Intracellular compartments, in particular the cytoplasm or nucleus, have generally been poorly accessible or inaccessible to radiolabeled biomolecules (e.g.,
monoclonal antibodies [mAbs],
peptides, or
oligonucleotides [ODNs]). However, recently
cell-penetrating peptides (CPPs) and nuclear localizing
peptide sequences (NLSs) have been shown to have the capability of inserting biomolecules into cells and transporting them to the cell nucleus. This discovery now presents intriguing new opportunities to design
radiopharmaceuticals that could potentially probe, through imaging, the expression of key intracellular or intranuclear regulatory
proteins that define the
tumor phenotype, predict outcome, or act as sensitive reporters of response or resistance to treatment. CPPs could also more efficiently internalize radiolabeled antisense ODNs or
peptide nucleic acids (PNAs) into
tumor cells to enhance the sensitivity of imaging gene expression at the
mRNA level. Perhaps one of the most exciting new developments to emerge is the use of NLS to route mAbs and
peptides conjugated to nanometer-micrometer range Auger-electron-emitting
radionuclides (e.
g., (111)In) to the nucleus of
cancer cells following their receptor-mediated internalization. In the nucleus, these electrons are highly potent in causing lethal
DNA strand breaks. In some cases, NLSs are present naturally in
peptide growth factors or their receptors, where they function to deliver internalized
ligands to the nucleus, or alternatively, they can be introduced synthetically. This update reviews the properties of CPPs and NLS and focuses on their use for inserting radiolabeled biomolecules into
cancer cells for imaging or targeted Auger electron
radiotherapy of
malignancies.