Inactivation of Malaria Parasites in Blood: PDT vs Inhibition of Hemozoin Formation

Malaria causes hundreds of thousands of human deaths every year, and the World Health Assembly has made it a priority. To help eliminate this disease, there is a pressing need for the development and implementation of new strategies to improve the prevention and treatment, due in part to antimalarial drug resistances. This chapter focuses on two strategies to inactivate the malaria parasite in blood, which are photodynamic therapy (PDT) and inhibition of hemozoin formation. The PDT strategy permits either a control of the proliferation of mosquito larvae to develop some photolarvicides for the prevention or a photoinactivation of the malaria parasite in red blood cells (RBCs) to minimize infection transmission by transfusion. The inhibition of hemozoin formation strategy is used for the development of new antimalarial drug by understanding its formation mechanism

Preventing Societal Health Risks Emerging in the Development Of Nanomedicine - What Should Prevail?

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Real-time control of photobleaching trajectory during photodynamic therapy

International audienceIntroduction: obstacles and challenges to the clinical use of the photodynamic therapy (PDT) are numerous: large inter-individual variability, heterogeneity of therapeutic predictability, lack of in vivo monitoring concerning the reactive oxygen species (ROS) production, etc. All of these factors affect in their ways the therapeutic response of the treatment and can lead to a wild uncertainty on its efficiency. Objective: to deal with these variability sources, we have designed and developed an innovative technology able to adapt in realtime the width of light impulses during the photodynamic therapy. The first objective is to accurately control the photobleaching trajectory of the photosensitizer during the treatment with a subsequent goal to improve the efficacy and reproducibility of this therapy.Methods: in this approach, the physician a priori defines the expected trajectory to be tracked by the photosensitizer photobleaching during the treatment. The photobleaching state of the PS is regularly measured during the treatment session and is used to change in real-time the illumination signal. This adaptive scheme of the photodynamic therapy has been implemented, tested and validated during in vitro tests.Results: these tests show that controlling the photobleaching trajectory is possible, confirming the technical feasibility of such an approach to deal with inter-individual variabilities in PDT. These results open new perspectives since the illumination signal can be different from a patient to another according to his individual response.Conclusions: this study has proven its interest by showing promising results in an in vitro context, which has to be confirmed by the current in vivo experiments. However, it is fair to say that in a near future, the proposed solution could lead, in fine, to an optimized and personalized PDT

La communication sous forme d’un jeu de plateau pour partager des données et des ressentis d’experts à propos d’un nouveau traitement contre le cancer

La conception de cartes à des fins de communication ou, de manière plus générale, la visualisation de données est un champ de recherches relativement ancien qui a subi de profonds changements au cours de ces dernières années. Si de nombreuses recherches y sont consacrées, très peu d’entre elles s’intéressent à une autre tendance forte du moment : l’emploi ou le détournement du jeu à des fins de communication. Ce papier traite de cette question en abordant le cas d’un support informationnel rappelant un jeu de stratégie sur plateau développé dans un but d’information à propos d’un nouveau procédé de lutte contre le cancer : la thérapie photodynamique.La conception de cartes à des fins de communication ou, de manière plus générale, la visualisation de données est un champ de recherches relativement ancien qui a subi de profonds changements au cours de ces dernières années. Si de nombreuses recherches y sont consacrées, très peu d’entre elles s’intéressent à une autre tendance forte du moment : l’emploi ou le détournement du jeu à des fins de communication. Ce papier traite de cette question en abordant le cas d’un support informationnel rappelant un jeu de stratégie sur plateau développé dans un but d’information à propos d’un nouveau procédé de lutte contre le cancer : la thérapie photodynamique

Metabolic profile of a peptideconjugated chlorin-type photosensitizer targeting neuropilin-1: an in vivo and in vitro study, Drug Metab

ABSTRACT: Because angiogenic endothelial cells of the tumor vasculature represent an interesting target to potentiate the antivascular effect of photodynamic therapy, we recently described the conjugation of a photosensitizer [5-(4-carboxyphenyl)-10,15,20-triphenylchlorin (TPC)], via a spacer [6-aminohexanoic acid (Ahx)], to a vascular endothelial growth factor receptor-specific heptapeptide [H-AlaThr-Trp-Leu-Pro-Pro-Arg-OH (ATWLPPR)] and showed that TPCAhx-ATWLPPR binds to neuropilin-1. Because peptides often display low stability in biological fluids, we examined the in vivo and in vitro stability of this conjugate by high-performance liquid chromatography and matrix-assisted laser desorption ionization/time of flight mass spectrometry. TPC-Ahx-ATWLPPR was stable in vitro in human and mouse plasma for at least 24 h at 37°C but, following i.v. injection in glioma-bearing nude mice, was degraded in vivo to various rates, depending on the organ considered. TPCAhx-A was identified as the main metabolic product, and biodistribution studies suggested that its appearance in plasma mainly resulted from the degradation of the peptidic moiety into organs of the reticuloendothelial system. According to in vitro cell culture experiments, TPC-Ahx-ATWLPPR was also significantly degraded after incorporation in human umbilical vein endothelial cells (HUVEC), mainly into TPC-Ahx-A and to a lesser extent into TPCAhx-AT and TPC-Ahx-ATWLPP. TPC-Ahx-ATWLPPR mostly localized into lysosomes, and when HUVEC were treated with the lysosomal enzymes' inhibitor ammonium chloride, this resulted in a significant decrease of the peptide degradation. This study provides essential information for the choice of the time of activation of the photosensitizer (drug-light interval) not to be exceeded and for the future design of more stable molecules

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

Proton MR spectroscopy and diffusion MR imaging monitoring to predict tumor response to interstitial photodynamic therapy for glioblastoma

International audienceDespite recent progress in conventional therapeutic approaches, the vast majority of glioblastoma recur locally, indicating that a more aggressive local therapy is required. Interstitial photodynamic therapy (iPDT) appears as a very promising and complementary approach to conventional therapies. However, an optimal fractionation scheme for iPDT remains the indispensable requirement. To achieve that major goal, we suggested following iPDT tumor response by a non-invasive imaging monitoring. Nude rats bearing intracranial glioblastoma U87MG xenografts were treated by iPDT, just after intravenous injection of AGuIX® nanoparticles, encapsulating PDT and imaging agents. Magnetic Resonance Imaging (MRI) and Magnetic Resonance Spectroscopy (MRS) allowed us an original longitudinal follow-up of post-treatment effects to discriminate early predictive markers. We successfully used conventional MRI, T2 star (T2*), Diffusion Weighted Imaging (DWI) and MRS to extract relevant profiles on tissue cytoarchitectural alterations, local vascular disruption and metabolic information on brain tumor biology, achieving earlier assessment of tumor response. From one day post-iPDT, DWI and MRS allowed us to identify promising markers such as the Apparent Diffusion Coefficient (ADC) values, lipids, choline and myoInositol levels that led us to distinguish iPDT responders from non-responders. All these responses give us warning signs well before the tumor escapes and that the growth would be appreciated