Li Jiehan, Luo Guang, Zhang Chuchu, Long Shuaiyu, Guo Leiming, Yang Ge, Wang Feng, Zhang Lingling, Shi Liyang, Fu Yang, Zhang Yingjie
School of Biomedical Sciences, Hunan University, Changsha, 410082, China.
Department of Gastroenterology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China.
Mater Today Bio. 2022 Mar 15;14:100238. doi: 10.1016/j.mtbio.2022.100238. eCollection 2022 Mar.
Melanoma is a highly aggressive tumor located in the skin, with limited traditional therapies. In order to reduce the side effects caused by traditional administration method and amplify the killing effect of immune system against tumor cells, an in situ injectable hydrogel drug delivery system is developed for the first time which co-delivers doxorubicin (Dox) and imiquimod (R837) for the synergistic therapy of melanoma. The mechanical properties and stability of the hydrogel are characterized and the optimal doses of hydrogel and drugs are also identified. As a result, the co-delivery system effectively suppresses melanoma growth and metastatic progression both and Further studies show that the co-delivery system causes immunogenic cell death, activation of antigen presenting cells, comprising dendritic cells and M1 macrophages, and secretion of related cytokines consisted of tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ), subsequently with the activation of T lymphocytes and natural killer cells in spleen and tumor area. The co-delivery system also decreases the suppressive immune responses, including infiltration of M2 macrophages and secretion of interleukin-10 (IL-10), . Besides, other death modes are induced by the co-delivery system, including apoptosis and non-apoptotic cell death. In a word, this co-delivery system induces melanoma cell death directly and activates immune system for further tumor killing simultaneously, which shows probability for precise targeted tumor therapy.
黑色素瘤是一种位于皮肤的高侵袭性肿瘤，传统治疗方法有限。为了减少传统给药方式引起的副作用并增强免疫系统对肿瘤细胞的杀伤作用，首次开发了一种原位可注射水凝胶药物递送系统，该系统共递送阿霉素（Dox）和咪喹莫特（R837）用于黑色素瘤的协同治疗。对水凝胶的力学性能和稳定性进行了表征，并确定了水凝胶和药物的最佳剂量。结果，该共递送系统有效地抑制了黑色素瘤的生长和转移进程。进一步的研究表明，该共递送系统导致免疫原性细胞死亡，激活包括树突状细胞和M1巨噬细胞在内的抗原呈递细胞，并分泌由肿瘤坏死因子-α（TNF-α）和干扰素-γ（IFN-γ）组成的相关细胞因子，随后激活脾脏和肿瘤区域的T淋巴细胞和自然杀伤细胞。该共递送系统还减少了抑制性免疫反应，包括M2巨噬细胞的浸润和白细胞介素-10（IL-10）的分泌。此外，该共递送系统还诱导了其他死亡模式，包括凋亡和非凋亡性细胞死亡。总之，这种共递送系统直接诱导黑色素瘤细胞死亡并同时激活免疫系统以进一步杀伤肿瘤，显示出精确靶向肿瘤治疗的可能性。
