Targeting Hypoxia-inducible Factor-1α With Tf–PEI–shRNA Complex via Transferrin Receptor–mediated Endocytosis Inhibits Melanoma Growth

Abstract

Malignant melanoma (MM) is a major public health problem. The development of effective, systemic therapies for MM is highly desired. We showed here that the transferrin receptor (TfR) was a suitable surface marker for targeting of gene therapy in MM and that the hypoxia-inducible factor-1α (HIF-1α) was an attractive therapeutic molecular target in MM. We observed that inhibition of HIF-1α blocked cell proliferation and induced cell apoptosis in vitro. We then showed that a transferrin–polyethylenimine–HIF-1α–short-hairpin RNA (Tf–PEI–HIF-1α–shRNA) complex could target MM specifically and efficiently both in vivo and in vitro, exploiting the high expression of the TfR in MM. The systemic delivery of sequence-specific small-interfering RNA (siRNA) against HIF-1α by the Tf– PEI–HIF-1α–shRNA complex dramatically inhibited tumor growth in the A375 MM xenograft model. The underlying concept of transfecting a HIF-1α shRNA expression vector complexed with Tf–PEI to block HIF-1α holds promise as a clinical approach to gene therapy for MM.