Noninvasive monitoring of liver metastasis development via combined multispectral photoacoustic imaging and fluorescence diffuse optical tomography.

Rationale:In vivo molecular imaging in preclinical animal models is a tool of choice for understanding the pathophysiological mechanisms involved in cancer development and for conducting drug development research. Moreover, combining several imaging modalities can provide multifaceted, complementary and cross-validated information. Photoacoustic imaging (PAI) is a promising imaging modality that can reflect blood vasculature and tissue oxygenation as well as detect exogenous molecules, but one shortcoming of PAI is a lack of organic photoacoustic contrast agents capable of providing tumor contrast. Methods: In the present study, we designed an animal model of liver metastases from colon cancer and monitored metastasis development by in vivo bioluminescence and X-ray microcomputed tomography. Contrast-agent-free PAI was used to detect the respective amounts of oxy- and deoxyhemoglobin and, thus, liver tissue oxygenation. two contrast agents, Angiostamp800 and indocyanin green (ICG), respectively with and without tumor targeting specificity, were then evaluated for their dual fluorescence and photoacoustic detectability and were then used for combined PAI and fluorescence diffuse optical tomography (fDOT) at various disease development stages. Findings: Contrast-agent-free PAI reflected tumor angiogenesis and gradual hypoxia during metastasis development. Multispectral PAI enabled noninvasive real-time monitoring of ICG blood pharmacokinetics, which demonstrated tumor-related liver dysfunction. Both PAI and fluorescence ICG signals were clearly modified in metastasis-bearing livers but did not allow for differentiation between different disease stages. In contrast, there was a significant improvement achieved by using the tumor-specific marker Angiostamp800, which provided gradually increasing PAI and fDOT signals during metastasis development. Conclusion: We demonstrated for the first time the value of using Angiostamp800 as a bimodal tumor-targeting contrast agent for combined PAI and fluorescence imaging of liver metastasis progression in vivo.

Near infrared fluorescence imaging of rabbit thyroid and parathyroid glands.

BACKGROUND: Near infrared fluorescence imaging using intravenous methylene blue (MB) is a novel technique that has potential to aid the parathyroid gland (PG) localization during thyroid and parathyroid surgery. The aim of this study was to examine MB fluorescence in the rabbit neck and determine the influence of MB dose and time following administration on fluorescence from thyroid and PGs. METHODS: Thyroid and external PGs were exposed in six New Zealand white rabbits under anesthesia. Varying doses of MB (0.025-3 mg/kg) were injected through the marginal ear vein. Near infrared fluorescence from exposed tissues was recorded at different time intervals (10-74 min) using Fluobeam 700. Specimens of identified glands were then resected for histologic assessment. RESULTS: Histology confirmed accurate identification of all excised thyroid and PGs; these were the only neck structures to demonstrate significant fluorescence. The parathyroid demonstrated lower fluorescence intensities and reduced washout times at all MB doses compared with the thyroid gland. A dose of 0.1 mg/kg MB was adequate to identify fluorescence; this also delineated the blood supply of the external PGs. CONCLUSIONS: The study demonstrates that near infrared fluorescence with intravenous MB helps differentiate between thyroid and PGs in the rabbit. This has potential to improve outcomes in thyroid and parathyroid surgery by increasing the accuracy of parathyroid identification; however, the findings require replication in human surgery. The use of low doses of MB may also avoid the side effects associated with currently used doses in humans (3-7 mg/kg).

Reverse micelle-loaded lipid nanocarriers: a novel drug delivery system for the sustained release of doxorubicin hydrochloride.

In this study, we are pioneering new nanotechnology for the encapsulation of anticancer drugs (doxorubicin (DOX) and/or docetaxel (DOCE)), whatever their solubility and water affinity. The purpose of this study is to highlight the potential of this recently patented technology, by carrying out a thorough physicochemical characterisation of these multiscaled nanocarriers, followed by the study of an encapsulation and release model of hydrophilic anticancer drug. The formulation process is based on a low-energy nano-emulsification method and allows the generation of a structure composed of oil-based nanocarriers loaded with reverse micelles. Thanks to this, hydrophilic contents can be solubilised in the oily core of this kind of nano-emulsion along with lipophilic content. The results emphasise some original structure particularities due to the multistep formulation process, and the diffusion-based behaviour revealed for the DOX release profile that is shown to be intimately linked to the morphology of the particles.

Nano-emulsions and nanocapsules by the PIT method: an investigation on the role of the temperature cycling on the emulsion phase inversion.

This paper focuses on the phenomenological understanding of temperature cycling process, applied to the phase inversion temperature (PIT) method. The role of this particular thermal treatment on emulsions phase inversion, as well as its ability to generate nano-emulsions have been investigated. In order to propose a general study, we have based our investigations on a given formulation of nano-emulsions classically proposed in the literature [Heurtault, B., Saulnier, P., Pech, B., Proust, J. E., Benoit, J.P., 2002. A novel phase inversion-based process for the preparation of lipid nanocarriers. Pharm. Res. 19, 875; Lamprecht, A., Bouligand, Y, Benoit, J.P., 2002. New lipid nanocapsules exhibit sustained release properties for amiodarone. J. Control. Release 84, 59-68], using a polyethoxylated model nonionic surfactant, a polyoxyehtylene-660-12-hydroxy stearate, stabilizing the emulsion composed of caprilic triglycerides (triglycerides medium chains), salt water (and also phospholipidic amphiphiles neutral for the formulation). Characterization of nano-emulsions was performed by dynamic light scattering (DLS) which provides the hydrodynamic diameter, but also the polydispersity index (PDI), as a fundamental criteria to judge the quality of the dispersion. Another aspect of the characterization was done following the emulsion inversion and structure by electrical conductivity through the temperature scan. Overall, the role such a temperature cycling process on the formulation of nano-emulsions appears to be relatively important, and globally enhanced as the surfactant concentration is lowered. Actually, both the hydrodynamic diameter and the PDI decrease as a function of the number and temperature cycles up to stabilize a steady state. Eventually, such a cycling process allows the generation of nano-emulsions in ranges of compositions largely expanded when compared with the classical PIT method. These general and interesting trends emerge from the results, are discussed and essentially explained by regarding the behavior of the nonionic surfactants towards the water/oil interface, linking partitioning coefficients, temperature variation, and surfactant water/oil interfacial concentration. In that way, this paper proposes new insights into the phenomena governing the PIT method, by originally investigating the temperature cycling process.

Modeling heating curve for gas hydrate dissociation in porous media.

A method for modeling the heating curve for gas hydrate dissociation in porous media at isochoric conditions (constant cell volume) is presented. This method consists of using an equation of state of the gas, the cumulative volume distribution (CVD) of the porous medium, and a van der Waals-Platteeuw-type thermodynamic model that includes a capillary term. The proposed method was tested to predict the heating curves for methane hydrate dissociation in a mesoporous silica glass for saturated conditions (liquid volume = pore volume) and for a fractional conversion of water to hydrate of 1 (100% of the available water was converted to hydrate). The shape factor (F) of the hydrate-water interface was found equal to 1, supporting a cylindrical shape for the hydrate particles during hydrate dissociation. Using F = 1, it has been possible to predict the heating curve for different ranges of pressure and temperature. The excellent agreement between the calculated and experimental heating curves supports the validity of our approach.