Fibroblast Activation Protein-Targeted Radioligand Therapy for Treatment of Solid Tumors.

Fibroblast activation protein (FAP) has received increasing attention as an oncologic target because of its prominent expression in solid tumors but virtual absence from healthy tissues. Most radioligand therapies (RLTs) targeting FAP, however, suffer from inadequate tumor retention or clearance from healthy tissues. Herein we report a FAP-targeted RLT comprising an FAP6 ligand conjugated to DOTA and an albumin binder (4-p-iodophenylbutyric acid, or IP) for enhanced pharmacokinetics. We evaluated the performance of the resulting FAP6-IP-DOTA conjugate in 4 tumor models, 3 of which express FAP only on cancer-associated fibroblasts, that is, analogously to human tumors. Methods: Single-cell RNA-sequencing data were analyzed from 34 human breast, ovarian, colorectal, and lung cancers to quantify FAP-overexpressing cells. FAP6-DOTA conjugates were synthesized with or without an albumin binder (IP) and investigated for binding to human FAP-expressing cells. Accumulation of 111In- or 177Lu-labeled conjugates in KB, HT29, U87MG, and 4T1 murine tumors was also assessed by radioimaging or biodistribution analyses. Radiotherapeutic potency was quantitated by measuring tumor volumes versus time. Results: Approximately 5% of all cells in human tumors overexpressed FAP (cancer-associated fibroblasts comprised ∼77% of this FAP-positive subpopulation, whereas ∼2% were cancer cells). FAP6 conjugates bound to FAP-expressing cells with high affinity (dissociation constant, ∼1 nM). 177Lu-FAP6-IP-DOTA achieved an 88-fold higher tumor dose than 177Lu-FAP6-DOTA and improved all tumor-to-healthy-organ ratios. Single doses of 177Lu-FAP6-IP-DOTA suppressed tumor growth by about 45% in all tested tumor models without causing reproducible toxicities. Conclusion: We conclude that 177Lu-FAP6-IP-DOTA constitutes a promising candidate for FAP-targeted RLT of solid tumors.

Evaluation of advanced methods and materials for construction of scintillation detector light guides.

New techniques for fabrication of optically clear structures (3D printing and casting) can be applied to fabrication of light guides, especially complex -shaped ones, for scintillation detectors. In this investigation, we explored the spectral transmissivity of sample light guides created with different fabrication methods and materials. A spectrophotometer was used to measure the transmissivity of the samples to determine their compatibility with a number of commonly used inorganic scintillators (NaI(Tl), BGO, LaBr3, LaCr3, CSI(Tl) and LYSO). These measurements showed that stereolithography with a Stratasys 3D printer using Somos WaterClear Ultra 10122® produced the most compatible light guide with common organic scintillators, especially LYSO (peak emission λ=420 nm) (a scintillator commonly used in positron emission tomography (PET) imaging). Additionally, Polytek Poly-Optic® 1730 clear urethane produced a cast light guide that was the most optically compatible with these scintillators. To demonstrate the ability to create a unique shaped scintillation detector using 3D-printing and casting methods, a small arc-shaped piece of LYSO was coupled to a 4 × 4 array of 4 mm2 silicon photomultipliers (SiPM) using light guides made from these materials. For comparative purposes, a light guide was also fabricated using standard acrylic, a material often used in current light guides. All detectors produced similar event position maps. The energy resolution for 18F (511 keV photopeak) was 13% for the acrylic light-guide-based detector, while it was 18% for the printed light-guide-based detector and 20% for the cast light-guide-based detector. Results from this study demonstrate that advanced fabrication methods have the potential to facilitate creation of light guides for scintillation detectors. Continued advancements in materials and methods will likely result in improved optical performance for 3D-printed structures.

Deep residual-convolutional neural networks for event positioning in a monolithic annular PET scanner.

PET scanners based on monolithic pieces of scintillator can potentially produce superior performance characteristics (high spatial resolution and detection sensitivity, for example) compared to conventional PET scanners. Consequently, we initiated development of a preclinical PET system based on a single 7.2 cm long annulus of LYSO, called AnnPET. While this system could facilitate creation of high-quality images, its unique geometry results in optics that can complicate estimation of event positioning in the detector. To address this challenge, we evaluated deep-residual convolutional neural networks (DR-CNN) to estimate the three-dimensional position of annihilation photon interactions. Monte Carlo simulations of the AnnPET scanner were used to replicate the physics, including optics, of the scanner. It was determined that a ten-layer-DR-CNN was most suited to application with AnnPET. The errors between known event positions, and those estimated by this network and those calculated with the commonly used center-of-mass algorithm (COM) were used to assess performance. The mean absolute errors (MAE) for the ten-layer-DR-CNN-based event positions were 0.54 mm, 0.42 mm and 0.45 mm along thex(axial)-,y(transaxial)- andz- (depth-of-interaction) axes, respectively. For COM estimates, the MAEs were 1.22 mm, 1.04 mm and 2.79 mm in thex-,y- andz-directions, respectively. Reconstruction of the network-estimated data with the 3D-FBP algorithm (5 mm source offset) yielded spatial resolutions (full-width-at-half-maximum (FWHM)) of 0.8 mm (radial), 0.7 mm (tangential) and 0.71 mm (axial). Reconstruction of the COM-derived data yielded spatial resolutions (FWHM) of 1.15 mm (radial), 0.96 mm (tangential) and 1.14 mm (axial). These findings demonstrated that use of a ten-layer-DR-CNN with a PET scanner based on a monolithic annulus of scintillator has the potential to produce excellent performance compared to standard analytical methods.

A dedicated breast-PET/CT scanner: Evaluation of basic performance characteristics.

PURPOSE: Application of advanced imaging techniques, such as PET and x ray CT, can potentially improve detection of breast cancer. Unfortunately, both modalities have challenges in the detection of some lesions. The combination of the two techniques, however, could potentially lead to an overall improvement in diagnostic breast imaging. The purpose of this investigation is to test the basic performance of a new dedicated breast-PET/CT. METHODS: The PET component consists of a rotating pair of detectors. Its performance was evaluated using the NEMA NU4-2008 protocols. The CT component utilizes a pulsed x ray source and flat panel detector mounted on the same gantry as the PET scanner. Its performance was assessed using specialized phantoms. The radiation dose to a breast during CT imaging was explored by the measurement of free-in-air kerma and air kerma measured at the center of a 16 cm-diameter PMMA cylinder. Finally, the combined capabilities of the system were demonstrated by imaging of a micro-hot-rod phantom. RESULTS: Overall, performance of the PET component is comparable to many pre-clinical and other dedicated breast-PET scanners. Its spatial resolution is 2.2 mm, 5 mm from the center of the scanner using images created with the single-sliced-filtered-backprojection algorithm. Peak NECR is 24.6 kcps; peak sensitivity is 1.36%; the scatter fraction is 27%. Spatial resolution of the CT scanner is 1.1 lp/mm at 10% MTF. The free-in-air kerma is 2.33 mGy, while the PMMA-air kerma is 1.24 mGy. Finally, combined imaging of a micro-hot-rod phantom illustrated the potential utility of the dual-modality images produced by the system. CONCLUSION: The basic performance characteristics of a new dedicated breast-PET/CT scanner are good, demonstrating that its performance is similar to current dedicated PET and CT scanners. The potential value of this system is the capability to produce combined duality-modality images that could improve detection of breast disease. The next stage in development of this system is testing with more advanced phantoms and human subjects.

Small animal, positron emission tomography-magnetic resonance imaging system based on a clinical magnetic resonance imaging scanner: evaluation of basic imaging performance.

Development of advanced preclinical imaging techniques has had an important impact on the field of biomedical research, with positron emission tomography (PET) imaging the most mature of these efforts. Developers of preclinical PET scanners have joined the recent multimodality imaging trend by combining PET imaging with other modalities, such as magnetic resonance imaging (MRI). Our group has developed a combined PET-MRI insert for the imaging of animals up to the size of rats in a clinical 3T MRI scanner. The system utilizes a sequential scanner configuration instead of the more common coplanar geometry. The PET component of the system consists of a ring of 12 liquid-cooled, SiPM-based detector modules ( diameter = 15.2 cm ). System performance was evaluated with the NEMA NU 4-2008 protocol. Spatial resolution is ∼ 1.71 mm 5 cm from the center of the field-of-view measured from single-slice rebinned filtered backprojection-reconstructed images. Peak noise equivalent count rate is 17.7 kcps at 8.5 MBq; peak sensitivity is 2.9%. The MRI component of the system is composed of a 12-cm-diameter birdcage transmit/receive coil with a dual-preamplifier interface possessing very low noise preamplifiers. System performance was evaluated using American College of Radiology-based methods. Image homogeneity is 99%; the ghosting ratio is 0.0054. The signal-to-noise ratio is 95 and spatial resolution is ∼ 0.25 mm . There was no discernable cross-modality interference.

Preclinical positron emission tomography scanner based on a monolithic annulus of scintillator: initial design study.

Positron emission tomography (PET) scanners designed for imaging of small animals have transformed translational research by reducing the necessity to invasively monitor physiology and disease progression. Virtually all of these scanners are based on the use of pixelated detector modules arranged in rings. This design, while generally successful, has some limitations. Specifically, use of discrete detector modules to construct PET scanners reduces detection sensitivity and can introduce artifacts in reconstructed images, requiring the use of correction methods. To address these challenges, and facilitate measurement of photon depth-of-interaction in the detector, we investigated a small animal PET scanner (called AnnPET) based on a monolithic annulus of scintillator. The scanner was created by placing 12 flat facets around the outer surface of the scintillator to accommodate placement of silicon photomultiplier arrays. Its performance characteristics were explored using Monte Carlo simulations and sections of the NEMA NU4-2008 protocol. Results from this study revealed that AnnPET's reconstructed spatial resolution is predicted to be [Formula: see text] full width at half maximum in the radial, tangential, and axial directions. Peak detection sensitivity is predicted to be 10.1%. Images of simulated phantoms (mini-hot rod and mouse whole body) yielded promising results, indicating the potential of this system for enhancing PET imaging of small animals.

Concept of an upright wearable positron emission tomography imager in humans.

BACKGROUND: Positron Emission Tomography (PET) is traditionally used to image patients in restrictive positions, with few devices allowing for upright, brain-dedicated imaging. Our team has explored the concept of wearable PET imagers which could provide functional brain imaging of freely moving subjects. To test feasibility and determine future considerations for development, we built a rudimentary proof-of-concept prototype (Helmet_PET) and conducted tests in phantoms and four human volunteers. METHODS: Twelve Silicon Photomultiplier-based detectors were assembled in a ring with exterior weight support and an interior mechanism that could be adjustably fitted to the head. We conducted brain phantom tests as well as scanned four patients scheduled for diagnostic F(18-) FDG PET/CT imaging. For human subjects the imager was angled such that field of view included basal ganglia and visual cortex to test for typical resting-state pattern. Imaging in two subjects was performed ~4 hr after PET/CT imaging to simulate lower injected F(18-) FDG dose by taking advantage of the natural radioactive decay of the tracer (F(18) half-life of 110 min), with an estimated imaging dosage of 25% of the standard. RESULTS: We found that imaging with a simple lightweight ring of detectors was feasible using a fraction of the standard radioligand dose. Activity levels in the human participants were quantitatively similar to standard PET in a set of anatomical ROIs. Typical resting-state brain pattern activation was demonstrated even in a 1 min scan of active head rotation. CONCLUSION: To our knowledge, this is the first demonstration of imaging a human subject with a novel wearable PET imager that moves with robust head movements. We discuss potential research and clinical applications that will drive the design of a fully functional device. Designs will need to consider trade-offs between a low weight device with high mobility and a heavier device with greater sensitivity and larger field of view.

TandemPET- A High Resolution, Small Animal, Virtual Pinhole-Based PET Scanner: Initial Design Study.

Mice are the perhaps the most common species of rodents used in biomedical research, but many of the current generation of small animal PET scanners are non-optimal for imaging these small rodents due to their relatively low resolution. Consequently, a number of researchers have investigated the development of high-resolution scanners to address this need. In this investigation, the design of a novel, high-resolution system based on the dual-detector, virtual-pinhole PET concept was explored via Monte Carlo simulations. Specifically, this system, called TandemPET, consists of a 5 cm × 5 cm high-resolution detector made-up of a 90 × 90 array of 0.5 mm × 0.5 mm × 10 mm (pitch= 0.55 mm) LYSO detector elements in coincidence with a lower resolution detector consisting of a 68 × 68 array of 1.5 mm × 1.5 mm × 10 mm LYSO detector elements (total size= 10.5 cm × 10.5 cm). Analyses indicated that TandemPET's optimal geometry is to position the high-resolution detector 3 cm from the center-of-rotation, with the lower resolution detector positioned 9 cm from center. Measurements using modified NEMA NU4-2008-based protocols revealed that the spatial resolution of the system is ~0.5 mm FWHM, after correction of positron range effects. Peak sensitivity is 2.1%, which is comparable to current small animal PET scanners. Images from a digital mouse brain phantom demonstrated the potential of the system for identifying important neurological structures.