Peptides in receptor-mediated radiotherapy: from design to the clinical application in cancers

Abstract

Short peptides can show high affinity for specific receptors overexpressed on tumor cells. Some of these are already used in cancerology as diagnostic tools and others are in clinical trials for therapeutic applications. Therefore, peptides exhibit great potential as a diagnostic tool but also as an alternative or an additional antitumoral approach upon the covalent attachment of a therapeutic moiety such as a radionuclide or a cytotoxic drug. The chemistry offers flexibility to graft onto the targeting-peptide either fluorine or iodine directly, or metallic radionuclides through appropriate chelating agent. Since short peptides are straightforward to synthesize, there is an opportunity to further improve existing peptides or to design new ones for clinical applications. However, several considerations have to be taken into account to optimize the recognition properties of the targeting-peptide to its receptor, to improve its stability in the biological fluids and its residence in the body, or to increase its overall therapeutic effect. In this review, we highlight the different aspects which need to be considered for the development of an efficient peptide receptor-mediated radionuclide therapy in different neoplasms.

Keywords: bifunctional chelator; cancer; radionuclides; radiotherapy; targeting-peptide.

Figure 1

Examples of peptide constructs used in radiotherapy or imaging.

Figure 2

Main functional groups used to covalently link the peptide moiety (A) and examples of BFCs (B). BAT is a derivative of TETA; CPTA is a derivative of cyclam, and PCBA is a derivative of cyclen (see Table 1). BAT is conjugated to peptide using the linking agent 2IT (2-iminothiolane) which forms a thioether bond between BAT and the peptide. CPTA and PCBA are conjugated to peptide via an amide linkage. Adapted from Rogers et al. (82).