Background and Aims Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer death in the USA. Surgical resection is the only effective treatment; however, only 20% of patients are candidates for surgery. The ability to detect early PDAC would increase the availability of surgery and improve patient survival. This study assessed the feasibility of using the enzymatic activity of cathepsin E (Cath E), a protease highly and specifically expressed in PDAC, as a novel biomarker for the detection of pancreas-bearing pancreatic intraepithelial neoplasia (PanIN) lesions and PDAC. Methods Pancreas from normal, chronic pancreatitis and PDAC patients was assessed for Cath E expression by quantitative real-time PCR and immunohistochemistry. Human PDAC xenografts and genetically engineered mouse models (GEMM) of PDAC were injected with a Cath E activity selective fluorescent probe and imaged using an optical imaging system. Results The specificity of Cath E expression in PDAC patients and GEMM of pancreatic cancer was confirmed by quantitative real-time PCR and immunohistochemistry. The novel probe for Cath E activity specifically detected PDAC in both human xenografts and GEMM in vivo. The Cath E sensitive probe was also able to detect pancreas with PanIN lesions in GEMM before tumour formation. Conclusions The elevated Cath E expression in PanIN and pancreatic tumours allowed in-vivo detection of human PDAC xenografts and imaging of pancreas with PanIN and PDAC tumours in GEMM. Our results support the usefulness of Cath E activity as a potential molecular target for PDAC and early detection imaging.
The gastrin releasing peptide receptor (GRP-R) is over-expressed on a number of tumors and cancer cell lines including pancreas, prostate, breast, gastrointestinal and small cell lung cancer (SCLC). Radiolabeled bombesin (BBN) analogues have exhibited high binding affinity and specificity to the GRP-R. A bombesin analogue with an antagonist targeting-vector at the C-terminus, DOTAaminohexanoyl-[D-Phe 6 , Leu-NHCH 2 CH 2 CH 3 13 , des Met 14 ] BBN [6][7][8][9][10][11][12][13][14] (1, "Bomproamide"), has been synthesized and displays high binding affinity (IC 50 = 1.36 ± 0.09 nM) against 125 I-Tyr 4 -BBN in in vitro competitive assays using PC-3 cells. Maximum internalization of 111 In-1 reached 14% in PC-3 cells after 45 minutes of incubation. Rapid (0.25-hour PI) and high (12.21 ± 3.2 %ID/g) pancreatic uptake of 111 In-1 was observed in healthy CF-1 mice and 90% of the activity was blocked by co-injection of 100 μg of BBN. Rapid (0.25-hour PI) and high uptake (6.90 ± 1.06 %ID/g) was observed in PC-3 prostate cancer xenografts in SCID mice, as well as visualized clearly in a SPECT/ CT study. These results support the use of a bombesin construct with an antagonist C-terminal vector as a candidate of choice for specific in vivo imaging of tumors over-expressing GRP-receptors.
Cardiovascular fibrosis resulted from pressure overload or ischemia could alter myocardial stiffness and lead to ventricular dysfunction. Fluorescently labeled collagen-binding protein CNA 35, derived from the surface component of Staphylococcus aureus, and a novel synthetic biphenylalanine containing peptide are applied to stain fibrosis associated collagen and myocytes, respectively. Detailed pathological characteristics of cardiovascular fibrosis could be identified clearly in 2 hours. This staining pair requires only simple staining and brief washing, generating less than 10 ml of waste. The image information collected by this novel fluorescent staining pair is compatible with it collected by the traditional Masson's Trichrome and Picrosirius Red staining which are widely used to stain cardiovascular fibrosis and isolated cells.
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