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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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Release kinetics of cisplatin from SEONDEX-HA*CPt in PBS at 37°C in comparison with pure cisplatin dissolved in PBS.Note: The influence of HAse present in the dialysis tubes is also shown.Abbreviations: PBS, phosphate-buffered saline; SEONDEX, dextran-coated SPIONs; SPIONs, superparamagnetic iron oxide nanoparticles; CPt, cisplatin; HA, hyaluronic acid; HAse, hyaluronidase.
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f10-ijn-9-3659: Release kinetics of cisplatin from SEONDEX-HA*CPt in PBS at 37°C in comparison with pure cisplatin dissolved in PBS.Note: The influence of HAse present in the dialysis tubes is also shown.Abbreviations: PBS, phosphate-buffered saline; SEONDEX, dextran-coated SPIONs; SPIONs, superparamagnetic iron oxide nanoparticles; CPt, cisplatin; HA, hyaluronic acid; HAse, hyaluronidase.

Mentions: Before the biological impact on cells was evaluated, the drug release kinetics of SEONDEX-HA*CPt were investigated in physiological saline at 37°C. Figure 10 depicts the time-dependent cumulative release of cisplatin, which shows two stages. Firstly, an initial burst release (26.2%) occurred within 30 minutes, which is typical for a surface-bound drug. Afterwards, the kinetics were dominated by a continuous release of cisplatin until 48 hours due to inverse ligand substitution of chloride atoms in phosphate-buffered saline. Pure cisplatin dissolved in phosphate-buffered saline was used as a control in order to investigate how long it took the drug to escape the dialysis tube after its liberation. The initial release of the control was 60% and after 1 hour around had 90% diffused out of the tube. This comparison illustrates that SEONDEX-HA*CPt successfully retarded release of the drug. This is an important feature because liberation of cisplatin should be minimal during transport of the drug vehicle to the target site. High levels of HAse activity have been found in various tumors.49,50 Its presence in dialysis tubes increased the cisplatin release rate, due to enzymatic degradation of HA. Consistently, the initial release within the first 30 minutes increased from 26.2% to 42.4% and the whole drug was released rapidly within 24 hours. Since SEONDEX-HA*CPt dispersed in an aqueous solution did not release a measurable amount of cisplatin within 48 hours, it can be concluded that the release mechanism in vivo and in vitro is determined by a combination of HA degradation and inverse ligand substitution and diffusion through the polymer shell.


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)

Release kinetics of cisplatin from SEONDEX-HA*CPt in PBS at 37°C in comparison with pure cisplatin dissolved in PBS.Note: The influence of HAse present in the dialysis tubes is also shown.Abbreviations: PBS, phosphate-buffered saline; SEONDEX, dextran-coated SPIONs; SPIONs, superparamagnetic iron oxide nanoparticles; CPt, cisplatin; HA, hyaluronic acid; HAse, hyaluronidase.
© Copyright Policy
Related In: Results  -  Collection

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

f10-ijn-9-3659: Release kinetics of cisplatin from SEONDEX-HA*CPt in PBS at 37°C in comparison with pure cisplatin dissolved in PBS.Note: The influence of HAse present in the dialysis tubes is also shown.Abbreviations: PBS, phosphate-buffered saline; SEONDEX, dextran-coated SPIONs; SPIONs, superparamagnetic iron oxide nanoparticles; CPt, cisplatin; HA, hyaluronic acid; HAse, hyaluronidase.
Mentions: Before the biological impact on cells was evaluated, the drug release kinetics of SEONDEX-HA*CPt were investigated in physiological saline at 37°C. Figure 10 depicts the time-dependent cumulative release of cisplatin, which shows two stages. Firstly, an initial burst release (26.2%) occurred within 30 minutes, which is typical for a surface-bound drug. Afterwards, the kinetics were dominated by a continuous release of cisplatin until 48 hours due to inverse ligand substitution of chloride atoms in phosphate-buffered saline. Pure cisplatin dissolved in phosphate-buffered saline was used as a control in order to investigate how long it took the drug to escape the dialysis tube after its liberation. The initial release of the control was 60% and after 1 hour around had 90% diffused out of the tube. This comparison illustrates that SEONDEX-HA*CPt successfully retarded release of the drug. This is an important feature because liberation of cisplatin should be minimal during transport of the drug vehicle to the target site. High levels of HAse activity have been found in various tumors.49,50 Its presence in dialysis tubes increased the cisplatin release rate, due to enzymatic degradation of HA. Consistently, the initial release within the first 30 minutes increased from 26.2% to 42.4% and the whole drug was released rapidly within 24 hours. Since SEONDEX-HA*CPt dispersed in an aqueous solution did not release a measurable amount of cisplatin within 48 hours, it can be concluded that the release mechanism in vivo and in vitro is determined by a combination of HA degradation and inverse ligand substitution and diffusion through the polymer shell.

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