Experimental Radionuclide Therapy of HER2-Expressing Xenografts Using Two-Step Targeting Nuclisome Particles

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-celltargeting 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 5 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 5 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. The potential use of short-range, low-energy Augerelectron-emitting radionuclides for tumor therapy was first suggested some 40 y ago when it was realized that these nuclides could induce severe damage to cellular DNA (1). It was observed that, as a consequence of the multiple electron cascades during decay, complex double-strand breaks were produced when the nuclides were introduced within DNA. Since most of the energy deposition from these electrons is highly localized in a small volume, it early became clear that their therapeutic value was limited to situations in which positioning of the nuclides within or close to DNA was achievable. Several successful attempts were made to accomplish DNA association ...

Tendencies for higher co-expression of EGFR and HER2 and downregulation of HER3 in prostate cancer lymph node metastases compared with corresponding primary tumors

“…Bifunctional molecules, with capacity to bind two different receptors at the same time are, as indicated above, a possible approach for therapy. Liposomes containing toxic substances and conjugated with targeting agents may be of use for the killing of disseminated tumor cells in the systemic circulation (51).…”

Novel radioisotope-based nanomedical approaches

“…Furthermore, when the nuclisomes targeted to HER2 were given to mice carrying human ovarian cancer xenografts, they accumulated in the tumors and there was a significant difference between treated and mock treated animals since more than 50% of the surviving mice were tumor-free. In addition, no macroscopic or microscopic radiotoxic side effects were observed in the mice (31,57,58) supporting the nuclisome approach in specific also in vivo and the feasibility of the AE-based radiotherapy in general.…”

“…Tumor targeting has focused on the use of antibodies (28,29), peptides, which serve as ligands for cell surface receptors (14,30), and nanoparticles (31).…”

Nanotargeted Radiopharmaceuticals for Nuclear Imaging and Radiotherapy

“…For radiotherapeutics, ideal radioisotopes are those with an abundance of low γ-penetrating radiations, example: high specific activity β-emitters, α-particle emitters or auger electron emitters. [94][95][96][97] This is because when the radiopharmaceuticals reach the disease target, the energy from the radioisotope should be deposited at that site and not irradiate nearby normal tissues. The energy of particles from different radioisotopes and their ranges in tissues will vary, as well as their half-lives, and the most appropriate radioisotope will be different depending on the application, the disease and the accessibility of the disease tissue.…”