Title: Preclinical targeted radiotherapy and estimated human dosimetry of 177Lu-DOTA-PEG4-LLP2A for VLA-4 targeted treatment of metastatic melanoma

Objectives 177Lu-DOTA-PEG4-LLP2A targeting very late antigen-4 (VLA-4) was previously demonstrated to have high uptake in aggressive B16F10 mouse melanoma tumor xenografts (Beaino et al. Mol Pharm 2015; 12:1929). The aim of this study was to probe the effectiveness of treatment of this tracer in C57BL/6 mice bearing B16F10 tumors and estimate radiation absorbed doses in human based on normal mouse biodistribution.

Methods B16F10 cells were injected subcutaneously into C57BL/6 mice (n=7 for 177Lu-DOTA-PEG4-LLP2A treatment, n=6 for control). The tumor mice were treated with an average of 0.8 mCi of 177Lu-DOTA-PEG4-LLP2A (Specific activity: 1 mCi/µg), and post-treatment tumor volume measurements were taken daily for 14 days. Biodistribution of 177Lu-DOTA-PEG4-LLP2A was performed in normal ICR mice at times from 1 h to 7 d post-injection. Radiation-absorbed dose projections in humans were evaluated by the basis of the residence times for 177Lu-DOTA-PEG4-LLP2A using the OLINDA/EXM version 1.0 computer program.

Results There was a statistically significant difference (p < 0.05) in tumor sizes between the 177Lu-DOTA-PEG4-LLP2A treated group and non-treated group, demonstrating efficacy of this treatment. There was no obvious toxicity in the treated mice over their survival period. The estimated human dosimetry calculations from normal mouse biodistribution data showed that the spleen and red marrow are dose-limiting organs.

Conclusions Therapy and dosimetry studies suggest the potential applications of 177Lu-DOTA-PEG4-LLP2A in the treatment of metastatic melanoma, particular in fractionated doses and/or combined with other types of therapy.