Identification of a Vascular Endothelial Growth Factor Receptor-3 Binding Peptide TMVP1 for Enhancing Drug Delivery Efficiency and Therapeutic Efficacy Against Tumor Lymphangiogenesis

<b><i>Background:</i></b> Vascular endothelial growth factor receptor-3 (VEGFR-3) plays an indispensable role in lymphangiogenesis. Previous findings suggest that blocking the VEGFR-3 signaling pathway can inhibit lymph node metastasis effectively, thus reducing the incidence of distant metastasis. The development of new VEGFR-3-targeting drugs for early detection and effective treatments is, therefore, urgently required. <b><i>Methods:</i></b> <i>In vitro</i> biopanning of a phage-displayed peptide library was used to identify specific peptides binding to the extracellular domain of VEGFR-3. We obtained a novel VEGFR-3-targeting peptide, TMVP1 (LARGR). Our combined immunofluorescence and radiolabeling studies revealed that FITC-TMVP1 and ^99mTc-labeled TMVP1 specifically accumulated in VEGFR-3-positive lymphatic vessels of tumors after intravenous administration in tumor xenograft models <i>in vivo</i>. To enhance the therapeutic efficacy of anticancer drugs, TMVP1 was fused to a proapoptotic peptide, _D(KLAKLAK)². <b><i>Results:</i></b> The fusion peptide strongly inhibited tumor lymphangiogenesis <i>in vitro</i> and <i>in vivo</i> and specifically suppressed lung metastasis in a 4T1 breast cancer xenograft model. The accumulation of the TMVP1 in lymphatic vessels was specific. <b><i>Conclusions:</i></b> Our results suggest that TMVP1 is a potential therapeutic strategy for developing new diagnostic tracers or alternative anticancer agents for tumor lymphangiogenesis and lymphatic metastasis.