~(177)Lu-iabeIed monoinericf dimeric and multimeric RGD peptides for the therapy of tumors expressing alpha[v) beta (3) integrins

摘要

The conjugation of peptides to gold nanopartides {AuNPs) produces bioeompatible and stable multimeric systems with target-specific molecular recognition. Peptides based on the cyclic Arg-GIy-Asp (RGD) sequence have been reported as high-affinity agents for the a(v)p{3) integrin. The aim of this research was to prepare a multimeric system of ~(177)Lu-labeled gold nanopartides conjugated to c(RGDfK)C (cyclo(Arg-Gly-Asp-Phe-Lys)Cys) and to compare the radiation-absorbed dose with that of ~(177)Lu-Iabeled monomerie and dimeric RGD peptides to a{v)fl[3) integrin-positive U87MG tumors in mice. DOTA-GGC (1A7,10-tetraazacydododecane-N-N',N",N'"-tetraacetic acid-Gly-Gly-Cys) and c(RGDfK)C peptides were synthesized and conjugated to AuNPs by a spontaneous reaction of the thiol groups. Transmission electron microscopy, ultraviolet-visible. X-ray photoelectron spectroscopy, Raman and far-infrared spectroscopy techniques demonstrated that AuNPs were f unctionalised with the peptides. For the' 77Lu-AuNP-c(RGDf K)C to be obtained, the% 77Lu-D0TA-GGC radiopeptide was first prepared and added to a solution of AuNPs followed by c(RGDfK)C (25 pJ, 5 jam) at 18 degC for 15 min. ~(177)Lu-DOTA-GGQ ~(177)Lu-DOTA-cRGDfK and ~(177)Lu-DOTA-E-c(RGDfK)2 were prepared by adding ~(177)LuCI3 (370 MBq) to 5 |xl (1 mg/ml) of the DOTA derivative diluted with 50 pi of 1 M acetate buffer pH 5. The mixture was incubated at 90 degC in a block heater for 30 min. Radiochemkal purity was determined by ultrafiltration and HPLC analyses. Biokinetic studies were accomplished in athymic mice with U87MG-induced tumors. The radiochemieal purity for all ~(177)Lu-RGD derivatives was 96 +- 2%. ~(177)Lu-absorbed doses per injected activity delivered to U87MG tumors were 0357 +- 0.052 Gy/MBq (multimer), 0.252 +- 0.027 Gy/MBq (dimer) and 0.102+-0.018Gy/MBq (monomer). ~(177)Lu-labeled dimeric and multlmerie RGD peptides demonstrated properties suitable for targeted radionuclide therapy of tumors expressing alpha[v) beta (3) integrins.