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VLA‐4 Targeted Radiopharmaceuticals for Seeing and Treating Metastatic Melanoma
Author(s) -
Anderson Carolyn,
Beaino Wissam,
Nedrow Jessie
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.104.2
Subject(s) - melanoma , cancer research , positron emission tomography , metastasis , chemistry , radiation therapy , targeted therapy , medicine , cancer , pathology , nuclear medicine
Melanoma is a malignant tumor derived from epidermal melanocytes and is known for its therapeutic resistance, aggressive clinical behavior, and predisposition for late metastasis. Very late antigen 4 (VLA‐4) is a transmembrane non‐covalent heterodimer (also called integrin alpha 4 beta 1) overexpressed in melanoma tumors that plays an important role in tumor growth, angiogenesis and metastasis by promoting adhesion and migration of cancer cells. There has been increasing interest in targeting this receptor for cancer imaging and therapy. Here we evaluated analogs of the high VLA‐4 binding peptidomimetic ligand, LLP2A, for PET‐CT imaging (labeled with Ga‐68; positron emitter, half‐life = 68 min) and targeted radiotherapy (labeled with Lu‐177; beta minus emitter, half‐life = 6.7 d). The DOTA‐PEG4‐LLP2A analog was labeled with Ga‐68 and Lu‐177, and the two agents showed high affinity to VLA‐4 in B16F10 mouse melanoma cells (IC50 = 1.56 nM and Kd = 4.1 nM, respectively). B16F10 subcutaneous tumors in C57/BL6 mice avidly took up the Lu‐177‐labeled agent, with a tumor:blood ratio of 185 at 24 h post‐injection, while the Ga‐68‐labeled analog had a tumor:blood of 6 at 1 h post‐injection. Ga‐68‐DOTA‐PEG4‐LLP2A visualized 1‐2 mm B16F10 metastases in albino C57/BL6 mice by small animal PET/CT. Ga‐68‐DOTA‐PEG4‐LLP2A is ready for translation to humans as a PET imaging agent to determine expression levels of VLA‐4 as a biomarker for aggressive, metastatic disease. Therapy studies with Lu‐177‐DOTA‐PEG4‐LLP2A in B16F10 tumor‐bearing mice are underway.