Alpha-Particle Emitting 213Bi-Anti-EGFR Immunoconjugates Eradicate Tumor Cells Independent of Oxygenation

Abstract

Hypoxia is a central problem in tumor treatment because hypoxic cells are less sensitive to chemo- and radiotherapy than normoxic cells. Radioresistance of hypoxic tumor cells is due to reduced sensitivity towards low Linear Energy Transfer (LET) radiation. High LET α-emitters are thought to eradicate tumor cells independent of cellular oxygenation. Therefore, the aim of this study was to demonstrate that cell-bound α-particle emitting 213Bi immunoconjugates kill hypoxic and normoxic CAL33 tumor cells with identical efficiency. For that purpose CAL33 cells were incubated with 213Bi-anti-EGFR-MAb or irradiated with photons with a nominal energy of 6 MeV both under hypoxic and normoxic conditions. Oxygenation of cells was checked via the hypoxia-associated marker HIF-1α. Survival of cells was analysed using the clonogenic assay. Cell viability was monitored with the WST colorimetric assay. Results were evaluated statistically using a t-test and a Generalized Linear Mixed Model (GLMM). Survival and viability of CAL33 cells decreased both after incubation with increasing 213Bi-anti-EGFR-MAb activity concentrations (9.25 kBq/ml–1.48 MBq/ml) and irradiation with increasing doses of photons (0.5–12 Gy). Following photon irradiation survival and viability of normoxic cells were significantly lower than those of hypoxic cells at all doses analysed. In contrast, cell death induced by 213Bi-anti-EGFR-MAb turned out to be independent of cellular oxygenation. These results demonstrate that α-particle emitting 213Bi-immunoconjugates eradicate hypoxic tumor cells as effective as normoxic cells. Therefore, 213Bi-radioimmunotherapy seems to be an appropriate strategy for treatment of hypoxic tumors.

Branched amphiphilic peptide capsules: Cellular uptake and retention of encapsulated solutes

“…The limited range of α-particles (50–100 μm) confines their toxicity to a small radius from the site of the isotope decay, enabling more specific tumor killing capability without damage to the surrounding normal tissue; as opposed to β − -particles, which have a much longer range [26]. Furthermore the cytocidal effectiveness of α-particles has been shown to be independent of oxygen concentration [63], dose rate and cell cycle position [64]. Additionally, studies performed on a leukemia model indicated that α-emitter radionuclides exhibited cytotoxicity superior to that of β − -radiation or γ-radiation and are capable of killing cancer cells which are resistant to chemotherapeutic drugs such as doxorubicin [65].…”

Targeted Radionuclide Therapy of Prostate Cancer—From Basic Research to Clinical Perspectives

“…Their high effectiveness results from induction of lethal DNA double strand breaks. Cell survival studies have shown that in contrast to β − -radiation, α particle-killed cells independently of their oxygenation state, cell cycle position or fluency [124]. Due to these advantages, targeted α-particle therapy is the most rapidly developing field in nuclear medicine and radiopharmacy [125].…”

α- Versus β-Emitting Radionuclides for Pretargeted Radioimmunotherapy of Carcinoembryonic Antigen–Expressing Human Colon Cancer Xenografts

“…However, a-particles present significantly higher energies than b-particles (4-9 MeV vs. 0.1-2.2 MeV), which combined with short path lengths results in high linear energy transfer and a greater probability of generating DNA double-strand breaks on interaction with cell nuclei. This occurs independently of tissue oxygenation, dose rate, and cellular resistance to photon irradiation and chemotherapy (1)(2)(3)(4)(5). Therefore, a-particles are highly cytotoxic and promising candidates for targeted radiotherapy.…”