Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
Department of Chemical and Biological Engineering, University at Buffalo, State University of New York. Buffalo, New York 14260, USA.
Theranostics. 2020 Feb 10;10(7):3049-3063. doi: 10.7150/thno.42385. eCollection 2020.
Simultaneously targeted treatment of tumor cells and their surrounding growth-supporting immune cells is a promising strategy to reshape immunosuppressive tumor microenvironment (TME) and potentiate host innate and adaptive antitumor immune responses. : We designed a series of melittin-(RADA) hybrid peptide sequences with varying self-assembling motifs of RADA and screened out a melittin-(RADA) peptide that has an optimal gel-formation ability and antitumor activity. : The formed melittin-(RADA) (MR) hydrogel scaffold could be loaded with a specific Ca/calmodulin-dependent protein kinase II (CAMKII) inhibitor, KN93, originally found to have both direct tumoricidal activity and macrophages-reprogramming ability, for potent immunotherapy against melanoma and hepatoma ascites in mice models. Our MR hydrogel has an interweaving nanofiber-like structure, possesses direct antitumor and controlled drug release properties and promotes the enhanced intracellular uptake of loaded cargo. Compared to free KN93, the MR-KN93 hydrogel (MRK) improved the killing effects and levels of immunogenic cell death (ICD) on tumor cells significantly. Due to the dual role of KN93, the injection of the MRK hydrogel retarded the growth of subcutaneous melanoma tumors dramatically and resulted in a high number of mature dendritic cells of draining lymph nodes, significantly enhancing the portion of cytotoxic T cells and reduced number of M2-like tumor-associated macrophages (TAMs) in tumors. Using a mouse model of malignant ascites (MAs), where traditional therapy was ineffective, we demonstrated that the MRK hydrogel treatment offered a significantly prolonged survival compared to controls. Following treatment with the MRK hydrogel, macrophages had elevated programmed cell death protein ligand-1 (PD-L1) expression, promising follow-up combined anti-PD-1 therapy that confers a cure rate of approximately 30% against MAs in mice models. : Thus, the MRK hydrogel may serve as a prospective platform for antitumor applications.
同时靶向肿瘤细胞及其周围支持生长的免疫细胞的治疗是一种很有前途的策略，可以重塑免疫抑制性肿瘤微环境 (TME)，增强宿主固有和适应性抗肿瘤免疫反应。我们设计了一系列具有不同自组装基序 RADA 的蜂毒素-(RADA)杂合肽序列，并筛选出一种具有最佳凝胶形成能力和抗肿瘤活性的蜂毒素-(RADA)肽。形成的蜂毒素-(RADA)(MR)水凝胶支架可以负载一种特定的钙/钙调蛋白依赖性蛋白激酶 II (CAMKII)抑制剂 KN93，最初发现它具有直接杀伤肿瘤活性和巨噬细胞重编程能力，可用于针对小鼠模型中的黑色素瘤和肝癌腹水的强力免疫治疗。我们的 MR 水凝胶具有交织的纳米纤维状结构，具有直接的抗肿瘤和控制药物释放特性，并促进负载货物的增强细胞内摄取。与游离 KN93 相比，MR-KN93 水凝胶 (MRK) 显著提高了对肿瘤细胞的杀伤效果和免疫原性细胞死亡 (ICD) 水平。由于 KN93 的双重作用，MRK 水凝胶的注射显著延缓了皮下黑色素瘤肿瘤的生长，并导致引流淋巴结中成熟树突状细胞的数量显著增加，显著增强了细胞毒性 T 细胞的比例，并减少了肿瘤中的 M2 样肿瘤相关巨噬细胞 (TAMs) 的数量。在一种恶性腹水 (MAs) 的小鼠模型中，传统治疗无效，我们证明与对照组相比，MRK 水凝胶治疗提供了显著延长的生存时间。在用 MRK 水凝胶治疗后，巨噬细胞的程序性细胞死亡蛋白配体 1 (PD-L1) 表达水平升高，有望进行后续的联合抗 PD-1 治疗，在小鼠模型中对 MAs 的治愈率约为 30%。因此，MRK 水凝胶可能成为抗肿瘤应用的有前途的平台。
