基于乙二胺四乙酸插层锌铝双金属氢氧化物的晚期肿瘤抗转移免疫治疗研究

doi:10.15541/jim20240154

无机材料学报 ›› 2024, Vol. 39 ›› Issue (9): 1044-1052.DOI: 10.15541/jim20240154

基于乙二胺四乙酸插层锌铝双金属氢氧化物的晚期肿瘤抗转移免疫治疗研究

李世奇¹^,²(), 鲍群群³(), 胡萍¹^,²(), 施剑林¹^,²()

1.中国科学院上海硅酸盐研究所, 高性能陶瓷和超微结构国家重点实验室, 上海 200050
2.中国科学院大学材料科学与光电工程中心, 北京 100049
3.同济大学附属第十人民医院, 上海 200435

收稿日期:2024-03-28 修回日期:2024-05-24 出版日期:2024-09-20 网络出版日期:2024-05-16
通讯作者: 鲍群群, 助理研究员. E-mail: bqqshnu@163.com;
胡萍, 研究员. E-mail: huping@mail.sic.ac.cn;
施剑林, 研究员. E-mail: jlshi@mail.sic.ac.cn
作者简介:李世奇(1999-), 男, 硕士研究生. E-mail: lishiqiucas@163.com
基金资助:
国家重点研发计划(2022YFB3804500);国家自然科学基金(22322509);国家自然科学基金(52072394);国家自然科学基金(22335006);上海市优秀学科带头人计划(23XD1424200);上海市科委基础研究项目(23DX1900200);中国科学院前沿科学重点计划(ZDBS-LYSLH029);上海市青年科技英才扬帆计划(22YF1433400)

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)

摘要/Abstract

摘要：

癌细胞的全身性转移是目前癌症晚期患者的主要死亡原因。由于肿瘤细胞的快速增殖和细胞外基质的异常沉积, 晚期癌症大体积瘤体组织致密且刚度较高, 这为晚期实体肿瘤的治疗带来了极大的困难。一方面, 由于大体积肿瘤的结构特性, 使得常规药物难以渗透至其内部, 免疫细胞难以浸润; 另一方面, 硬基质上的肿瘤细胞具有更强的侵袭能力, 这容易引起肿瘤的全身性转移。为了解决这一问题, 本研究制备了乙二胺四乙酸(EDTA)插层锌铝双金属氢氧化物纳米材料(EDTA/LDH), 基于两个平行的Ca²⁺剥夺机制, 开展了EDTA/LDH材料体系对晚期大体积实体瘤的抗转移免疫治疗研究。该材料在肿瘤微酸环境中, 通过静电力作用贴附在肿瘤细胞膜上, 并释放EDTA以螯合细胞连接蛋白中的Ca²⁺, 切断部分细胞连接, 从而降低大体积瘤体的致密程度, 促进免疫细胞向瘤体内浸润。此外, 该材料在机体内被巨噬细胞作为“异物”吞噬, 引起钙库操纵性钙内流, 激活巨噬细胞抗肿瘤免疫效应, 抑制多形核髓系抑制性细胞(PMN-MDSCs)和调节性T细胞(Tregs)的促肿瘤侵袭作用。本研究将为晚期恶性实体瘤的抗转移治疗提供借鉴性思路和方法。

关键词: 晚期癌症, 免疫治疗, 无机纳米材料, 离子调控

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

中图分类号:

R318
R730

李世奇, 鲍群群, 胡萍, 施剑林. 基于乙二胺四乙酸插层锌铝双金属氢氧化物的晚期肿瘤抗转移免疫治疗研究[J]. 无机材料学报, 2024, 39(9): 1044-1052.

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.

图/表 6

图1 EDTA/LDH材料体系针对大体积恶性化实体瘤的抗转移免疫治疗示意图

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

图2 EDTA/LDH材料体系的表征

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

图3 EDTA/LDH 对大体积恶性实体瘤的疗效评估

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

图4 EDTA/LDH抑制恶性肿瘤转移的效果评估(n=5)

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

图5 EDTA/LDH抗恶性肿瘤转移的免疫机制

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

图S1 小鼠脾脏尺寸统计数据

Fig. S1 Mouse spleen diameter statistics

参考文献 28

[1]	VIGANÓ A, BRUERA E, JHANGRI G S, et al. Clinical survival predictors in patients with advanced cancer. Archives of Internal Medicine, 2000, 160(6): 861. PMID
[2]	KODACK D P, ASKOXYLAKIS V, FERRARO G B, et al. Emerging strategies for treating brain metastases from breast cancer. Cancer Cell, 2015, 27(2): 163. DOI PMID
[3]	MUNOZ A, ELDRIDGE W J, JAKOBSEN N M, et al. Cellular shear stiffness reflects progression of arsenic-induced transformation during G₁. Carcinogenesis, 2019, 40(10): 1298.
[4]	PENG Y, CHEN Z, CHEN Y, et al. ROCK isoforms differentially modulate cancer cell motility by mechanosensing the substrate stiffness. Acta Biomaterialia, 2019, 88: 86. DOI PMID
[5]	WANG W, LOLLIS E M, BORDELEAU F, et al. Matrix stiffness regulates vascular integrity through focal adhesion kinase activity. Faseb Journal, 2019, 33(1): 1199. DOI PMID
[6]	YAMADA K M, SIXT M. Mechanisms of 3D cell migration. Nature Reviews Molecular Cell Biology, 2019, 20(12): 738. DOI PMID
[7]	JOYCE M H, LU C, JAMES E R, et al. Phenotypic basis for matrix stiffness-dependent chemoresistance of breast cancer cells to doxorubicin. Front Oncol, 2018, 8: 337. DOI PMID
[8]	TODOROVSKI V, FOX A H, CHOI Y S. Matrix stiffness-sensitive long noncoding RNA NEAT1 seeded paraspeckles in cancer cells. Molecular Biology of the Cell, 2020, 31(16): 1654. DOI PMID
[9]	DENG B, ZHAO Z, KONG W, et al. Biological role of matrix stiffness in tumor growth and treatment. Journal of Translational Medicine, 2022, 20(1): 540. DOI PMID
[10]	FENG J, TANG Y, XU Y, et al. Substrate stiffness influences the outcome of antitumor drug screening in vitro. Clinical Hemorheology and Microcirculation, 2013, 55(1): 121.
[11]	LADOUX B, MEGE R M. Mechanobiology of collective cell behaviours. Nature Reviews Molecular Cell Biology, 2017, 18(12): 743. DOI PMID
[12]	NOLTE M, MARGADANT C. Controlling immunity and inflammation through integrin-dependent regulation of TGF-β. Trends in Cell Biology, 2020, 30(1): 49. DOI PMID
[13]	KUCZEK D E, LARSEN A M H, THORSETH M L, et al. Collagen density regulates the activity of tumor-infiltrating T cells. Journal for Immunotherapy of Cancer, 2019, 7(1): 68. DOI PMID
[14]	CONDAMINE T, RAMACHANDRAN I, YOUN JI, et al. Regulation of tumor metastasis by myeloid-derived suppressor cells. Annual Review of Medicine. 2015, 66: 97. DOI PMID
[15]	SCENEAY J, CHOW M T, CHEN A, et al. Primary tumor hypoxia recruits CD11b⁺/Ly6C^med/Ly6G⁺ immune suppressor cells and compromises NK cell cytotoxicity in the premetastatic niche. Cancer Research, 2012, 72(16): 3906.
[16]	HALVORSEN E C, MAHMOUD S M, BENNEWITH K L. Emerging roles of regulatory T cells in tumour progression and metastasis. Cancer and Metastasis Reviews, 2014, 33(4): 1025.
[17]	TAN W, ZHANG W, STRASNER A, et al. Tumour-infiltrating regulatory T cells stimulate mammary cancer metastasis through RANKL-RANK signalling. Nature, 2011, 470(7335): 548.
[18]	BAO Q, FU H, GUO Y, et al. Calcium-deprivation-activated immune responses for solid tumor regression. Chem, 2024, 10(4): 1175.
[19]	BAO Q, HU P, REN W, et al. Tumor cell dissociation removes malignant bladder tumors. Chem, 2020, 6(9): 22839.
[20]	GARCIA M A, NELSON W J, CHAVEZ N. Cell-cell junctions organize structural and signaling networks. Cold Spring Harbor Perspectives in Biology, 2018, 10(4): a029181.
[21]	WHITE C, FRESQUEZ A. Store-Operated calcium entry regulates macrophage chemotaxis. Faseb Journal, 2020, 34(S1): 1.
[22]	CHEN Y F, LIN P C, YEH Y M, et al. Store-operated Ca²⁺ entry in tumor progression: from molecular mechanisms to clinical implications. Cancers, 2019, 11(7): 1332.
[23]	GASPAR D, VEIGA A S, CASTANHO M A. From antimicrobial to anticancer peptides. a review. Frontiers in Microbiology, 2013, 4: 63880.
[24]	TAN J, TAY J, HEDRICK J, et al. Synthetic macromolecules as therapeutics that overcome resistance in cancer and microbial infection. Biomaterials, 2020, 252: 120078.
[25]	KITAKAZE M, FUJINO S, MIYOSHI N, et al. Tumor-infiltrating T cells as a risk factor for lymph node metastasis in patients with submucosal colorectal cancer. Scientific Reports, 2023, 13: 2077.
[26]	DENG X W, TERUNUMA H. Harnessing NK cells to control metastasis. Vaccines, 2022, 10(12): 2018.
[27]	OBENAUF A C, MASSAGUÉ J. Surviving at a distance: organ-specific metastasis. Trends in Cancer, 2015, 1(1): 761.
[28]	GAO Y, ROSEN J M, ZHAN X H F. The tumor-immune ecosystem in shaping metastasis. American Journal of Physiology-Cell Physiology, 2023, 324(3): C707. DOI PMID

基于乙二胺四乙酸插层锌铝双金属氢氧化物的晚期肿瘤抗转移免疫治疗研究

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

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