Novel Dual-Mode NIR-II/MRI Nanoprobe Targeting PD-L1 Accurately Evaluates the Efficacy of Immunotherapy for Triple-Negative Breast Cancer

Abstract

Wan-Ling Liu,1– 4,* Yong-Qu Zhang,1– 5,* Xiang-Jie Luo,6 Yuan-Yuan Zhu,1– 4 Liang Song,7 Zi-He Ming,1– 4 Li-Xin Zhang,1– 4 Meng-Jun Li,1– 4 Rui-Chan Lv,8 Guo-Jun Zhang,1– 4,9,* Min Chen2– 4,* 1Department of Breast-Thyroid-Surgery and Cancer Center, Xiang’an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, People’s Republic of China; 2Fujian Key Laboratory of Precision Diagnosis and Treatment in Breast Cancer, Xiang’an Hospital of Xiamen University, Xiamen, People’s Republic of China; 3Xiamen Key Laboratory of Endocrine-Related Cancer Precision Medicine, Xiamen, People’s Republic of China; 4Xiamen Research Center of Clinical Medicine in Breast & Thyroid Cancers, Xiamen, People’s Republic of China; 5Department of Breast Center, Cancer Hospital of Shantou University Medical College, Shantou, People’s Republic of China; 6College of Chemistry and Chemical Engineering, Xiamen University, Xiamen, People’s Republic of China; 7Xiamen Institute of Rare Earth Materials, Haixi Institute, Chinese Academy of Sciences and Technology University, Xiamen, People’s Republic of China; 8Engineering Research Center of Molecular and Neuro Imaging, Ministry of Education, School of Life Science and Technology, Xidian University, Xi’an, Shanxi, People’s Republic of China; 9Cancer Research Center, School of Medicine, Xiamen University, Xiamen, People’s Republic of China*These authors contributed equally to this workCorrespondence: Min Chen; Guo-Jun Zhang, Email [email protected]; [email protected]: Durable responses to immune-checkpoint blocking therapy (ICT) targeting programmed cell death protein-1/ligand-1 (PD-1/PD-L1) have improved outcomes for patients with triple negative breast cancer (TNBC). Unfortunately, only 19– 23% of patients benefit from ICT. Hence, non-invasive strategies evaluating responses to therapy and selecting patients who will benefit from ICT are critical issues for TNBC immunotherapy.Methods: We developed a novel nanoparticle-Atezolizumab (NPs-Ate) consisting of indocyanine green (ICG), gadolinium-diethylenetriamine pentaacetic acid (Gd-DTPA), human serum albumin (HSA), and Atezolizumab. The efficiency of Gd-DTPA linking was verified using mass spectrometry, and the size of NPs-Ate was characterized using Nano-flow cytometry. The synthesized NPs-Ate were evaluated for fluorescence stability, penetration depth, and target specificity. TNBC cell lines and tumor-bearing mice models were used to identify the feasibility of this dual-modal second near-infrared/magnetic resonance imaging (NIR-II/MRI) system. Additionally, ICT combination with chemotherapy or radiotherapy in TNBC tumor-bearing mice models were used to assess dynamic changes of PD-L1 and predicted therapeutic responses with NPs-Ate.Results: Atezolizumab, a monoclonal antibody, was successfully labeled with ICG and Gd-DTPA to generate NPs-Ate. This demonstrated strong fluorescence signals in our NIR-II imaging system, and relaxivity (γ 1) of 9.77 mM− 1 s− 1. In tumor-bearing mice, the NIR-II imaging signal background ratio (SBR) reached its peak of 11.51 at 36 hours, while the MRI imaging SBR reached its highest as 1.95 after 12 hours of tracer injection. NPs-Ate specifically targets cells and tumors expressing PD-L1, enabling monitoring of PD-L1 status during immunotherapy. Combining therapies led to inhibited tumor growth, prolonged survival, and increased PD-L1 expression, effectively monitored using the non-invasive NPs-Ate imaging system.Conclusion: The NIR-II/MRI NPs-Ate effectively reflected PD-L1 status during immunotherapy. Real-time and non-invasive immunotherapy and response/prognosis monitoring under NIR-II/MRI imaging guidance in TNBC is a promising and innovative technology with potential for extensive clinical applications in the future.Keywords: dual-modal imaging, triple-negative breast cancer, immune-checkpoint blocking therapy, programmed cell death protein ligand-1, monitoring therapeutic response

Keywords

• dual-modal imaging
• triple-negative breast cancer
• immune-checkpoint blocking therapy
• programmed cell death protein ligand-1
• monitoring therapeutic response.