In Vivo FRET Imaging to Predict the Risk Associated with Hepatic Accumulation of Squalene-Based Prodrug Nanoparticles.

Förster resonance energy transfer (FRET) is used here for the first time to monitor the in vivo fate of nanoparticles made of the squalene-gemcitabine prodrug and two novel derivatives of squalene with the cyanine dyes 5.5 and 7.5, which behave as efficient FRET pair in the NIR region. Following intravenous administration, nanoparticles initially accumulate in the liver, then they show loss of their integrity within 2 h and clearance of the squalene bioconjugates is observed within 24 h. Such awareness is a key prerequisite before introduction into clinical settings.journal article2018 Feb2017 11 30importedSupporting information : librement accessible sur le site de l'éditeur

Composite soy lecithin-decylpolyglucoside vesicles: A theoretical and experimental study

In the present work, vesicles made with soy lecithin and a commercial mixture of alkyl polyglucosides were prepared and characterized. Vesicles with a constant amount of soy lecithin and an increasing amount of a decylpolyglucoside surfactant, (OrNS10), were formulated and their physicochemical properties were studied with the airn to design a drug delivery system suitable for different applications. To this put-pose, morphology, size distribution, zeta-potential and apparent viscosity of the prepared vesicles were studied. Vesicles were also characterized by using optical and light polarized microscopy, transmission electron microscopy and photon correlation spectroscopy. A stability study was also performed by checking mean size and C-potential value variation of the several formulations during 4 weeks. Moreover, theoretical advances on geometric and thermodynamic aspects related to lipid vesicle formation were applied to this study. (c) 2007 Elsevier B.V. All rights reserved

Penetration enhancer-containing vesicles for cutaneous drug delivery

The function of vesicles as topical delivery systems is controversial with variable effects being reported in relation to the type of vesicles and their composition. A wide variety of lipids and surfactants can be used to prepare vesicles, and vesicle composition and preparation method influence their physicochemical properties (size, charge, lamellarity, thermodynamic state, deformability) and, therefore, their efficacy as drug delivery systems. In this chapter, composition, preparation, and results obtained by using penetration enhancer-containing vesicles, liposomes prepared by associating different penetration enhancers to phospholipids, are described. These systems have shown to improve cutaneous drug delivery, thanks to a combination of properties of vesicle carriers and penetration enhancers

Conjugation of squalene to gemcitabine as unique approach exploiting endogenous lipoproteins for drug delivery

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JDQ443, a Structurally Novel, Pyrazole-Based, Covalent Inhibitor of KRAS^G12C for the Treatment of Solid Tumors

Rapid emergence of tumor resistance via RAS pathway reactivation has been reported from clinical studies of covalent KRASG12C inhibitors. Thus, inhibitors with broad potential for combination treatment and distinct binding modes to overcome resistance mutations may prove beneficial. JDQ443 is an investigational covalent KRASG12C inhibitor derived from structure-based drug design followed by extensive optimization of two dissimilar prototypes. JDQ443 is a stable atropisomer containing a unique 5-methylpyrazole core and a spiro-azetidine linker designed to position the electrophilic acrylamide for optimal engagement with KRASG12C C12. A substituted indazole at pyrazole position 3 results in novel interactions with the binding pocket that do not involve residue H95. JDQ443 showed PK/PD activity in vivo and dose-dependent antitumor activity in mouse xenograft models. JDQ443 is now in clinical development, with encouraging early phase data reported from an ongoing Phase Ib/II clinical trial (NCT04699188)

JDQ443, a Structurally Novel, Pyrazole-Based, Covalent Inhibitor of KRAS^G12C for the Treatment of Solid Tumors

Rapid emergence of tumor resistance via RAS pathway reactivation has been reported from clinical studies of covalent KRASG12C inhibitors. Thus, inhibitors with broad potential for combination treatment and distinct binding modes to overcome resistance mutations may prove beneficial. JDQ443 is an investigational covalent KRASG12C inhibitor derived from structure-based drug design followed by extensive optimization of two dissimilar prototypes. JDQ443 is a stable atropisomer containing a unique 5-methylpyrazole core and a spiro-azetidine linker designed to position the electrophilic acrylamide for optimal engagement with KRASG12C C12. A substituted indazole at pyrazole position 3 results in novel interactions with the binding pocket that do not involve residue H95. JDQ443 showed PK/PD activity in vivo and dose-dependent antitumor activity in mouse xenograft models. JDQ443 is now in clinical development, with encouraging early phase data reported from an ongoing Phase Ib/II clinical trial (NCT04699188)