Thierry Bastogne

Improvement of meta-tetra(Hydroxyphenyl)chlorin-Like Photosensitizer Selectivity with Folate-Based Targeted Delivery. Synthesis and in Vivo Delivery Studies

The cell membrane folate receptor (FR) is a molecular target for tumor-selective drug delivery, including delivery of photosensitizers for anticancer photodynamic therapy (PDT). Tumor selectivity of meta-tetra(hydroxyphenyl)chlorin ( m-THPC), a photosensitizer used in PDT clinical trials, demonstrates a low tumor-to-normal epithelial uptake ratio. We report on the synthesis and on the photophysical properties of a m-THPC-like photosensitizer 1 conjugated to folic acid (compound 8). A comparative study of the accumulation of photosensitizers 1 and 8 is described. Nude mice were xenografted with FR-alpha-positive KB or HT-29 cells lacking FR-alpha as a negative control. Using optical fiber fluorimetry, we demonstrated that conjugate 8 exhibited enhanced accumulation in KB tumors compared to 1 4 h after injection. No significant difference between KB and HT-29 tumors was observed in case of compound 1. Tumor-to-normal tissue ratio exhibited a very interesting selectivity for conjugate 8 (5:1) in KB tumors 4 h postinjection.

Nanoparticles for radiation therapy enhancement: the key parameters

This review focuses on the radiosensitization strategies that use high-Z nanoparticles. It does not establish an exhaustive list of the works in this field but rather propose constructive criticisms pointing out critical factors that could improve the nano-radiation therapy. Whereas most reviews show the chemists and/or biologists points of view, the present analysis is also seen through the prism of the medical physicist. In particular, we described and evaluated the influence of X-rays energy spectra using a numerical analysis. We observed a lack of standardization in preclinical studies that could partially explain the low number of translation to clinical applications for this innovative therapeutic strategy. Pointing out the critical parameters of high-Z nanoparticles radiosensitization, this review is expected to contribute to a larger preclinical and clinical development.

A PMF-based subspace method for continuous-time model identification. Application to a multivariable winding process

This paper presents a methodology for system identification of continuous-time state-space models from finite sampled input-output signals. The estimation problem of the consecutive time-derivatives and integrals of the input-output signals is considered. The appropriate frequency characteristcs of a linear filtering based on the Poisson moment functionals in regards to the derivative or integral estimation problem is shown. The proposed method combines therefore the Poisson moment functionals technique with subspace based state-space system identification methods. The developed algorithm is based on a generalized singular value decomposition to compensate the noise colouring caused by the linear prefiltering of the input-output data. Rules of thumb are presented to choose the design parameters and new regards to the selection of the Poisson filter cut-off frequency are introduced. Finally, the proposed method is applied to a multivariable winding processes. The experimental results emphasize the applicability of the developed methodology.

Multifunctional Peptide-Conjugated Hybrid Silica Nanoparticles for Photodynamic Therapy and MRI

Photodynamic therapy (PDT) is an emerging theranostic modality for various cancer as well as non-cancer diseases. Its efficiency is mainly based on a selective accumulation of PDT and imaging agents in tumor tissue. The vascular effect is widely accepted to play a major role in tumor eradication by PDT. To promote this vascular effect, we previously demonstrated the interest of using an active- targeting strategy targeting neuropilin-1 (NRP-1), mainly over-expressed by tumor angiogenic vessels. For an integrated vascular-targeted PDT with magnetic resonance imaging (MRI) of cancer, we developed multifunctional gadolinium-based nanoparticles consisting of a surface-localized tumor vasculature targeting NRP-1 peptide and polysiloxane nanoparticles with gadolinium chelated by DOTA derivatives on the surface and a chlorin as photosensitizer. The nanoparticles were surface-functionalized with hydrophilic DOTA chelates and also used as a scaffold for the targeting peptide grafting. In vitro investigations demonstrated the ability of multifunctional nanoparticles to preserve the photophysical properties of the encapsulated photosensitizer and to confer photosensitivity to MDA-MB-231 cancer cells related to photosensitizer concentration and light dose. Using binding test, we revealed the ability of peptide-functionalized nanoparticles to target NRP-1 recombinant protein. Importantly, after intravenous injection of the multifunctional nanoparticles in rats bearing intracranial U87 glioblastoma, a positive MRI contrast enhancement was specifically observed in tumor tissue. Real-time MRI analysis revealed the ability of the targeting peptide to confer specific intratumoral retention of the multifunctional nanoparticles.

Multivariable identification of a winding process by subspace methods for tension control

Abstract The challenging problem of multivariable tension control in winding systems is addressed in this paper. Two control configurations, the SS model and the ST model configurations (SS: speed-speed and ST: speed-torque), are considered and applied to a pilot winding plant. The relevance of using linear models in such multivariable systems is examined. Tension simulations based on a proposed linear ST model yield interesting results in both open and closed-loops. Emphasis is also laid on the applicability of subspace methods to winding tension state-space model identification. Such methods simplify the problem of multivariable identification by reducing the associated polynomial model structural identification to the easier problem of order estimation. It is shown that the design of a Linear Quadratic Gaussian (LQG) controller capable of ensuring efficient performance over the entire winding zone can be based on an ‘average’ state-space model identified around a nominal operating point.

Systems biology approach for in vivo photodynamic therapy optimization of ruthenium-porphyrin compounds

Two arene ruthenium porphyrin compounds showing interesting photodynamic activity in vitro, [Ru(η(6)-p-Pr(i)C(6)H(4)Me)(PMP)Cl(2)] (PMP=5-(3-pyridyl)-10,15,20-triphenylporphyrin) and [Ru(4)(η(6)-p-Pr(i)C(6)H(4)Me)(4)(PTP)Cl8] (PTP=5,10,15,20-tetra(3-pyridyl)porphyrin) coined Rut1 and Rut4 respectively, have been evaluated in vivo. Porphyrins alone and the arene ruthenium porphyrin derivatives (Rut1 and Rut4) showed comparable spectroscopic and photophysical properties. The in vivo study consisted in selecting the optimal arene ruthenium porphyrin photosensitizer by using an original experimental design approach on mice bearing an ectopic human oral carcinoma xenograft. The model of experimental design demonstrated to be well suited to the empirical model-building of photodynamic therapy (PDT) response. Arene ruthenium porphyrins concentration and fluence level demonstrated no statistically significant influence on the tumor growth. On the contrary, the presence of ruthenium groups improved the in vivo photodynamic efficiency. By optical fiber fluorimetry, we demonstrated that both compounds exhibited enhanced accumulation in KB tumors from 24h to 96 h post-intravenous injection. These experiments were completed by inductively coupled plasma mass spectrometry quantification of ruthenium in different organs including tumor tissue. Despite a statistically significant in vivo photodynamic efficiency for Rut4, cellular localization in human oral carcinoma KB cells using fluorescence microscopy demonstrated that both conjugates Rut1 and Rut4 accumulated only in cytoplasm of KB cells but not in the nucleus.

Response surface methodology: an extensive potential to optimize in vivo photodynamic therapy conditions.

PURPOSE Photodynamic therapy (PDT) is based on the interaction of a photosensitizing (PS) agent, light, and oxygen. Few new PS agents are being developed to the in vivo stage, partly because of the difficulty in finding the right treatment conditions. Response surface methodology, an empirical modeling approach based on data resulting from a set of designed experiments, was suggested as a rational solution with which to select in vivo PDT conditions by using a new peptide-conjugated PS targeting agent, neuropilin-1. METHODS AND MATERIALS A Doehlert experimental design was selected to model effects and interactions of the PS dose, fluence, and fluence rate on the growth of U87 human malignant glioma cell xenografts in nude mice, using a fixed drug-light interval. All experimental results were computed by Nemrod-W software and Matlab. RESULTS Intrinsic diameter growth rate, a tumor growth parameter independent of the initial volume of the tumor, was selected as the response variable and was compared to tumor growth delay and relative tumor volumes. With only 13 experimental conditions tested, an optimal PDT condition was selected (PS agent dose, 2.80 mg/kg; fluence, 120 J/cm(2); fluence rate, 85 mW/cm(2)). Treatment of glioma-bearing mice with the peptide-conjugated PS agent, followed by the optimized PDT condition showed a statistically significant improvement in delaying tumor growth compared with animals who received the PDT with the nonconjugated PS agent. CONCLUSIONS Response surface methodology appears to be a useful experimental approach for rapid testing of different treatment conditions and determination of optimal values of PDT factors for any PS agent.

The CONTSID Toolbox: A Software Support for Data-based Continuous-time Modelling

This chapter describes the continuous-time system identification (CONTSID) toolbox for MATLAB®, which supports continuous-time (CT) transfer function and state-space model identification directly from regularly or irregularly time-domain sampled data, without requiring the determination of a discrete-time (DT) model. The motivation for developing the CONTSID toolbox was first to fill in a gap, since no software support was available to serve the cause of direct time-domain identification of continuous-time linear models but also to provide the potential user with a platform for testing and evaluating these data-based modelling techniques. The CONTSID toolbox was first released in 1999 [15]. It has gone through several updates, some of which have been reported at recent symposia [11, 12, 16]. The key features of the CONTSID toolbox can be summarised as follows: it supports most of the time-domain methods developed over the last thirty years [17] for identifying linear dynamic continuous-time parametric models from measured input/output sampled data; it provides transfer function and state-space model identification methods for single-input single-output (SISO) and multiple-input multiple-output (MIMO) systems, including both traditional and more recent approaches; it can handle irregularly sampled data in a straightforward way; it may be seen as an add-on to the system identification (SID) toolbox for MATLAB® [26]. To facilitate its use, it has been given a similar setup to the SID toolbox; it provides a flexible graphical user interface (GUI) that lets the user analyse the experimental data, identify and evaluate models in an easy way.

Neuropilin-1 Targeting Photosensitization-Induced Early Stages of Thrombosis via Tissue Factor Release

PurposeThis article characterizes the vascular effects following vascular-targeted photodynamic therapy with a photosensitizer which actively targets endothelial cells.MethodsThis strategy was considered by coupling a chlorin to a heptapeptide targeting neuropilin-1 in human malignant glioma-bearing nude mice. A laser Doppler microvascular perfusion monitor was used to monitor microvascular blood perfusion in tumor tissue. Endothelial cells’ ultra structural integrity was observed by transmission electron microscopy. The consequences of photosensitization on tumor vessels, tissue factor expression, fibrinogen consumption, and thrombogenic effects were studied by immunohistochemical staining.ResultsTreatment of glioma-bearing mice with the conjugate showed a statistically significant tumor growth delay. Vascular effect was characterized by a decrease in tumor tissue blood flow at about 50% baseline during treatment not related to variations in temperature. This vascular shutdown was mediated by tumor blood vessels’ congestion. A pro-thrombotic behavior of targeted endothelial cells in the absence of ultra structural changes led to the induction of tissue factor expression from the earliest times post-treatment. Expression of tissue factor-initiated thrombi formation was also related to an increase in fibrinogen consumption.ConclusionUsing a peptide-conjugated photosensitizer targeting neuropilin-1, induction of tissue factor expression immediately post-treatment, led to the establishment of thrombogenic effects within the vessel lumen.

Identification of a Managed River Reach by a Bayesian Approach

This paper considers the problem of identification, and more particularly of time-delay estimation, of a river reach managed to produce hydroelectric power. Difficulties lie in the obligation to use data collected during a combined feedback/feedforward control carried out by a human operator. We propose a Bayesian identification method, non-supervised and simple to implement, estimating jointly the time-delay and a finite-impulse response (FIR). It is based on the detection of an abrupt change in the FIR at a time equal to the time-delay. Experimental results show the effectiveness of the proposed method to estimate the river reach time-delay from data collected in imposed experimental conditions.