Full Length ArticleStudies on the adsorption and desorption of mitoxantrone to lauric acid/albumin coated iron oxide nanoparticles
Graphical abstract
Introduction
Superparamagnetic iron oxide nanoparticles (SPIONs) are a very promising vehicle for drug delivery, imaging and several other biomedical applications [1], [2], [3], [4], [5]. In Magnetic Drug Targeting (MDT), particles are accumulated in a certain body region using magnetic field gradients [6]. Aggregation behaviour of SPIONs is crucial for proper application and is mostly determined by interface properties. The different approaches of interface modification are used to get particles of proper size in determined medium i.e., the most promising approaches for water based solutions are electrostatic [7] or steric [8] approaches. Furthermore, these coating molecules are also used as binding moieties for pharmacologically active substances. Drugs can thus be concentrated accordingly if they are bound to the SPIONs with sufficient stability. We have demonstrated earlier that the bioavailability of drugs can thus be enhanced over 56-fold, which greatly increases efficacy of therapy and reduces side effects [3]. A pharmaceutically active moiety can be attached to the particles by either covalent binding or adsorption. While both binding strategies offer advantages and disadvantages [9] it is important to understand the binding location of drugs in order to understand the drug release in vivo as well as the influence of drug binding on important particle characteristics such as colloidal stability, hydrodynamic size or surface charge. For potential use in complex biosystems, i.e. in vivo, it is thus preferable to understand the mechanism of drug binding to the particles and its influence on their ordering and stability [10]. Recently we have reported about a hybrid lauric acid/human serum albumin coated formulation called SEONLA−HSA. These particles showed very promising properties for MDT after the cytotoxic drug mitoxantrone (MTO) was added to the particle suspension to yield SEONLA−HSA*MTO [11]. The stabilisation mechanism of SEONLA−HSA seemingly is a mixture between electrostatic and steric stabilisation. While MTO showed a slow, pseudo-zero order release kinetics from SEONLA−HSA*MTO the exact binding location remains unclear. Due to its chemical nature MTO possesses charged, polar groups as well as a conjugated π system. This gives rise to its amphiphilic nature, as the logarithm of its partition coefficient in n-octanol/water (logP value) lies at −3.1 [12]. MTO shows significant and specific binding to albumin [13] as well as being a strong complexing agent for iron [14]. Classical methods such as nuclear magnetic resonance (NMR) based spectroscopy are not able to investigate the binding mechanism of MTO to the particles due to the magnetic properties of the particles. Fourier transform infrared spectroscopy (FTIR) or fluorescence spectroscopy did not produce conclusive results. This, together with the proposed binding modality of MTO to SEONLA−HSA, leaves speculation whether the drug is located at the iron oxide core, in the albumin hull around the particles or even just in the surrounding Helmholtz layers around the individual colloid particles.
In the present study we investigated adsorption and desorption of MTO to different compounds including human serum albumin (HSA), uncoated iron oxide particles and lauric acid/HSA coated particles. We investigated adsorption efficiency and also the desorption kinetics of MTO from the respective compounds using high performance liquid chromatography coupled with ultraviolet detection (HPLC-UV). The effect of surface adsorption on colloidal properties of the system was investigated using dynamic light scattering (DLS), surface titration techniques and FTIR. We furthermore studied structure and interactions of particle clusters using small-angle scattering (SAS) methods [41]. Application of X-rays [37] and neutrons [39], [40] as probes gives us the possibility to visualize different parts of clusters (iron and LA/HSA/MTO) and find out the possible location of MTO by comparison of the alternation of structure and interaction among clusters after drug addition. With our findings we show the effects of surface adsorption and desorption of small molecules on the cluster interaction as well as on the colloidal properties of such materials.
Section snippets
Chemicals and reagents
Iron (II) chloride tetrahydrate (FeCl2⋅4H2O) EMSURE quality and deuterium oxide (D2O) were purchased from Merck (Darmstadt, Germany). Iron (III) chloride hexahydrate (FeCl3⋅6H2O) Ph. Eur. quality, heavy metal-free dialysis tubes (Spectrapor 7, MWCO 8 kDa), ammonium chloride Ph.Eur quality, hydrochloric acid 25%, sodium chloride, sodium hydroxide, sodium hydrogencarbonate, magnesium sulphate, methanol, formic acid, nitric acid 65% and ammonia solution 25% Ph.Eur quality were supplied by Roth
Adsorption of MTO to SEON0, SEONLA−HSA and HSA
The adsorption equilibrium of MTO to the different compounds is displayed in Fig. 1. Up to a concentration of 100 μg MTO/2 mg iron (or the corresponding HSA concentration) MTO absorbs almost quantitatively to all compounds (above 94.8 ± 0.89%). The SEON0 suspensions precipitated quickly after addition of MTO at concentrations of 250 μg/ml and above. The adsorption yield rapidly decreases to only 8.9 ± 0.25% at this concentration. We attribute this to reduction of surface area due to permanent
Conclusions
The adsorption/desorption and titration studies confirmed the original hypothesis that MTO possesses strong adsorption to naked iron oxide surface, naked HSA and the LA-HSA coated particles (SEONLA−HSA) altogether. At the concentrations which we tested in FTIR, desorption, titration and SAS by neutrons and X-rays we can therefore safely assume that the drug is bound to the particles almost quantitatively. FTIR study and the pH-dependent Zeta potential analysis confirm the presence of LA-HSA on
Conflicts of interest
The authors declare no conflict of interest.
Acknowledgments
This study was supported by the DFG AL 552/8-1, Excellencecluster Engineering of Advanced Materials (EAM) and the Manfred Roth Stiftung, Fürth. The excellent support of Dr. Clement Blanchet (EMBL) and the staff of PETRA III during SAXS measurements is kindly acknowledged. This work benefited from the use of the SasView application, originally developed under NSF award DMR-0520547. SasView contains code developed with funding from the European Union's Horizon 2020 research and innovation
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These authors contributed equally to this work.