Peptide-based immuno-PET/CT monitoring of dynamic PD-L1 expression during glioblastoma radiotherapy.

in Journal of pharmaceutical analysis by Yong Wang, Kewen He, Yang Zhang, Yunhao Chen, Shijie Wang, Kunlong Zhao, Zhiguo Liu, Man Hu

TLDR

  • The study developed a novel peptide-based radiolabeled tracer, [F]AlF-NOTA-PCP2, targeting PD-L1, and evaluated its imaging capabilities in orthotopic glioblastoma models, showing potential for noninvasively monitoring PD-L1 expression after radiotherapy.
  • Key Insights: The study demonstrated the feasibility of using [F]AlF-NOTA-PCP2 to track PD-L1 expression in brain tumors, which could guide immunotherapy and improve patient outcomes.

Abstract

Real-time, noninvasive programmed death-ligand 1 (PD-L1) testing using molecular imaging has enhanced our understanding of the immune environments of neoplasms and has served as a guide for immunotherapy. However, the utilization of radiotracers in the imaging of human brain tumors using positron emission tomography/computed tomography (PET/CT) remains limited. This investigation involved the synthesis of [F]AlF-NOTA-PCP2, which is a novel peptide-based radiolabeled tracer that targets PD-L1, and evaluated its imaging capabilities in orthotopic glioblastoma (GBM) models. Using this tracer, we could noninvasively monitor radiation-induced PD-L1 changes in GBM. [F]AlF-NOTA-PCP2 exhibited high radiochemical purity (>95%) and stability up to 4 h after synthesis. It demonstrated specific, high-affinity binding to PD-L1and, with a dissociation constant of 0.24 nM. PET/CT imaging, integrated with contrast-enhanced magnetic resonance imaging, revealed significant accumulation of [F]AlF-NOTA-PCP2 in orthotopic tumors, correlating with blood-brain barrier disruption. After radiotherapy (15 Gy), [F]AlF-NOTA-PCP2 uptake in tumors increased from 9.51% ± 0.73% to 12.04% ± 1.43%, indicating enhanced PD-L1 expression consistent with immunohistochemistry findings. Fractionated radiation (5 Gy × 3) further amplified PD-L1 upregulation (13.9% ± 1.54% ID/cc) compared with a single dose (11.48% ± 1.05% ID/cc). Taken together, [F]AlF-NOTA-PCP2 may be a valuable tool for noninvasively monitoring PD-L1 expression in brain tumors after radiotherapy.

Overview

  • The study aimed to develop a novel peptide-based radiolabeled tracer, [F]AlF-NOTA-PCP2, that targets programmed death-ligand 1 (PD-L1) and evaluates its imaging capabilities in orthotopic glioblastoma (GBM) models.
  • The study explored the use of [F]AlF-NOTA-PCP2 to noninvasively monitor radiation-induced PD-L1 changes in GBM and evaluated its binding affinity to PD-L1 and stability.
  • The primary objective was to develop [F]AlF-NOTA-PCP2 as a valuable tool for noninvasively monitoring PD-L1 expression in brain tumors after radiotherapy.

Comparative Analysis & Findings

  • [F]AlF-NOTA-PCP2 exhibited high radiochemical purity (>95%) and stability up to 4 h after synthesis, indicating its potential as a reliable imaging agent.
  • The study found that [F]AlF-NOTA-PCP2 demonstrated specific, high-affinity binding to PD-L1 with a dissociation constant of 0.24 nM, suggesting its potential for targeted imaging.
  • PET/CT imaging revealed significant accumulation of [F]AlF-NOTA-PCP2 in orthotopic tumors, correlating with blood-brain barrier disruption, and showed increased uptake after radiotherapy, indicating enhanced PD-L1 expression.

Implications and Future Directions

  • The study's findings suggest that [F]AlF-NOTA-PCP2 may be a valuable tool for noninvasively monitoring PD-L1 expression in brain tumors after radiotherapy, which could guide immunotherapy and improve patient outcomes.
  • Future studies could explore the use of [F]AlF-NOTA-PCP2 to monitor PD-L1 expression in other types of brain tumors and to evaluate its potential as a predictive biomarker for immunotherapy response.
  • The study highlights the need for further research to better understand the mechanisms of radiation-induced PD-L1 upregulation and to develop effective strategies for overcoming immunosuppressive barriers in brain tumors.
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