Auger radiation-induced, antisense-mediated cytotoxicity of tumor cells using a 3-component streptavidin-delivery nanoparticle with 111In
Department of Radiology, Division of Nuclear Medicine; Department of Pathology
Medical Subject Headings
Animals; Cell Line, Tumor; Cell Survival; DNA, Antisense; Drug Carriers; Female; Indium Radioisotopes; Mice; Mice, Nude; Nanoparticles; Neoplasms; Radiopharmaceuticals; Streptavidin; Treatment Outcome
Nanomedicine | Neoplasms | Radiochemistry | Radiology | Therapeutics
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 (111)In 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 (111)In-labeled antiRIalpha 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 (99m)Tc-MORF/tat/trastuzumab than after incubation with free (99m)Tc-MORF and significantly higher with the antisense than with the sense MORF. In mice, tumor and normal-tissue accumulations of the (99m)Tc-MORF/tat/trastuzumab nanoparticle were comparable to those of free (99m)Tc-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+/RIalpha+ 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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Citation: J Nucl Med. 2009 Apr;50(4):582-90. doi: 10.2967/jnumed.108.056366. Epub 2009 Mar 16.Link to article on publisher's site.
antisense oligomer, delivery nanoparticle, radiotherapy, Auger electron–emitting radionuclide, streptavidin
Liu, Xinrong; Wang, Yi; Nakamura, Kayoko; Kawauchi, Sumi; Akalin, Ali; Cheng, Dengfeng; Chen, Ling; Rusckowski, Mary; and Hnatowich, Donald J., "Auger radiation-induced, antisense-mediated cytotoxicity of tumor cells using a 3-component streptavidin-delivery nanoparticle with 111In" (2009). Radiology Publications and Presentations. 101.