Complexes of Indomethacin with 4-Carbomethoxy-pyrrolidone PAMAM Dendrimers Show Improved Anti-inflammatory Properties and Temperature-Dependent Binding and Release Profile.

COX-2 inhibitors such as nonsteroidal anti-inflammatory drugs (NSAIDs) are the most common treatment for chronic inflammatory diseases like arthritis and atherosclerosis. However, they are associated with severe side effects such as cardiovascular events or stomach bleeding, due to coinhibition of other enzymes (COX1) and off-target accumulation. PAMAM dendrimers can solubilize lipophilic drugs and increase their circulation time; furthermore, PAMAM dendrimers seem to have some accumulation in inflammatory sides. Three different generations of 4-carbomethoxypyrrolidone (Pyr) surface-modified PAMAM dendrimers were complexed with the NSAID drug indomethacin, and their in-solution thermodynamic profiles were studied by means of NMR experiments. The binding stoichiometry was found dependent on solvent system and dendrimer generation. Larger dendrimers (G3-Pyr) were found to bind indomethacin through entropy driven binding mode, while G1-Pyr and G2-Pyr expressed an enthalpy driven complex formation, which means that the binding constants have a generational temperature dependency. G1/2-Pyr showed reduced binding with increasing temperature, which could be important for drug release at inflammatory sites, which have, in general, elevated temperatures. In vitro studies elucidated that the indomethacin drug remained its activity when delivered as a dendrimer-indomethacin complex. A slight reduction in toxicity profile was noticed for G2/G3-Pyr-indomethacin dendrimers. Both free indomethacin and dendrimer-indomethacin complex inhibited a variety of pro-inflammatory cytokines in LPS treated cells. However, only the indo-dendrimer complexes showed a significant reduction of IL-1ß in LPS-treated THP-1 cells, which was not present in the control with free indomethacin.

A method to account for the effect of hydrodynamics on polar organic compound uptake by passive samplers.

Mass transfer coefficients of the water boundary layer (kw ) were measured using alabaster dissolution kinetics in a diffusion cell that was operated at stirring rates between 90 min-1 and 600 min-1 , aiming to provide a more robust characterization of the effect of hydrodynamics on the uptake of polar compounds by passive samplers, as compared with characterizations in terms of stirring rates and water flow velocities. The measured kw helped to quantitatively understand calcium sulfate transport through a poly(ethersulfone) membrane and 2 water boundary layers (at both sides of the membrane). Alabaster-based kw value were used to understand atrazine transport in the diffusion cell, allowing the conclusion that atrazine transport in the membrane is via the pore space, rather than via the polymer matrix. The merits of measuring alabaster dissolution rates for passive sampler calibration and application in the field are discussed. The authors propose that passive sampler calibrations be carried out under controlled kw conditions, rather than under controlled stirring rates or flow velocities. This would facilitate the interpretation of passive sampler calibration studies and the translation of laboratory-based water sampling rates to flow conditions that apply in the field. Environ Toxicol Chem 2017;36:1517-1524. © 2016 SETAC.