Drug delivery to atherosclerotic plaques using superparamagnetic iron oxide nanoparticles.

INTRODUCTION: Magnetic drug targeting utilizes superparamagnetic iron oxide nanoparticles (SPIONs) to accumulate drugs in specified vasculature regions. METHODS: We produced SPIONs conjugated with dexamethasone phosphate (SPION-DEXA). The efficacy of magnetic drug targeting was investigated in a rabbit model of atherosclerosis induced by balloon injury and high cholesterol diet. RESULTS: In vitro, SPION-DEXA were well-tolerated by endothelial cells. SPION-DEXA were internalized by human peripheral blood mononuclear cells and induced CD163 expression comparable with the free drug. In vivo, magnetic targeting of SPIONs to abdominal aorta was confirmed by histology. Upon vascular injury followed by high-cholesterol diet, early administration of SPION-DEXA enhanced the inflammatory burden in the plaques. Increased macrophage content and larger intima- media thickness were observed in animals treated with SPION-DEXA compared with controls. In advanced atherosclerosis, no beneficial effect of local glucocorticoid therapy was detectable. CONCLUSION: Magnetic drug targeting represents an efficient platform to deliver drugs to diseased arteries in vivo. However, targeting of vascular injury in the lipid-rich environment using dexamethasone-conjugated SPIONs may cause accelerated inflammatory response.

Surface Modification of SPIONs in PHBV Microspheres for Biomedical Applications.

Surface modification of superparamagnetic iron oxide nanoparticles (SPIONs) has been introduced with lauric acid and oleic acid via co-precipitation and thermal decomposition methods, respectively. This modification is required to increase the stability of SPIONs when incorporated in hydrophobic, biodegradable and biocompatible polymers such as poly (3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV). In this work, the solid-in-oil-in-water (S/O/W) emulsion-solvent extraction/evaporation method was utilized to fabricate magnetic polymer microspheres incorporating SPIONs in PHBV. The prepared magnetic PHBV microspheres exhibited particle sizes <1 µm. The presence of functional groups of lauric acid, oleic acid and iron oxide in the PHBV microspheres was confirmed by Fourier Transform Infrared spectroscopy (FTIR). X-ray diffraction (XRD) analysis was performed to further confirm the success of the combination of modified SPIONs and PHBV. Thermogravimetric analysis (TGA) indicated that PHBV microspheres were incorporated with SPIONsLauric as compared with SPIONsOleic. This was also proven via magnetic susceptibility measurement as a higher value of this magnetic property was detected for PHBV/SPIONsLauric microspheres. It was revealed that the magnetic PHBV microspheres were non-toxic when assessed with mouse embryotic fibroblast cells (MEF) at different concentrations of microspheres. These results confirmed that the fabricated magnetic PHBV microspheres are potential candidates for use in biomedical applications.

Studies on the adsorption and desorption of mitoxantrone to lauric acid/albumin coated iron oxide nanoparticles.

A rational use of superparamagnetic iron oxide nanoparticles (SPIONs) in drug delivery, diagnostics, and other biomedical applications requires deep understanding of the molecular drug adsorption/desorption mechanisms for proper design of new pharmaceutical formulations. The adsorption and desorption of the cytostatic Mitoxantrone (MTO) to lauric acid-albumin hybrid coated particles SPIONs (SEONLA-HSA) was studied by Fourier transform infrared spectroscopy (FTIR), dynamic light scattering (DLS), surface titration, release experiments and small-angle neutron and X-ray scattering. Such MTO-loaded nanoparticles have shown very promising results in in vivo animal models before, while the exact binding mechanism of the drug was unknown. SEONLA-HSA formulations have shown better stability under drug loading in comparison with uncoated nanoparticle and sustainable drug release to compare with protein solution. Adsorption of MTO to SEONLA-HSA leads to decreasing of absolute value of zeta potential and repulsive interaction among particles, which points to the location of separate molecules of MTO on the outer surface of LA-HSA shell.

Selection of potential iron oxide nanoparticles for breast cancer treatment based on in vitro cytotoxicity and cellular uptake.

Superparamagnetic iron oxide nanoparticles (SPIONs) are promising tools for the treatment of different diseases. Their magnetic properties enable therapies involving magnetic drug targeting (MDT), hyperthermia or imaging. Depending on the intended treatment, specific characteristics of SPIONs are required. While particles used for imaging should circulate for extended periods of time in the vascular system, SPIONs intended for MDT or hyperthermia should be accumulated in the target area to come into close proximity of, or to be incorporated into, specific tumor cells. In this study, we determined the impact of several accurately characterized SPION types varying in size, zeta potential and surface coating on various human breast cancer cell lines and endothelial cells to identify the most suitable particle for future breast cancer therapy. We analyzed cellular SPION uptake, magnetic properties, cell proliferation and toxicity using atomic emission spectroscopy, magnetic susceptometry, flow cytometry and microscopy. The results demonstrated that treatment with dextran-coated SPIONs (SPIONDex) and lauric acid-coated SPIONs (SPIONLA) with an additional protein corona formed by human serum albumin (SPIONLA-HSA) resulted in very moderate particle uptake and low cytotoxicity, whereas SPIONLA had in part much stronger effects on cellular uptake and cellular toxicity. In summary, our data show significant dose-dependent and particle type-related response differences between various breast cancer and endothelial cells, indicating the utility of these particle types for distinct medical applications.

A novel human artery model to assess the magnetic accumulation of SPIONs under flow conditions.

Magnetic targeting utilises the properties of superparamagnetic iron oxide nanoparticles (SPIONs) to accumulate particles in specified vasculature regions under an external magnetic field. As the behaviour of circulating particles varies depending on nanoparticle characteristics, magnetic field strength and flow dynamics, we established an improved ex vivo model in order to estimate the magnetic capture of SPIONs in physiological-like settings. We describe here a new, easy to handle ex vivo model of human umbilical artery. Using this model, the magnetic targeting of different types of SPIONs under various external magnetic field gradients and flow conditions was investigated by atomic emission spectroscopy and histology. Among tested particles, SPION-1 with lauric acid shell had the largest capacity to accumulate at the specific artery segment. SPION-2 (lauric acid/albumin-coated) were also successfully targeted, although the observed peak in the iron content under the tip of the magnet was smaller than for SPION-1. In contrast, we did not achieve magnetic accumulation of dextran-coated SPION-3. Taken together, the umbilical artery model constitutes a time- and cost-efficient, 3R-compliant tool to assess magnetic targeting of SPIONs under flow. Our results further imply the possibility of an efficient in vivo targeting of certain types of SPIONs to superficial arteries.

Toxicity of Mitoxantrone-loaded Superparamagnetic Iron Oxide Nanoparticles in a HT-29 Tumour Spheroid Model.

BACKGROUND/AIM: Cancer research is commonly carried out in two-dimensional (2D) cell cultures, which poorly reflect in vivo settings where the growing tumours are exposed to mechanical forces and biochemical gradients. In this study we established a HF-29 colon carcinoma tumor spheroid model to investigate the effect of free mitoxantrone (MTO) and its nanoparticle-bound form (SPION(MTO)) under 3D cell culture conditions. MATERIALS AND METHODS: Tumour spheroids were generated by seeding HT-29 colon carcinoma cells on agarose-coated cell culture wells. Growth of the spheroids was monitored daily by transmission microscopy upon treatment with free MTO, SPION(MTO) or unloaded SPION. RESULTS AND CONCLUSION: Unloaded SPION did not affect the spheroid size compared to untreated controls, while both free MTO and SPION(MTO) inhibited growth of the spheroids in a dose- and time-dependent manner. In comparison to free MTO, the effect of SPION(MTO) on spheroid growth was slightly delayed. Further analyses are necessary to investigate if MTO infiltrates spheroids in its nanoparticle-bound form or whether it is released from SPION before infiltration.

Effect of BSA-coated Superparamagnetic Iron Oxide Nanoparticles on Granulosa Cells.

BACKGROUND: Since superparamagnetic iron oxide nanoparticles (SPION) possess unique features, they provide a huge platform for medical applications, especially for cancer diagnosis and therapy (e.g. imaging, and drug targeting). However, heterogeneous effects on mammalian cells with regard to reproductive tissue are described. An experimental study was carried out to study the effects of SPIONs on both the expression of steroid hormone receptor and viability of granulosa cells, which play a key role in ovarian health and fertility. MATERIALS AND METHODS: Human granulosa cells were cultured in vitro and incubated with different concentrations of SPIONs. After 48 h, steroid receptor expression and cell viability were evaluated. RESULTS: Treatment of granulosa cells with SPIONs did not affect estrogen receptor ß1 or progesterone receptor-A expression and had no significant effect on cell viability. CONCLUSION: Nanoparticles precoated with bovine serum albumin (BSA) do not alter granulosa cell phenotype, whereas literature suggests that other nanoparticles induce apoptosis and reduce steroid receptor expression. Our data indicate an overall better outcome using SPIONs coated with BSA.

Tissue Plasminogen Activator Binding to Superparamagnetic Iron Oxide Nanoparticle-Covalent Versus Adsorptive Approach.

Functionalized superparamagnetic iron oxide nanoparticles are frequently used to develop vehicles for drug delivery, hyperthermia, and photodynamic therapy and as tools used for magnetic separation and purification of proteins or for biomolecular imaging. Depending on the application, there are various possible covalent and non-covalent approaches for the functionalization of particles, each of them shows different advantages and disadvantages for drug release and activity at the desired location.Particularly important for the production of adsorptive and covalent bound drugs to nanoparticles is the pureness of the involved formulation. Especially the covalent binding strategy demands defined chemistry of the drug, which is stabilized by excess free amino acids which could reduce reaction efficiency. In this study, we therefore used tangential flow filtration (TFF) method to purify the drugs before the reaction and used the frequently applied and clinically available recombinant tissue plasminogen activator (tPA; Actilyse(®)) as a proof of concept. We then coupled the tPA preparation to polyacrylic acid-co-maleic acid (PAM)-coated superparamagnetic iron oxide nanoparticles (SPIONs) using an amino-reactive activated ester reaction and compared these particles to PAM-coated SPIONs with electrostatically adsorbed tPA.Using dynamic light scattering (DLS) and pH-dependent electrokinetic mobility measurements, we showed that surface properties of the SPIONs were significantly greater affected after activation of the particles compared to the adsorption controls. Different in vitro assays were used to investigate the activity of tPA after coupling to the particles and purification of the ferrofluid. Covalent linkage significantly improves the reactivity and long-term stability of the conjugated SPION-tPA system compared to simple adsorption. In conclusion, we have shown an effective way to produce SPIONs with covalent and non-covalent ultra-filtrated drugs. We showed that using activated ester reaction, immobilization of the protein was significantly better than in adsorptive approaches. Investigation of those functionalized SPIONs revealed diverging attributes, which should be taken into account when developing nanoparticles for different applications.

Nanoparticles for intravascular applications: physicochemical characterization and cytotoxicity testing.

AIM: We report the physicochemical analysis of nanosystems intended for cardiovascular applications and their toxicological characterization in static and dynamic cell culture conditions. METHODS: Size, polydispersity and ζ-potential were determined in 10 nanoparticle systems including liposomes, lipid nanoparticles, polymeric and iron oxide nanoparticles. Nanoparticle effects on primary human endothelial cell viability were monitored using real-time cell analysis and live-cell microscopy in static conditions, and in a flow model of arterial bifurcations. RESULTS & CONCLUSIONS: The majority of tested nanosystems were well tolerated by endothelial cells up to the concentration of 100 µg/ml in static, and up to 400 µg/ml in dynamic conditions. Pilot experiments in a pig model showed that intravenous administration of liposomal nanoparticles did not evoke the hypersensitivity reaction. These findings are of importance for future clinical use of nanosystems intended for intravascular applications.

Pharmaceutical formulation of HSA hybrid coated iron oxide nanoparticles for magnetic drug targeting.

In this work we present a new formulation of superparamagnetic iron oxide nanoparticles (SPIONs) for magnetic drug targeting. The particles were reproducibly synthesized from current good manufacturing practice (cGMP) - grade substances. They were surface coated using fatty acids as anchoring molecules for human serum albumin. We comprehensively characterized the physicochemical core-shell structure of the particles using sophisticated methods. We investigated biocompatibility and cellular uptake of the particles using an established flow cytometric method in combination with microwave-plasma assisted atomic emission spectroscopy (MP-AES). The cytotoxic drug mitoxantrone was adsorbed on the protein shell and we showed that even in complex media it is slowly released with a close to zero order kinetics. We also describe an in vitro proof-of-concept assay in which we clearly showed that local enrichment of this SPION-drug conjugate with a magnet allows site-specific therapeutic effects.

Genotoxicity of Superparamagnetic Iron Oxide Nanoparticles in Granulosa Cells.

Nanoparticles that are aimed at targeting cancer cells, but sparing healthy tissue provide an attractive platform of implementation for hyperthermia or as carriers of chemotherapeutics. According to the literature, diverse effects of nanoparticles relating to mammalian reproductive tissue are described. To address the impact of nanoparticles on cyto- and genotoxicity concerning the reproductive system, we examined the effect of superparamagnetic iron oxide nanoparticles (SPIONs) on granulosa cells, which are very important for ovarian function and female fertility. Human granulosa cells (HLG-5) were treated with SPIONs, either coated with lauric acid (SEONLA) only, or additionally with a protein corona of bovine serum albumin (BSA; SEON(LA-BSA)), or with dextran (SEON(DEX)). Both micronuclei testing and the detection of γH2A.X revealed no genotoxic effects of SEON(LA-BSA), SEON(DEX) or SEON(LA). Thus, it was demonstrated that different coatings of SPIONs improve biocompatibility, especially in terms of genotoxicity towards cells of the reproductive system.

Nanomedical innovation: the SEON-concept for an improved cancer therapy with magnetic nanoparticles.

Nanomedicine offers tremendous opportunities for the development of novel therapeutic and diagnostic tools. During the last decades, extensive knowledge was gained about stabilizing and the coating of nanoparticles, their functionalization for drug binding and drug release and possible strategies for therapies and diagnostics of different diseases. Most recently, more and more emphasis has been placed on nanotoxicology and nanosafety aspects. The section of experimental oncology and nanomedicine developed a concept for translating this knowledge into clinical application of magnetic drug targeting for the treatment of cancer and other diseases using superparamagnetic iron oxide nanoparticles. This approach includes reproducible synthesis, detailed characterization, nanotoxicological testing, evaluation in ex vivo models, preclinical animal studies and production of superparamagnetic iron oxide nanoparticles according to good manufacturing practice regulations.

Treatment Efficiency of Free and Nanoparticle-Loaded Mitoxantrone for Magnetic Drug Targeting in Multicellular Tumor Spheroids.

Major problems of cancer treatment using systemic chemotherapy are severe side effects. Magnetic drug targeting (MDT) employing superparamagnetic iron oxide nanoparticles (SPION) loaded with chemotherapeutic agents may overcome this dilemma by increasing drug accumulation in the tumor and reducing toxic side effects in the healthy tissue. For translation of nanomedicine from bench to bedside, nanoparticle-mediated effects have to be studied carefully. In this study, we compare the effect of SPION, unloaded or loaded with the cytotoxic drug mitoxantrone (MTO) with the effect of free MTO, on the viability and proliferation of HT-29 cells within three-dimensional multicellular tumor spheroids. Fluorescence microscopy and flow cytometry showed that both free MTO, as well as SPION-loaded MTO (SPION(MTO)) are able to penetrate into tumor spheroids and thereby kill tumor cells, whereas unloaded SPION did not affect cellular viability. Since SPION(MTO) has herewith proven its effectivity also in complex multicellular tumor structures with its surrounding microenvironment, we conclude that it is a promising candidate for further use in magnetic drug targeting in vivo.

Shell matters: Magnetic targeting of SPIONs and in vitro effects on endothelial and monocytic cell function.

Superparamagnetic iron oxide nanoparticles (SPIONs) are versatile and easily functionalized agents with high potential for diagnostic and therapeutic intravascular applications. In this study, we analyzed the responses of endothelial (ECs) and monocytic cells to three different types of SPIONs, in order to assess the influence of physico-chemical properties on the biological reactions to SPIONs. The following formulations were used: (1) Lauric acid-coated and BSA-stabilized SPION-1,(2) Lauric acid/BSA-coated SPION-2 and (3) dextran-coated SPION-3. SPION-1 were strongly internalized by ECs and reduced their viability in static conditions. Additionally, they had a dose-dependent inhibitory effect on monocytic cell chemotaxis to MCP-1, but did not affect monocytic cell recruitment by ECs. SPION-2 uptake was less pronounced, both in ECs and monocytic cells, and these particles were better tolerated by the vascular cells. Not being internalized by endothelial or monocytic cells, SPION-3 did not induce relevant effects on cell viability, motility or endothelial-monocytic cell interactions.Taken together, localized accumulation of circulating SPION under physiologic-like flow conditions and their cellular uptake depends on the physicochemical characteristics. Our findings suggest that SPION-2 are suitable for magnetic targeting of atherosclerotic plaques. Due to their excellent biocompatibility and low internalization, SPION-3 may represent a suitable imaging agent for intravascular applications.

Tangential Flow Ultrafiltration Allows Purification and Concentration of Lauric Acid-/Albumin-Coated Particles for Improved Magnetic Treatment.

Superparamagnetic iron oxide nanoparticles (SPIONs) are frequently used for drug targeting, hyperthermia and other biomedical purposes. Recently, we have reported the synthesis of lauric acid-/albumin-coated iron oxide nanoparticles SEON(LA-BSA), which were synthesized using excess albumin. For optimization of magnetic treatment applications, SPION suspensions need to be purified of excess surfactant and concentrated. Conventional methods for the purification and concentration of such ferrofluids often involve high shear stress and low purification rates for macromolecules, like albumin. In this work, removal of albumin by low shear stress tangential ultrafiltration and its influence on SEON(LA-BSA) particles was studied. Hydrodynamic size, surface properties and, consequently, colloidal stability of the nanoparticles remained unchanged by filtration or concentration up to four-fold (v/v). Thereby, the saturation magnetization of the suspension can be increased from 446.5 A/m up to 1667.9 A/m. In vitro analysis revealed that cellular uptake of SEON(LA-BSA) changed only marginally. The specific absorption rate (SAR) was not greatly affected by concentration. In contrast, the maximum temperature Tmax in magnetic hyperthermia is greatly enhanced from 44.4 °C up to 64.9 °C by the concentration of the particles up to 16.9 mg/mL total iron. Taken together, tangential ultrafiltration is feasible for purifying and concentrating complex hybrid coated SPION suspensions without negatively influencing specific particle characteristics. This enhances their potential for magnetic treatment.

Magnetic nanoparticle-based drug delivery for cancer therapy.

Nanoparticles have belonged to various fields of biomedical research for quite some time. A promising site-directed application in the field of nanomedicine is drug targeting using magnetic nanoparticles which are directed at the target tissue by means of an external magnetic field. Materials most commonly used for magnetic drug delivery contain metal or metal oxide nanoparticles, such as superparamagnetic iron oxide nanoparticles (SPIONs). SPIONs consist of an iron oxide core, often coated with organic materials such as fatty acids, polysaccharides or polymers to improve colloidal stability and to prevent separation into particles and carrier medium [1]. In general, magnetite and maghemite particles are those most commonly used in medicine and are, as a rule, well-tolerated. The magnetic properties of SPIONs allow the remote control of their accumulation by means of an external magnetic field. Conjugation of SPIONs with drugs, in combination with an external magnetic field to target the nanoparticles (so-called "magnetic drug targeting", MDT), has additionally emerged as a promising strategy of drug delivery. Magnetic nanoparticle-based drug delivery is a sophisticated overall concept and a multitude of magnetic delivery vehicles have been developed. Targeting mechanism-exploiting, tumor-specific attributes are becoming more and more sophisticated. The same is true for controlled-release strategies for the diseased site. As it is nearly impossible to record every magnetic nanoparticle system developed so far, this review summarizes interesting approaches which have recently emerged in the field of targeted drug delivery for cancer therapy based on magnetic nanoparticles.

Flow cytometry for intracellular SPION quantification: specificity and sensitivity in comparison with spectroscopic methods.

Due to their special physicochemical properties, iron nanoparticles offer new promising possibilities for biomedical applications. For bench to bedside translation of super-paramagnetic iron oxide nanoparticles (SPIONs), safety issues have to be comprehensively clarified. To understand concentration-dependent nanoparticle-mediated toxicity, the exact quantification of intracellular SPIONs by reliable methods is of great importance. In the present study, we compared three different SPION quantification methods (ultraviolet spectrophotometry, magnetic particle spectroscopy, atomic adsorption spectroscopy) and discussed the shortcomings and advantages of each method. Moreover, we used those results to evaluate the possibility to use flow cytometric technique to determine the cellular SPION content. For this purpose, we correlated the side scatter data received from flow cytometry with the actual cellular SPION amount. We showed that flow cytometry provides a rapid and reliable method to assess the cellular SPION content. Our data also demonstrate that internalization of iron oxide nanoparticles in human umbilical vein endothelial cells is strongly dependent to the SPION type and results in a dose-dependent increase of toxicity. Thus, treatment with lauric acid-coated SPIONs (SEON(LA)) resulted in a significant increase in the intensity of side scatter and toxicity, whereas SEON(LA) with an additional protein corona formed by bovine serum albumin (SEON(LA-BSA)) and commercially available Rienso(®) particles showed only a minimal increase in both side scatter intensity and cellular toxicity. The increase in side scatter was in accordance with the measurements for SPION content by the atomic adsorption spectroscopy reference method. In summary, our data show that flow cytometry analysis can be used for estimation of uptake of SPIONs by mammalian cells and provides a fast tool for scientists to evaluate the safety of nanoparticle products.

Different storage conditions influence biocompatibility and physicochemical properties of iron oxide nanoparticles.

Superparamagnetic iron oxide nanoparticles (SPIONs) have attracted increasing attention in many biomedical fields. In magnetic drug targeting SPIONs are injected into a tumour supplying artery and accumulated inside the tumour with a magnet. The effectiveness of this therapy is thus dependent on magnetic properties, stability and biocompatibility of the particles. A good knowledge of the effect of storage conditions on those parameters is of utmost importance for the translation of the therapy concept into the clinic and for reproducibility in preclinical studies. Here, core shell SPIONs with a hybrid coating consisting of lauric acid and albumin were stored at different temperatures from 4 to 45 °C over twelve weeks and periodically tested for their physicochemical properties over time. Surprisingly, even at the highest storage temperature we did not observe denaturation of the protein or colloidal instability. However, the saturation magnetisation decreased by maximally 28.8% with clear correlation to time and storage temperature. Furthermore, the biocompatibility was clearly affected, as cellular uptake of the SPIONs into human T-lymphoma cells was crucially dependent on the storage conditions. Taken together, the results show that the particle properties undergo significant changes over time depending on the way they are stored.

Development of a lauric acid/albumin hybrid iron oxide nanoparticle system with improved biocompatibility.

The promising potential of superparamagnetic iron oxide nanoparticles (SPIONs) in various nanomedical applications has been frequently reported. However, although many different synthesis methods, coatings, and functionalization techniques have been described, not many core-shell SPION drug delivery systems are available for clinicians at the moment. Here, bovine serum albumin was adsorbed onto lauric acid-stabilized SPIONs. The agglomeration behavior, zeta potential, and their dependence on the synthesis conditions were characterized with dynamic light scattering. The existence and composition of the core-shell-matrix structure was investigated by transmission electron microscopy, Fourier transform infrared spectroscopy, and zeta potential measurements. We showed that the iron oxide cores form agglomerates in the range of 80 nm. Moreover, despite their remarkably low tendency to aggregate even in a complex media like whole blood, the SPIONs still maintained their magnetic properties and were well attractable with a magnet. The magnetic properties were quantified by vibrating sample magnetometry and a superconducting quantum interference device. Using flow cytometry, we further investigated the effects of the different types of nanoparticle coating on morphology, viability, and DNA integrity of Jurkat cells. We showed that by addition of bovine serum albumin, the toxicity of nanoparticles is greatly reduced. We also investigated the effect of the particles on the growth of primary human endothelial cells to further demonstrate the biocompatibility of the particles. As proof of principle, we showed that the hybrid-coated particles are able to carry payloads of up to 800 µg/mL of the cytostatic drug mitoxantrone while still staying colloidally stable. The drug-loaded system exhibited excellent therapeutic potential in vitro, exceeding that of free mitoxantrone. In conclusion, we have synthesized a biocompatible ferrofluid that shows great potential for clinical application. The synthesis is straightforward and reproducible and thus easily translatable into a good manufacturing practice environment.

Development and characterization of magnetic iron oxide nanoparticles with a cisplatin-bearing polymer coating for targeted drug delivery.

A highly selective and efficient cancer therapy can be achieved using magnetically directed superparamagnetic iron oxide nanoparticles (SPIONs) bearing a sufficient amount of the therapeutic agent. In this project, SPIONs with a dextran and cisplatin-bearing hyaluronic acid coating were successfully synthesized as a novel cisplatin drug delivery system. Transmission electron microscopy images as well as X-ray diffraction analysis showed that the individual magnetite particles were around 4.5 nm in size and monocrystalline. The small crystallite sizes led to the superparamagnetic behavior of the particles, which was exemplified in their magnetization curves, acquired using superconducting quantum interference device measurements. Hyaluronic acid was bound to the initially dextran-coated SPIONs by esterification. The resulting amide bond linkage was verified using Fourier transform infrared spectroscopy. The additional polymer layer increased the vehicle size from 22 nm to 56 nm, with a hyaluronic acid to dextran to magnetite weight ratio of 51:29:20. A maximum payload of 330 µg cisplatin/mL nanoparticle suspension was achieved, thus the particle size was further increased to around 77 nm with a zeta potential of -45 mV. No signs of particle precipitation were observed over a period of at least 8 weeks. Analysis of drug-release kinetics using the dialysis tube method revealed that these were driven by inverse ligand substitution and diffusion through the polymer shell as well as enzymatic degradation of hyaluronic acid. The biological activity of the particles was investigated in a nonadherent Jurkat cell line using flow cytometry. Further, cell viability and proliferation was examined in an adherent PC-3 cell line using xCELLigence analysis. Both tests demonstrated that particles without cisplatin were biocompatible with these cells, whereas particles with the drug induced apoptosis in a dose-dependent manner, with secondary necrosis after prolonged incubation. In conclusion, combination of dextran-coated SPIONs with hyaluronic acid and cisplatin represents a promising approach for magnetic drug targeting in the treatment of cancer.