Title

Auger radiation-induced, antisense-mediated cytotoxicity of tumor cells using a 3-component streptavidin-delivery nanoparticle with 111In

UMMS Affiliation

Department of Radiology, Division of Nuclear Medicine; Department of Pathology

Date

4-1-2009

Document Type

Article

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

Disciplines

Nanomedicine | Neoplasms | Radiochemistry | Radiology | Therapeutics

Abstract

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.

Rights and Permissions

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.

Comments

At the time of publication, Kayoko Nakamura was not yet associated with the University of Massachusetts Medical Center.

Related Resources

Link to Article in PubMed

Keywords

antisense oligomer, delivery nanoparticle, radiotherapy, Auger electron–emitting radionuclide, streptavidin

PubMed ID

19289423