title: Uptake, internalization and nuclear translocation of radioimmunotherapeutic agents.
abstract: 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.
authors.affiliation: Cancer Research UK/Medical Research Council Gray Institute for Radiation Oncology & Biology, Department of Oncology, University of Oxford, OX3 7DQ, UK.
authors.forename: Christopher R T
authors.initials: CR
authors.lastname: Hillyar
authors.forename: Bart
authors.initials: B
authors.lastname: Cornelissen
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Vallis
mesh_terms: D021581:Active Transport, Cell Nucleus; D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism*; D057846:Cell-Penetrating Peptides / Q000378:metabolism*; D004705:Endocytosis; D006801:Humans; D018796:Immunoconjugates / Q000378:metabolism* / Q000627:therapeutic use; D009369:Neoplasms / Q000276:immunology / Q000378:metabolism / Q000532:radiotherapy*; D016499:Radioimmunotherapy / Q000379:methods; D019275:Radiopharmaceuticals / Q000378:metabolism* / Q000627:therapeutic use; D059016:Tumor Microenvironment
chemical_list: D057846:Cell-Penetrating Peptides; D018796:Immunoconjugates; D019275:Radiopharmaceuticals