Vascular-Targeted Photodynamic Therapy (VTP)

International audienc

Identifiability and sensitivity analysis of a Photodynamic Therapy model

International audiencePhotodynamic therapy (PDT) is an alternative treatment for cancer that involves the administration of a photosensitizing agent, which is activated by light at a specific wavelength. The photo-toxic phase of this therapy can be described by a dynamic model composed of six nonlinear differential equations. The model parameters can be used to compare photosensitizing agents in their capability to produce cytotoxic species. The practical issue is their estimation from in vivo experimental data. In this paper, a new approach is proposed to analyze the photophysical parameters estimability through a local practical identifiability study combined with a global sensitivity analysis. Results show that only three parameters can reasonably be estimated in a given and realistic experimental framework. Input design (light signal) and model reduction are currently in progress

Bcl-2/Bax protein ratio predicts 5-fluorouracil sensitivity independently of p53 status

p53 tumour-suppressor gene is involved in cell growth control, arrest and apoptosis. Nevertheless cell cycle arrest and apoptosis induction can be observed in p53-defective cells after exposure to DNA-damaging agents such as 5-fluorouracil (5-FU) suggesting the importance of alternative pathways via p53-independent mechanisms. In order to establish relationship between p53 status, cell cycle arrest, Bcl-2/Bax regulation and 5-FU sensitivity, we examined p53 mRNA and protein expression and p53 protein functionality in wild-type (wt) and mutant (mt) p53 cell lines. p53 mRNA and p53 protein expression were determined before and after exposure to equitoxic 5-FU concentration in six human carcinoma cell lines differing in p53 status and displaying marked differences in 5-FU sensitivity, with IC 50 values ranging from 0.2–22.6 mM. 5-FU induced a rise in p53 mRNA expression in mt p53 cell lines and in human papilloma virus positive wt p53 cell line, whereas significant decrease in p53 mRNA expression was found in wt p53 cell line. Whatever p53 status, 5-FU altered p53 transcriptional and translational regulation leading to up-regulation of p53 protein. In relation with p53 functionality, but independently of p53 mutational status, after exposure to 5-FU equitoxic concentration, all cell lines were able to arrest in G1. No relationship was evidenced between G1 accumulation ability and 5-FU sensitivity. Moreover, after 5-FU exposure, Bax and Bcl-2 proteins regulation was under p53 protein control and a statistically significant relationship (r= 0.880,P= 0.0097) was observed between Bcl-2/Bax ratio and 5-FU sensitivity. In conclusion, whatever p53 status, Bcl-2 or Bax induction and Bcl-2/Bax protein ratio were correlated to 5-FU sensitivity. © 2000 Cancer Research Campaig

Limits of variance-based sensitivity analysis for non- identifiability testing in high dimensional dynamic models

International audienceIn systems biology, a common approach to model biological processes is to use large systems of nonlinear differential equations. The associated parameter estimation problem then requires a prior handling of the global identifiability question in a realistic experimental framework. The lack of a method able to solve this issue has indirectly encouraged the use of global sensitivity analysis to select the subset of parameters to estimate. Nevertheless, the links between these two global analyses are not yet fully explored. The present work reveals new bridges between sensitivity analyses and global non-identifiability, through the use of functions derived from the Sobol' high dimensional representation of the model output. We particularly specify limits of variance-based sensitivity tools to completely conclude on global non-identifiability of parameters in a given experimental context

Carbohydrate-based peptidomimetics targeting neuropilin-1: synthesis, molecular docking study and in vitro biological activities

International audienceNeuropilin-1 (NRP-1), a transmembrane glycoprotein acting as a co-receptor of VEGF-A, is expressed by cancer and angiogenic endothelial cells and is involved in the angiogenesis process. Taking advantage of functionalities and stereodiversities of sugar derivatives, the design and the synthesis of carbohydrate based peptidomimetics are here described. One of these compounds (56) demonstrated inhibition of VEGF-A165 binding to NRP-1 (IC50 = 39 μM) and specificity for NRP-1 over VEGF-R2. Biological evaluations were performed on human umbilical vein endothelial cells (HUVECs) through activation of downstream proteins (AKT and ERK phosphorylation), viability/proliferation assays and in vitro measurements of anti-angiogenic abilities

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

Identification of Pharmacokinetics Models in the presence of Timing Noise

International audienceThe problem addressed in this paper deals with the parameter estimation of in vitro uptake kinetics of drugs into living cells in presence of timing noise. Effects of the timing noise on the bias and variance of the output error are explicitly determined. A bounded-error parameter estimation approach is proposed as a suited solution to handle this problem. Application results are presented which emphasize the effectiveness of the methodology in such an experimental framework