 20%时，大大增强了 Dox 在过表达 IL-11Rα 的 143B 骨肉瘤细胞中的内化、凋亡活性和迁移抑制作用。IL11-PDox 的主动靶向作用在原位和复发的 143B 骨肉瘤模型中得到了支持，表现为肿瘤生长和肺转移的显著抑制，以及与游离 Dox 对照组相比的显著生存获益。我们进一步验证了 IL11-PDox 可以有效抑制患者来源的骨肉瘤异种移植物。针对白细胞介素 11 受体α的化疗药物纳米递药为晚期骨肉瘤提供了一种潜在的治疗策略。
