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1.  INHALABLE CURCUMIN: OFFERING THE POTENTIAL FOR TRANSLATION TO IMAGING AND TREATMENT OF ALZHEIMER’S DISEASE 
Curcumin is a promising compound that can be used as a theranostic agent to aid research in Alzheimer’s disease. Beyond its ability to bind to amyloidal plaques, the compound can also cross the blood brain barrier. Presently, curcumin can be applied only to animal models, as the formulation needed for iv injection renders it unfit for human use. Here, we describe a novel technique to aerosolize a curcumin derivative, FMeC1 and facilitate its safe delivery to the brain. Aside from the translational applicability of this approach, a study in the 5XFAD mouse model suggested that inhalation exposure to an aerosolized FMeC1 modestly improved the distribution of the compound in the brain. Additionally, immunohistochemistry data confirms that following aerosol delivery, FMeC1 binds amyloidal plaques expressed in the hippocampal areas and cortex.
doi:10.3233/JAD-140798
PMCID: PMC4297252  PMID: 25227316
atomization; inhalation exposure; aerosol; clinical translation; curcumin; amyloid plaques; amyloid imaging; Alzheimer’s disease
2.  A Novel Reporter System for Molecular Imaging and High Throughput Screening of Anticancer Drugs 
Chembiochem : a European journal of chemical biology  2013;14(12):10.1002/cbic.201300142.
Apoptosis is irreversible programmed cell death characterized by a cellular cascade activation of caspase-3, which subsequently degrades proteins and other components of cells with a motif sequence. Here we report a novel reporter system to detect apoptosis, growth arrest and cell death based on controlled and self-amplified protein degradation. The key element of the reporter system is an apoptotic sensor chimerical protein which consists of three components, the procaspase 3, ubiquitin (Ub), and a strong consensus sequence of N-degron. Between each of these units, there is a DEVD (Asp-Glu-Val-Asp) sequence, which acts as the cleavage target of caspase-3. This non-conventional signal loss approach is much more sensitive than other native methods based on signal gain. The superior sensitivity is demonstrated by its effective application in 386-well HTS with lower drug concentrations and short incubation time. The HTS selection process using this reporter system is very simple and economic. The simplicity eliminates potential errors introduced by multiple steps; there is no need for any substrate. Furthermore the cells in the assay need not be disrupted and the morphology of the cells can provide additional information on mechanisms; the intact cells after HTS can also be used for other analytic analysis. This system thus has a potentially important role in the discovery and development of new anticancer drugs, it also appears to be very versatile, can be used both in vitro and in vivo, with different linked reporter genes, it can be used for a variety of imaging applications.
doi:10.1002/cbic.201300142
PMCID: PMC3819221  PMID: 23881799
Apoptosis; HTS; Drug discovery; Caspase; Molecular imaging
3.  A comprehensive analysis of transfection-assisted delivery of iron oxide nanoparticles to dendritic cells 
Polylysine (PL) has been used to facilitate dendritic cell (DC) uptake of super paramagnetic iron oxide (SPIO) nanoparticles for use in magnetic resonance imaging (MRI). In this work, we examined the effect of PL on cell toxicity and induction of cell maturation as manifested by the up-regulation of surface molecules. We found that PL became toxic to bone marrow-derived DCs (BMDCs) at the 10 μg/ ml threshold. Incubation of BMDCs with 20 μg/ml of PL for 1 h resulted in approximately 90% cell death. However, addition of SPIO nanoparticles rescued DCs from PL-induced death as the combination of SPIO with PL did not cause cytotoxicity until the PL concentration was 1000 μg/ml. Prolonged exposure to PL induced BMDC maturation as noted by the expression of surface molecules such as MHC class II, CD40, CCR7 and CD86. However, the combination of SPIO and PL did not induce BMDC maturation at 1 h. However prolonged exposure to SPIO nanoparticles induced CD40 expression and protein expression of TNFα and KC. The data suggest that the use of PL to enhance the labeling of DCs with SPIO nanoparticles is a dedicated work. Appropriate calibration of the incubation time and concentrations of PL and SPIO nanoparticles is crucial to the development of MRI technology for noninvasive imaging of DCs in vivo.
doi:10.1016/j.nano.2013.05.010
PMCID: PMC4031028  PMID: 23747738
Iron oxide nanoparticles; Dendritic cells; Polylysine; Transfection; Nanotechnology
4.  MULTIFUNCTIONAL NANOBEACON FOR IMAGING THOMSEN- FRIEDENREICH ANTIGEN-ASSOCIATED COLORECTAL CANCER 
This research aimed to validate the specificity of the newly developed nanobeacon for imaging the Thomsen-Friedenreich (TF) antigen, a potential biomarker of colorectal cancer. The imaging agent is comprised of a submicron-sized polystyrene nanosphere encapsulated with a Coumarin 6 dye. The surface of the nanosphere was modified with peanut agglutinin (PNA) and poly(N-vinylacetamide (PNVA) moieties. The former binds to Gal-β(1–3)GalNAc with high affinity while the latter enhances the specificity of PNA for the carbohydrates. The specificity of the nanobeacon was evaluated in human colorectal cancer cells and specimens, and the data was compared with immunohistochemical staining and flow cytometric analysis. Additionally, distribution of the nanobeacon in vivo was assessed using an “ intestinal loop” mouse model. Quantitative analysis of the data indicated that approximately 2 μg of PNA were detected for each mg of the nanobeacon. The nanobeacon specifically reported colorectal tumors by recognizing the tumor-specific antigen through the surface-immobilized PNA. Removal of TF from human colorectal cancer cells and tissues resulted in a loss of fluorescence signal, which suggests the specificity of the probe. Most importantly, the probe was not absorbed systematically in the large intestine upon topical application. As a result, no registered toxicity was associated with the probe. These data demonstrate the potential use of this novel nanobeacon for imaging the TF antigen as a biomarker for the early detection and prediction of the progression of colorectal cancer at the molecular level.
doi:10.1002/ijc.27903
PMCID: PMC3566327  PMID: 23055136
5.  Quantitative Estimates of the Variability of In Vivo Sonographic Measurements of the Mouse Aorta for Studies of Abdominal Aortic Aneurysms and Related Arterial Diseases 
Objectives
Burgeoning interest in reducing the morbidity and mortality associated with abdominal aortic aneurysms (AAAs) has led to experimental strategies to elucidate the disease process and attain pharmacologic regression using the apolipoprotein E−/− (ApoE−/−) mouse model of angiotensin-induced AAAs and in vivo sonography. However, the variability of in vivo sonographic measurements of the mouse aorta has not been established. Thus, our purpose was to determine quantitative estimates of the variability of in vivo sonographic measurements of the mouse aorta as a guide for the design and assessment of studies focused on regression of AAAs and related arterial diseases.
Methods
We used Bland-Altman, locally weighted scatterplot-smoothing regression, and resampling (bootstrapping) methods for variability analyses of multiple in vivo short- and long-axis sonographic measurements of ApoE−/− mouse aortas. We measured distinct aortic sites in vivo at the baseline and after angiotensin-induced AAAs and ex vivo using digital calipers.
Results
We analyzed 236 data points from 10 male mice (14 weeks old; mean weight ± SD, 29.7 ± 1.6 g). Overall intramouse differences between short- and long-axis and in vivo and ex vivo measurements were 0.038 (95% confidence interval [CI], 0.031–0.046) and 0.085 (95% CI, 0.062–0.109) mm, respectively. Intermouse differences in short-axis measurements were 0.047 (95% CI, 0.042–0.053), 0.049 (95% CI, 0.044–0.055), and 0.039 (95% CI, 0.036-0.042) mm for infrarenal, suprarenal, and thoracic measurements, respectively; differences in long-axis measurements were 0.054 (95% CI, 0.044–0.064), 0.029 (95% CI, 0.024–0.034), and 0.046 (95% CI, 0.037–0.054) mm. Bland-Altman and locally weighted scatterplot-smoothing analyses showed excellent agreement between measures with no variation in discrepancies vis-à-vis the target measurement.
Conclusions
These data establish previously undefined estimates of measurement variability relevant for in vivo sonographic studies of AAA regression in a commonly studied mouse model.
PMCID: PMC3810347  PMID: 21632991
abdominal aortic aneurysm; mouse model; sonography; variability
6.  Identification of promethazine as an amyloid-binding molecule using a fluorescence high-throughput assay and MALDI imaging mass spectrometry☆ 
NeuroImage : Clinical  2013;2:620-629.
The identification of amyloid-binding compounds is a crucial step in the development of imaging probes and therapeutics for the detection and cure of Alzheimer's disease. Unfortunately, the process typically lags during the translation from in vitro to in vivo studies due to the impenetrable nature of the blood brain barrier (BBB). Here, we integrate fluorescence assay with MALDI imaging mass spectrometry to screen known compounds and repurpose their properties to enable the second function of binding to amyloid plaques. Through this approach, we identified an antihistamine compound, promethazine, that can bind to amyloid plaques. Finally, we demonstrate that promethazine is retained in the amyloid-burdened brain compared to a normal brain and that its distribution within the brain corroborates with that of amyloid plaques.
Highlights
•We developed a fluorescence assay for screening amyloid-binding compounds.•The known compounds have been repurposed for secondary role.•We used MALDI-IMS to confirm the lead identified from fluorescence assays.•We identify promethazine as an amyloid-binding compound.
doi:10.1016/j.nicl.2013.04.015
PMCID: PMC3778261  PMID: 24179813
Alzheimer's disease; Neuroimaging; Promethazine; Amyloid plaques; MALDI-IMS
7.  Molecular imaging probe development: a chemistry perspective 
Molecular imaging is an attractive modality that has been widely employed in many aspects of biomedical research; especially those aimed at the early detection of diseases such as cancer, inflammation and neurodegenerative disorders. The field emerged in response to a new research paradigm in healthcare that seeks to integrate detection capabilities for the prediction and prevention of diseases. This approach made a distinct impact in biomedical research as it enabled researchers to leverage the capabilities of molecular imaging probes to visualize a targeted molecular event non-invasively, repeatedly and continuously in a living system. In addition, since such probes are inherently compact, robust, and amenable to high-throughput production, these probes could potentially facilitate screening of preclinical drug discovery, therapeutic assessment and validation of disease biomarkers. They could also be useful in drug discovery and safety evaluations. In this review, major trends in the chemical synthesis and development of positron emission tomography (PET), optical and magnetic resonance imaging (MRI) probes are discussed.
PMCID: PMC3430472  PMID: 22943038
Positron emission tomography; radiochemistry; MRI; optical probes; molecular imaging
8.  MULTIMODAL IMAGING OF DENDRITIC CELLS USING A NOVEL HYBRID MAGNETO-OPTICAL NANOPROBE 
A transfecting agent-coated hybrid imaging nanoprobe (HINP) comprised of visible and near-infrared (NIR) light emitting quantum dots (QDs) tethered to superparamagnetic iron oxide (SPIO) nanoparticles was developed. The surface modification of QDs and SPIO particles and incorporation of dual QDs within the SPIO were characterized by dynamic light scattering (DLS), quartz crystal microbalance (QCM) analysis and atomic force microscopy (AFM). The optical contrasting properties of HINP were characterized by absorption and photoluminescence spectroscopy and fluorescence imaging. Multicolor HINP was used in imaging the migration of dendritic cells (DCs) by optical, two-photon and magnetic resonance imaging techniques.
doi:10.1016/j.nano.2010.12.004
PMCID: PMC3148276  PMID: 21215329
Molecular Imaging; Dendritic cells; Nanotechnology; Magnetic Resonance Imaging
9.  Molecular imaging probe development: a chemistry perspective 
Molecular imaging is an attractive modality that has been widely employed in many aspects of biomedical research; especially those aimed at the early detection of diseases such as cancer, inflammation and neurodegenerative disorders. The field emerged in response to a new research paradigm in healthcare that seeks to integrate detection capabilities for the prediction and prevention of diseases. This approach made a distinct impact in biomedical research as it enabled researchers to leverage the capabilities of molecular imaging probes to visualize a targeted molecular event non-invasively, repeatedly and continuously in a living system. In addition, since such probes are inherently compact, robust, and amenable to high-throughput production, these probes could potentially facilitate screening of preclinical drug discovery, therapeutic assessment and validation of disease biomarkers. They could also be useful in drug discovery and safety evaluations. In this review, major trends in the chemical synthesis and development of positron emission tomography (PET), optical and magnetic resonance imaging (MRI) probes are discussed.
PMCID: PMC3430472  PMID: 22943038
Positron emission tomography; radiochemistry; MRI; optical probes; molecular imaging
10.  Fluorescent magnetic hybrid nanoprobe for multimodal bioimaging 
Nanotechnology  2011;22(27):275606.
A fluorescent magnetic hybrid imaging nanoprobe (HINP) was fabricated by conjugation of superparamagnetic Fe3O4 nanoparticles and visible light-emitting (~600 nm) fluorescent CdTe/CdS quantum dots (QDs). The assembly strategy used the covalent linking of the oxidized dextran shell of magnetic particles to the glutathione ligands of QDs. Synthesized HINP formed stable water-soluble colloidal dispersions. The structure and properties of the particles were characterized by transmission electron and atomic force microscopy, energy dispersive X-ray analysis and inductively coupled plasma optical emission spectroscopy, dynamic light scattering analysis, optical absorption and photoluminescence spectroscopy, and fluorescent imaging. The luminescence imaging region of the nanoprobe was extended to the near-infrared (NIR) (~800 nm) by conjugation of superparamagnetic nanoparticles with synthesized CdHgTe/CdS QDs. Cadmium, mercury based QDs in HINP can be easily replaced by novel water soluble glutathione stabilized AgInS2/ZnS QDs to present a new class of cadmium-free multimodal imaging agents. Observed NIR photoluminescence of fluorescent magnetic nanocomposites supports their use for bioimaging. The developed HINP provides dual-imaging channels for simultaneous optical and magnetic resonance imaging.
doi:10.1088/0957-4484/22/27/275606
PMCID: PMC3133788  PMID: 21597146
11.  A potential of peanut agglutinin-immobilized fluorescent nanospheres as a safe candidate of diagnostic drugs for colonoscopy 
Summary
There is a reasonable likelihood that peanut agglutinin--immobilized fluorescent nanospheres will be developed as a colonoscopic imaging agent from a safety perspective.
doi:10.1016/j.ejps.2010.12.011
PMCID: PMC3057359  PMID: 21216286
Imaging; Endoscopic imaging agent; Colonoscopy; Colorectal cancer; Safety
12.  Convergent synthesis and evaluation of 18F-labeled azulenic COX2 probes for cancer imaging 
Frontiers in Oncology  2013;2:207.
The overall objectives of this research are to (i) develop azulene-based positron emission tomography (PET) probes and (ii) image COX2 as a potential biomarker of breast cancer. Several lines of research have demonstrated that COX2 is overexpressed in breast cancer and that its presence correlates with poor prognoses. While other studies have reported that COX2 inhibition can be modulated and used beneficially as a chemopreventive strategy in cancer, no viable mechanism for achieving that approach has yet been developed. This shortfall could be circumvented through in vivo imaging of COX2 activity, particularly using sensitive imaging techniques such as PET. Toward that goal, our laboratory focuses on the development of novel 18F-labled COX2 probes. We began the synthesis of the probes by transforming tropolone into a lactone, which was subjected to an [8 + 2] cycloaddition reaction to yield 2-methylazulene as the core ring of the probe. After exploring numerous synthetic routes, the final target molecule and precursor PET compounds were prepared successfully using convergent synthesis. Conventional 18F labeling methods caused precursor decomposition, which prompted us to hypothesize that the acidic protons of the methylene moiety between the azulene and thiazole rings were readily abstracted by a strong base such as potassium carbonate. Ultimately, this caused the precursors to disintegrate. This observation was supported after successfully using an 18F labeling strategy that employed a much milder phosphate buffer. The 18F-labeled COX2 probe was tested in a breast cancer xenograft mouse model. The data obtained via successive whole-body PET/CT scans indicated probe accumulation and retention in the tumor. Overall, the probe was stable in vivo and no defluorination was observed. A biodistribution study and Western blot analysis corroborate with the imaging data. In conclusion, this novel COX2 PET probe was shown to be a promising agent for cancer imaging and deserves further investigation.
doi:10.3389/fonc.2012.00207
PMCID: PMC3539664  PMID: 23316477
azulene; COX2; breast cancer; PET; CT; convergence synthesis; molecular imaging
13.  NEAR-INFRARED DYES: Probe Development and Applications in Optical Molecular Imaging 
Current organic synthesis  2011;8(4):521-534.
The recent emergence of optical imaging has brought forth a unique challenge for chemists: development of new biocompatible dyes that fluoresce in the near-infrared (NIR) region for optimal use in biomedical applications. This review describes the synthesis of NIR dyes and the design of probes capable of noninvasively imaging molecular events in small animal models.
doi:10.2174/157017911796117223
PMCID: PMC3150548  PMID: 21822405
Cyanine; fluorescence; FRET; imaging; optical; probe; rhodamine
14.  Induction of Antitumor Immunity by Dendritic Cells Loaded with Membrane-Translocating Mucin 1 Peptide Antigen1 
Translational Oncology  2011;4(1):1-8.
To investigate the role of enhanced antigen presentation in dendritic cell (DC)-based immunotherapy. Here, we describe the development of a cell-penetrating mucin 1 (MUC1) antigen and its immunotherapeutic potential against tumors. After animal groups received two immunizations of MUC1-MPA11P-pulsed DCs, we observed a marked tumor regression compared with the mice treated with DCs alone or DCs pulsed with MUC1 peptide. We confirmed the migration and homing of DCs in the popliteal lymph node using magnetic resonance imaging during the study. In summary, enhanced antigen uptake using an MPA11P delivery molecule improves cell therapy.
PMCID: PMC3026404  PMID: 21286372
15.  Intermolecular [8+2] cycloaddition reactions of 2H-3-methoxycarbonylcyclohepta[b]furan-2-one with vinyl ethers: an approach to bicyclo[5.3.0]azulene derivatives 
Tetrahedron letters  2002;43(1):19-20.
Substituted bicyclo[5.3.0]azulene compounds are synthesized by intermolecular [8+2] cycloaddition reactions of lactone 1 with vinyl ethers—acetal decomposition products—are described. The reactions were found to be temperature and solvent dependent.
doi:10.1016/S0040-4039(01)02061-5
PMCID: PMC2926969  PMID: 20740048
16.  A practical approach for the preparation of monofunctional azulenyl squaraine dye 
Tetrahedron letters  2003;44(20):3975-3978.
The synthesis of monofunctional azulenyl squaraine dye NIRQ700 is described. The essential azulene intermediate 3, 1-(methoxycarbonyl)-2-methylazulene, was achieved via [8+2] cycloaddition between lactone 2, 2H-3-methoxycarbonyl-cyclohepta[b]furan-2-one, and the in situ generated vinyl ethers under high temperature and pressure conditions. Methylation on the cycloheptatriene ring of 2-methyl azulene 6 via Meisenheimer-type intermediate following Schrott's method formed the carboxylic acid intermediate 9, 3-(2-methyl-azulen-4-yl)-propionic acid. Condensation of 9 with squaric acid provided the title compound NIRQ700 at moderate yields. The non-fluorescent squaraine dye NIRQ700 absorbed in a 600–700 nm range and potentially can be used to quench a number of available NIR fluorochromes in order to extend the spectrum of biological quenching assays.
doi:10.1016/S0040-4039(03)00819-0
PMCID: PMC2926986  PMID: 20740053
17.  Functionalization of iron oxide nanoparticles with a versatile epoxy amine linker 
Journal of materials chemistry  2010;20(23):4776-4780.
A synthetically diverse linker molecule consisting of both a terminal epoxide and a terminal amine has been synthesized and shown to have the desired reactivity. Proof of principle experimentation showed that the prepared linker molecule possessed the ability to be reactive towards dextran coated iron nanoparticles, essentially converting the surface alcohols to amines with an efficiency on average of 50 linkers per nanoparticle. Once the surface of the nanoparticles had been functionalized, the iron nanoparticles were subsequently functionalized with both folic acid and fluorescein isothiocyanate, with an average efficiency of 20 and 3 molecules per nanoparticle, respectively. The labeled nanoparticles were then incubated with both folate receptor positive and negative cell lines, which showed a preferential accumulation of the particles in the receptor positive cell line. In addition to the fluorescence based assays, accumulation of the nanoparticles was demonstrated using T2-weighted MRI imaging, which showed that the iron core of the nanoparticle was present within the desired cell line. Overall, this linker has shown the ability to functionalize the surface of nanoparticles and can theoretically be used to label a wide variety of other targeting agents or imaging agents for in vivo therapies or diagnostics.
doi:10.1039/c0jm00808g
PMCID: PMC2910430  PMID: 20668643
18.  A near-infrared dye for multichannel imaging† 
A large Stokes shift dye, composed of water-solubility and near-infrared feature, was developed for multichannel imaging applications.
doi:10.1039/b719028j
PMCID: PMC2646119  PMID: 18401510
19.  Tracking the Migration of Dendritic Cells By In Vivo Optical Imaging1 
Neoplasia (New York, N.Y.)  2007;9(12):1130-1137.
We report herein a method to track the migration of dendritic cells (DCs) using optical imaging. With the assistance of the delivery module, fluorescein isothiocyanate (FITC) could internalize inside DCs within 15 minutes of incubation. The fluorescent signal was mostly cytoplasmic and could be detected using in vivo imaging. Furthermore, we observed that the probe did not interfere with the DCs maturation as we assessed the expression of several surface markers. The labeled DCs secreted interleukin-12 (IL-12) and tumor necrosis factor-alpha (TNF-α) and stimulated the proliferation of CD4+ T lymphocytes responding to lipopolysaccharide (LPS) stimulation. We have systematically compared the probe uptake between mature and immature DCs. The study showed that the latter phagocytosed the probe slightly better than the former. Intravital imaging of treated mice showed the migration of DCs to lymph nodes (LNs), which is confirmed by immunohistochemistry. Taken together, we demonstrated the potential use of optical imaging for tracking the migration of DCs and homing in vivo. The delivery molecules could also be used on other imaging modalities or for delivery of antigens.
PMCID: PMC2134909  PMID: 18084620
Dendritic cells; optical imaging; delivery; lymph node; antigen-presenting cells.

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