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This PDF file contains the front matter associated with SPIE
Proceedings Volume 6867, including the Title Page, Copyright
information, Table of Contents, and the
Conference Committee listing.
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The ability to obtain multi-color fluorescent imaging in vivo simultaneously using multi-targeted imaging probes could
be of potential benefit from both a research and a clinical perspective. However, the simultaneous acquisition of more
than 2 separate organic fluorophores usually requires more than one excitation source, since a single excitation source
may not optimally excite all the fluorophores. In this study, we employed a multi-excitation approach in order to acquire
optimized images with multiple near infrared (NIR) organic fluorophores at the same time. Using 3 sets of excitation
filters (595±20nm, 640±25nm, 688±17nm) to acquire 3 distinct spectra and spectral unmixing software (CRi, Woburn,
MA), it was possible to resolve the emission spectra of each of the NIR fluorophores using commercial software
(Nuance, CRi, Woburn, MA) To demonstrate the utility of this approach 2 mouse models were investigated; In one
model, mice bearing four implanted malignancies were injected with a cocktail of 3 fluorescently labeled monoclonal
antibodies, each with its own distinct NIR fluorophore. In the second model five different lymph node drainage basins
were imaged with 5-color dendrimer-based lymphatic imaging agents tagged with 5 different NIR fluorophores. We
successfully detected each of the targeted tumors in the first model and all of the lymph nodes by their distinct color in
the second model; neither of which would have been possible using the single excitation method. In conclusion, multi-excitation
NIR spectral fluorescence imaging is feasible in a reasonable time frame and opens the possibility for in vivo
immunohistochemical imaging (IHCi).
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Nowadays, several tumor imaging modalities such as MRI, PET and fluorescence imaging techniques have been
extensively investigated. One of the central problems associated with these conventional tumor-targeted imaging
methods, however, is the fact that the signal contrast between tumor and surrounding tissues relies on the efficient
targeting to the tumor and the rapid sequestration or excretion of unbound agent. Among these modalities, only
fluorescence imaging technique has a significant feature, in that great signal activation could be achieved which
potentially leads to the selective imaging of cancer with higher tumor-to-background ratio. In this symposium, I will
present some examples of fluorescence cancer imaging based on highly activatable strategies with using precisely
designed novel fluorescence probes.
Recently, we developed highly sensitive fluorescence probes for β-galactosidase which is applicable for living cell
system. By utilizing these probes, we could establish a novel and highly activatable strategy for sensitive and selective
optical imaging of imbedded tumor in the peritoneum. We took a two step procedure in that a lectin is used to localize
β-galactosidase to cancer cells as an activating enzyme, and subsequent administration of a highly-sensitive fluorescence
probe for the enzyme have afforded remarkable fluorescence activation selectively in tumor mass. Since the
tumor-targeted enzyme can catalyze numerous substrate turnovers, a great number of fluorescent molecules could be
produced and hence the rapid and sensitive detection of tumor in vivo with high tumor-to-background ratio could be
achieved. Moreover, the consequent close-up investigation using fluorescence microscopy revealed that cancer microfoci
as small as 200 μm could be successfully visualized.
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Optical imaging is a rapidly developing field of research aimed at non-invasively interrogating animals for disease
progression, determining the effects of a drug on a particular pathology, assessing the pharmacokinetic behavior of a
drug, or identifying molecular biomarkers of disease. One of the key components of molecular imaging is the
development of specific, targeted imaging contrast agents to assess these biological processes. The development of
robust fluorochrome-labeled optical agents is a process that is often underestimated in terms of its complexity. We
describe here the development process and performance issues for three different optical agents: IRDye 800CW EGF
(epidermal growth factor), IRDye(R) 800CW 2-DG (2-deoxy D-glucose), and an IRDye 680 BoneTagTM. In vitro
competitive assays were developed for two of the markers to demonstrate specificity. Specificity was confirmed in
animal studies. Uptake of IRDye 800CW 2-DG was also examined by near-infrared confocal microscopy. Histological
examinations were performed on target and non-target tissues following the completion of the imaging studies. The
issues unique to the development of each labeled marker are discussed.
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Described herein is an application of the copper(I)-catalyzed Huisgen [3+2] cycloaddition between azides and alkynes,
or click chemistry, for the universal two-step detection of biological macromolecules. The first step involves the
metabolic incorporation of an azide or alkyne probe into a macromolecule of interest. The second step involves the
click chemistry conjugation of the labeled macromolecule with a partner alkyne or azide-reactive fluorescent probe to
form a stable triazole ring conjugate. The fluorescently tagged molecules can be subsequently detected by a number of
different fluorescent readout platforms including flow cytometry, fluorescence imaging, and 1-D/2-D gel imaging. We
demonstrate application of this technology in two different labeling schemes. First, the labeling of newly synthesized
DNA in a novel cell proliferation assay, and second, in the labeling of specific glycoprotein subclasses for biomarker
discovery applications. In each case, azide or alkyne probes are introduced metabolically with subsequent detection
using click chemistry. Utilization of the cellular enzymatic machinery for high-fidelity target molecule labeling
combined with the superior efficiency of click chemistry detection results in highly versatile macromolecular labeling
platforms that are unmatched in sensitivity and selectivity.
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Colorectal cancer is a major cause of cancer death. Morbidity, mortality and healthcare costs can be reduced if the
disease can be detected at an early stage. Screening is a viable approach as there is a clear link to risk factors such as
age. We have developed a fluorescent contrast agent for use during colonoscopy. The agent is administered
intravenously and is targeted to an early stage molecular marker for colorectal cancer. The agent consists of a targeting
section comprising a peptide, and a fluorescent reporter molecule. Clinical imaging of the agent is to be performed with
a far red fluorescence imaging channel (635 nm excitation/660-700 nm emission) as an adjunct to white light colonoscopy. Preclinical proof of mechanism results are presented. The compound has a Kd of ~3nM. Two human xenograft tumour models were used. Tumour cells were implanted and grown subcutaneously in nude mice. Imaging using a fluorescence reflectance imaging system and quantitative biodistribution studies were performed. Substances tested include the
targeted agent, and a scrambled sequence of the peptide (no binding) used as a negative control. Competition studies were also performed by co-administration of 180 times excess unlabelled peptide. Positive imaging contrast was shown in the tumours, with a clear relationship to expression levels (confirmed with quantitative biodistribution data). There was a significant difference between the positive and negative control substances, and a significant reduction in contrast
in the competition experiment.
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Colorectal cancer is a major cause of cancer death. A significant unmet clinical need exists in the area of screening for
earlier and more accurate diagnosis and treatment. We have identified a fluorescence imaging agent targeted to an early
stage molecular marker for colorectal cancer. The agent is administered intravenously and imaged in a far red imaging
channel as an adjunct to white light endoscopy.
There is experimental evidence of preclinical proof of mechanism for the agent. In order to assess potential clinical
efficacy, imaging was performed with a prototype fluorescence endoscope system designed to produce clinically relevant
images. A clinical laparoscope system was modified for fluorescence imaging. The system was optimised for
sensitivity. Images were recorded at settings matching those expected with a clinical endoscope implementation (at
video frame rate operation). The animal model was comprised of a HCT-15 xenograft tumour expressing the target at
concentration levels expected in early stage colorectal cancer. Tumours were grown subcutaneously. The imaging agent
was administered intravenously at a dose of 50nmol/kg body weight. The animals were killed 2 hours post
administration and prepared for imaging. A 3-4mm diameter, 1.6mm thick slice of viable tumour was placed over the
opened colon and imaged with the laparoscope system. A receiver operator characteristic analysis was applied to
imaging results. An area under the curve of 0.98 and a sensitivity of 87% [73, 96] and specificity of 100% [93, 100]
were obtained.
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Lori K. Chinen, Karen P. Galen, K. T. Kuan, Mary E. Dyszlewski, Hiroaki Ozaki, Hiroaki Sawai, Raghootama S. Pandurangi, Frederick G. Jacobs, Richard B. Dorshow, et al.
Real-time, non-invasive assessment of glomerular filtration rate (GFR) is essential not only for monitoring critically
ill patients at the bedside, but also for staging and monitoring patients with chronic kidney disease. In our pursuit to
develop exogenous luminescent probes for dynamic optical monitoring of GFR, we have prepared and evaluated Eu3+
complexes of several diethylenetriamine pentaacetate (DTPA)-monoamide ligands bearing molecular "antennae" to
enhance metal fluorescence via the intramolecular ligand-metal fluorescence resonance energy transfer (FRET) process.
The results show that Eu-DTPA-monoamide complex 13a, which contains a quinoxanlinyl antenna, exhibits large (c.a.
2700-fold) Eu3+ fluorescence enhancement over Eu-DTPA (4c). Indeed, complex 13a exhibits the highest fluorescent
enhancement observed thus far in the DTPA-type metal complexes. The renal clearance profile of the corresponding
radioactive 111In complex 13c is similar to that of 111In-DTPA, albeit 13c clears slower than 111In-DTPA. The biodistribution
data indicates that 13c, and, by inference, 13a clear via a complex mechanism that includes glomerular filtration.
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The ability to continuously monitor renal function via the glomerular filtration rate (GFR) in the clinic is currently an
unmet medical need. To address this need we have developed a new series of hydrophilic fluorescent probes designed
to clear via glomerular filtration for use as real time optical monitoring agents at the bedside. The ideal molecule should
be freely filtered via the glomerular filtration barrier and be neither reabsorbed nor secreted by the renal tubule. In
addition, we have hypothesized that a low volume of distribution into the interstitial space could also be advantageous.
Our primary molecular design strategy employs a very small pyrazine-based fluorophore as the core unit. Modular
chemistry for functionalizing these systems for optimal pharmacokinetics (PK) and photophysical properties have been
developed. Structure-activity relationship (SAR) and pharmacokinetic (PK) studies involving hydrophilic pyrazine
analogues incorporating polyethylene glycol (PEG), carbohydrate, amino acid and peptide functionality have been a
focus of this work. Secondary design strategies for minimizing distribution into the interstitium while maintaining
glomerular filtration include enhancing molecular volume through PEG substitution. In vivo optical monitoring
experiments with advanced candidates have been correlated with plasma PK for measurement of clearance and hence
GFR.
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Plasmon-resonant gold nanorods have been demonstrated recently as contrast agents for optical coherence
tomography (OCT). To evaluate their ability to produce contrast in a structurally heterogeneous environment,
nanorods were injected at discrete locations into an excised sample of human breast invasive ductal carcinoma. The
distribution of nanorods within the tissue was revealed using spectroscopic OCT imaging techniques, by analyzing
the evolution of the backscattered light spectrum over tissue depth. We compare a variety of signal processing
methods including spatial averaging and least-squares fitting to the a priori extinction spectrum of the nanorods,
with the goal of optimizing the detection sensitivity to the nanorods in these tissues. Because nanorods can be
conjugated with proteins specific to biomolecular targets, they may potentially be used with these imaging methods
to provide molecular contrast in human tissues.
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Optical coherence tomography (OCT) is an emerging biomedical imaging modality that has been developed over the last
15 years. More recently, OCT has been used for the intraoperative imaging of tumor margins in breast cancer and
axillary lymph nodes providing a real time in-vivo assessment of the tissue morphology. Traditional OCT images are
limited by only being able to observe morphological structures. As diagnostic medicine continues to push for earlier
detection, one must develop functional imaging modalities that would detect molecular information in-vivo allowing a
real-time microscopic analysis of the tissue specimen. A novel modality of OCT called magnetomotive-OCT (MMOCT)
has been developed by our group, employing an induced modulated magnetic field with a magnetic contrast agent
to create the added contrast to structural OCT images. Modified protein microspheres with a BSA protein shell
functionalized with RGD peptide sequences for targeting and an oil core have been designed and synthesized. Magnetic
nanoparticles (Fe3O4) and Nile Red dye have been encapsulated into its oil core. These microspheres have previously
been demonstrated to target cancer cells by functionalizing them with a layer of RGD peptides and could be
functionalized with monoclonal antibodies. Preliminary results show that these magnetic microspheres, which are 2.0-
5.0 microns in size, are readily detectable under MM-OCT when embedded in a 5% agarose gel, in a 3-D scaffold of
macrophage cells previously incubated with the microspheres, and when injected in-vivo into a tumor from an NMUcarcinogen
rat animal model for breast cancer.
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Hybrid nanomaterials consisted of II-VI semiconductor quantum dots covered by layers of functionalizing organic
compounds, may be prepared to develop good biolabeling and consequent bioimaging applications. In this study we
present some well succeeded results related to the preparation, functionalization, and to the use of II-VI semiconductor
quantum dots, prepared via colloidal synthesis in aqueous medium, as highly luminescent labels for bioimaging. The
resulting systems possess the combined properties of both forming elements: the optical properties of the quantum dots
and the biological functionalities provided by the organic capping layers, which leads to specific association to biological
systems.These nanostructured materials nanoparticles presented good optical properties and excellent resistance to
photodegradation. Their conjugation to biological samples was evaluated by their fluorescence intensities and patterns,
by using conventional fluorescence and laser scanning confocal microscopies. The resulting images showed very good
quality concerning morphological features of the analyzed cells and tissues.
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Structural alteration of serum albumin, the major extracellular multifunctional protein in mammals, has been linked to a
number of diseases. Herein we present a method based on fluorescence lifetime analysis of near-infrared (NIR) probes bound to albumin to interrogate its structural state without prior isolation of the protein. Molecular modeling study revealed that albumin binds polymethine dyes via two binding sites with different sizes and polarities. As a result, a NIR molecular probe typically exhibits two distinct lifetimes with corresponding fractional contributions. The distribution of fractional contributions along with individual fluorescence lifetimes represents unique parameters for characterizing albumin architecture. To evaluate the effect of size and polarity of binding sites on fluorescence lifetime we studied NIR probes in solutions with different viscosity and polarity. We established that viscosity has negligible effect on polymethine dyes lifetime while the change in polarity has a profound impact. We also established a correlation between fluorescence lifetime and solvent polarity function for a number of NIR dyes for quantitative description of binding sites polarity. After screening a library of dyes, we identified a probe with optimal fluorescence lifetime properties to assess structure-related differences of albumins. The results show that changes in the lifetime of NIR dyes reflect the perturbation of albumin's tertiary structures. Because of the reduced absorption of light by blood in the NIR region, the method developed can be used to determine structural changes of albumins in whole blood.
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2-pyridone (2Py) and 3-pyridone (3Py) were examined in different solvents and their binding to human serum albumin
(HSA) was studied using steady-state spectroscopy and time-resolved fluorescence. Solvation of 2Py and 3Py by water
was examined in binary mixtures of 1,4-dioxane and water. Analysis of the absorption and fluorescence data reveals the
solvation of the hydrogen bonding center in 2Py by one water molecule and in 3Py by three water molecules. A
zwitterionic tautomer of 3Py is formed in water and shows distinct absorption peaks from the absorption of the neutral
tautomer. Fluorescence of 3Py was observed in polar solvents only, whereas 2Py is fluorescent in polar and nonpolar
solvents. The absorption and fluorescence spectra of 2Py in different solvents indicate less solute-solvent interaction in
nonpolar solvents. This observation was confirmed by the measured longer fluorescence lifetime of 2Py in cyclohexane
compared to that in water. The mechanism of binding of 2Py and 3Py as probe ligands to HSA was investigated by
following the intensity change and lifetime of HSA fluorescence after excitation at 280 nm. The presence of 2Py and
3Py causes a reduction in the fluorescence intensity and lifetime of HSA. This observation indicates that subdomain IIA
binding site (Sudlow site I) is the host of the probes and the reduction in the fluorescence of HSA is due to energy
transfer from the Trp-214 residue to the probe in each case. The distance between Trp-214 and each of the probes was
calculated using Förster theory for energy transfer to be 1.99 nm for HSA/2Py and 2.44 nm for HSA/3Py. The shorter
distance in the former complex indicates more efficient energy transfer than in the latter. This was confirmed by
estimating the quenching rate constant (kq) in each complex. kq was calculated to be 1.44 x 1012 M-1s-1 for HSA/2Py and
3.45 x 1011 M-1s-1 for HSA/3Py. The calculated distances and the kq values indicate a static quenching mechanism
operative in the two complexes. The binding constants were estimated to be K = (3.4 ± 0.4) x 104 M-1 for the HSA/2Py
complex and K = (2.3 ± 0.3) x 104 M-1 for the HSA/3Py complex. The number of binding sites of HSA was calculated to
be one in both complexes. The latter results, along with the quenching results, indicate that both probes, 2Py and 3Py,
bind only in Sudlow site I in subdomain IIA.
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Triplex forming oligos (TFOs) that target psoralen photoadducts to specific DNA sequences have generated interest as a
potential agent in gene therapy. TFOs also offer an opportunity to study the mechanism of DNA repair in detail. In an
effort to understand the mechanism of DNA repair at a specific DNA sequence in real-time, we have designed a plasmid
containing a psoralen reaction site adjacent to a TFO binding site corresponding to a sequence within the human
interstitial collagenase gene. Two 2-aminopurine residues incorporated into the purine-rich strand of the TFO binding
site and located within six nucleotides of the psoralen reaction site serve as molecular probes for excision repair events
involving the psoralen photoadducts on that DNA strand. In duplex DNA, the 2-aminopurine fluorescence is quenched.
However, upon thermal or formamide-induced denaturation of duplex DNA to single stranded DNA, the 2-aminopurine
fluorescence increases by eight fold. These results suggest that monitoring 2-aminopurine fluorescence from plasmids
damaged by psoralen TFOs may be a method for measuring excision of single-stranded damaged DNA from the plasmid
in cells. A fluorescence-based molecular probe to the plasmid may significantly simplify the real-time observation of
DNA repair in both populations of cells as well as single cells.
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In this article we present a method for the highly specific identification of single nucleotide polymorphism (SNP)
responsible for rifampicin resistance of Mycobacterium tuberculosis. This approach applies fluorescently labeled
hairpin-structured oligonucleotides (smart probes) and confocal single-molecule fluorescence spectroscopy. Smart
probes are fluorescently labeled at the 5'-end. The dye's fluorescence is quenched in the closed hairpin conformation due
to close proximity of the guanosine residues located at the 3'-end. As a result of the hybridization to the complementary
target sequence the hairpin structure and thus fluorescence quenching gets lost and a strong fluorescence increase
appears. To enhance the specificity of the SNP detection unlabeled "blocking oligonucleotides" were added to the
sample. These oligonucleotides hybridizes to the DNA sequence containing the mismatch thus masking this sequence
and hereby preventing the smart probe from hybridizing to the mismatched sequence.
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Since the early nineties, multiphoton microscopy has become a powerful tool to investigate morphological and
physiological parameters in vivo or on thick ex vivo sections. To stain structures of interest many dyes have been developed and two-photon properties (cross section, excitation and
emission spectra) of existing ones have been characterized.
Recently, our team has shown a new property of sulforhodamine B (SRB). This dye has the ability to bind specifically
elastic fibers. The observation of elastin using its endofluorescence properties was already widely described but required
long exposition delays up to 10s and the imaging depth was limited to approximately 50 μm. With a multiphoton microscope and SRB, it is possible to observe elastic fibers directly in the living animal or on thick tissue sections with a micrometric spatial resolution in less than one second per image with an imaging depth of ~ 200
μm. Moreover, with an appropriate set of filters, we can acquire simultaneously the SRB and the second harmonic generation (SHG) signals of collagen fibers. Here, we report various applications of this new staining method on different arterial rings. The layers of the arterial wall, as well as, the elastic lamellae are observed and are numbered. With the addition of a nuclear stain such as the Hoechst 33342, a more accurate morphological study of the arterial walls can be accomplished. Finally, an intravital observation of the saphenous artery morphology is presented.
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