ABSTRACT
Early and accurate detection of primary or metastatic tumors is of great value in staging, treatment management, and prognosis. Tumor angiogenesis plays an essential role in the growth, invasion, and metastatic spread of solid cancers, and so, is a promising approach for tumor imaging. The GX1 (CGNSNPKSC) peptide was identified by phage display library and has been investigated as a marker for human cancers. This study aims to evaluate the 99mTc-HYNIC-PEG4-c (GX1) as a biomarker for tumor imaging. Our results showed that GX1 specifically binds to tumor cells in vitro. SKMEL28 and MDA-MB231 cells achieved total binding peak at 60 min of incubation. For B16F10 and MKN45 cells, the total and specific binding were similar during all time points, while A549 cell line showed rapid cellular total uptake of the tracer at 30 min of incubation. Biodistribution showed low non-specific uptakes and rapid renal excretion. Melanoma tumors showed enhanced GX1 uptake in animal model at 60 min, and it was significantly blocked by cold peptide. The radiotracer showed tumor specificity, especially in melanomas that are highly vascularized tumors. In this sense, it should be considered in future studies, aiming to evaluate degree of angiogenesis, progression, and invasion of tumors.
Subject(s)
Isotope Labeling , Melanoma/diagnostic imaging , Neoplasms, Experimental/diagnostic imaging , Neovascularization, Pathologic/diagnostic imaging , Peptides , Radiopharmaceuticals , A549 Cells , Animals , Humans , Melanoma/metabolism , Mice , Neoplasms, Experimental/metabolism , Neovascularization, Pathologic/metabolism , Neovascularization, Pathologic/pathology , Peptides/chemistry , Peptides/pharmacokinetics , Peptides/pharmacology , Radiopharmaceuticals/chemistry , Radiopharmaceuticals/pharmacokinetics , Radiopharmaceuticals/pharmacologyABSTRACT
INTRODUCTION: Radiolabeled GLP-1 and its analog Exendin-4, have been employed in diabetes and insulinoma. No protocol in conventional Diet-Induced Obesity (DIO), and Diet-Restricted Obesity (DRO), has been identified. Aiming to assess pancreatic beta cell uptake in DIO and DRO, a protocol was designed. METHODS: GLP-1-ßAla-HYNIC and HYNIC-ßAla-Exendin-4 were labeled with technetium-99m. Four Swiss mouse models were adopted: Controls (C), Alloxan Diabetes Controls (ADC), DIO and DRO. Biodistribution and ex-vivo planar imaging were documented. RESULTS: Radiolabeling yield was in the range of 97% and both agents were hydrophilic. Fasting Blood Glucose (FBG) was 79.2±8.2mg/dl in C, 590.4±23.3mg/dl in ADC, 234.3±66.7mg/dl in DIO, and 96.6±9.3 in DRO (p=0.010). Biodistribution confirmed predominantly urinary excretion. DIO mice exhibited depressed uptake in liver and pancreas, for both radiomarkers, in the range of ADC. DRO only partially restored such values. 99mTc-HYNIC-ßAla-Exendin-4 demonstrated better results than GLP-1-ßAla-HYNIC-99mTc. CONCLUSIONS: 1) Diet-induced obesity remarkably depressed beta cell uptake; 2) Restriction of obesity failed to normalize uptake, despite robust improvement of FBG; 3) HYNIC-ßAla-Exendin-4 was the most useful marker; 4) Further studies are recommended in obesity and dieting, including bariatric surgery.
Subject(s)
Diet/adverse effects , Glucagon-Like Peptide 1/metabolism , Liver/metabolism , Obesity/metabolism , Pancreas/metabolism , Peptides/metabolism , Venoms/metabolism , Amino Acid Sequence , Animals , Biological Transport , Disease Models, Animal , Exenatide , Female , Glucagon-Like Peptide 1/pharmacokinetics , Isotope Labeling , Liver/diagnostic imaging , Mice , Obesity/diagnostic imaging , Obesity/etiology , Pancreas/diagnostic imaging , Peptides/chemistry , Peptides/pharmacokinetics , Tissue Distribution , Venoms/chemistry , Venoms/pharmacokineticsABSTRACT
BACKGROUND AND OBJECTIVE: Radiotracer diagnosis of insulinoma, can be done using somatostatin or glucagon-like peptide 1 (GLP-1). Performance of GLP-1 antagonists tends to be better than of agonists. METHODS: We investigated the uptake of the antagonist exendin (9-39), radiolabeled with technetium- 99m. Two different sites of the biomolecule were selected for chelator attachment. RESULTS: HYNIC-ßAla chelator attached to serine (C- terminus) of exendin, was associated with higher tumor uptake than to aspartate (N- terminus). CONCLUSION: The chelator position in the biomolecule influenced receptor uptake.
Subject(s)
Chelating Agents/pharmacology , Glucagon-Like Peptide 1/antagonists & inhibitors , Insulinoma/diagnostic imaging , Pancreatic Neoplasms/diagnostic imaging , Peptide Fragments/pharmacology , Radiopharmaceuticals/pharmacology , Animals , Cell Line, Tumor , Chromatography, High Pressure Liquid , Male , Mice , Mice, SCID , Radionuclide Imaging , Sensitivity and Specificity , Technetium/pharmacology , Tissue DistributionABSTRACT
Early and accurate detection of primary or metastatic tumors is of great value in staging, treatment management, and prognosis. Tumor angiogenesis plays an essential role in the growth, invasion, and metastatic spread of solid cancers, and so, is a promising approach for tumor imaging. The GX1 (CGNSNPKSC) peptide was identified by phage display library and has been investigated as a marker for human cancers. This study aims to evaluate the 99mTc-HYNIC-PEG4-c (GX1) as a biomarker for tumor imaging. Our results showed that GX1 specifically binds to tumor cells in vitro. SKMEL28 and MDA-MB231 cells achieved total binding peak at 60 min of incubation. For B16F10 and MKN45 cells, the total and specific binding were similar during all time points, while A549 cell line showed rapid cellular total uptake of the tracer at 30 min of incubation. Biodistribution showed low non-specific uptakes and rapid renal excretion. Melanoma tumors showed enhanced GX1 uptake in animal model at 60 min, and it was significantly blocked by cold peptide. The radiotracer showed tumor specificity, especially in melanomas that are highly vascularized tumors. In this sense, it should be considered in future studies, aiming to evaluate degree of angiogenesis, progression, and invasion of tumors.
ABSTRACT
Early and accurate detection of primary or metastatic tumors is of great value in staging, treatment management, and prognosis. Tumor angiogenesis plays an essential role in the growth, invasion, and metastatic spread of solid cancers, and so, is a promising approach for tumor imaging. The GX1 (CGNSNPKSC) peptide was identified by phage display library and has been investigated as a marker for human cancers. This study aims to evaluate the 99mTc-HYNIC-PEG4-c (GX1) as a biomarker for tumor imaging. Our results showed that GX1 specifically binds to tumor cells in vitro. SKMEL28 and MDA-MB231 cells achieved total binding peak at 60 min of incubation. For B16F10 and MKN45 cells, the total and specific binding were similar during all time points, while A549 cell line showed rapid cellular total uptake of the tracer at 30 min of incubation. Biodistribution showed low non-specific uptakes and rapid renal excretion. Melanoma tumors showed enhanced GX1 uptake in animal model at 60 min, and it was significantly blocked by cold peptide. The radiotracer showed tumor specificity, especially in melanomas that are highly vascularized tumors. In this sense, it should be considered in future studies, aiming to evaluate degree of angiogenesis, progression, and invasion of tumors.