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

Unterweger H, Tietze R, Janko C, Zaloga J, Lyer S, Dürr S, Taccardi N, Goudouri OM, Hoppe A, Eberbeck D, Schubert DW, Boccaccini AR, Alexiou C - Int J Nanomedicine (2014)

Bottom Line: In this project, SPIONs with a dextran and cisplatin-bearing hyaluronic acid coating were successfully synthesized as a novel cisplatin drug delivery system.The resulting amide bond linkage was verified using Fourier transform infrared spectroscopy.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.

View Article: PubMed Central - PubMed

Affiliation: ENT Department, Section of Experimental Oncology and Nanomedicine (SEON), Else Kroener-Fresenius-Stiftung-Professorship, University Hospital Erlangen, Germany.

ABSTRACT
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.

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Magnetite particle distributions derived from measuring 50 particles of the TEM images with ImageJ software.Notes: The sizes for SEONDEX 2.0 ranged from 3.0 nm to 6.5 nm and had a mean value of 4.5±0.7 nm (A). The sizes for SEONDEX 4.5 ranged from 3.0 nm to 6.5 nm and had a mean value of 4.4±0.9 nm (B). It can be concluded that the magnetite size distributions for all SEONDEX samples were quite narrow and in the same order of magnitude, independent of the dextran content. ImageJ software (version 1.48; National Institutes of Health, Bethesda, MD, USA).Abbreviations: TEM, transmission electron microscopy; SPIONs, superparamagnetic iron oxide nanoparticles; SEONDEX, dextran-coated SPIONs.
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f3-ijn-9-3659: Magnetite particle distributions derived from measuring 50 particles of the TEM images with ImageJ software.Notes: The sizes for SEONDEX 2.0 ranged from 3.0 nm to 6.5 nm and had a mean value of 4.5±0.7 nm (A). The sizes for SEONDEX 4.5 ranged from 3.0 nm to 6.5 nm and had a mean value of 4.4±0.9 nm (B). It can be concluded that the magnetite size distributions for all SEONDEX samples were quite narrow and in the same order of magnitude, independent of the dextran content. ImageJ software (version 1.48; National Institutes of Health, Bethesda, MD, USA).Abbreviations: TEM, transmission electron microscopy; SPIONs, superparamagnetic iron oxide nanoparticles; SEONDEX, dextran-coated SPIONs.

Mentions: The first intermediate was dextran-coated SPIONs (SEONDEX), which was the prerequisite for formation of SEONDEX-HA. The dextran content during coprecipitation had an influence on the Z-average, which was acquired with dynamic light scattering and is shown in Figure 1. It is noteworthy that a dextran content of less than 2.0 g (in a total volume of 20 mL) was not sufficient to prevent formation of unstable agglomerates, at least with the given concentrations and precipitation parameters, such as stirring velocity, temperature, and input speed of the base. Therefore, formation of a stable colloid was first achieved with 2.0 g of dextran and had a Z-average of 37.5±0.6 nm. Basically, a further increase in dextran content led to a decrease in the hydrodynamic size until a saturation value of about 21.1±0.9 nm was reached for 4.5 g dextran. This observation makes sense because dextran adsorbs on the particle surface and confines the space for magnetite particle growth as well as agglomeration. The more polymer present in the solution, the more the confinement, until no agglomeration of magnetite particles can take place and only individual particles are dispersed in the dextran matrix. This hypothesis is strengthened with the assortment of TEM images shown in Figure 2. The overview image for SEONDEX 2.0 (number after SEONDEX applies to the dextran content used during coprecipitation; in this case, 2.0 means 2.0 g in a total volume of 20 mL) shows an agglomeration of roundish magnetite particles embedded in a polymer matrix. Figure 3 shows magnetite particle size distributions for SEONDEX 2.0 (Figure 3A) and 4.5 (Figure 3B) derived from measuring 250 particles in the TEM figures (data not shown) with ImageJ software. For both samples, the sizes ranged from 3.0 nm to 6.6 nm and had a mean value of 4.6±0.8 nm for SEONDEX 2.0 and 4.3±0.9 nm for SEONDEX 4.5, respectively. Therefore, it can be concluded that the core size distributions for all SEONDEX samples were quite narrow and in the same order of magnitude, independent of the dextran content. The narrow distribution can be explained by the fact that during coprecipitation the iron salts as well as the added ammonia were quickly and homogenously distributed within the dextran matrix due to the high rotary speed of the stirrer. In the TEM images for SEONDEX 2.0 with a higher magnification, it is possible to see the lattice planes of individual particles, which indicate that the individual magnetite particles were monocrystalline. In order to further examine the crystalline phases of SEONDEX, an X-ray diffraction pattern was recorded for SEONDEX 2.0 and SEONDEX 4.5 (Figure 4). The SEONDEX 2.0 sample shows typical peaks for the face-centered cubic spinel structure of magnetite, with the major peak at 35.3° corresponding to the (311) plane.44 Because of the small crystallites, other peaks for magnetite at 30.3° (220), 43.3° (400), 57.2° (511), and 62.5° (440) are less distinctive.45 In the case of the sample with the highest dextran content during coprecipitation, SEONDEX 4.5, the (311) peak almost vanishes, indicating a lower crystallinity.


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

Unterweger H, Tietze R, Janko C, Zaloga J, Lyer S, Dürr S, Taccardi N, Goudouri OM, Hoppe A, Eberbeck D, Schubert DW, Boccaccini AR, Alexiou C - Int J Nanomedicine (2014)

Magnetite particle distributions derived from measuring 50 particles of the TEM images with ImageJ software.Notes: The sizes for SEONDEX 2.0 ranged from 3.0 nm to 6.5 nm and had a mean value of 4.5±0.7 nm (A). The sizes for SEONDEX 4.5 ranged from 3.0 nm to 6.5 nm and had a mean value of 4.4±0.9 nm (B). It can be concluded that the magnetite size distributions for all SEONDEX samples were quite narrow and in the same order of magnitude, independent of the dextran content. ImageJ software (version 1.48; National Institutes of Health, Bethesda, MD, USA).Abbreviations: TEM, transmission electron microscopy; SPIONs, superparamagnetic iron oxide nanoparticles; SEONDEX, dextran-coated SPIONs.
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Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4128796&req=5

f3-ijn-9-3659: Magnetite particle distributions derived from measuring 50 particles of the TEM images with ImageJ software.Notes: The sizes for SEONDEX 2.0 ranged from 3.0 nm to 6.5 nm and had a mean value of 4.5±0.7 nm (A). The sizes for SEONDEX 4.5 ranged from 3.0 nm to 6.5 nm and had a mean value of 4.4±0.9 nm (B). It can be concluded that the magnetite size distributions for all SEONDEX samples were quite narrow and in the same order of magnitude, independent of the dextran content. ImageJ software (version 1.48; National Institutes of Health, Bethesda, MD, USA).Abbreviations: TEM, transmission electron microscopy; SPIONs, superparamagnetic iron oxide nanoparticles; SEONDEX, dextran-coated SPIONs.
Mentions: The first intermediate was dextran-coated SPIONs (SEONDEX), which was the prerequisite for formation of SEONDEX-HA. The dextran content during coprecipitation had an influence on the Z-average, which was acquired with dynamic light scattering and is shown in Figure 1. It is noteworthy that a dextran content of less than 2.0 g (in a total volume of 20 mL) was not sufficient to prevent formation of unstable agglomerates, at least with the given concentrations and precipitation parameters, such as stirring velocity, temperature, and input speed of the base. Therefore, formation of a stable colloid was first achieved with 2.0 g of dextran and had a Z-average of 37.5±0.6 nm. Basically, a further increase in dextran content led to a decrease in the hydrodynamic size until a saturation value of about 21.1±0.9 nm was reached for 4.5 g dextran. This observation makes sense because dextran adsorbs on the particle surface and confines the space for magnetite particle growth as well as agglomeration. The more polymer present in the solution, the more the confinement, until no agglomeration of magnetite particles can take place and only individual particles are dispersed in the dextran matrix. This hypothesis is strengthened with the assortment of TEM images shown in Figure 2. The overview image for SEONDEX 2.0 (number after SEONDEX applies to the dextran content used during coprecipitation; in this case, 2.0 means 2.0 g in a total volume of 20 mL) shows an agglomeration of roundish magnetite particles embedded in a polymer matrix. Figure 3 shows magnetite particle size distributions for SEONDEX 2.0 (Figure 3A) and 4.5 (Figure 3B) derived from measuring 250 particles in the TEM figures (data not shown) with ImageJ software. For both samples, the sizes ranged from 3.0 nm to 6.6 nm and had a mean value of 4.6±0.8 nm for SEONDEX 2.0 and 4.3±0.9 nm for SEONDEX 4.5, respectively. Therefore, it can be concluded that the core size distributions for all SEONDEX samples were quite narrow and in the same order of magnitude, independent of the dextran content. The narrow distribution can be explained by the fact that during coprecipitation the iron salts as well as the added ammonia were quickly and homogenously distributed within the dextran matrix due to the high rotary speed of the stirrer. In the TEM images for SEONDEX 2.0 with a higher magnification, it is possible to see the lattice planes of individual particles, which indicate that the individual magnetite particles were monocrystalline. In order to further examine the crystalline phases of SEONDEX, an X-ray diffraction pattern was recorded for SEONDEX 2.0 and SEONDEX 4.5 (Figure 4). The SEONDEX 2.0 sample shows typical peaks for the face-centered cubic spinel structure of magnetite, with the major peak at 35.3° corresponding to the (311) plane.44 Because of the small crystallites, other peaks for magnetite at 30.3° (220), 43.3° (400), 57.2° (511), and 62.5° (440) are less distinctive.45 In the case of the sample with the highest dextran content during coprecipitation, SEONDEX 4.5, the (311) peak almost vanishes, indicating a lower crystallinity.

Bottom Line: In this project, SPIONs with a dextran and cisplatin-bearing hyaluronic acid coating were successfully synthesized as a novel cisplatin drug delivery system.The resulting amide bond linkage was verified using Fourier transform infrared spectroscopy.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.

View Article: PubMed Central - PubMed

Affiliation: ENT Department, Section of Experimental Oncology and Nanomedicine (SEON), Else Kroener-Fresenius-Stiftung-Professorship, University Hospital Erlangen, Germany.

ABSTRACT
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.

Show MeSH
Related in: MedlinePlus