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- Gedda, Lars, et al.
(författare)
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Experimental radionuclide therapy of HER2-expressing xenografts using two-step targeting Nuclisome-particles
- 2012
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Ingår i: Journal of Nuclear Medicine. - : Society of Nuclear Medicine. - 0161-5505 .- 1535-5667 .- 2159-662X. ; 53:3, s. 480-487
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Tidskriftsartikel (refereegranskat)abstract
- The therapeutic potential of Auger-electron emitting radionuclides is strongly dependent on their close vicinity to DNA, since the energy deposition is mainly localized within a few cubic nanometers around the site of decay. Thus, apart from specificity, successful tumor therapy relies on a nuclear delivery strategy. We recently presented a two-step targeting strategy to transport Auger-electron-emitting radionuclides into the cell nucleus by means of nuclide-filled liposomes (Nuclisome particles), that is, polyethylene glycol-stabilized, tumor-cell-targeting liposomes loaded with (125)I-labeled anthracyclines. In the present study, the survival of mice intraperitoneally inoculated with human HER2-expressing SKOV-3 tumor cells and treated with HER2-targeting Nuclisome particles was studied.METHODS:BALB/c nu/nu mice were inoculated with 10(7) SKOV-3 cells intraperitoneally and thereafter directly injected with Nuclisome particles with increasing specific radioactivity. Groups of 10-12 mice were treated with 0.01 MBq/mouse up to 2 MBq/mouse, and survival was monitored and compared with that in control groups (n = 33). Organs were analyzed for HER2 expression and radiotoxic effects histologically. Absorbed doses were estimated using dose factors from the online Radiation Dose Assessment Resource model.RESULTS:The results showed a clear correlation between administered radioactive dose and survival. No such dose-dependent survival was observed for mice treated with Nuclisome particles lacking HER2-targeting ability. With HER2-targeting Nuclisome particles, a significant increase in survival, compared with that of untreated control mice, could already be seen at an administered activity of 0.1 MBq/mouse (P = 0.0301). At the highest activity administered, 2 MBq/mouse (P < 0.0001), 70% of the mice survived the study and most were tumor-free. Neither macroscopic nor microscopic radiotoxic side effects were observed. Dosimetric calculations, assuming nonreceptor targeting, revealed that the radioactive doses to normal tissues were low.CONCLUSION:Taken together the results show that with successful targeting to the tumor-cell nucleus it is possible to obtain a therapeutic effect from Auger-electron-emitting radionuclides administered at radioactive doses low enough to spare normal tissue from radiotoxic side effects.
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