Synthesis and evaluation of tricarbonyl Re-188 labeled cRGD peptide as a potential radiotherapeutic agent in mice bearing α_vβ₃ integrin-overexpressing tumor xenografts

Objectives The α_vβ₃ integrin plays a very significant role in tumor induced angiogenesis and metastatic tumor. In this study, we synthesized a novel radiotherapeutic peptide containing a ¹⁸⁸Re(CO)₃ core instead of diagnostic radionuclide (Tc-99m) in tricarbonyl Tc-99m labeled RGD peptide which has improved biokinetics as well as highly tumor uptake. Its biodistribution and therapeutic effect was investigated in tumor xenograft mouse model.

Methods Tricarbonyl Re-188 labeled cRGD peptide was synthesized by incorporating [¹⁸⁸Re(CO)₃]⁺ into the precursor. Cell binding assay was performed in HUVEC for IC₅₀ evaluation. Scintigraphic imaging and biodistribution studies were investigated in Balb/c nude mice bearing U87-MG tumor. The antitumor activity of Re-188 labeled RGD peptide was evaluated by monitoring of tumor growth, microvessel formation in tumor and obtained animal SPECT/CT image using tricarbonyl Tc-99m labeled cRGD peptide.

Results The overall radiochemical yield of Re-188 labeled RGD peptide was 50-55%. A calculated IC₅₀ value was 0.5 nM. Biodistribution in U87MG tumor xenograft mouse model showed low blood activity (0.1 ± 0.01 %ID/g at 2 h), rapid hepatic clearance (3.77 ± 0.13 %ID/g at 10 min vs 0.35 ± 0.05 %ID/g at 8 h) and significantly high tumor accumulation (12.31 ± 1.73 %ID/g at 30 min). In anti-angiogenic study for 4 weeks, non-radiolabeled Re-cRGD peptide (5 mg/kg) and tricarbonyl Re-188 labeled cRAD peptide (11.1 MBq) treated mice produce 17.69% and 8.96%, reduction respectively, in the tumor volume compare to the untreated control. However, Re-188 labeled RGD peptide (11.1 MBq) treated mice significantly suppressed tumor growth by 69.39%. The anti-angiogenic effect was confirmed in immunohistochemistry.

Conclusions Theses results demonstrated that tricarbonyl Re-188 labeled cRGD peptide enhanced anti-angiotherapeutic effects against solid tumor which may make it a promising radiotherapeutic peptide to treat various cancers and angiogenic disease