Construction and Application of a PD-L1-Targeted Multimodal Diagnostic and Dual-Functional Theranostics Nanoprobe

Abstract

Chengxue He,1,2,* YanHui Guo,3,* Nina Zhou,2,* Zhen Wang,4,* Teli Liu,2 Xiaoxia Xu,2 Feng Wang,2 Hua Zhu,2 Zhi Yang,1,2 Xianteng Yang,1,5 Lei Xia2 1Medical College, Guizhou University, Guiyang, GuiZhou Province, People’s Republic of China; 2Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), NMPA Key Laboratory for Research and Evaluation of Radiopharmaceuticals (National Medical Products Administration), Department of Nuclear Medicine, Peking University Cancer Hospital & Institute, Beijing, People’s Republic of China; 3Department of Radiology, Peking University Third Hospital, Beijing, People’s Republic of China; 4Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education, Beijing), Department of Hepato-Pancreato-Biliary Surgery, Sarcoma Center, Peking University Cancer Hospital & Institute, Beijing, People’s Republic of China; 5Department of Orthopedics, Guizhou Provincial People’s Hospital, Guiyang, GuiZhou Province, People’s Republic of China*These authors contributed equally to this workCorrespondence: Lei Xia; Zhi Yang, Tel [phone], Email [email protected]; [email protected]: In recent years, PD-L1 has been primarily utilized as an immune checkpoint marker in cancer immunotherapy. However, due to tumor heterogeneity, the response rate to such therapies often falls short of expectations. In addition to its role in immunotherapy, PD-L1 serves as a specific target on the surface of tumor cells for targeted diagnostic and therapeutic interventions. There is an absence of a fully developed PD-L1-targeted diagnostic and therapeutic probe for clinical use, which constrains the exploration and clinical exploitation of this target.Methods and Results: In this study, we engineered a PD-L1-targeted probe with multimodal imaging and dual therapeutic functionalities utilizing organic melanin nanoparticles. Functionalization with the WL12-SH peptide endowed the nanoprobe with specific targeting capabilities. Subsequent radiolabeling with 89Zr (half-life: 100.8 hours) and chelation of Mn2+ ions afforded the probe the capacity for simultaneous PET and MRI imaging modalities. Cellular uptake assays revealed pronounced specificity, with -positive cells exhibiting significantly higher uptake than -negative counterparts (p < 0.05). Dual-modal PET/MRI imaging delineated rapid and sustained accumulation at the neoplastic site, yielding tumor-to-non-tumor (T/NT) signal ratios at 24 hours post-injection of 16.67± 3.45 for PET and 6.63± 0.64 for MRI, respectively. We conjugated the therapeutic radionuclide 131I (half-life: 8.02 days) to the construct and combined low-dose radiotherapy and photothermal treatment (PTT), culminating in superior antitumor efficacy while preserving a high safety profile. The tumors in the cohort receiving the dual-modality therapy exhibited significantly reduced volume and weight compared to those in the control and monotherapy groups.Conclusion: We developed and applied a novel -targeted multimodal theranostic nanoprobe, characterized by its high specificity and superior imaging capabilities as demonstrated in PET/MRI modalities. Furthermore, this nanoprobe facilitates potent therapeutic efficacy at lower radionuclide doses when used in conjunction with PTT. Keywords: theranostics, PET/MRI, melanin nanoparticles, photothermal therapy

Keywords

• theranostics
• pet/mri
• melanin nanoparticles
• photothermal therapy