Multimodal Radiobioconjugates of Magnetic Nanoparticles Labeled with 44Sc and 47Sc for Theranostic Application.

This study was performed to synthesize multimodal radiopharmaceutical designed for the diagnosis and treatment of prostate cancer. To achieve this goal, superparamagnetic iron oxide (SPIO) nanoparticles were used as a platform for targeting molecule (PSMA-617) and for complexation of two scandium radionuclides, 44Sc for PET imaging and 47Sc for radionuclide therapy. TEM and XPS images showed that the Fe3O4 NPs have a uniform cubic shape and a size from 38 to 50 nm. The Fe3O4 core are surrounded by SiO2 and an organic layer. The saturation magnetization of the SPION core was 60 emu/g. However, coating the SPIONs with silica and polyglycerol reduces the magnetization significantly. The obtained bioconjugates were labeled with 44Sc and 47Sc, with a yield higher than 97%. The radiobioconjugate exhibited high affinity and cytotoxicity toward the human prostate cancer LNCaP (PSMA+) cell line, much higher than for PC-3 (PSMA-) cells. High cytotoxicity of the radiobioconjugate was confirmed by radiotoxicity studies on LNCaP 3D spheroids. In addition, the magnetic properties of the radiobioconjugate should allow for its use in guide drug delivery driven by magnetic field gradient.

Synthesis and morphological studies of Tc-99m-labeled lupulone-conjugated Fe3O4@TiO2 nanocomposite, and in vitro cytotoxicity activity on prostate cancer cell lines.

The purpose of this study was to develop a multifunctional theranostic probe for imaging (magnetic resonance imaging [MRI] and single-photon emission computed tomography [SPECT]) and therapy (photodynamic therapy). For this purpose, Tc-99m-labeled lupulone-conjugated Fe3O4@TiO2 nanocomposites (99mTc-DTPA-Fe3O4@TiO2-HLP and 99mTc-DTPA-Fe3O4@TiO2-ALP nanocomposites) were synthesized. The average diameter of the nanocomposites was 171 ± 20 nm as seen on transmission electron microscopy images. Fe3O4@TiO2 nanocomposites exhibited fluorescence spectra at an emission wavelength of 314 nm. Lupulone-conjugated Fe3O4@TiO2 nanocomposites were spherical-shaped with a suitable dispersion and without visible aggregation, and their radiolabeling yields were over 85%. Healthy (RWPE-1 normal human prostate epithelial cell line) and cancer prostate cell lines (PC-3 human prostate cancer cell line) were used to determine the in vitro biological behavior of the nanocomposites. The PC-3 cells treated with lupulone-conjugated Fe3O4@TiO2 nanocomposites showed a lower cell viability compared with RWPE-1 cells treated with lupulone-conjugated Fe3O4@TiO2 nanocomposites. Lupulone-modified Fe3O4@TiO2 nanocomposites may serve in the future as a multifunctional probe for positron emission tomography (PET)/MRI, photodynamic therapy, and hyperthermia therapy of cancer.

Toxicity testing of indocyanine green and fluorodeoxyglucose conjugated iron oxide nanoparticles with and without exposure to a magnetic field.

Iron nanoparticles (MNPs) are known to induce membrane damage and apoptosis of cancer cells. In our study we determined whether FDG coupled with iron oxide magnetic nanoparticles can exert the same destructive effect on cancer cells. This research study presents data involving NIC-H727 human lung, bronchus epithelial cells exposed to conjugated fluorodeoxyglucose conjugated with iron-oxide magnetic nanoparticles and indocyanine green (ICG) dye (FDG-MNP-ICG), with and without the application of a magnetic field. Cell viability inferred from MTT assay revealed that FDG-MNPs had no significant toxicity towards noncancerous NIC-H727 human lung, bronchus epithelial cells. However, percentage cell death was much higher using a magnetic field, for the concentration of FDG-MNP-ICC used in our experiments. Magnetic field was able to destroy cells containing MNPs, while MNPs alone had significantly lower effects. Additionally, MNPs alone in these low concentrations had less adverse effects on healthy (non-target) cells.

Effects of fluorodeoxyglucose magnetic nanoparticles on NCI-H727 and SH-SY5Y cancer cells.

We present a report regarding the cytotoxic effects of iron-based magnetic nanoparticles conjugated with fluorodeoxyglucose (FDG-mNPs) on the viability of NCI-H727 and SH-SY5Y cancer cells. MTT assays were performed to determine cell viability in treated cancer cells grown under standard 2D culture conditions. FDG-mNP concentrations of 0.075 mg/mL, 0.15 mg/mL, and 0.3 mg/mL decreased mean cell viability of NCI-H727 cells to 92.5%, 82.9%, and 75% respectively. FDG-mNPs was also shown to have a detrimental effect on the viability of SY5Y cells: a decrease of 5.7%, 18.6%, and 36.4% was found for SY5Y cells treated with 0.075 mg/mL, 0.15 mg/mL, and 0.3 mg/mL concentrations of FDG-mNPs, respectively. When NCI-H727 and SH-SY5Y cancer cells were grown as 3D spheroids, morphology was visibly changed and the number of viable cells was decerased in spheroids treated with FDG-mNPs compared with untreated spheroids. The results of our study demonstrated that FDG-mNP has toxic effects on NCI-H7272 and SY5Y cancer cells, and we conclude that conjugated FDG-mNPs are promising in the development of clinical applications for the destruction of cancer cells.

Effects of Fluorodeoxyglucose Conjugated and Unconjugated Iron Oxide Magnetic Nanoparticles on Macrophages: a Pilot Study

Abstract The effects of fluorodeoxyglucose conjugated iron oxide magnetic nanoparticles (FDGMNP) on macrophages are presented using a yeast substrate. Iron oxide magnetic nanoparticles (MNP) were synthesized by partially reducing FeCl3, then conjugated with (3-aminopropyl) triethoxysilane (APTES) after silication with tetraethyl orthosilicate. Silanated MMP nanoparticles were combined with fluorodeoxyglucose (FDG). Fluorodeoxyglucose iron oxide magnetic nanoparticles (FDGMNP) and its unconjugated control (MNP) were added (1mL) to the cells from the murine macrophage-like, Abelson murine leukemia virus transformed cell line RAW 264.7 (American Type Culture Collection number TIB-71) cell culture wells at different concentrations from 90-3.6 μg/mL. Cells were placed on the magnet plate for 30 min before incubating at 37°C, 5% CO2 overnight. MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide tetrazolium) assay was performed to measure cell viability. Our results demonstrate that iron based nanoparticles can be linked to macrophages (elements of the immune system that attack bacteria) without the function of the macrophages being affected, ie no detrimental effects to the macrophages were evident in these experiments. We conclude that neither FDGMNP nor MNP had a detrimental effect on macrophage function.

Tissue Morphology and Gene Expression Characterisation of Transplantable Adenocarcinoma Bearing Mice Exposed to Fluorodeoxyglucose-Conjugated Magnetic Nanoparticles.

Fluorodeoxyglucose-conjugated magnetic nanoparticles, designed to target cancer cells with high specificity when heated by an alternating magnetic field, could provide a low-cost, non-toxic treatment for cancer. However, it is essential that the in vivo impacts of such technologies on both tumour and healthy tissues are characterised fully. Profiling tissue gene expression by semi-quantitative reverse transcriptase real-time PCR can provide a sensitive measurement of tissue response to treatment. However, the accuracy of such analyses is dependent on the selection of stable reference genes. In this study, we determined the impact of fluorodeoxyglucose-conjugated magnetic nanoparticles on tumour and non-tumour tissue gene expression and morphology in MAC16 adenocarcinoma established male NMRI mice. Mice received an injection of 8 mg/kg body weight fluorodeoxyglucose-conjugated magnetic nanoparticles either intravenously in to the tail vein, directly into the tumour or subcutaneously directly overlying the tumour. Tissues from mice were sampled between 70 minutes and 12 hours post injection. Using the bioinformatic geNorm tool, we established the stability of six candidate reference genes (Hprt, Pgk1, Ppib, Sdha, Tbp and Tuba); we observed Pgk1 and Ppib to be the most stable. We then characterised the expression profiles of several apoptosis genes of interest in our adenocarcinoma samples, observing differential expression in response to mode of administration and exposure duration. Using histological assessment and fluorescent TUNNEL staining, we observed no detrimental impact on either tumour or non-tumour tissue morphology or levels of apoptosis. These observations define the underlying efficacy of fluorodeoxyglucose-conjugated magnetic nanoparticles on tumour and non-tumour tissue morphology and gene expression, setting the basis for future studies.