Valérie Jouan-Hureaux

Monte Carlo simulations guided by imaging to predict the in vitro ranking of radiosensitizing nanoparticles

This article addresses the in silico–in vitro prediction issue of organometallic nanoparticles (NPs)-based radiosensitization enhancement. The goal was to carry out computational experiments to quickly identify efficient nanostructures and then to preferentially select the most promising ones for the subsequent in vivo studies. To this aim, this interdisciplinary article introduces a new theoretical Monte Carlo computational ranking method and tests it using 3 different organometallic NPs in terms of size and composition. While the ranking predicted in a classical theoretical scenario did not fit the reference results at all, in contrast, we showed for the first time how our accelerated in silico virtual screening method, based on basic in vitro experimental data (which takes into account the NPs cell biodistribution), was able to predict a relevant ranking in accordance with in vitro clonogenic efficiency. This corroborates the pertinence of such a prior ranking method that could speed up the preclinical development of NPs in radiation therapy.

Titania and silica nanoparticles coupled to Chlorin e6 for anti-cancer photodynamic therapy

In this study, light-sensitive photosensitizers (Chlorin e6, Ce6) were linked to TiO2 and SiO2 nanoparticles (NPs) in order to develop new kinds of NP-based drug delivery systems for cancer treatment by PDT. TiO2 or SiO2 NPs were modified either by the growth of a polysiloxane layer constituted of two silane reagents ((3-aminopropyl)triethoxysilane (APTES) and tetraethyl orthosilicate (TEOS)) around the core (PEGylated NPs: TiO2@4Si-Ce6-PEG, SiO2@4Si-Ce6-PEG) or simply modified by APTES alone (APTES-modified NPs: TiO2-APTES-Ce6, SiO2-APTES-Ce6). Ce6 was covalently attached onto the modified TiO2 and SiO2 NPs via an amide bond. The absorption profile of the hybridized NPs was extended to the visible region of the light. The physicochemical properties of these NPs were explored by TEM, HR-TEM, XRD, FTIR and zeta potential. The photophysical characteristics including the light absorption, the fluorescence properties and the production reactive oxygen species (1O2 and HO) were also addressed. In vitro experiments on glioblastoma U87 cells were performed to evaluate the photodynamic efficiency of the new hybridized NPs. The cells were exposed to different concentrations of NPs and illuminated (λexc = 652 nm, fluence rate 10 J/cm2). In contrast to the PEGylated NPs, the APTES-modified nanosystems were found to be more efficient for PDT. An interesting photodynamic effect was observed in the case of TiO2-APTES-Ce6 NPs. After illumination, the viability of U87 was decreased by 89% when they were exposed to 200 μg/mL of TiO2-APTES-Ce6 NPs, which corresponds to 0.22 μM of Ce6. The same effect can be obtained with free photosensitizer but using a higher concentration of 10 μM of Ce6.

PDTeam's project: Targeting to improve PDT selectivity

Since 15 years, our main goal consists in improving the selectivity of PDT treatment. Different strategies are developed in Nancy by the PDTeam. The ability to directly target a therapeutic agent to a tumoral site minimizes systemic drug exposure, thus providing the potential for increasing the therapeutic index. Selective accumulation of the photosensitizers in cancer cells or neo-vasculature is required to avoid collateral damages. We develop (i) photosensitizers coupled to moieties such as folic acid (in collaboration with INSERM ONCOTHAI, U1189, Lille) to directly target receptors over-expressed on ovarian peritoneal metastasis [[1], [2], [3]], (ii) photosensitizers coupled to peptides (in collaboration with UMR 7369, CNRS-URCA, Reims) to directly target LRP-1 overexpressed on glioblastome cancerous cells, (iii) multifunctional nanoparticles coupled to peptide (in collaboration with ILM, UMR 5306 CNRS-Universite Claude Bernard, Lyon) to target NRP-1 over-expressed on neo-vessels [[4], [5]]. We also design scintillating nanoparticles that allow the combination of radiotherapy and PDT. Novel hybrid system of scintillating nanoparticles and PDT photosensitizers enable excitation of the constructed nano-devices using by X-rays, which can penetrate deeply into tissues [[6], [7]]. This new modality could allow treatment of deep tumors using lower radiation dose than conventional radiotherapy. The last strategy is the elaboration of photomolecular beacons, to produce reactive oxygen species specifically at the tumoral site. This approach consists in using the activity of enzymatic cleavage of biomarkers over-expressed in tumoral areas such as matrix metalloproteinases (MMPs) [8].