Characterization of magnetic viral complexes for targeted delivery in oncology.

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

Investigation into the metabolism of 1,8-cineole in an intestinal cell culture model and acquisition of its immune-modulatory effect via gene expression analysis

1,8-Cineole, a common and widely used odorant with antiphlogistic and anti-inflammatory properties, was investigated in this study with regard to potential physiological effects targeting mainly its intestinal effects. Accordingly, the aim of the study was to utilize a combinatory methodological approach to both monitor potential biotransformatory effects on a chemo-analytical basis, as well as physiological and immunological tools to monitor further effects of biofeedback. Reverse transcription quantitative real-time polymerase chain reaction was used to monitor the occurrence of relative expression changes for particular marker genes, following 1,8-cineole treatment. Furthermore, a potential effect of 1,8-cineole on the proliferation and fitness of the intestinal cells using impedance sensing was studied. Generally, our studies showed that the applied model system did neither lead to any significant metabolite formation, nor did the applied dosages result in any major modifications with regard to gene expression. Also, it was shown that cineole had no effect on the intestinal porcine epithelial cells applied in pharmacological or physiological concentrations; neither during the attachment and spreading process nor on confluent cell layers. Only the exposure to high concentrations of cineole (> 1 g/l) affected the cells and led to massive cell detachment. Overall, our studies show that even common higher 1,8-cineole dosages do not seem to lead to any major physiological or aversive response, only until a critical concentration is reached that then directly leads to cell death within the intestinal model

Characterization of Magnetic Viral Complexes for Targeted Delivery in Oncology

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 r 2 and r 2 * 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 r 2 and 35 -82 % increase of r 2 * 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