Evaluation of a radiolabelled cyclic DTPA-RGD analogue for tumour imaging and radionuclide therapy

Tumours depend on sufficient blood supply for their growth. They are able t o promote new blood vessel formation (neoangiogenesis) via angiogenic facto rs. Inhibition of this process results in tumour involution or necrosis. RG D (Arg-Gly-Asp) peptides are described to antagonise neoangiogenesis, e.g., by binding to alpha(v)beta(3) receptors on blood vessels. In order to visu alise neoangiogenesis in tumours in vitro and in vivo, we introduced and te sted an RGD analogue [c(Arg-Gly-Asp-D-Tyr-Lys)], coupled to the chelator di ethyleletriamepentaacetic acid (DTPA). This analogue can be radiolabelled w ith both In-111 and I-125. In autoradiography and immunohistochemistry stud ies, the I-125-labelled analogue appeared to bind specifically and with hig h affinity to alpha(v)beta(3), receptors on neovascular blood vessel sectio ns of different major human cancers, like prostate and breast cancer, which express these receptors. This radioiodinated radiopharmaceutical also boun d to and internalised in human carcinoid Bon cells and rat pancreatic CA209 48 tumour cells. Internalisation was receptor-specific and appeared to be t ime and temperature dependent, In vivo in rats, we investigated administrat ion of different peptide amounts (0.1, 0.5, and 100 pg) The best amount of the radiolabelled analogue to be administered to rats appeared to be 0.1 mu g/rat, as uptake decreased with increasing peptide amount. We also found r eceptor-specific accumulation of the In-111-labelled analogue in the transp lantable pancreatic tumour CA20948. The introduction of the DTPA group in t his peptide resulted in renal clearance of the radiopharmaceutical, in cont rast to the non-DTPA-conjugated compound that is cleared predominantly via the liver. In-111 emits Auger and conversion electrons besides gamma radiat ion, therefore, this radiopharmaceutical is suitable not only for tumour sc intigraphy but also has potential for radionuclide therapy of major human c ancers as well. Moreover, after coupling to the chelator DOTA, the analogue could be radiolabelled in a stable way with beta-emitters, e.g., Y-90 and Lu-177, enlarging its potential. (C) 2000 Wiley-Liss, Inc.