Evaluation of <sup>68</sup>Ga- and <sup>177</sup>Lu-DOTA-PEG<sub>4</sub>‑LLP2A for VLA-4-Targeted PET Imaging and Treatment
of Metastatic Melanoma
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Abstract
Malignant melanoma is a highly aggressive
cancer, and the incidence
of this disease is increasing worldwide at an alarming rate. Despite
advances in the treatment of melanoma, patients with metastatic disease
still have a poor prognosis and low survival rate. New strategies,
including targeted radiotherapy, would provide options for patients
who become resistant to therapies such as BRAF inhibitors. Very late
antigen-4 (VLA-4) is expressed on melanoma tumor cells in higher levels
in more aggressive and metastatic disease and may provide an ideal
target for drug delivery and targeted radiotherapy. In this study,
we evaluated <sup>177</sup>Lu- and <sup>68</sup>Ga-labeled DOTA-PEG<sub>4</sub>-LLP2A as a VLA-4-targeted radiotherapeutic with a companion
PET agent for diagnosis and monitoring metastatic melanoma treatment.
DOTA-PEG<sub>4</sub>-LLP2A was synthesized by solid-phase synthesis.
The affinity of <sup>177</sup>Lu- and <sup>68</sup>Ga-labeled DOTA-PEG<sub>4</sub>-LLP2A to VLA-4 was determined in B16F10 melanoma cells by
saturation binding and competitive binding assays, respectively. Biodistribution
of the LLP2A conjugates was determined in C57BL/6 mice bearing B16F10
subcutaneous tumors, while PET/CT imaging was performed in subcutaneous
and metastatic models. <sup>177</sup>Lu-DOTA-PEG<sub>4</sub>-LLP2A
showed high affinity to VLA-4 with a <i>K</i><sub>d</sub> of 4.1 ± 1.5 nM and demonstrated significant accumulation in
the B16F10 melanoma tumor after 4 h (31.5 ± 7.8%ID/g). The tumor/blood
ratio of <sup>177</sup>Lu-DOTA-PEG<sub>4</sub>-LLP2A was highest at
24 h (185 ± 26). PET imaging of metastatic melanoma with <sup>68</sup>Ga-DOTA-PEG<sub>4</sub>-LLP2A showed high uptake in sites
of metastases and correlated with bioluminescence imaging of the tumors.
These data demonstrate that <sup>177</sup>Lu-DOTA-PEG<sub>4</sub>-LLP2A
has potential as a targeted therapeutic for treating melanoma as well
as other VLA-4-expressing tumors. In addition, <sup>68</sup>Ga-DOTA-PEG<sub>4</sub>-LLP2A is a readily translatable companion PET tracer for
imaging of metastatic melanoma