Intratumour injection of immunoglobulins labelled with the α-particle emitter 211At: analyses of tumour retention, microdistribution and growth delay

Abstract

Summary To determine the effects of 21'At-labelled antibodies in solid tumour tissue, nude mice carrying OHS human osteosarcoma xenografts received intratumour injections at dosages of 1, 2 or 4 MBq g-' tumour. The radioisotope was conjugated to either the osteosarcoma-specific monoclonal antibody TP-3 or the non-specific polyclonal antibody higGic. Tumour retention of injected radioimmunoconjugate (RIC), measured as the percentage of injected activity dosage per gram, was significantly higher for the [211At]TP-3 (203 ± 93 at 24.1 h post injection) compared with the [211At]hIgGic (57 ± 22 at 23.2 h post injection). The radioactive count rates in body (measured at neck and abdomen) were significantly lower with the TP-3 than with the higGK. Microautoradiography of the tumour radionuclide distribution was different for the two RICs, i.e. the [211At]TP-3 was to a larger extent concentrated near the injection site, whereas the [211At]hIgGic was more evenly distributed all over the tumour. The tumour growth was significantly delayed as a function of the injected activity dosage but without significant difference between the specific and the non-specific RIC. According to this study, it is possible to deliver highly selective radiation doses to solid tumours using intratumour injection of a-particle-emitting RICs. Improved tumour retention caused by antigen binding indicates that reduced normal tissue exposure can be obtained with antigen-specific antibodies. The heterogeneous tumour dose distribution observed is, however, a major impediment to the use of a-particle emitters against solid tumours.

The α-Camera: A Quantitative Digital Autoradiography Technique Using a Charge-Coupled Device for Ex Vivo High-Resolution Bioimaging of α-Particles

“…Many studies (10,12,(27)(28)(29) have shown how quantitative autoradiography could improve dosimetry models and estimations within targeted a-radiotherapy. Future studies with the a-camera will include dosimetry modeling and estimations.…”

Targeted alpha therapy with the 224Ra/212Pb-TCMC-TP-3 dual alpha solution in a multicellular tumor spheroid model of osteosarcoma

“…In contrast, the cytotoxic effect was significantly improved when spheroids were treated with ≥ 2.7 kBq/ml of the 212 Pb-TCMC-TP-3 radioimmunoconjugate ( p < 0.005, Figure 2 and Supplementary Table 3 ). The therapeutic efficacy of 211 At-TP-3 was extensively explored three decades ago and showed promising potential for OS in vitro and in vivo , similar to a more recent study evaluating a 213 Bi radioimmunoconjugate ( 33 – 35 , 38 , 92 ). Unfortunately, challenges related to the production of 211 At and the very short half-life of 213 Bi limits the applicability of these radionuclides in targeted therapy.…”

“…Unfortunately, the mechanisms of action related to the radioresistance are not well investigated and remain unresolved (30). Targeted therapies using mAbs labeled with the beta emitting 188 Re or 177 Lu, and the alpha emitting 211 At or 213 Bi have been studied for OS in vitro and in vivo (31)(32)(33)(34)(35)(36)(37)(38). However, beta particles have low linear energy transfer (LET, ∼ 0.2 keV/µm), making them less effective for treating radioresistant tumor cells (39).…”

Laser Polarization Effect on Adiabatic Inversion of Degenerate Two-Level System

“…Recent advances in isotope production and radiochemistry have facilitated an interest in alpha-particle emitters for the treatment of micrometastatic disease (Rotmench et al 1997, Zalutsky et al 1997, Kennel and Mirzadeh, 1998, Larsen and Bruland, 1998, Li et al 2002, Allen et al 2003, Huber et al 2003, Palm et al 2003, Waldmann, 2003, Beyer et al 2004, Seidl et al 2004, Sofou et al 2004, Couturier et al 2005, Nilsson et al 2005. The radiobiological advantages of alpha particles include short range (typically 30-90 µm), high linear energy transfer (LET) and independence of dose rate and oxygen effects (Hall et al 1972).…”