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Non-invasive longitudinal imaging of tumor progression using an (111)indium labeled CXCR4 peptide antagonist.

ABSTRACT: The chemokine receptor 4 (CXCR4) is a biomarker that is over-expressed in ductal carcinoma in situ (DCIS). Hence, CXCR4-targeted (molecular) imaging approaches may have diagnostic value in such a challenging, premalignant lesion. The indium labeled CXCR4 peptide-antagonist, (111)In-DTPA-Ac-TZ14011, was used to visualize CXCR4-expression in a mammary intraepithelial neoplastic outgrowth (MIN-O) mouse tumor model resembling human DCIS. MIN-O lesion development was longitudinally monitored using SPET/CT and tracer uptake was compared to uptake in control lesions. Expression of CXCR4 was validated using immunohistochemistry and flow cytometric analysis. The uptake of (111)In-DTPA-Ac-TZ14011 was related to tumor angiogenesis using (111)In-cDTPA-[RGDfK]. Twenty-four hours after tracer injection, MIN-O lesions could be discriminated from low CXCR4-expressing control tumors, while the degree of angiogenesis based on the ?(v)?(3) integrin expression in both tumor types was similar. The uptake of (111)In-DTPA-Ac-TZ14011 in early MIN-O lesions was significantly lower than in larger intermediate and late-stage lesions, two-and-a-half-times (p=0.03) and seven-times (p=0.002), respectively. Intermediate and late stage lesions show a higher degree of membranous CXCR4-staining at immunohistochemistry and flow cytometric analysis. From this study we can conclude that (111)In-DTPA-Ac-TZ14011 can be used to visualize the CXCR4-expression in MIN-O lesions longitudinally.

SUBMITTER: Buckle T

PROVIDER: S-EPMC3478110 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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Non-invasive longitudinal imaging of tumor progression using an (111)indium labeled CXCR4 peptide antagonist.

Buckle Tessa T van Berg Nynke S NS Kuil Joeri J Bunschoten Anton A Oldenburg Joppe J Borowsky Alexander D AD Wesseling Jelle J Masada Ryo R Oishi Shinya S Fujii Nobutaka N van Leeuwen Fijs Wb FW

American journal of nuclear medicine and molecular imaging 20111215 1

The chemokine receptor 4 (CXCR4) is a biomarker that is over-expressed in ductal carcinoma in situ (DCIS). Hence, CXCR4-targeted (molecular) imaging approaches may have diagnostic value in such a challenging, premalignant lesion. The indium labeled CXCR4 peptide-antagonist, (111)In-DTPA-Ac-TZ14011, was used to visualize CXCR4-expression in a mammary intraepithelial neoplastic outgrowth (MIN-O) mouse tumor model resembling human DCIS. MIN-O lesion development was longitudinally monitored using SP ...[more]

PMID: 23133805

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Project description:PURPOSE:CXCR4 is overexpressed on tumor cells from many types of human cancers. A high level of CXCR4 expression often correlates with poor prognosis, chemotherapy resistance, and metastasis. The development of CXCR4-specific radiotracers for positron emission tomography (PET) imaging will allow in vivo evaluation of receptor expression level for diagnosis or therapeutic evaluation. PROCEDURES:Two new (18)F-labeled radiotracers based on an Ac-TC14012 peptide, [(18)F]FP-Ac-TC14012 and [(18)F]FB-Ac-TC14012, were synthesized and characterized. The affinities of the 2-fluoropropionate (FP)-conjugated or 4-fluorobenzoate (FB)-conjugated peptides to CXCR4-transfected Chinese hamster ovarian (CHO) cells were evaluated in a competitive binding assay with [(125)I]CXCL12 radioligand. The cell uptake and retention of [(18)F]FP-labeled and [(18)F]FB-labeled peptides were measured. The tumor targetability and pharmacokinetics of these two tracers were also evaluated by microPET imaging and biodistribution studies. RESULTS:The labeled peptides retained high binding affinity to CXCR4 and showed much higher uptake in CXCR4-positive CHO cells than in CXCR4-negative cells in vitro. The smaller and more hydrophilic [(18)F]FP prosthetic group resulted in higher affinity and lower nonspecific cell uptake compared to the [(18)F]FB-labeled peptide. Both radiotracers showed much higher accumulation in CXCR4-positive than CXCR4-negative tumor xenografts in mice and allowed clear visualization of CXCR4 expression by PET. Among the two, [(18)F]FP-Ac-TC14012 showed higher tumor uptake and better tumor-to-background contrast. Unlike their N-terminal 4-F-benzoate analogs, these two tracers had minimal blood retention, likely due to reduced red blood cell binding. Metabolic organs, such as the liver and kidney, also showed high uptake. When blocked with low-dose cold peptide (10 ?g), the tumor uptake was significantly increased, most likely due to the increased concentration in blood circulation, as evidenced by decreased liver uptake. CONCLUSION:These results demonstrate that the [(18)F]FP-labeled Ac-TC14012 peptide with high tumor uptake, low nonspecific binding, and good tumor-to-background contrast promises [(18)F]FP-Ac-TC14012 as a PET tracer for in vivo PET imaging of CXCR4 expression.

Project description:PurposeCurrent clinical measurements for tumor treatment efficiency rely often on changes in tumor volume measured as shrinkage by CT or MRI, which become apparent after multiple lines of treatment and pose a physical and psychological burden on the patient. Detection of therapy-induced cell death in the tumor can be a fast measure for treatment efficiency. However, there are no reliable clinical tools for detection of tumor necrosis. Previously, we studied the necrosis avidity of cyanine-based fluorescent dyes, which suffered long circulation times before tumor necrosis could be imaged due to low hydrophilicity. We now present the application of radiolabeled 800CW, a commercially available cyanine with high hydrophilicity, to image tumor necrosis in a mouse model.ProceduresWe conjugated 800CW to DOTA via a PEG linker, for labeling with single-photon emission-computed tomography isotope indium-111, yielding [111In]In-DOTA-PEG4-800CW. We then investigated specific [111In]In-DOTA-PEG4-800CW uptake by dead cells in vitro, using both fluorescence and radioactivity as detection modalities. Finally, we investigated [111In]In-DOTA-PEG4-800CW uptake into necrotic tumor regions of a 4T1 breast tumor model in mice.ResultsWe successfully prepared a precursor and developed a reliable procedure for labeling 800CW with indium-111. We detected specific [111In]In-DOTA-PEG4-800CW uptake by dead cells, using both fluorescence and radioactivity. Albeit with a tumor uptake of only 0.37%ID/g at 6 h post injection, we were able to image tumor necrosis with a tumor to background ratio of 7:4. Fluorescence and radioactivity in cryosections from the dissected tumors were colocalized with tumor necrosis, confirmed by TUNEL staining.Conclusions[111In]In-DOTA-PEG4-800CW can be used to image tumor necrosis in vitro and in vivo. Further research will elucidate the application of [111In]In-DOTA-PEG4-800CW or other radiolabeled hydrophilic cyanines for the detection of necrosis caused by chemotherapy or other anti-cancer therapies. This can provide valuable prognostic information in treatment of solid tumors.

Project description:(90)Y has been used to label various new therapeutic radiopharmaceuticals. However, measuring the radiation dose delivered by (90)Y is challenging because of the absence of suitable ? emissions and its low abundance of positron emissions. For the treatment of prostate cancer, radiolabeled gastrin-releasing peptide receptor (GRPr) antagonists have yielded promising results in mouse models. In this study, we evaluated whether Cerenkov luminescence imaging (CLI) could be used to determine radiation doses of a (90)Y-labeled GRPr antagonist in nude mice.Mice bearing subcutaneous prostate cancer xenografts were injected with 0.74-18.5 MBq of the (90)Y-labeled GRPr antagonist DOTA-AR and underwent in vivo and ex vivo CLI at 1-48 h after injection. After imaging, animals were sacrificed, their tumors and organs were harvested, and the activity concentration was measured by liquid scintillation counting. In a second set of experiments, Cerenkov photon counts for tumor and kidney on in vivo CLI were converted to activity concentrations using conversion factors determined from the first set of experiments.(90)Y-DOTA-AR concentration in the 3 tumor models ranged from 0.5% to 4.8% of the injected activity per gram at 1 h after injection and decreased to 0.05%-0.15 injected activity per gram by 48 h after injection. A positive correlation was found between tumor activity concentrations and in vivo CLI signal (r(2) = 0.94). A similar correlation was found for the renal activity concentration and in vivo Cerenkov luminescence (r(2) = 0.98). Other organs were not distinctly visualized on the in vivo images, but ex vivo CLI was also correlated with the radioactivity concentration (r(2) = 0.35-0.94). Using the time-activity curves from the second experiment, we calculated radiation doses to tumor and kidney of 0.33 ± 0.12 (range, 0.21-0.66) and 0.06 ± 0.01 (range, 0.05-0.08) Gy/MBq, respectively.CLI is a promising, low-cost modality to measure individual radiation doses of (90)Y-labeled compounds noninvasively. The use of Cerenkov imaging is expected to facilitate the development and comparison of (90)Y-labeled compounds for targeted radiotherapy.

Project description:Gastrin-releasing peptide (GRP) receptors (GRPr) are frequently overexpressed in human prostate cancer, and radiolabeled GRPr affinity ligands have shown promise for in vivo imaging of prostate cancer with PET. The goal of this study was to develop a dual-modality imaging probe that can be used for noninvasive PET imaging and optical imaging of prostate cancer.MethodsWe designed and synthesized an IRDye 650 and DOTA-conjugated GRPr antagonist, HZ220 (DOTA-Lys(IRDye 650)-PEG4-[D-Phe6, Sta13]-BN(6-14)NH2), by reacting DOTA-Lys-PEG4-[D-Phe6, Sta13]-BN(6-14)NH2 (HZ219) with IRDye 650 N-hydroxysuccinimide (NHS) ester. Receptor-specific binding of gallium-labeled HZ220 was characterized in PC-3 prostate cancer cells (PC-3), and tumor uptake in mice was imaged with PET/CT and fluorescence imaging. Receptor binding affinity, in vivo tumor uptake, and biodistribution were compared with the GRPr antagonists HZ219, DOTA-PEG4-[D-Phe6, Sta13]-BN(6-14)NH2 (DOTA-AR), and DOTA-(4-amino-1-carboxymethyl-piperidine)-[D-Phe6, Sta13]-BN(6-14)NH2 (DOTA-RM2).ResultsAfter hydrophilic-lipophilic balance cartridge purification, 68Ga-HZ220 was obtained with a radiochemical yield of 56% ± 8% (non-decay-corrected), and the radiochemical purity was greater than 95%. Ga-HZ220 had a lower affinity for GRPr (inhibitory concentration of 50% [IC50], 21.4 ± 7.4 nM) than Ga-DOTA-AR (IC50, 0.48 ± 0.18 nM) or Ga-HZ219 (IC50, 0.69 ± 0.18 nM). Nevertheless, 68Ga-HZ220 had an in vivo tumor accumulation similar to 68Ga-DOTA-AR (4.63 ± 0.31 vs. 4.07 ± 0.29 percentage injected activity per mL [%IA/mL] at 1 h after injection) but lower than that of 68Ga-DOTA-RM2 (10.4 ± 0.4 %IA/mL). The tumor uptake of 68Ga-HZ220 was blocked significantly with an excessive amount of GRP antagonists. IVIS spectrum imaging also visualized PC-3 xenografts in vivo and ex vivo with a high-contrast ratio. Autoradiography and fluorescent-based microscopic imaging with 68Ga-HZ220 consistently colocated the expression of GRPr. 68Ga-HZ220 displayed a higher kidney uptake than both 68Ga-DOTA-AR and 68Ga-DOTA-RM2 (16.9 ± 6.5 vs. 4.48 ± 1.63 vs. 5.01 ± 2.29 %IA/mL).Conclusion68Ga-HZ220 is a promising bimodal ligand for noninvasive PET imaging and intraoperative optical imaging of GRPr-expressing malignancies. Bimodal nuclear/fluorescence imaging may not only improve cancer detection and guide surgical resections, but also improve our understanding of the uptake of GRPr ligands on the cellular level.

Dataset Information

Non-invasive longitudinal imaging of tumor progression using an (111)indium labeled CXCR4 peptide antagonist.

Publications

Non-invasive longitudinal imaging of tumor progression using an (111)indium labeled CXCR4 peptide antagonist.

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