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1.  Silica Nanoparticles as Substrates for Chelator-free Labeling of Oxophilic Radioisotopes 
Nano Letters  2015;15(2):864-868.
Chelator-free nanoparticles for intrinsic radiolabeling are highly desirable for whole-body imaging and therapeutic applications. Several reports have successfully demonstrated the principle of intrinsic radiolabeling. However, the work done to date has suffered from much of the same specificity issues as conventional molecular chelators, insofar as there is no singular nanoparticle substrate that has proven effective in binding a wide library of radiosotopes. Here we present amorphous silica nanoparticles as general substrates for chelator-free radiolabeling and demonstrate their ability to bind six medically relevant isotopes of various oxidation states with high radiochemical yield. We provide strong evidence that the stability of the binding correlates with the hardness of the radioisotope, corroborating the proposed operating principle. Intrinsically labeled silica nanoparticles prepared by this approach demonstrate excellent in vivo stability and efficacy in lymph node imaging.
PMCID: PMC4412311  PMID: 25559467
Intrinsic labeling; chelator-free; radionuclide; silica nanoparticle; nuclear imaging; lymph node
3.  Molecular Imaging Using Nanoparticle Quenchers of Cerenkov Luminescence 
Cerenkov luminescence (CL) imaging is an emerging technique that collects the visible photons produced by radioisotopes. Here, we have investigated molecular imaging strategies by modulating CL signal off. Utilizing a combination of clinically approved agents, and their analogues, we demonstrate the noninvasive molecularly specific detection of cancer. CL was modulated in vitro in a dose dependent manner using approved small molecules (Lymphazurin), as well as the clinically approved Feraheme and other preclinical superparamagnetic iron oxide nanoparticles (SPIO). To evaluate the quenching of CL in vivo, two strategies were pursued. [18F]-FDG was imaged by PET and CL in tumors prior to and following accumulation of nanoparticles. Initially, non-targeted particles were administered to mice bearing tumors in order to attenuate CL. For targeted imaging, a dual tumor model (expressing the human somatostatin receptor subtype-2 (hSSTr2) and a control negative cell line) was used. Targeting hSSTr2 with octreotate-conjugated SPIO, we demonstrate quenched CL enabling non-invasive distinction between tumors’ molecular expression profiles. In this work, we demonstrate quenching of Cerenkov emissions in several proof of principle models using a combination of approved agents and nanoparticle platforms to provide disease relevant information including tumor vascularity and specific antigen expression.
PMCID: PMC4167912  PMID: 24861843
molecular targeting; quenching nanoparticles; activatable imaging; Cerenkov luminescence; Activatable Cerenkov Luminescence
4.  Nanoparticles for Imaging: Top or Flop? 
Radiology  2014;273(1):10-28.
Diagnostic nano- and microparticles are favorably suited for labeling the mononuclear phagocytic system (eg, liver, spleen, lymph nodes), and the use of diagnostic nanoparticles is indicated for ex vivo labeling of cells, scaffolds, and other kinds of tissue-engineered implants that are to be visualized in vivo.
Nanoparticles are frequently suggested as diagnostic agents. However, except for iron oxide nanoparticles, diagnostic nanoparticles have been barely incorporated into clinical use so far. This is predominantly due to difficulties in achieving acceptable pharmacokinetic properties and reproducible particle uniformity as well as to concerns about toxicity, biodegradation, and elimination. Reasonable indications for the clinical utilization of nanoparticles should consider their biologic behavior. For example, many nanoparticles are taken up by macrophages and accumulate in macrophage-rich tissues. Thus, they can be used to provide contrast in liver, spleen, lymph nodes, and inflammatory lesions (eg, atherosclerotic plaques). Furthermore, cells can be efficiently labeled with nanoparticles, enabling the localization of implanted (stem) cells and tissue-engineered grafts as well as in vivo migration studies of cells. The potential of using nanoparticles for molecular imaging is compromised because their pharmacokinetic properties are difficult to control. Ideal targets for nanoparticles are localized on the endothelial luminal surface, whereas targeted nanoparticle delivery to extravascular structures is often limited and difficult to separate from an underlying enhanced permeability and retention (EPR) effect. The majority of clinically used nanoparticle-based drug delivery systems are based on the EPR effect, and, for their more personalized use, imaging markers can be incorporated to monitor biodistribution, target site accumulation, drug release, and treatment efficacy. In conclusion, although nanoparticles are not always the right choice for molecular imaging (because smaller or larger molecules might provide more specific information), there are other diagnostic and theranostic applications for which nanoparticles hold substantial clinical potential.
PMCID: PMC4186876  PMID: 25247562
5.  Cerenkov Imaging 
Advances in cancer research  2014;124:213-234.
Cerenkov luminescence (CL) has been used recently in a plethora of medical applications like imaging and therapy with clinically relevant medical isotopes. The range of medical isotopes used is fairly large and expanding. The generation of in vivo light is useful since it circumvents depth limitations for excitation light. Cerenkov luminescence imaging (CLI) is much cheaper in terms of infrastructure than positron emission tomography (PET) and is particularly useful for imaging of superficial structures. Imaging can basically be done using a sensitive camera optimized for low-light conditions, and it has a better resolution than any other nuclear imaging modality. CLI has been shown to effectively diagnose disease with regularly used PET isotope (18F-FDG) in clinical setting. Cerenkov luminescence tomography, Cerenkov luminescence endoscopy, and intraoperative Cerenkov imaging have also been explored with positive conclusions expanding the current range of applications. Cerenkov has also been used to improve PET imaging resolution since the source of both is the radioisotope being used. Smart imaging agents have been designed based on modulation of the Cerenkov signal using small molecules and nanoparticles giving better insight of the tumor biology.
PMCID: PMC4329979  PMID: 25287690
6.  Dawn of Advanced Molecular Medicine: Nanotechnological Advancements in Cancer Imaging and Therapy 
Critical reviews in oncogenesis  2014;19(0):143-176.
Nanotechnology plays an increasingly important role not only in our everyday life (with all its benefits and dangers) but also in medicine. Nanoparticles are to date the most intriguing option to deliver high concentrations of agents specifically and directly to cancer cells; therefore, a wide variety of these nanomaterials has been developed and explored. These span the range from simple nanoagents to sophisticated smart devices for drug delivery or imaging. Nanomaterials usually provide a large surface area, allowing for decoration with a large amount of moieties on the surface for either additional functionalities or targeting. Besides using particles solely for imaging purposes, they can also carry as a payload a therapeutic agent. If both are combined within the same particle, a theranostic agent is created. The sophistication of highly developed nanotechnology targeting approaches provides a promising means for many clinical implementations and can provide improved applications for otherwise suboptimal formulations. In this review we will explore nanotechnology both for imaging and therapy to provide a general overview of the field and its impact on cancer imaging and therapy.
PMCID: PMC4183929  PMID: 25271430
nanoparticles; oncology; drug delivery; chemotherapy; targeted therapeutics
7.  Nanoparticles for Imaging: Top or Flop? 
Radiology  2014;273(1):10-28.
Nanoparticles are frequently suggested as diagnostic agents. However, except for iron oxide nanoparticles, diagnostic nanoparticles have been barely incorporated into clinical use so far. This is predominantly due to difficulties in achieving acceptable pharmacokinetic properties and reproducible particle uniformity as well as to concerns about toxicity, biodegradation, and elimination. Reasonable indications for the clinical utilization of nanoparticles should consider their biologic behavior. For example, many nanoparticles are taken up by macrophages and accumulate in macrophage-rich tissues. Thus, they can be used to provide contrast in liver, spleen, lymph nodes, and inflammatory lesions (eg, atherosclerotic plaques). Furthermore, cells can be efficiently labeled with nanoparticles, enabling the localization of implanted (stem) cells and tissue-engineered grafts as well as in vivo migration studies of cells. The potential of using nanoparticles for molecular imaging is compromised because their pharmacokinetic properties are difficult to control. Ideal targets for nanoparticles are localized on the endothelial luminal surface, whereas targeted nanoparticle delivery to extravascular structures is often limited and difficult to separate from an underlying enhanced permeability and retention (EPR) effect. The majority of clinically used nanoparticle-based drug delivery systems are based on the EPR effect, and, for their more personalized use, imaging markers can be incorporated to monitor biodistribution, target site accumulation, drug release, and treatment efficacy. In conclusion, although nanoparticles are not always the right choice for molecular imaging (because smaller or larger molecules might provide more specific information), there are other diagnostic and theranostic applications for which nanoparticles hold substantial clinical potential.
PMCID: PMC4186876  PMID: 25247562
nanoparticle; theranostics; molecular imaging; contrast agent; imaging
8.  Environment-responsive Nanophores for Therapy and Treatment Monitoring via Molecular MRI Quenching 
Nature communications  2014;5:3384.
The effective delivery of therapeutics to disease sites significantly contributes to drug efficacy, toxicity and clearance. Here we demonstrate that clinically approved iron oxide nanoparticles (Ferumoxytol) can be utilized to carry one or multiple drugs. These so called ‘nanophores’ retain their cargo within their polymeric coating through weak electrostatic interactions and release it in slightly acidic conditions (pH 6.8 and below). The loading of drugs increases the nanophores’ transverse T2 and longitudinal T1 NMR proton relaxation times, which is proportional to amount of carried cargo. Chemotherapy with translational nanophores is more effective than the free drug in vitro and in vivo, without subjecting the drugs or the carrier nanoparticle to any chemical modification. Evaluation of cargo incorporation and payload levels in vitro and in vivo can be assessed via benchtop magnetic relaxometers, common NMR instruments or MRI scanners.
PMCID: PMC4108301  PMID: 24594970
9.  Non-invasive mapping of deep-tissue lymph nodes in live animals using a multimodal PET/MRI nanoparticle 
Nature communications  2014;5:3097.
The invasion status of tumour-draining lymph nodes (LNs) is a critical indicator of cancer stage and is important for treatment planning. Clinicians currently use planar scintigraphy and single-photon emission computed tomography (SPECT) with 99mTc-radiocolloid to guide biopsy and resection of LNs. However, emerging multimodality approaches such as positron emission tomography combined with magnetic resonance imaging (PET/MRI) detect sites of disease with higher sensitivity and accuracy. Here we present a multimodal nanoparticle, 89Zr-ferumoxytol, for the enhanced detection of LNs with PET/MRI. For genuine translational potential, we leverage a clinical iron oxide formulation, altered with minimal modification for radiolabelling. Axillary drainage in naive mice and from healthy and tumour-bearing prostates was investigated. We demonstrate that 89Zr-ferumoxytol can be used for high-resolution tomographic studies of lymphatic drainage in preclinical disease models. This nanoparticle platform has significant translational potential to improve preoperative planning for nodal resection and tumour staging.
PMCID: PMC4080716  PMID: 24445347
10.  Quantitative imaging of disease signatures through radioactive decay signal conversion 
Nature medicine  2013;19(10):1345-1350.
In the era of personalized medicine there is an urgent need for in vivo techniques able to sensitively detect and quantify molecular activities. Sensitive imaging of gamma rays is widely used, but radioactive decay is a physical constant and signal is independent of biological interactions. Here we introduce a framework of novel targeted and activatable probes excited by a nuclear decay-derived signal to identify and measure molecular signatures of disease. This was accomplished utilizing Cerenkov luminescence (CL), the light produced by β-emitting radionuclides such as clinical positron emission tomography (PET) tracers. Disease markers were detected using nanoparticles to produce secondary Cerenkov-induced fluorescence. This approach reduces background signal compared to conventional fluorescence imaging. In addition to information from a PET scan, we demonstrate novel medical utility by quantitatively determining prognostically relevant enzymatic activity. This technique can be applied to monitor other markers and facilitates a shift towards activatable nuclear medicine agents.
PMCID: PMC3795968  PMID: 24013701
Activatable probes; Molecular imaging; Nanoparticles; Cerenkov luminescence
11.  Clinical Cerenkov Luminescence Imaging of 18F-FDG 
The aim of this study was to determine the feasibility of Cerenkov luminescence (CL) imaging of patients undergoing diagnostic 18F-FDG scans to detect nodal disease.
Patients undergoing routine 18F-FDG PET/CT for various malignancies consented to being scanned for CL. White-light and Cerenkov images (5-min acquisition) of the surface of the patient contralateral to and at the site of nodal 18F-FDG uptake were acquired using a cooled, intensified charge-coupled-device camera.
The camera demonstrated linear correlation between activity and counts into the low nanocurie range using 18F-FDG. Imaging of patients revealed the presence of 18F-FDG uptake in nodes that demonstrated uptake on PET. A correlation between maximum standardized uptake value from PET and counting rate per area on the CL imaging was established.
CL imaging with diagnostic doses of 18F-FDG is feasible and can aid in detecting disease in the clinical setting.
PMCID: PMC3903390  PMID: 24078721
Cerenkov luminescence imaging; 18F-FDG; PET/CT; clinical
12.  Gadolinium-Encapsulating Iron Oxide Nanoprobe as Activatable NMR/MRI Contrast Agent 
ACS nano  2012;6(8):7281-7294.
Herein we report a novel gadolinium-encapsulating iron oxide nanoparticle-based activatable NMR/MRI nanoprobe. In our design, Gd-DTPA is encapsulated within the polyacrylic acid (PAA) polymer coating of a superparamagnetic iron oxide nanoparticle (IO-PAA) yielding a composite magnetic nanoprobe (IO-PAA-Gd-DTPA) with quenched longitudinal spin-lattice magnetic relaxation (T1). Upon release of the Gd-DTPA complex from the nanoprobe's polymeric coating in acidic media, an increase in the T1 relaxation rate (1/T1) of the composite magnetic nanoprobe was observed, indicating a dequenching of the nanoprobe with a corresponding increase in the T1-weighted MRI signal. When a folate-conjugated nanoprobe was incubated in HeLa cells, a cancer cell line overexpressing folate receptors, an increase in the 1/T1 signal was observed. This result suggests that upon receptor-mediated internalization, the composite magnetic nanoprobe degraded within the cell's lysosome acidic (pH = 5.0) environment, resulting in an intracellular release of Gd-DTPA complex with subsequent T1 activation. No change in T1 was observed when the Gd-DTPA complex was chemically conjugated on the surface of the nanoparticle's polymeric coating or when encapsulated in the polymeric coating of a non-magnetic nanoparticle. These results confirmed that the observed (T1) quenching of the composite magnetic nanoprobe is due to the encapsulation and close proximity of the Gd ion to the nanoparticles superparamagnetic iron oxide (IO) core. In addition, when an anticancer drug (Taxol) was co-encapsulated with the Gd-DTPA within the folate receptor targeting composite magnetic nanoprobe, the T1 activation of the probe coincide with the rate of drug release and corresponding cytotoxic effect in cell culture studies. Taken together, these results suggest that our activatable T1 nanoagent could be of great importance for the detection of acidic tumors and assessment of drug targeting and release by MRI.
PMCID: PMC3429787  PMID: 22809405
Activatable MRI imaging; magnetic relaxation; iron oxide nanoprobe; Gd-DTPA complex; theranostic application
13.  Positron Lymphography: Multimodal, High-Resolution, Dynamic Mapping and Resection of Lymph Nodes After Intradermal Injection of 18F-FDG 
The lymphatic system plays a critical role in the maintenance of healthy tissues. Its function is an important indicator of the presence and extent of disease. In oncology, metastatic spread to local lymph nodes (LNs) is a strong predictor of poor outcome. Clinical methods for the visualization of LNs involve regional injection and tracking of 99mTc-sulfur colloid (99mTc-SC) along with absorbent dyes. Intraoperatively, these techniques suffer from the requirement of administration of multiple contrast media (99mTc-SC and isosulfan blue), unwieldy γ-probes, and a short effective surgical window for dyes. Preclinically, imaging of transport through the lymphatics is further hindered by the resolution of lymphoscintigraphy and SPECT. We investigated multimodal imaging in animal models using intradermal administration of 18F-FDG for combined diagnostic and intraoperative use. PET visualizes LNs with high sensitivity and resolution and low background. Cerenkov radiation (CR) from 18F-FDG was evaluated to optically guide surgical resection of LNs.
Imaging of 18F-FDG uptake used PET and sensitive luminescent imaging equipment (for CR). Dynamic PET was performed in both sexes and multiple strains (NCr Nude, C57BL/6, and Nu/Nu) of mice. Biodistribution confirmed the uptake of 18F-FDG and was compared with that of 99mTc-SC. Verification of uptake and the ability to use 18F-FDG CR to guide nodal removal were confirmed histologically.
Intradermal injection of 18F-FDG clearly revealed lymphatic vessels and LNs by PET. Dynamic imaging revealed rapid and sustained labeling of these structures. Biodistribution of the radiotracer confirmed the active transport of radioglucose in the lymphatics to the local LNs and over time into the general circulation. 18F-FDG also enabled visualization of LNs through CR, even before surgically revealing the site, and guided LN resection.
Intradermal 18F-FDG can enhance the preclinical investigation of the lymphatics through dynamic, high-resolution, and quantitative tomographic imaging. Clinically, combined PET/Cerenkov imaging has significant potential as a single-dose, dual-modality tracer for diagnostics (PET/CT) and guided resection of LNs (Cerenkov optical).
PMCID: PMC3537831  PMID: 22872741
lymph node mapping; PET/CT; Cerenkov; intraoperative
14.  Targeting the Internal Epitope of Prostate-Specific Membrane Antigen with 89Zr-7E11 Immuno-PET 
The potential of the positron-emitting 89Zr has been recently investigated for the design of radioimmunoconjugates for immuno-PET. In this study, we report the preparation and in vivo evaluation of 89Zr-desferrioxamine B (DFO)-7E11, a novel 89Zr-labeled monoclonal antibody (mAb) construct for targeted imaging of prostate-specific membrane antigen (PSMA), a prototypical cell surface marker highly overexpressed in prostate cancer. The ability of 89Zr-DFO-7E11 to delineate tumor response to therapy was also investigated, because it binds to the intracellular epitope of PSMA, which becomes available only on membrane disruption in dead or dying cells.
7E11 as a marker of dying cells was studied by flow cytometry and microscopy of cells after antiandrogen-, radio-, and chemotherapy in LNCaP and PC3 PSMA–positive cells. The in vivo behavior of 89Zr-DFO-7E11 was characterized in mice bearing subcutaneous LNCaP (PSMA-positive) tumors by biodistribution studies and immuno-PET. The potential of assessing tumor response was evaluated in vivo after radiotherapy.
In vitro studies correlated 7E11 binding with markers of apoptosis (7–amino-actinomycin-D and caspase-3). In vivo biodistribution experiments revealed high, target-specific uptake of 89Zr-DFO-7E11 in LNCaP tumors after 24 h (20.35 ± 7.50 percentage injected dose per gram [%ID/g]), 48 h (22.82 ± 3.58 %ID/g), 96 h (36.94 ± 6.27 %ID/g), and 120 h (25.23 ± 4.82 %ID/g). Excellent image contrast was observed with immuno-PET. 7E11 uptake was statistically increased in irradiated versus control tumor as measured by immuno-PET and biodistribution studies. Binding specificity was assessed by effective blocking studies at 48 h.
These findings suggest that 89Zr-DFO-7E11 displays high tumor–to–background tissue contrast in immuno-PET and can be used as a tool to monitor and quantify, with high specificity, tumor response in PSMA-positive prostate cancer.
PMCID: PMC3537833  PMID: 21908391
PET; 89Zr; PSMA; 7E11; monoclonal antibodies; prostate cancer
15.  Will nanotechnology influence targeted cancer therapy? 
Seminars in radiation oncology  2011;21(2):80-87.
The rapid development of techniques that enable synthesis (and manipulation) of matter on the nanometer scale, as well as the development of new nano-materials, will play a large role in disease diagnosis and treatment, specifically in targeted cancer therapy. Targeted nanocarriers are an intriguing means to selectively deliver high concentrations of cytotoxic agents or imaging labels directly to the cancer site. Often solubility issues and an unfavorable biodistribution can result in a suboptimal response of novel agents even though they are very potent. New nanoparticulate formulations allow simultaneous imaging and therapy (“theranostics”), which can provide a realistic means for the clinical implementation of such otherwise suboptimal formulations. In this review we will not attempt to provide a complete overview of the rapidly enlarging field of nanotechnology in cancer; rather, we will present properties specific to nanoparticles, and examples of their uses, which demonstrate their importance for targeted cancer therapy.
PMCID: PMC3062202  PMID: 21356476
16.  Cerenkov imaging - a new modality for molecular imaging 
Cerenkov luminescence imaging (CLI) is an emerging hybrid modality that utilizes the light emission from many commonly used medical isotopes. Cerenkov radiation (CR) is produced when charged particles travel through a dielectric medium faster than the speed of light in that medium. First described in detail nearly 100 years ago, CR has only recently applied for biomedical imaging purposes. The modality is of considerable interest as it enables the use of widespread luminescence imaging equipment to visualize clinical diagnostic (all PET radioisotopes) and many therapeutic radionuclides. The amount of light detected in CLI applications is significantly lower than other that in other optical imaging techniques such as bioluminescence and fluorescence. However, significant advantages include the use of approved radiotracers and lack of an incident light source, resulting in high signal to background ratios. As well, multiple subjects may be imaged concurrently (up to 5 in common bioluminescent equipment), conferring both cost and time benefits. This review summarizes the field of Cerenkov luminescence imaging to date. Applications of CLI discussed include intraoperative radionuclide-guided surgery, monitoring of therapeutic efficacy, tomographic optical imaging capabilities, and the ability to perform multiplexed imaging using fluorophores excited by the Cerenkov radiation. While technical challenges still exist, Cerenkov imaging has materialized as an important molecular imaging modality.
PMCID: PMC3477724  PMID: 23133811
Cerenkov radiation; PET; optical imaging; fluorescence
17.  Intraoperative Imaging of Positron Emission Tomographic Radiotracers Using Cerenkov Luminescence Emissions 
Molecular imaging  2011;10(3):177-186.
Imaging the location and extent of cancer provides invaluable information before, during, and after surgery. The majority of “image-guided” methods that use, for example, positron emission tomography (PET) involve preoperative imaging and do not provide real-time information during surgery. It is now well established that the inherent optical emissions (Cerenkov radiation) from various β-emitting radionuclides can be visualized by Cerenkov luminescence imaging (CLI). Here we report the full characterization of CLI using the positron-emitting radiotracer 89Zr-DFO-trastuzumab for target-specific, quantitative imaging of HER2/neu-positive tumors in vivo. We also provide the first demonstration of the feasibility of using CLI for true image-guided, intraoperative surgical resection of tumors. Analysis of optical CLIs provided accurate, quantitative information on radiotracer biodistribution and tissue uptake that correlated well with the concordant PET images. CLI, PET, and biodistribution studies revealed target-specific uptake of 89Zr-DFO-trastuzumab in BT-474 (HER2/neu positive) versus MDA-MB-468 (HER2/neu negative) xenografts in the same mice. Competitive inhibition (blocking) studies followed by CLI also confirmed the in vivo immunoreactivity and specificity of 89Zr-DFO-trastuzumab for HER2/neu. Overall, these results strongly support the continued development of CLI as a preclinical and possible clinical tool for use in molecular imaging and surgical procedures for accurately defining tumor margins.
PMCID: PMC3083828  PMID: 21496448
18.  Cerenkov luminescence imaging of medical isotopes 
The development of novel multimodality imaging agents and techniques represents the current frontier of research in the field of medical imaging science. However, the combination of nuclear tomography with optical techniques has yet to be established. Here, we report the use of the inherent optical emissions from the decay of radiopharmaceuticals for Cerenkov luminescence imaging (CLI) of tumors in vivo and correlate the results with those obtained from concordant immuno-PET studies.
In vitro phantom studies were used to validate the visible light emission observed from a range of radionuclides including the positron emitters 18F, 64Cu, 89Zr, and 124I; β-emitter 131I; and α-particle emitter 225Ac for potential use in CLI. The novel radiolabeled monoclonal antibody 89Zr-desferrioxamine B-[DFO-J591 for immuno-PET of prostate-specific membrane antigen (PSMA) expression was used to coregister and correlate the CLI signal observed with the immuno-PET images and biodistribution studies.
Phantom studies confirmed that Cerenkov radiation can be observed from a range of positron-,β-, and α-emitting radionuclides using standard optical imaging devices. The change in light emission intensity versus time was concordant with radionuclide decay and was also found to correlate linearly with both the activity concentration and the measured PET signal (percentage injected dose per gram). In vivo studies conducted in male severe combined immune deficient mice bearing PSMA-positive, subcutaneous LNCaP tumors demonstrated that tumor-specific uptake of 89Zr-DFO-J591 could be visualized by both immuno-PET and CLI. Optical and immuno-PET signal intensities were found to increase over time from 24 to 96 h, and biodistribution studies were found to correlate well with both imaging modalities.
These studies represent the first, to our knowledge, quantitative assessment of CLI for measuring radiotracer uptake in vivo. Many radionuclides common to both nuclear tomographic imaging and radiotherapy have the potential to be used in CLI. The value of CLI lies in its ability to image radionuclides that do not emit either positrons or γ-rays and are, thus, unsuitable for use with current nuclear imaging modalities. Optical imaging of Cerenkov radiation emission shows excellent promise as a potential new imaging modality for the rapid, high-throughput screening of radiopharmaceuticals
PMCID: PMC3068779  PMID: 20554722
Imaging technology; Cerenkov; PET; optical imaging; 89Zr; 124I; 131I; 64Cu; 225Ac; 18F; radioimmunoconjugate; prostate-specific membrane antigen (PSMA); J591; monoclonal antibodies
19.  Drug/Dye-Loaded, Multifunctional Iron Oxide Nanoparticles for Combined Targeted Cancer Therapy and Dual Optical/MR-Imaging** 
A biocompatible, multimodal and theranostic functional IONPs was synthesized using a novel waterbased method and exerted excellent properties for targeted cancer therapy, optical and magnetic resonance imaging (MRI). For the first time, a facile, modified solvent diffusion method is used for the co-encapsulation of both an anti-cancer drug and near infrared dyes. The resulting folate-derivatized theranostics nanoparticles could allow for targeted optical/MR-imaging and targeted killing of folate expressing cancer cells.
PMCID: PMC3057065  PMID: 19384879
magnetic nanoparticles; click chemistry; targeted drug delivery; magnetic resonance imaging; drug release
20.  Imaging Primary Lung Cancers in Mice to Study Radiation Biology 
To image a genetically engineered mouse model of non-small cell lung cancer with micro-CT to measure tumor response to radiation therapy.
Methods and Materials
The Cre-loxP system was utilized to generate primary lung cancers in mice with mutation in K-ras alone or in combination with p53 mutation. Mice were serially imaged by micro-CT and tumor volumes were determined. A comparison of tumor volume by micro-CT and tumor histology was performed. Tumor response to radiation therapy (15.5 Gy) was assessed with micro-CT.
The tumor volume measured with free-breathing micro-CT scans was greater than the volume calculated by histology. Nevertheless, this imaging approach demonstrated that lung cancers with mutant p53 grew more rapidly than lung tumors with wild-type p53 and also showed that radiation therapy increased the doubling time of p53 mutant lung cancers five-fold.
Micro-CT is an effective tool to noninvasively measure the growth of primary lung cancers in genetically engineered mice and assess tumor response to radiation therapy. This imaging approach will be useful to study the radiation biology of lung cancer.
PMCID: PMC2847457  PMID: 20206017
Genetically Engineered Mouse Models of Cancer; Lung Cancer; Micro-CT; K-Ras; p53
21.  Noninvasive in vivo imaging of monocyte trafficking to atherosclerotic lesions 
Circulation  2008;117(3):388-395.
Monocytes play a key role in atherogenesis, but their participation has been largely discerned via ex vivo analyses of atherosclerotic lesions. We sought to establish a noninvasive technique to determine monocyte trafficking to atherosclerotic lesions in live animals.
Methods and Results
Using a micro-single-photon-emission-computed-tomography (microSPECT/CT) small animal imaging system and an FDA-approved radiotracer ([111Indium] oxyquinoline, 111In-oxine), we demonstrate here that monocyte recruitment to atherosclerotic lesions can be visualized in a noninvasive, dynamic, and three-dimensional fashion in live animals. We demonstrate in vivo that monocytes are recruited avidly to plaques within days of adoptive transfer. Using microSPECT/CT imaging as a screening tool, we were able to investigate modulatory effects on monocyte recruitment in live animals. We found that HMG-CoA-reductase inhibitors rapidly and substantially reduce monocyte recruitment to existing atherosclerotic lesions as imaged here in vivo.
This novel approach to track monocytes to atherosclerotic plaques in vivo should have broad applications and create new insights into the pathogenesis of atherosclerosis and other inflammatory diseases.
PMCID: PMC2705289  PMID: 18172031
Imaging; atherosclerosis; plaque; cells
22.  Intracranial administration of deglycosylated C-terminal-specific anti-Aβ antibody efficiently clears amyloid plaques without activating microglia in amyloid-depositing transgenic mice 
Antibodies against the Aß peptide clear Aß deposits when injected intracranially. Deglycosylated antibodies have reduced effector functions compared to their intact counterparts, potentially avoiding immune activation.
Deglycosylated or intact C-terminal specific high affinity anti-Aβ antibody (2H6) were intracranially injected into the right frontal cortex and hippocampus of amyloid precursor protein (APP) transgenic mice. The untreated left hemisphere was used to normalize for the extent of amyloid deposition present in each mouse. Control transgenic mice were injected with an antibody against a drosophila-specific protein (amnesiac). Tissues were examined for brain amyloid deposition and microglial responses 3 days after the injection.
The deglycosylated 2H6 antibody had lower affinity for several murine Fcγ receptors and human complement than intact 2H6 without a change in affinity for Aß. Immunohistochemistry for Aβ and thioflavine-S staining revealed that both diffuse and compact deposits were reduced by both antibodies. In animals treated with the intact 2H6 antibody, a significant increase in Fcγ-receptor II/III immunostaining was observed compared to animals treated with the control IgG antibody. No increase in Fcγ-receptor II/III was found with the deglycosylated 2H6 antibody. Immunostaining for the microglial activation marker CD45 demonstrated a similar trend.
These findings suggest that the deglycosylated 2H6 is capable of removing both compact and diffuse plaques without activating microglia. Thus, antibodies with reduced effector functions may clear amyloid without concomitant immune activation when tested as immunotherapy for Alzheimer's disease.
PMCID: PMC1479322  PMID: 16686956
23.  The neuronal scaffold protein Shank3 mediates signaling and biological function of the receptor tyrosine kinase Ret in epithelial cells 
The Journal of Cell Biology  2004;167(5):945-952.
Shank proteins, initially also described as ProSAP proteins, are scaffolding adaptors that have been previously shown to integrate neurotransmitter receptors into the cortical cytoskeleton at postsynaptic densities. We show here that Shank proteins are also crucial in receptor tyrosine kinase signaling. The PDZ domain–containing Shank3 protein was found to represent a novel interaction partner of the receptor tyrosine kinase Ret, which binds specifically to a PDZ-binding motif present in the Ret9 but not in the Ret51 isoform. Furthermore, we show that Ret9 but not Ret51 induces epithelial cells to form branched tubular structures in three-dimensional cultures in a Shank3-dependent manner. Ret9 but not Ret51 has been previously shown to be required for kidney development. Shank3 protein mediates sustained Erk–MAPK and PI3K signaling, which is crucial for tubule formation, through recruitment of the adaptor protein Grb2. These results demonstrate that the Shank3 adaptor protein can mediate cellular signaling, and provide a molecular mechanism for the biological divergence between the Ret9 and Ret51 isoform.
PMCID: PMC2172453  PMID: 15569713
24.  Novel p62dok family members, dok-4 and dok-5, are substrates of the c-Ret receptor tyrosine kinase and mediate neuronal differentiation 
The Journal of Cell Biology  2001;154(2):345-354.
Docking proteins are substrates of tyrosine kinases and function in the recruitment and assembly of specific signal transduction molecules. Here we found that p62dok family members act as substrates for the c-Ret receptor tyrosine kinase. In addition to dok-1, dok-2, and dok-3, we identified two new family members, dok-4 and dok-5, that can directly associate with Y1062 of c-Ret. Dok-4 and dok-5 constitute a subgroup of dok family members that is coexpressed with c-Ret in various neuronal tissues. Activated c-Ret promotes neurite outgrowth of PC12 cells; for this activity, Y1062 in c-Ret is essential. c-Ret/dok fusion proteins, in which Y1062 of c-Ret is deleted and replaced by the sequences of dok-4 or dok-5, induce ligand-dependent axonal outgrowth of PC12 cells, whereas a c-Ret fusion containing dok-2 sequences does not elicit this response. Dok-4 and dok-5 do not associate with rasGAP or Nck, in contrast to p62dok and dok-2. Moreover, dok-4 and dok-5 enhance c-Ret–dependent activation of mitogen-activated protein kinase. Thus, we have identified a subclass of p62dok proteins that are putative links with downstream effectors of c-Ret in neuronal differentiation.
PMCID: PMC2150770  PMID: 11470823
signal transduction; yeast two-hybrid system; docking proteins; neural development; endothelia
25.  Integrated Nanosensors to Determine Levels and Functional Activity of Human Telomerase1 
Neoplasia (New York, N.Y.)  2008;10(10):1066-1072.
Telomerase is a key oncogenic enzyme, and a number of novel telomerase inhibitors are currently under development. Because inhibition can be achieved either at the protein or at the enzymatic activity level, independent measurements of these parameters are important in the development of effective therapeutic agents. In the current study, we have developed a set of functional magnetic nanosensors capable of measuring the concentration of telomerase, as well as its enzymatic activity in parallel. The method is based on a magnetic relaxation switch assay, which can be performed in crude tissue samples and is fast and extremely sensitive. Using this method, we were able to detect different amounts of telomerase protein and activity in various cancer and normal cell lines. Furthermore, we were able to study the effect of phosphorylation on telomerase activity. This system not only could provide a rapid assay for the evaluation of antitelomerase therapies but could also be implemented to the study of other cancer markers.
PMCID: PMC2546593  PMID: 18813356

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