5 research outputs found
Radiochemistry and In Vivo Imaging of [<sup>45</sup>Ti]Ti-THP-PSMA
Titanium-45 (45Ti) is
a radionuclide with excellent
physical characteristics for use in positron emission tomography (PET)
imaging, including a moderate half-life (3.08 h), decay by positron
emission (85%), and a low mean positron energy of 0.439 MeV. However,
challenges associated with titanium chemistry have led to the underdevelopment
of this radionuclide for incorporation into radiopharmaceuticals.
Expanding on our recent studies, which showed promising results for
the complexation of 45Ti with the tris hydroxypyridinone
(THPMe) chelator, the current work aimed to optimize the
chemistry and imaging attributes of [45Ti]Ti-THP-PSMA as
a new PET radiopharmaceutical. Methods. Radiolabeling
of THP-PSMA was optimized with [45Ti]Ti-citrate at varying
pHs and masses of the precursor. The stability of the radiolabeled
complex was assessed in mouse serum for up to 6 h. The affinity of
[45Ti]Ti-THP-PSMA for prostate-specific membrane antigen
(PSMA) was assessed using LNCaP (PSMA +) and PC3 (PSMA -) cell lines.
In vivo imaging and biodistribution analysis were performed in tumor-bearing
xenograft mouse models to confirm the specificity of the tumor uptake. Results. > 95% of radiolabeling was achieved with a high
specific
activity of 5.6 MBq/nmol under mild conditions. In vitro cell binding
studies showed significant binding of the radiolabeled complex with
the PSMA-expressing LNCaP cell line (11.9 Ā± 1.5%/mg protein-bound
activity) compared to that with the nonexpressing PC3 cells (1.9 Ā±
0.4%/mg protein-bound activity). In vivo imaging and biodistribution
studies confirmed specific uptake in LNCaP tumors (1.6 Ā± 0.27%
ID/g) compared to that in PC3 tumors (0.39 Ā± 0.2% ID/g). Conclusion. This study showed a simple one-step radiolabeling
method for 45Ti with THP-PSMA under mild conditions (pH
8 and 37 Ā°C). In vitro cell studies showed promise, but in vivo
tumor xenograft studies indicated low tumor uptake. Overall, this
study shows the need for more chelators for 45Ti for the
development of a PET radiopharmaceutical for cancer imaging
Rhenium and Technetium-oxo Complexes with Thioamide Derivatives of Pyridylhydrazine Bifunctional Chelators Conjugated to the Tumour Targeting Peptides Octreotate and Cyclic-RGDfK
This research aimed
to develop new tumor targeted theranostic agents taking advantage
of the similarities in coordination chemistry between technetium and
rhenium. A Ī³-emitting radioactive isotope of technetium is commonly
used in diagnostic imaging, and there are two Ī²<sup>ā</sup> emitting radioactive isotopes of rhenium that have the potential
to be of use in radiotherapy. Variants of the 6-hydrazinonicotinamide
(HYNIC) bifunctional ligands have been prepared by appending thioamide
functional groups to 6-hydrazinonicotinamide to form pyridylthiosemicarbazide
ligands (SHYNIC). The new bidentate ligands were conjugated to the
tumor targeting peptides Tyr<sup>3</sup>-octreotate and cyclic-RGD.
The new ligands and conjugates were used to prepare well-defined {Mī»O}<sup>3+</sup> complexes (where M = <sup>99m</sup>Tc or <sup>nat</sup>Re
or <sup>188</sup>Re) that feature two targeting peptides attached
to the single metal ion. These new SHYNIC ligands are capable of forming
well-defined rhenium and technetium complexes and offer the possibility
of using the <sup>99m</sup>Tc imaging and <sup>188/186</sup>Re therapeutic
matched pairs
Comparison of <sup>64</sup>Cu-Complexing Bifunctional Chelators for Radioimmunoconjugation: Labeling Efficiency, Specific Activity, and <i>in Vitro</i>/<i>in Vivo</i> Stability
High radiolabeling efficiency, preferably to high specific
activity,
and good stability of the radioimmunoconjugate are essential features
for a successful immunoconjugate for imaging or therapy. In this study,
the radiolabeling efficiency, <i>in vitro</i> stability,
and biodistribution of immunoconjugates with eight different bifunctional
chelators labeled with <sup>64</sup>Cu were compared. The anti-CD20
antibody, rituximab, was conjugated to four macrocyclic bifunctional
chelators (<i>p</i>-SCN-Bn-DOTA, <i>p</i>-SCN-Bn-Oxo-DO3A, <i>p</i>-SCN-NOTA, and <i>p</i>-SCN-PCTA), three DTPA
derivatives (<i>p</i>-SCN-Bn-DTPA, <i>p</i>-SCN-CHX-Aā³-DTPA,
and ITC-2B3M-DTPA), and a macrobicyclic hexamine (sarcophagine) chelator
(sar-CO<sub>2</sub>H) = (1-NH<sub>2</sub>-8-NHCOĀ(CH<sub>2</sub>)<sub>3</sub>CO<sub>2</sub>H)Āsar where sar = sarcophagine = 3,6,10,13,16,19-hexaazabicyclo[6.6.6]Āicosane).
Radiolabeling efficiency under various conditions, <i>in vitro</i> stability in serum at 37 Ā°C, and <i>in vivo</i> biodistribution
and imaging in normal mice over 48 h were studied. All chelators except
sar-CO<sub>2</sub>H were conjugated to rituximab by thiourea bond
formation with an average of 4.9 Ā± 0.9 chelators per antibody
molecule. Sar-CO<sub>2</sub>H was conjugated to rituximab by amide
bond formation with 0.5 chelators per antibody molecule. Efficiencies
of <sup>64</sup>Cu radiolabeling were dependent on the concentration
of immunoconjugate. Notably, the <sup>64</sup>Cu-NOTA-rituximab conjugate
demonstrated the highest radiochemical yield (95%) under very dilute
conditions (31 nM NOTA-rituximab conjugate). Similarly, sar-CO-rituximab,
containing 1/10th the number of chelators per antibody compared to
that of other conjugates, retained high labeling efficiency (98%)
at an antibody concentration of 250 nM. In contrast to the radioimmunoconjugates
containing DTPA derivatives, which demonstrated poor serum stability,
all macrocyclic radioimmunoconjugates were very stable in serum with <6%
dissociation of <sup>64</sup>Cu over 48 h. <i>In vivo</i> biodistribution profiles in normal female Balb/C mice were similar
for all the macrocyclic radioimmunoconjugates with most of the activity
remaining in the blood pool up to 48 h. While all the macrocyclic
bifunctional chelators are suitable for molecular imaging using <sup>64</sup>Cu-labeled antibody conjugates, NOTA and sar-CO<sub>2</sub>H show significant advantages over the others in that they can be
radiolabeled rapidly at room temperature, under dilute conditions,
resulting in high specific activity
Bisphosphonate-Anchored PEGylation and Radiolabeling of Superparamagnetic Iron Oxide: Long-Circulating Nanoparticles for <i>in Vivo</i> Multimodal (T1 MRI-SPECT) Imaging
The efficient delivery of nanomaterials to specific targets for <i>in vivo</i> biomedical imaging is hindered by rapid sequestration by the reticuloendothelial system (RES) and consequent short circulation times. To overcome these two problems, we have prepared a new stealth PEG polymer conjugate containing a terminal 1,1-bisphosphonate (BP) group for strong and stable binding to the surface of ultrasmall-superparamagnetic oxide nanomaterials (USPIOs). This polymer, PEG(5)-BP, can be used to exchange the hydrophobic surfactants commonly used in the synthesis of USPIOs very efficiently and at room temperature using a simple method in 1 h. The resulting nanoparticles, PEG(5)-BP-USPIOs are stable in water or saline for at least 7 months and display a near-zero Ī¶-potential at neutral pH. The longitudinal (<i>r</i><sub>1</sub>) and transverse (<i>r</i><sub>2</sub>) relaxivities were measured at a clinically relevant magnetic field (3 T), revealing a high <i>r</i><sub>1</sub> of 9.5 mM<sup>ā1</sup> s<sup>ā1</sup> and low <i>r</i><sub>2</sub>/<i>r</i><sub>1</sub> ratio of 2.97, making these USPIOs attractive as T1-weighted MRI contrast agents at high magnetic fields. The strong T1-effect was demonstrated <i>in vivo</i>, revealing that PEG(5)-BP-USPIOs remain in the bloodstream and enhance its signal 6-fold, allowing the visualization of blood vessels and vascular organs with high spatial definition. Furthermore, the optimal relaxivity properties allow us to inject a dose 4 times lower than with other USPIOs. PEG(5)-BP-USPIOs can also be labeled using a radiolabeled-BP for visualization with single photon emission computed tomography (SPECT), and thus affording dual-modality contrast. The SPECT studies confirmed low RES uptake and long blood circulation times (<i>t</i><sub>1/2</sub> = 2.97 h). These results demonstrate the potential of PEG(5)-BP-USPIOs for the development of targeted multimodal imaging agents for molecular imaging
Exploiting the Metal-Chelating Properties of the Drug Cargo for <i>In Vivo</i> Positron Emission Tomography Imaging of Liposomal Nanomedicines
The
clinical value of current and future nanomedicines can be improved
by introducing patient selection strategies based on noninvasive sensitive
whole-body imaging techniques such as positron emission tomography
(PET). Thus, a broad method to radiolabel and track preformed nanomedicines
such as liposomal drugs with PET radionuclides will have a wide impact
in nanomedicine. Here, we introduce a simple and efficient PET radiolabeling
method that exploits the metal-chelating properties of certain drugs
(<i>e.g.</i>, bisphosphonates such as alendronate and anthracyclines
such as doxorubicin) and widely used ionophores to achieve excellent
radiolabeling yields, purities, and stabilities with <sup>89</sup>Zr, <sup>52</sup>Mn, and <sup>64</sup>Cu, and without the requirement
of modification of the nanomedicine components. In a model of metastatic
breast cancer, we demonstrate that this technique allows quantification
of the biodistribution of a radiolabeled stealth liposomal nanomedicine
containing alendronate that shows high uptake in primary tumors and
metastatic organs. The versatility, efficiency, simplicity, and GMP
compatibility of this method may enable submicrodosing imaging studies
of liposomal nanomedicines containing chelating drugs in humans and
may have clinical impact by facilitating the introduction of image-guided
therapeutic strategies in current and future nanomedicine clinical
studies