Anti-metastatic Immunotherapy of Advanced Tumors Based on EDTA Intercalated Zinc-aluminum Layered Double Hydroxide

doi:10.15541/jim20240154

Journal of Inorganic Materials ›› 2024, Vol. 39 ›› Issue (9): 1044-1052.DOI: 10.15541/jim20240154

Special Issue: 【生物材料】抗菌与肿瘤治疗(202506)

• RESEARCH ARTICLE • Previous Articles Next Articles

Anti-metastatic Immunotherapy of Advanced Tumors Based on EDTA Intercalated Zinc-aluminum Layered Double Hydroxide

LI Shiqi¹^,²(), BAO Qunqun³(), HU Ping¹^,²(), SHI Jianlin¹^,²()

1. State Key Laboratory of High Performance Ceramics and Superfine Microstructures, Shanghai Institute of Ceramics, Chinese Academy of Sciences, Shanghai 200050, China
2. Center of Materials Science and Optoelectronics Engineering, University of Chinese Academy of Sciences, Beijing 100049, China
3. Shanghai Tenth People’s Hospital, Medical School of Tongji University, Shanghai 200435, China

Received:2024-03-28 Revised:2024-05-24 Published:2024-09-20 Online:2024-05-16
Contact: BAO Qunqun, assistant professor. E-mail: bqqshnu@163.com;
HU Ping, professor. E-mail: huping@mail.sic.ac.cn;
SHI Jianlin, professor. E-mail: jlshi@mail.sic.ac.cn
About author:LI Shiqi (1999-), male, Master candidate. E-mail: lishiqiucas@163.com
Supported by:
National Key R&D Program of China(2022YFB3804500);National Natural Science Foundation of China(22322509);National Natural Science Foundation of China(52072394);National Natural Science Foundation of China(22335006);Program of Shanghai Academic/Technology Research Leader(23XD1424200);The Basic-Research-Program of Shanghai Municipal Goverment(23DX1900200);Key Research Program of Frontier Sciences, Chinese Academy of Sciences(ZDBS-LYSLH029);Shanghai Yangfan Program(22YF1433400)

Abstract

Abstract:

Systemic metastasis of cancer cells is currently the main cause of death for patients with advanced cancer. Due to the rapid proliferation of tumor cells and abnormal deposition of extracellular matrix, the large-volume tumor tissue in advanced cancer is dense and stiff, which brings great difficulties to the treatment of advanced solid tumors: conventional drugs having difficulty in penetrating and immune cells facing challenges to infiltrate into their interior. Meanwhile, tumor cells on hard matrices have stronger invasive ability, which is prone to cause systemic metastasis of tumors. To solve this problem, this study prepared ethylenediaminetetraacetic acid (EDTA) intercalated zinc-aluminum layered double hydroxide nanomaterials (EDTA/LDH). Based on two parallel Ca²⁺ deprivation mechanism, the anti-metastasis immunotherapy of EDTA/LDH material system for advanced large-volume solid tumors was studied. In the slightly acidic tumor microenvironment, the material system adheres to the tumor cell membrane through electrostatic force, releases EDTA to chelate Ca²⁺ in cell adhesion proteins, cuts off part of the cell connections, reduces the stiffness of large tumors, and promotes the infiltration of immune cells into the tumor tissue. In addition, the material system is phagocytosed by macrophages as a "foreign body", causing calcium store-operated calcium influx, activating the anti-tumor immune effect of macrophages, and inhibiting the tumor-promoting invasion of polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) and regulatory T cells (Tregs). This study will provide reference ideas and methods for the anti-metastasis treatment of advanced malignant solid tumors.

Key words: advanced cancer, immunotherapy, inorganic nanomaterial, ion regulation

CLC Number:

R318
R730

LI Shiqi, BAO Qunqun, HU Ping, SHI Jianlin. Anti-metastatic Immunotherapy of Advanced Tumors Based on EDTA Intercalated Zinc-aluminum Layered Double Hydroxide[J]. Journal of Inorganic Materials, 2024, 39(9): 1044-1052.

Figures/Tables 6

Fig. 1 Schematic diagram of EDTA/LDH material system for anti-metastatic immunotherapy of large-volume malignant solid tumors

Fig. 2 Characterization of EDTA/LDH material system (a) TEM image; (b) Element mappings; (c) EDS pattern; (d) FT-IR spectra; (e) XRD patterns; (f) DLS/Zeta potential

Fig. 3 Evaluation of the efficacy of EDTA/LDH in large-volume malignant solid tumors (a) Schematic diagram of mouse 4T1 tumor model construction and treatment process; (b) Survival curves; (c) Tumor volume on day 0 and day 16; (d) Body weight curves; (e) Images and quantification of tumor mechanical forces measured by SWE; (f) Tumor areas; (g) Tumor mean stiffnesses Statistical significances (*p < 0.05, **p < 0.01 and ***p < 0.001) were calculated by one-way ANOVA

Fig. 4 Evaluation of the efficacy of EDTA/LDH in inhibiting the metastasis of malignant tumors (n=5) (a) Photos of tumors and organs of mice in the control group and the treatment group; (b) H&E slices of tumors and organs of mice in the control group and the treatment group

Fig. 5 Immune mechanism of EDTA/LDH against malignant tumor metastasis (a) Tumor H&E sections and E-cadherin immunohistochemical analysis; (b) Immunofluorescence analysis, CD8+ T (CD8+), Treg (Foxp3+), PMN-MDSC (CD11b+ Ly6G+), M1 macrophages (F4/80+ CD86+) and NK (CD16+) being labeled

Fig. S1 Mouse spleen diameter statistics

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Anti-metastatic Immunotherapy of Advanced Tumors Based on EDTA Intercalated Zinc-aluminum Layered Double Hydroxide

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