Uptake, internalization and nuclear translocation of radioimmunotherapeutic agents

Radioimmunotherapy (RIT) agents that incorporate short-range particle-emitting radionuclides exploit the high linear energy transfer of α-particles and Auger electrons. Both are densely ionizing, generate complex DNA double-strand breaks and so are profoundly cytotoxic. Internalizing RIT agents enter tumor cells through receptor-mediated endocytosis and by incorporation of cell-penetrating peptides. Once internalized, some RIT agents mediate escape from endosomes and/or translocate to the nucleus. In the classical nuclear import pathway, α/β-importins recognize nuclear localization sequences in RIT agents. Translocation through nuclear pores enables RIT agents to bind to nuclear targets induced by, for example, cellular stress, growth factors or anticancer therapy, such as γH2AX or p27(KIP-1). This review discusses RIT agents designed to exploit the mechanisms underlying these complex processes and compares them with noninternalizing RIT agents.