Targeted delivery to tumors in vivo with sigma‐2 ligands

Abstract

Radiolabeled sigma‐2 (σ2) receptor‐specific ligands image pancreas adenocarcinoma allografts in vivo and fluorescently labeled σ2 ligands are rapidly internalized and distributed throughout membrane‐encapsulated organelles. Based on these data, we hypothesized that σ2 ligands could target the delivery of therapeutic compounds to tumors in vivo. To test this hypothesis we synthesized a novel amino acid with a σ2 ligand side chain. This amino acid was incorporated as the N‐terminal residue in a series of pro‐apoptotic peptides without appreciable alteration of the Kd for the σ2 receptor (~10–20 nM). One of these peptides is the BH3‐domain of the pro‐apoptotic Bcl‐2 family member Bim. ~2‐BH3 causes dose‐dependent apoptosis to pancreas adenocarcinoma cells in vitro and is approximately the sum of the apoptotic activity of the σ2 ligand and the TAT‐BH3 peptide (Figure). When administered to tumor bearing mice this chimeric molecule is capable of halting tumor growth without appreciable effects on organ function or blood chemistry. Seven day treatment with this peptide increased median time to death in these mice from 33 days to 45 days (P < 0.0001). These data support the hypothesis that σ2 ligands target the delivery of cancer therapy in vivo and demonstrate a platform approach to delivering peptides selectively to cancer cells in the immunocompetent host.