4 research outputs found
Electrochemical Separation: Promises, Opportunities, and Challenges To Develop Next-Generation Radionuclide Generators To Meet Clinical Demands
This
review provides a comprehensive summary of the role of the
electrochemical separation process to develop next-generation radionuclide
generators to meet future research and clinical demands. This innovative
technology paradigm, straddling the disciplines of electrochemistry
and separation science, is poised to serve as a springboard to spur
new breakthroughs and bring evolutionary progress in radionuclide
generator technology. Without doubt, the major impetus for the advancement
in radionuclide generator technology stems from nuclear medicine requirements,
as a means of obtaining short-lived radionuclides on demand for the
formulation of a gamut of diagnostic and therapeutic radiopharmaceuticals.
The tremendous prospects associated with the use of electrochemical
radionuclide generators in nuclear medicine dictate that a holistic
consideration should given to all governing factors that determine
their success. The purpose of this paper is to present a concise and
comprehensive review of the latest research and development activities
in the utility of electrochemical separation process in development
of radionuclide generators that have already established footholds
of acceptance in nuclear medicine and are expected to change the future
landscape of radionuclide generator technology. This review provides
a summary of the principle, factors that govern the electrochemical
separation, desirable characteristics of the generator systems developed
with typical examples, critical assessment of recent developments,
contemporary status, key challenges, and apertures to the near future
Mesoporous Alumina (MA) Based Double Column Approach for Development of a Clinical Scale <sup>99</sup>Mo/<sup>99m</sup>Tc Generator Using (n,γ)<sup>99</sup>Mo: An Enticing Application of Nanomaterial
This
paper describes the utility of mesoporous alumina (MA), a high capacity
nanomaterial based sorbent, for the development of a clinical grade <sup>99</sup>Mo/<sup>99m</sup>Tc generator using (n,γ)<sup>99</sup>Mo. Synthesis of MA was performed using a glucose template in an
aqueous system. Structural characterization of the nanosorbent was
carried out by analytical techniques such as X-ray diffraction (XRD),
small-angle X-ray scattering (SAXS), atomic force microscopy (AFM),
scanning electron miscroscopy (SEM), transmission electron microscopy
(TEM), thermogravimetry-differential thermal analysis (TG-DTA), Fourier
transform infrared (FTIR) spectroscopy, and Brunauer–Emmett–Teller
(BET) surface area analysis. The material synthesized was mesoporous
and nanocrystalline, with average crystallite size of 2–3 nm
with a large surface area of 230 ± 10 m<sup>2</sup> g<sup>–1</sup>. In order to evaluate the surface charge of MA in aqueous solution,
the zeta potential was determined at different pH environments. Adsorption
characteristics of the sorbent such as time course of the adsorption,
distribution ratios of <sup>99</sup>Mo and <sup>99m</sup>Tc ions,
Mo sorption capacity under static and dynamic conditions, <sup>99</sup>Mo adsorption pattern and <sup>99m</sup>Tc elution pattern were determined
to assess its effectiveness in the preparation of <sup>99</sup>Mo/<sup>99m</sup>Tc generator. The measured distribution ratio values indicate
that <sup>99</sup>Mo is both strongly and selectively retained by
MA at acidic pH and <sup>99m</sup>Tc could be readily eluted from
it, using 0.9% NaCl solution. The static sorption capacity and practical
sorption capacity under dynamic conditions of MA was determined to
be 225 ± 20 and 168 ± 12 mg Mo per gram of sorbent, respectively.
With a view to realize the scope of developing clinical scale generator,
a novel tandem column generator concept was used in which two <sup>99</sup>Mo loaded columns were connected in series. In this method <sup>99m</sup>Tc eluted from the first column was fed to the second column
to achieve higher radioactive concentration (RAC) as well as purity
of <sup>99m</sup>Tc. A 26 GBq (700 mCi) <sup>99</sup>Mo/<sup>99m</sup>Tc generator was developed using (n,γ)<sup>99</sup>Mo having
specific activity of ∼18.5 GBq (500 mCi)/g of Mo. The <sup>99m</sup>Tc eluted from the generator possessed high radionuclidic,
radiochemical, and chemical purity and was amenable for the preparation
of <sup>99m</sup>Tc-labeled radiopharmaceuticals. The technology can
be adapted by those countries having research reactors with flux >1
× 10<sup>14</sup> n·cm<sup>–2</sup>·s<sup>–1</sup> to produce <sup>99</sup>Mo by (n,γ) route. The capacity of
the generator can be scaled up to 260 GBq (7 Ci) using (n,γ)<sup>99</sup>Mo produced from a reactor with flux >1 × 10<sup>15</sup> n·cm<sup>–2</sup>·s<sup>–1</sup>
<sup>44</sup>Sc: An Attractive Isotope for Peptide-Based PET Imaging
The
overexpression of integrin α<sub>v</sub>β<sub>3</sub> has
been linked to tumor aggressiveness and metastasis in several
cancer types. Because of its high affinity, peptides containing the
arginine–glycine–aspartic acid (RGD) motif have been
proven valuable vectors for noninvasive imaging of integrin α<sub>v</sub>β<sub>3</sub> expression and for targeted radionuclide
therapy. In this study, we aim to develop a <sup>44</sup>Sc-labeled
RGD-based peptide for <i>in vivo</i> positron emission tomography
(PET) imaging of integrin α<sub>v</sub>β<sub>3</sub> expression
in a preclinical cancer model. High quality <sup>44</sup>Sc (<i>t</i><sub>1/2</sub>, 3.97 h; β<sup>+</sup> branching ratio,
94.3%) was produced inexpensively in a cyclotron, via proton irradiation
of natural Ca metal targets, and separated by extraction chromatography.
A dimeric cyclic-RGD peptide, (cRGD)<sub>2</sub>, was conjugated to
1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) and
radiolabeled with <sup>44</sup>Sc in high yield (>90%) and specific
activity (7.4 MBq/nmol). Serial PET imaging of mice bearing U87MG
tumor xenografts showed elevated <sup>44</sup>Sc-DOTA-(cRGD)<sub>2</sub> uptake in the tumor tissue of 3.93 ± 1.19, 3.07 ± 1.17,
and 3.00 ± 1.25 %ID/g at 0.5, 2, and 4 h postinjection, respectively
(<i>n</i> = 3), which were validated by <i>ex vivo</i> biodistribution experiments. The integrin α<sub>v</sub>β<sub>3</sub> specificity of the tracer was corroborated, both <i>in vitro</i> and <i>in vivo</i>, by competitive cell
binding and receptor blocking assays. These results parallel previously
reported studies showing similar tumor targeting and pharmacokinetic
profiles for dimeric cRGD peptides labeled with <sup>64</sup>Cu or <sup>68</sup>Ga. Our findings, together with the advantageous radionuclidic
properties of <sup>44</sup>Sc, capitalize on the relevance of this
isotope as an attractive alternative isotope to more established radiometals
for small molecule-based PET imaging, and as imaging surrogate of <sup>47</sup>Sc in theranostic applications
Matching the Decay Half-Life with the Biological Half-Life: ImmunoPET Imaging with <sup>44</sup>Sc-Labeled Cetuximab Fab Fragment
Scandium-44
(<i>t</i><sub>1/2</sub> = 3.9 h) is a relatively
new radioisotope of potential interest for use in clinical positron
emission tomography (PET). Herein, we report, for the first time,
the room-temperature radiolabeling of proteins with <sup>44</sup>Sc
for <i>in vivo</i> PET imaging. For this purpose, the Fab
fragment of Cetuximab, a monoclonal antibody that binds with high
affinity to epidermal growth factor receptor (EGFR), was generated
and conjugated with <i>N</i>-[(R<i>)</i>-2-amino-3-(<i>para</i>-isothiocyanato-phenyl)Âpropyl]-<i>trans</i>-(<i>S</i>,<i>S</i>)-cyclohexane-1,2-diamine-<i>N</i>,<i>N</i>,<i>N</i>′,<i>N</i>″,<i>N</i>″-pentaacetic acid (CHX-A″-DTPA).
The high purity of Cetuximab-Fab was confirmed by SDS-PAGE and mass
spectrometry. The potential of the bioconjugate for PET imaging of
EGFR expression in human glioblastoma (U87MG) tumor-bearing mice was
investigated after <sup>44</sup>Sc labeling. PET imaging revealed
rapid tumor uptake (maximum uptake of ∼12% ID/g at 4 h postinjection)
of <sup>44</sup>Sc–CHX-A″-DTPA–Cetuximab-Fab
with excellent tumor-to-background ratio, which might allow for same
day PET imaging in future clinical studies. Immunofluorescence staining
was conducted to correlate tracer uptake in the tumor and normal tissues
with EGFR expression. This successful strategy for immunoPET imaging
of EGFR expression using <sup>44</sup>Sc–CHX-A″-DTPA–Cetuximab-Fab
can make clinically translatable advances to select the right population
of patients for EGFR-targeted therapy and also to monitor the therapeutic
efficacy of anti-EGFR treatments