Human epidermal growth factor receptor type 2 (HER2) is a well-established tumor biomarker that is overexpressed in a wide variety of cancers and that serves as a molecular target for therapeutic intervention. HER2 also serves as a prognostic indicator of patient survival and as a predictive marker of the response to antineoplastic therapy. The development of (18)F-labeled biomolecules for PET imaging of HER2 (HER2 PET) is very important because it may provide a powerful tool for the early detection of HER2-positive tumor recurrence and for the monitoring of HER2-based tumor treatment.
In this study, anti-HER2 monomeric and dimeric protein scaffold molecules [Z(HER2:477) and (Z(HER2:477))(2), respectively] were radiofluorinated at a reasonable radiochemical yield (13%-18%) by use of site-specific oxime chemistry. The resulting radiofluorinated protein scaffold molecules were then evaluated as potential molecular probes for small-animal HER2 PET by use of a SKOV3 tumor-bearing mouse model.
The 4-(18)F-fluorobenzaldehyde conjugated aminooxy-protein scaffolds [(18)F-N-(4-fluorobenzylidene)oxime (FBO)-Z(HER2:477) and (18)F-FBO-(Z(HER2:477))(2)] both displayed specific HER2-binding ability in vitro. Biodistribution and small-animal PET imaging studies further revealed that (18)F-FBO-Z(HER2:477) showed rapid and high SKOV3 tumor accumulation and quick clearance from normal tissues, whereas (18)F-FBO-(Z(HER2:477))(2) showed poor in vivo performance (low tumor uptake and tumor-to-normal tissue ratios). The specificity of (18)F-FBO-Z(HER2:477) for SKOV3 tumors was confirmed by its lower uptake on pretreatment of tumor-bearing mice with the HER2-targeting agents Z(HER2) and trastuzumab. Moreover, small-animal PET imaging studies revealed that (18)F-FBO-Z(HER2:477) produced higher-quality tumor imaging than (18)F-FBO-(Z(HER2:477))(2). (18)F-FBO-Z(HER2:477) could clearly identify HER2-positive tumors with good contrast.
Overall, these data demonstrate that (18)F-FBO-Z(HER2:477) is a promising PET probe for imaging HER2 expression in living mice. It has a high potential for translation to clinical applications. The radiofluorination method developed can also be used as a general strategy for the site-specific labeling of other proteins with (18)F. The protein scaffold molecules used here are attractive for the further development of PET probes for other molecular targets.
"Reducing the nonspecific liver accumulation continues to be a major obstacle in HCC imaging . Our previous studies and reports by other groups have found that affibodies were mainly cleared through the kidneys which showed high renal accumulation, with relatively lower liver uptake    . Thus, it is advantageous to use affibody-based probes to image biomarkers expressed in HCC because of the preferred renal clearance. "
[Show abstract][Hide abstract] ABSTRACT: Hepatocellular carcinoma (HCC) is a highly aggressive and lethal cancer. It is typically asymptomatic at the early stage, with only 10%-20% of HCC patients being diagnosed early enough for appropriate surgical treatment. The delayed diagnosis of HCC is associated with limited treatment options and much lower survival rates. Therefore, the early and accurate detection of HCC is crucial to improve its currently dismal prognosis. The epidermal growth factor receptor (EGFR) has been reported to be involved in HCC tumorigenesis and to represent an attractive target for HCC imaging and therapy. In this study, an affibody molecule, Ac-Cys-ZEGFR:1907, targeting the extracellular domain of EGFR, was used for the first time to assess its potential to detect HCC xenografts. By evaluating radio- or fluorescent-labeled Ac-Cys-ZEGFR:1907 as a probe for positron emission tomography (PET) or optical imaging of HCC, subcutaneous EGFR-positive HCC xenografts were found to be successfully imaged by the PET probe. Thus, affibody-based PET imaging of EGFR provides a promising approach for detecting HCC in vivo.
"Preparation of 18F-P3BZA was conducted the same as described in our previous publication15. The cellular uptake studies were performed on MCF-7-TYR, MCF-7 and B16F10 cells using the slightly modified procedure as reported previously4950. Briefly, cells (0.2 × 106 per well) were seeded in 12-well plates and incubated overnight at 37°C. Cells were then incubated with 0.5 mL of DMEM medium containing 3.7 kBq (0.1 μCi) of 18F-P3BZA at 37°C. "
[Show abstract][Hide abstract] ABSTRACT: Development of reporter genes for multimodality molecular imaging is highly important. In contrast to the conventional strategies which have focused on fusing several reporter genes together to serve as multimodal reporters, human tyrosinase (TYR) - the key enzyme in melanin production - was evaluated in this study as a stand-alone reporter gene for in vitro and in vivo photoacoustic imaging (PAI), magnetic resonance imaging (MRI) and positron emission tomography (PET). Human breast cancer cells MCF-7 transfected with a plasmid that encodes TYR (named as MCF-7-TYR) and non-transfected MCF-7 cells were used as positive and negative controls, respectively. Melanin targeted N-(2-(diethylamino)ethyl)-(18)F-5-fluoropicolinamide was used as a PET reporter probe. In vivo PAI/MRI/PET imaging studies showed that MCF-7-TYR tumors achieved significant higher signals and tumor-to-background contrasts than those of MCF-7 tumor. Our study demonstrates that TYR gene can be utilized as a multifunctional reporter gene for PAI/MRI/PET both in vitro and in vivo.
"U87MG Cell Binding Assay: Cell binding assays were performed as previously described 37, 39. Briefly, 2 × 105 U87MG cells were incubated with 0.06 nM 125I-labeled echistatin and varying concentrations of peptides (2.5D, 2.5F, 19F-FP-2.5D "
[Show abstract][Hide abstract] ABSTRACT: Purpose: Cystine knot (knottin) peptides, engineered to bind with high affinity to integrin receptors, have shown promise as molecular imaging agents in living subjects. The aim of the current study was to evaluate tumor uptake and in vivo biodistribution of 18F-labeled knottins in a U87MG glioblastoma model.
Procedures: Engineered knottin mutants 2.5D and 2.5F were synthesized using solid phase peptide synthesis and were folded in vitro, followed by radiolabeling with 4-nitrophenyl 2-18F-fluoropropionate (18F-NFP). The resulting probes, 18F-FP-2.5D and 18F-FP-2.5F, were evaluated in nude mice bearing U87MG tumor xenografts using microPET and biodistribution studies.
Results: MicroPET imaging studies with 18F-FP-2.5D and 18F-FP-2.5F demonstrated high tumor uptake in U87MG xenograft mouse models. The probes exhibited rapid clearance from the blood and kidneys, thus leading to excellent tumor-to-normal tissue contrast. Specificity studies confirmed that 18F-FP-2.5D and 18F-FP-2.5F had reduced tumor uptake when co-injected with a large excess of the peptidomimetic c(RGDyK) as a blocking agent.
Conclusions: 18F-FP-2.5D and 18F-FP-2.5F showed reduced gallbladder uptake compared with previously published 18F-FB-2.5D. 18F-FP-2.5D and 18F-FP-2.5F enabled integrin-specific PET imaging of U87MG tumors with good imaging contrasts. 18F-FP-2.5D demonstrated more desirable pharmacokinetics compared to 18F-FP-2.5F, and thus has greater potential for clinical translation.
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