Dataset Information

Diagnosis of LVAD Thrombus using a High-Avidity Fibrin-Specific 99mTc Probe.

ABSTRACT: Treatment of advanced heart failure with implantable LVADs is increasing, driven by profound unmet patient need despite potential serious complications: bleeding, infection, and thrombus. The experimental objective was to develop a sensitive imaging approach to assess early thrombus accumulation in LVADs under operational high flow and high shear rates. Methods: A monomeric bifunctional ligand with a fibrin-specific peptide, a short spacer, and 99mTc chelating amino acid sequence (F1A) was developed and compared to its tetrameric PEG analogue (F4A). Results:99mTc attenuation by LVAD titanium (1 mm) was 23%. 99mTc-F1A affinity to fibrin was Kd ~10 µM, whereas, the bound 99mTc-F4A probe was not displaced by F1A (120,000:1). Human plasma interfered with 99mTc-F1A binding to fibrin clot (p<0.05) in vitro, whereas, 99mTc-F4A targeting was unaffected. The pharmacokinetic half-life of 99mTc-F4A was 28% faster (124±41 min) than 99mTc-F1A (176±26 min) with both being bioeliminated through the urinary system with negligible liver or spleen biodistribution. In mice with carotid thrombus, 99mTc-F4A binding to the injured carotid was much greater (16.3±3.3 %ID/g, p=0.01) than that measured with an irrelevant negative control, 99mTc-I4A (3.4±1.6 %ID/g). In an LVAD mock flow-loop (1:1, PBS:human plasma:heparin) operating at maximal flow rate, 99mTc-F4A bound well to phantom clots in 2 min (p<0.05), whereas 99mTc-F1A had negligible targeting. Excised LVADs from patients undergoing pump exchange or heart transplant were rewired, studied in the mock flow loop, and found to have spatially variable fibrin accumulations in the inlet and outlet cannulas and bearings. Conclusions:99mTc-F4A is a high-avidity prototype probe for characterizing thrombus in LVADs that is anticipated to help optimize anticoagulation, reduce thromboembolic events, and minimize pump exchange.

SUBMITTER: Cui G

PROVIDER: S-EPMC5817118 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Diagnosis of LVAD Thrombus using a High-Avidity Fibrin-Specific 99mTc Probe.

Cui Grace G Akers Walter J WJ Scott Michael J MJ Nassif Michael M Allen John S JS Schmieder Anne H AH Paranandi Krishna S KS Itoh Akinobu A Beyder Dmitry D DD Achilefu Samuel S Ewald Gregory A GA Lanza Gregory M GM

Theranostics 20180202 4

Treatment of advanced heart failure with implantable LVADs is increasing, driven by profound unmet patient need despite potential serious complications: bleeding, infection, and thrombus. The experimental objective was to develop a sensitive imaging approach to assess early thrombus accumulation in LVADs under operational high flow and high shear rates. Methods: A monomeric bifunctional ligand with a fibrin-specific peptide, a short spacer, and 99mTc chelating amino acid sequen ...[more]

PMID: 29464007

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Project description:INTRODUCTION:The ?v?3 integrin, which is expressed by angiogenic epithelium and some tumor cells, is an attractive target for the development of both imaging agents and therapeutics. While optimal implementation of ?v?3-targeted therapeutics will require a priori identification of the presence of the target, the clinical evaluation of these compounds has typically not included parallel studies with ?v?3-targeted diagnostics. This is at least partly due to the relatively limited availability of PET radiopharmaceuticals in comparison to those labeled with (99m)Tc. In an effort to begin to address this limitation, we evaluated the tumor uptake of (99m)Tc-NC100692, a cyclic RGD peptide that binds to ?v?3 with ~1-nM affinity, in an ?v?3-positive tumor model as well as its in vivo specificity. METHODS:MicroSPECT imaging was used to assess the ability of cilengitide, a therapeutic with high affinity for ?v?3, to block and displace (99m)Tc-NC100692 in an orthotopic U87 glioma tumor. The specificity of (99m)Tc-NC100692 was quantitatively evaluated in mice bearing subcutaneous U87MG tumors, by comparison of the biodistribution of (99m)Tc-NC100692 with that of the non-specific structural analogue (99m)Tc-AH-111744 and by blocking uptake of (99m)Tc-NC100692 with excess unlabeled NC100692. RESULTS:MicroSPECT imaging studies demonstrated that uptake of (99m)Tc-NC100692 in the intracranial tumor model was both blocked and displaced by the ?v?3-targeted therapeutic cilengitide. Biodistribution studies provided quantitative confirmation of these imaging results. Tumor uptake of (99m)Tc-NC100692 at 1h post-injection was 2.8 ± 0.7% ID/g compared to 0.38 ± 0.1% ID/g for (99m)Tc-AH-111744 (p < 0.001). Blocking (99m)Tc-NC100692 uptake by pre-injecting the mice with excess unlabeled NC100692 reduced tumor uptake by approximately five-fold, to 0.68 ± 0.3% ID/g (p = 0.01). CONCLUSION:These results confirm that (99m)Tc-NC100692 does, in fact, target the ?v?3 integrin and may, therefore, be useful in identifying patients prior to anti-?v?3 therapy as well as monitoring the response of these patients to therapy.

Dataset Information

Diagnosis of LVAD Thrombus using a High-Avidity Fibrin-Specific 99mTc Probe.

Publications

Diagnosis of LVAD Thrombus using a High-Avidity Fibrin-Specific <sup>99m</sup>Tc Probe.

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