A novel lipophenol quercetin derivative to prevent macular degeneration: Intravenous and oral formulations for preclinical pharmacological evaluation.

Drugs with properties against oxidative and carbonyl stresses are potential candidates to prevent dry age-related macular degeneration (Dry-AMD) and inherited Stargardt disease (STGD1). Previous studies have demonstrated the capacity of a new lipophenol drug: 3-O-DHA-7-O-isopropyl-quercetin (Q-IP-DHA) to protect ARPE19 and primary rat RPE cells respectively from A2E toxicity and under oxidative and carbonyl stress conditions. In this study, first, a new methodology has been developed to access gram scale of Q-IP-DHA. After classification of the lipophenol as BCS Class IV according to physico-chemical and biopharmaceutical properties, an intravenous formulation with micelles (M) and an oral formulation using lipid nanocapsules (LNC) were developed. M were formed with Kolliphor® HS 15 and saline solution 0.9 % (mean size of 16 nm, drug loading of 95 %). The oral formulation was optimized and successfully allowed the formation of LNC (25 nm, 96 %). The evaluation of the therapeutic potency of Q-IP-DHA was performed after IV administration of micelles loaded with Q-IP-DHA (M-Q-IP-DHA) at 30 mg/kg and after oral administration of LNC loaded with Q-IP-DHA (LNC-Q-IP-DHA) at 100 mg/kg in mice. Results demonstrated photoreceptor protection after induction of retinal degeneration by acute light stress making Q-IP-DHA a promising preventive candidate against dry-AMD and STGD1.

Formulation and Evaluation of SNEDDS Loaded with Original Lipophenol for the Oral Route to Prevent Dry AMD and Stragardt's Disease.

Dry age-related macular degeneration (Dry AMD) and Stargardt's disease (STGD1) are common eye diseases, characterized by oxidative and carbonyl stress (COS)-inducing photoreceptor degeneration and vision loss. Previous studies have demonstrated the protective effect of photoreceptors after the intravenous administration of a new lipophenol drug, phloroglucinol-isopropyl-DHA (IP-DHA). In this study, we developed an oral formulation of IP-DHA (BCS Class IV) relying on a self-nanoemulsifying drug delivery system (SNEDDS). SNEDDS, composed of Phosal® 53 MCT, Labrasol®, and Transcutol HP® at a ratio of 25/60/15 (w/w/w), led to a homogeneous nanoemulsion (NE) with a mean size of 53.5 ± 4.5 nm. The loading of IP-DHA in SNEDDS (SNEDDS-IP-DHA) was successful, with a percentage of IP-DHA of 99.7% in nanoemulsions. The in vivo study of the therapeutic potency of SNEDDS-IP-DHA after oral administration on mice demonstrated photoreceptor protection after the induction of retinal degeneration with acute light stress (73-80%) or chronic light stress (52-69%). Thus, SNEDDS formulation proved to increase the solubility of IP-DHA, improving its stability in intestinal media and allowing its passage through the intestinal barrier after oral force-fed administration, while maintaining its biological activity. Therefore, SNEDDS-IP-DHA is a promising future preventive treatment for dry AMD and STGD1.

Automation of Cranial Nerve Tractography by Filtering Tractograms for Skull Base Surgery.

Fiber tractography enables the in vivo reconstruction of white matter fibers in 3 dimensions using data collected by diffusion tensor imaging, thereby helping to understand functional neuroanatomy. In a pre-operative context, it provides essential information on the trajectory of fiber bundles of medical interest, such as cranial nerves. However, the optimization of tractography parameters is a time-consuming process and requires expert neuroanatomical knowledge, making the use of tractography difficult in clinical routine. Tractogram filtering is a method used to isolate the most relevant fibers. In this work, we propose to use filtering as a post-processing of tractography to avoid the manual optimization of tracking parameters and therefore making a step forward automation of tractography. To question the feasibility of automated tractography of cranial nerves, we perform an analysis of main cranial nerves on a series of patients with skull base tumors. A quantitative evaluation of the filtering performance of two state-of-the-art and a new entropy-based methods is carried out on the basis of reference tractograms produced by experts. Our approach proves to be more stable in the selection of the optimal filtering threshold and turns out to be interesting in terms of computational time complexity.

Alignment effects on a neutron imaging system using coded apertures.

A high resolution neutron imaging system is being developed and tested on the OMEGA laser facility for inertial confinement fusion experiments. This diagnostic uses a coded imaging technique with a penumbral or an annular aperture. The sensitiveness of these techniques to misalignment was pointed out with both experiments and simulations. Results obtained during OMEGA shots are in good agreement with calculations performed with the Monte Carlo code GEANT4. Both techniques are sensitive to the relative position of the source in the field of view. The penumbral imaging technique then demonstrates to be less sensitive to misalignment compared to the ring. These results show the necessity to develop a neutron imaging diagnostic for megajoule class lasers taking into account our alignment capabilities on such facilities.