Engineering Mesoporous Silica Nanoparticles for Targeted Alpha Therapy against Breast Cancer

Targeted alpha therapy, where highly cytotoxic doses are delivered to tumor cells while sparing surrounding healthy tissue, has emerged as a promising treatment against cancer. Radionuclide conjugation with targeting vectors and dose confinement, however, are still limiting factors for the widespread application of this therapy. In the current study, we developed multifunctional silica nanoconstructs for targeted alpha therapy that show targeting capabilities against breast cancer cells, cytotoxic responses at therapeutic dosages, and enhanced clearance. The silica nanoparticles were conjugated to transferrin, which promoted particle accumulation in cancerous cells, and 3,4,3-LI(1,2-HOPO), a chelator with high selectivity and binding affinity for f-block elements. High cytotoxic effects were observed when the nanoparticles were loaded with ²²⁵Ac, a clinically relevant radioisotope. Lastly, in vivo studies in mice showed that the administration of radionuclides with nanoparticles enhanced their excretion and minimized their deposition in bones. These results highlight the potential of multifunctional silica nanoparticles as delivery systems for targeted alpha therapy and offer insight into design rules for the development of new nanotherapeutic agents.