Rare-Earth-Doped Nanoparticles for Short-Wave Infrared Fluorescence Bioimaging and Molecular Targeting of αVß3-Expressing Tumors.

The use of short-wave infrared (SWIR) light for fluorescence bioimaging offers the advantage of reduced photon scattering and improved tissue penetration compared to traditional shorter wavelength imaging approaches. While several nanomaterials have been shown capable of generating SWIR emissions, rare-earth-doped nanoparticles (REs) have emerged as an exceptionally bright and biocompatible class of SWIR emitters. Here, we demonstrate SWIR imaging of REs for several applications, including lymphatic mapping, real-time monitoring of probe biodistribution, and molecular targeting of the αvß3 integrin in a tumor model. We further quantified the resolution and depth penetration limits of SWIR light emitted by REs in a customized imaging unit engineered for SWIR imaging of live small animals. Our results indicate that SWIR light has broad utility for preclinical biomedical imaging and demonstrates the potential for molecular imaging using targeted REs.

X-ray-induced shortwave infrared biomedical imaging using rare-earth nanoprobes.

Shortwave infrared (SWIR or NIR-II) light provides significant advantages for imaging biological structures due to reduced autofluorescence and photon scattering. Here, we report on the development of rare-earth nanoprobes that exhibit SWIR luminescence following X-ray irradiation. We demonstrate the ability of X-ray-induced SWIR luminescence (X-IR) to monitor biodistribution and map lymphatic drainage. Our results indicate X-IR imaging is a promising new modality for preclinical applications and has potential for dual-modality molecular disease imaging.

Non-ablative doses of focal ionizing radiation alters function of central neural circuits.

BACKGROUND: Modulation of pathological neural circuit activity in the brain with a minimum of complications is an area of intense interest. OBJECTIVE: The goal of the study was to alter neurons' physiological states without apparent damage of cellular integrity using stereotactic radiosurgery (SRS). METHODS: We treated a 7.5 mm-diameter target on the visual cortex of Göttingen minipigs with doses of 40, 60, 80, and 100 Gy. Six months post-irradiation, the pigs were implanted with a 9 mm-wide, eight-shank multi-electrode probe, which spanned the radiation focus as well as the low-exposure neighboring areas. RESULTS: Doses of 40 Gy led to an increase of spontaneous firing rate, six months post-irradiation, while doses of 60 Gy and greater were associated with a decrease. Subjecting the animals to visual stimuli resulted in typical visual evoked potentials (VEP). At 40 Gy, a significant reduction of the P1 peak time, indicative of higher network excitability was observed. At 80 Gy, P1 peak time was not affected, while a minor reduction at 60 Gy was seen. No distance-dependent effects on spontaneous firing rate, or on VEP were observed. Post-mortem histology revealed no evidence of necrosis at doses below 60 Gy. In an in vitro assay comprising of iPS-derived human neuron-astrocyte co-cultures, we found a higher vulnerability of inhibitory neurons than excitatory neurons with respect to radiation, which might provide the cellular mechanism of the disinhibitory effect observed in vivo. CONCLUSION: We provide initial evidence for a rather circuit-wide, long-lasting disinhibitory effect of low sub-ablative doses of SRS.

Small-field beam data acquisition, detector dependency, and film-based validation for a novel self-shielded stereotactic radiosurgery system.

PURPOSE: This study reports a single-institution experience with beam data acquisition and film-based validation for a novel self-shielded sterotactic radiosurgery unit and investigates detector dependency on field output factors (OFs), off-axis ratios (OARs), and percent depth dose (PDD) measurements within the context of small-field dosimetry. METHODS: The delivery platform for this unit consists of a 2.7-MV S-band linear accelerator mounted on coupled gimbals that rotate around a common isocenter (source-to-axis distance [SAD] = 450 mm), allowing for more than 260 noncoplanar beam angles. Beam collimation is achieved via a tungsten collimator wheel with eight circular apertures ranging from 4 mm to 25 mm in diameter. Three diodes (PTW 60012 Diode E, PTW 60018 SRS Diode, and Sun Nuclear EDGE) and a synthetic diamond detector (PTW 60019 micro Diamond [µD] detector) were used for OAR, PDD, and OF measurements. OFs were also acquired with a PTW 31022 PinPoint ionization chamber. Beam scanning was performed using a 3D water tank at depths of 7, 50, 100, 200, and 250 mm with a source-to-surface distance of 450 mm. OFs were measured at the depth of maximum dose (dmax  = 7 mm) with the SAD at 450 mm. Gafchromic EBT3 film was used to validate OF and profile measurements and as a reference detector for estimating correction factors for active detector OFs. Deviations in field size, penumbra, and PDDs across the different detectors were quantified. RESULTS: Relative OFs (ROFs) for the diodes were within 1.4% for all collimators except for 5 and 7.5 mm, for which SRS Diode measurements were higher by 1.6% and 2.6% versus Diode E. The µD ROFs were within 1.4% of the diode measurements. PinPoint ROFs were lower by >10% for the 4-mm and 5-mm collimators versus the Diode E and µD. Corrections to OFs using EBT3 film as a reference were within 1.2% for all diodes and the µD detector for collimators 10 mm and greater and within 2.0%, 2.8%, and 1.1% for the 7.5-, 5-, and 4-mm collimators, respectively. The maximum difference in full width at half maximum (FWHM) between the Diode E and the other active detectors was for the 25-mm collimator and was 0.09 mm (µD), 0.16 mm (SRS Diode), and 0.65 mm (EDGE). Differences seen in PDDs beyond the depth of dmax were <1% across the three diodes and the µD. FWHM and penumbra measurements made using EBT3 film were within 1.34% and 3.26%, respectively, of the processed profile data entered into the treatment planning system. CONCLUSIONS: Minimal differences were seen in OAR and PDD measurements acquired with the diodes and the µD. ROFs measured with the three diodes were within 2.6% and within 1.4% versus the µD. Gafchromic Film measurements provided independent verification of the OAR and OF measurements. Estimated corrections to OFs using film as a reference were <1.6% for the Diode E, EDGE, and µD detector.

Automated multi-parameter high-dose-rate brachytherapy quality assurance via radioluminescence imaging.

The purpose of this study is to leverage radioluminescence imaging for the development of an automated high-dose-rate (HDR) brachytherapy quality assurance (QA) system that enables simultaneous measurements of dwell position, dwell time, wire velocity, and relative source strength in a single test. The system consists of a radioluminescence phosphor sheet (a mixture of Gd2O2S:Tb and PDMS) positioned atop a HDR needle applicator, a complementary metal-oxide-semiconductor digital camera used to capture the emitted radioluminescence signals from the scintillator sheet, and an in-house graphical user interface for signal processing. The signal processing was used to extract source intensity, location, and elapsed time, yielding the final measurements on dwell position, dwell time, and wire velocity. The source strength relative to the well chamber calibration (in unit of Air-Kerma strength, Sk ) is measured by establishing a calibration curve that correlates Sk with the detector response. Validation experiments are performed using three customized treatment plans. With these plans, the dwell position and dwell time are verified for a range of 110.0 cm-117.5 cm and 2 s-16 s, respectively, and the linear correlation with Sk is demonstrated for the source strength varying between 28 348 U (cGy cm2 h-1) and 41 906 U. The wire velocity, i.e. the speed of the radioactive source averaged over the distance in between dwell positions, is calculated for various distances ranging from 5 mm to 50 mm. Results show that the mean deviations of the measured dwell position and dwell time are 0.1 mm (range from 0 to 0.2 mm) and 32.5 ms (range from 0 to 60.0 ms) with respect to the planned values, respectively, and the system response is highly linear with Sk ( R2 = 0.998). Moreover, the measured wire velocities are comparable to previously reported values. Benefitting from the compact hardware design and image processing algorithms, the system provides a practical, reliable, and comprehensive solution for HDR QA.

Synergistically Enhancing the Therapeutic Effect of Radiation Therapy with Radiation Activatable and Reactive Oxygen Species-Releasing Nanostructures.

Nanoparticle-based radio-sensitizers can amplify the effects of radiation therapy on tumor tissue even at relatively low concentrations while reducing the potential side effects to healthy surrounding tissues. In this study, we investigated a hybrid anisotropic nanostructure, composed of gold (Au) and titanium dioxide (TiO2), as a radio-sensitizer for radiation therapy of triple-negative breast cancer (TNBC). In contrast to other gold-based radio sensitizers, dumbbell-like Au-TiO2 nanoparticles (DATs) show a synergistic therapeutic effect on radiation therapy, mainly because of strong asymmetric electric coupling between the high atomic number metals and dielectric oxides at their interfaces. The generation of secondary electrons and reactive oxygen species (ROS) from DATs triggered by X-ray irradiation can significantly enhance the radiation effect. After endocytosed by cancer cells, DATs can generate a large amount of ROS under X-ray irradiation, eventually inducing cancer cell apoptosis. Significant tumor growth suppression and overall improvement in survival rate in a TNBC tumor model have been successfully demonstrated under DAT uptake for a radio-sensitized radiation therapy.

Using a handheld stereo depth camera to overcome limited field-of-view in simulation imaging for radiation therapy treatment planning.

PURPOSE: A correct body contour is essential for reliable treatment planning in radiation therapy. While modern medical imaging technologies provide highly accurate patient modeling, there are times when a patient's anatomy cannot be fully captured or there is a lack of easy access to computed tomography (CT) simulation. Here, we provide a practical solution to the surface contour truncation problem by using a handheld stereo depth camera (HSDC) to obtain the missing surface anatomy and a surface-surface image registration to stich the surface data into the CT dataset for treatment planning. METHODS: For a subject with truncated simulation CT images, a HSDC is used to capture the surface information of the truncated anatomy. A mesh surface model is created using a software tool provided by the camera manufacturer. A surface-to-surface registration technique is used to merge the mesh model with the CT and fill in the missing surface information thereby obtaining a complete surface model of the subject. To evaluate the accuracy of the proposed approach, experiments were performed with the following steps. First, we selected three previously treated patients and fabricated a phantom mimicking each patient using the corresponding CT images and a 3D printer. Second, we removed part of the CT images of each patient to create hypothetical cases with image truncations. Next, a HSDC was used to image the 3D-printed phantoms and the HSDC-derived surface models were registered with the hypothetically truncated CT images. The contours obtained using the approach were then compared with the ground truth contours derived from the original simulation CT without image truncation. The distance between the two contours was calculated in order to evaluate the accuracy of the method. Finally, the dosimetric impact of the approach is assessed by comparing the volume within the 95% isodose line and global maximum dose (Dmax ) computed based on the two surface contours for the breast case that exhibited the largest contour variation in the treated breast. RESULTS: A systematic strategy of using a 3D HSDC to compensate for missing surface information caused by the truncation of CT images was established. Our study showed that the proposed technique was able to reliably provide the full contours for treatment planning in the case of severe CT image truncation(s). The root-mean-square error for the registration between the aligned HDSC surface model and the ground truth data was found to be 2.1 mm. The average distance between the two models was 0.4 ± 1.7 mm (mean ± SD). Maximum deviations occurred in areas of high concavity or when the skin was close to the couch. The breast tissue covered by 95% isodose line decreased by 3% and Dmax increased by 0.2% with the use of the HSDC model. CONCLUSIONS: The use of HSDC for obtaining missing surface data during simulation has a number of advantages, such as, ease of use, low cost, and no additional ionizing radiation. It may provide a clinically practical solution to deal with the longstanding problem of CT image truncations in radiation therapy treatment planning.

Radiosurgical Treatment Verification Using Removable Megavoltage Radiation Detectors.

Introduction Accurate dose delivery is critical to the success of stereotactic radiosurgery. Unfortunately, verification of the accuracy of treatment delivery remains a challenging problem. Existing radiosurgery delivery paradigms are limited in their ability to verify the accurate delivery of radiation beams using data sampled from the beam after it has traversed the patient. The Zap-X Radiosurgery System (Zap Surgical Systems, San Carlos, CA) addresses this issue by implementing a fully integrated treatment delivery system that utilizes a factory commissioned megavoltage (MV) imager to measure the transmitted beam. The measured intensity is then compared with an expected value in order to confirm that treatment is proceeding as expected. The purpose of this study was to evaluate a prototype system and investigate the accuracy of an attenuation model used in generating the expected transmitted intensity values. Methods A prototype MV imager was used to measure transmitted beam intensities at various exposure levels and through several thicknesses of solid water. The data were used to evaluate imager linearity and model accuracy. Results Experimental results indicate that a quadratic attenuation model is appropriate for predicting beam attenuation and that the imager exhibits excellent dose linearity. Conclusions The MV imager system is shown to be capable of accurately acquiring the data needed to confirm treatment validity.

Synthesis, Characterization, and Biomedical Applications of a Targeted Dual-Modal Near-Infrared-II Fluorescence and Photoacoustic Imaging Nanoprobe.

Our development of multifunctional dual-modal imaging probes aims to integrate the benefits from both second near-infrared (NIR-II) fluorescence (1000-1700 nm) and photoacoustic imaging with an ultimate goal of improving overall cancer diagnosis efficacy. Herein we designed a donor-acceptor chromophore based nanoparticle (DAP) as a dual-modal image contrast agent has strong absorption in the NIR-I window and a strong fluorescence emission peak in the NIR-II region. The dual-modal DAPs composed of D-π-A-π-D-type chromophores were PEGylated through nanoprecipitation. The multifunctional DAP surface was thus available for subsequent bioconjugation of EGFR Affibody (Ac-Cys-ZEGFR:1907) to target EGFR-positive cancers. The Affibody-conjugated DAPs appeared as highly monodisperse nanoparticles (∼30 nm) with strong absorption in the NIR-I window (at ca. 680 nm) and an extremely high fluorescence in the NIR-II region (maximum peak at 1000 nm). Consequently, the Affibody-DAPs show significantly enhanced photoacoustic and NIR-II fluorescence contrast effects in both in vitro and in vivo experiments. Moreover, the Affibody-DAPs have the capability to selectively target EGFR-positive tumors in an FTC-133 subcutaneous mouse model with relatively high photoacoustic and fluorescent signals. By taking advantage of high spatial resolution and excellent temporal resolution, photoacoustic/NIR-II fluorescence imaging with targeted dual-modal contrast agents allows us to specifically image and detect various cancers and diseases in an accurate manner.

A depth-sensing technique on 3D-printed compensator for total body irradiation patient measurement and treatment planning.

PURPOSE: The purpose of total body irradiation (TBI) techniques is to deliver a uniform radiation dose to the entire volume of a patient's body. Due to variations in the thickness of the patient, it is difficult to produce such a uniform dose distribution throughout the body. In many techniques, a compensator is used to adjust the dose delivered to various sections of the patient. The current study aims to develop and validate an innovative method of using depth-sensing cameras and 3D printing techniques for TBI treatment planning and compensator fabrication. METHODS: A tablet with an integrated depth-sensing camera and motion tracking sensors was used to scan a RANDO™ phantom positioned in a TBI treatment booth to detect and store the 3D surface in a point cloud format. The accuracy of the detected surface was evaluated by comparing extracted body thickness measurements with corresponding measurements from computed tomography (CT) scan images. The thickness, source to surface distance, and off-axis distance of the phantom at different body section were measured for TBI treatment planning. A detailed compensator design was calculated to achieve a uniform dose distribution throughout the phantom. The compensator was fabricated using a 3D printer, silicone molding, and a mixture of wax and tungsten powder. In vivo dosimetry measurements were performed using optically stimulated luminescent detectors. RESULTS: The scan of the phantom took approximately 30 s. The mean error for thickness measurements at each section of phantom relative to CT was 0.48 ± 0.27 cm. The average fabrication error for the 3D-printed compensator was 0.16 ± 0.15 mm. In vivo measurements for an end-to-end test showed that overall dose differences were within 5%. CONCLUSIONS: A technique for planning and fabricating a compensator for TBI treatment using a depth camera equipped tablet and a 3D printer was demonstrated to be sufficiently accurate to be considered for further investigation.

Automating quality assurance of digital linear accelerators using a radioluminescent phosphor coated phantom and optical imaging.

Performing mechanical and geometric quality assurance (QA) tests for medical linear accelerators (LINAC) is a predominantly manual process that consumes significant time and resources. In order to alleviate this burden this study proposes a novel strategy to automate the process of performing these tests. The autonomous QA system consists of three parts: (1) a customized phantom coated with radioluminescent material; (2) an optical imaging system capable of visualizing the incidence of the radiation beam, light field or lasers on the phantom; and (3) software to process the captured signals. The radioluminescent phantom, which enables visualization of the radiation beam on the same surface as the light field and lasers, is placed on the couch and imaged while a predefined treatment plan is delivered from the LINAC. The captured images are then processed to self-calibrate the system and perform measurements for evaluating light field/radiation coincidence, jaw position indicators, cross-hair centering, treatment couch position indicators and localizing laser alignment. System accuracy is probed by intentionally introducing errors and by comparing with current clinical methods. The accuracy of self-calibration is evaluated by examining measurement repeatability under fixed and variable phantom setups. The integrated system was able to automatically collect, analyze and report the results for the mechanical alignment tests specified by TG-142. The average difference between introduced and measured errors was 0.13 mm. The system was shown to be consistent with current techniques. Measurement variability increased slightly from 0.1 mm to 0.2 mm when the phantom setup was varied, but no significant difference in the mean measurement value was detected. Total measurement time was less than 10 minutes for all tests as a result of automation. The system's unique features of a phosphor-coated phantom and fully automated, operator independent self-calibration offer the potential to streamline the QA process for modern LINACs.

Flexible radioluminescence imaging for FDG-guided surgery.

PURPOSE: Flexible radioluminescence imaging (Flex-RLI) is an optical method for imaging 18F-fluorodeoxyglucose (FDG)-avid tumors. The authors hypothesize that a gadolinium oxysulfide: terbium (GOS:Tb) flexible scintillator, which loosely conforms to the body contour, can enhance tumor signal-to-background ratio (SBR) compared with RLI, which utilizes a flat scintillator. The purpose of this paper is to characterize flex-RLI with respect to alternative modalities including RLI, beta-RLI (RLI with gamma rejection), and Cerenkov luminescence imaging (CLI). METHODS: The photon sensitivity, spatial resolution, and signal linearity of flex-RLI were characterized with in vitro phantoms. In vivo experiments utilizing 13 nude mice inoculated with the head and neck (UMSCC1-Luc) cell line were then conducted in accordance with the institutional Administrative Panel on Laboratory Animal Care. After intravenous injection of 18F-FDG, the tumor SBR values for flex-RLI were compared to those for RLI, beta-RLI, and CLI using the Wilcoxon signed rank test. RESULTS: With respect to photon sensitivity, RLI, beta-RLI, and flex-RLI produced 1216.2, 407.0, and 98.6 times more radiance per second than CLI. Respective full-width half maximum values across a 0.5 mm capillary tube were 6.9, 6.4, 2.2, and 1.5 mm, respectively. Flex-RLI demonstrated a near perfect correlation with 18F activity (r = 0.99). Signal uniformity for flex-RLI improved after more aggressive homogenization of the GOS powder with the silicone elastomer during formulation. In vivo, the SBR value for flex-RLI (median 1.29; interquartile range 1.18-1.36) was statistically greater than that for RLI (1.08; 1.02-1.14; p < 0.01) by 26%. However, there was no statistically significant difference in SBR values between flex-RLI and beta-RLI (p = 0.92). Furthermore, there was no statistically significant difference in SBR values between flex-RLI and CLI (p = 0.11) in a more limited dataset. CONCLUSIONS: Flex-RLI provides high quality images with SBRs comparable to those from CLI and beta-RLI in a single 10 s acquisition.

Monitoring external beam radiotherapy using real-time beam visualization.

PURPOSE: To characterize the performance of a novel radiation therapy monitoring technique that utilizes a flexible scintillating film, common optical detectors, and image processing algorithms for real-time beam visualization (RT-BV). METHODS: Scintillating films were formed by mixing Gd2O2S:Tb (GOS) with silicone and casting the mixture at room temperature. The films were placed in the path of therapeutic beams generated by medical linear accelerators (LINAC). The emitted light was subsequently captured using a CMOS digital camera. Image processing algorithms were used to extract the intensity, shape, and location of the radiation field at various beam energies, dose rates, and collimator locations. The measurement results were compared with known collimator settings to validate the performance of the imaging system. RESULTS: The RT-BV system achieved a sufficient contrast-to-noise ratio to enable real-time monitoring of the LINAC beam at 20 fps with normal ambient lighting in the LINAC room. The RT-BV system successfully identified collimator movements with sub-millimeter resolution. CONCLUSIONS: The RT-BV system is capable of localizing radiation therapy beams with sub-millimeter precision and tracking beam movement at video-rate exposure.