3 research outputs found
Silica Nanoparticles as Substrates for Chelator-free Labeling of Oxophilic Radioisotopes
Chelator-free nanoparticles for intrinsic
radiolabeling are highly
desirable for whole-body imaging and therapeutic applications. Several
reports have successfully demonstrated the principle of intrinsic
radiolabeling. However, the work done to date has suffered from much
of the same specificity issues as conventional molecular chelators,
insofar as there is no singular nanoparticle substrate that has proven
effective in binding a wide library of radiosotopes. Here we present
amorphous silica nanoparticles as general substrates for chelator-free
radiolabeling and demonstrate their ability to bind six medically
relevant isotopes of various oxidation states with high radiochemical
yield. We provide strong evidence that the stability of the binding
correlates with the hardness of the radioisotope, corroborating the
proposed operating principle. Intrinsically labeled silica nanoparticles
prepared by this approach demonstrate excellent in vivo stability
and efficacy in lymph node imaging
PET Imaging of Extracellular pH in Tumors with <sup>64</sup>Cu- and <sup>18</sup>F‑Labeled pHLIP Peptides: A Structure–Activity Optimization Study
pH (low) insertion
peptides (pHLIP peptides) target acidic extracellular
environments in vivo due to pH-dependent cellular membrane insertion.
Two variants (Var3 and Var7) and wild-type (WT) pHLIP peptides have
shown promise for in vivo imaging of breast cancer. Two positron emitting
radionuclides (<sup>64</sup>Cu and <sup>18</sup>F) were used to label
the NOTA- and NO2A-derivatized Var3, Var7, and WT peptides for in
vivo biodistribution studies in 4T1 orthotopic tumor-bearing BALB/c
mice. All of the constructs were radiolabeled with <sup>64</sup>Cu
or [<sup>18</sup>F]-AlF in good yield. The in vivo biodistribution
of the 12 constructs in 4T1 orthotopic allografted female BALB/c mice
indicated that NO2A-cysVar3, radiolabeled with either <sup>18</sup>F (4T1 uptake; 8.9 ± 1.7%ID/g at 4 h p.i.) or <sup>64</sup>Cu
(4T1 uptake; 8.2 ± 0.9%ID/g at 4 h p.i. and 19.2 ± 1.8%
ID/g at 24 h p.i.), shows the most promise for clinical translation.
Additional studies to investigate other tumor models (melanoma, prostate,
and brain tumor models) indicated the universality of tumor targeting
of these tracers. From this study, future clinical translation will
focus on <sup>18</sup>F- or <sup>64</sup>Cu-labeled NO2A-cysVar3
ImmunoPET Imaging of Endogenous and Transfected Prolactin Receptor Tumor Xenografts
Antibodies
labeled with positron-emitting isotopes have been used
for tumor detection, predicting which patients may respond to tumor
antigen-directed therapy, and assessing pharmacodynamic effects of
drug interventions. Prolactin receptor (PRLR) is overexpressed in
breast and prostate cancers and is a new target for cancer therapy.
We evaluated REGN2878, an anti-PRLR monoclonal antibody, as an immunoPET
reagent. REGN2878 was labeled with Zr-89 after conjugation with desferrioxamine
B or labeled with I-131/I-124. In vitro determination of the half-maximal
inhibitory concentration (IC50) of parental REGN2878, DFO-REGN2878,
and iodinated REGN2878 was performed by examining the effect of the
increasing amounts of these on uptake of trace-labeled I-131 REGN2878.
REGN1932, a non-PRLR binding antibody, was used as a control. Imaging
and biodistribution studies were performed in mice bearing tumor xenografts
with various expression levels of PRLR, including MCF-7, transfected
MCF-7/PRLR, PC3, and transfected PC3/PRLR and T4D7v11 cell lines.
The specificity of uptake in tumors was evaluated by comparing Zr-89
REGN2878 and REGN1932, and in vivo competition compared Zr-89 REGN2878
uptake in tumor xenografts with and without prior injection of 2 mg
of nonradioactive REGN2878. The competition binding assay of DFO-REGN2878
at ratios of 3.53–5.77 DFO per antibody showed IC50 values
of 0.4917 and 0.7136 nM, respectively, compared to 0.3455 nM for parental
REGN2878 and 0.3343 nM for I-124 REGN2878. Imaging and biodistribution
studies showed excellent targeting of Zr-89 REGN2878 in PRLR-positive
xenografts at delayed times of 189 h (presented as mean ± 1 SD,
percent injected activity per mL (%IA/mL) 74.6 ± 33.8%IA/mL).
In contrast, MCF-7/PRLR tumor xenografts showed a low uptake (7.0
± 2.3%IA/mL) of control Zr-89 REGN1932 and a very low uptake
and rapid clearance of I-124 REGN2878 (1.4 ± 0.6%IA/mL). Zr-89
REGN2878 has excellent antigen-specific targeting in various PRLR
tumor xenograft models. We estimated, using image-based kinetic modeling,
that PRLR antigen has a very rapid in vivo turnover half-life of ∼14
min from the cell membrane. Despite relatively modest estimated tumor
PRLR expression numbers, PRLR-expressing cells have shown final retention
of the Zr-89 REGN2878 antibody, with an uptake that appeared to be
related to PRLR expression. This reagent has the potential to be used
in clinical trials targeting PRLR