Click on an contribution preview the abstract content.
Click on an contribution preview the abstract content.
Triggered radiosensitizer release by radiosensitizer-loaded thermosensitive liposomes and hyperthermia improves efficacy of radiotherapy: an in vitro proof of concept study (#271)
H. Besse1, C. Bos1, M. Zandvliet2, C. Moonen1, R. Deckers1
1 University Medical Center Utrecht, Center of Imaging Sciences, Utrecht, Netherlands
To increase the efficacy of radiotherapy (RT), it could be combined with drugs, radiosensitizers. This results in clinical improvement1, although it also leads to increased toxicity2.
Here, a new concept, local radiosensitizer delivery, is introduced in which radiosensitizers are released from thermosensitive liposomes (TSL) by local hyperthermia (HT) followed by RT.
In this study we investigate in vitro if triggered release of a radiosensitizer, doxorubicin (DOX), from a TSL (ThermoDox) by HT improves the efficacy of RT and if the radiosensitization effect of DOX is concentration dependent.
HT1080, human fibrosarcoma, cells were used. Cells were exposed to ThermoDox (0.02 µg/ml) or DOX (0.01, 0.02 or 0.06 µg/ml) for 1 hour in a water bath of 37°C or 43°C. 45 minutes after ThermoDox or DOX incubation, cells were irradiated by a linear accelerator (Elekta, 6MV). Subsequently cell viability was measured by clonogenic assay.
RT combined with ThermoDox at 37°C showed similar efficacy compared to RT as a single treatment, Figure 1, due to retention of DOX in the liposomes at 37°C3. ThermoDox and DOX at 43°C showed equal efficacy. However, ThermoDox at 43°C resulted in less radiosensitization at high RT doses when compared to DOX at 43°C, a difference that is not yet understood. DOX showed direct toxicity on cell survival, and proved an effective enhancement of the RT, although the enhancement of RT was only to some extend DOX concentration dependent, Figure 2.
ThermoDox in combination with HT improves the efficacy of RT in vitro, whereas in the absence of HT the efficacy was similar to that of only RT. This provides a first indication that in the concept of local radiosensitizer delivery, local heating of the tumor tissue will reduce systemic toxicity as well as toxicity to normal tissue in the beam path. Unfortunately, higher local concentrations of DOX will not lead to an extra sensitization boost in the tumor. In summary this study provided the first proof that local radiosensitizer delivery may improve efficacy, while reducing systemic toxicity.
1Pisters, ASO, 2002; 2Myrehaug, L&L, 2008; 3Needham, FD, 2013
ERC Sound Pharma – 268906 (CM)
Keywords: Triggered radiosensitizer delivery, chemoradiation, radiosensitizer, thermosensitive liposomes, radiotherapy
Kit-based labelling of heat-sensitive biomolecules using the inverse electron demand Diels-Alder cycloaddition reaction (#226)
F. Cleeren1, E. M. F. Billaud1, G. Bormans1
1 University of Leuven, Laboratory for radiopharmaceutical research, Leuven, Belgium
The fast reaction kinetics of the bioorthogonal inverse-electron demand Diels-Alder (IEDDA) reaction in aqueous medium between 1,2,4,5-tetrazines (Tz) and trans-cyclooctene (TCO) derivatives makes it possible to achieve quantitative yields (>95% within 5 min), avoiding the need of a final purification step and resulting in a kit-based labelling approach. Using this strategy, a protein of interest can be labelled at room temperature with different markers such as diagnostic radionuclides (e.g. fluorine-18), therapeutic radionuclides (e.g. Astatine-211) or fluorescent dyes (e.g. Cy5).
HSA was derivatised with the commercial available Tz-PEG-4-NHS to obtain Tz-PEG4-HSA. The Tz-to-protein ratio was determined by SEC-HPLC at a wavelength of 520 nm (characteristic tetrazine absorption). Kits with a volume of 1 ml and a concentration of 5 mg/ml, 1 mg/ml, 0.5 mg/ml, 0.1 mg/ml and 0.01 mg/ml of Tz-PEG4-HSA in PBS (0.1M pH 7.4) were prepared. Cy5-TCO (3.7 nmoles) or the 18F-labelled TCO-derivative, [18F]31 (7.4 MBq or 185 MBq, 100 GBq/µmol), were added to these kits. The labelling yields were monitored in function of time with iTLC and SEC-HPLC. A biodistribution study with [18F]F-HSA (2-7.5 MBq) was carried out in healthy female Wistar rats at 1 h (n=2), 3 h (n=4), and 6 h (n=2) post injection.
HSA was successfully derivatised with Tz-PEG-4-NHS to obtain Tz-PEG4-HSA with a Tz-to-protein ratio of 5. The IEDDA reaction between Tz-PEG4-HSA (1 mg/ml) and Cy5-TCO was quantitative (>98%). For all kits ranging from 5 mg/ml to 0.1 mg/ml, the reaction with 7.4 MBq [18F]3 was quantitative (>98%), only for the 0.01 mg/ml kit, a radiochemical yield of 90% was observed. When using the 5 mg/ml kit, the IEDDA reaction between Tz-PEG4-HSA and [18F]3 (185 MBq) was as well quantitative (>98%), affording 185 MBq [18F]F-HSA in 5 minutes, without the need for a final purification step. Biodistribution of [18F]F-HSA in rats showed high retention in blood with SUV: 14 ± 1.7, 10.2 ± 0.7, and 7.7 ± 0.5 at 1 h, 3 h, and 6 h, respectively. The blood biological half-life (Tb) was calculated to be 6.0 h, indicating that the introduction of PEG4-Tz residues into HSA and subsequent radiolabelling using the IEDDA-method did not alter the structural and functional integrity of HSA.
This generic kit-based labelling approach makes it possible to label heat-sensitive proteins easily with an arsenal of different markers without the need of a final purification step. As proof of concept, we succesfully labelled HSA with Cy5 and fluorine-18 in quantitative yields by exploiting the fast reaction kinetics of the IEDDA reaction. More experiments with different proteins of interest are warranted and the development of TCO-derivatives with therapeutic radionuclides would further increase the potential applications of this promising approach.
Billaud, E.M.F., Shahbazali, E., Ahamed, M., Cleeren, F., Noël, T., Koole, M., Verbruggen, A., Hessel, V., and Bormans G. (2017) Micro-Flow Photosynthesis of New Dienophiles for Inverse-Electron-Demand Diels-Alder Reactions. Potential applications for pretargeted in vivo PET imaging. Chem. Sci. 8, 1251-1258.
Keywords: kit-based labelling, IEDDA
Synthesis of Europium doped VSOP, customized enhancer solution and improved microscopy fluorescence methodology for unambiguous histological detection (#469)
A. Ariza de Schellenberger1, R. Hauptmann2, J. Millward3, E. Schellenberger4, Y. Kobayashi5, M. Taupitz2, C. Infante-Duarte6, J. Schnorr2, S. Wagner2
1 Charité - Universitätsmedizin Berlin, Radiology /Elastography, Berlin, Berlin, Germany
Intrinsic iron of biological tissues frequently makes the identification of iron oxide nanoparticles by iron based detection methods unambiguous. Here we report a complete methodology to synthesized very small iron oxide nanoparticles (VSOP) doped with europium (Eu) in their iron oxide core (Eu-VSOP) and their definite qualitative and quantitative detection by fluorescence.
VSOP were doped with different amounts of Eu (III) chloride addition relative to Fe (III) chloride during synthesis. A customized histo-Eu-enhancer (HEE) solution was prepared with the same antenna system used by the DELFIA® enhancer solution (Perkin Elmer) but, with a modified dihydrogen phosphate-hydrogen phosphate-buffer system (Figure 1). Eu-VSOP was administrated to C57BL/6 mice at a dose of 0.2 mmol/kg with approval by the regional animal study committee of Berlin (LAGeSo). After 24 hours, histological sections of spleen were incubated for 10 min with the HEE or the commercial DELFIA® enhancer and covered with mounting medium. Micrographs were obtained with an Axio Observer.Z1 (Carl Zeiss, Germany) 5 min, 30 min, and 60 min later. Eu was detected with a customized filter set.
The Eu-content of 0.7 to 2.7 % relative to iron of the synthesized Eu-VSOP was sufficient for fluorescent detection and did not alter other important particle parameters.
The Eu-VSOP showed in vitro and in vivo biocompatibility as investigated in additional studies with these nanoparticles1,2
The customized HEE solution demonstrated higher buffer capacity in solutions and more stable Eu-fluorescent signal in histological sections than the commercial DELFIA® enhancer. The customized HEE solution allows the detection of Eu-VSOP using a standard fluorescence spectrophotometer and a fluorescence microscope equipped with a custom filter set with an excitation filter (BP 350/50 nm), a beam splitter (380 nm LP), and an emission filter (HC 615/20 nm) (AHF Analysentechnik, Germany).
The fluorescent detection of Eu-doped iron oxide nanoparticles (IONP) provides a straightforward tool to unambiguously characterize IONP biodistribution and toxicology at tissue and cellular level and provides a sensitive analytical tool to detect Eu-doped IONP in dissolved organ tissue and biological fluids with fluorescence instruments.
1. Scharlach C, Müller L, Wagner S, Kobayashi Y, Kratz H, Ebert M, et al. LA-ICP-MS allows quantitative microscopy of europium-doped iron oxide nanoparticles and is a possible alternative to ambiguous prussian blue iron staining. J Biomed Nanotechnol. 2016;12: 1001-010.
2. Ariza de Schellenberger A, Kratz H, Farr T, Loewa N, Hauptmann R, Wagner S, et al. Labeling of mesenchymal stem cells for MRI with single-cell sensitivity. Int J Nanomedicine. 2016; 1517-531.
Keywords: VSOP, Europium, Fluorescence, MRI
Establishing a universally applicable kit radiolabeling solution for 68Ga-PSMA11 (#340)
J. R. Zeevaart1, 2, J. Suthiram1, 5, J. Wagener1, B. Marjanovic-Painter1, J. Mahapane4, T. Lengana3, M. Sathekge3, T. Ebenhan1, 5
1 Necsa, Radiochemistry, Pelindaba, South Africa
Targeting prostate-specific membrane antigen is an efficient biomarker in nuclear medicine. With Gallium-68 (68Ga) opportunely available to hospital radiopharmacies the foundation is set to develop a flexible, cost-efficient kit radiolabeling solution for Glu-NH-CO-NH-LysAhx-68Ga(HBEDCC) (68Ga-PSMA11) including a handling protocol equivalent to routinely used Technetium-99m kit preparations. We recently developed a PSMA11 kit radiolabeling solution (1). We report on an improved, universally applicable 68Ga-PSMA11 kit preparation and show its impact for human application in a large population.
During 2017 a total of 175 kit preparations of 68Ga-PSMA11 were performed from 5 individually manufactured batches (N=18-49). Each vial, containing as low as 5 nmol PSMA11 in sodium acetate trihydrate buffer, was reconstituted with 68Ga eluted from 3 different generator types. Quality control measures included percentage radiolabeling efficiency, radiochemical and radionuclidic purity, pH and sterility. Additionally, kit shelf-life, generator age and radiolabeling reproducibility per batch were monitored. Given ethical consent, 68Ga-PSMA11 was administered intravenously to 260 patients followed by positron emission tomography/computed tomography imaging at 60 min. Clinical data was analyzed with regards to any adverse effects, injected activity doses, specific activity and tracer masses.
Adding 0.8-1.1 mL 68GaCl3 (0.6 M HCl) per kit yielded 95.2–100% purity of 68Ga-PSMA11 (417±163 MBq) in 164/175 (94%) preparations; the radiolabeling reproducibility per batch was 84–100%. Alternately, ≥95% purity was achieved with ≤5 ml 68GaCl3 (>0.1 M HCl) of two TiO2-generator types (N=12; 100%). 68Ga-PSMA11 kit labeling met with all requirements for radiopharmaceutical production and was safely administered to patients (66±9 yrs). A 5.5-10.5 ml intravenous 68Ga-PSMA11 bolus contained 2.0±0.7 MBq/kg tracer formulated in saline (pH 6.5-7) containing 2.2±1.0 nmol PSMA11/patient (specific activity 0.80±0.32 GBq/nmol). Even with tracer doses of 0.85-0.97 MBq/kg, PET images were of excellent quality with no unexpected tracer distribution. Escalated doses of 3.5-4.9 MBq/kg (N=11) did not cause any adverse effects in humans. No significant difference was found between the 1st (2.2±1.1 MBq/kg; N=171) and the 2nd/3rd patient doses (1.7±0.4 MBq/kg; N=89), injected from the same kit (P=0.108).
The 68Ga-PSMA11 kit preparation met the quality requirements and release criteria for human use with a 94% success rate. From a single kit radiosynthesis, 2-3 doses suitable for patients were obtained and safely injected. Good clinical practice was demonstrated for a large patient population with significant improvements and lower radiation exposure to operating personnel. Our kit-based radiolabeling resulting in a safe-to-administer radiopharmaceutical accompanied with an easy-to-learn, reproducible labeling method.
(1) Ebenhan, T. et al. Molecules 2015, 20(8):14860-14878
The authors would like to thank NTP Radioisotopes SOC for their financial contribution towards this project.
Keywords: 68Ga-PSMA-11, prostate cancer, kit radiolabeling, PSMA, PET/CT imaging
PLGA nanoparticles for combined SPECT/PET and 19F MRI in vivo cell tracking (#202)
M. Krekorian1, 2, N. K. van Riessen1, G. Sandker2, E. Swider1, A. H. J. Staal1, O. Koshkina1, S. Heskamp2, M. Srinivas1, E. H. J. G. Aarntzen2
1 Radboudumc, Tumor Immunology, Nijmegen, Netherlands
Nuclear imaging techniques are particularly well-suited for in vivo tracking of intravenously injected cells, due to its high sensitivity, quantitative nature and whole-body imaging capability. However, spatial resolution is limited in clinical setting. Previously, we have developed PLGA-based nanoparticle (PLGA-np), containing 19F for MR imaging and different fluorescent dyes for optical imaging, which are suitable for clinical use4 (Fig. 1). Here, we add 111In-DTPA to the currently available NPs to include SPECT in the multimodal tracking of cells in vivo, in a single agent.
The production of PLGA-np encapsulating perfluoro-15-crown-5 ether (PFCE) has been described previously4. For this study, we modified the PLGA-np with an amine cap (poly(lactic-co-glycolic acid)-NH2 dihydrazide, PLGA-np-AA). Subsequently, 10 mg/mL NPs, of both normal and PLGA-np-AA, were conjugated with 10 times molar excess p-SCN-Bn-DTPA in MilliQ (pH 9.0) at 37 °C and 550 rpm in a ThermoMixer. After washing, the NPs were labelled with 3 MBq/mg of 111InCl3 for 30 minutes at room temperature in either 0.5 M HEPES, MES or NH4Ac buffer at pH 5.5. Radiochemical yield was measured using a dose calibrator before and after washing with PBS. Radiochemical purity was measured with instant iTLC in an eluent (pH 6.0) and analysed using a phosphor imager (Typhoon FLA 7000).
The results show specific radiolabelling of the PLGA-np-AA via conjugation of 111In-DTPA to the amine cap on PLGA. Labelling efficiency in HEPES, MES, and NH4Ac was 83%, 65%, and 97%, respectively. Labelling of the non-modified PLGA-np, had <10% radiochemical yield (Fig. 2). After washing, radiochemical yield for HEPES, MES, and NH4Ac was 70%, 50%, and more than 90%, respectively. After the last wash, radiochemical purity of all the samples exceeded 99%. Although the total radioactivity in the pellet progressively decreased during washing steps, iTLC of the supernatant demonstrated that this was due to manual disruption of the pellet; and not disintegration of the particle nor it’s conjugation. Pilot experiments indicate high labelling capacity of >16 MBq/mg NPs.
Further optimization and cell labelling with the radiolabelled PLGA-np-AA and in vivo studies are ongoing.
The ability to combine nuclear imaging, with MRI in a single agent allows for sensitive localisation of low numbers of labelled immune cells in clinical setting. We have shown a specific radiolabelling of amine capped PLGA-np compared to normal PLGA-np. Furthermore, NH4Ac buffer showed highest labelling efficiency compared to the other two buffers. Under yet un-optimized conditions, radiolabelling of amine-capped PLGA-np is highly efficient, yielding >16 MBq 111In per 1 mg nanoparticles.
1. Srinivas, M., Heerschap, A., Ahrens, E. T., Figdor, C. G. & de Vries, I. J. M. 19F MRI for quantitative in vivo cell tracking. Trends Biotechnol. 28, 363–370 (2010).
2. Srinivas, M. et al. Imaging of cellular therapies. Adv. Drug Deliv. Rev. 62, 1080–1093 (2010).
3. Aarntzen, E. H. J. G. et al. In vivo imaging of therapy-induced anti-cancer immune responses in humans. Cell. Mol. Life Sci. 70, 2237–2257 (2013).
4. Srinivas, M. et al. PLGA-encapsulated perfluorocarbon nanoparticles for simultaneous visualization of distinct cell populations by 19 F MRI. Nanomedicine 10, 2339–2348 (2015).
This work is supported by a Radboudumc PhD grant and the European Research Council (ERC) Starting Grant (CoNQUeST Grant no.336454) to MS.
Schematic representation for cell labelling and cell tracking in clinical setting. Nanoparticles with multimodal imaging agents including, perfluorocarbon for MRI, radionuclide for SPECT/PET, fluorescent dye, and inorganic particles for CT are incubated with isolated human cells. After which the labelled cells are reinjected in patients and followed with multimodal imaging techniques.
Relative radio-labelling of PLGA-np and PLGA-np-AA in 0.5 M buffers including, HEPES, MES, and NH4Ac. Specific radio-labelling of PLGA-np-AA is shown with NH4Ac having the highest labelling yield of the three buffers. The blue bars indicate the labelling of the particles are incubation with the radionuclide and spin down, while the orange bars indicate the labelling after the last wash step.
Keywords: PLGA, SPECT/PET, MRI, In-111, Cell tracking
Fluorinating strategies for the synthesis and characterization of gold nanoparticles with potential application in 19F-MRI (#220)
J. Blanco1, P. Castellnou1, D. Padro1, M. Carril1, 2
1 CIC biomaGUNE, San Sebastian, Spain
19F-MRI is a field with promising features.1 However, in order to achieve a good quality of image, 19F-MRI based probes require a high load of equivalent fluorine atoms. One of the challenges in this field is to find balance between increasing fluorine signal and the intrinsic hydrophobicity of fluorinated probes. The use of nanoparticles (NPs) bearing a high number of identical fluorinated ligands could be an appealing strategy to deal with this challenge.2 We present herein different fluorination strategies to obtain fluorinated nanoparticles with potential use as contrast agents in 19F-MRI.
Different thiol-ending fluorinated ligands and fluorinated building blocks for labelling gold nanoparticles were prepared by standard organic synthetic reactions. Likewise, gold nanoparticles of 2-3 nm were produced by in situ reduction of gold salts in the presence of thiolated ligands and sodium borohydride following described procedures.2 All ligands and nanoparticles were characterized by 1H and 19F NMR. In addition, HRMS was used for characterization of the organic compounds, and UV-VIS, TEM and ICP-MS for the gold nanoparticles. 19F-MRI images for some of the NPs were obtained in a 11.7T horizontal bore BrukerBiospec employing a 40 mm diameter 1H/19F coil, which also allowed the acquisition of a reference proton image before the 19F-MRI image recording.
Several fluorine labels with equivalent fluorine atoms were successfully synthesised. Those with a thiol ending group were used directly for the synthesis of NPs and accordingly characterized. Those without a thiol ending group were used for labelling already synthesised gold nanoparticles with carboxylate groups on the surface, through EDC/NHS chemistry. The fluorination strategies employed are summarised in figure 1. The labelling progress was monitored by the appearance of 19F-NMR signal of the so-obtained nanoparticles. Some of this NPs were tested as potential contrast agents in 19F-MRI in phantoms.
It has been possible to prepare novel fluorine labels with equivalent fluorine atoms for improved 19F-MRI signal. These fluorine derivatives have been used to successfully label nanoparticles as potential imaging probes. The presented methodology is presented as a universal labelling strategy for other systems beyond gold nanoparticles, as long as carboxylate groups are available.
1. J. Ruiz-Cabello et al. NMR Biomed. 2011, 24, 114
2. Michelena et al. Chem. Commun. 2017, 5, 2447.
This work was funded by MINECO (CTQ2015-68413-R. MC acknowledges Ikerbasque for a Research Fellow position.
Keywords: 19F MRI, gold nanoparticles, fluorination, contrast agents
Antibody conjugation with trans-cyclooctene and Desferoxamine to enable in vivo click reaction for pretargeting strategies (#178)
I. V. J. Feiner1, V. Gómez-Vallejo1, J. Calvo2, J. Llop1
1 CIC biomaGUNE, Radiochemistry and Nuclear Imaging, San Sebastián, Gipuzkoa, Spain
In pretargeting, a conjugated monoclonal antibody (mAb) is injected intravenously. After its distribution and clearance from blood, a second component is injected and binds in vivo to the mAb via bioorthogonal ‘click reaction’. In this approach, the determination of the number of functionalities per mAb is paramount to predict pretargeting efficacy.1 A selected mAb was conjugated with trans-Cyclooctene (TCO) and/or p-isothiocyanatobenzyl-desferrioxamine (Df-bz-NCS, for radiolabeling) through lysine residues and the number of moieties per mAb was determined using a variety of analytical methods
The mAb (Avastin®, Bevacizumab) was diluted in PBS to a concentration of 1 mg/mL. The pH was adjusted to 8.7-9.0 with 0.1 M Na2CO3 solution. TCO-NHS (3 mg/mL in DMSO) and/or Df-bz-NCS (3.7 mg/mL in DMSO) was added in different ratios. After incubation (60 min, RT/37 ºC, 500 rpm) non reacted TCO/Df-bz-NCS was removed by spin filtration (50 kDa) and the conjugated mAb washed with buffer (200 mM sucrose, 50 mM NaOAc, pH 5.5). To determine the number of moieties per mAb several analytical methods including UPLC/ESI-TOF MS and UV/VIS spectrometry were used.
UPLC/ESI-TOF MS gave a good qualitative insight of the different species present after conjugation, although quantitative data could not be obtained due to poor resolution of the chromatographic method. Application of Hydrophobic Interaction Chromatography (HIC) to separate all individual species is currently ongoing. To apply UV/VIS spectrophotometry, a tetrazine-fluorophore (mTzCy3) was attached via click reaction to the TCO-modified mAb. The resulting spectra of mAb-TCO-mTzCy3 could be used to directly determine both the concentration of mAb and of mTzCy3, which is equal to the concentration of TCO (Table 1).
Furthermore we could label mAbs, functionalized with both moieties at the same time, with mTzCy3 to proof the existence of TCO with an average number of 2.4 ± 0.2** TCO/mAb, as well as with 89Zr to proof the existence of chelator.
Using lysine residues to conjugate mAbs leads to a high heterogeneity of conjugates. Furthermore, TCO and Df-bz-NCS are very small moieties (152 g/mol and 753 g/mol) compared to the high molecular weight of antibodies (150000 g/mol) which difficult characterization and analysis of the receiving conjugates. However, UPLC/ESI-TOF MS gave insight of the verity of existing conjugates whereas UV/VIS spectrophotometry enabled the determination of the quantitative average of TCO units per mAb. In addition, we were able to attach both moieties at the same time on the same mAb.
1. A. Wakankar, Y. Chen, Y. Gokarn and F.S. Jacobson, mAbs, 2011, 3(2), 161.
This project has received funding from the European Union’s H2020-MSCA-ITN Framework Programme, project reference 675417.
Keywords: pretargeting, antibodies, TCO, DFO, Zr-89
Superparamagnetic iron oxide nanoparticles with unique MRI and MPI properties (#239)
S. M. Dadfar1, M. Darguzyte1, A. I. Kelekçi1, D. Camozzi2, J. Metselaar1, S. Banala1, N. Güvener1, M. Straub1, V. Schulz1, F. Kiessling1, T. Lammers1
1 Uniklinik RWTH Aachen, Experimental Molecular Imaging, Aachen, Germany
Superparamagnetic iron oxide nanoparticles (SPION) are widely used for magnetic resonance and magnetic particle imaging (MRI, MPI) [1-2]. In this study, we describe an easily implementable and broadly applicable sequential centrifugation protocol to obtain monodisperse SPION from a polydisperse starting dispersion. As a result of their refined size distribution, they presented with substantially improved performance in MRI and MPI compared to the crude starting dispersion, as well as to commercial SPION formulations, such as Resovist® and Sinerem®.
We started off by preparing prototypic citrate-coated SPION via the standard co-precipitation technique. Based on this highly polydisperse starting batch, which we refer to as the “crude sample”, five sequential centrifugation rounds were performed to obtain much more monodisperse SPION subfractions (Figure 1).
Figures 2a shows T1- and T2-weighted MR images and quantification of key MRI parameters i.e. relaxivities (r1, r2) of the crude (C), C1-C5, Resovist® (R), and Sinerem® (S) samples. After sequential centrifugation, the r2 values of the monodisperse SPION gradually increased up until the third round of centrifugation. The sample C3 possessed the most optimal MRI capabilities with an r2 value of 3 and 5 times higher than Resovist® and Sinerem®, respectively. Also, Figure 2b compares the normalized SNR values of the samples. Obviously, the SNR values for the C2 and C3 samples are much higher than those for Resovist® and Sinerem® and the C2 sample shows a SNR up to 2.3 times higher than Resovist®. To demonstrate the actual MPI imaging capabilities of our SPION, we fabricated an “E” shaped phantom. Then, the phantoms were filled with the crude, C2 and Resovist® samples. It is clearly visible that C2 gives the best results in terms of intensity (up to 2 times higher than Resovist®).
In summary, we developed an effective consecutive centrifugation technique to prepare monodisperse SPION with five different sizes from polydisperse ones synthesized by co-precipitation method. Because of narrow size distribution of the optimized SPION, they presented remarkable performance in MRI and MPI compared to commercial SPION formulations.
1) R Jin, B Lin, D Li, H Ai, Superparamagnetic iron oxide nanoparticles for MR imaging and therapy: design considerations and clinical applications, Current Opinion in Pharmacology, 2014, 18, 18-27.
2) Du, Y.; Lai, P. T.; Leung, C. H.; Pong, P. W., Design of superparamagnetic nanoparticles for magnetic particle imaging (MPI). International journal of molecular sciences 2013, 14, 18682-18710.
Keywords: SPION, MRI, MPI, hyperthermia, centrifugation