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Specific uptake of 99mTc-NC100692, an ?v?3-targeted imaging probe, in subcutaneous and orthotopic tumors.

ABSTRACT: 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.

SUBMITTER: Dearling JL

PROVIDER: S-EPMC4267260 | biostudies-literature | 2013 Aug

REPOSITORIES: biostudies-literature

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Specific uptake of 99mTc-NC100692, an αvβ3-targeted imaging probe, in subcutaneous and orthotopic tumors.

Dearling Jason L J JL Barnes Jessica W JW Panigrahy Dipak D Zimmerman Robert E RE Fahey Frederic F Treves S Ted ST Morrison Matthew S MS Kieran Mark W MW Packard Alan B AB

Nuclear medicine and biology 20130520 6

<h4>Introduction</h4>The αvβ3 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 αvβ3-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 αvβ3-targeted diagnostics. This is at least partly due to the relatively limited availabil ...[more]

PMID: 23701702

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Project description:BackgroundNanobodies, derived from camelid antibodies made of only heavy chains, are the smallest, biologic, antigen-binding fragments (~15kDa) with faster pharmacokinetics and better tumor penetration efficiency than standard antibodies. The present study evaluates the efficacy of a fluorescent, anti-carcinoembryonic antigen (CEA) nanobody for rapid tumor labeling in an orthotopic mouse model of pancreatic cancer.MethodsAnti-CEA or control nanobodies were conjugated with the near-infrared fluorophore IRDye 800CW. Fragments of BxPC-3 (high-CEA expressing) or MiaPACA-2 (low-CEA expressing) human pancreatic cancer cell lines were orthotopically implanted into the pancreatic tail of nude mice. After tumors reached 7 to 10 mm in size, 2 nmol anti-CEA or control nanobody-IRDye800CW were injected intravenously. Mice were imaged at various time points hours post-injection.ResultsAnti-CEA nanobodies clearly labeled BxPC3 orthotopic pancreatic tumors 3 hours after injection. The signal was present as early as 15 minutes after injection and was robust at 1 to 3 hours after injection with a tumor-to-background ratio of 2.66. In contrast, there was very low accumulation in the low CEA-expressing, MiaPACA2 pancreatic orthotopic tumors. The fluorophore-conjugated nanobody was specific for CEA-expressing tumors, while the control nanobody did not show any tumor-specific signal. Both nanobodies had strong kidney uptake as expected for small-molecule probes. The fluorescence signal was detectable using 2 clinical, Food and Drug Administration-approved, 800 nm imaging devices as well as small animal imaging systems.ConclusionThis anti-CEA, nanobody-based, fluorescent probe labeled pancreatic orthotopic tumors within 15 minutes of intravenous injection. Fluorescent anti-CEA nanobodies have labeling kinetics that approach the speed of nonspecific dyes such as indocyanine green but with the specificity of antibodies. The use of fluorescently-labeled, intact antibodies leads to a labeling delay of 48 to 96 hours between probe administration and the necessarily delayed time of operation, which can be avoided with nanobodies. The kinetics of a nanobody-based probe makes it a practical agent for same-day, patient administration and fluorescence-guided surgery.

Dataset Information

Specific uptake of 99mTc-NC100692, an ?v?3-targeted imaging probe, in subcutaneous and orthotopic tumors.

Publications

Specific uptake of 99mTc-NC100692, an αvβ3-targeted imaging probe, in subcutaneous and orthotopic tumors.

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