Use In Cancer Imaging Research Articles

Imaging Metabolically Active Fat: A Literature Review and Mechanistic Insights.

Currently, obesity is one of the leading causes death in the world. Shortly before 2000, researchers began describing metabolically active adipose tissue on cancer-surveillance 18F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) in adult humans. This tissue generates heat through mitochondrial uncoupling and functions similar to classical brown and beige adipose tissue in mice. Despite extensive research, human brown/beige fat’s role in resistance to obesity in humans has not yet been fully delineated. FDG uptake is the de facto gold standard imaging technique when studying brown adipose tissue, although it has not been rigorously compared to other techniques. We, therefore, present a concise review of established and emerging methods to image brown adipose tissue activity in humans. Reviewed modalities include anatomic imaging with CT and magnetic resonance imaging (MRI); molecular imaging with FDG, fatty acids, and acetate; and emerging techniques. FDG-PET/CT is the most commonly used modality because of its widespread use in cancer imaging, but there are mechanistic reasons to believe other radiotracers may be more sensitive and accurate at detecting brown adipose tissue activity. Radiation-free modalities may help the longitudinal study of brown adipose tissue activity in the future.

An improved kit formulation for one-pot synthesis of [99m Tc]Tc-HYNIC-E[c(RGDfK)]2 for routine clinical use in cancer imaging.

Radiolabeled Arg-Gly-Asp (RGD) peptide derivatives have immense potential for non-invasive monitoring of malignancies overexpressing integrin αv β3 receptors. Easy availability of suitable radiotracers would augment the utility of this class of molecular imaging agents. Towards this, the present article describes the development of an improved lyophilized kit for the routine clinical formulation of [99m Tc]Tc complex of HYNIC-conjugated dimeric cyclic RGD peptide derivative E-[c(RGDfK)]2 (E = glutamic acid, f = phenyl alanine, K = lysine) without using Sn2+ and systematic evaluation of its efficacy. Five batches of the kits were prepared, and [99m Tc]Tc-HYNIC-E[c(RGDfK)]2 radiotracer was synthesized with high radiochemical purity (98.6 ± 0.5%) and specific activity (124.8 GBq/μmol) using the kits. Biodistribution studies in C57BL/6 mice bearing melanoma tumor exhibited significant accumulation of the radiotracer in tumor (5.32 ± 0.56 %ID/g at 60 min p.i.), and this uptake was also found to be receptor-specific by blocking studies. Preliminary human clinical investigations carried out in 10 breast cancer patients revealed high radiotracer uptake in the tumor along with good tumor-to-background contrast. The developed kit formulation showed an exceptionally high shelf-life of at least 18 months. These results demonstrated promising attributes of the developed kit formulation and warrant more extensive clinical investigations.

Recent Progress in the Development of Poly(lactic-co-glycolic acid)-Based Nanostructures for Cancer Imaging and Therapy.

Diverse nanosystems for use in cancer imaging and therapy have been designed and their clinical applications have been assessed. Among a variety of materials available to fabricate nanosystems, poly(lactic-co-glycolic acid) (PLGA) has been widely used due to its biocompatibility and biodegradability. In order to provide tumor-targeting and diagnostic properties, PLGA or PLGA nanoparticles (NPs) can be modified with other functional materials. Hydrophobic or hydrophilic therapeutic cargos can be placed in the internal space or adsorbed onto the surface of PLGA NPs. Protocols for the fabrication of PLGA-based NPs for cancer imaging and therapy are already well established. Moreover, the biocompatibility and biodegradability of PLGA may elevate its feasibility for clinical application in injection formulations. Size-controlled NP’s properties and ligand–receptor interactions may provide passive and active tumor-targeting abilities, respectively, after intravenous administration. Additionally, the introduction of several imaging modalities to PLGA-based NPs can enable drug delivery guided by in vivo imaging. Versatile platform technology of PLGA-based NPs can be applied to the delivery of small chemicals, peptides, proteins, and nucleic acids for use in cancer therapy. This review describes recent findings and insights into the development of tumor-targeted PLGA-based NPs for use of cancer imaging and therapy.

In Vivo Magnetic Resonance and Fluorescence Dual-Modality Imaging of Tumor Angiogenesis in Rats Using GEBP11 Peptide Targeted Magnetic Nanoparticles.

Angiogenesis is an essential process for tumor progression. Tumor vasculature-targeting peptides have shown great potential for use in cancer imaging and therapy. Our previous studies have shown that GEBP11, a novel vasculature-specific binding peptide that exhibits high affinity and specificity to tumor angiogenesis, is a promising candidate for the diagnosis and targeted radiotherapy of gastric cancer. In the present study, we developed a novel magnetic resonance and fluorescence (MR/Fluo) dual-modality imaging probe by covalently coupling 2,3-dimercaptosuccinnic acid-coated paramagnetic nanoparticles (DMSA-MNPs) and Cy5.5 to the GEBP11 peptide. The probe Cy5.5-GEBP11-DMSA-MNPs (CGD-MNPs), with a hydrodynamic diameter of 82.8 ± 6.5 nm, exhibited good imaging properties, high stability and little cytotoxicity. In vivo MR/Fluo imaging revealed that CGD-MNPs were successfully applied to visualize tumor angiogenesis in SGC-7901 xenograft mouse models. Prussian blue and CD31 immunohistochemical staining confirmed that CGD-MNPs co-localized with tumor blood vessels. In conclusion, CGD-MNPs are promising candidates for use as MR and fluorescence imaging probes for visualizing gastric cancer angiogenesis in vivo.

Correlative Light-Electron Microscopy Shows RGD-Targeted ZnO Nanoparticles Dissolve in the Intracellular Environment of Triple Negative Breast Cancer Cells and Cause Apoptosis with Intratumor Heterogeneity.

ZnO nanoparticles (NPs) are reported to show a high degree of cancer cell selectivity with potential use in cancer imaging and therapy. Questions remain about the mode by which the ZnO NPs cause cell death, whether they exert an intra- or extracellular effect, and the resistance among different cancer cell types to ZnO NP exposure. The present study quantifies the variability between the cellular toxicity, dynamics of cellular uptake, and dissolution of bare and RGD (Arg-Gly-Asp)-targeted ZnO NPs by MDA-MB-231 cells. Compared to bare ZnO NPs, RGD-targeting of the ZnO NPs to integrin αvβ3 receptors expressed on MDA-MB-231 cells appears to increase the toxicity of the ZnO NPs to breast cancer cells at lower doses. Confocal microscopy of live MDA-MB-231 cells confirms uptake of both classes of ZnO NPs with a commensurate rise in intracellular Zn(2+) concentration prior to cell death. The response of the cells within the population to intracellular Zn(2+) is highly heterogeneous. In addition, the results emphasize the utility of dynamic and quantitative imaging in understanding cell uptake and processing of targeted therapeutic ZnO NPs at the cellular level by heterogeneous cancer cell populations, which can be crucial for the development of optimized treatment strategies.

NIR-light-induced surface-enhanced Raman scattering for detection and photothermal/photodynamic therapy of cancer cells using methylene blue-embedded gold nanorod@SiO2 nanocomposites

Methylene blue-loaded gold nanorod@SiO2 (MB-GNR@SiO2) core@shell nanoparticles are synthesized for use in cancer imaging and photothermal/photodynamic dual therapy. For the preparation of GNR@SiO2 nanoparticles, we found that the silica coating rate of hexadecylcetyltrimethylammonium bromide (CTAB)-capped GNRs is much slower than that of PEGylated GNRs due to the densely coated CTAB bilayer. Encapsulated MB molecules have both monomer and dimer forms that result in an increase in the photosensitizing effect through different photochemical pathways. As a consequence of the excellent plasmonic properties of GNRs at near-infrared (NIR) light, the embedded MB molecules showed NIR light-induced SERS performance with a Raman enhancement factor of 3.0 × 1010, which is enough for the detection of a single cancer cell. Moreover, the MB-GNR@SiO2 nanoparticles exhibit a synergistic effect of photodynamic and photothermal therapies of cancer under single-wavelength NIR laser irradiation.

Development and evaluation of a dual-modality (MRI/SPECT) molecular imaging bioprobe

Specific bioprobes for single photon emission computed tomography (SPECT) and magnetic resonance imaging (MRI) have enormous potential for use in cancer imaging in near-future clinical settings. The authors describe the development of dual modality molecular imaging bioprobes, in the form of magnetic nanoparticles (NPs) conjugated to antibodies, for SPECT and MRI of mesothelin-expressing cancers. The bioprobes were developed by conjugating 111In labeled antimesothelin antibody mAbMB to superparamagnetic iron oxide NPs. Our experimental findings provide evidence that such bioprobes retain their magnetic properties as well as the ability to specifically localize in mesothelin-expressing tumors. It is anticipated that combining SPECT with MR will help obtain both functional and anatomical imaging information with high signal sensitivity and contrast, thereby providing a powerful diagnostic tool for early diagnosis and treatment planning of mesothelin-expressing cancers. From the Clinical EditorThis team of investigators presents a dual-modality functionalized contrast material that enables tumor visualization both via MRI and SPECT. Similar systems are likely to be utilized in future cancer research.

Synthesis and Characterization of New Porphyrazine-Gd(III) Conjugates as Multimodal MR Contrast Agents

Magnetic resonance imaging (MRI) has long been used clinically and experimentally as a diagnostic tool to obtain three-dimensional, high-resolution images of deep tissues. These images are enhanced by the administration of contrast agents such as paramagnetic Gd(III) complexes. Herein, we describe the preparation of a series of multimodal imaging agents in which paramagnetic Gd(III) complexes are conjugated to a fluorescent tetrapyrrole, namely, a porphyrazine (pz). Zinc metalated pzs conjugated to one, four, or eight paramagnetic Gd(III) complexes are reported. Among these conjugates, Zn-Pz-8Gd(III) exhibits an ionic relaxivity four times that of the monomeric Gd(III) agent, presumably because of increased molecular weight and a molecular relaxivity that is approximately thirty times larger, while retaining the intense electronic absorption and emission of the unmodified pz. Unlike current clinical MR agents, Zn-Pz-1Gd(III) is taken up by cells. This probe demonstrates intracellular fluorescence by confocal microscopy and provides significant contrast enhancement in MR images, as well as marked phototoxicity in assays of cellular viability. These results suggest that pz agents possess a new potential for use in cancer imaging by both MRI and near-infrared (NIR) fluorescence, while acting as a platform for photodynamic therapy.

Changes in the Use and Costs of Diagnostic Imaging Among Medicare Beneficiaries With Cancer, 1999-2006

Emerging technologies, changing diagnostic and treatment patterns, and changes in Medicare reimbursement are contributing to increasing use of imaging in cancer. Imaging is the fastest growing expense for Medicare but has not been examined among beneficiaries with cancer. To examine changes in the use of imaging and how those changes contribute to the overall cost of cancer care. Analysis of a nationally representative 5% sample of claims from the US Centers for Medicare & Medicaid Services from 1999 through 2008. Patients were Medicare beneficiaries with incident breast cancer, colorectal cancer, leukemia, lung cancer, non-Hodgkin lymphoma, or prostate cancer. Use and cost of imaging by modality, year, and cancer type. There were 100,954 incident cases of breast cancer, colorectal cancer, leukemia, lung cancer, non-Hodgkin lymphoma, and prostate cancer from 1999 through 2006. Significant mean annual increases in imaging use occurred among all cancer types for positron emission tomography (35.9%-53.6%), bone density studies (6.3%-20.0%), echocardiograms (5.0%-7.8%), magnetic resonance imaging (4.4%-11.5%), and ultrasound (0.7%-7.4%). Conventional radiograph rates decreased or stayed the same. As of 2006, beneficiaries with lung cancer and beneficiaries with lymphoma incurred the largest overall imaging costs, exceeding a mean of $3000 per beneficiary within 2 years of diagnosis. By 2005, one-third of beneficiaries with breast cancer underwent bone scans and half of beneficiaries with lung cancer or lymphoma underwent positron emission tomography scans. Mean 2-year imaging costs per beneficiary increased at a rate greater than the increase in mean total costs per beneficiary for all cancer types. Imaging costs among Medicare beneficiaries with cancer increased from 1999 through 2006, outpacing the rate of increase in total costs among Medicare beneficiaries with cancer.

Overview of nanoparticle use in cancer imaging

Current cross-sectional imaging modalities are inaccurate in characterizing nodal metastatic disease because of their use of size and/or morphology as differentiating factors. PET has overcome some of these limitations but it is constrained by its spacial resolution particularly for detecting small nodal metastases. These challenges have led to the development of lymphotropic contrast agents. Ferumoxtran-10 is one such MRI lymphotropic contrast agent that consists of ultrasmall superparamagnetic iron-oxide based nanoparticles targeted at the reticuloendothelial system. After intravenous administration ferumoxtran-10 is phagocytosed by macrophages which then accumulate within benign lymph nodes. Disturbances in lymph flow or in nodal architecture caused by metastases lead to abnormal patterns of accumulation of the particles, which are detectable by MRI. On postcontrast T2- and T2*-weighted MRI benign lymph nodes show a drop in signal intensity and homogenous darkening whereas areas of malignant infiltration show lack of nanoparticle uptake and remain signal-intense. Summary ROC curve analysis for per-lymph-node data showed an overall sensitivity of 88% and overall specificity of 96% for ferumoxtran-10-enhanced MRI. Ferumoxtran-10-enhanced MRI offers higher diagnostic precision than unenhanced MRI and is sensitive and specific for the detection of lymph-node metastases, especially in malignant diseases of the abdomen and pelvis.

Antibiofouling amphiphilic polymer-coated superparamagnetic iron oxide nanoparticles: synthesis, characterization, and use in cancer imaging in vivo

Superparamagnetic iron oxide nanoparticles (SPIONs) are widely used as T2-contrast agents for magnetic resonance imaging (MRI). Herein we develop various antibiofouling amphiphilic polymer-coated SPIONs using a one-step nanoemulsion method. This methodology yielded ultrasmall polymer-coated SPIONs, of average diameter less than 30 nm, which were stable under physiological conditions. In vitrocell cytotoxicity tests revealed that no SPION showed toxicity even at relatively high concentrations. In vivo MRI with Lewis lung carcinoma (LLC) tumor-bearing mice resulted in an approximately 30% T2 signal drop in tumor tissues, indicating that the SPIONs reached such tissues via passive targeting. In summary, the ultrasmall, stable, amphiphilic polymer-coated SPIONs can be used as MRI contrast agents for cancer imaging.

GLUT7: a new intestinal facilitated hexose transporter

The very last member of the SLC2A gene family of facilitated hexose transporters to be cloned was SLC2A7 (hGLUT7). It has been assigned to the class II of the GLUT family on the basis of sequence similarity, and its closest family member is GLUT5, an intestinal fructose transporter. GLUT7 is primarily expressed in the small intestine and colon, although mRNA has been detected in the testis and prostate as well. The protein is expressed in the apical membrane of the small intestine and colon, and it has a high affinity (<0.5 mM) for glucose and fructose. The abundance of the protein in the small intestine does change in parallel with the dietary carbohydrate. However, the distribution of GLUT7 along the small intestine does not entirely match with the availability of glucose and fructose, suggesting that the physiological substrate for this transporter has yet to be identified. Unlike GLUT13, the proton-coupled myoinositol transporter (HMIT), there is no evidence for the coupling of protons to the hexose movement via GLUT7. One area of study in which GLUT7 has provided a useful comparison with GLUT1 has been in the development of the hypothesis that the facilitated hexose transporters may have a selectivity filter at the exofacial opening of the translocation pore, which helps to determine which hexoses can be transported. If substantiated, the elucidation of this mechanism may prove useful in the design of hexose analogs for use in cancer imaging and therapeutics.

1-11C-Acetate Kinetics of Prostate Cancer

(18)F-FDG is in widespread use in cancer imaging but has limited utility in staging and monitoring of prostate cancer. 1-(11)C-Labeled acetate, a substrate for the citric acid cycle, is superior. The kinetics of prostate tumors were investigated. Ten patients with primary prostate cancer, 10 with recurrent tumor, and 2 men with benign prostate hypertrophy were studied. After administration of 5.5 MBq/kg 1-(11)C-acetate, dynamic PET of the pelvis was acquired for 20 min. Images were reconstructed with iterative algorithms, and corrections for attenuation and scatter were applied. Factor analysis produced factor images, representing iliac vessels and the prostate from which blood-input and tissue-output functions were derived with simple thresholding techniques. Five different kinetic models were applied to the dynamic data to estimate the rate constants. The standard 3-compartment, 2-tissue model was able to describe 1-(11)C-acetate kinetics of the prostate. The model could be reduced to 3 parameters by setting the tissue blood fraction and release from the second tissue compartment (k(4)) to zero. Correction for metabolites appeared to be necessary. This reduced model performed marginally better than a 2-compartment model. A significant correlation was found between the influx rate constant (K) and acetate uptake (standardized uptake value) for primary tumors (r = 0.91), whereas there was no correlation for recurrent tumors (r = -0.17). Patlak graphical analysis provided accurate parameter estimates. A 3-compartment, 3-parameter model is able to describe adequately the acetate kinetics in prostate cancer. Significant differences between primary and recurrent cancer were found for transport k(1), influx K, distribution volume V(d), as well as early (6-10 min) and late (15-20 min) 1-(11)C-acetate uptake.