Construction and evaluation of PSMA and integrin α2β1 targeted hetero-bivalent agents for the PET imaging and internal irradiation therapy of prostate cancer

•Hetero-bivalent agents targeting Integrin α2β1 and PSMA were developed.•PET probe/internal irradiation therapy drug were constructed based on the agents.•Small prostate cancer metastases can be detected in early stage by PET imaging.•Tumors with different phenotype were inhibited by internal irradiation therapy. Prostate specific membrane antigen (PSMA) ligands play significant roles in the radiotheranositcs of prostate cancer (PC), but also face challenges of false negative results and lesion loss, especially when encountering bone metastases. Aiming at prostate cancer bone metastasis (PCBM) and taking integrin α2β1 as the second target of PSMA, in this work we constructed two hetero-bivalent agents (lIP-L and cIP-L). The added diagnostic value of integrin α2β1 to PSMA was firstly evaluated using RNA of 512 PC patient and 52 healthy individuals as analysis sample. PET tracers ([68Ga]Ga-lIP-L and [68Ga]Ga-cIP-L) and internal irradiation therapy drug (IRT, [177Lu]Lu-cIP-L) were then developed. Dual-receptor specificity and affinity were determined on PC-3 and LNCaP cell. Biodistribution and circulation behaviors were investigated. PET imaging and IRT were performed on PC-3 and LNCaP tumor-bearing mice. [68Ga]Ga-lIP-L and [68Ga]Ga-cIP-L demonstrated high affinity and specificity to both integrin α2β1 and PSMA. Moreover, [68Ga]Ga-cIP-L showed capacity to monitor the development of bone metastases and identify bone metastases including metastases at spine, rib, tibia, vertebra and skull at very small and early stage. Last but not least, [177Lu]Lu-cIP-L also demonstrated dual-target specificity and showed strong antitumor effects on both PC-3 and LNCaP tumors. Hence, we considered that lIP-L and cIP-L showed great potential to be translated as powerful radiotheranostic tools for the early and accurate detection/treatment of prostate cancer.