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Cerebrospinal fluid (CSF) is known to be reabsorbed by the lymphatic vessels and drain into the lymph nodes (LNs) through peripheral lymphatic vessels. In the peripheral lymphatics, the contractile pumping action of lymphangions mediates lymph drainage; yet it is unknown whether lymphatic vessels draining cranial and spinal CSF show similar function. Herein, we used non-invasive near-infrared fluorescence imaging (NIRFI) to image (i) indocyanine green (ICG) distribution along the neuraxis and (ii) routes of ICG-laden CSF outflow into the lymphatics following intrathecal lumbar administration. We demonstrate lymphatic contractile function in peripheral lymphatics draining from the nasal lymphatics to the mandibular LNs. In addition, we observed afferent sciatic lymphatic vessels, which also show contractile activity and transport spinal CSF into the sciatic LNs. This drainage pattern was also visualized by NIRFI following intrathecal thoracic injection. In situ intravital imaging following intrathecal lumbar injection of blue dye shows similar distributions to that seen in vivo with ICG. NIRFI could be used as a tool to probe CSF pathology including neurological disorders by imaging CSF outflow dynamics to lymphatics., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Introduction: Bifunctional chelators have been shown to impact the biodistribution of monoclonal antibody (mAb)-based imaging agents. Recently, radiolabeled 1,4,7-triazacyclononane,1-glutaric acid-4,7-acetic acid (NODAGA)-peptide complexes have demonstrated improved in vivo stability and performance compared to their 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) counterparts. Here, we investigated if similar utility could be achieved with mAbs and compared (64)Cu-labeled DOTA and NODAGA-immunoconjugates for the detection of epithelial cell adhesion molecule (EpCAM) in a prostate cancer model., Methods: DOTA and NODAGA-immunoconjugates of an EpCAM targeting mAb (mAb7) were synthesized and radiolabeled with (64)Cu (DOTA: 40°C for 1hr; NODAGA: 25°C for 1hr). The average number of chelators per mAb was quantified by isotopic dilution, and the biological activity of the immunoconjugates was evaluated by flow cytometry and ELISA. Radioligand assays were performed to compare cellular uptake and determine the dissociation constant (Kd) and maximum number of binding sites (Bmax) for the immunoconjugates using DsRed-transfected PC3-cells. A PC3-DsRed xenograft tumor model was established in nude mice and used to perform biodistribution studies to compare organ uptake and pharmacokinetics., Results: (64)Cu-DOTA-mAb7 and (64)Cu-NODAGA-mAb7 were prepared with chelator/protein ratios of 2-3 and obtained in comparable radiochemical yields ranging from 59 to 71%. Similar immunoreactivity was observed with both agents, and mock labeling studies indicated that incubation at room temperature or 40°C did not affect potency. (64)Cu-NODAGA-mAb7 demonstrated higher in vitro cellular uptake while (64)Cu-DOTA-mAb7 had higher Kd and Bmax values. From the biodistribution data, we found similar tumor uptake (13.44±1.21%ID/g and 13.24±4.86%ID/g for (64)Cu-DOTA-mAb7 and (64)Cu-NODAGA-mAb7, respectively) for both agents at 24hr, although normal prostate tissue was significantly lower for (64)Cu-NODAGA-mAb7. (64)Cu-NODAGA-mAb7 also had less accumulation in the liver, suggesting excellent retention of the chelation complex in vivo. This was further confirmed by the higher blood activity of (64)Cu-NODAGA-mAb7, which corresponds to increased bioavailability afforded by the enhanced in vivo stability of the agent. Although tumor/muscle ratios were comparable, tumor/prostate ratios were >2-fold and 1.5-fold higher for (64)Cu-NODAGA-mAb7 at 24 and 48hr, respectively, and suggest better ability to discriminate tumor tissue with (64)Cu-NODAGA-mAb7 in our prostate cancer model., Conclusions: To the best of our knowledge, this study represents the first comparison of (64)Cu-labeled DOTA and NODAGA immunoconjugates in vivo. Our results show favorable in vivo performance for (64)Cu-NODAGA-mAb7 which builds upon previous data on our hybrid mAb7 imaging agent by increasing the detection sensitivity for metastatic prostate tumors, as well as for other types of cancer that express EpCAM., (Copyright © 2014 Elsevier Inc. All rights reserved.)

The lymphatic system provides a route for dissemination of metastatic cancer cells. Yet to date transient changes in lymphatic drainage pathways and function as a result of tumor growth and metastasis have not been completely elucidated. Herein, we non-invasively imaged functional and architectural lymphatic changes in mice with regional, palpable lymph node (LN) involvement using dynamic near-infrared (NIR) fluorescence imaging with intradermal injection of indocyanine green (ICG) to both tumor-free mice and mice bearing C6/LacZ rat glioma tumors in the tail or hindlimb. We found that lymphatic drainage pathways were transiently altered and the contractile function of regional conducting lymphatic vessels was reduced or lost with progressive disease. Therefore, transient changes in the regional lymphatic architecture and function that occur with progressive disease, can be imaged using NIR fluorescence, and may provide a new method to stage disease., (2010 Elsevier B.V. All rights reserved.)

While the lymphatic system is increasingly associated with diseases of prevalence, study of these diseases is difficult owing to the paucity of imaging techniques with the sensitivity and temporal resolution to discriminate lymphatic function. Herein, we review the known, pertinent features of the human lymphatic system in health and disease and set the context for a number of emerging studies that use near-infrared fluorescence imaging to non-invasively assess tumor draining lymphatic basins in cancer patients, intraoperatively guide resection of first draining lymph nodes, and to interrogate the difference between normal and aberrant lymphatic structure and function.

Two-speed photon migration in densely packed powder blends wherein the particle diameters are much larger than the incident wavelength are simulated with (i) dynamic simulation of particle sedimentation for generating powder structure, (ii) the complete-random-mixture model for predicting the active pharmaceutical ingredient (API) distribution within the powder bed, and (iii) Monte Carlo for tracking the photon trajectories. The simulation results reveal that while both absorption and isotropic scattering coefficients increase with solid-volume fraction ranging from 0.12 to 0.64, the absorption-to-isotropic-scattering ratio is (i) independent of the solid-volume fraction for particle refractive index ranging from 1.2 to 1.8 and (ii) linearly dependent upon the API volume concentration ranging from 0% to 5%. Frequency domain photon migration measurements of resin powder beds of varying particle size verified the developed simulation method. Measurements of lactose powder beds of varying particle size, solid-volume fraction, and ferric oxide particles content verified the simulation results that evidence independence of the absorption-to-isotropic-scattering ratio upon solid-volume fraction., (Copyright 2006 Wiley-Liss, Inc. and the American Pharmacists Association.)

A system of dual-component powder mixtures, varying in excipient particle size and concentration of active pharmaceutical ingredient (API), is analyzed using frequency domain photon migration (FDPM) techniques. The results show that the FDPM-measured absorption coefficient increases linearly with increasing API concentration whereas the isotropic scattering coefficient shows no sensitivity to changes in API concentration. It is further seen that the absorption coefficient of blends, owing to the API, is not only linearly dependent on its concentration, but that this relationship is furthermore related to the excipient particle size. Finally, a comparison between near-infrared absorbance and FDPM-measured isotropic scattering as a function of reciprocal particle size is made to highlight FDPM as a powerful particle sizing tool without need for calibration. Overall, this study presents FDPM as a comprehensive method for detection of API concentration independent of excipient particle size., (Copyright 2004 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 93:1879-1889, 2004)

Frequency-domain photon migration (FDPM) measurements of time-dependent light propagation are conducted to provide the powder absorbance for quantitative prediction of terazosin as the active pharmaceutical ingredient (API) in a low-dose (0.72 wt %) oral tablet formulation. Calibration of the FDPM-derived powder absorbance at discrete wavelengths of 514, 650, 687, and 785 nm was performed for API contents ranging between 0 and 1.5 wt % in mixtures showing maximum sensitivity at 650 nm. The relative standard deviation (RSD) of FDPM absorption coefficient measurement at 650 nm in a well-mixed 1.08 wt % terazosin blend was <1.6%, of which no more than 0.12% arose from FDPM instrumental error and the remainder was attributable to the complete-random-mixture model. The applicability of FDPM as an on-line sensor for powder-blending operations was further evaluated by analyzing grab samples taken directly from five locations of a 2-cu-ft Gallay blender at intervals of 5 min within the blending process. FDPM results indicate that homogeneity was largely achieved in the first 10 min, during which the RSD of API content across five sampling locations decreased from 27% to 8%, and the RSD decreased to 5% after 25 min of blending. Evolution of homogeneity within the blending process assessed through FDPM measurements was fit to the first-order model of particle blending further evidencing applicability for monitoring powder-blending processes., (Copyright 2004 Wiley-Liss, Inc. and the American Pharmacists Association)

The deep tissue propagation of near-infrared (NIR) light between 700-900 nm offers new opportunities for diagnostic imaging when employing sensitive detection techniques and NIR excitable fluorescent agents that target and report disease and metabolism. Herein, we highlight approaches for illuminating tissues and monitoring the re-emitted fluorescence for tomographic reconstruction, strategies for developing fluorescent dye constructs, and clinical opportunities for fluorescence-enhanced NIR optical imaging.

The use of near-infrared (NIR) light to interrogate deep tissues has enormous potential for molecular-based imaging when coupled with NIR excitable dyes. More than a decade has now passed since the initial proposals for NIR optical tomography for breast cancer screening using time-dependent measurements of light propagation in the breast. Much accomplishment in the development of optical mammography has been demonstrated, most recently in the application of time-domain, frequency-domain, and continuous-wave measurements that depend on endogenous contrast owing to angiogenesis and increased hemoglobin absorbance for contrast. Although exciting and promising, the necessity of angiogenesis-mediated absorption contrast for diagnostic optical mammography minimizes the potential for using NIR techniques to assess sentinel lymph node staging, metastatic spread, and multifocality of breast disease, among other applications. In this review, we summarize the progress made in the development of optical mammography, and focus on the emerging work underway in the use of diagnostic contrast agents for the molecular-based, diagnostic imaging of breast.

The measurement and analysis of frequency-domain photon migration (FDPM) measurements of powder absorbance in pharmaceutical powders is described in the context of other optical techniques. FDPM consists of launching intensity-modulated light into a powder and detecting the phase delay and amplitude modulation of the re-emitted light as a function of the modulation frequency. From analysis of the data using the diffusion approximation to the radiative transport equation, the absorption coefficient can be obtained. Absorption coefficient measurements of riboflavin in lactose mixtures are presented at concentrations of 0.1 to 1% (w/w) at near-infrared wavelengths where solution absorption cross sections are difficult to accurately measure using traditional transmission measurements in nonscattering solutions. FDPM measurements in powders enabled determinations of absorption coefficients that increase linearly with concentration (w/w) according to Beer-Lambert relationship. The extension of FDPM for monitoring absorbance of low-dose and ultralow-dose powder blending operations is presented.