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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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Transmission electron microscopy. TEM images of magnetically labeled and transduced cells for both cell lines and MNP-VP complexes. The scale bars are 500 nm.
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Figure 4: Transmission electron microscopy. TEM images of magnetically labeled and transduced cells for both cell lines and MNP-VP complexes. The scale bars are 500 nm.

Mentions: To investigate the arrangement and aggregation of free and intracellular MNPs and MNP-VP complexes as well as their intracellular localization, transmission electron microscopy (TEM) was performed. Figure 3 shows TEM images of free MNPs and the different MNP-VP complexes for both types of VPs and MNPs. The suspended MNPs and MNP-VP complexes were mostly dispersed. Figure 4 compiles representative photomicrographs of the MNP and MNP-VP complex internalization in both cell lines. Free MNPs mainly clustered in the cytoplasm, in the RDB cells in endosomes while in McA cells the particles are more dispersed in the cytoplasm (figure 4, top row). In contrast to the free particles, MNP-VP complexes were localized exclusively in endosomes, independent of the cell type. Inside the endosomes, the magnetic and viral particles were arranged in a similar aggregate structure as the free MNPs in the cytoplasm.


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)

Transmission electron microscopy. TEM images of magnetically labeled and transduced cells for both cell lines and MNP-VP complexes. The scale bars are 500 nm.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4402492&req=5

Figure 4: Transmission electron microscopy. TEM images of magnetically labeled and transduced cells for both cell lines and MNP-VP complexes. The scale bars are 500 nm.
Mentions: To investigate the arrangement and aggregation of free and intracellular MNPs and MNP-VP complexes as well as their intracellular localization, transmission electron microscopy (TEM) was performed. Figure 3 shows TEM images of free MNPs and the different MNP-VP complexes for both types of VPs and MNPs. The suspended MNPs and MNP-VP complexes were mostly dispersed. Figure 4 compiles representative photomicrographs of the MNP and MNP-VP complex internalization in both cell lines. Free MNPs mainly clustered in the cytoplasm, in the RDB cells in endosomes while in McA cells the particles are more dispersed in the cytoplasm (figure 4, top row). In contrast to the free particles, MNP-VP complexes were localized exclusively in endosomes, independent of the cell type. Inside the endosomes, the magnetic and viral particles were arranged in a similar aggregate structure as the free MNPs in the cytoplasm.

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