In vitro investigation of the behaviour of magnetic particles by a circulating artery model

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Abstract

Magnetic drug targeting is the use of coated magnetic nanoparticles as carriers for cytostatic drugs. After intraarterial application of these carriers, they are attracted with an external magnetic field to, for example, an experimental VX2 tumour. The biological compatibility of this system depends on several physiological and physical parameters. We established an in vitro model to simulate in vivo conditions in a circulating system consisting of a circuit with an intact bovine femoral artery close to an external magnetic field. Nanoparticle suspensions were applied by a side inlet. After the magnetisation procedure particle size, concentration and distribution was examined.

Introduction

Arterial delivery of cytostatic loaded magnetic nanoparticles is a new approach of side specific drug deposition in tumours. The advantage of arterial delivery of magnetic nanoparticles compared to intravenous application is that considerably less particles are cleared by cells of the mononuclear phagocyte system (MPS) and the particles therefore do not end up in the macrophages of the liver, spleen and lung [1], [2]. Furthermore, in previous animal studies (experimental VX2 tumour on rabbits) we could show the great advantage of intraarterial application compared to the intravenous administration resulting in a much higher accumulation of the particles and the drug in the target region, respectively [2], [3].

Our nanoparticles for intraarterial drug delivery consist of colloidal dispersed magnetite with a functionalised coating (phosphated starch) which is loaded with the cytostatic agent mitoxantrone via ionic binding to the phosphate groups [4]. The resulting drug loaded compound consists of multidomain particles of magnetite cores with unaltered size embedded in the coating with an average size of about 100–250 nm. In a DLS measurement you can detect only the hydrodynamic diameter of this multidomain particle, further described as nanoparticle [2], [3]. After intraarterial application of this compound in the tumour-region supplying vessels, an external magnetic field, focused to the tumour, attracts the nanoparticles into the tumour supplying vessels. The drug is released from the particle surface after a defined time and infiltrates the tumour tissue and the surrounding area. With only 20% of the regular systemic drug concentration total tumour remission was achieved in an experimental VX2-rabbit-tumour model [4], [5], [6].

Despite these results, further examinations regarding intracorporal particle stability, interactions of the nanoparticles with blood components and their influence on vascular tissue are necessary. For the supplementation of animal experiments we introduced a circulating artery model for the examination of nanoparticle behaviour in an artificial vessel system. In these examinations we plan to optimise magnetic field, flow rate and duration of the magnetic field application for a prospective clinical feasibility study.

Section snippets

Materials and methods

Artery Preparation: Freshly isolated bovine femoral arteries harvested in the local slaughter house were transported in 4 °C PBS buffer (137 mM NaCl, 2.7 mM KCl, 10 mM Na2HPO4, 2 mM KH2PO4 pH 7.4,) supplemented with Heparin (500 i.E.). Side branches of the artery were ligated and the artery was flushed with Krebs–Ringer/BSA buffer (0.114 M NaCl, 3 mM KCl, 2.5 mM CaCl2, 1 mM KH2PO4, 0.8 mM MgSO4, 24 mM NaHCO3, 1 g/l glucose, 6.25 g albumin, Sigma, Germany) supplemented with nitroprusside (10−5 M, Sigma,

Results

Particle administration under pulsatile flow in supplemented Krebs Ringer buffer showed an excellent observability of events after administration of ferrofluids in a blood-like flow with applied magnetic field. Particles of both different coatings were equally attractable adjacent to the tip of the electromagnet. With the magnet on, no particles could be visually detected at the outflow of the artery.

When the magnet was switched off after 15 min, the particles were released into the magnetically

Discussion and conclusion

The present artery circuit can be used as an artificial model for the prescreening of nanoparticle suspensions under different conditions, simulating different application parameters. The system was originally used for the cultivation of autologous endothelialised vein allografts in coronary bypass surgery [7].

Physiological biocompatibility and functionality depends on the magnetic attractability of the nanoparticles, the electrostatic repulsion of the particles as a function of the coating and

Acknowledgements

This work is supported by the priority program 1104 of the German Research Foundation (DFG) and partially by the BMBF project Nanomagnetomedizin (FKZ 13N8536).

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