Multifunctional dendrimer-peptide conjugates for MET receptor-specific imaging of cancer cells

The Mesenchymal Epithelial Transition (MET) receptor tyrosine kinase is frequently upregulated or mutated in various cancers. Targeting MET signaling pathway has been utilized as a treatment for cancer, since MET overexpression is often associated with poor prognosis. Selective imaging of MET-overexpressing tumor cells would thus provide a high diagnostic value; however, it remains elusive due to a lack of targeted imaging contrast agents. Herein, we have developed a multifunctional diagnostic dendrimer-peptide conjugate (DPC) system with a strong avidity to MET-expressing cancer cells. The system was prepared by conjugating MET-inhibiting peptides (C7) to generation 7 (G7) poly(amidoamine) (PAMAM) dendrimers. Due to the dendrimer-mediated multivalent binding effect, the DPCs exhibited a significantly stronger binding to the human MET protein than free C7, as measured using surface plasmon resonance. Confocal microscopy revealed increased binding of the DPCs to the MET-expressing EBC-1 and UW-Lung-21 cells, whereas a MET knock-out cell line showed negligible interactions with the DPCs. The DPCs were then conjugated with Zirconium-89 for positron emission tomography and computed tomography (PET/CT) scanning, demonstrating their selective accumulation to MET-expressing tumors in vivo. Additionally, the plasma half-life of the DPCs was measured at ∼53 hours, which was significantly longer than free C7. These results collectively suggest that this DPC system has potential as a targeted imaging platform specific to MET-expressing tumors, which would be applicable to various cancer types. [Display omitted] •The binding kinetics of C7 peptides was significantly improved upon conjugation to dendrimers through multivalency (avidity).•DPCs can be labeled with either a fluorescent tag or 89Zr for highly sensitive PET/CT imaging of tumors in vivo.•DPCs exhibit a substantially longer terminal plasma half-life (~53 hrs) compared to the free peptides (typically 2-30 mins).•This DPC platform can potentially target other overexpressed receptors, leading to a new platform of targeted imaging agents.