Targeted Delivery to Tumor-associated Pericytes via an Affibody with High Affinity for PDGFR? Enhances the in vivo Antitumor Effects of Human TRAIL.

ABSTRACT: Human tumor necrosis factor-related apoptosis-inducing ligand (hTRAIL) has exhibited superior in vitro 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 ? (PDGFR?)-expressing pericytes are enriched in tumor tissues derived both from patients with colon cancer and from mice bearing colorectal tumor xenografts. A ZPDGFR? affibody showed high affinity (nM) for PDGFR? and was predominantly distributed on tumor-associated PDGFR?-positive pericytes. Co-administration with the ZPDGFR? affibody did not significantly enhance the antitumor effect of hTRAIL in mice bearing tumor xenografts. Fusion to the ZPDGFR? affibody endows hTRAIL with PDGFR?-binding ability but does not interfere with its death receptor binding and activation. The fused ZPDGFR? affibody mediated PDGFR?-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 ZPDGFR? affibody initially accumulated on tumor-associated pericytes and then diffused to the tumor parenchyma over time. Fusion to the ZPDGFR? 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 ZPDGFR? affibody is an alternative strategy for tumor-targeted delivery of anticancer agents.

SUBMITTER: Tao Z 

PROVIDER: S-EPMC5505058 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature