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Assembling a new generation of radiopharmaceuticals with supramolecular theranostics

Nature Reviews Chemistry volume 8, pages 893–914 (2024)Cite this article

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Abstract

Supramolecular chemistry has been used to tackle some of the major challenges in modern science, including cancer therapy and diagnosis. Supramolecular platforms provide synthetic flexibility, rapid generation through self-assembly, facile labelling, unique topologies, tunable reversibility of the enabling noncovalent interactions, and opportunities for host–guest chemistry and mechanical bonding. In this Review, we summarize recent advances in the design and radiopharmaceutical application of discrete self-assembled coordination complexes and mechanically interlocked molecules — namely, metallacages and rotaxanes, respectively — as well as in situ-forming supramolecular aggregates, specifically pinpointing their potential as next-generation radiotheranostic agents. The outlook of such supramolecular constructs for potential applications in the clinic is discussed.

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Fig. 1: Radiopharmaceutical design concepts.
Fig. 2: Strategies for the coordination-driven self-assembly of metallacages.
Fig. 3: Post-synthetic modification of metallacages.
Fig. 4: Synthesis of rotaxanes and example of their biomedical application.
Fig. 5: Intracellular in situ self-assembly of SAs.
Fig. 6: Design and examples of radiolabelled MCgs.
Fig. 7: Radiolabelled rotaxanes and their applications.
Fig. 8: Radiopharmaceutical application of SAs.

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Acknowledgements

We acknowledge funding from EU Horizon Europe research and innovation program, EIC Pathfinder Open network “SMARTdrugs” (grant agreement ID: 101129886). The TUM International Graduate School of Science and Engineering (IGSSE) is kindly acknowledged for financial support (International Project Team: Supramolecular Organometallic and Coordination Complexes for Medical Applications, SOCoMED).

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Authors and Affiliations

  1. Department of Chemistry, School of Natural Sciences, Technical University of Munich, Garching bei München, Germany

    Guillermo Moreno-Alcántar, Marike Drexler & Angela Casini

  2. Munich Data Science Institute (MDSI), Technical University of Munich, Garching bei München, Germany

    Angela Casini

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  1. Guillermo Moreno-Alcántar
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A.C. researched data and contributed to discussion of content, writing and editing of this manuscript. G-M.A. and M.D. researched data for the article and contributed to discussion of content, writing and reviewing/editing the manuscript before submission. A.C., G-M.A. and M.D. contributed to the design and production of the graphical material.

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Correspondence to Angela Casini.

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Glossary

Adsorptive mediated transcytosis

A transcellular pathway triggered by electrostatic interactions between the cell membrane and a positively charged molecule.

Bitopic ligands

Organic ligands featuring two coordination sites for metal ions that cannot bind the same metal centre like chelating ligands do.

Coordination-driven self-assembly

(CDSA). The spontaneous and reversible organization of molecular units into ordered structures by non-covalent ligand to metal interactions. 

Daughter nuclides

Nuclides produced by the radioactive decay of other nuclides. They may be stable or decay further.

Dosimetry

The study or measurement of radiation dose.

Enzyme-instructed self-assembly

(EISA). A process in which an enzyme converts soluble precursors into the molecular building blocks necessary to construct supramolecular aggregates.

Heteroleptic assemblies

Metal complexes or assemblies in which the metal ion is coordinated by more than one type of ligand.

Homoleptic compounds

Metal complexes or assemblies in which all ligands are identical.

Multimodal imaging

The integration of two or more imaging modalities during the same examination.

Multitopic ligands

Organic ligands featuring more than two coordination sites for metal ions that cannot bind the same metal centre like chelating ligands do.

Photoacoustic imaging

A non-invasive biomedical imaging modality that generates ultrasonic waves by irradiating a probe with pulsed laser and reconstructs the image of light energy absorption distribution in the tissue.

Photothermal therapy

A cancer therapeutic strategy that mostly utilizes near-infrared light-absorbing agents to eradicate cancer cells by heating.

Self-immolation

Stimuli-induced decomposition into predefined components, which can then exert a certain (biological) activity.

Therapeutic index

A quantitative measure of drug safety in which the lethal dose is set in relation to the therapeutically effective dose: therapeutic index = TD50/ED50. ED50 is the dose required to produce a therapeutic effect in 50% of the population; TD50 is the dose required to produce a toxic effect in 50% of the population; both are calculated from dose–response curves.

Therapeutic window

The dose range of a drug that provides safe and effective therapy with minimal adverse effects.

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Moreno-Alcántar, G., Drexler, M. & Casini, A. Assembling a new generation of radiopharmaceuticals with supramolecular theranostics. Nat Rev Chem 8, 893–914 (2024). https://doi.org/10.1038/s41570-024-00657-4

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