AS1411 is a G-rich DNA oligonucleotide that functions as an aptamer of the protein nucleolin, found at high levels on the surface of cancer cells but not on the surface of normal cells. Herein, we have studied AS1411 as a supramolecular carrier for the delivery of an acridine-based G-quadruplex ligand, C₈, to HeLa cancer cells. Two AS1411 derivatives, LNA-AS1411 and U-AS1411, were also tested, in an attempt to compare AS1411 pharmacological properties. The results showed that AS1411-C₈ complexation was made with great binding strength and that it lowered the ligand’s cytotoxicity towards non-malignant cells. This effect was suggested to be due to a decreased internalization of the complexed versus free C₈ as shown by flow cytometry. The AS1411 derivatives, despite forming a stable complex with C₈, lacked the necessary tumour-selective behaviour. The binding of C₈ to AS1411 G-quadruplex structure did not negatively affect the recognition of nucleolin by the aptamer. The AS1411-C₈ repressed c-MYC expression at the transcriptional level, possibly due to C₈ ability to stabilize the c-MYC promoter G-quadruplexes. Overall, this study demonstrates the usefulness of AS1411 as a supramolecular carrier of the G-quadruplex binder C₈ and the potential of using its tumour-selective properties for the delivery of ligands for cancer therapy.

In developed countries, cancer is the second leading cause of death, being only surpassed by cardiovascular diseases. To develop tumor-targeted tools to localize and treat cancer at an early stage is a multidisciplinary area fuelled by the convergence of biology, medicine, chemistry, physics and engineering. Chemists, in particular, play a critical role in this effort, as they are continuously challenged to use innovative chemical strategies to develop ‘smart drugs’. The in vitro observation that peptide receptors are overexpressed in certain tumors, as compared to endogenous expression levels, has prompted the use of such receptors as targets and the design of radiolabelled peptide-based tools for targeted nuclear molecular imaging and therapy. Such approach has gained increased interest over the last two decades, driven in particular by the success of OctreoScan^® and by the increasing knowledge concerning overexpression of regulatory peptide receptors in tumor tissues. Selected peptides that target a variety of disease related receptors are in place and have been labeled with different radiometals, using mainly the bifunctional approach. This review begins by summarizing some relevant aspects of the coordination chemistry of the metals studied for labeling peptides. Then, we provide an overview of the chemical strategies explored to improve the biological performance of different families of radiometallated peptides for nuclear molecular imaging and/or targeted radionuclide tumor therapy.

Auger electron (AE) radiopharmaceutical therapy (RPT) may have the same therapeutic efficacy as α-particles for oncologic small disease, with lower risks of normal-tissue toxicity. The seeds of using AE emitters for RPT were planted several decades ago. Much knowledge has been gathered about the potency of the biologic effects caused by the intense shower of these low-energy AEs. Given their short range, AEs deposit much of their energy in the immediate vicinity of their site of decay. However, the promise of AE RPT has not yet been realized, with few agents evaluated in clinical trials and none becoming part of routine treatment so far. Instigated by the 2022 “Technical Meeting on Auger Electron Emitters for Radiopharmaceutical Developments” at the International Atomic Energy Agency, this review presents the current status of AE RPT based on the discussions by experts in the field. A scoring system was applied to illustrate hurdles in the development of AE RPT, and we present a selected list of well-studied and emerging AE-emitting radionuclides. Based on the number of AEs and other emissions, physical half-life, radionuclide production, radiochemical approaches, dosimetry, and vector availability, recommendations are put forward to enhance and impact future efforts in AE RPT research. Visual Abstract