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

Abstract

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 β (PDGFRβ)-targeted radioactive tracer for assessing liver fibrosis by positron emission tomography (PET) imaging of aHSCs. Comparative transcriptomics, immunofluorescence staining and flow cytometry were used to evaluate PDGFRβ as biomarker for human aHSCs and determine the correlation of PDGFRβ with the severity of liver fibrosis. The high affinity affibody for PDGFRβ (ZPDGFRβ) was labeled with gallium-68 (68Ga) for PET imaging of mice with carbon tetrachloride (CCl4)-induced liver fibrosis. Binding of the [68Ga]Ga-labeled ZPDGFRβ ([68Ga]Ga-DOTA-ZPDGFRβ) for aHSCs in human liver tissues was measured by autoradiography. PDGFRβ overexpressed in aHSCs was highly correlated with the severity of liver fibrosis in patients and CCl4-treated mice. The 68Ga-labeled ZPDGFRβ affibody ([68Ga]Ga-DOTA-ZPDGFRβ) showed PDGFRβ-dependent binding to aHSCs. According to the PET imaging, hepatic uptake of [68Ga]Ga-DOTA-ZPDGFRβ increased with the accumulation of aHSCs and collagens in the fibrotic livers of mice. In contrast, hepatic uptake of [68Ga]Ga-DOTA-ZPDGFRβ 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 PDGFRβ-targeted PET imaging. [68Ga]Ga-DOTA-ZPDGFRβ also bound human aHSCs and visualized fibrosis in patient-derived liver tissues. PDGFRβ is a reliable biomarker for both human and mouse aHSCs. PDGFRβ-targeted PET imaging could be used for noninvasive monitoring of liver fibrosis in mice and has great potential for clinical translation.