In situ injectable hydrogel-loaded drugs induce anti-tumor immune responses in melanoma immunochemotherapy

Jiehan Li; Guang Luo; Chuchu Zhang; Shuaiyu Long; Leiming Guo; Ge Yang; Feng Wang; Lingling Zhang; Liyang Shi; Yang Fu; Yingjie Zhang

doi:10.1016/j.mtbio.2022.100238

In situ injectable hydrogel-loaded drugs induce anti-tumor immune responses in melanoma immunochemotherapy

Mater Today Bio. 2022 Mar 15:14:100238. doi: 10.1016/j.mtbio.2022.100238. eCollection 2022 Mar.

Authors

Jiehan Li^{1

2}, Guang Luo³, Chuchu Zhang^{1

4}, Shuaiyu Long¹, Leiming Guo⁵, Ge Yang⁶, Feng Wang⁷, Lingling Zhang³, Liyang Shi⁴, Yang Fu^{2

8}, Yingjie Zhang^{1

4}

Affiliations

¹ School of Biomedical Sciences, Hunan University, Changsha, 410082, China.
² Department of Gastroenterology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China.
³ Department of Laboratory Medicine, The Third Xiangya Hospital, Central South University, Changsha, 410013, China.
⁴ College of Biology, Hunan University, Changsha, 410082, China.
⁵ Department of R&D, Shanghai Creative Immune Therapeutics Co., Ltd, Shanghai, 200072, China.
⁶ Department of Ophthalmology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China.
⁷ Department of Gastroenterology, The Tenth People's Hospital of Shanghai, Tongji University, Shanghai, 200072, China.
⁸ The Collaborative Innovation Center of Henan Province for Cancer Chemoprevention, Zhengzhou, 450052, China.

Abstract

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 in vitro and in vivo. 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), in vivo. 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.

Keywords: Anti-tumor immune response; Cell death; Immunogenic cell death; Injectable hydrogel; Melanoma.