In vivo study of DOTA-oligomers conjugated to 3-Tyr-octreotate

Abstract

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Objectives: The use of tumour specific-peptides in the therapy and diagnosis of malignant disease is a modality that has recently shown rapid progress. To improve the efficiency in the diagnosis and treatment of disseminated occult disease, the use of chelator-oligomers together with carrier substances such as tumour specific peptides represents an attractive prospect. Using a stepwise synthesis strategy the defined synthesis of Tyr3-octreotate conjugated to up to nine DOTA ligands per peptide could be performed (Mier W, Graham KAN, Wang Q et al. Synthesis of peptide conjugated chelator oligomers for endoradiotherapy and MRT imaging. Tetrahedron Lett 2004; 45: 5453-5.). The peptide derivatives retain a relatively high receptor binding affinity. The aim of this study was the investigation of the effect of the large chelator moiety on the biodistribution of these peptides.

Methods: Four (DOTA)n-TATE (n = 1,3,6,9) derivatives were labelled with In-111. The products were analyzed by RP-HPLC. No uncomplexed radiometal could be determined after 30 min at 60 °C. At 1 h post injection biodistribution experiments were performed by systemic application (injection via the tail vein) in nude mice bearing the SSTR positive AR4-2J tumours.

Results: It was found that the biodistribution of these peptides is dominated by the DOTA chelates. At 1 h p.i. all of the compounds investigated revealed high uptake in the kidneys. The highest value in the kidneys was observed for the DOTA-trimer conjugate. Consequently, a substantially decreased uptake in the tumour and the SSTR-positive tissues had to be observed (%ID/g tumour: DOTATOC = 8.90; (DOTA)3TATE = 3.57; (DOTA)6TATE = 0.50 and (DOTA)9TATE = 0.45).

Conclusions: Due to the hydrophilicity of the chelator-oligomers a relative large uptake into kidneys could be expected. However, the complete loss of tumour uptake for (DOTA)6TATE and (DOTA)9TATE is surprising because of their high SSTR affinity. This result reveals that the receptor affinity is not the predominant factor controlling accumulation in the tumour. This data shows the necessity of a balanced polarity charge of the SSTR affine peptides for therapeutic applications.