Development of dual targeting heterodimer 177Lu-LNC1009 for cancer theranostics

Introduction: Heterodimer LNC1007 (NOTA-FAPI-RGD) that targets both fibroblast activation protein (FAP) and integrin α_vβ₃ has been developed and labeled with ⁶⁸Ga and ¹⁸F for PET imaging of FAP positive and/or integrin α_vβ₃ positive tumors. In this study, we synthesized dual targeting LNC1009 (DOTA-EB-FAPI-RGD) that is derived from LNC1007 but with albumin binder Evans blue (EB) moiety and radiolabeled with ¹⁷⁷Lu for cancer imaging and therapy.

Methods: LNC1009 was designed and synthesized based on EB moiety, FAPI-02 inhibitor and cyclic RGDfK peptide. Binding affinity and targeting specificity were verified through cell uptake and competition binding assay. SPECT imaging and preclinical pharmacokinetics of ¹⁷⁷Lu-LNC1009 were determined in U87MG xenograft model to identify the treatment potential. For the comparison, SPECT images of ¹⁷⁷Lu-DOTA-NC1007, ¹⁷⁷Lu-EB-RGD, and ¹⁷⁷Lu-LNC1004 (¹⁷⁷Lu-EB-FAPI) were also performed in U87MG tumor model.

Results: The ¹⁷⁷Lu-LNC1009 had good stability in saline for at least 96 h, and showed favorable binding affinity and specificity in vitro and in vivo. SPECT imaging of ¹⁷⁷Lu-LNC1009 showed significantly improved tumor uptake and retention than those of ¹⁷⁷Lu-DOTA-FAPI-RGD. In addition, ¹⁷⁷Lu-LNC1009 also exhibited higher tumor-to-background ratios and lower normal organs uptake than ¹⁷⁷Lu-LNC1004 and ¹⁷⁷Lu-EB-RGD, which indicated the enormous potential for cancer therapy.

Conclusions: ¹⁷⁷Lu-LNC1009 was successfully synthesized and radiolabeled with high radiochemical purity and stability. With significantly improved absolute tumor uptake and decreased normal organ uptake, ¹⁷⁷Lu-LNC1009 has the potential to enhance therapy effect that promises clinical translation for the treatment of many types of solid tumors that are FAP⁺/α_vβ₃^-, FAP^-/α_vβ₃⁺, or FAP⁺/α_vβ₃⁺.

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