Targeting Nanocarriers with Anisamide: Fact or Artifact?

Encapsulating chemotherapeutics in nanoparticles can reduce the side effects of intravenous administration and improve their antitumor efficacy. Additionally, surface decoration of the nanocarriers with tumor-targeting ligands may enhance their specificity for cancer cells overexpressing the corresponding ligand-binding counterpart. The focus here is on anisamide, a low-molecular-weight benzamide derivative used as a tumor-directing moiety in functionalized nanosystems, based on its alleged interaction with Sigma receptors. The scintigraphic agents that initially inspired the use of anisamide for tumor targeting are described, and the published anisamide-tethered nanocarrier formulations are reviewed, together with a critical overview of the ligand's tumor-targeting properties. Moreover, anisamide's putative but dubious cellular target, the Sigma-1 receptor, is discussed with regard to its subcellular localization and implications in cancer. Data from in vivo studies reveal that the effect of anisamide on the antitumor efficacy of the decorated nanosystems varies considerably among the published reports. Together with the evidence questioning the interaction of anisamide with the Sigma receptors, the variability of anisamide's effect on the tumor deposition and the antitumor efficacy of the decorated drug carriers calls into question the extent of the ligand's tumor-targeting effect. Further research is necessary to elucidate the ligand's utility in tumor targeting.