This study investigated the application of VivoVist™, a high-contrast micro-CT contrast agent, in spectral Photon-Counting (PC) micro-CT imaging in mouse models. With a long blood half-life, superior concentration, and reduced toxicity VivoVist, composed of barium (Ba)-based nanoparticles, offers a cost-effective solution for enhancing Computed Tomography (CT) imaging. To evaluate its efficacy, we employed an in-house developed spectral micro-CT with a photon-counting detector. VivoVist was administered through retro-orbital injection in a non-tumor-bearing C57BL/6 mouse and in two mice with MOC2 buccal tumors, with scans taken at various post-injection intervals. We used a multi-channel iterative reconstruction algorithm to provide multi-energy tomographic images with a voxel size of 125 microns or 75 microns for high-resolution scans; we performed post-reconstruction spectral decomposition with water, calcium (Ca), iodine (I), and barium (Ba) as bases. Our results revealed effective separation of Ba from I-based contrast agents with minimal cross-contamination and superior contrast enhancement for VivoVist at 39 keV. We also observed VivoVist's potential in delineating vasculature in the brain and its decreasing concentration in the blood over time post-injection, with increased uptake in the liver and spleen. We also explored the simultaneous use of VivoVist and liposomal iodinated nanoparticles in a cancer study involving radiation therapy. Our findings reveal that VivoVist, combined with radiation therapy, did not significantly increase liposomal iodine accumulation within head and neck squamous cell carcinoma tumors. In conclusion, our work confirms VivoVist's promising role in enhancing PCCT imaging and its potential in studying combination therapy, warranting further investigation into its applications in diagnostics and radiotherapy.
Extracellular deposits of amyloid-β (Aβ) aggregates are pathological hallmarks of Alzheimer’s disease (AD). In our previous work, we showed that an amyloid-targeted liposomal gadolinium (Gd) contrast agent, ADx-001, demonstrated dose-related varying performance (accuracy 50% - 100%) for in vivo MRI-based detection of amyloid plaques in a mouse model of AD. The goal of this study was to determine if nano-radiomics (radiomic analysis of nanoparticle contrast-enhanced images) could improve performance in differentiating amyloid-positive transgenic (TG) APP/PSEN1 mice and age-matched amyloid-negative Wild Type (WT) mice. Nanoparticle contrast-enhanced MRI (nCE-MRI) was performed using a T1w-SE sequence in wild type (amyloid negative) and transgenic APP/PSEN1 mice (amyloid positive). The effect of ADx-001 dose and plaque burden on the performance of radiomics was determined. nCE-MRI was performed at three ADx-001 dose levels (0.10, 0.15, 0.20 mmol Gd/kg) in mice with high plaque burden and single ADx-001 dose level (0.20 mmol Gd/kg) in mice with low plaque burden. Following semi-automatic registration and segmentation of brain atlas on mouse MR images, two sets of radiomic features (RFs), including the RFs recommended by Image Biomarker Standardization Initiative, were calculated and evaluated for their performance in classifying TG and WT mice. Linear and nonlinear classifiers using RFs were examined to improve the model performance. 5-fold cross-validation was performed to confirm the accuracy of group separation. Nano-radiomic analysis in mice with high plaque burden achieved superb classification performance in terms of accuracy, sensitivity, and specificity, with one universal classifier for all dose levels of ADx-001. In comparison, conventional MR metric of signal enhancement demonstrated dose-related varying performance with suboptimal accuracy (⪅0.7) at lower dose levels. In mice with low plaque burden, radiomic analysis outperformed conventional MR metric for detection of amyloid pathology. In conclusion, nano-radiomics exhibited excellent performance for early detection and amyloid burden classification in a mouse model of Alzheimer’s disease.
Photon Counting Detectors (PCD) have emerged as a transformative technology in CT and micro-CT imaging, offering enhanced contrast resolution and quantitative material separation in a single scan, a notable advancement from traditional energy-integrating detectors. The unique properties of bismuth tungstate (Bi2WO6) nanoparticles (NPs), hold promise in many applications, including contrast-enhanced CT imaging and photothermal therapy, especially in addressing tumor hypoxia challenges. However, despite these promising traits, the performance of PCCT imaging using Bi2WO6 NPs has not been fully explored. Our study bridges this gap by employing both simulations and real experiments. Using iterative PCCT reconstruction, we achieved significant noise reduction, from a noise standard deviation up to 786 Hounsfield Units (HU) down to 54 HU, enabling material decomposition. The dual K-edge of Bi2WO6, coupled with a precise 2:1 Bismuth to Tungsten ratio, offers a unique, quantifiable signature for PCCT imaging: the enhancement of Bi2WO6 remains largely constant over the diagnostic x-ray range (stddev: 1.24 HU/mg/mL over 25-91 keV energy thresholds, 125 kVp spectrum; iodine stddev: 11.62 HU/mg/mL). Improved separation of contrast material from intrinsic tissues promises to enhance all facets of clinical CT, including new avenues for radiation dose and metal artifact reduction. Potential new clinical applications include targeted radiation therapy, where Bi2WO6 NPs could intensify treatment efficacy and optimize chemotherapeutic delivery.
Superior material discrimination provided by photon counting detector (PCD) technology promises to transform X-ray CT into a functional and molecular imaging modality while maintaining its high spatial resolution, fast scanning times, and relatively low cost. Our group has developed pre-clinical photon-counting CT (PCCT) prototype systems and applied them, in combination with nanoparticle contrast agents, for cancer and cardiac imaging. This work aims to compare the PCCT imaging performance using a gallium arsenide (GaAs) and a cadmium telluride (CdTe) based PCD, both with 150- μm pixels and 4 energy thresholds. The two PCDs were integrated in the same PCCT system. Phantoms containing elemental solutions of Iodine, Gadolinium, Tantalum, Hafnium, Bismuth and Calcium were imaged with each detector to establish the spectral separation capabilities for PCCT. Moreover, combined dual detectors PCCT imaging was also tested. A joint iterative reconstruction followed by image-based material decomposition was used to provide material maps of different elements. The accuracy of the estimated concentrations within the material decompositions were compared. Our results have shown that GaAs-based PCCT imaging has an overall higher sensitivity (by ~15%) to Iodine than CdTe when using identical acquisition parameters. The CdTe imaging, has higher quantum efficiency at high keVs, supporting higher source kVps and energy threshold settings for imaging the K-edges of Bismuth or other high-Z NPs (such as Gold). Based on the average vial measurements, hybrid GaAs-CdTe PCCT decompositions have the most accurate decompositions for nearly all materials except for Bismuth. The combination of CdTe and GaAs PCDs into a dual source PCCT system will provide high sensitivity in separating multi-element contrast agents from intrinsic tissues.
Developing novel contrast agents for multi-energy photon-counting (PC)CT will require a clear translation pathway from preclinical validation to clinical applications. To begin this development, we have used a clinical PCCT scanner (Siemens NAEOTOM Alpha) to study the spectral separation of a few contrast elements (Iodine, I; Gadolinium, Gd; Hafnium, Hf; Tantalum, Ta; Bismuth, Bi; Calcium, Ca) with currently available scanning protocols (fixed: 120 kVp, 20 and 65 keV thresholds). We also explored the capabilities of clinical and preclinical PCCT to image mice with sarcoma tumors injected with nanoparticles (NP). Our results indicate that Ta or Hf are complementary to I or Gd, providing excellent spectral separation for future multi-agent studies. Based on preclinical PCCT with four energy thresholds, we also conclude that additional energy thresholds will benefit clinical PCCT. Furthermore, we demonstrate the role that multi-channel denoising and reconstruction algorithms will play in pushing the bounds of spatial and spectral resolution with clinical PCCT. Performing co-clinical research will facilitate the translation of novel imaging algorithms and NP contrast agents for PCCT
The photon-counting (PC) detector technology promises to enhance the number of CT applications due to the spectral information. Of high interest for the cancer research community is imaging the tumor delivery of Cisplatin (CisPt), a chemotherapeutic agent utilized for treatment of numerous malignancies. CisPt contains platinum (Pt), a high-Z element material with a K-edge (78.4 keV) in the diagnostic spectrum. Our group has developed a preclinical prototype photon counting (PC) CT and applied it in cancer studies using nanoparticles. This study aims to investigate if CisPt can be imaged by K-edge spectral PCCT. Simulations and phantom experiments were performed to investigate CisPt detection using PCCT. We have selected scanning parameters (125 kVp) and energy thresholds (28, 34, 70, 78 keV) to enable K-edge separation of Pt and iodine (I) from calcium (Ca). The simulations include modeling of the polychromatic spectrum, and the PC detector response with spectral distortions. Two digital phantoms were used with maximum concentrations corresponding to low (2 mg/mL) and high (10 mg/mL) concentrations of I and Pt. A physical phantom with CisPt, I and Ca solutions was imaged both on our PC micro-CT and a novel clinical PCCT system. Material decompositions confirm the separation of Pt, Ca and I. However, low concentrations (<1 mg/mL) of CisPt are unlikely to be separated. Nevertheless, a liposomal nanoparticle-based CisPt formulation can enhance tumor delivery, via enhanced permeability and retention (EPR) and benefit from PCCT monitoring. Thus, depending on the levels of tumor accumulation, PCCT imaging of nanoparticles containing CisPt may become possible.
The purpose of this study was to investigate if radiomic analysis based on spectral micro-CT with nanoparticle contrastenhancement can differentiate tumors based on tumor-infiltrating lymphocyte (TIL) burden. High mutational load transplant soft tissue sarcomas were initiated in Rag2+/- and Rag2-/- mice to model varying TIL burden. Mice received radiation therapy (20 Gy) to the tumor-bearing hind limb and were injected with a liposomal iodinated contrast agent. Five days later, animals underwent conventional micro-CT imaging using an energy integrating detector (EID) and spectral micro-CT imaging using a photon-counting detector (PCD). Tumor volumes, and iodine uptakes were measured. The radiomic features (RF) were grouped into feature-spaces corresponding to EID, PCD, and spectral decomposition images. RFs were ranked to reduce redundancy and increase relevance based on TIL burden. A leave one out strategy was used to assess separation using a neural network classifier. Tumor iodine concentration was the only significantly different conventional tumor metric between Rag2+/- (TILs present) and Rag2-/- (TIL-deficient) tumors. RFs further enabled differentiation between Rag2+/- and Rag2-/- tumors. The PCD-derived RFs provided the highest accuracy (0.84) followed by decomposition-derived RFs (0.78) and the EID-derived RFs (0.65). Such non-invasive approaches could aid in tumor stratification for cancer therapy studies.
High-Z based nanoparticles (NP) are emerging as promising agents for both cancer radiotherapy (RT) and CT imaging. NPs can be delivered to tumors via the enhanced permeability and retention (EPR) effect and they preferentially accumulate in tumor’s perivascular region. Both gold and iodine NPs produce low-energy, short-range photoelectrons during RT, boosting radiation dose. Using spectral CT imaging, we sought to investigate (1) if iodine nanoparticles augmentation of RT increases vascular permeability in solid tumors, and (2) if iodine-RT induced changes in tumor vascular permeability improves delivery of nanoparticle-based chemotherapeutics. In vivo studies were performed in a carcinogen-induced and genetically engineered primary mouse model of soft tissue sarcoma. Tumor-bearing mice in test group were intravenously injected with liposomal-iodine (Lip-I) (1.32 g I/kg) on day 0. On day 1, both test (with Lip-I) and control (without Lip-I) mice received RT (single dose, 10 Gy). One day post-RT (day 2), all mice were intravenously injected with liposomal gadolinium (Lip-Gd) (0.32 g Gd/kg), a surrogate of nanoparticle chemotherapeutic agent. Three days later (day 5) mice were imaged on our hybrid spectral micro-CT system. A dual source pre-clinical CT prototype system that combines a photon counting detector (PCD) and an energy integrating detector (EID) in a single hybrid system served as our imaging device. The results demonstrate that Lip-I augmented RT, resulting in increased tumor vascular permeability compared to control mice treated with RT alone. Consequently, Lip-I +RT treated mice demonstrated a 4- fold higher intra-tumoral accumulation of Lip-Gd compared to RT alone treated mice. In conclusion, our work suggests that Lip-I augments RT-induced effects on tumor vasculature, resulting in increased vascular permeability and higher intratumoral deposition of chemotherapeutic nanoparticles.
Recent advances in CT hardware have renewed interest in the development of contrast agents for molecular CT imaging. Nanoparticle
platforms are attractive for CT imaging agent development due to their ability to carry a high payload of imaging moieties, thereby
facilitating signal amplification at target site, and ease of surface modification to enable selective in vivo targeting against cells/molecules
of interest. In this work, we performed investigations for optimizing an iodine-based liposomal nanoparticle platform for molecular CT
imaging applications. Since signal intensity is directly proportional to the imaging moiety concentration, optimization studies were
performed to rationally design an iodinated nanoparticle construct with maximal iodine carrying capacity. The effect of particle size,
liposomal bilayer composition, iodine moiety and starting iodine concentration were systematically investigated. The in vitro stability
of the optimal formulation was evaluated using plasma assay and the in vivo stability was tested by performing longitudinal micro-CT
imaging in live animals. Simulations were performed to study the effects of iodine per nanoparticle and iodine contrast sensitivity on
detectability of nanoparticles per image voxel. In vitro optimization studies demonstrated that particle size, type of iodine moiety and
starting iodine concentration strongly influenced the iodine loading per nanoparticle. A nanoparticle composition was identified that
demonstrated highest iodine loading capacity (∼ 8 million iodine atoms per particle). Micro-CT imaging demonstrated in vivo stability
of the high-iodine containing nanoparticle construct. Simulation studies demonstrated a non-linear effect of iodine contrast sensitivity
and image voxel size on the limit of nanoparticle detectability.
KEYWORDS: Tumors, Computed tomography, Nanoparticles, Angiography, In vivo imaging, Magnetic resonance imaging, Mouse models, Blood vessels, Therapeutics, Imaging systems
The architecture of intra-tumoral vascular network continuously evolves with tumor progression. Non-invasive methods that facilitate 3D in vivo interrogation of tumor vascular architecture could improve understanding of tumor progression and metastasis. In this work, we studied evolving tumor vasculature using high-resolution CT images and a blood-pool, nanoparticle iodinated contrast agent. In vivo studies were performed in a transgenic mouse model of neuroblastoma that exhibit spontaneous bilateral tumors in the adrenals. Animals were divided into three groups based on tumor age: early-age tumor, intermediate-age tumor, old-age tumor. Tumor progression was monitored using T2-weighted MRI. Contrast-enhanced CT imaging was performed at two points: the first imaging session (leak map) was performed 4 days after administration of the nanoparticle agent to interrogate changes in tumor vascular permeability. Immediately thereafter, a second dose of contrast agent was administered and CT imaging was performed within 1 hour to capture high-resolution angiograms of tumor vasculature. CT angiograms demonstrated the highly-vascularized nature of these tumors. Old-age tumors exhibited a higher fractional volume of avascular regions and an increased number of large superficial blood vessels on tumor periphery. Old-age tumors also demonstrated the presence of intra-vessel tumor thrombus and the invasion of tumor into the inferior vena cava. Leak maps images demonstrated signal enhancement throughout the tumor in early-age tumors, including the core region, suggestive of the presence of highly permeable blood vessels through the tumor volume. Old-age tumors exhibited relatively lower signal enhancement, indicative of a less 'leaky' tumor vascular network compared to early and intermediate-stage tumors.
Advances in CT hardware have propelled the development of novel CT contrast agents. Combined with the spectral capabilities of X-ray CT, molecular imaging is possible using multiple heavy-metal contrast agents. Nanoparticle platforms make particularly attractive agents because of (1) their ability to carry a large payload of imaging moieties, and (2) their ease of surface modification to facilitate molecular targeting. While several novel imaging moieties based on high atomic number elements are being explored, iodine (I) and gadolinium (Gd) are particularly attractive because they are already in clinical use. In this work, we investigate the feasibility for in vivo discrimination of iodine and gadolinium nanoparticles using dual energy micro-CT. Phantom experiments were performed to measure the CT enhancement for I and Gd over a range of voltages from 40 to 80 kVp using a dual-source micro-CT system with energy integrating detectors having cesium iodide scintillators. The two voltages that provide maximum discrimination between I and Gd were determined to be 50 kVp with Cu filtration and 40 kVp without any filtration. Serial dilutions of I and Gd agents were imaged to determine detection sensitivity using the optimal acquisition parameters. Next, an in vivo longitudinal small animal study was performed using Liposomal I (Lip-I) and Liposomal Gd (Lip-Gd) nanoparticles. The mouse was intravenously administered Lip-Gd and imaged within 1 h post-contrast to visualize Gd in the vascular compartment. The animal was reimaged at 72 h post-contrast with dual-energy micro-CT at 40 kVp and 50 kVp to visualize the accumulation of Lip-Gd in the liver and spleen. Immediately thereafter, the animal was intravenously administered Lip-I and re-imaged. The dual energy sets were used to estimate the concentrations of Gd and I via a two-material decomposition with a non-negativity constraint. The phantom results indicated that the relative contrast enhancement per mg/ml of I to Gd was 0.85 at 40 kVp and 1.79 at 50 kVp. According to the Rose criterion (CNR<5), the detectability limits were 2.67 mg/ml for I and 2.46 mg/ml for Gd. The concentration maps confirmed the expected biodistribution, with Gd concentrated in the spleen and with I in the vasculature of the kidney, liver, and spleen. Iterative reconstruction provided higher sensitivity to detect relatively low concentrations of gadolinium. In conclusion, dual energy micro-CT can be used to discriminate and simultaneously image probes containing I and Gd.
Spectral CT imaging is expected to play a major role in the diagnostic arena as it provides material decomposition on
an elemental basis. One fascinating possibility is the ability to discriminate multiple contrast agents targeting different
biological sites. We investigate the feasibility of dual energy micro-CT for discrimination of iodine (I) and gold (Au)
contrast agents when simultaneously present in the body. Simulations and experiments were performed to measure
the CT enhancement for I and Au over a range of voltages from
40-to-150 kVp using a dual source micro-CT system.
The selected voltages for dual energy micro-CT imaging of Au and I were 40 kVp and 80 kVp. On a massconcentration
basis, the relative average enhancement of Au to I was 2.75 at 40 kVp and 1.58 at 80 kVp. We have
demonstrated the method in a preclinical model of colon cancer to differentiate vascular architecture and
extravasation. The concentration maps of Au and I allow quantitative measure of the bio-distribution of both agents.
In conclusion, dual energy micro-CT can be used to discriminate probes containing I and Au with immediate impact
in pre-clinical research.
KEYWORDS: Tumors, Nanoparticles, Positron emission tomography, Computed tomography, Blood, Signal attenuation, Image enhancement, Lymphatic system, In vivo imaging, Breast cancer
Multi-modality PET-CT imaging is playing an important role in the field of oncology. While PET imaging facilitates
functional interrogation of tumor status, the use of CT imaging is primarily limited to anatomical reference. In an
attempt to extract comprehensive information about tumor cells and its microenvironment, we used a nanoparticle xray
contrast agent to image tumor vasculature and vessel 'leakiness' and 18F-FDG to investigate the metabolic status
of tumor cells. In vivo PET/CT studies were performed in mice implanted with 4T1 mammary breast cancer
cells.Early-phase micro-CT imaging enabled visualization 3D vascular architecture of the tumors whereas delayedphase
micro-CT demonstrated highly permeable vessels as evident by nanoparticle accumulation within the tumor.
Both imaging modalities demonstrated the presence of a necrotic core as indicated by a hypo-enhanced region in the
center of the tumor. At early time-points, the CT-derived fractional blood volume did not correlate with 18F-FDG
uptake. At delayed time-points, the tumor enhancement in 18F-FDG micro-PET images correlated with the delayed
signal enhanced due to nanoparticle extravasation seen in CT images. The proposed hybrid imaging approach could
be used to better understand tumor angiogenesis and to be the basis for monitoring and evaluating anti-angiogenic and
nano-chemotherapies.
Dual-energy contrast-enhanced breast tomosynthesis has been proposed as a technique to improve the
detection of early-stage cancer in young, high-risk women. This study focused on optimizing this technique
using computer simulations. The computer simulation used analytical calculations to optimize the signal
difference to noise ratio (SdNR) of resulting images from such a technique at constant dose. The optimization
included the optimal radiographic technique, optimal distribution of dose between the two single-energy
projection images, and the optimal weighting factor for the dual energy subtraction. Importantly, the SdNR
included both anatomical and quantum noise sources, as dual energy imaging reduces anatomical noise at
the expense of increases in quantum noise. Assuming a tungsten anode, the maximum SdNR at constant
dose was achieved for a high energy beam at 49 kVp with 92.5 μm copper filtration and a low energy beam at
49 kVp with 95 μm tin filtration. These analytical calculations were followed by Monte Carlo simulations that
included the effects of scattered radiation and detector properties. Finally, the feasibility of this technique was
tested in a small animal imaging experiment using a novel iodinated liposomal contrast agent. The results
illustrated the utility of dual energy imaging and determined the optimal acquisition parameters for this
technique. This work was supported in part by grants from the Komen Foundation (PDF55806), the Cancer
Research and Prevention Foundation, and the NIH (NCI R21 CA124584-01). CIVM is a NCRR/NCI National
Resource under P41-05959/U24-CA092656.
Imaging tumor angiogenesis in small animals is extremely challenging due to the size of the tumor vessels.
Consequently, both dedicated small animal imaging systems and specialized intravascular contrast agents are
required. The goal of this study was to investigate the use of a liposomal contrast agent for high-resolution micro-CT
imaging of breast tumors in small animals. A liposomal blood pool agent encapsulating iodine with a concentration
of 65.5 mg/ml was used with a Duke Center for In Vivo Microscopy (CIVM) prototype micro-computed
tomography (micro-CT) system to image the R3230AC mammary carcinoma implanted in rats. The animals were
injected with equivalent volume doses (0.02 ml/kg) of contrast agent. Micro-CT with the liposomal blood pool
contrast agent ensured a signal difference between the blood and the muscle higher than 450 HU allowing the
visualization of the tumors 3D vascular architecture in exquisite detail at 100-micron resolution. The micro-CT data
correlated well with the histological examination of tumor tissue. We also studied the ability to detect vascular
enhancement with limited angle based reconstruction, i.e. tomosynthesis. Tumor volumes and their regional vascular
percentage were estimated. This imaging approach could be used to better understand tumor angiogenesis and be the
basis for evaluating anti-angiogenic therapies.
Access to the requested content is limited to institutions that have purchased or subscribe to SPIE eBooks.
You are receiving this notice because your organization may not have SPIE eBooks access.*
*Shibboleth/Open Athens users─please
sign in
to access your institution's subscriptions.
To obtain this item, you may purchase the complete book in print or electronic format on
SPIE.org.
INSTITUTIONAL Select your institution to access the SPIE Digital Library.
PERSONAL Sign in with your SPIE account to access your personal subscriptions or to use specific features such as save to my library, sign up for alerts, save searches, etc.