Biodisponibilité (médecine) | EPFL Graph Search

En pharmacologie, la biodisponibilité est la proportion d'une substance qui atteint la grande circulation sanguine d'un organisme sous forme inchangée, en général un médicament. C'est un type d'. Par définition, lorsqu'un médicament est administré par voie intraveineuse, sa biodisponibilité est de 100 %. Cependant, lorsqu'un médicament est administré par d'autres voies, sa biodisponibilité est souvent inférieure en raison de l'absorption dans les intestins par l'endothélium et de l'effet de premier passage. Ainsi, mathématiquement, la biodisponibilité est égale au rapport entre la comparaison de l'aire sous la courbe de la concentration plasmatique du médicament en fonction du temps (ASC) pour la formulation extravasculaire et l'ASC pour la formulation intravasculaire. L'ASC est utilisée car elle est proportionnelle à la dose qui a pénétré dans la grande circulation. La biodisponibilité d'un médicament est une moyenne ; pour tenir compte de la , l'écart-type est indiqué par ±

Liposome nano-formulation with cationic polar lipid DOTAP and cholesterol as a suitable pH-responsive carrier for molecular therapeutic drug (all-trans retinoic acid) delivery to lung cancer cells

Lucia Bonati

The molecular targeted drug ATRA demands a suitable carrier that delivers to the cancer site due to its poor bioavailability and drug resistance. ATRA, being a lipid with carboxylic acid, has been nano-formulated as a cationic lipo-ATRA with DOTAP:cholesterol:ATRA (5:4:1) and its pH-responsive release, intracellular drug accumulation, and anticancer effect on human lung cancer (A549) cell line analysed. The analysis of the physicochemical characteristics of the developed lipo-ATRA (0.8 mu mol) revealed that the size of 231 +/- 2.35 d.nm had a zeta potential of 6.4 +/- 1.19 and an encapsulation efficiency of 93.7 +/- 3.6%. The ATRA release from lipo-ATRA in vitro was significantly (p

WILEY2021

Controlling and Monitoring Intracellular Drug Delivery Using PHPMA-Based Polymer Nanomedicines

Claudia Battistella

Polymer nanomedicine is an attractive approach for the delivery of anticancer drugs. Firstly designed to increase drug bioavailability, polymer conjugates and polymer nanoparticles have rapidly emerged in the field of cancer therapy after the discovery of the enhanced permeation and retention (EPR) effect. The leaky and disordered tumor neovascularization provides opportunities to guide the accumulation of polymer nanomedicines to the tumor tissue therefore enhancing therapy selectivity and reducing off-target-associated side effects. However, since many chemotherapeutics act on targets that are located in well-defined subcellular compartments, controlling the intracellular fate of polymer nanomedicines and/or their payload is another important factor that contributes to therapy efficiency. Polymer conjugates and polymer nanoparticles generally access the cell interior via endocytosis. The physiochemical and biochemical parameters that distinguish the endolysosomal compartments from the extracellular environment have been widely exploited to trigger intracellular drug release from the polymer carriers. Amongst a range of other polymers and polymer nanoparticles that have been investigated over the past 30 years, poly(N-(2-hydroxypropyl) methacrylamide) (PHPMA)-based conjugates have been extensively explored for the endolysosomal release of anticancer drugs. While the modern polymer chemistry toolbox provides many opportunities to tailor the molecular weight and functionality of PHPMA and to introduce features that allow the polymer to respond to the different endolysosomal environments, the development of tools and methods to monitor these processes is also crucial for the future development of advanced delivery systems. The aim of this Thesis is to design dual-functional PHPMA polymers that offer the possibility to control the endolysosomal release of anticancer drug combinations as well as to monitor the PHPMA endolysosomal trafficking. Chapter 1 of this Thesis provides an overview of the different approaches that have been described in literature to control and monitor the intracellular delivery of polymer nanomedicines. Chapter 2 describes a synthetic approach to prepare alpha- and alpha,omega-fluorine labeled pentafluorophenyl methacrylate (PPFMA) polymers via reversible addition fragmentation chain transfer (RAFT) polymerization. In Chapter 3 post-polymerization modification of the alpha-fluorine labeled PPFMA precursor will be used to prepare a series of PHPMA conjugates carrying either the anticancer drug doxorubicin (Dox) or the P-glycoprotein inhibitor zosuquidar (Zos) or both drugs at the polymer side chains. The ability of the conjugates to overcome doxorubicin efflux and therefore reverse P-gp-mediated multidrug resistance in resistant ovarian carcinoma cells will be assessed. Finally, Chapter 4 will study the cellular internalization and endolysosomal trafficking of PHPMA. The synthesis of a dual-labeled PHPMA polymer containing both a fluorescent as well as a fluorinated label will be used for flow cytometry and confocal fluorescence microscopy studies and to demonstrate the potential of nanoscale secondary ion mass spectrometry (NanoSIMS) to map and localize fluorine-containing polymers in cells.

EPFL2017

Bioaccessibility of Organic Compounds Associated with Tire Particles Using a Fish In Vitro Digestive Model: Solubilization Kinetics and Effects of Food Coingestion

Florian Frédéric Vincent Breider, Dominique Grandjean, Luke Christopher Harris, Thibault Béranger Masset, Kristin Schirmer

Tire and road wear particles (TRWP) account for an important part of the polymer particles released into the environment. There are scientific knowledge gaps as to the potential bioaccessibility of chemicals associated with TRWP to aquatic organisms. This study investigated the solubilization and bioaccessibility of seven of the most widely used tire-associated organic chemicals and four of their degradation products from cryogenically milled tire tread (CMTT) into fish digestive fluids using an in vitro digestion model based on Oncorhynchus mykiss. Our results showed that 0.06–44.1% of the selected compounds were rapidly solubilized into simulated gastric and intestinal fluids within a typical gut transit time for fish (3 h in gastric and 24 h in intestinal fluids). The environmentally realistic scenario of coingestion of CMTT and fish prey was explored using ground Gammarus pulex. Coingestion caused compound-specific changes in solubilization, either increasing or decreasing the compounds’ bioaccessibility in simulated gut fluids compared to CMTT alone. Our results emphasize that tire-associated compounds become accessible in a digestive milieu and should be studied further with respect to their bioaccumulation and toxicological effects upon passage of intestinal epithelial cells.

2022

Controlling and Monitoring Intracellular Drug Delivery Using PHPMA-Based Polymer Nanomedicines

Claudia Battistella

EPFL2017