System identification of the intrabrain tumoral uptake of multifunctional nanoparticles

International audienceRecent developments on multifunctional nano-systems have opened new perspectives for tumor control by proposing new nano-actuators and nano-sensors in in vivo anti-cancer treatments. But the delivery control of these nano-agents into the cancer cells is one of the major factors that directly affect the efficiency of nanotherapies. In this study, we show that system identification methods (CONTSID Matlab toolbox), generally used in control engineering, can bring efficient solutions to help biologists to estimate crucial parameters of the nanoparticles pharmacokinetics from experimental data. The in vivo results presented herein clearly emphasize the relevance of these data-driven modeling approaches associated with magnetic resonance imaging

Phenomenological modeling of tumor diameter growth based on a mixed effects model

International audienceOver the last few years, taking advantage of the linear growth of diameter kinetics, tumor diameter-based rather than tumor volume-based models have been developed for the phenomenological modeling of tumor growth. In this study, we propose a new tumor diameter growth function composed of two linear parts and one exponential term to characterize early, late and steady-state treatment effects. Model parameters consist of growth rates, growth delays and time constants and are meaningful for biologists. Biological experiments provide in vivo longitudinal data. The latter are analyzed using a mixed effects model based on the new diameter growth function, to take into account inter-mouse variability and treatment factors. The relevance of the tumor growth mixed model is firstly assessed by analyzing the effects of three therapeutic strategies for cancer treatment (radiotherapy, concomitant radiochemotherapy and photodynamic therapy) administered on mice. Then, effects of the radiochemotherapy treatment duration are estimated within the mixed model. The results highlight the model suitability for analyzing therapeutic efficiency, comparing treatment responses and optimizing, when used in combination with optimal experiment design, anti-cancer treatment modalities

Contributions of experiment designs in photodynamic therapy: photosensitizer design, treatment analysis and optimization.

Abstract published in Photodiagnosis and Photodynamic Therapy, 8(2):137, 2011International audienceIntroduction One of the difficulties in the development of the photodynamic therapy (PDT) is inherent to the multidisciplinary feature of this treatment gathering mainly clinicians, physicists, biologists, and chemists. Another issue is the great number of biophysical and biochemical parameters involved in the design of new photosensitizers as well as in the in vivo application of this treatment. We present a global development approach based on the methodology and tools of experimental design. Three study cases are developed to assess to potential relevance of such an empirical model-based approach for the development of PDT. Methods & Results In a first study, an in vitro screening experimental design was carried out. The addressed question dealt with the determination of influent factors on the phototoxicity of a new photosensitizer based on quantum dots. Five factors were examined: the nature of quantum dots, the excitation light wavelength, the incubation time with cells, the photoactivable compound concentration and the fluence level. Relevance of each factor was finally estimated and compared to identify the significant parameters. In comparison with a typical factorial design, the total number of experiments (42 trials) was divided by 5. In a second study, an in vivo factorial experimental design was applied to detect potential synergic effects between four therapeutic factors: the phenotype of the cancer cell line, the food type, the nature of photosensitizer and the post-injection time, on the in vivo selectivity (cancer/normal tissue) of the tested photosensitizers. Results particularly pointed out the presence of a statistically significant synergic effect between these four factors and provided the optimal modalities to maximize the response in term of tumor-to-normal tissue ratio. In a third study, a Doehlert experimental design associated with a response surface model was used to determine the in vivo PDT modalities (photosensitizer concentration, irradiance and fluence) to both minimize the post-treatment growth rate of the tumor and maximize its growth delay. Only 13 experimental conditions were tested and the relevance of the optimized condition was corroborated by in vivo validation experiments. Conclusion These studies have confirmed the applicability and attractive contributions of experimental design techniques in the development and determination of optimal modalities of new photosensitizers in PDT. Their main advantages are to a priori organize experiments according to specific questions while minimizing the experimental cost and controlling as much as possible the experimental uncertainty

Specific detection of methionine 27 mutation in histone 3 variants (H3K27M) in fixed tissue from high-grade astrocytomas

Studies in pediatric high-grade astrocytomas (HGA) by our group and others have uncovered recurrent somatic mutations affecting highly conserved residues in histone 3 (H3) variants. One of these mutations leads to analogous p.Lys27Met (K27M) mutations in both H3.3 and H3.1 variants, is associated with rapid fatal outcome, and occurs specifically in HGA of the midline in children and young adults. This includes diffuse intrinsic pontine gliomas (80 %) and thalamic or spinal HGA (>90 %), which are surgically challenging locations with often limited tumor material available and critical need for specific histopathological markers. Here, we analyzed formalin-fixed paraffin-embedded tissues from 143 pediatric HGA and 297 other primary brain tumors or normal brain. Immunohistochemical staining for H3K27M was compared to tumor genotype, and also compared to H3 tri-methylated lysine 27 (H3K27me3) staining, previously shown to be drastically decreased in samples carrying this mutation. There was a 100 % concordance between genotype and immunohistochemical analysis of H3K27M in tumor samples. Mutant H3K27M was expressed in the majority of tumor cells, indicating limited intra-tumor heterogeneity for this specific mutation within the limits of our dataset. Both H3.1 and H3.3K27M mutants were recognized by this antibody while non-neoplastic elements, such as endothelial and vascular smooth muscle cells or lymphocytes, did not stain. H3K27me3 immunoreactivity was largely mutually exclusive with H3K27M positivity. These results demonstrate that mutant H3K27M can be specifically identified with high specificity and sensitivity using an H3K27M antibody and immunohistochemistry. Use of this antibody in the clinical setting will prove very useful for diagnosis, especially in the context of small biopsies in challenging midline tumors and will help orient care in the context of the extremely poor prognosis associated with this mutation. Electronic supplementary material The online version of this article (doi:10.1007/s00401-014-1337-4) contains supplementary material, which is available to authorized users

Thérapie photodynamique vasculaire intersticielle stéréotaxique de tumeurs cérébrales : intérêt des nanoparticules multifonctionnelles ciblant la neuropiline-1

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Vascular interstitial stereotaxic photodynamic treatment of cerebral tumors guided by imaging : Interest of multifunctional nanoparticles targeting neuropilin-1

La thérapie photodynamique (PDT) appliquée aux tumeurs cérébrales est évaluée comme une stratégie complémentaire par rapport aux thérapies conventionnelles. De nombreux travaux mettent en exergue le rôle prépondérant joué par l'effet vasculaire de la PDT dans l'éradication tumorale. Ainsi, une accumulation sélective du photosensibilisateur au niveau des néo-vaisseaux tumoraux favorise cet effet et donc, l'efficacité du traitement photodynamique. La stratégie vasculaire consistant à coupler un photosensibilisateur à un peptide ligand pour cibler le récepteur neuropiline-1 (NRP-1) surexprimé par les cellules endothéliales angiogéniques a été validée, démontrant également l'induction de l'expression du facteur tissulaire immédiatement après PDT. Grâce à l'utilisation de nanoparticules multifonctionnelles, des améliorations ont été apportées à la stratégie initiale pour une PDT interstitielle (iPDT) guidée par l'imagerie. Fonctionnalisées par le peptide ligand, vecteur du photosensibilisateur et d'un agent de contraste puis rendues furtives, les nanoparticules sélectionnées présentent les propriétés originales requises pour une action combinée en IRM et PDT ciblée. Les nano-objets sont affins pour NRP-1 et conservent leur caractéristique photo-activable. Les essais sur rats nude xénogreffés en orthotopique par un modèle de gliome malin humain, valident la faisabilité du concept de iPDT guidée par l'IRM en temps réel. Après injection des nanoparticules par voie intraveineuse, un rehaussement positif du signal IRM est observé au niveau de la zone tumorale pour optimiser l'implantation de la fibre optique. Les résultats obtenus par IRM de perfusion et, l'expression protéique de NRP-1 au niveau du tissu et des berges tumorales, valident la sélectivité des nanoparticules fonctionnalisées. La combinaison des techniques d'imagerie non-invasives (IRM, SRM, TEP/CT) a permis le suivi thérapeutiquePhotodynamic therapy (PDT) for brain tumors appears to be complementary to conventional treatments. Number studies show the major role of the vascular effect in the tumor eradication by PDT. To promote this vascular effect, a selective targeting of neuropilin-1 (NRP-1), mainly over-expressed by tumor angiogenic vessels, was investigated using a photosensitizer coupled to a ligand peptide. We validated the interest of using this active-targeting strategy to promote this vascular effect by the induction of tissue factor expression immediately post-PDT. For interstitial PDT (iPDT) of brain tumors guided by real-time imaging, multifunctional nanoparticles consisting of a surface-localized tumor vasculature targeting NRP-1 and encapsulated PDT and imaging agents, have been developed. The selected nanoparticles are favourable to a photosensitizer targeting strategy for iPDT combined with MRI.Characterization studies of the nanoparticles reveal a photodynamic efficiency and demonstrate a molecular affinity of the functionalized nanoparticle to NRP-1 target. After intravenous injection of the multifunctional nanoparticles into rats with intracranial glioma, we demonstrate a positive contrast enhancement of the tumor tissue by MRI, allowing the optimization of the optical fiber implantation. Perfusion MRI data and NRP-1 protein expression of the tumor and brain adjacent to tumor tissues check selectivity of the functionalized nanoparticle. The combination of non-invasive techniques of imaging (MRI, MRS, PET/CT) validates this concept of iPDT guided by MR

Traitement photodynamique interstitiel vasculaire stéréotaxique des tumeurs cérébrales guidé par imagerie (intérêt des nanoparticules multifonctionnelles ciblant neuropiline-1)

La thérapie photodynamique (PDT) appliquée aux tumeurs cérébrales est évaluée comme une stratégie complémentaire par rapport aux thérapies conventionnelles. De nombreux travaux mettent en exergue le rôle prépondérant joué par l'effet vasculaire de la PDT dans l'éradication tumorale. Ainsi, une accumulation sélective du photosensibilisateur au niveau des néo-vaisseaux tumoraux favorise cet effet et donc, l'efficacité du traitement photodynamique. La stratégie vasculaire consistant à coupler un photosensibilisateur à un peptide ligand pour cibler le récepteur neuropiline-1 (NRP-1) surexprimé par les cellules endothéliales angiogéniques a été validée, démontrant également l'induction de l'expression du facteur tissulaire immédiatement après PDT. Grâce à l'utilisation de nanoparticules multifonctionnelles, des améliorations ont été apportées à la stratégie initiale pour une PDT interstitielle (iPDT) guidée par l'imagerie. Fonctionnalisées par le peptide ligand, vecteur du photosensibilisateur et d'un agent de contraste puis rendues furtives, les nanoparticules sélectionnées présentent les propriétés originales requises pour une action combinée en IRM et PDT ciblée. Les nano-objets sont affins pour NRP-1 et conservent leur caractéristique photo-activable. Les essais sur rats nude xénogreffés en orthotopique par un modèle de gliome malin humain, valident la faisabilité du concept de iPDT guidée par l'IRM en temps réel. Après injection des nanoparticules par voie intraveineuse, un rehaussement positif du signal IRM est observé au niveau de la zone tumorale pour optimiser l'implantation de la fibre optique. Les résultats obtenus par IRM de perfusion et, l'expression protéique de NRP-1 au niveau du tissu et des berges tumorales, valident la sélectivité des nanoparticules fonctionnalisées. La combinaison des techniques d'imagerie non-invasives (IRM, SRM, TEP/CT) a permis le suivi thérapeutiquePhotodynamic therapy (PDT) for brain tumors appears to be complementary to conventional treatments. Number studies show the major role of the vascular effect in the tumor eradication by PDT. To promote this vascular effect, a selective targeting of neuropilin-1 (NRP-1), mainly over-expressed by tumor angiogenic vessels, was investigated using a photosensitizer coupled to a ligand peptide. We validated the interest of using this active-targeting strategy to promote this vascular effect by the induction of tissue factor expression immediately post-PDT. For interstitial PDT (iPDT) of brain tumors guided by real-time imaging, multifunctional nanoparticles consisting of a surface-localized tumor vasculature targeting NRP-1 and encapsulated PDT and imaging agents, have been developed. The selected nanoparticles are favourable to a photosensitizer targeting strategy for iPDT combined with MRI.Characterization studies of the nanoparticles reveal a photodynamic efficiency and demonstrate a molecular affinity of the functionalized nanoparticle to NRP-1 target. After intravenous injection of the multifunctional nanoparticles into rats with intracranial glioma, we demonstrate a positive contrast enhancement of the tumor tissue by MRI, allowing the optimization of the optical fiber implantation. Perfusion MRI data and NRP-1 protein expression of the tumor and brain adjacent to tumor tissues check selectivity of the functionalized nanoparticle. The combination of non-invasive techniques of imaging (MRI, MRS, PET/CT) validates this concept of iPDT guided by MRINANCY1-Bib. numérique (543959902) / SudocSudocFranceF

Cranial anchor

The invention relates to a cranial anchor comprising a plate (100) with a plurality of fixation holes (131, 132, 133), a cannula (110) protruding from an upper face of the plate, and a clip (115) for preliminary positioning that protrudes from a bottom face of the plate, with a hollow guide tube (120) being drilled through the cannula and the plate in order to permit the passage of a probe. Application to the field of the neurosciences, for example to the measurement of intracranial physiological parameters, to intracranial treatment by therapy, etc. (FR)L'invention concerne une ancre crânienne comprenant un plateau (100) présentant plusieurs trous de fixation (131, 132, 133), une canule (1 10) faisant saillie depuis une face supérieure du plateau et un clip (1 15) de prépositionnement faisant saillie depuis une face de dessous du plateau, la canule et le plateau étant percés d'un tube (120) creux de guidage permettant le passage d'une sonde. Application au domaine des neurosciences, par exemple à la mesure de paramètres physiologiques incracrâniens, au traitement thérapeutique intracrânien, et

Pharmacokinetic modeling of nanoparticles-based PS vectors into glioblastoma from MRI imaging in PDT

International audienceRecent developments on multifunctional nano-systems have opened new perspectives for tumor control by proposing new nano-actuators and nano-sensors in in vivo anti-cancer treatments. One of these challenging perspectives is the use of nanoparticles as vector to deliver the right dose of PS (Photosensitizer agent) into the tumor. But the delivery control of these nano-agents into the cancer cells is one of the major factors that directly affect the efficiency of the photodynamic therapy. Several previous works have already shown that the intracellular uptake could not be predicted from the nano-object chemical properties. In 2004, the FDA's Critical Path Report proposed, among other solutions, the increased use of model-based approaches to drug development, including pharmacokinetic and pharmacodynamic (PK/PD) modeling. In this study, we propose a non-supervised estimation method, developed to estimate the pharmacokinetic parameters of two multifunctional nanoparticles involved in photodynamic therapy. We show that continuous-time model identification methods (available in the CONTSID toolbox for Matlab), generally used in control engineering, can bring efficient solutions to help biologists to estimate crucial parameters of the nanoparticles pharmacokinetics from experimental data. The in vivo results presented clearly emphasize the relevance of these data-driven modeling approaches associated with magnetic resonance imaging