Abstract
Angiogenesis plays a key role in cancer progression and correlates with disease aggressiveness and poor clinical outcomes. Affinity ligands discovered by screening phage display random peptide libraries can be engineered to molecularly target tumor blood vessels for noninvasive imaging and early detection of tumor aggressiveness. In this study, we tested the ability of a phage-display-selected peptide sequence recognizing specifically bone marrow- derived pro-angiogenic tumor-homing cells, the QFP-peptide, radiolabeled with 64Cu radioisotope to selectively image tumor vasculature in vivo by positron emission tomography (PET). To prepare the targeted PET tracer we modified QFP-phage with the DOTA chelator and radiolabeled the purified QFP-phage-DOTA intermediate with 64Cu to obtain QFP-targeted radioconjugate with high radiopharmaceutical yield and specific activity. We evaluated the new PET tracer in vivo in a subcutaneous (s.c.) Lewis lung carcinoma (LLC) mouse model and conducted tissue distribution, small animal PET/CT imaging study, autoradiography, histology, fluorescence imaging, and dosimetry assessments. The results from this study show that, in the context of the s.c. LLC immunocompetent mouse model, the QFP-tracer can target tumor blood vessels selectively. However, further optimization of the biodistribution and dosimetry profile of the tracer is necessary to ensure efficient radiopharmaceutical applications enabled by the biological specificity of the QFP-peptide.
Highlights
Angiogenesis is a hallmark of cancer and is generally associated with aggressive cancer growth and poor patient prognosis
Bone marrow-derived endothelial cells have been detected in patients with multiple myeloma [6], primary breast cancer [7], non-small cell lung cancer [8], and malignant gliomas [9]
Circulating progenitor cells of bone marrow origin have been exploited as a potential biomarker to guide the applications of antiangiogenic therapy in cancer patients [11]
Summary
Angiogenesis is a hallmark of cancer and is generally associated with aggressive cancer growth and poor patient prognosis. Antibodies and proteins have been considered as targeted imaging agents, these high molecular weight biologicals demonstrate poor accumulation and penetration in solid tumors, slow in vivo clearance, and sensitivity to labeling conditions To overcome these limitations, development efforts have focused on smaller moieties such as peptides. Designed and characterized new 64Cu-labeled bombesin targeting vector for molecular imaging studies in GRP-expressing tumor models and demonstrated high in vivo affinity and selectivity in prostate. By screening a phage display dodecapeptide library in vivo, we were first to discover a novel amino acid sequence, the QFP-peptide (QFPPKLTNNSML), that binds with high affinity to bone marrow-derived circulating tumor-homing cells [36] and the motivation to pursue further characterization. Control experiments were run in parallel with a nontargeted radiotracer and the results were compared
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