A Cholecystokinin B Receptor-Specific DNA Aptamer for Targeting Pancreatic Ductal Adenocarcinoma.

Abstract

Pancreatic ductal adenocarcinomas (PDACs) constitutively express the G-protein-coupled cholecystokinin B receptor (CCKBR). In this study, we identified DNA aptamers (APs) that bind to the CCKBR and describe their characterization and targeting efficacy. Using dual SELEX selection against "exposed" CCKBR peptides and CCKBR-expressing PDAC cells, a pool of DNA APs was identified. Further downselection was based on predicted structures and properties, and we selected eight APs for initial characterizations. The APs bound specifically to the CCKBR, and we showed not only that they did not stimulate proliferation of PDAC cell lines but rather inhibited their proliferation. We chose one AP, termed AP1153, for further binding and localization studies. We found that AP1153 did not activate CCKBR signaling pathways, and three-dimensional Confocal microscopy showed that AP1153 was internalized by PDAC cells in a receptor-mediated manner. AP1153 showed a binding affinity of 15 pM. Bioconjugation of AP1153 to the surface of fluorescent NPs greatly facilitated delivery of NPs to PDAC tumors in vivo. The selectivity of this AP-targeted NP delivery system holds promise for enhanced early detection of PDAC lesions as well as improved chemotherapeutic treatments for PDAC patients.

• Authors: Gary A Clawson, Thomas Abraham, Weihua Pan, Xiaomeng Tang, Samuel S Linton, Christopher O McGovern, Welley S Loc, Jill P Smith, Peter J Butler, Mark Kester, James H Adair, Gail L Matters
• Journal: Nucleic acid therapeutics (Nucleic Acid Ther) Vol. 27 Issue 1 Pg. 23-35 (Feb 2017) ISSN: 2159-3345 [Electronic] United States
• PMID: 27754762 (Publication Type: Journal Article)

Chemical References

• Aptamers, Nucleotide
• Nanoconjugates
• Receptor, Cholecystokinin B

Topics

• Animals
• Aptamers, Nucleotide (genetics, metabolism, therapeutic use)
• COS Cells
• Carcinoma, Pancreatic Ductal (metabolism, therapy)
• Cell Line, Tumor
• Chlorocebus aethiops
• Drug Delivery Systems
• Humans
• Imaging, Three-Dimensional
• Male
• Mice
• Mice, Nude
• Microscopy, Confocal
• Nanoconjugates (administration & dosage, chemistry)
• Optical Imaging
• Pancreatic Neoplasms (metabolism, therapy)
• Receptor, Cholecystokinin B (genetics, metabolism, therapeutic use)
• Theranostic Nanomedicine
• Xenograft Model Antitumor Assays