Henrik Kempe

The use of magnetite nanoparticles for implant-assisted magnetic drug targeting in thrombolytic therapy.

Implant-assisted targeting of magnetic particles under the influence of an external magnetic field has previously been verified through mathematical modeling, in vitro studies, and in vivo studies on rat carotid arteries as a feasible method for localized drug delivery. The present study focuses on the development of nanoparticles for the treatment of in-stent thrombosis. Magnetic nanoparticles in the size-range 10-30 nm were synthesized in a one-pot procedure by precipitation of ferrous hydroxide followed by oxidation to magnetite. The nanoparticles were silanized with tetraethyl orthosilicate in the presence of triethylene glycol and/or polyethylene glycol. The surface coated magnetite nanoparticles were activated with either N-hydroxysulfosuccinimide or tresyl chloride for covalent immobilization of tissue plasminogen activator (tPA). Hysteresis loops showed saturation magnetizations of 55.8, 44.1, and 43.0 emu/g for the naked nanoparticles, the surface coated nanoparticles, and the tPA-nanoparticle conjugates, respectively. The hemolytic activity of the nanoparticles in blood was negligible. An initial in vivo biocompatibility test in pig, carried out by intravascular injection of the nanoparticles in a stented brachial artery, showed no short-term adverse effects. In vitro evaluation in a flow-through model proved that the nanoparticles were captured efficiently to the surface of a ferromagnetic coiled wire at the fluid velocities typical for human arteries. A preliminary test of the tPA-nanoparticle conjugates in a pig model suggested that the conjugates may be used for treatment of in-stent thrombosis in coronary arteries.

Simulation of chromatographic processes applied to separation of proteins

The advantages of using a detailed mathematical model for fixed bed chromatography is demonstrated by the personal computer program SIMCHROM. The chromatography model includes axial dispersion in the bulk liquid, external and internal mass transfer resistances and an instationary non-linear adsorption model. Frontal and pulse chromatography can be studied for single and multicomponent systems. The simulation program can easily be used to make parametric evaluations to study the influence of variations in physical, kinetical and operating parameters. The special features of the present intrinsic model is demonstrated by comparing the SIMCHROM results With simulations using simplified lumped models. Experimental data describing affinity chromatography of lysozyme on Cibacron Blue Sepharose CL-6B is used as a model system. The intrinsic model is able to describe variations in the physical, kinetic and operating parameters better than the simplified models. This results in a more reliable prediction of the performance of the chromatography process as well as a better understanding of che underlying mechanisms responsible for the separation

Influence of salt ions on binding to molecularly imprinted polymers

AbstractSalt ions were found to have an influence on template binding to two model molecularly imprinted polymers (MIPs), targeted to penicillin G and propranolol, respectively, in water–acetonitrile mixtures. Water was detrimental to rebinding of penicillin G whereas propranolol bound in the entire water–acetonitrile range tested. In 100% aqueous solution, 3-M salt solutions augmented the binding of both templates. The effects followed the Hofmeister series with kosmotropic ions promoting the largest increase. Binding was mainly of a non-specific nature under these conditions. In acetonitrile containing low amounts of water, the specific binding to the MIPs increased with the addition of salts. Binding of penicillin G followed the Hofmeister series while an ion-exchange mechanism was observed for propranolol. The results suggest that hydration of kosmotropic ions reduces the water activity in water-poor media providing a stabilizing effect on water-sensitive MIP–template interactions. The effects were utilized to develop a procedure for molecularly imprinted solid-phase extraction (MISPE) of penicillin G from milk with a recovery of 87%. FigureBinding augmentation to a penicillin G imprinted MIP at the addition of kosmotropic ions.

Nanomedicine’s promising therapy: magnetic drug targeting

Magnetic drug targeting is a promising therapy that can benefit patients, as well as provide novel opportunities for pharmaceutical and medical technology/device industries.

A Methodology for Estimation of Mass Transfer Parameters in a Detailed Chromatography Model Based on Frontal Experiments

A methodology for estimation of the unknown physical parameters in a detailed model for chromatographic processes is proposed. The model describes the concentration of the solute in the mobile phase and considers external/internal mass transfer resistance. The external volume and its mixing effect are also considered. The unknown model parameters estimated are the bed void, the axial dispersion coefficient, the liquid film mass transfer coefficient, the effective diffusion coefficient and the apparent bead porosity. All the parameters in the model were subsequently determined in three classes of experiments, the external mixing behaviour, the mobile phase behaviour and the stationary phase behaviour. The estimates are based on the sum of the least squares of the residuals between the experimental breakthrough curves and the model response. The methodology is exemplified by frontal experiments with lysozyme, bovine serum albumin and immuno globulin γ on a well-defined column set-up. When the mixing properties in the external volume had to be accounted for, to avoid adding broadening behaviour to the dispersion coefficient, the film mass transfer coefficient and the diffusion coefficient were also investigated. The results show that it is possible to estimate the unknown parameters using the proposed methodology.

QSRR analysis of β-lactam antibiotics on a penicillin G targeted MIP stationary phase

The imprinting factors of the β-lactam antibiotics penicillin V, methicillin, nafcillin, oxacillin, cloxacillin, dicloxacillin, and piperacillin on a poly(methacrylic acid-co-trimethylolpropane trimethacrylate) molecularly imprinted stationary phase targeted for penicillin G were correlated with molecular descriptors obtained by molecular computation. One-parameter linear regression and multivariate data analysis by principal component analysis and partial least square regression indicated that descriptors associated with molecular topology, shape, size, and volume were highly correlated with the imprinting factor and influential on the derived models.