Alpha Particle-Emitting Radiopharmaceuticals as Cancer Therapy: Biological Basis, Current Status, and Future Outlook for Therapeutics Discovery.

Critical advances in radionuclide therapy have led to encouraging new options for cancer treatment through the pairing of clinically useful radiation-emitting radionuclides and innovative pharmaceutical discovery. Of the various subatomic particles used in therapeutic radiopharmaceuticals, alpha (α) particles show great promise owing to their relatively large size, delivered energy, finite pathlength, and resulting ionization density. This review discusses the therapeutic benefits of α-emitting radiopharmaceuticals and their pairing with appropriate diagnostics, resulting in innovative "theranostic" platforms. Herein, the current landscape of α particle-emitting radionuclides is described with an emphasis on their use in theranostic development for cancer treatment. Commonly studied radionuclides are introduced and recent efforts towards their production for research and clinical use are described. The growing popularity of these radionuclides is explained through summarizing the biological effects of α radiation on cancer cells, which include DNA damage, activation of discrete cell death programs, and downstream immune responses. Examples of efficient α-theranostic design are described with an emphasis on strategies that lead to cellular internalization and the targeting of proteins involved in therapeutic resistance. Historical barriers to the clinical deployment of α-theranostic radiopharmaceuticals are also discussed. Recent progress towards addressing these challenges is presented along with examples of incorporating α-particle therapy in pharmaceutical platforms that can be easily converted into diagnostic counterparts.

PET Oncological Radiopharmaceuticals: Current Status and Perspectives.

Molecular imaging is the visual representation of biological processes that take place at the cellular or molecular level in living organisms. To date, molecular imaging plays an important role in the transition from conventional medical practice to precision medicine. Among all imaging modalities, positron emission tomography (PET) has great advantages in sensitivity and the ability to obtain absolute imaging quantification after corrections for photon attenuation and scattering. Due to the ability to label a host of unique molecules of biological interest, including endogenous, naturally occurring substrates and drug-like compounds, the role of PET has been well established in the field of molecular imaging. In this article, we provide an overview of the recent advances in the development of PET radiopharmaceuticals and their clinical applications in oncology.

Three Reversible Redox States of Thiolate-Bridged Dirhodium Complexes without Metal-Metal Bonds.

An unusual dinuclear rhodium complex with the anionic 2-mercapto-6-methylpyridinate (mmp) bridging ligand is reported which is capable of undergoing significant variations in its structural and coordination environments as a result of two reversible redox events at accessible potentials (E1/2 = 0.014, 0.52 V vs Ag/AgCl). The large degree of separation between these redox states (ΔE = 0.51 V, KC = 4.17 × 108) allows for the chemical isolation of three distinct complexes 1, 2, and 3, in which the oxidation states of each Rh center are Rh2I,I, Rh2I,II, and Rh2II,II, respectively, and whose solid-state structures were elucidated by single crystal X-ray diffraction studies. Complex 2 is an unprecedented type of mixed valence dirhodium species whose electron paramagnetic resonance spectrum revealed a delocalization of the unpaired electron through the thiolate-bridging ligand. Intervalence charge transfer occurs between the Rh centers, as evidenced by a broad absorption in the near-infrared region (λmax = 1187 nm). The structure of 3 is quite rare in that it lacks the typical RhII-RhII σ bond, but significant orbital overlap between the Rh 4dz2 and S 3pz orbitals results in a strong antiferromagnetic coupling (computed J = -1516.9 cm-1). Complex 3 also absorbs low-energy light (λmax = 779 nm). Spectroscopic and magnetic measurements are supported by density functional theory methods, which further elucidate the nature of the ground state energies, frontier orbital characters, excited state transitions, and presence of weak Rh-Rh natural bond orbital interactions.