Combining External Beam Radiation and Radionuclide Therapies: Rationale, Radiobiology, Results and Roadblocks.

The emergence of effective radionuclide therapeutics, such as radium-223 dichloride, [177Lu]Lu-DOTA-TATE and [177Lu]Lu-PSMA ligands, over the last 10 years is driving a rapid expansion in molecular radiotherapy (MRT) research. Clinical trials that are underway will help to define optimal dosing protocols and identify groups of patients who are likely to benefit from this form of treatment. Clinical investigations are also being conducted to combine new MRT agents with other anticancer drugs, with particular emphasis on DNA repair inhibitors and immunotherapeutics. In this review, the case is presented for combining MRT with external beam radiotherapy (EBRT). The technical and dosimetric challenges of combining two radiotherapeutic modalities have impeded progress in the past. However, the need for research into the specific radiobiological effects of radionuclide therapy, which has lagged behind that for EBRT, has been recognised. This, together with innovations in imaging technology, MRT dosimetry tools and EBRT hardware, will facilitate the future use of this important combination of treatments.

Spatial distribution of Auger electrons emitted from internalised radionuclides in cancer cells: the photoresist autoradiography (PAR) method.

Microdosimetric evaluation of Auger electron-emitting radionuclides involves a detailed evaluation of energy deposition at a nanometre scale. To perform Monte Carlo modelling of such energy deposition, accurate information regarding the spatial distribution of the radionuclide is required. A recent addition to the methods for determining the spatial distribution of cellular internalised radionuclides is based on detection in a polymer photoresist (e.g. polymethyl methacralate), followed by atomic force microscopy analysis of the resultant 3D pattern. In comparison with present practice, the method offers greater spatial resolution and improved quantification. The volume of the pattern is proportional to the total dose, thereby permitting assessment of variability of accumulated activity, while the variation in depth across the pattern reflects the lateral spatial distribution in the local fluence per unit area. An added advantage is the similarity in response to ionising radiation of an organic polymer compared to that of biological material. A pattern in the resist from radiation emitted by a radionuclide treated cell gives additional spatial information about the energy deposited in the resist.

Alpha and recoil track detection in poly(methyl methacrylate) (PMMA)--towards a method for in vitro assessment of radiopharmaceuticals internalized in cancer cells.

A method for detection and characterization of single MeV α-particle and recoil tracks in PMMA photoresist by atomic force microscopy (AFM) analysis has been demonstrated. The energy deposition along the track is shown to lead to a latent pattern in the resist due to contrast reversal. It has been shown that the pattern, consisting of conical spikes, can be developed by conventional processing as a result of the dissolution rate of poly(methyl methacrylate) (PMMA) being greater than that for the modified material in the cylindrical volume of the track core. The spikes can be imaged and counted by routine AFM analysis. Investigations by angular-resolved near-grazing incidence reveal additional tracks that correspond to recoil tracks. The observations have been correlated with modelling, and shown to be in qualitative agreement with prevailing descriptions of collision cascades. The results may be relevant to technologies that are based on detection and characterization of single energetic ions. In particular, the direct visualization of the collision cascade may allow more accurate estimates of the actual interaction volume, which in turn will permit more precise assessment of dose distribution of α-emitting radionuclides used for targeted radiotherapy. The results could also be relevant to other diagnostic or process technologies based on interaction of energetic ions with matter.

Advances in anticancer radiopharmaceuticals.

This review highlights recent progress in the development of anticancer radiopharmaceuticals. Molecularly targeted radiotherapy refers to the selective delivery of radionuclides that emit charged particles, such as α particles, ß or Auger electrons, to cancer cells via a targeting vector. The discovery of new molecular targets through systems biology and other approaches has widened the scope for radiopharmaceutical development. Innovations in antibody engineering and humanisation, recombinant DNA technology, conjugation chemistry and, increasingly, nanotechnology have provided new approaches to the delivery of radionuclides to cancer cells. The increased availability of radioisotopes that have not traditionally been considered for therapy, such as α particle emitters, has also broadened the indications for targeted radiotherapy.

The effect of pulsed 900-MHz GSM mobile phone radiation on the acrosome reaction, head morphometry and zona binding of human spermatozoa.

Several recent studies have indicated that radiofrequency electromagnetic fields (RF-EMF) have an adverse effect on human sperm quality, which could translate into an effect on fertilization potential. This study evaluated the effect of RF-EMF on sperm-specific characteristics to assess the fertilizing competence of sperm. Highly motile human spermatozoa were exposed for 1 h to 900-MHz mobile phone radiation at a specific absorption rate of 2.0 W/kg and examined at various times after exposure. The acrosome reaction was evaluated using flow cytometry. The radiation did not affect sperm propensity for the acrosome reaction. Morphometric parameters were assessed using computer-assisted sperm analysis. Significant reduction in sperm head area (9.2 ± 0.7 µm² vs. 18.8 ± 1.4 µm²) and acrosome percentage of the head area (21.5 ± 4% vs. 35.5 ± 11.4%) was reported among exposed sperm compared with unexposed controls. Sperm-zona binding was assessed directly after exposure using the hemizona assay. The mean number of zona-bound sperm of the test hemizona and controls was 22.8 ± 12.4 and 31.8 ± 12.8 (p < 0.05), respectively. This study concludes that although RF-EMF exposure did not adversely affect the acrosome reaction, it had a significant effect on sperm morphometry. In addition, a significant decrease in sperm binding to the hemizona was observed. These results could indicate a significant effect of RF-EMF on sperm fertilization potential.

Comparison between propidium iodide and 7-amino-actinomycin-D for viability assessment during flow cytometric analyses of the human sperm acrosome.

Evaluation of the acrosome reaction can shed light on the fertilising competence of spermatozoa. To eliminate false-positive results when evaluating the acrosome status of human sperm cells, two viability probes propidium iodide (PI) and 7-amino-actinomycin D (7-AAD) were compared for their ability to stain nonviable cells post-fixation and permeabilisation. Both the mean fluorescence and % dead cells differed significantly with time (P < 0.0001). Unlike PI, 7-AAD did not leach from cells and fluorescence remained stable for up to 4 h. Furthermore, 7-AAD proved to be a proficient marker to exclude dead sperm cells during flow cytometric evaluation of ionophore-induced acrosome reaction.