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基于化疗药物清除剂的联合疗法治疗三阴性乳腺癌。

Chemotherapeutic drug scavenger-based combination therapy toward treating triple-negative breast cancer.

作者信息

Yin Qingqing, Zhong Yutong, Chen Mengchun, Mao Weian, Yang Yuan, Li Li, Tian Dongyan, Liu Shuangshuang, Chen Ying, Quan Jiale, Li Shiyu, Zhuge Deli, Zhang Xufei, Wang Ledan, Wang Fang, Chen Yiming, Lu Xiaosheng, Lin Xiaoji, Chen Yijie, Yan Linzhi

机构信息

Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325027, China.

Department of Pharmacy, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325027, China.

出版信息

J Nanobiotechnology. 2025 Jul 1;23(1):473. doi: 10.1186/s12951-025-03571-z.


DOI:10.1186/s12951-025-03571-z
PMID:40598423
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12211420/
Abstract

Triple-negative breast cancer (TNBC) is resistant to most antitumor treatments, leaving chemotherapy as the primary option. Although doxorubicin (Dox) in combination with other therapies is promising for TNBC management, the combined effect is still compromised by the dose-limiting toxicities of Dox. Here, we developed a chemotherapeutic drug scavenger (CDS) by encapsulating GC-rich DNA-preferred binding targets of Dox-within an erythrocyte membrane functionalized with a normal tissue-targeting (NTT) peptide. Mimicking the structure of the cell nucleus, CDS selectively absorbs and neutralizes Dox in susceptible normal organs while sparing tumor tissues. This targeted detoxification allows for safe escalation of the Dox dose to 15 mg/kg, three times the standard 5 mg/kg, without observable toxicity. Such a high Dox dose enabled by CDS pretreatment significantly inhibited the post-operative residual/metastasized 4T1 tumor growth, regardless of the early or later stages of the tumor. Also, delivery of a high dose of Dox into the 4T1 tumor could profoundly increase the G2/M arrest, facilitating the combination therapy with a low-powered radiation of 2 Gy. Further, tumor exposure to high Dox amounts could convert the 4T1 tumor microenvironment from 'cold' to 'hot', leading to improved infiltration of immune cells, including T cells, dendritic cells, and macrophages. Overall, this study demonstrates how the safe injection of high amounts of Dox enabled by CDS detoxification could augment and extend Dox's functionality combined with surgery, radiotherapy, and cell therapy for TNBC treatment.

摘要

三阴性乳腺癌(TNBC)对大多数抗肿瘤治疗具有抗性,化疗成为主要选择。尽管阿霉素(Dox)与其他疗法联合应用对TNBC治疗有前景,但联合效应仍因Dox的剂量限制性毒性而受到影响。在此,我们通过将富含鸟嘌呤-胞嘧啶(GC)的Dox优先结合靶点封装在经正常组织靶向(NTT)肽功能化的红细胞膜内,开发了一种化疗药物清除剂(CDS)。CDS模仿细胞核结构,在敏感的正常器官中选择性吸收并中和Dox,同时使肿瘤组织免受影响。这种靶向解毒使得Dox剂量能够安全地提高到15mg/kg,是标准的5mg/kg的三倍,且无明显毒性。CDS预处理实现的如此高剂量的Dox显著抑制了术后残留/转移的4T1肿瘤生长,无论肿瘤处于早期还是晚期。此外,向4T1肿瘤输送高剂量的Dox可显著增加G2/M期阻滞,促进与2Gy低强度辐射的联合治疗。此外,肿瘤暴露于高剂量的Dox可使4T1肿瘤微环境从“冷”态转变为“热”态,导致包括T细胞、树突状细胞和巨噬细胞在内的免疫细胞浸润增加。总体而言,本研究展示了CDS解毒实现的高剂量Dox安全注射如何增强并扩展Dox与手术、放疗和细胞疗法联合用于TNBC治疗的功能。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6f75/12211420/f97f1c70336e/12951_2025_3571_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6f75/12211420/93ce88a297c4/12951_2025_3571_Figa_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6f75/12211420/59dafa7e1ca7/12951_2025_3571_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6f75/12211420/3b46bbd16aec/12951_2025_3571_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6f75/12211420/9f64a9a29bca/12951_2025_3571_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6f75/12211420/f97f1c70336e/12951_2025_3571_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6f75/12211420/93ce88a297c4/12951_2025_3571_Figa_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6f75/12211420/59dafa7e1ca7/12951_2025_3571_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6f75/12211420/3b46bbd16aec/12951_2025_3571_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6f75/12211420/9f64a9a29bca/12951_2025_3571_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6f75/12211420/f97f1c70336e/12951_2025_3571_Fig5_HTML.jpg

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Chemotherapeutic drug scavenger-based combination therapy toward treating triple-negative breast cancer.

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本文引用的文献

[1]
Doxorubicin Detoxification in Healthy Organs Improves Tolerability to High Drug Doses for Enhanced Antitumor Therapy.

ACS Nano. 2023-4-25

[2]
Triple negative breast cancer: Pitfalls and progress.

NPJ Breast Cancer. 2022-8-20

[3]
Impact of the Histologic Pattern of Residual Tumor After Neoadjuvant Chemotherapy on Recurrence and Survival in Stage I-III Breast Cancer.

Ann Surg Oncol. 2022-11

[4]
Cytoprotective Effect of Vitamin D on Doxorubicin-Induced Cardiac Toxicity in Triple Negative Breast Cancer.

Int J Mol Sci. 2021-7-12

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Wiley Interdiscip Rev Nanomed Nanobiotechnol. 2021-11

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Biomater Sci. 2021-6-4

[7]
Prospective Evaluation of Doxorubicin Cardiotoxicity in Patients with Advanced Soft-tissue Sarcoma Treated in the ANNOUNCE Phase III Randomized Trial.

Clin Cancer Res. 2021-7-15

[8]
Nanostructured Polymeric, Liposomal and Other Materials to Control the Drug Delivery for Cardiovascular Diseases.

Pharmaceutics. 2020-11-28

[9]
Injectable Liquid Crystal Formation System for Reshaping Tumor Immunosuppressive Microenvironment to Boost Antitumor Immunity: Postoperative Chemoimmunotherapy.

Small. 2020-12

[10]
BECN1 promotes radiation-induced G2/M arrest through regulation CDK1 activity: a potential role for autophagy in G2/M checkpoint.

Cell Death Discov. 2020-8-5

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