Integrin α6-Targeted Positron Emission Tomography Imaging of Colorectal Cancer

Xiao, Yi; Zhou, Chao; Ye, Jia Cong; Yang, Xiangdong; Li, Zhi Jian; Zheng, Xiao; Yan, Mingxia; Li, Xin Ling; Zhang, Wei Guang; Fan, Wei; Zeng, Mu Sheng; Li, Jian Jun; Guo, Feng

doi:10.1021/acsomega.9b01920

Cited by 15 publications

(13 citation statements)

References 27 publications

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“…The advent of molecular imaging has provided additional opportunities for non-invasive observation of aberrant molecular events in vivo. As an important component of the tumor targeted probe, targeting molecules (including antibodies and their fragments [ 10 ], peptides [ 11 ], and small molecules [ 12 ]) play the pivotal role of molecular probe. Due to their smaller molecular weight, peptides appear to bind to more hidden antigenic epitopes that other macromolecules cannot reach [ 13 ].…”

Section: Discussionmentioning

confidence: 99%

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Identification of an IGF2BP2-Targeted Peptide for Near-Infrared Imaging of Esophageal Squamous Cell Carcinoma

et al. 2022

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Esophageal squamous cell carcinoma (ESCC) is one of the most lethal malignancies globally. Peptide-based tumor-targeted imaging is critical for ESCC imaging. In this study, we aim to identify a peptide-targeting IGF2BP2 that specifically binds to human ESCC for near-infrared imaging of esophageal cancer. Applying phage display techniques, we identified a peptide target for IGF2BP2 which was confirmed to be highly expressed in ESCC cell lines or tumor tissue and may serve as an imaging target for ESCC. We conjugated the peptide to the NIRF group, Cy5, and further evaluated the targeting efficacy of the probe at a cellular level and in animal tumor models. The Cy5 conjugated peptide (P12-Cy5) showed a high binding affinity to human ESCC cells in vitro. In vivo, optical imaging also validated the tumor-targeting ability of P12-Cy5 in KYSE-30-bearing subcutaneous ESCC tumor models. Furthermore, the results of biodistribution showed a significantly higher fluorescence intensity in tumors compared to scrambled peptide, which is consistent with in vivo observations. In summary, an IGF2BP2-targeted peptide was successfully identified. In vitro and in vivo experiments confirmed that P12-Cy5 has high affinity, specificity and tumor-targeting properties. Thus, P12-Cy5 is a prospective NIR probe for the imaging of ESCC.

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Section: Discussionmentioning

confidence: 99%

“…As the key factor in NIR fluorescence imaging, NIR imaging probes usually consist of NIR dyes and targeting moieties (including antibodies and their fragments [ 10 ], peptides [ 11 ], small molecules [ 12 ], etc.) that interact specifically with molecules during tumorigenesis and evolution.…”

Section: Introductionmentioning

confidence: 99%

Identification of an IGF2BP2-Targeted Peptide for Near-Infrared Imaging of Esophageal Squamous Cell Carcinoma

et al. 2022

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“…In our previous study, we have identified a peptide CRWYDENAC (dubbed RWY) that could bind specifically to integrin α6 by phage display technology ( Feng G et al, 2019 ). We further translated the RWY peptide into an integrin α6-targeted PET probe and MRI probe that have been successfully applied for tumor imaging of the integrin α6 expression ( Feng GK et al, 2019 ; Xiao et al, 2019 ; Zhang Y et al, 2020 ; Gao et al, 2020 ). Recently, our group improved the characteristics of the peptide by alanine scanning and obtained a novel integrin α6-targeting peptide CRWYDANAC (dubbed S5) which exhibited a higher specificity and affinity to integrin α6 ( Mei et al, 2020 ; Lin et al, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

Integrin α6-Targeted Molecular Imaging of Central Nervous System Leukemia in Mice

Zhang

Chen

et al. 2022

Front. Bioeng. Biotechnol.

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Central nervous system leukemia (CNS-L) is caused by leukemic cells infiltrating into the meninges or brain parenchyma and remains the main reason for disease relapse. Currently, it is hard to detect CNS-L accurately by clinically available imaging models due to the relatively low amount of tumor cells, confined blood supply, and the inferior glucose metabolism intensity. Recently, integrin α6-laminin interactions have been identified to mediate CNS-L, which suggests that integrin α6 may be a promising molecular imaging target for the detection of CNS-L. The acute lymphoblastic leukemia (ALL) cell line NALM6 stabled and transfected with luciferase was used to establish the CNS-L mouse model. CNS-L-bearing mice were monitored and confirmed by bioluminescence imaging. Three of our previously developed integrin α6-targeted peptide-based molecular imaging agents, Cy5-S5 for near-infrared fluorescence (NIRF), Gd-S5 for magnetic resonance (MR), and 18F-S5 for positron emission tomography (PET) imaging, were employed for the molecular imaging of these CNS-L-bearing mice. Bioluminescence imaging showed a local intensive signal in the heads among CNS-L-bearing mice; meanwhile, Cy5-S5/NIRF imaging produced intensive fluorescence intensity in the same head regions. Moreover, Gd-S5/MR imaging generated superior MR signal enhancement at the site of meninges, which were located between the skull bone and brain parenchyma. Comparatively, MR imaging with the clinically available MR enhancer Gd-DTPA did not produce the distinguishable MR signal in the same head regions. Additionally, 18F-S5/PET imaging also generated focal radio-concentration at the same head regions, which generated nearly 5-times tumor-to-background ratio compared to the clinically available PET radiotracer 18F-FDG. Finally, pathological examination identified layer-displayed leukemic cells in the superficial part of the brain parenchyma tissue, and immunohistochemical staining confirmed the overexpression of the integrin α6 within the lesion. These findings suggest the potential application of these integrin α6-targeted molecular imaging agents for the accurate detection of CNS-L.

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“…5 In subsequent studies, the 18 F-labeled RWY peptide ( 18 F-RWY) was evaluated as a positron emission tomography (PET) radiotracer for HCC and colorectal cancer imaging. 4,6 The RWY peptide was also used to develop a SPECT radiotracer 99m Tc-RWY for integrin α 6 -positive tumor imaging. 7 The first major challenge with RWY peptide is the presence of an S−S bond in its cyclic framework.…”

Section: ■ Introductionmentioning

confidence: 99%

“…In our previous collaborative study, cyclic 9-mer peptide with the sequence cycloCRWYDENAC (RWY peptide, Figure A) was screened out by phage display, which specifically targets integrin α 6 . In subsequent studies, the 18 F-labeled RWY peptide ( 18 F-RWY) was evaluated as a positron emission tomography (PET) radiotracer for HCC and colorectal cancer imaging. , The RWY peptide was also used to develop a SPECT radiotracer 99m Tc-RWY for integrin α 6 -positive tumor imaging . The first major challenge with RWY peptide is the presence of an S–S bond in its cyclic framework.…”

Section: Introductionmentioning

confidence: 99%

An Integrin Alpha 6-Targeted Radiotracer with Improved Receptor Binding Affinity and Tumor Uptake

et al. 2020

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In this study, we reported a 99mTc-labeled integrin α6-targeted peptide as the molecular imaging probe for tumor imaging by single-photon emission computed tomography (SPECT). We found that replacing Cys–Cys cyclized RWY peptide (sequence: cCRWYDENAC) with lactam-bridged cyclic cKiE peptide (sequence: cKRWYDENAisoE) did not sacrifice the integrin α6-binding affinity and specificity of cKiE radiotracer. To further improve the radiotracer’s tumor targeting capability, the dimerized cKiE peptide (termed cKiE2) was designed, and the corresponding radiotracer 99mTc-cKiE2 was evaluated for tumor uptake and in vivo pharmacokinetics properties in tumor models. We found that cKiE2 showed higher binding affinity to integrin α6 than did monomeric RWY or cKiE peptide. The biodistribution results showed that the tumor uptake of 99mTc-cKiE2 was twice higher than that of 99mTc-RWY (3.20 ± 0.12 vs 1.26 ± 0.06 %ID/g, P < 0.001) at 0.5 h postinjection. The tumor to nontargeting tissue ratios were also enhanced in most normal organs. Specificity of 99mTc-cKiE2 for integrin α6 was demonstrated by competitive blocking of tumor uptake with excess cold peptide (3.20 ± 0.24 to 1.38 ± 0.23 %ID/g, P < 0.001). The integrin α6-positive tumors were clearly visualized by 99mTc-cKiE2/SPECT with low background except with a relatively high kidney uptake. The tumor uptake of 99mTc-cKiE2 correlates well with the tumor integrin α6 expression levels in a linear fashion (R2 = 0.9623). We also compared 99mTc-cKiE2 with an integrin αvβ3-targeted radiotracer 99mTc-3PRGD2 in the orthotopic hepatocellular carcinoma tumor models. We found that the orthotopic tumor was clearly visualized with 99mTc-cKiE2. 99mTc-3PRGD2 imaging did not show tumor contours in situ as clearly as 99mTc-cKiE2. The tumor-to-liver ratios of 99mTc-cKiE2 and 99mTc-3PRGD2 were 2.20 ± 0.17 and 0.85 ± 0.20. In conclusion, 99mTc-cKiE2 is an improved SPECT radiotracer for imaging integrin α6-positive tumors and has great potential for further clinical application.

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Integrin α6-Targeted Positron Emission Tomography Imaging of Colorectal Cancer

Cited by 15 publications

References 27 publications

Identification of an IGF2BP2-Targeted Peptide for Near-Infrared Imaging of Esophageal Squamous Cell Carcinoma

Identification of an IGF2BP2-Targeted Peptide for Near-Infrared Imaging of Esophageal Squamous Cell Carcinoma

Integrin α6-Targeted Molecular Imaging of Central Nervous System Leukemia in Mice

An Integrin Alpha 6-Targeted Radiotracer with Improved Receptor Binding Affinity and Tumor Uptake

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