Human tumor necrosis factor-related apoptosis-inducing ligand (hTRAIL) has exhibited superior cytotoxicity in a variety of tumor cells. However， hTRAIL showed a disappointing anticancer effect in clinical trials， although hTRAIL-based regimens were well tolerated. One important reason might be that hTRAIL was largely trapped by its decoy receptors， which are ubiquitously expressed on normal cells. Tumor-targeted delivery might improve the tumor uptake and thus enhance the antitumor effect of hTRAIL. Platelet-derived growth factor receptor β (PDGFRβ)-expressing pericytes are enriched in tumor tissues derived both from patients with colon cancer and from mice bearing colorectal tumor xenografts. A Z affi... More
Human tumor necrosis factor-related apoptosis-inducing ligand (hTRAIL) has exhibited superior cytotoxicity in a variety of tumor cells. However， hTRAIL showed a disappointing anticancer effect in clinical trials， although hTRAIL-based regimens were well tolerated. One important reason might be that hTRAIL was largely trapped by its decoy receptors， which are ubiquitously expressed on normal cells. Tumor-targeted delivery might improve the tumor uptake and thus enhance the antitumor effect of hTRAIL. Platelet-derived growth factor receptor β (PDGFRβ)-expressing pericytes are enriched in tumor tissues derived both from patients with colon cancer and from mice bearing colorectal tumor xenografts. A Z affibody showed high affinity (nM) for PDGFRβ and was predominantly distributed on tumor-associated PDGFRβ-positive pericytes. Co-administration with the Z affibody did not significantly enhance the antitumor effect of hTRAIL in mice bearing tumor xenografts. Fusion to the Z affibody endows hTRAIL with PDGFRβ-binding ability but does not interfere with its death receptor binding and activation. The fused Z affibody mediated PDGFRβ-dependent binding of hTRAIL to pericytes. In addition， hTRAIL bound on pericytes could kill tumor cells through juxtatropic activity or exhibit cytotoxicity in tumor cells after being released from pericytes. Intravenously injected hTRAIL fused to Z affibody initially accumulated on tumor-associated pericytes and then diffused to the tumor parenchyma over time. Fusion to the Z affibody increased the tumor uptake of hTRAIL， thus enhancing the antitumor effect of hTRAIL in mice bearing tumor xenografts. These results demonstrate that pericyte-targeted delivery mediated by a Z affibody is an alternative strategy for tumor-targeted delivery of anticancer agents.
