Uwe Holzwarth

The Scherrer equation versus the 'Debye-Scherrer equation'

Paul Scherrer and Peter Debye developed powder X-ray diffraction together, but it was Scherrer who figured out how to determine the size of crystallites from the broadening of diffraction peaks.

Radiolabelling of engineered nanoparticles for in vitro and in vivo tracing applications using cyclotron accelerators

We present in this article an outline of some cyclotron-based irradiation techniques that can be used to directly radiolabel industrially manufactured nanoparticles, as well as two techniques for synthesis of labelled nanoparticles using cyclotron-generated radioactive precursor materials. These radiolabelled nanoparticles are suitable for a range of different in vitro and in vivo tracing studies of relevance to the field of nanotoxicology. A basic overview is given of the relevant physics of nuclear reactions regarding both ion-beam and neutron production of radioisotopes. The various issues that determine the practicality and usefulness of the different methods are discussed, including radioisotope yield, nuclear reaction kinetics, radiation and thermal damage, and radiolabel stability. Experimental details are presented regarding several techniques applied in our laboratories, including direct light-ion activation of dry nanoparticle samples, neutron activation of nanoparticles and suspensions using an ion-beam driven activator, spark-ignition generation of nanoparticle aerosols using activated electrode materials, and radiochemical synthesis of nanoparticles using cyclotron-produced isotopes. The application of these techniques is illustrated through short descriptions of some selected results thus far achieved. It is shown that these cyclotron-based methods offer a very useful range of options for nanoparticle radiolabelling despite some experimental difficulties associated with their application. For direct nanoparticle radiolabelling, if care is taken in choosing the experimental conditions applied, useful activity levels can be achieved in a wide range of nanoparticle types, without causing substantial thermal or radiation damage to the nanoparticle structure. Nanoparticle synthesis using radioactive precursors presents a different set of issues and offers a complementary and equally valid approach when laboratory generation of the nanoparticles is acceptable for the proposed studies, and where an appropriate radiolabel can be incorporated into the nanoparticles during synthesis.

Excitation functions and yields for cyclotron production of radiorhenium via nat W(p,ߙxn)181-186gRe nuclear reactions and tests on the production of 186gRe using enriched 186W

Abstract Excitation functions and thin-target yields for the 181-186gRe radionuclides have been measured by the stacked-foil activation technique on tungsten foils of natural isotopic composition for different proton energies up to 22.0 MeV. A further check on the cross sections was done by irradiation of thick-targets and comparing the irradiated thick-target yields with those calculated by analytical integration from the thin-target yields. The production of 186gRe was also studied by the irradiation of thick-target of enriched 186W with a 13.6±0.2 MeV proton beam. The results for 186W(p,ߙn)186gRe were compared also to those calculated by the EMPIRE II code (version 2.19), due to 186gRe extensive applications in nuclear medicine for metabolic radiotherapy of tumours. It was found that the maximum percentage of 186gRe by irradiation of natural tungsten is about 20% only, which confirms the conclusion that high radionuclidic purity and specific activity of 186gRe necessitate the use of highly enriched 186W target.

A quantitative in vitro approach to study the intracellular fate of gold nanoparticles: from synthesis to cytotoxicity

Abstract Due to their physico-chemical characteristics, gold nanoparticles (AuNPs) seem to be suitable for biomedical and therapeutic applications even if conflicting data on their toxicological profiles are present in literature. In order to better understand if AuNPs could be safe we must consider different biological endpoints such as cytotoxicity, genotoxicity, inflammation and biopersistence. Starting from these considerations, one of the first issues to be assessed is to better understand if AuNPs can be internalized by cells. In this work, we propose a methodological approach to radioactivate AuNPs by neutron activation and the quantification of their internalization by two in vitro cell systems such as MDCK and HepG2 after 24 h of exposure. Despite a dose-dependent internalization, no evidence of cytotoxicity, determined by two different standard in vitro methods such as Neutral Red Uptake and Colony Forming Efficiency, was observed.

Cyclotron production of44Sc for clinical application

Abstract 44Sc is a promising β+-emitter for molecular imaging with intermediate half-life of 4 h. Due to the chemical similarity of Sc3+ to the Lu3+ and Y3+ cations, 44Sc-DOTA bioconjugates are expected to demonstrate similar properties in vivo as the 177Lu- and 90Y-bioconjugates, what is important in planning the radionuclide therapy. 44Sc can be obtained from the 44Ti/44Sc generator. An alternative method for 44Sc production can be the irradiation of 44Ca target at small cyclotrons. The aim of our work was to optimize the parameters of 44CaCO3 irradiation and to develop a simple procedure for 44Sc separation from the calcium target. For optimization study, 44CaCO3 targets were irradiated by protons in the energy range of 5.6–17.5 MeV with 9 MeV being found to be the best energy for 44Ca irradiations. A simple and fast separation procedure of 44Sc from calcium target was developed using chelating resin Chelex 100. DOTATATE conjugate was successfully radiolabelled with high yield at elevated temperature using the produced 44Sc. While 44CaCO3 is relatively expensive, the cost of 44Sc-DOTATATE production can be reduced by target recovery. Due to low proton energy required to produce GBq activity level of 44Sc, the availability of 44Sc radioisotope could be enhanced to open new opportunities for applications in medical imaging.

Biodistribution of Inhaled Gold Nanoparticles in Mice and the Influence of Surfactant Protein D

BACKGROUND The pulmonary route is very promising for drug delivery by inhalation. In this regard, nanoparticulate drug delivery systems are discussed, and one very promising nano carrier example is gold nanoparticles (Au NP). Directly after their deposition, inhaled Au NP come into contact with pulmonary surfactant protein D (SP-D). SP-D can agglomerate Au NP in vitro, and this may influence the clearance as well as the systemic translocation in vivo. The aim of the present study was to investigate the clearance and translocation of Au NP at a very early time point after inhalation, as well as the influence of SP-D. METHODS Aerosolized 20-nm radioactively labeled Au NP were inhaled by healthy adult female mice. One group of mice received dissolved 10 μg of SP-D by intratracheal instillation prior to the Au NP inhalation. After a 2-hr Au NP inhalation period, the mice were killed immediately, and the clearance and translocation to the blood stream were investigated. RESULTS The highest amount of Au NP was associated with the lung tissue. In the bronchoalveolar lavage fluid (BALF), more Au NP remained free compared with the amount associated with the BALF cells. The amount of Au NP cleared by the mucociliary escalator was low, probably because of this very early time point. Instillation of SP-D prior to Au NP inhalation had no statistically significant effect on the biodistribution of the Au NP. CONCLUSION Our data show that inhaled Au NP are retained in the mouse lungs and are translocated after a short time, and that SP-D has only a minor effect on Au NP translocation and clearance at a very early time point.

Thin-target excitation functions and optimization of simultaneous production of NCA copper-64 and gallium-66,67 by deuteron induced nuclear reactions on a natural zinc target

Copper-64 is a radionuclide suitable for labeling of a wide range of radiopharmaceuticals for PET imaging, as well as systemic or local radioimmunotherapy of tumors. Among the possible methods for cyclotron production of No Carrier Added (NCA) 64Cu (61Cu), we investigated the deuteron irradiation on natural Zn target, via (d,axn) and (d,2pxn) nuclear reactions. This paper reports the preliminary results about the experimental determination and theoretical calculation of thin-target excitation functions in the energy range up to 19 MeV for 61Cu, 64Cu, 66Ga, 67Ga, 65Zn and 69mZn. A fast selective radiochemical separation of NCA 64Cu from Zn target and Ga radionuclides, with quality control tests is described too.

Quantitative biokinetics of titanium dioxide nanoparticles after oral application in rats: Part 2

Abstract The biokinetics of a size-selected fraction (70 nm median size) of commercially available and 48V-radiolabeled [48V]TiO2 nanoparticles has been investigated in female Wistar-Kyoto rats at retention timepoints 1 h, 4 h, 24 h and 7 days after oral application of a single dose of an aqueous [48V]TiO2-nanoparticle suspension by intra-esophageal instillation. A completely balanced quantitative body clearance and biokinetics in all organs and tissues was obtained by applying typical [48V]TiO2-nanoparticle doses in the range of 30–80 μg•kg−1 bodyweight, making use of the high sensitivity of the radiotracer technique. The [48V]TiO2-nanoparticle content was corrected for nanoparticles in the residual blood retained in organs and tissue after exsanguination and for 48V-ions not bound to TiO2-nanoparticles. Beyond predominant fecal excretion about 0.6% of the administered dose passed the gastro-intestinal-barrier after one hour and about 0.05% were still distributed in the body after 7 days, with quantifiable [48V]TiO2-nanoparticle organ concentrations present in liver (0.09 ng•g−1), lungs (0.10 ng•g−1), kidneys (0.29 ng•g−1), brain (0.36 ng•g−1), spleen (0.45 ng•g−1), uterus (0.55 ng•g−1) and skeleton (0.98 ng•g−1). Since chronic, oral uptake of TiO2 particles (including a nano-fraction) by consumers has continuously increased in the past decades, the possibility of chronic accumulation of such biopersistent nanoparticles in secondary organs and the skeleton raises questions about the responsiveness of their defense capacities, and whether these could be leading to adverse health effects in the population at large. After normalizing the fractions of retained [48V]TiO2-nanoparticles to the fraction that passed the gastro-intestinal-barrier and reached systemic circulation, the biokinetics was compared to the biokinetics determined after IV-injection (Part 1). Since the biokinetics patterns differ largely, IV-injection is not an adequate surrogate for assessing the biokinetics after oral exposure to TiO2 nanoparticles.

A Novel Method for n.c.a. 64Cu Production by the 64Zn(d,2p)64Cu Reaction and Dual Ion-exchange Column Chromatography

A novel production method for n.c.a. 64Cu based on deuteron irradiation of 64Zn is presented. The production takes place through the 64Zn(d, 2p) 64Cu reaction using a deuteron beam of 19.5 MeV energy on highly enriched 64Zn disks. An average yield over three irradiations of 31 MBq/μA h (850 μCi/μA h) and saturation yield of 575 MBq/μA (15.5 mCi/μA) at the end of the beam (EOB) was measured by γ-ray spectrometry. Two of the three runs, of low irradiation charge, were used for radiochemistry. The copper isotopes were separated from other radionuclidic impurities by the combination of cation and anion exchange chromatography. An average radiochemical yield of 90% was estimated for the two runs performed in this study, and the specific activity as determined using flame atomic absorption spectrometry was about 4 MBq/μg, 2 hours after EOB. An extrapolation of the present results to production conditions (50 μA, 10 h) indicates approximately 8 GBq/μg (220 mCi/μg) of specific activity. The overall uncertainty in these values is estimated to 15%.

Quantitative biokinetics of titanium dioxide nanoparticles after intratracheal instillation in rats: Part 3

Abstract The biokinetics of a size-selected fraction (70 nm median size) of commercially available and 48V-radiolabeled [48V]TiO2 nanoparticles has been investigated in healthy adult female Wistar-Kyoto rats at retention time-points of 1 h, 4 h, 24 h, 7 d and 28 d after intratracheal instillation of a single dose of an aqueous [48V]TiO2-nanoparticle suspension. A completely balanced quantitative biodistribution in all organs and tissues was obtained by applying typical [48V]TiO2-nanoparticle doses in the range of 40–240 μg·kg−1 bodyweight and making use of the high sensitivity of the radiotracer technique. The [48V]TiO2-nanoparticle content was corrected for residual blood retained in organs and tissues after exsanguination and for 48V-ions not bound to TiO2-nanoparticles. About 4% of the initial peripheral lung dose passed through the air-blood-barrier after 1 h and were retained mainly in the carcass (4%); 0.3% after 28 d. Highest organ fractions of [48V]TiO2-nanoparticles present in liver and kidneys remained constant (0.03%). [48V]TiO2-nanoparticles which entered across the gut epithelium following fast and long-term clearance from the lungs via larynx increased from 5 to 20% of all translocated/absorbed [48V]TiO2-nanoparticles. This contribution may account for 1/5 of the nanoparticle retention in some organs. After normalizing the fractions of retained [48V]TiO2-nanoparticles to the fraction that reached systemic circulation, the biodistribution was compared with the biodistributions determined after IV-injection (Part 1) and gavage (GAV) (Part 2). The biokinetics patterns after IT-instillation and GAV were similar but both were distinctly different from the pattern after intravenous injection disproving the latter to be a suitable surrogate of the former applications. Considering that chronic occupational inhalation of relatively biopersistent TiO2-particles (including nanoparticles) and accumulation in secondary organs may pose long-term health risks, this issue should be scrutinized more comprehensively.