Dual-receptor PET imaging of ovarian cancer using a 68Ga-labeled heterodimer targeting folate receptor and HER2

Radiolabeled folate derivatives have been extensively investigated for positron emission tomography (PET) imaging of ovarian cancer due to the frequent overexpression of folate receptor α (FRα). However, clinical translation has been hindered, at least in part, by suboptimal tumor uptake of FRα-targeted radiotracers. In this study, we developed and characterized a ⁶⁸Ga-labeled heterodimeric radiotracer, ⁶⁸Ga-folate-KR, designed to concurrently target FRα and human epidermal growth factor receptor 2 (HER2), another receptor commonly overexpressed in ovarian cancer. Transcriptomics analysis confirmed the co-upregulation of <i>FOLR1</i> and <i>HER2</i> in ovarian cancer tissues relative to normal ovarian tissue, supporting the rationale for dual-receptor targeting. In vitro binding assays demonstrated specific binding of ⁶⁸Ga-folate-KR to both receptors. PET imaging and biodistribution studies in SKOV3 tumor-bearing mice revealed significantly enhanced tumor uptake and improved tumor-to-nontumor contrast compared to the monomeric radiotracers ⁶⁸Ga-folate and ⁶⁸Ga-KR. Competitive blocking experiments further confirmed the in vivo dual-receptor targeting capability of ⁶⁸Ga-folate-KR. Collectively, our results highlight that ⁶⁸Ga-folate-KR enables more sensitive PET detection of ovarian cancer xenografts. With further optimization, dual-receptor-targeted radiotracers hold promise for clinical translation in both lesion detection and therapy response monitoring in ovarian cancer.