Nanoparticles have demonstrated potential for promoting drug delivery to tumor sites and enhancing uptake. Here, we report tetraiodothyroacetic acid (tetrac) as a promising new targeting moiety for delivery of anticancer drugs to tumor tissues. Tetrac, an antagonist that blocks the binding of thyroid hormone to integrin αvβ3, was covalently linked to the activated end of pegylated lipid and used to formulate tetrac-tagged pegylated liposomes (TPL). After incubating with TPL for 9h, cellular accumulation efficiency into A375 human melanoma cells, which express integrin αvβ3 at high density, was high (98.5%± 0.5% of cells), whereas that in KB cells, which express integrin at a very low density, was much lower (35.1%± 4.5%). Molecular imaging revealed that TPL preferentially distributed to tumor tissues after systemic administration in mice, where as non-targeting pegylated liposomes were distributed to tumors at background levels. Treatment with the alkyl lysophospholipid anticancer drug edelfosine, encapsulated in TPL, significantly reduced the survival of A375 tumor cells compared to cells treated with edelfosine in pegylated liposomes or with lysophosphatidylcholine encapsulated in TPL. Moreover, intravenous administration of edelfosine in TPL significantly reduced the growth of tumors and prolonged the survival of A375-xenografted mice, providing 100% protection for up to 50 days and some protection until 66 days (0% survival endpoint). In contrast, no untreated mice or mice treated with edelfosine-loaded pegylated liposomes survived up to 50 or 48 days, respectively, after tumor inoculation. These results suggest the potential of tetrac as a new ligand moiety for enhancing the delivery of anticancer drug-loaded nanoparticles to tumors and enhancing the therapeutic efficacy of encapsulated anticancer drugs.
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