IntroductionProteins accumulate in the nucleus to signal specific entry of molecules through the nuclear pore complex (NPC) [1-3]. This mechanism was first observed in nucleoplasmin, an acidic protein that binds histones H2A and H2B during nucleosome assembly[4-8]. In vertebrates, the nuclear pore complex weighs 125 Mda in mass and contains 50 to 100 polypeptides. Thus, for macromolecules to cross the NPC, a signal-mediated transport mechanism is necessary. Although several nuclear transport pathways exist, classical nuclear localization signals (NLS) containing one or more groups of basic amino acids are well known and characterized ( 9 ). Nuclear localization signals (NLS) are stretches of residues in proteins that facilitate the import of protein residues into the nucleus. The nuclear localization signal exists in the form of protein peptides linked to carrier proteins to transport nuclear proteins into the nucleus. Small molecules less than 40 to 45 kda diffuse freely in and out of the nucleus through nuclear pore complexes between the cytoplasm and the nucleus using soluble carrier proteins (10). However, nuclear import of larger molecules is an energy-dependent process, mediated by specific targeting signals called nuclear localization sequences (NLS).[10] These oligopeptides of less than 10 AA bind directly to a group of proteins called importins. The structural and functional domains of importin-α consist of a short basic N-terminal called the Importin-β binding domain (11-13) and a large NLS binding domain of armadillo repeats (Arm) (14). cargo proteins in the nucleus, and importin-α is further recognized by importin-β to form a heterotrimeric complex that interacts with hydrop...... middle of organs paper ......al , respectively[52-60].NLS-conjugated and 111In-labeled trastuzumab using diethylenetriaminepentaacetic acid (DTPA) for receptor-mediated drug internalization by low-energy augur radioimmunotherapy showed increased internalization 111Intrastuzumab (composed of 6 NLS peptides) in SK-BR-3, MDA-MB-361 and MDA-MB-231 cells of 7.2% ±0.9%, 1.3% ±6 0.1% and 0.2% ± 0.05% to 14.4% ± 6 1.8%, 6.3% ± 0.2% and 0.9% ± 0.2%, respectively[61]. The expression levels of HER2/neu in human breast cancer cells SK-BR-3, MDA-MB-361 and MDA-MB-231 were very high, intermediate and low, respectively [61]. Thus, by selectively exploiting biological parameters The property of NLS peptides to enhance drug delivery to the target nucleus offers a wide range of therapeutic options in chemotherapy, causing immunomodulatory effects and in radio-immunotherapy..