PDGFRβ-specific affibody-directed delivery of a photosensitizer, IR700, is efficient for vascular-targeted photodynamic therapy of colorectal cancer

<p>Vascular-targeted photodynamic therapy (PDT) is an important strategy for cancer therapy. Conventional vascular-targeted PDT has been achieved by passive photosensitizer (PS) delivery, which involves a high risk of adverse effects. Active PS delivery is urgently required for vascular-targeted PDT. Although endothelial cells and pericytes are major cellular components of tumor blood vessels, little attention has been paid to pericyte-targeted PDT for cancer therapy. PDGFRβ is abundantly expressed in the pericytes of various tumors. In this experiment, a dimeric Z<sub>PDGFRβ</sub> affibody with a 0.9 nM affinity for PDGFRβ was produced. The Z<sub>PDGFRβ</sub> affibody showed PDGFRβ-dependent pericyte binding. Intravenously injected Z<sub>PDGFRβ</sub> affibody was predominantly distributed on pericytes and thus accumulated in LS174T tumor grafts. The conjugate of the Z<sub>PDGFRβ</sub> affibody and IR700 dye, i.e. Z<sub>IR700</sub>, bound to PDGFRβ<sup>+</sup> pericytes but not to PDGFRβ<sup>−</sup> LS174T tumor cells. Accordingly, Z<sub>IR700</sub>-mediated PDT <i>in vitro</i> induced the death of pericytes but not of LS174T tumor cells. In mice bearing LS174T tumor grafts, Z<sub>IR700</sub>-mediated PDT damaged tumor blood vessels, thus inducing tumor destruction by intensifying tissue hypoxia. The average mass of tumor grafts administered with Z<sub>IR700</sub>-mediated PDT was approximately 20–30% of that of the control, indicating that pericyte-targeted PDT is efficient for cancer therapy. In addition, Z<sub>IR700</sub>-mediated PDT increased the tumor uptake of TNF-related apoptosis-inducing ligand (TRAIL) injected post-illumination. Consequently, combination therapy of Z<sub>IR700</sub>-mediated PDT and TRAIL showed greater tumor suppression than Z<sub>IR700</sub>-mediated PDT- or TRAIL-based monotherapy. These results demonstrated that active vascular-targeted PDT could be achieved by using Z<sub>PDGFRβ</sub> affibody-directed delivery of PS.</p>