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Amphipathic Peptide-Based Fusion Peptides and Immunoconjugates for the Targeted Ablation of Prostate Cancer Cells

The Center for Engineering in Medicine, Massachusetts General Hospital, Harvard Medical School, Shriners Hospital for Children, Boston, Massachusetts

Requests for reprints: Martin L. Yarmush, The Center for Engineering in Medicine, Massachusetts General Hospital, Harvard Medical School, Shriners Hospital for Children, 51 Blossom Street, Boston, MA 02114. Phone: 617-371-4882; E-mail: ireis{at}sbi.org.

We describe the design, generation, and in vitro evaluation of targeted amphipathic fusion peptides and immunoconjugates for the ablation of prostate cancer cells. The overexpression of the prostate-specific membrane antigen (PSMA) was exploited as means to specifically deliver cytotoxic peptides to prostate cancer cells. Cationic amphipathic lytic peptides were chosen as cytotoxic agents due to their ability to depolarize mitochondrial membranes and induce apoptosis. Specific delivery of the lytic peptide was facilitated by PSMA-targeting peptides and antibodies. Our results indicate that although the use of PSMA-targeted peptides only modestly enhanced the cytotoxic activity of the lytic peptide, peptide-antibody conjugates were two orders of magnitude more potent than untargeted peptide. In addition to quantifying the cytotoxic activities of the individual constructs, we also investigated the mechanisms of cell death induced by the fusion peptides and immunoconjugates. Although fusion peptides induced oncotic/necrotic death in cells, treatment with immunoconjugates resulted in apoptotic death. In summary, immunoconjugates based on lytic peptides are a promising class of therapeutics for prostate cancer therapy and warrant further investigation. [Cancer Res 2007;67(13):6368–75]