When antisense oligomers are intracellular, they migrate to and are retained in the nucleus of tumor cells and therefore may be used to carry Auger electron–emitting radionuclides such as ¹¹¹In for effective tumor radiotherapy. Methods: Our nanoparticle consists of streptavidin that links 3 biotinylated components: the antiHer2 antibody trastuzumab (to improve pharmacokinetics), the tat peptide (to improve cell membrane transport), and the ¹¹¹In-labeled antiRIα messenger RNA antisense morpholino (MORF) oligomer. Results: As evidence of unimpaired function, tumor cell and nuclear accumulations were orders of magnitude higher after incubation with ^99mTc-MORF/tat/trastuzumab than after incubation with free ^99mTc-MORF and significantly higher with the antisense than with the sense MORF. In mice, tumor and normal-tissue accumulations of the ^99mTc-MORF/tat/trastuzumab nanoparticle were comparable to those of free ^99mTc-trastuzumab, confirming the improved pharmacokinetics due to the trastuzumab component. Although kidneys, liver, and other normal tissues also accumulated the nanoparticle, immunohistochemical evaluation of tissue sections in mice receiving the Cy3-MORF/tat/trastuzumab nanoparticle showed evidence of nuclear accumulation only in tumor tissue. In a dose escalation study, as measured by the surviving fraction, the nanoparticle significantly increased the kill of SK-BR-3 breast cancer Her2+/RIα+ cells, compared with all controls. Conclusion: Significant radiation-induced antisense-mediated cytotoxicity of tumor cells in vitro was achieved using an Auger electron–emitting antisense MORF oligomer administered as a member of a 3-component streptavidin-delivery nanoparticle.

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