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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.

SUBMITTER: Clawson GA

PROVIDER: S-EPMC5312616 | biostudies-literature | 2017 Feb

REPOSITORIES: biostudies-literature

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

Clawson Gary A GA Abraham Thomas T Pan Weihua W Tang Xiaomeng X Linton Samuel S SS McGovern Christopher O CO Loc Welley S WS Smith Jill P JP Butler Peter J PJ Kester Mark M Adair James H JH Matters Gail L GL

Nucleic acid therapeutics 20161018 1

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 character ...[more]

PMID: 27754762

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Project description:BackgroundPancreatic ductal adenocarcinoma (PDAC) exhibits the poorest prognosis of all solid tumors with a 5-year survival rate of less than 10% and a median survival of 6 months after diagnosis. Numerous targeted agents have been developed and evaluated to improve the survival benefit in patients with PDAC. Unfortunately, most agents have been proven futile mainly owing to the dense stroma and the sophisticated signaling pathways of PDAC. Here, we show the potent effectiveness of Aptamer-SH2 superbinder-(Arg)9 conjugate on the treatment of PDAC. In this conjugate, DNA aptamer selected against PDAC cell line confers the function of specifically recognizing and binding to the PDAC cells and activated pancreatic stellate cells (PSCs) in stroma; cell penetrating peptide (Arg)9 facilitates the intracellular delivery of fused proteins; SH2 superbinder conducts the drastic blockade of multiple phosphotyrosines (pY)-based signaling pathways in tumor cells.MethodsPDAC-associated pY were reanalyzed by bioinformatics screen. XQ-2d and SH2 superbinder-(Arg)9 were crosslinked with BMH to form XQ-2d-SH2 CM-(Arg)9 conjugate. Immunofluorescence was utilized to assess the potency of the conjugate entering cells. MTT and wound healing assays were performed to evaluate the proliferation or migration of PANC-1 and BxPC-3 cells, respectively. Western blot and Pulldown assays revealed that conjugate influenced several pY-based signaling pathways. Tumor-bearing mice were used to validate XQ-2d-SH2 CM-(Arg)9, which restrained the growth and metastasis of cancer cells.ResultsXQ-2d-His-SH2 CM-(Arg)9 conjugate restrained proliferation, invasion, and metastasis of PDAC cells with potent efficacy via blocking the activity of several pY-related signaling cascades. XQ-2d-His-SH2 CM-(Arg)9 could eliminate the dense stroma of PDAC and then arrive at tumor tissues.ConclusionsXQ-2d-SH2 CM-(Arg)9 conjugate may efficiently destroy the pancreatic stroma and show potent antitumor efficacy with minimal toxic effect by regulating tumor cell proliferation and metastasis in vitro and in vivo, which makes it to be a promising targeted therapy of PDAC.

Dataset Information

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

Publications

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

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