Targeted Alpha Therapy as a Multiscale Design Problem: From Radioactive Decay to Therapeutic Outcome.

Targeted Alpha Therapy (TAT) is often defined by the favorable physical properties of alpha particles, particularly their high linear energy transfer and short tissue range. However, these properties alone do not determine therapeutic success. The clinical behavior of alpha-emitting radiopharmaceuticals depends on whether radioactive decay can be matched to an appropriate biological scale and maintained within a chemically and pharmacokinetically coherent system. This review presents TAT as a multiscale design problem in which radionuclide production, radioactive decay, recoil, coordination chemistry, vector compatibility, tissue geometry, microdosimetry, biodistribution, and clinical outcome are interdependent rather than separate considerations. Established and emerging alpha emitters, including radium-223, astatine-211, lead-212/bismuth-212, actinium-225/bismuth-213, thorium-227 and terbium-149, are examined as distinct design solutions rather than interchangeable therapeutic options. Their comparison shows that no single radionuclide is universally optimal, as each occupies a distinct position within a landscape defined by physical, chemical and biological constraints. Viewing TAT as a multiscale design problem shifts radionuclide selection from the search for a universally superior emitter toward the rational matching of radionuclide properties to therapeutic context.