Among other nanoparticle systems, gold nanoparticles have been explored as radiosensitizers. While most of the research in this area has focused on either gold nanoparticles with diameters of less than 2 nm or particles with micrometer dimensions, it has been shown that nanoparticles 50 nm in diameter have the highest cellular uptake. We present the results of in vitro studies that focus on the radiosensitization properties of nanoparticles in the size range from 14-74 nm. Radiosensitization was dependent on the number of gold nanoparticles internalized within the cells. Gold nanoparticles 50-nm in diameter showed the highest radiosensitization enhancement factor (REF) (1.43 at 220 kVp) compared to gold nanoparticles of 14 and 74 nm (1.20 and 1.26, respectively). Using 50-nm gold nanoparticles, the REF for lower- (105 kVp) and higher- (6 MVp) energy photons was 1.66 and 1.17, respectively. DNA double-strand breaks were quantified using radiation-induced foci of gamma-H2AX and 53BP1, and a modest increase in the number of foci per nucleus was observed in irradiated cell populations with internalized gold nanoparticles. The outcome of this research will enable the optimization of gold nanoparticle-based sensitizers for use in therapy.

The development of targeted anti-cancer therapies through the study of cancer genomes is intended to increase survival rates and decrease treatment-related toxicity. We treated a transposon–driven, functional genomic mouse model of medulloblastoma with ‘humanized’ in vivo therapy (microneurosurgical tumour resection followed by multi-fractionated, image-guided radiotherapy). Genetic events in recurrent murine medulloblastoma exhibit a very poor overlap with those in matched murine diagnostic samples (<5%). Whole-genome sequencing of 33 pairs of human diagnostic and post-therapy medulloblastomas demonstrated substantial genetic divergence of the dominant clone after therapy (<12% diagnostic events were retained at recurrence). In both mice and humans, the dominant clone at recurrence arose through clonal selection of a pre-existing minor clone present at diagnosis. Targeted therapy is unlikely to be effective in the absence of the target, therefore our results offer a simple, proximal, and remediable explanation for the failure of prior clinical trials of targeted therapy.

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Purpose:To assess image quality and image-guidance capabilities of a cone-beam CT based smallanimal image-guided irradiation unit ͑micro-IGRT͒. Methods: A micro-IGRT system has been developed in collaboration with the authors' laboratory as a means to study the radiobiological effects of conformal radiation dose distributions in small animals. The system, the X-Rad 225Cx, consists of a 225 kVp x-ray tube and a flat-panel amorphous silicon detector mounted on a rotational C-arm gantry and is capable of both fluoroscopic x-ray and cone-beam CT imaging, as well as image-guided placement of the radiation beams. Image quality ͑voxel noise, modulation transfer, CT number accuracy, and geometric accuracy characteristics͒ was assessed using water cylinder and micro-CT test phantoms. Image guidance was tested by analyzing the dose delivered to radiochromic films fixed to BB's through the endto-end process of imaging, targeting the center of the BB, and irradiation of the film/BB in order to compare the offset between the center of the field and the center of the BB. Image quality and geometric studies were repeated over a 5-7 month period to assess stability. Results: CT numbers reported were found to be linear ͑R 2 Ն 0.998͒ and the noise for images of homogeneous water phantom was 30 HU at imaging doses of approximately 1 cGy ͑to water͒. The presampled MTF at 50% and 10% reached 0.64 and 1.35 mm −1 , respectively. Targeting accuracy by means of film irradiations was shown to have a mean displacement error of ͓⌬x,⌬y,⌬z͔ = ͓−0.12, −0.05, −0.02͔ mm, with standard deviations of ͓0.02, 0.20, 0.17͔ mm. The system has proven to be stable over time, with both the image quality and image-guidance performance being reproducible for the duration of the studies. Conclusions:The micro-IGRT unit provides soft-tissue imaging of small-animal anatomy at acceptable imaging doses ͑Յ1 cGy͒. The geometric accuracy and targeting systems permit dose placement with submillimeter accuracy and precision. The system has proven itself to be stable over 2 yr of routine laboratory use ͑Ͼ1800 irradiations͒ and provides a platform for the exploration of targeted radiation effects in small-animal models.