A novel α<sub>V</sub>β<sub>3</sub> ligand-modified HPMA copolymers for anticancer drug delivery

<p>The integrin α<sub>V</sub>β<sub>3</sub> receptor emerged as one of the most promising targets owing to its high expression on the surface of various malignant tumour cells and tumour angiogenesis endothelial cells, but with little expression in mature endothelial cells and the majority of normal cells. Here, we report a new targeting ligand FQSIYPpIK (FQS) with high affinity to integrin α<sub>V</sub>β<sub>3</sub> receptor. To take the advantage of the particular interaction between FQS and integrin α<sub>V</sub>β<sub>3</sub> receptor, FQS was linked to <i>N</i>-(2-hydroxypropyl) methacrylamide (HPMA) copolymers. A model drug doxorubicin (DOX) was simultaneously conjugated to the same HPMA copolymers via pH-sensitive hydrazone linkages (FQS–HPMA–DOX). In <i>in vitro</i> study, FQS–HPMA–DOX could be internalised into α<sub>V</sub>β<sub>3</sub> receptor-overexpressed B16F10 cells via a highly specific ligand − receptor pathway (5.0 times and 4.5 times higher cellular internalisation than HPMA–DOX and a scrambled peptide (s)-FQS (sequence: SYFIPKQIp)-modified copolymers ((s)-FQS–HPMA–DOX)). It is worth noting that compared with the classical α<sub>V</sub>β<sub>3</sub> ligand cRGDfK-modified HPMA copolymers (cRGDfK–HPMA–DOX), FQS–HPMA–DOX also showed superior targeting efficiency. In <i>in vivo</i> study in the B16F10 melanoma bearing mice model showed the antitumour efficiency of FQS–HPMA–DOX (83.9%) were significantly higher than HPMA–DOX (44.9%) and cRGDfK–HPMA–DOX (77.5%). These results suggest that FQS peptide can act as an effective targeting ligand for the delivery of therapeutic agents.</p>