Lipid-based Janus nanoparticles for pharmaceutical and cosmetic applications: Kinetics and mechanisms of destabilization with time and temperature.

The aim of this paper is to investigate the time and thermal stability of innovative multicompartmental nanoparticles. These particles, having a hydrophilic side and a hydrophobic side, belong to the family of Janus particles and are promising tools to carry active ingredients with opposite solubilities in a unique nanocarrier. The stability of nanoparticles obtained with mainly two types of polyoxylglycerides (Labrafil® M2125 CS and Labrafil® M1944 CS) has been investigated. The suspensions describe a two-step maturation/destabilization process with an Ostwald ripening phase followed by the coalescence of the particles. The effect of lipid composition and temperature on these steps has been investigated in deep as stability with temperature is a critical parameter to consider in order to envisage the development of any formulation for pharmaceutical or cosmetic uses. These nanoparticles were particularly stable at room temperature as their hydrodynamic diameter did not change significantly for 20 months. Contrarily, a strong dependency to temperature appears when storage temperature increases from 25 °C to 43 °C. Indeed, Labrafil® M1944 CS seemed to undergo a progressive destabilization where a significant increase of particles size is visible from 25 °C and phase separation occurred after 4 months at 32 °C. At the opposite, Labrafil® M2125 CS remained stable until 36 °C and reached a threshold temperature between 32 °C and 36 °C after which Labrafil® M2125 CS underwent a consequent increase of particles size at the longer time, i.e. after 6 months. Moreover, Labrafil® M2125 CS formulation was stable at least 3 months at 43 °C.

Imatinib: Major photocatalytic degradation pathways in aqueous media and the relative toxicity of its transformation products.

Imatinib (IMA) is a highly potent tyrosine kinase inhibitor used as first-line anti-cancer drug in the treatment of chronic myeloid leukemia. Due to its universal mechanism of action, IMA also has endocrine and mutagenic disrupting effects in vivo and in vitro, which raises the question of its environmental impact. However, to date, very little information is available on its environmental fate and the potential role of its transformation products (TPs) on aquatic organisms. Given the IMA resistance to hydrolysis and direct photolysis according to the literature, we sought to generate TPs through oxidative and radical conditions using the AOPs pathway. Thus, the reactivity of the cytotoxic drug IMA in water in the presence of OH and h+ was investigated for the first time in the present work. In this regard, a non-targeted screening approach was applied in order to reveal its potential TPs. The tentative structural elucidation of the detected TPs was performed by LC-HRMSn. The proposed approach allowed detecting a total of twelve TPs, among which eleven are being described for the first time in this work. Although the structures of these TPs could not be positively confirmed due to lack of standards, their chemical formulas and product ions can be added to databases, which will allow their screening in future monitoring studies. Using the quantitative structure-activity relationship (QSAR) approach and rule-based software, we have shown that the detected TPs possess, like their parent molecule, comparable acute toxicity as well as mutagenic and estrogenic potential. In addition to the in silico studies, we also found that the samples obtained at different exposure times to oxidative conditions, including those where IMA is no longer detected, retained toxicity in vitro. Such results suggest further studies are needed to increase our knowledge of the impact of imatinib on the environment.

Mechanism of interaction of sitamaquine with Leishmania donovani.

OBJECTIVES: This study focuses on the mechanism of interaction of sitamaquine with Leishmania donovani membranes, and its accumulation within the parasites. METHODS: A biomimetic model of the outer layer of a Leishmania plasma membrane was used to examine the interactions of sitamaquine with lipids. The plasma membranes of L. donovani promastigotes were depleted of sterol using cholesterol oxidase, in order to assess the importance of sterols in drug-membrane interactions. Sterols were quantified and sitamaquine susceptibility was assessed using the MTT test. Kinetics of sitamaquine accumulation and efflux were measured under different conditions. RESULTS: Sitamaquine interacts first with phospholipid anionic polar head groups and then with phospholipid acyl chains to insert within biological membranes and accumulates rapidly in the Leishmania cytosol according to a sterol-independent process. The rapid sitamaquine efflux observed was related to an energy-dependent mechanism since the intracellular amount of sitamaquine was enhanced three times in the absence of glucose and the efflux was inhibited in energy-depleted conditions. (1)H NMR analysis of motile lipid showed that sitamaquine did not affect lipid trafficking in Leishmania. CONCLUSIONS: We propose that sitamaquine rapidly accumulates in Leishmania by diffusion along an electrical gradient and is concentrated in the cytosol by an energy- and sterol-independent process. The affinity of sitamaquine for membranes was transitory and an energy-dependent efflux was demonstrated, suggesting the presence of an as yet uncharacterized transporter.