Molecular targeting and development of a new radioreceptor therapeutic strategy for non-iodophil epithelial follicular thyroid and neuroendocrine-like tumors.

Introduction: Interest in SST-analogue-based treatments is increasing, largely because of the success in vivo targeting of SSTRs in neuroendocrine and neuroendocrine-like tumors. The main factor limiting therapeutic efficacy of such SST-analogs is their selectivity for particular SSTRs. In this study, it was evaluated the binding properties and biodistribution profile of a new SST-analogue (Peptide 1) recently prepared, retaining high selectivity for SSTR-2 Materials and methods: Among the DOTA-SST analogues synthesized DOTA-Peptide 1 was selected based on affinity profile. The 177Lu/111In-DOTA-Peptide1 was tested both in vitro, on different cell line expressing human SSTR2, in vivo in tumor xenografts-bearing nude mice and balc-c health mice. Immunofluorescence studies were performed for determination of the peptide-receptor complex internalisation. Results: Internalisation studies demonstrated that the uptake of 177Lu/111In-DOTA-Peptide1 is time-dependent, with a high specific internalisation after 4-24 hr of incubation (177LuDOTA-Peptide1: 38.23%±3.2; 57.68%±3 respectively. 111In-DOTA-Peptide1:6.59%±0.92 27.23%±1.6). Efflux studies exhibited a time-dependent pattern, with more than 50% retention of 177Lu/111In-DOTA-Peptide 1 after 4 hr of incubation. Pharmacokinetic studies performed in nude mice bearing tumor showed high radioligand accumulation in the tumors at 1 and 4 hr post injection (22.69±5.36 and 23.69±1.74 %ID/g, respectively). The other organs demonstrated low uptake with the exception of the kidneys (physiologic site of accumulation). At the 24 hr a good clearance was observed for all non-tumor and non-specific tissues (the only exception being the kidney, where the uptake remained high at 6.69±0.70%ID/g). Immunofluorescence studies demonstrate that the intenalisation of the complex is time dependent. Conclusion: DOTA-Peptide 1 was characterized pharmacologically. These preliminary results indicate that 177Lu/111In-DOTA-Peptide 1 is a promising new SST-based radioligand for possible diagnosis and PRRT of tumors specifically expressing SSTR2.