Platelet-derived growth factor receptor -targeted positron emission tomography imaging for the noninvasive monitoring of liver fibrosis

Purpose Noninvasive quantifying activated hepatic stellate cells (aHSCs) by molecular imaging is helpful for assessing disease progression and therapeutic responses of liver fibrosis. Our purpose is to develop platelet-derived growth factor receptor beta (PDGFR beta)-targeted radioactive tracer for assessing liver fibrosis by positron emission tomography (PET) imaging of aHSCs.Methods Comparative transcriptomics, immunofluorescence staining and flow cytometry were used to evaluate PDGFR beta as biomarker for human aHSCs and determine the correlation of PDGFR beta with the severity of liver fibrosis. The high affinity affibody for PDGFR beta (Z(PDGFR beta)) was labeled with gallium-68 (Ga-68) for PET imaging of mice with carbon tetrachloride (CCl4)-induced liver fibrosis. Binding of the [Ga-68]Ga-labeled Z(PDGFR beta) ([Ga-68]Ga-DOTA-Z(PDGFR beta)) for aHSCs in human liver tissues was measured by autoradiography.Results PDGFR beta overexpressed in aHSCs was highly correlated with the severity of liver fibrosis in patients and CCl4-treated mice. The Ga-68-labeled Z(PDGFR beta) affibody ([Ga-68]Ga-DOTA-Z(PDGFR beta)) showed PDGFR beta-dependent binding to aHSCs. According to the PET imaging, hepatic uptake of [Ga-68]Ga-DOTA-Z(PDGFR beta) increased with the accumulation of aHSCs and collagens in the fibrotic livers of mice. In contrast, hepatic uptake of [Ga-68]Ga-DOTA-Z(PDGFR beta) decreased with spontaneous recovery or treatment of liver fibrosis, indicating that the progression and therapeutic responses of liver fibrosis in mice could be visualized by PDGFR beta-targeted PET imaging. [Ga-68]Ga-DOTA-Z(PDGFR beta) also bound human aHSCs and visualized fibrosis in patient-derived liver tissues.Conclusions PDGFR beta is a reliable biomarker for both human and mouse aHSCs. PDGFR beta-targeted PET imaging could be used for noninvasive monitoring of liver fibrosis in mice and has great potential for clinical translation.