Background The mechanisms underpinning neoadjuvant chemotherapy-induced vascular endothelial injury in breast cancer remain elusive. Our study aims to demonstrate that Neutrophil Extracellular Traps (NETs) play a pivotal role in neoadjuvant chemotherapy-induced vascular endothelial injury in breast cancer, elucidating that chemotherapy-induced upregulation of Solute Carrier 11a1 (Slc11a1) modulates Reactive Oxygen Species (ROS) generation, which may be critical for NETs formation.Methods We investigated the impact of neoadjuvant chemotherapy for breast cancer on NETs formation and vascular endothelial injury by analyzing NETs dsDNA and serum markers in patients, cells, and chemotherapy mouse models. RNA sequencing of neutrophils from chemotherapy mouse models was performed to identify the potential NETs formation-associated gene Slc11a1, which was further validated through cellular and animal experiments by assessing Slc11a1 expression, intracellular ferrous ion content, and ROS levels. Knockdown of Slc11a1 in human neutrophils and mouse models were also performed to further confirm the phenotypic results.Results Our study revealed that plasma NETs formation and endothelial injury markers were significantly elevated in breast cancer patients undergoing docetaxel & carboplatin (TCb) neoadjuvant chemotherapy, compared to controls. In these patients, NETs formation was associated with the augmentation of endothelial injury markers. Chemotherapy mouse models demonstrated that TCb treatment markedly elevated NETs formation and endothelial injury, which can be mitigated by CI-amidine, a protein-arginine deiminase inhibitor. In human neutrophils, we demonstrated that the TCb chemotherapeutic agents (combination of docetaxel and carboplatin) induced the formation of NETs, which subsequently facilitated damage to human umbilical vein endothelial cells in vitro. RNA sequencing of mouse neutrophils identified Slc11a1 as a key NETs formation-related gene, which was upregulated by TCb chemotherapy in neutrophils, leading to increased intracellular ferrous ion content and ROS generation. Knockdown of Slc11a1 in human neutrophils and mouse models demonstrated its reversal effect on TCb-induced ferrous ion upregulation, ROS generation, and NETs formation.Conclusion sOur research underscores the capacity of TCb neoadjuvant chemotherapy in breast cancer to augment NETs formation in neutrophils through Slc11a1-mediated ROS generation, which is linked to vascular endothelial injury. Our study elucidates the potential mechanisms underlying perioperative vascular endothelial injury in breast cancer patients undergoing neoadjuvant chemotherapy, offering novel insights into perioperative therapeutic management strategies for these patients.
Chen Biqing,Gao Jiayin,Sun Haizhu,Zhao Yinghan,Liu Yan,Lv Xinpeng,Qiu Xiaohong,Li Yang
Chemotherapy remains a cornerstone in the treatment of multiple solid and gynecologic malignancies, including endometrial cancer, ovarian cancer, and breast cancer. Carboplatin, epirubicin, gemcitabine, paclitaxel, topotecan, and docetaxel are widely used in combination regimens; however, there is still a lack of sensitive, rapid, and multiplex technologies for real-time monitoring of chemotherapeutic drug concentrations. In this study, we developed a carboxyl-polyethylene glycol (PEG)-modified magnetite (Fe₃O₄@PEG) nanoplatform combined with artificial intelligence (AI)-driven spectral analysis to achieve ultra-sensitive and multiplex detection of six chemotherapeutic drugs. Fe₃O₄ nanoparticles were synthesized by co-precipitation and subsequently functionalized with carboxyl-PEG to enhance drug capture efficiency and resistance to matrix interference. Using a confocal Raman imaging system, SERS spectra of single and mixed drug systems were collected, and convolutional neural networks (CNNs) were employed for automated feature extraction and classification to enable qualitative and quantitative analysis. The constructed SERS platform achieved 10⁻⁷–10⁻⁸ milligrams per milliliter (mg/mL) detection limits for all six drugs in serum matrices, with classification accuracies exceeding 95% in multiplex mixtures. For improved quantitative accuracy and normalization, the 2078 cm⁻ 1 Raman peak of deuterated methanol (CD₃OD) was employed as an internal standard to correct for potential fluctuations in laser intensity and sample concentration. Within the simulated therapeutic concentration range, quantitative regression yielded R 2 ≥ 0.98. This AI-SERS platform offers advantages of multiplex detection, trace-level sensitivity, and strong anti-matrix interference, holding great promise for pharmacokinetic monitoring and individualized chemotherapy optimization across a broad range of solid tumors. Graphical abstract Schematic illustration of an AI-integrated Fe 3 O 4 @PEG–SERS nanoplatform for multiplex detection of six chemotherapeutic agents (carboplatin, epirubicin, gemcitabine, paclitaxel, topotecan, and docetaxel). Carboxyl-PEG–modified magnetite nanoparticles enhance drug adsorption and stability, while convolutional neural networks enable accurate qualitative and quantitative spectral analysis for personalized chemotherapy optimization.
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