Abstract
PurposeThis study aims at preclinical evaluation of a recently reported lactose analogue, 1'-18F-fluoroethyl-β-D-lactose (18F-FEL), in binding to hepatocarcinoma-intestine-pancreas and pancreatitis-associated protein (HIP/PAP) in vitro and in vivo.MethodsIn this study, a multifunctional module was employed for the automated synthesis of 18F-FEL. Additional radiochemical purity, biodistribution, in vitro and in vivo competition, metabolic stability and micro-PET studies were performed using T3M4 and SK-BR-3 xenografts. Expression of HIP/PAP in T3M4 and SK-BR-3 tumor sections and cell lines were tested with immunohistochemistry (IHC) and western blot analysis.ResultsThe synthesis of 18F-FEL was completed in 30 min, with a radiochemical yield of 20 ± 5% and specific activity of 14.2 ± 7.1 GBq/μmol. 18F-FEL exhibited high HIP/PAP-binding affinity with a half maximal inhibitory concentration (IC50) of 22.0 ± 4.0 nM. 18F-FEL demonstrated high stability and specific tumor accumulation, which was reduced by approximately 80% in a PET competition assay by co-injection of β-D-lactose. High expression of HIP/PAP was detected in T3M4 tumors and cell line, but negative result was found for SK-BR-3 cell line.Conclusion18F-FEL has a high binding property to HIP/PAP, high stability and excellent pharmacokinetics in vivo and therefore warrants further evaluation in a proof-of-concept study in humans.
Highlights
Despite the new cases of cancer keeps on an increasing trend ever since 1975, death rates have been falling on average 1.5% each year over 2005-2014 [1]
The synthesis of 18F-FEL was completed in 30 min, with a radiochemical yield of 20 ± 5% and specific activity of 14.2 ± 7.1 GBq/μmol. 18F-FEL exhibited high hepatocarcinomaintestine-pancreas and pancreatitis-associated protein (HIP/PAP)-binding affinity with a half maximal inhibitory concentration (IC50) of 22.0 ± 4.0 nM. 18F-FEL demonstrated high stability and specific tumor accumulation, which was reduced by approximately 80% in a PET competition assay by co-injection of βD-lactose
High expression of HIP/PAP was detected in T3M4 tumors and cell line, but negative result was found for SK-BR-3 cell line
Summary
Despite the new cases of cancer keeps on an increasing trend ever since 1975, death rates have been falling on average 1.5% each year over 2005-2014 [1]. HIP/PAP, known as REG 3A, is a 16 kD secreted plasma protein. HIP/ PAP belongs to the group of VII of a family of proteins that contain a C-type lectin like domain, which binds to carbohydrates, and it is known as “lactose-binding protein” [2, 3]. The overexpression of HIP/PAP has been linked to many different diseases including hepatocellular carcinoma [4,5,6], cholangiocarcinoma [7], glucagon-producing enteropancreatic endocrine tumors [8], pancreatic ductal adenocarcinoma [9], colorectal cancer [10], gastric adenocarcinomas [11] and biliary malignancies [12]. HIP/PAP is a promising target for the detection of diseases above
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