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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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Light microscope images of Jurkat cells after 30 hours of treatment with cisplatin fluid.Notes: SEONDEX-HA*CPt, and SEONDEX-HA. SEONDEX-HA without the drug did not induce cell death, whereas cisplatin fluid and SEONDEX-HA*CPt with cisplatin concentration from 1 μg/mL onwards induced blebbing and shredding of the plasma membrane in a dose-dependent manner.Abbreviations: PBS, phosphate-buffered saline; SEONDEX, dextran-coated SPIONs; SPIONs, superparamagnetic iron oxide nanoparticles; CPt, cisplatin; HA, hyaluronic acid; conc., concentration.
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f12-ijn-9-3659: Light microscope images of Jurkat cells after 30 hours of treatment with cisplatin fluid.Notes: SEONDEX-HA*CPt, and SEONDEX-HA. SEONDEX-HA without the drug did not induce cell death, whereas cisplatin fluid and SEONDEX-HA*CPt with cisplatin concentration from 1 μg/mL onwards induced blebbing and shredding of the plasma membrane in a dose-dependent manner.Abbreviations: PBS, phosphate-buffered saline; SEONDEX, dextran-coated SPIONs; SPIONs, superparamagnetic iron oxide nanoparticles; CPt, cisplatin; HA, hyaluronic acid; conc., concentration.

Mentions: The impact of the particles and fluid cisplatin is also shown in the light microscope images recorded after 30 hours of treatment (Figure 12). The controls and the particles without drug displayed Jurkat cells with viable morphology. In comparison, the cisplatin fluid and SEONDEX-HA*CPt samples exhibited blebbing and shredding of the plasma membrane, starting from 1 μg/mL cisplatin and increasing in severity with increasing concentration. In addition to Annexin V/propidium iodide measurement, the mitochondrial membrane potential of the cells was analyzed by Hoechst 33342/DiI staining. The principle for this method is that healthy cells have a proton gradient in the inner mitochondrial plasma membrane, generating the conversion from adenosine diphosphate to adenosine triphosphate. A decrease in this mitochondrial potential is an indicator of apoptosis and necrosis and can be detected with DiI, a compound that penetrates the cytosol of cells and accumulates in active mitochondria.51 After treatment of the cells with SEONDEX-HA for 48 hours, the mitochondrial membrane potential was not significantly affected (Figure S1). The results for fluid cisplatin and SEONDEX-HA*CPt are in good agreement with the Annexin V/propidium iodide measurements, showing a dose-dependent increase in membrane potential reduction and also a delayed effect of SEONDEX-HA*CPt compared with fluid cisplatin.


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)

Light microscope images of Jurkat cells after 30 hours of treatment with cisplatin fluid.Notes: SEONDEX-HA*CPt, and SEONDEX-HA. SEONDEX-HA without the drug did not induce cell death, whereas cisplatin fluid and SEONDEX-HA*CPt with cisplatin concentration from 1 μg/mL onwards induced blebbing and shredding of the plasma membrane in a dose-dependent manner.Abbreviations: PBS, phosphate-buffered saline; SEONDEX, dextran-coated SPIONs; SPIONs, superparamagnetic iron oxide nanoparticles; CPt, cisplatin; HA, hyaluronic acid; conc., concentration.
© Copyright Policy
Related In: Results  -  Collection

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

f12-ijn-9-3659: Light microscope images of Jurkat cells after 30 hours of treatment with cisplatin fluid.Notes: SEONDEX-HA*CPt, and SEONDEX-HA. SEONDEX-HA without the drug did not induce cell death, whereas cisplatin fluid and SEONDEX-HA*CPt with cisplatin concentration from 1 μg/mL onwards induced blebbing and shredding of the plasma membrane in a dose-dependent manner.Abbreviations: PBS, phosphate-buffered saline; SEONDEX, dextran-coated SPIONs; SPIONs, superparamagnetic iron oxide nanoparticles; CPt, cisplatin; HA, hyaluronic acid; conc., concentration.
Mentions: The impact of the particles and fluid cisplatin is also shown in the light microscope images recorded after 30 hours of treatment (Figure 12). The controls and the particles without drug displayed Jurkat cells with viable morphology. In comparison, the cisplatin fluid and SEONDEX-HA*CPt samples exhibited blebbing and shredding of the plasma membrane, starting from 1 μg/mL cisplatin and increasing in severity with increasing concentration. In addition to Annexin V/propidium iodide measurement, the mitochondrial membrane potential of the cells was analyzed by Hoechst 33342/DiI staining. The principle for this method is that healthy cells have a proton gradient in the inner mitochondrial plasma membrane, generating the conversion from adenosine diphosphate to adenosine triphosphate. A decrease in this mitochondrial potential is an indicator of apoptosis and necrosis and can be detected with DiI, a compound that penetrates the cytosol of cells and accumulates in active mitochondria.51 After treatment of the cells with SEONDEX-HA for 48 hours, the mitochondrial membrane potential was not significantly affected (Figure S1). The results for fluid cisplatin and SEONDEX-HA*CPt are in good agreement with the Annexin V/propidium iodide measurements, showing a dose-dependent increase in membrane potential reduction and also a delayed effect of SEONDEX-HA*CPt compared with fluid cisplatin.

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