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Characterization of magnetic viral complexes for targeted delivery in oncology.

Almstätter I, Mykhaylyk O, Settles M, Altomonte J, Aichler M, Walch A, Rummeny EJ, Ebert O, Plank C, Braren R - Theranostics (2015)

Bottom Line: Assembly and cell internalization of MNP-VP complexes resulted in 81 - 97 % reduction of r2 and 35 - 82 % increase of r2(*) compared to free MNPs.In a proof-of-principle study the non-invasive detection of MNP-VPs by MRI was shown in vivo in an orthotopic rat hepatocellular carcinoma model.In conclusion, MNP assembly and compartmentalization have a major impact on relaxivities, therefore calibration measurements are required for the correct quantification in biodistribution studies.

View Article: PubMed Central - PubMed

Affiliation: 1. Department of Diagnostic and Interventional Radiology, Klinikum rechts der Isar der Technischen Universität München, Munich, Germany;

ABSTRACT
Oncolytic viruses are promising new agents in cancer therapy. Success of tumor lysis is often hampered by low intra-tumoral titers due to a strong anti-viral host immune response and insufficient tumor targeting. Previous work on the co-assembly of oncolytic virus particles (VPs) with magnetic nanoparticles (MNPs) was shown to provide shielding from inactivating immune response and improve targeting by external field gradients. In addition, MNPs are detected by magnet resonance imaging (MRI) enabling non-invasive therapy monitoring. In this study two selected core-shell type iron oxide MNPs were assembled with adenovirus (Ad) or vesicular stomatitis virus (VSV). The selected MNPs were characterized by high r2 and r2(*) relaxivities and thus could be quantified non-invasively by 1.5 and 3.0 tesla MRI with a detection limit below 0.001 mM iron in tissue-mimicking phantoms. Assembly and cell internalization of MNP-VP complexes resulted in 81 - 97 % reduction of r2 and 35 - 82 % increase of r2(*) compared to free MNPs. The relaxivity changes could be attributed to the clusterization of particles and complexes shown by transmission electron microscopy (TEM). In a proof-of-principle study the non-invasive detection of MNP-VPs by MRI was shown in vivo in an orthotopic rat hepatocellular carcinoma model. In conclusion, MNP assembly and compartmentalization have a major impact on relaxivities, therefore calibration measurements are required for the correct quantification in biodistribution studies. Furthermore, our study provides first evidence of the in vivo applicability of selected MNP-VPs in cancer therapy.

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In vivo targeting of SO-Mag-VSV complexes. A Pre- and 24 hour post-injection T2-weighted MR images of orthotopic HCC after SO-Mag-VSV complex (top row) or naked VSV (bottom row) injection. The corresponding histograms (A, right) illustrate the signal loss after magnetic complex application in an emerging signal shoulder in the lower signal range. B Overview (top) and high magnification micrographs of prussian blue staining 24 hours after SO-Mag-VSV complex injection. The asterisk marks the injection site and the magnet was placed above the boxed area (top); scale bars 2,000 µm (top) and 500 µm (bottom), respectively. C Intra-tumoral virus titer and non-heme iron of whole tumors sampled 30 minutes post infection with SO-Mag-VSV complexes (n=4, blue) and naked VSV (n=3, black).
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Figure 9: In vivo targeting of SO-Mag-VSV complexes. A Pre- and 24 hour post-injection T2-weighted MR images of orthotopic HCC after SO-Mag-VSV complex (top row) or naked VSV (bottom row) injection. The corresponding histograms (A, right) illustrate the signal loss after magnetic complex application in an emerging signal shoulder in the lower signal range. B Overview (top) and high magnification micrographs of prussian blue staining 24 hours after SO-Mag-VSV complex injection. The asterisk marks the injection site and the magnet was placed above the boxed area (top); scale bars 2,000 µm (top) and 500 µm (bottom), respectively. C Intra-tumoral virus titer and non-heme iron of whole tumors sampled 30 minutes post infection with SO-Mag-VSV complexes (n=4, blue) and naked VSV (n=3, black).

Mentions: To test targeting and non-invasive detectability of MNP-VP in vivo, orthotopic hepatocellular carcinoma (HCC) bearing rats were intra-tumorally injected with SO-Mag-VSV complexes in the presence of an external magnetic field. MR imaging at 24 hours post injection clearly delineated intratumoral decrease in signal intensity (figure 9A top). Regional histogram analysis quantified the signal intensity shift of SO-Mag-VSV complex-injected tumors in the lower signal range (figure 9A right). Histological analysis showed MNP-VP complex accumulation at the side of magnet placement (figure 9B). Ex vivo analysis revealed increased VSV titer and non-heme iron content of SO-Mag-VSV complex-injected compared to naked VSV-injected tumors (figure 9C).


Characterization of magnetic viral complexes for targeted delivery in oncology.

Almstätter I, Mykhaylyk O, Settles M, Altomonte J, Aichler M, Walch A, Rummeny EJ, Ebert O, Plank C, Braren R - Theranostics (2015)

In vivo targeting of SO-Mag-VSV complexes. A Pre- and 24 hour post-injection T2-weighted MR images of orthotopic HCC after SO-Mag-VSV complex (top row) or naked VSV (bottom row) injection. The corresponding histograms (A, right) illustrate the signal loss after magnetic complex application in an emerging signal shoulder in the lower signal range. B Overview (top) and high magnification micrographs of prussian blue staining 24 hours after SO-Mag-VSV complex injection. The asterisk marks the injection site and the magnet was placed above the boxed area (top); scale bars 2,000 µm (top) and 500 µm (bottom), respectively. C Intra-tumoral virus titer and non-heme iron of whole tumors sampled 30 minutes post infection with SO-Mag-VSV complexes (n=4, blue) and naked VSV (n=3, black).
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Related In: Results  -  Collection

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Figure 9: In vivo targeting of SO-Mag-VSV complexes. A Pre- and 24 hour post-injection T2-weighted MR images of orthotopic HCC after SO-Mag-VSV complex (top row) or naked VSV (bottom row) injection. The corresponding histograms (A, right) illustrate the signal loss after magnetic complex application in an emerging signal shoulder in the lower signal range. B Overview (top) and high magnification micrographs of prussian blue staining 24 hours after SO-Mag-VSV complex injection. The asterisk marks the injection site and the magnet was placed above the boxed area (top); scale bars 2,000 µm (top) and 500 µm (bottom), respectively. C Intra-tumoral virus titer and non-heme iron of whole tumors sampled 30 minutes post infection with SO-Mag-VSV complexes (n=4, blue) and naked VSV (n=3, black).
Mentions: To test targeting and non-invasive detectability of MNP-VP in vivo, orthotopic hepatocellular carcinoma (HCC) bearing rats were intra-tumorally injected with SO-Mag-VSV complexes in the presence of an external magnetic field. MR imaging at 24 hours post injection clearly delineated intratumoral decrease in signal intensity (figure 9A top). Regional histogram analysis quantified the signal intensity shift of SO-Mag-VSV complex-injected tumors in the lower signal range (figure 9A right). Histological analysis showed MNP-VP complex accumulation at the side of magnet placement (figure 9B). Ex vivo analysis revealed increased VSV titer and non-heme iron content of SO-Mag-VSV complex-injected compared to naked VSV-injected tumors (figure 9C).

Bottom Line: Assembly and cell internalization of MNP-VP complexes resulted in 81 - 97 % reduction of r2 and 35 - 82 % increase of r2(*) compared to free MNPs.In a proof-of-principle study the non-invasive detection of MNP-VPs by MRI was shown in vivo in an orthotopic rat hepatocellular carcinoma model.In conclusion, MNP assembly and compartmentalization have a major impact on relaxivities, therefore calibration measurements are required for the correct quantification in biodistribution studies.

View Article: PubMed Central - PubMed

Affiliation: 1. Department of Diagnostic and Interventional Radiology, Klinikum rechts der Isar der Technischen Universität München, Munich, Germany;

ABSTRACT
Oncolytic viruses are promising new agents in cancer therapy. Success of tumor lysis is often hampered by low intra-tumoral titers due to a strong anti-viral host immune response and insufficient tumor targeting. Previous work on the co-assembly of oncolytic virus particles (VPs) with magnetic nanoparticles (MNPs) was shown to provide shielding from inactivating immune response and improve targeting by external field gradients. In addition, MNPs are detected by magnet resonance imaging (MRI) enabling non-invasive therapy monitoring. In this study two selected core-shell type iron oxide MNPs were assembled with adenovirus (Ad) or vesicular stomatitis virus (VSV). The selected MNPs were characterized by high r2 and r2(*) relaxivities and thus could be quantified non-invasively by 1.5 and 3.0 tesla MRI with a detection limit below 0.001 mM iron in tissue-mimicking phantoms. Assembly and cell internalization of MNP-VP complexes resulted in 81 - 97 % reduction of r2 and 35 - 82 % increase of r2(*) compared to free MNPs. The relaxivity changes could be attributed to the clusterization of particles and complexes shown by transmission electron microscopy (TEM). In a proof-of-principle study the non-invasive detection of MNP-VPs by MRI was shown in vivo in an orthotopic rat hepatocellular carcinoma model. In conclusion, MNP assembly and compartmentalization have a major impact on relaxivities, therefore calibration measurements are required for the correct quantification in biodistribution studies. Furthermore, our study provides first evidence of the in vivo applicability of selected MNP-VPs in cancer therapy.

Show MeSH
Related in: MedlinePlus