42 research outputs found
In vivo Biodistribution of Radiolabeled Acoustic Protein Nanostructures
Purpose: Contrast-enhanced ultrasound plays an expanding role in oncology, but its applicability to molecular imaging is hindered by a lack of nanoscale contrast agents that can reach targets outside the vasculature. Gas vesicles (GVs)—a unique class of gas-filled protein nanostructures—have recently been introduced as a promising new class of ultrasound contrast agents that can potentially access the extravascular space and be modified for molecular targeting. The purpose of the present study is to determine the quantitative biodistribution of GVs, which is critical for their development as imaging agents.
Procedures: We use a novel bioorthogonal radiolabeling strategy to prepare technetium-99m-radiolabeled ([99mTc])GVs in high radiochemical purity. We use single photon emission computed tomography (SPECT) and tissue counting to quantitatively assess GV biodistribution in mice.
Results: Twenty minutes following administration to mice, the SPECT biodistribution shows that 84 % of [99mTc]GVs are taken up by the reticuloendothelial system (RES) and 13 % are found in the gall bladder and duodenum. Quantitative tissue counting shows that the uptake (mean ± SEM % of injected dose/organ) is 0.6 ± 0.2 for the gall bladder, 46.2 ± 3.1 for the liver, 1.91 ± 0.16 for the lungs, and 1.3 ± 0.3 for the spleen. Fluorescence imaging confirmed the presence of GVs in RES.
Conclusions: These results provide essential information for the development of GVs as targeted nanoscale imaging agents for ultrasound
In vivo Biodistribution of Radiolabeled Acoustic Protein Nanostructures
Purpose: Contrast-enhanced ultrasound plays an expanding role in oncology, but its applicability to molecular imaging is hindered by a lack of nanoscale contrast agents that can reach targets outside the vasculature. Gas vesicles (GVs)—a unique class of gas-filled protein nanostructures—have recently been introduced as a promising new class of ultrasound contrast agents that can potentially access the extravascular space and be modified for molecular targeting. The purpose of the present study is to determine the quantitative biodistribution of GVs, which is critical for their development as imaging agents.
Procedures: We use a novel bioorthogonal radiolabeling strategy to prepare technetium-99m-radiolabeled ([99mTc])GVs in high radiochemical purity. We use single photon emission computed tomography (SPECT) and tissue counting to quantitatively assess GV biodistribution in mice.
Results: Twenty minutes following administration to mice, the SPECT biodistribution shows that 84 % of [99mTc]GVs are taken up by the reticuloendothelial system (RES) and 13 % are found in the gall bladder and duodenum. Quantitative tissue counting shows that the uptake (mean ± SEM % of injected dose/organ) is 0.6 ± 0.2 for the gall bladder, 46.2 ± 3.1 for the liver, 1.91 ± 0.16 for the lungs, and 1.3 ± 0.3 for the spleen. Fluorescence imaging confirmed the presence of GVs in RES.
Conclusions: These results provide essential information for the development of GVs as targeted nanoscale imaging agents for ultrasound
SN 2022crv: IIb, Or Not IIb: That is the Question
We present optical and near-infrared observations of SN~2022crv, a stripped
envelope supernova in NGC~3054, discovered within 12 hrs of explosion by the
Distance Less Than 40 Mpc Survey. We suggest SN~2022crv is a transitional
object on the continuum between SNe Ib and SNe IIb. A high-velocity hydrogen
feature (20,000 -- 16,000 ) was conspicuous in
SN~2022crv at early phases, and then quickly disappeared around maximum light.
By comparing with hydrodynamic modeling, we find that a hydrogen envelope of
\msun{} can reproduce the behaviour of the hydrogen feature
observed in SN~2022crv. The early light curve of SN~2022crv did not show
envelope cooling emission, implying that SN~2022crv had a compact progenitor
with extremely low amount of hydrogen. The analysis of the nebular spectra
shows that SN~2022crv is consistent with the explosion of a He star with a
final mass of 4.5 -- 5.6 \msun{} that has evolved from a 16 -- 22
\msun{} zero-age main sequence star in a binary system with about 1.0 -- 1.7
\msun{} of oxygen finally synthesized in the core. The high metallicity at the
supernova site indicates that the progenitor experienced a strong stellar wind
mass loss. In order to retain a small amount of residual hydrogen at such a
high metallicity, the initial orbital separation of the binary system is likely
larger than 1000~. The near-infrared spectra of SN~2022crv
show a unique absorption feature on the blue side of He I line at
1.005~m. This is the first time that such a feature has been
observed in a Type Ib/IIb, and could be due to \ion{Sr}{2}. Further detailed
modelling on SN~2022crv can shed light on the progenitor and the origin of the
mysterious absorption feature in the near infrared.Comment: 33 pages, 23 figures, submitted to Ap
Automated synthesis of [18F]DCFPyL via direct radiofluorination and validation in preclinical prostate cancer models
Background:
Prostate-specific membrane antigen (PSMA) is frequently overexpressed and upregulated in prostate cancer. To date, various 18F- and 68Ga-labeled urea-based radiotracers for PET imaging of PSMA have been developed and entered clinical trials. Here, we describe an automated synthesis of [18F]DCFPyL via direct radiofluorination and validation in preclinical models of prostate cancer.
Methods:
[18F]DCFPyL was synthesized via direct nucleophilic heteroaromatic substitution reaction in a single reactor TRACERlab FXFN automated synthesis unit. Radiopharmacological evaluation of [18F]DCFPyL involved internalization experiments, dynamic PET imaging in LNCaP (PSMA+) and PC3 (PSMA−) tumor-bearing BALB/c nude mice, biodistribution studies, and metabolic profiling. In addition, reversible two-tissue compartmental model analysis was used to quantify pharmacokinetics of [18F]DCFPyL in LNCaP and PC3 tumor models.
Results:
Automated radiosynthesis afforded radiotracer [18F]DCFPyL in decay-corrected radiochemical yields of 23 ± 5 % (n = 10) within 55 min, including HPLC purification. Dynamic PET analysis revealed rapid and high uptake of radioactivity (SUV5min 0.95) in LNCaP tumors which increased over time (SUV60min 1.1). Radioactivity uptake in LNCaP tumors was blocked in the presence of nonradioactive DCFPyL (SUV60min 0.22). The muscle as reference tissue showed rapid and continuous clearance over time (SUV60min 0.06). Fast blood clearance of radioactivity resulted in tumor-blood ratios of 1.0 after 10 min and 8.3 after 60 min. PC3 tumors also showed continuous clearance of radioactivity over time (SUV60min 0.11). Kinetic analysis of PET data revealed the two-tissue compartmental model as best fit with K
1 = 0.12, k
2 = 0.18, k
3 = 0.08, and k
4 = 0.004 min−1, confirming molecular trapping of [18F]DCFPyL in PSMA+ LNCaP cells.
Conclusions:
[18F]DCFPyL can be prepared for clinical applications simply and in good radiochemical yields via a direct radiofluorination synthesis route in a single reactor automated synthesis unit. Radiopharmacological evaluation of [18F]DCFPyL confirmed high PSMA-mediated tumor uptake combined with superior clearance parameters. Compartmental model analysis points to a two-step molecular trapping mechanism based on PSMA binding and subsequent internalization leading to retention of radioactivity in PSMA+ LNCaP tumors.Medicine, Faculty ofNon UBCRadiology, Department ofReviewedFacult
Preparation and Evaluation of Radiolabeled Antibody Recruiting Small Molecules That Target Prostate-Specific Membrane Antigen for Combined Radiotherapy and Immunotherapy
The feasibility of
developing a single agent that can deliver radioactive
iodine and also direct cellular immune function by engaging endogenous
antibodies as an antibody-recruiting small molecule (ARM) was determined.
A library of new prostate-specific membrane antigen (PSMA)-binding
ligands that contained antibody-recruiting 2,4-dinitrophenyl (DNP)
groups and iodine were synthesized and screened in vitro and in vivo.
A lead compound (<b>9b</b>) showed high affinity for PSMA and
the ability to bind anti-DNP antibodies. Biodistribution studies of
the iodine-125 analogue showed 3% ID/g in LNCaP xenograft tumors at
1 h postinjection with tumor-to-blood and tumor-to-muscle ratios of
10:1 and 44:1, respectively. The radiolabeled analogue was bound and
internalized by LNCaP cells, with both functions blocked using a known
PSMA inhibitor. A second candidate showed high tumor uptake (>10%
ID/g) but had minimal binding to anti-DNP antibodies. The compounds
reported represent the first examples of small molecules developed
specifically for combination immunotherapy and radiotherapy for prostate
cancer
Correction: A 99mTc-Labelled Tetrazine for Bioorthogonal Chemistry. Synthesis and Biodistribution Studies with Small Molecule trans-Cyclooctene Derivatives.
[This corrects the article DOI: 10.1371/journal.pone.0167425.]
A Bone-Seeking <i>trans</i>-Cyclooctene for Pretargeting and Bioorthogonal Chemistry: A Proof of Concept Study Using <sup>99m</sup>Tc- and <sup>177</sup>Lu-Labeled Tetrazines
A high yield synthesis
of a novel, small molecule, bisphosphonate-modified <i>trans</i>-cyclooctene (TCO-BP, <b>2</b>) that binds to
regions of active bone metabolism and captures functionalized tetrazines
in vivo, via the bioorthogonal inverse electron demand Diels–Alder
(IEDDA) cycloaddition, was developed. A <sup>99m</sup>Tc-labeled derivative
of <b>2</b> demonstrated selective localization to shoulder
and knee joints in a biodistribution study in normal mice. Compound <b>2</b> reacted rapidly with a <sup>177</sup>Lu-labeled tetrazine
in vitro, and pretargeting experiments in mice, using <b>2</b> and the <sup>177</sup>Lu-labeled tetrazine, yielded high activity
concentrations in shoulder and knee joints, with minimal uptake in
other tissues. Pretargeting experiments with <b>2</b> and a
novel <sup>99m</sup>Tc-labeled tetrazine also produced high activity
concentrations in the knees and shoulders. Critically, both radiolabeled
tetrazines showed negligible uptake in the skeleton and joints when
administered in the absence of <b>2</b>. Compound <b>2</b> can be utilized to target functionalized tetrazines to bone and
represents a convenient reagent to test novel tetrazines for use with
in vivo bioorthogonal pretargeting strategies
A <sup>99m</sup>Tc-Labelled Tetrazine for Bioorthogonal Chemistry. Synthesis and Biodistribution Studies with Small Molecule <i>trans</i>-Cyclooctene Derivatives
<div><p>A convenient strategy to radiolabel a hydrazinonicotonic acid (HYNIC)-derived tetrazine with <sup>99m</sup>Tc was developed, and its utility for creating probes to image bone metabolism and bacterial infection using both active and pretargeting strategies was demonstrated. The <sup>99m</sup>Tc-labelled HYNIC-tetrazine was synthesized in 75% yield and exhibited high stability <i>in vitro</i> and <i>in vivo</i>. A <i>trans</i>-cyclooctene (TCO)-labelled bisphosphonate (TCO-BP) that binds to regions of active calcium metabolism was used to evaluate the utility of the labelled tetrazine for bioorthogonal chemistry. The pretargeting approach, with <sup>99m</sup>Tc-HYNIC-tetrazine administered to mice one hour after TCO-BP, showed significant uptake of radioactivity in regions of active bone metabolism (knees and shoulders) at 6 hours post-injection. For comparison, TCO-BP was reacted with <sup>99m</sup>Tc-HYNIC-tetrazine before injection and this active targeting also showed high specific uptake in the knees and shoulders, whereas control <sup>99m</sup>Tc-HYNIC-tetrazine alone did not. A TCO-vancomycin derivative was similarly employed for targeting <i>Staphylococcus aureus</i> infection <i>in vitro</i> and <i>in vivo</i>. Pretargeting and active targeting strategies showed 2.5- and 3-fold uptake, respectively, at the sites of a calf-muscle infection in a murine model, compared to the contralateral control muscle. These results demonstrate the utility of the <sup>99m</sup>Tc-HYNIC-tetrazine for preparing new technetium radiopharmaceuticals, including those based on small molecule targeting constructs containing TCO, using either active or pretargeting strategies.</p></div