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.