As an alternative to classical brachytherapy, intratumoral injection of radionuclide-labeled nanoparticles (nanobrachytherapy, NBT) has been investigated as a superior delivery method over an intravenous route for radionuclide therapy of solid tumors. We created superparamagnetic iron oxide nanoparticles (SPIONs) coated with meso-1,2-dimercaptosuccinic acid (DMSA) and radiolabeled with Lutetium-177 (¹⁷⁷Lu), generating ¹⁷⁷Lu-DMSA@SPIONs as a potential antitumor agent for nanobrachytherapy. Efficient radiolabeling of DMSA@SPIONS by ¹⁷⁷Lu resulted in a stable bond with minimal leakage in vitro. After an intratumoral injection to mouse colorectal CT-26 or breast 4T1 subcutaneous tumors, the nanoparticles remained well localized at the injection site for weeks, with limited leakage. The dose of 3.70 MBq/100 µg/50 µL of ¹⁷⁷Lu-DMSA@SPIONs applied intratumorally resulted in a high therapeutic efficacy, without signs of general toxicity. A decreased dose of 1.85 MBq/100 µg/50 µL still retained therapeutic efficacy, while an increased dose of 9.25 MBq/100 µg/50 µL did not significantly benefit the therapy. Histopathology analysis revealed that the ¹⁷⁷Lu-DMSA@SPIONs act within a limited range around the injection site, which explains the good therapeutic efficacy achieved by a single administration of a relatively low dose without the need for increased or repeated dosing. Overall, ¹⁷⁷Lu-DMSA@SPIONs are safe and potent agents suitable for intra-tumoral administration for localized tumor radionuclide therapy.

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.

Combined radionuclide therapy with magnetic nanoparticles has been a research focus as a promising approach for tumor therapy. In this study, superparamagnetic iron oxide nanoparticles (SPIONs) were synthesized using the co-precipitation method and coated with meso-1,2- dimercaptosuccinic acid (DMSA). Structural investigations showed that DMSA-coated SPIONs had a particle size of 140.3±6.5 nm in diameter with a spherical morphology. With a zeta potential of −35.1 mV, functionalization with DMSA led to increase the stability of the nanoparticles in solution. DMSA-SPIONs were radiolabeled with 177Lu in high radiolabeling yield (86.6 ± 2.1%, and after separation by magnetic decantation >99%), showing high in vitro stability in saline and human serum up to 96 h. After intratumoral injection into mouse colorectal CT-26 or breast 4T1 subcutaneous tumors, the radiolabeled nanoparticles remained well localized at the injection site over a 14-day period, with limited leakage.