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Background Flap monitoring in reconstructive surgery is particularly important because flap failure is a dramatic event for the patient and for the medical team. Noninvasive deep tissue oxygenation monitoring is a challenge. The aim of this experimental study was to assess the performance of time-resolved near-infrared spectroscopy compared with continuous-wave near-infrared spectroscopy and with invasive oxygen partial pressure measurement in pigs. Methods Thirty fasciocutaneous flaps based on the superficial epigastric inferior pedicle were harvested and buried under the transcutaneous dorsal muscle (approximately 1 cm thick). An optical probe was placed on the skin above each buried flap. For each pig, two buried flaps were performed, one submitted to arterial occlusion and one to venous occlusion. Oxyhemoglobin and deoxyhemoglobin concentrations were observed for over 40 minutes before clamping, almost 20 minutes during clamping and during a period of release of approximately 20 minutes. Variations in time-resolved near-infrared spectroscopy were compared to the oxygen partial pressure and continuous-wave near-infrared spectroscopy variations. Results All vascular events were detected by the time-resolved near-infrared spectroscopy. During arterial clamping, oxyhemoglobin decreased rapidly, whereas deoxyhemoglobin increased moderately. The divergence of oxyhemoglobin and deoxyhemoglobin curves indicated arterial occlusion. During venous clamping, deoxyhemoglobin increased, whereas oxyhemoglobin increased briefly then remained stable or decreased moderately. The initial increases in the oxyhemoglobin and deoxyhemoglobin curves indicated venous occlusion. Oxygen partial pressure failed to detect vascular events in three cases. Continuous-wave near-infrared spectroscopy could not clearly identify vascular occlusions. Conclusions Thus, the authors demonstrated the relevance of time-resolved near-infrared spectroscopy to buried flap monitoring. Time-resolved near-infrared spectroscopy could differentiate between arterial occlusion and venous occlusion.

Background In recent years, many devices have been developed to monitor free flaps. The Licox probe, which measures tissue oxygen pressure (PtO2 ), is one of the available devices. Our aim was to demonstrate that PtO2 could distinguish arterial from venous occlusion in a porcine fascio-cutaneous flap model. Materials and methods Twenty pigs (Sus scrofa domestica, Youna strain, males) were included in this study. The median weight was 87.6 kg (84.6-90.8). Bilateral fascio-cutaneous flaps based on the superficial inferior epigastric pedicle were harvested from each pig. Thirty-eight flaps were analyzed in this study and were monitored by a Licox system during vascular occlusion. The flaps were randomized into two groups according to the clamped vessel: the arterial group (n = 19) and the venous group (n = 19). After a stabilization period of almost 40 min, vascular clamping (arterial or venous) was performed using a microvascular clamp for almost 20 min. The curve profiles were compared between arterial and venous occlusion. Results The inflection point was reached significantly faster in the arterial group: 11 min (9-16) for arterial clamping and 17 min (13-23) for venous clamping (p = .001). A total of 18/19 (95%) pigs in the arterial group and 13/19 (68%) in the venous group (p = .09) reached a level lower than 10 mmHg. The median duration for pressure to drop below 10 mmHg was 9 min (6-12) for arterial clamping and 10 min (9-16) for venous clamping (p = .06). Conclusion We showed that PtO2 decreased faster in cases of arterial occlusion than in cases of venous occlusion in a pig model. Based on this observation, it may be possible to distinguish arterial from venous occlusion.

International audience; We synthesized a generation of water-soluble, atomically precise gold nanoclusters (Au NCs) with anisotropic surface containing a short dithiol pegylated chain (AuMHA/TDT). The AuMHA/TDT exhibit a high brightness (QY ∼ 6%) in the shortwave infrared (SWIR) spectrum with a detection above 1250 nm. Furthermore, they show an extended half-life in blood (t 1/2ß = 19.54 ± 0.05 h) and a very weak accumulation in organs. We also developed a non-invasive, whole-body vascular imaging system in the SWIR window with high-resolution, benefiting from a series of Monte Carlo image processing. The imaging process enabled to improve contrast by 1 order of magnitude and enhance the spatial resolution by 59%. After systemic administration of these nanoprobes in mice, we can quantify vessel complexity in depth (>4 mm), allowing to detect very subtle vascular disorders non-invasively in bone morphogenetic protein 9 (Bmp9)-deficient mice. The combination of these anisotropic surface charged Au NCs plus an improved SWIR imaging device allows a precise mapping at high-resolution and an in depth understanding of the organization of the vascular network in live animals. KEYWORDS: shortwave infrared fluorescence, gold nanoclusters, vascular disorder, Monte Carlo restoration imaging processing, bone morphogenetic protein 9 (Bmp9)

International audience; Alterations in glycosylation cause the emergence of tumor-associated carbohydrate antigens (TACAs) during tumorigenesis. Truncation of O-glycans reveals the Thomsen nouveau (Tn) antigen, an N-acetylgalactosamine (GalNAc) frequently attached to serine or threonine amino acids, that is accessible on the surface of cancer cells but not on healthy cells. Interestingly, GalNac can be recognized by macrophage galactose lectin (MGL), a type C lectin receptor expressed in immune cells. In this study, recombinant MGL fragments were tested in vitro for their cancer cell-targeting efficiency by flow cytometry and confocal microscopy and in vivo after administration of fluorescent MGL to tumor-bearing mice. Our results demonstrate the ability of MGL to target Tn-positive human tumors without inducing toxicity. This outcome makes MGL, a fragment of a normal human protein, the first vector candidate for in vivo diagnosis and imaging of human tumors and, possibly, for therapeutic applications.

As the number of cancers is steadily increasing, doctors are in need of automatic tools with better and faster analysis methods to help them with the diagnosis. One way to tackle this challenge is to propose label-free methods capable to analyze a large number of samples. Recent development in photonics components could enable to use infrared light to detect abnormal tissues and Mid-IR imaging can provide an unequivocal information about the biochemical composition of human cells. The combination of a set of Quantum Cascade Lasers (QCLs) and lensfree imaging with uncooled bolometer matrix will allow the biochemical mapping over a wide field of view. This experimental setup coupled to machine learning algorithms (Random Forest, Neural Networks, K-means) can help to classify the biological cells in a fast and reproducible way. Images from the frozen section tissue of nude mice bearing human orthotropic oral cavity tumors from the CAL33 cell line have been acquired and analyzed. Using amide and DNA absorption bands, we achieved up to 94% of successful predictions of cancer cells with a population of 325 pixels corresponding to muscle tissues and 325 pixels corresponding to cancer tissues. This work may lead to the development of an imaging device, that could be used for cancer diagnosis at hospital.

We present a method of high resolution, non-invasive, in vivo vascular imaging obtained using watersoluble and bright SWIR-emitting gold nanoclusters presenting an anisotropic surface charge combined with SWIR detection and Monte Carlo processing of the images. We applied this approach to quantify vessel complexity in mice presenting vascular disorders.

We evaluated the impact of light-scattering effects on spatial resolution in different shortwave infrared (SWIR) sub-regions by analyzing two SWIR emissive phantoms made of polydimethylsiloxane (PDMS)-gold nanoclusters (Au NCs) composite covered with mice skin, or capillary tubes filled with Au NCs or IRDye 800CW at different depth in intralipids and finally, after administration of the Au NCs intravenously in mice. Our findings highlighted the benefit of working at the highest tested spectral range of the SWIR region with a 50% enhancement of spatial resolution measured in artificial model when moving from NIR-II (1000-1300 nm) to NIR-IIa (1300-1450 nm) region, and a 25% reduction of the scattering from the skin determined by point spread function analysis from the NIR-II to NIR-IIb region (1500-1700 nm). We also confirmed that a series of Monte Carlo restoration of images significantly improved the spatial resolution in vivo in mice in deep tissues both in the NIR-II and NIR-IIa spectral windows.

We present here a new approach for non-invasive high resolution whole-body vascular imaging in depth by combining water-soluble and bright SWIR-emitting gold nanoclusters revealing an anisotropic surface charge with Monte Carlo image processing of the images. We applied and validated this approach to quantify vessel complexity in transgenic mice presenting vascular disorders.

International audience; 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.

Photoacoustic imaging (PAI) provides real time non-invasive and contrast agent free monitoring of some endogenous compounds concentrations that provides improved insights into tissue vascularization and oxygenation which are particularly important during tumor progression. This study assessed the input of PAI for examination of melanoma brain metastases in an orthotopic mouse model and further focused on spatial analyses within the tumor tissue. Hemoglobin content appeared to be higher in tumors than in healthy brains. Spatial analyses further showed that angiogenesis was mainly at the tumor periphery. Concomitantly, while healthy brains were highly oxygenated, the tumors were hypoxic and subjected to a gradient of hypoxia from the periphery to the core. In tumor-bearing brains, spectroscopic PAI clearly revealed the presence of melanin, generating a signal 3 times higher than the background signal in healthy brains. When inserted into tissue mimicking phantoms, the photoacoustic signal of B16F10 melanin-containing cells was linearly correlated to their concentration and the detection limit was 625 cells. In vivo biological characterization of tumor models by non-invasive imaging of vasculature and tissue hypoxia represents an interesting opportunity for better understanding cancer progression; it is opening new research prospects to improve diagnostic, therapy, and early assessment of tumor treatment efficacy.

Porphyrin- or phthalocyanine-bridged silsesquioxane nanoparticles (BSPOR and BSPHT) were prepared. Their endocytosis in MCF-7 cancer cells was shown with two-photon excited fluorescence (TPEF) imaging. With two-photon excited photodynamic therapy (TPE-PDT), BSPOR was more phototoxic than BSPHT, which in contrast displayed a very high signal for photoacoustic imaging in mice.

Herein, we report a novel approach for the design of a colorimetric aptasensor based on functionalized gold nanoparticle probes. This approach relies on the conjugation of nanoparticles by two functional DNA and RNA hairpins that engage specific kissing (loop-loop) interactions in response to the addition of a small analyte ligand, leading to particle aggregation and then red-to-purple colour change of the colloidal solution.

Advanced ovarian cancer is the most lethal gynecological cancer, with a high rate of chemoresistance and relapse. Photodynamic therapy offers new prospects for ovarian cancer treatment, but current photosensitizers lack tumor specificity, resulting in low efficacy and significant side-effects. In the present work, the clinically approved photosensitizer verteporfin was encapsulated within nanostructured lipid carriers (NLC) for targeted photodynamic therapy of ovarian cancer. Cellular uptake and phototoxicity of free verteporfin and NLC-verteporfin were studied in vitro in human ovarian cancer cell lines cultured in 2D and 3D-spheroids, and biodistribution and photodynamic therapy were evaluated in vivo in mice. Both molecules were internalized in ovarian cancer cells and strongly inhibited tumor cells viability when exposed to laser light only. In vivo biodistribution and pharmacokinetic studies evidenced a long circulation time of NLC associated with efficient tumor uptake. Administration of 2 mg.kg&minus, 1 free verteporfin induced severe phototoxic adverse effects leading to the death of 5 out of 8 mice. In contrast, laser light exposure of tumors after intravenous administration of NLC-verteporfin (8 mg.kg&minus, 1) significantly inhibited tumor growth without visible toxicity. NLC-verteporfin thus led to efficient verteporfin vectorization to the tumor site and protection from side-effects, providing promising therapeutic prospects for photodynamic therapy of cancer.

Blood oxygenation in depth is a critical parameter to be monitored in many clinical applications. We are developing a pre-clinical instrument to monitor oxygenation up to 1.5 cm deep in biological tissues. The measures, based on time of flight, are in vivo, noninvasive and without injection of any contrast agent. Developments have been implemented in a tomographic reconstruction algorithm to make it reconstruct chromophores by layers. These developments are presented here along with simulations we used to set up the algorithm. Buried flaps on 20 pigs were undergone for pre-clinical tests of our reconstruction algorithm and instrument.

International audience; Standard chemotherapies that interfere with microtubule dynamics are a chemotherapeutic option used for the patients with advanced malignancies that invariably relapse after targeted therapies. However, major efforts are needed to reduce their toxicity, optimize their efficacy, and reduce cancer chemoresistance to these agents. We previously identified a pyrrolo[2,3d]pyrimidine-based microtubule-depolymerizing agent (PP-13) that binds to the colchicine site of β-tubulin and exhibits anticancer properties in solid human cancer cells, including che-moresistant subtypes. Here, we investigated the therapeutic potential of PP-13 in vitro and in vivo. PP-13 induced a mitotic blockade and apoptosis in several cancer cells cultured in two-dimensions or three-dimensions spheroids, in conjunction with reduced cell proliferation. Capillary-like tube formation assays using HUVECs showed that PP-13 displayed antiangiogenic properties. It also inhibited cancer cell motility and invasion, in in vitro wound-healing and transwell migration assays. Low concentration PP-13 (130 nmol.L −1) treatment significantly reduced the metastatic invasiveness of human cancer cells engrafts on chicken chorioallantoic membrane. In nude mice, 0.5 or 1 mg.kg −1 PP-13 intraperitoneally administered three-times a week reduced the sizes of paclitaxel-refractory orthotopic breast tumors, delayed the progression of metastasis, and decreased the global metastatic load compared to 0.5 mg.kg −1 paclitaxel or vehicle alone. PP-13 did not show any apparent early adverse effect in vivo. These data suggest that PP-13 is a promising alternative to standard chemotherapy in antimitotic drug-refractory tumors, especially through its impact on metastasis.

Resume Objectifs Etudier le role de l’imagerie de fluorescence proche infrarouge dans la detection et la resection des adenopathies cervicales metastatiques des cancers des VADS. Materiel et methodes Des cellules de cancer des VADS d’origine humaine CAL33 ont ete implantees au niveau de la cavite buccale de la souris nue. Les souris ont ete suivies apres la resection tumorale afin de detecter le developpement de metastases ganglionnaires. Un traceur fluorescent specifique a l’integrine αvβ3 , qui est exprime par les cellules CAL33, a ete injecte en intraveineux chez les souris survivantes entre le deuxieme et le quatrieme mois post-explantation tumorale. Une camera d’imagerie de fluorescence proche infrarouge a permis de detecter la captation du traceur fluorescent au sein des adenopathies cervicales metastatiques et de guider le geste d’exerese des adenopathies qui ont ete par la suite analysees histologiquement. Resultats Des adenopathies metastatiques ont ete observees chez 42,8 % des souris survivantes entre le deuxieme et le quatrieme mois post-explantation des tumeurs orthotopiques. L’imagerie de fluorescence proche infrarouge a permis de detecter en temps reel les adenopathies metastatiques cliniques et infracliniques pendant le geste de l’exerese chirurgicale. Ces resultats ont ete confirmes histologiquement. Conclusion L’imagerie de fluorescence proche infrarouge offre un contraste en temps reel entre le tissu sain et le tissu cancereux, ce qui permet de detecter les adenopathies metastatiques en peroperatoire. Cette etape preclinique est indispensable avant de tester cette technique chez l’etre humain.

International audience; We report in this study the in vivo biodistribution of ultra-small luminescent gold (Au) particles (∼1.5 nm core size; 17 kDa) so-called nanoclusters (NCs) stabilized by bidentate zwitterionic molecules in subcutaneous (s.c.) and orthotopic glioblastoma mice models. Particular investigations on renal clearance and tumor uptake were performed using highly sensitive advanced imaging techniques such as multi-elemental Laser-Induced Breakdown Spectroscopy (LIBS) imaging and In-line X-ray Synchrotron Phase Contrast Tomography (XSPCT). Results show a blood circulation time of 6.5±1.3 min accompanied with an efficient and fast renal clearance through the cortex of the kidney with a 66% drop between 1 h and 5 h. With a similar size range, these Au NCs are 5 times more fluorescent than the well-described NCs Au25GSH18 in the near-infrared (NIR) region and present a significantly stronger tumor uptake and retention illustrated by an in vivo s.c. tumor-to-skin ratio of 1.8 measured by non-invasive optical imaging and an ex vivo tumor-to-muscle of 6.1. This work highlights the pivotal role of the surface coating to design optimum Au NCs candidates for cancer treatment.

Targeting the tumour microenvironment is a promising strategy to detect and/or treat cancer. The design of selective compounds that co-target several receptors frequently overexpressed in solid tumours may allow a reliable and selective detection of tumours. Here we report the modular synthesis of compounds encompassing ligands of αVβ3 integrin and neuropilin-1 that are overexpressed in the tumour microenvironment. These compounds were then evaluated through cellular experiments and imaging of tumours in mice. We observed that the peptide that displays both ligands is more specifically accumulating in the tumours than in controls. Simultaneous interaction with αVβ3 integrin and NRP1 induces NRP1 stabilization at the cell membrane surface which is not observed with the co-injection of the controls.

Targeting the tumour microenvironment is a promising strategy to detect and/or treat cancer. The design of selective compounds that co-target several receptors frequently overexpressed in solid tumours may allow a reliable and selective detection of tumours. Here we report the modular synthesis of compounds encompassing ligands of αVβ3 integrin and neuropilin-1 that are overexpressed in the tumour microenvironment. These compounds were then evaluated through cellular experiments and imaging of tumours in mice. We observed that the peptide that displays both ligands is more specifically accumulating in the tumours than in controls. Simultaneous interaction with αVβ3 integrin and NRP1 induces NRP1 stabilization at the cell membrane surface which is not observed with the co-injection of the controls.

International audience; Angiogenesis strongly depends on the activation of integrins, especially integrin αvβ3, and of neuropilin-1 (NRP-1), a co-receptor of VEGFR2. Dual-targeted molecules that simultaneously block both of them are expected have increased anti-angiogenic and antitumor activity. Toward this goal, we generated bifunctional 40 nm-sized silica nanoparticles (NPs) coated with controlled amounts of cRGD and ATWLPPR peptides and studied their affinity, selectivity and biological activity in HUVECs. Sub-nanomolar concentrations of NPs grafted either with ATWLPPR alone or in combination with cRGD exhibit potent and specific antagonist activity against VEGFR2/AKT signaling. However, a 1 nM concentration of the cRGD/ATWLPPR-heteromultivalent particles (RGD/ATW-NPs) also blocks the phosphorylation of VEGFR2 while co-inducing an unexpected long-lasting activation of AKT via IGF-1R/IR-AKT/GSK3β/eNOS signaling that stimulates cell survival and abrogates the intrinsic toxicity of silica-NPs to serum-starved HUVECs. We also showed that their repeated intravenous administration was associated with the proliferation of human U87MG tumor cells engrafted in nude mice and a dilatation of the tumor blood vessels. We present biochemical evidence for the complex cross-talk generated by the binding of the heteromultivalent NPs with αvβ3-integrin and with NRP1. In particular, we show for the first time that such heteromultivalent NPs can trans-activate IGF-1/insulin receptors and exert dose-dependent pro-survival activity. This study demonstrates the difficulties in designing targeted silica-based NPs for antiangiogenic therapies and the possible risks posed by undesirable side effects.

International audience; Combinations of therapeutic agents could synergistically enhance the response of lung cancer cells. Co-delivery systems capable of transporting chemotherapeutics with different physicochemical properties and with the simultaneous release of drugs remain elusive. Here, we assess the ability of nanoparticles of 30-nm diameter obtained from the self-assembly of hyaluronan-based copolymer targeting CD44 receptors to encapsulate both gefitinib and vorinostat for effective combinational lung cancer treatment. Drug loading was performed by nanoprecipitation. Drug release experiments showed a slow release of both drugs after 5 days. Using two- and three-dimensional lung adenocarcinoma cell cultures, we observed that the nanoparticles were mostly found at the periphery of the CD44-expressing spheroids. These drug-loaded nanoparticles were as cytotoxic as free drugs in the two- and three-dimensional systems and toxicity was due to apoptosis induction. In mouse models, intravenous injection of hyaluronan-based nanoparticles showed a selective delivery to subcutaneous CD44-overexpressing tumors, despite a significant liver capture. In addition, the systemic toxicity of the free drugs was reduced by their co-delivery using the nanoparticles. Finally, intrapulmonary administration of drug-loaded nanoparticles, to avoid a possible hepatic toxicity due to their accumulation in the liver, showed a stronger inhibition of orthotopic lung tumor growth compared to free drugs. In conclusion, hyaluronan-based nanoparticles provide active targeting partially mediated by CD44, less-toxic drug release and improved antitumor efficiency.

Background Appropriate animal models are required to test novel therapeutics for head and neck squamous cell carcinoma (HNSCC) such as near-infrared (NIR) imaging-guided surgery. Methods We developed an optimized animal model of orthotopic HNSCC (in female athymic NMRI (Naval Medical Research Institute) nude mice) with a prolonged survival time. Resection of the orthotopic tumors was performed 30 days after implantation with or without the aid of a miniaturized clinical grade NIR optical imaging device, after systemic administration of a fluorescent RGD-based probe that targets αvβ3 integrin. Results NIR optical imaging-guided surgery increased the recurrence-free survival rate by 50% through the detection of fluorescent cancer residues as small as 185 µm; these fragments could remain unidentified if resection was performed exclusively under unaided visual guidance. Conclusion NIR optical imaging-guided surgery showed an improved HNSCC tumor resection quality in our optimized orthotopic animal model. © 2015 Wiley Periodicals, Inc. Head Neck, 2015

Angiogenesis strongly depends on the activation of integrins, especially integrin α

A new class of "polymultivalent" ligands combining several ligand clusters and a water-soluble biocompatible polymer is introduced. These original conjugates bear two levels of multivalency. They are prepared by covalent coupling of a controlled number of tetrameric cRGD peptide clusters along a well-defined copolymer synthesized by RAFT polymerization. The presence of multiple copies of peptide clusters on the same polymer backbone resulted in a much-higher relative potency than the free cluster reference. Thanks to the "polymultivalency", up to ∼2 orders of magnitude potency enhancement was reached in a competitive cell adhesion assay (nanomolar-range IC

Like several 50nm-large nanocarriers, lipid nanoparticles (LNPs) can passively accumulate in tumors through the Enhanced Permeability and Retention (EPR) effect. In this study, we developed PEGylated LNPs loaded with IR780 iodide as a contrast agent for NIR fluorescence imaging and modified them with cyclic RGD peptides in order to target integrin avβ3. We demonstrate a specific targeting of the receptor with cRGD-LNPs but not with cRAD-LNP and standard LNP using HEK293(β3), HEK293(β3)-αvRFP, DU145 and PC3 cell lines. We also demonstrate that cRGD-LNPs bind to αvβ3, interfere with cell adhesion to vitronectin and co-internalize with αvβ3 within one hour. We then investigated their biodistribution and tumor targeting in mice bearing DU145 or M21 tumors. We observed no significant differences between cRGD-LNP and the non-targeted ones regarding their biodistribution and accumulation/retention in tumors. This suggested that despite an efficient formulation of the cRGD-LNPs, the cRGD-mediated targeting was not increasing the total amount of LNP that can already accumulate passively in the subcutaneous tumors via the EPR effect.

Nanoparticles are useful tools in oncology because of their capacity to passively accumulate in tumors in particular via the enhanced permeability and retention (EPR) effect. However, the importance and reliability of this effect remains controversial and quite often unpredictable. In this preclinical study, we used optical imaging to detect the accumulation of three types of fluorescent nanoparticles in eight different subcutaneous and orthotopic tumor models, and dynamic contrast-enhanced and vessel size index Magnetic Resonance Imaging (MRI) to measure the functional parameters of these tumors. The results demonstrate that the permeability and blood volume fraction determined by MRI are useful parameters for predicting the capacity of a tumor to accumulate nanoparticles. Translated to a clinical situation, this strategy could help anticipate the EPR effect of a particular tumor and thus its accessibility to nanomedicines.

International audience; New approaches that are more efficient and able to specifically reach lung tumors are needed. We developed new hyaluronan-based nanoparticles targeting CD44 receptors of two different sizes and compared their lung cancer cells targeting efficacy in vitro and in vivo. The nanoparticles' cellular uptake was dose-dependent, and specific to hyaluronan receptors, particularly CD44. The binding and internalization differed according to nanoparticle size. In vivo biodistribution studies in two orthotopic lung tumor models showed that intrapulmonary nebulized nanoparticles accumulated in lungs, but not in the tumor nodules. In contrast, despite a significant liver capture, intravenous injection led to a better accumulation of the nanoparticles in the lung tumors compared with the surrounding healthy lung tissues. We demonstrated that the hyaluronan-based nanoparticles size plays significant role in cellular uptake and biodistribution. Small nanoparticles showed active targeting of CD44-overexpressing tumors, suggesting that they could be used as drug-delivery system. From the Clinical Editor: Combating cancers remains an important goal in clinical medicine. In this study, the authors investigated the ability of two hyaluronan-based nanoparticles targeting CD44 receptors to home in on lung cancer cells in an in-vivo orthotropic model. The preferential uptake of smaller sized nanoparticles via intravenous route has further enhanced the existing knowledge of future drug designs

Near-infrared fluorescence image-guided surgery, FIGS, has lately shown a huge potential in oncologic and lymphatic related surgeries. In some indications such as liver or heart surgery, fluorescence-reachable anatomic structures are limited by the access to the surgical field. Nevertheless, most of the systems available on the market are too large to image the sides of cavities. Small devices are clearly required to improve workability of fluorescence imaging systems. The current work describes the evaluation of Fluostick a CE med certified instrument dedicated to narrow area imaging. This small size device is made of an optical head connected to a control box. We tested this instrumentation at the preclinical level for the optical-guided surgery of head and neck tumors.

The miniaturization of fluorescence imaging technologies is the purpose of some studies and prototypes have been developed for specific applications. Head and neck cancers are one of the fields where improvement of the footprint of fluorescence imaging system is really needed. Some other miniaturizations of fluorescence technology projects have been explored, especially for in vivo microscopy applications. Finally, developments for preclinical procedures or clinical studies only have been achieved, but none have yet reached approval. The purpose of this study is to show the development and the first results of a CE-marked miniaturized, handheld, fluorescence image-guided surgery system named Fluostick™.

International audience; Lung cancer is the most common and most fatal cancer worldwide. Thus, improving early diagnosis and therapy is necessary. Previously, gadolinium-based ultra-small rigid platforms (USRPs) were developed to serve as multimodal imaging probes and as radiosensitizing agents. In addition, it was demonstrated that USRPs can be detected in the lungs using ultrashort echo-time magnetic resonance imaging (UTE-MRI) and fluorescence imaging after intrapulmonary administration in healthy animals. The goal of the present study is to evaluate their theranostic properties in mice with bioluminescent orthotopic lung cancer, after intrapulmonary nebulization or conventional intravenous administration. It is found that lung tumors can be detected non-invasively using fluorescence tomography or UTE-MRI after nebulization of USRPs, and this is confirmed by histological analysis of the lung sections. The deposition of USRPs around the tumor nodules is sufficient to generate a radiosensitizing effect when the mice are subjected to a single dose of 10 Gy conventional radiation one day after inhalation (mean survival time of 112 days versus 77 days for irradiated mice without USRPs treatment). No apparent systemic toxicity or induction of inflammation is observed. These results demonstrate the theranostic properties of USRPs for the multimodal detection of lung tumors and improved radiotherapy after nebulization.

Appropriate animal models are required to test novel therapeutics for head and neck squamous cell carcinoma (HNSCC) such as near-infrared (NIR) imaging-guided surgery.We developed an optimized animal model of orthotopic HNSCC (in female athymic NMRI (Naval Medical Research Institute) nude mice) with a prolonged survival time. Resection of the orthotopic tumors was performed 30 days after implantation with or without the aid of a miniaturized clinical grade NIR optical imaging device, after systemic administration of a fluorescent RGD-based probe that targets αv β3 integrin.NIR optical imaging-guided surgery increased the recurrence-free survival rate by 50% through the detection of fluorescent cancer residues as small as 185 µm; these fragments could remain unidentified if resection was performed exclusively under unaided visual guidance.NIR optical imaging-guided surgery showed an improved HNSCC tumor resection quality in our optimized orthotopic animal model. © 2015 Wiley Periodicals, Inc. Head Neck 38: E246-E255, 2016.

Introduction Lung cancer is the leading cause of mortality by cancer in the world. There is an urgent need to propose new therapeutic approaches in addition to conventional therapy. To be efficient and to decrease side effects, treatments must specifically reach tumors. In this context, this work aims to develop a new nanocarrier, able to target tumors and to measure its benefit in cancer therapy. The nanoparticles (Np) we used here combine a biodegradable polypeptide, and the Hyaluronan (Hya), the natural ligand of the CD44 receptors upregulated on cancer cells. Methods The ability of Hya fragments with different molecular weights (5000 and 35000 Da), or Np with different sizes (30 and 300 nm), to target the CD44 receptors was studied in vitro using lung cancer cell lines (H358, H460, A549, H322), in which CD44 expression level was measured. We investigated Hya and Np accumulation in tumor in vivo using an orthotopic lung cancer model, after administration by systemic route (IV injections) or pulmonary route (nebulization). We also analysed the accumulation of an anti-CD44 antibody in vivo. Noninvasive optical imaging techniques (2D and 3D fluorescence) allowed the real-time follow-up of the Np in mice. Results Binding of Hya fragments on cell lines was dose-dependent, with a higher affinity for the low molecular weight Hya. Np bound lung cancer cells and were internalized at 37 °C. This interaction was partially dependent to CD44 expression level. In vivo, we observed a better accumulation of the anti-CD44 antibody administered by nebulization, in tumor-bearing mice, compared to healthy mice. In contrast, no specific accumulation of Hya or Np was observed in tumors after nebulization. The nebulized Np showed long time retention in lungs. We observed a higher accumulation of Np, but not Hya, in the lungs of tumor-bearing mice compared to healthy mice, after IV injection. Conclusions We show that CD44 receptor is a pertinent target for lung cancer treatment. Despite the promising results obtained after anti-CD44 antibody nebulization, this way of administration seems less efficient to target tumor with Np. Our results will allow us to select the best Np formulation to load anticancer drugs. We will then evaluate the potential antitumor activity of drug-loaded Np using lung cancer model in mice.