Peptide Receptor Radionuclide Therapy: An Overview

Abstract

Peptide receptor radionuclide therapy (PRRT) is a site-directed targeted therapeutic strategy that specifically uses radiolabeled peptides as biological targeting vectors designed to deliver cytotoxic levels of radiation dose to cancer cells, which overexpress specific receptors. Interest in PRRT has steadily grown because of the advantages of targeting cellular receptors in vivo with high sensitivity as well as specificity and treatment at the molecular level. Recent advances in molecular biology have not only stimulated advances in PRRT in a sustainable manner but have also pushed the field significantly forward to several unexplored possibilities. Recent decades have witnessed unprecedented endeavors for developing radiolabeled receptor-binding somatostatin analogs for the treatment of neuroendocrine tumors, which have played an important role in the evolution of PRRT and paved the way for the development of other receptor-targeting peptides. Several peptides targeting a variety of receptors have been identified, demonstrating their potential to catalyze breakthroughs in PRRT. In this review, the authors discuss several of these peptides and their analogs with regard to their applications and potential in radionuclide therapy. The advancement in the availability of combinatorial peptide libraries for peptide designing and screening provides the capability of regulating immunogenicity and chemical manipulability. Moreover, the availability of a wide range of bifunctional chelating agents opens up the scope of convenient radiolabeling. For these reasons, it would be possible to envision a future where the scope of PRRT can be tailored for patient-specific application. While PRRT lies at the interface between many disciplines, this technology is inextricably linked to the availability of the therapeutic radionuclides of required quality and activity levels and hence their production is also reviewed.

Comparative Evaluation of the Biodistribution Profiles of a Series of Nonpeptidic Neurotensin Receptor-1 Antagonists Reveals a Promising Candidate for Theranostic Applications

“…Several preclinical studies and a few clinical studies have previously addressed NTR1 as a target for nuclear oncology (5,6). Most of these studies focused on modifications of the natural peptide ligand neurotensin, which is labile toward enzymatic cleavage in vivo.…”

αVβ3 Integrin-Targeted Radionuclide Therapy with 64Cu-cyclam-RAFT-c(-RGDfK-)4

“…Molecular-targeted radionuclide therapy (MTRT), which is a promising cancer treatment option, is performed by the systemic administration of a specific molecular vehicle, that is, antibody, peptide or small organic molecule that is radiolabeled with a cytocidal energy-releasing radionuclide (a-or b À -particle emitter or Auger electron emitter) to elicit a therapeutic effect on the targeted tumoral lesions (1)(2)(3)(4). The key advantages such as rapid blood clearance, tissue penetration capability, low immunogenicity, and relatively easy and cost-effective production, have made the peptide-based MTRT more attractive as a treatment strategy with clinical-translational potential (4)(5)(6).…”

“…The key advantages such as rapid blood clearance, tissue penetration capability, low immunogenicity, and relatively easy and cost-effective production, have made the peptide-based MTRT more attractive as a treatment strategy with clinical-translational potential (4)(5)(6). MTRT with radiolabeled somatostatin analogues (peptide ligands), targeting somatostatin receptor highly expressed neuroendocrine tumors, have been used in clinical practice with convincing therapeutic efficacy (6,7).…”

“…MTRT with radiolabeled somatostatin analogues (peptide ligands), targeting somatostatin receptor highly expressed neuroendocrine tumors, have been used in clinical practice with convincing therapeutic efficacy (6,7). Of the candidate target molecules for MTRT, a V b 3 integrin (a V b 3 ) is a promising one (4,5). It is a transmembrane glycoprotein receptor and an important cell adhesion molecule that plays important roles in tumor growth, invasion, metastasis, and angiogenesis.…”

“…We have developed a tetrameric cRGD peptide-based radiopharmaceutical 64 Cu-cyclam-RAFT-c(-RGDfK-) 4 containing 4 copies of a cRGD monomer grafted onto one side of a cyclic decapeptide scaffold named RAFT (regioselectively addressable functionalized template) and a copper chelator 1,4,8,11-tetraazacyclotetradecane (cyclam) on the other side of the RAFT (24,25). This radiocompound possesses a greatly improved a V b 3 -binding specificity and affinity as well as a high internalization capability due to the multimeric presentation of cRGD motifs (25)(26)(27), and is capable of being applied for both imaging and therapy because of the suitable half-life (12.7 hours) of copper-64 ( 64 Cu) with multiple decay modes-b þ (17.8%) used for positron emission tomography (PET), b À (38.4%) and Auger electron (43%) used for therapeutic radiation (28).…”