Related Experiment Video
Updated: Jul 1, 2026
Harnessing the Bioorthogonal Inverse Electron Demand Diels-Alder Cycloaddition for Pretargeted PET Imaging
Published on: February 3, 2015
Integrating PD-L1-targeted radioligand with protein degradation for precision tumor theranostics
Qinglin Zhang1, Qi Liu1, Jia Liu2
1State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, National Innovation Platform for Industry-Education Integration in Vaccine Research, Fujian Engineering Research Center of Molecular Theranostic Technology, Center for Molecular Imaging and Translational Medicine, School of Public Health, Xiamen University, Xiamen, Fujian 361102, China.
Abstract:
Targeting programmed death ligand 1 (PD-L1) with proteolysis-targeting chimera (PROTAC) remains challenging due to the inability of visualized synergistic methods. Here, we report an integrated PD-L1-Targeted Radioligand with Protein Degradation (PRPD) platform that synergistically merges positron emission tomography (PET) imaging, targeted protein degradation, radiostimulation and radioligand therapy into a single small-molecule construct. We developed this radiotheranostic platform by designing amino acid-based linkers to conjugate PD-L1-targeting moiety, E3 ubiquitin ligase ligand, and 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) chelator. PET imaging enabled visualization of PD-L1 biodistribution, transforming degrader dosing from an empirical "black box" into an image-guided intervention. [68Ga]Ga/[177Lu]Lu-DOTA-BLP showed specific, time-dependent tumor uptake in MC38-bearing mice, which was blocked by BMS1166. Mechanistically, the radioligand induced DNA damage and upregulated PD-L1 expression, thereby "priming" the tumor for enhanced targeted degradation. Combining a single 7.4 MBq dose of [177Lu]Lu-DOTA-BLP with DOTA-BLP significantly enhanced tumor suppression and survival versus monotherapy, with minimal toxicity. Collectively, this work established a PRPD strategy that provides a visual, synergistic, and precision-guided approach for dynamic protein degradation in immuno-oncology.
Insights
This study introduces a novel radioligand platform for precise cancer therapy. It visualizes and degrades PD-L1 protein, enhancing tumor suppression and survival with minimal toxicity.
Area of Science:
- Biochemistry
- Molecular Biology
- Radiochemistry
Background:
- Targeting programmed death ligand 1 (PD-L1) with proteolysis-targeting chimeras (PROTACs) is challenging due to a lack of visualized synergistic methods.
- Current methods for PD-L1 targeting lack visual guidance for optimizing therapeutic interventions.
Purpose of the Study:
- To develop an integrated platform (PRPD) merging PET imaging, targeted protein degradation, and radioligand therapy for PD-L1.
- To enable image-guided intervention for PD-L1-targeted protein degradation and therapy.
Main Methods:
- Designed a small-molecule construct conjugating a PD-L1-targeting moiety, E3 ubiquitin ligase ligand, and DOTA chelator using amino acid-based linkers.
- Utilized positron emission tomography (PET) imaging for PD-L1 biodistribution visualization.
- Administered [68Ga]Ga/[177Lu]Lu-DOTA-BLP in MC38 tumor-bearing mice and assessed tumor uptake, DNA damage, PD-L1 expression, and therapeutic efficacy.
Main Results:
- The PRPD platform successfully merged PET imaging and targeted protein degradation.
- [68Ga]Ga/[177Lu]Lu-DOTA-BLP demonstrated specific, time-dependent tumor uptake, blocked by BMS1166.
- The radioligand induced DNA damage and upregulated PD-L1, enhancing targeted degradation. Combined therapy significantly improved tumor suppression and survival with low toxicity.
Conclusions:
- Established a PRPD strategy for visual, synergistic, and precision-guided dynamic protein degradation in immuno-oncology.
- Demonstrated the potential of image-guided intervention for optimizing degrader dosing and therapeutic outcomes.
- The developed radiotheranostic platform offers a promising approach for enhanced cancer treatment.
