Cheng Yuanyuan, Chen Qian, Guo Zhaoyang, Li Mengwen, Yang Xiaoying, Wan Guoyun, Chen Hongli, Zhang Qiqing, Wang Yinsong
The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics (Theranostics), School of Pharmacy, Tianjin Medical University, Tianjin 300070, P.R. China.
The Key Laboratory of Biomedical Material, School of Life Science and Technology, Xinxiang Medical University, Xinxiang 453003, P.R. China.
ACS Nano. 2020 Nov 24;14(11):15161-15181. doi: 10.1021/acsnano.0c05392. Epub 2020 Nov 4.
Metastasis is one of the main causes of failure in the treatment of triple-negative breast cancer (TNBC). Immunotherapy brings hope and opportunity to solve this challenge, while its clinical applications are greatly inhibited by the tumor immunosuppressive environment. Here, an intelligent biomimetic nanoplatform was designed based on dendritic large-pore mesoporous silica nanoparticles (DLMSNs) for suppressing metastatic TNBC by combining photothermal ablation and immune remodeling. Taking advantage of the ordered large-pore structure and easily chemically modified property of DLMSNs, the copper sulfide (CuS) nanoparticles with high photothermal conversion efficiency were deposited inside the large pores of DLMSNs, and the immune adjuvant resiquimod (R848) was loaded controllably. A homogenous cancer cell membrane was coated on the surfaces of these DLMSNs, followed by conjugation with the anti-PD-1 peptide AUNP-12 through a polyethylene glycol linker with an acid-labile benzoic-imine bond. The thus-obtained AM@DLMSN@CuS/R848 was applied to holistically treat metastatic TNBC and . The data showed that AM@DLMSN@CuS/R848 had a high TNBC-targeting ability and induced efficient photothermal ablation on primary TNBC tumors under 980 nm laser irradiation. Tumor antigens thus generated and increasingly released R848 by response to the photothermal effect, combined with AUNP-12 detached from AM@DLMSN@CuS/R848 in the weakly acidic tumor microenvironment, synergistically exerted tumor vaccination, and T lymphocyte activation functions on immune remodeling to prevent TNBC recurrence and metastasis. Taken together, this study provides an intelligent biomimetic nanoplatform to enhance therapeutic outcomes in metastatic TNBC.
转移是三阴性乳腺癌(TNBC)治疗失败的主要原因之一。免疫疗法为解决这一挑战带来了希望和机遇,但其临床应用受到肿瘤免疫抑制环境的极大限制。在此,基于树枝状大孔介孔二氧化硅纳米颗粒(DLMSNs)设计了一种智能仿生纳米平台,通过结合光热消融和免疫重塑来抑制转移性TNBC。利用DLMSNs有序的大孔结构和易于化学修饰的特性,将具有高光热转换效率的硫化铜(CuS)纳米颗粒沉积在DLMSNs的大孔内,并可控地负载免疫佐剂瑞喹莫德(R848)。在这些DLMSNs的表面包覆一层均匀的癌细胞膜,然后通过具有酸不稳定苯甲亚胺键的聚乙二醇接头与抗PD-1肽AUNP-12偶联。将由此获得的AM@DLMSN@CuS/R848应用于整体治疗转移性TNBC。数据表明,AM@DLMSN@CuS/R848具有高TNBC靶向能力,并在980 nm激光照射下对原发性TNBC肿瘤诱导高效的光热消融。由此产生的肿瘤抗原并通过对光热效应的响应而不断释放R848,结合在弱酸性肿瘤微环境中从AM@DLMSN@CuS/R848上脱离的AUNP-12,协同发挥肿瘤疫苗接种和T淋巴细胞激活功能,对免疫重塑起到作用,以防止TNBC复发和转移。综上所述,本研究提供了一种智能仿生纳米平台,以提高转移性TNBC的治疗效果。
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