Abstract
Integrin αvβ6 is a cell surface receptor minimally expressed by healthy tissue but elevated in lung, colon, skin, ovarian, cervical, and pancreatic cancers. A molecular PET agent for integrin αvβ6 could provide significant clinical utility by facilitating both cancer staging and treatment monitoring to more rapidly identify an effective therapeutic approach. Methods: Here, we evaluated 2 cystine knot peptides, R01 and S02, previously engineered with a 3–6 nM affinity for integrin αvβ6, for 18F radiolabeling and PET imaging of BxPC3 pancreatic adenocarcinoma xenografts in mice. Cystine knot peptides were labeled with N-succinimidyl-4-18F-fluorobenzoate and evaluated for binding affinity and serum stability. Peptides conjugated with 18F-fluorobenzoate (2–3 MBq) were injected via the tail vein into nude mice xenografted with BxPC3 (integrin αvβ6–positive) or 293 (integrin αvβ6–negative) tumors. Small-animal PET scans were acquired at 0.5, 1, and 2 h after injection. Ex vivo γ-counting of dissected tissues was performed at 0.5 and 2 h. Results: 18F-fluorobenzoate peptides were produced in 93% (18F-fluorobenzoate-R01) and 99% (18F-fluorobenzoate-S02) purity. 18F-fluorobenzoate-R01 and 18F-fluorobenzoate-S02 had affinities of 1.1 ± 0.2 and 0.7 ± 0.4 nM, respectively, and were 87% and 94%, respectively, stable in human serum at 37°C for 2 h. 18F-fluorobenzoate-R01 and 18F-fluorobenzoate-S02 exhibited 2.3 ± 0.6 and 1.3 ± 0.4 percentage injected dose per gram (%ID/g), respectively, in BxPC3 xenografted tumors at 0.5 h (n = 4–5). Target specificity was confirmed by low tumor uptake in integrin αvβ6–negative 293 tumors (1.4 ± 0.6 and 0.5 ± 0.2 %ID/g, respectively, for 18F-fluorobenzoate-R01 and 18F-fluorobenzoate-S02; both P < 0.05; n = 3–4) and low muscle uptake (3.1 ± 1.0 and 2.7 ± 0.4 tumor to muscle for 18F-fluorobenzoate-R01 and 18F-fluorobenzoate-S02, respectively). Small-animal PET data were corroborated by ex vivo γ-counting of dissected tissues, which demonstrated low uptake in nontarget tissues with only modest kidney uptake (9.2 ± 3.3 and 1.9 ± 1.2 %ID/g, respectively, at 2 h for 18F-fluorobenzoate-R01 and 18F-fluorobenzoate-S02; n = 8). Uptake in healthy pancreas was low (0.3% ± 0.1% for 18F-fluorobenzoate-R01 and 0.03% ± 0.01% for 18F-fluorobenzoate-S02; n = 8). Conclusion: These cystine knot peptide tracers, in particular 18F-fluorobenzoate-R01, show translational promise for molecular imaging of integrin αvβ6 overexpression in pancreatic and other cancers.
Integrin αvβ6 is emerging as a potentially useful molecular marker of multiple cancers. Integrin αvβ6 overexpression has been demonstrated in oral squamous cell carcinoma (1), pancreatic ductal adenocarcinomas (2), intestinal gastric carcinomas (2), ovarian cancer (3), and stage III basal cell carcinoma (4). Moreover, overexpression is prognostic of reduced survival in colon carcinoma (5), non–small cell lung cancer (6), cervical squamous carcinoma (7), and gastric carcinoma (8). Also, integrin αvβ6 expression is associated with increased liver metastasis of colon cancer (9). Importantly, expression is undetectable in most normal tissues including ovary (3); kidney, lung, and skin (1); and pancreas (2). Thus, a molecular imaging agent targeted to integrin αvβ6 would provide significant clinical utility.
The linear peptide A20FMDV2, derived from the envelope protein of foot-and-mouth disease, has a concentration of half-maximal inhibition of 3 ± 1 nM for integrin αVβ6 (10). The 18F-radiolabeled peptide exhibited an uptake of 0.7 ± 0.1 percentage injected dose per gram (%ID/g) of tumor in xenografted mice but only a ratio of 1.2 ± 0.6 tumor to muscle at 1 h. Moreover, this peptide analyzed in the urine at 1 h was fully degraded to multiple metabolites. Polyethylene glycol conjugation of this peptide improved tumor uptake to 1.9 ± 0.4 %ID/g and tumor to muscle to 2.5, though significant metabolic breakdown was still present (11). An alternative linear peptide targeted to integrin αvβ6, HBP-1, yielded no tumor-to-blood contrast (12).
To identify a more stable and effective molecular imaging agent, we have recently engineered cystine knot peptides with a 3–6 nM affinity for integrin αvβ6 (13). 64Cu labeling of these peptides via a DOTA chelator enabled effective PET imaging of mice bearing BxPC3 pancreatic adenocarcinoma and A431 epidermoid carcinoma xenografted tumors. Tumor uptake with an arginine-rich scaffold was 4.7 ± 0.9 %ID/g at 1 h with 8.7 ± 1.5 tumor-to-muscle contrast, and the peptide was 80% stable in serum for 24 h. A serine-rich cystine knot peptide had 2.1 ± 0.5 %ID/g tumor, 9.4 ± 1.7 tumor to muscle, and greater than 95% serum stability at 24 h. The rapid tumor localization and background clearance of these small peptides enable imaging as early as 1 h after injection. Thus, 18F is a preferred radioisotope for clinical translation of these agents because of its greater positron yield and faster decay (for reduced radiation exposure).
In the current work, we evaluate two 18F-labeled integrin αvβ6–targeted cystine knot peptides for small-animal PET imaging of pancreatic adenocarcinoma xenografted tumors in mice. Pancreatic cancer is of particular interest because of its rapid lethality (6% five-y survival (14)). A molecular imaging tracer for PET would be clinically valuable for both cancer staging and treatment monitoring to more rapidly identify an effective therapeutic approach.
MATERIALS AND METHODS
Peptide Synthesis and Radiochemistry
Peptides R01 and S02 were synthesized using standard Fmoc chemistry, folded, and purified by reversed-phase high-performance liquid chromatography (RP-HPLC) as described previously (13). Protein mass was verified by matrix-assisted laser desorption/ionization–time-of-flight–mass spectrometry (MALDI-TOF-MS). The amine-reactive radiolabeling agent N-succinimidyl-4-18F-fluorobenzoate (18F-SFB) was synthesized using TRACERlab FX-FN (15,16). The triflate precursor 4-(ethoxycarbonyl)-N,N,N-trimethylbenzenaminium (3 mg) was reacted with the dried 18F-fluoride-Kryptofix-K2CO3 complex (6.8 GBq) at 90°C for 10 min (Kryptofix supplier, Sigma Aldrich). 18F-4-fluorobenzoic acid was prepared by reaction with tetrapropylammonium hydroxide (50 μmol) at 120°C for 3 min. Acetonitrile was added and evaporated to remove residual water. The reaction mixture was added to 10 mg of O-(N-succinimidyl)-1,1,3,3-tetramethyluronium tetrafluoroborate (10 mg) and heated at 90°C for 5 min to produce 18F-SFB. Acetic acid (8 mL; 5% v/v) was added and used to transfer the crude reaction mixture to a dilution flask with 12 mL of water. The mixture was passed through a C18 Plus cartridge (Waters), washed with 10% acetonitrile in water (10 mL), and eluted with acetonitrile (3 mL). 18F-SFB was dried under vacuum at 60°C, resuspended in dimethyl sulfoxide (50 μL), and reacted with folded peptide (∼300 μg) in 0.1 M sodium phosphate, pH 7.5 (300 μL), at 50°C for 45 min. 18F-fluorobenzoate-peptide was purified by semipreparative RP-HPLC on a C18 column using a gradient of 25%–65% over 35 min for R01 and 22.5%–27.5% over 35 min for S02. Solvent was removed by rotary evaporation, and peptide was prepared in phosphate-buffered saline.
Affinity Titration
R01 and S02 were labeled with cold SFB to produce fluorobenzoate-peptide. Yeast surface-display competition assays were performed to measure the binding affinity of fluorobenzoate-peptide as described previously (17). EBY100 Saccharomyces cerevisiae yeast were transformed with plasmid to encode R01. Yeast were grown, and R01 expression was induced. Yeast were washed and incubated with 100 pM to 300 nM fluorobenzoate-peptide and 10 nM soluble integrin αvβ6. Yeast were washed and labeled with a fluorescein-conjugated antiintegrin αv antibody. Fluorescence was quantified by flow cytometry. The concentration of half-maximal inhibition was calculated by minimizing the sum of squared error. The equilibrium dissociation constant was calculated using the Cheng–Prusoff equation (18).
Serum Stability
18F-fluorobenzoate-peptide in phosphate-buffered saline was mixed with an equal volume of human serum and incubated at 37°C, 300 rpm, for 2 h. Trifluoroacetic acid was added, and the soluble fraction was clarified with a 0.22-μm filter. The sample was separated by RP-HPLC on a C18 column with a gradient of 5%–85% acetonitrile in water (both with 0.1% trifluoroacetic acid) from 5 to 35 min and analyzed with a γ-ray detector.
Small-Animal Imaging and Tissue Biodistribution
Animal experiments were conducted in accordance with federal and institutional regulations under a protocol approved by the Stanford University Institutional Animal Care and Use Committee. Ten million integrin αvβ6–positive BxPC3 pancreatic adenocarcinoma cells or integrin αvβ6–negative HEK-293 cells were subcutaneously injected into the shoulder of 6-wk-old female nu/nu mice. Xenografted tumors were grown to a 10-mm diameter. Mice were anesthetized with isoflurane and injected via the tail vein with 2–3 MBq of 18F-fluorobenzoate-peptide. A rodent R4 microPET (Siemens) scanner was used to acquire 5-min static scans at 0.5, 1, and 2 h after injection or a 10-min dynamic scan. Tumor, kidney, liver, and hind leg muscle signals were quantified with AsiPro VM (Siemens) for static scans and AMIDE (Amide's a Medical Imaging Data Examiner) (19) for dynamic scans. For excised tissue biodistribution, at 0.5 and 2 h after injection mice were euthanized, tissues were collected and weighed, and activity was measured with a γ-ray counter. The decay-corrected activity per mass of tissue was calculated. All data are presented as mean ± SD. Statistical significance was tested using the 2-tailed Student t test, with a threshold of P less than 0.05. For coinjection studies, 250 μg of unlabeled R01 or S02 were coinjected along with the corresponding 18F-fluorobenzoate-peptide. Mice were analyzed for biodistribution in excised tissues.
RESULTS
Peptide Synthesis and Radiochemistry
Peptides R01 and S02 (Fig. 1) were synthesized using standard Fmoc chemistry. Mass was verified by MALDI-TOF-MS: R01, 3,908.7 Da (3,908.8 Da expected); and S02, 3,875.5 Da (3,874.7 Da expected). Peptides were folded and purified by RP-HPLC. The abstraction of 6 hydrogens during oxidation was verified by MALDI-TOF-MS: R01, 3,902.8 Da; and S02, 3,868.4 Da. 18F-SFB was synthesized in 1 h with a 23% ± 13% yield (decay-corrected to start of synthesis). Three hundred micrograms of folded peptide were reacted with approximately 1,000 MBq of 18F-SFB in 0.1 M sodium phosphate, pH 7.5, at 50°C for 45 min. 18F-fluorobenzoate-peptide was purified by RP-HPLC. Solvent was removed by rotary evaporation, and product was resuspended in phosphate-buffered saline. 18F-fluorobenzoate-R01 and 18F-fluorobenzoate-S02 were 93% and more than 99% pure as measured by analytic RP-HPLC. Decay-corrected yield from 18F-SFB was 7% ± 1% for 18F-fluorobenzoate-R01 and 6% ± 1% for 18F-fluorobenzoate-S02. 18F-fluorobenzoate-R01 and 18F-fluorobenzoate-S02 were 87% and 94% stable for 2 h at 37°C in human serum (Fig. 2). In a binding competition assay using 10 nM soluble integrin αVβ6, the concentration of half-maximal inhibition values of fluorobenzoate-R01 and fluorobenzoate-S02 were measured as 4.1 ± 0.6 and 2.7 ± 1.6 nM, respectively. These correspond to equilibrium dissociation constant values of 1.1 ± 0.2 and 0.7 ± 0.4 nM, respectively (Supplemental Fig. 1; supplemental materials are available online only at http://jnm.snmjournals.org).
Cystine knot peptides. R01 and S02 are cystine knot peptides that contain 3 disulfide bonds, an active binding loop (black), and a sole primary amine at N terminus. N-terminal amine was coupled with 18F-SFB in 0.1 M sodium phosphate, pH 7.5, at 50°C for 45 min. Peptide sequences are presented with conserved residues highlighted.
Serum stability. 18F-fluorobenzoate-R01 (A) and 18F-fluorobenzoate-S02 (B) were incubated in 50% human serum at 37°C for 2 h. Samples were separated by RP-HPLC on C18 column with gradient of 5%–85% acetonitrile in water (both with 0.1% trifluoroacetic acid) from 5 to 35 min and analyzed with a γ-ray detector.
Small-Animal PET Imaging
The radiolabeled peptides were used for small-animal PET imaging of mice bearing BxPC3 pancreatic adenocarcinoma xenografted tumors. Nude mice were inoculated with 107 BxPC3 cells, which express integrin αvβ6. When tumors reached approximately 10 mm in diameter, mice were injected with 2–3 MBq of 18F-fluorobenzoate-peptide, and PET scans were obtained. Tumor was clearly visualized relative to background as early as 0.5 h after injection for both peptides (Fig. 3). As was the case for the 64Cu-DOTA versions of the peptides (13), 18F-fluorobenzoate-R01 exhibits greater tumor uptake (2.3 ± 0.6 %ID/g) than 18F-fluorobenzoate-S02 (1.3% ± 0.4%), and both have comparable tumor-to-muscle ratios: 3.1 ± 1.0 and 2.9 ± 0.4 at 0.5 and 1 h, respectively, for 18F-fluorobenzoate-R01, and 2.7 ± 0.4 and 4.0 ± 1.0 at 0.5 and 1 h, respectively, for 18F-fluorobenzoate-S02 (Fig. 4).
Small-animal PET imaging. BxPC3 pancreatic adenocarcinoma cells (integrin αvβ6–positive) or 293 (integrin αvβ6–negative) were xenografted into nude mice. 18F-fluorobenzoate-R01 (2–3 MBq) (A) or 18F-fluorobenzoate-S02 (2–3 MBq) (B) were injected via tail vein. Five-minute static scans were acquired at 0.5, 1, and 2 h after injection. Decay-corrected coronal and transverse slices are presented. Tumor (T) and kidneys (K) are marked on images. Images are all normalized to quantitative color scale shown on right of each figure set.
Small-animal PET quantification of data in Figure 3. Signals in tumor and muscle were quantified with AsiPro VM. Value and error bars represent mean and SD for 18F-fluorobenzoate-R01 (A and B; n = 5 for BxPC3, n = 3 for 293) and 18F-fluorobenzoate-S02 (C and D; n = 4 for BxPC3, n = 4 for 293). *P < 0.05.
To further demonstrate integrin αvβ6 specificity, small-animal PET experiments were performed with xenografted tumors of 293 cells, which do not express integrin αvβ6 (13). 18F-fluorobenzoate-R01 exhibits 1.4 ± 0.6 %ID/g tumor signal, which is significantly less (P = 0.04) than BxPC3 xenografts (Figs. 3 and 4). Likewise, 18F-fluorobenzoate-S02 has lower uptake in 293 tumors than in BxPC3 tumors (0.5% ± 0.2%, P = 0.02).
Both tracers exhibit modest kidney uptake (27% ± 4% for 18F-fluorobenzoate-R01 and 18% ± 6% for 18F-fluorobenzoate-S02) and low liver uptake (2.0% ± 0.7% for 18F-fluorobenzoate-R01 and 0.9% ± 0.3% for 18F-fluorobenzoate-S02) (Supplemental Fig. 2).
Dynamic PET demonstrates the rapid distribution of the peptides, because tumor targeting is 95% complete within 5 min for both peptides (Fig. 5). The rapid tumor signal stabilization is consistent with the rapid clearance of both peptides: analysis of the radioactivity in the heart reveals blood clearance half-times of 1.6 min for 18F-fluorobenzoate-R01 and 1.8 min for 18F-fluorobenzoate-S02 (Fig. 5). Rapid dynamics are observed in other tissues (Supplemental Fig. 3).
Dynamic PET. BxPC3 pancreatic adenocarcinoma cells (integrin αvβ6–positive) or 293 (integrin αvβ6–negative) were xenografted into nude mice. 18F-fluorobenzoate-R01 (2–3 MBq) (A) or 18F-fluorobenzoate-S02 (2–3 MBq) (B) were injected via tail vein. Ten-minute dynamic scan was acquired via PET. Mean signals in ellipsoid regions of interest were quantified with AMIDE.
Tissue Biodistribution
Further tissue biodistribution was obtained via activity measurements of resected tissues from mice euthanized at 0.5 and 2 h after injection (Fig. 6). These data closely match the PET results for tumor, muscle, kidney, and liver. Tumor uptake is higher in target-positive (BxPC3) tumors than in target-negative (293) tumors at 0.5 h: 2.2 ± 0.5 vs. 0.6 ± 0.1 %ID/g for 18F-fluorobenzoate-R01 (P = 0.027) and 0.71 ± 0.13 vs. 0.11 ± 0.02 %ID/g for 18F-fluorobenzoate-S02 (P = 0.001). At 2 h, the uptake values are 1.4 ± 0.3 vs. 0.9 ± 0.6 %ID/g (18F-fluorobenzoate-R01, P = 0.13) and 0.24 ± 0.06 vs. 0.10 ± 0.05 %ID/g (18F-fluorobenzoate-S02, P = 0.006). Tumor-to-blood ratios of 6.0 ± 1.1 and 3.1 ± 0.8 were achieved at 2 h for 18F-fluorobenzoate-R01 and 18F-fluorobenzoate-S02, respectively. Low nontarget uptake is observed in other tissues aside from moderate uptake in the stomach (1.6% ± 0.4%, n = 8) and lungs (2.9% ± 1.2%, n = 8; though because of the low density of lungs, the uptake is only 0.7 ± 0.3 %ID/cm3) for 18F-fluorobenzoate-R01.
Biodistribution. BxPC3 pancreatic adenocarcinoma cells (integrin αvβ6–positive) or 293 (integrin αvβ6–negative) were xenografted into nude mice. 18F-fluorobenzoate-R01 (2–3 MBq) (A; 0.5 h: n = 3 for BxPC3, n = 3 for 293, n = 6 for nontumor values; 2 h: n = 5 for BxPC3, n = 3 for 293, n = 8 for nontumor values) or 18F-fluorobenzoate-S02 (2–3 MBq) (B; 0.5 h: n = 3 for BxPC3, n = 3 for 293, n = 6 for nontumor values; 2 h: n = 4 for BxPC3, n = 4 for 293, n = 8 for nontumor values) were injected via tail vein. Mice were euthanized at 0.5 or 2 h after injection. Tissues were collected, and decay-corrected activity relative to injected dose was determined per gram of tissue (%ID/g). Value and error bars represent mean and SD. Values are presented for Bl = blood; Bo = bone; Br = brain; Bx = BxPC3 tumor; H = heart; I = intestine; K = kidney; Li = liver; Lu = lungs; M = muscle; P= pancreas; Sk = skin; Sp = spleen; St = stomach.
DISCUSSION
We previously validated the engineered R01 and S02 peptides as targeting domains for molecular PET imaging of integrin αVβ6 using 64Cu (13). Radiolabeling these peptides with 18F better matches radioisotope kinetics (1.8-h half-time), with the rapid uptake in tumor and clearance from background (effective imaging at 1 h after injection) for more efficient use of dose, which is critical for clinical translation. The peptides were effectively labeled site-specifically at the N-terminal amine with 18F using SFB and retained high stability and activity. The tracers specifically target tumor (5.0 ± 1.8 and 4.7 ± 1.8 tumor to muscle and 6.0 ± 1.1 and 3.1 ± 0.8 tumor to blood for 18F-fluorobenzoate-R01 and 18F-fluorobenzoate-S02, respectively) in an integrin αVβ6–specific manner (statistically significantly reduced uptake in target-negative 293 xenografts).
We have also explored coinjection studies with unlabeled peptide. R01 coinjection decreases tumor uptake, albeit not to a statistically significant extent: 2.2 ± 0.5 %ID/g in BxPC3 tumors at 0.5 h versus 1.8 ± 0.4 %ID/g with cold peptide coinjection. S02 does not demonstrate tumor uptake reduction. The lack of impact is potentially due to blocking of dilute levels of nontumor integrin αvβ6, thereby freeing more peptide for tumor targeting (20). Although this avenue is under further investigation, the target-positive and target-negative tumor comparisons, via both PET and excised tissue analysis, demonstrate specificity.
In addition to improved positron yield and reduced dosimetry relative to 64Cu, the 18F versions of these peptides have greatly reduced liver and kidney uptake. R01 exhibits a 5-fold reduction in renal signal (in %ID/g) from 80 ± 16 for 64Cu-DOTA to 16 ± 4 for 18F-fluorobenzoate at 1 h. S02 decreases 4-fold from 29 ± 10 to 7 ± 3. Hepatic signal (in %ID/g) decreases from 3.1 ± 0.6 to 1.2 ± 0.2 for R01 and from 4.4 ± 1.2 to 0.3 ± 0.1 for S02. This renal reduction is in agreement with previously observed results for several Affibody domains. Affibody ZHER2:477 kidney uptake (in %ID/g) was reduced from 206 ± 22 to 19 ± 1 for the monomer and from 114 ± 11 to 7 ± 1 for the dimer when labeling was changed from 64Cu-DOTA (21) to 18F-N-(4-fluorobenzylidene)oxime (22). Similarly, Affibody ZHER2–342 kidney uptake (in %ID/g) decreased from 172 ± 13 at 4 h with 111In-DOTA (23) to 10 ± 3 at 2 h with N-2-(4-18F-fluorobenzamido)ethylmaleimide (24).
Tumor uptake is also reduced in the 18F-labeled peptides relative to the 64Cu-labeled peptides, although to a lesser extent than the beneficial kidney and liver reductions. R01 tumor signal (in %ID/g) decreases from 4.7 ± 0.9 at 1 h to 2.3 ± 0.6 and 1.9 ± 0.5 at 0.5 and 1 h, respectively. S02 decreases from 2.1 ± 0.5 at 1 h to 1.3 ± 0.4 and 0.7 ± 0.3 at 0.5 and 1 h, respectively. As noted above, molecular specificity remains high in relation to muscle, blood, and integrin αVβ6–negative tumors.
Thus, 18F-fluorobenzoate-R01 is a prime candidate for clinical translation. Though only semiquantitative comparisons can be made because of the use of different animal models, 18F-fluorobenzoate-R01 compares favorably to alternative integrin αVβ6 tracers. This probe has greater tumor uptake (2.3 ± 0.6 and 1.9 ± 0.5 at 0.5 and 1 h, respectively, for 18F-fluorobenzoate-R01 vs. 0.7 ± 0.2 for 18F-fluorobenzoate-A20FMDV2 at 1 h), tumor-to-muscle contrast (5.0 ± 1.8 vs. 1.3), and tumor-to-blood contrast (6.0 ± 1.1 vs. 3.3) than 18F-A20FMDV2, albeit with higher renal signal (27 ± 4 and 16 ± 4 at 0.5 h and 1 h, respectively, vs. 3.3 ± 0.8). The addition of polyethylene glycol to the A20FMDV2 peptide (11) increased the tumor (1.9 ± 0.4) and kidney (19 ± 5) to uptake values essentially equal to those observed for 18F-fluorobenzoate-R01. Importantly, 18F-fluorobenzoate-R01 is 87% stable in human serum for 2 h whereas urine analysis at 1 h after injection reveals 3 metabolites and no intact tracer for 18F-A20 and 1 major metabolite for 18F-PEG-A20FMDV2 (though data were not shown). Increased stability, a hallmark of the cystine knot scaffold (25), may reduce off-target effects from metabolites including reduced immunogenicity, which is now under study.
A clinical molecular imaging agent for integrin αVβ6 could have broad impact because increased expression is observed on multiple cancers (1–9). In particular, because of the metastatic potential and lethality of pancreatic cancer, there is a critical need for a molecular imaging agent for patient staging, treatment stratification, and therapy monitoring. Integrin αVβ6 expression is undetectable in healthy pancreas but has elevated expression in pancreatic ductal adenocarcinoma (2). It is noteworthy that the PET tracers in the current work exhibit low uptake in healthy pancreas (0.3% ± 0.1% for 18F-fluorobenzoate-R01 and 0.03% ± 0.01% for 18F-fluorobenzoate-S02), which is imperative for clinical translation toward this application.
CONCLUSION
These cystine knot peptide tracers, in particular 18F-fluorobenzoate-R01, show translational promise for molecular imaging of integrin αvβ6 overexpression in pancreatic and other cancers.
DISCLOSURE
The costs of publication of this article were defrayed in part by the payment of page charges. Therefore, and solely to indicate this fact, this article is hereby marked “advertisement” in accordance with 18 USC section 1734. This research was supported by the National Institutes of Health (grants CA119367, CA136465, CA083636, and CA114747), the Department of Energy (Stanford Molecular Imaging Research and Training Program), the Canary Foundation, and a postdoctoral fellowship from the American Cancer Society. No other potential conflict of interest relevant to this article was reported.
Footnotes
↵* Contributed equally to this work.
Published online May 13, 2013.
- © 2013 by the Society of Nuclear Medicine and Molecular Imaging, Inc.
REFERENCES
- Received for publication July 2, 2012.
- Accepted for publication January 14, 2013.
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