From Combinatorial Chemistry to Cancer-Targeting Peptides

Abstract

Several monoclonal antibodies that target cell surface receptors have gained approval by the U.S. Food and Drug Administration and are widely used in the treatment of some cancers. These include but are not limited to the anti-CD20 antibody Rituximab, used in lymphoma treatment, as well as anti-HER-2 antibody for breast cancer therapy. The efficacy of this cancer immunotherapy modality is, however, limited by the large size of the antibody (160 kd) and its relatively nonspecific binding to the reticuloendothelial system. This latter property is particularly problematic if the antibody is used as a vehicle to deliver radionuclides, cytotoxic drugs, or toxins to the tumor site. Peptides, peptidomimetic, or small molecules are thus attractive as alternative cell surface targeting agents for cancer imaging and therapy. Cancer cell surface targeting peptides can be derived from known native peptide hormones such as somatostatin and bombesin, or they can be identified through screening combinatorial peptide libraries against unknown cell surface receptor targets. Phage-display peptide library and one-bead one-compound (OBOC) combinatorial library methods have been successfully used to discover peptides that target cancer cells or tumor blood vessel endothelial cells. The phage-display peptide library method, because of its biological nature, can only display l-amino acid peptides. In contrast, the OBOC combinatorial library method allows for bead-surface display of peptides that contain l-amino acids, d-amino acids, unnatural amino acids, or other organic moieties. We have successfully used the OBOC method to discover and optimize ligands against unique cell surface receptors of prostate cancer, T- and B-cell lymphoma, as well as ovarian and lung cancers, and we have used some of these peptides to image xenografts in nude mice with high specificity. Here, we (i) review the literature on the use of phage-display and OBOC combinatorial library methods to discover cancer and tumor blood vessel targeting ligands, and (ii) report on the use of an ovarian cancer targeting ligand, OA02, as an in vivo PET imaging probe in a xenograft model in nude mice.

Cell-penetrating and cell-targeting peptides in drug delivery

“…This is probably the reason why the second technique was developed about a decade ago [131]. Hence, it has been defined as the "one-bead one-compound" (OBOC) strategy [132], and has led to the discovery of a large number of specific ligands (for a recent review [133]). Once the library has been assembled, various cell lines can be grown in the presence of the beads.…”

Sensitive electrospray mass spectrometry analysis of one-bead-one-compound peptide libraries labeled by quaternary ammonium salts

“…Once a peptide library has been screened against the interesting target, the chemical identification of the peptides on the hit beads is required. Chemical structure of the peptide attached to the selected bead can be identified and analyzed by mass spectrometry (MS) methods in a single experiment without time consuming deconvolution, required in other combinatorial library methods [3].…”

High-throughput in vivo screening of targeted molecular imaging agents

“…The OBOC approach (1, 2) has been successfully used for the identification of new ligands for unique cell-surface receptors of prostate, ovarian, and lung cancer, as well as T-and B-cell lymphoma (22). In addition, highly focused libraries have been prepared using the OBOC approach, resulting in the identification of a new peptidomimetic for imaging ␣ 4 ␤ 1 -expressing lymphomas in vivo (23).…”