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Building a multifunctional aptamer-based DNA nanoassembly for targeted cancer therapy.

ABSTRACT: The ability to self-assemble one-dimensional DNA building blocks into two- and three-dimensional nanostructures via DNA/RNA nanotechnology has led to broad applications in bioimaging, basic biological mechanism studies, disease diagnosis, and drug delivery. However, the cellular uptake of most nucleic acid nanostructures is dependent on passive delivery or the enhanced permeability and retention effect, which may not be suitable for certain types of cancers, especially for treatment in vivo. To meet this need, we have constructed a multifunctional aptamer-based DNA nanoassembly (AptNA) for targeted cancer therapy. In particular, we first designed various Y-shaped functional DNA domains through predesigned base pair hybridization, including targeting aptamers, intercalated anticancer drugs, and therapeutic antisense oligonucleotides. Then these functional DNA domains were linked to an X-shaped DNA core connector, termed a building unit, through the complementary sequences in the arms of functional domains and connector. Finally, hundreds (~100-200) of these basic building units with 5'-modification of acrydite groups were further photo-cross-linked into a multifunctional and programmable aptamer-based nanoassembly structure able to take advantage of facile modular design and assembly, high programmability, excellent biostability and biocompatibility, as well as selective recognition and transportation. With these properties, AptNAs were demonstrated to have specific cytotoxic effect against leukemia cells. Moreover, the incorporation of therapeutic antisense oligonucleotides resulted in the inhibition of P-gp expression (a drug efflux pump to increase excretion of anticancer drugs) as well as a decrease in drug resistance. Therefore, these multifunctional and programmable aptamer-based DNA nanoassemblies show promise as candidates for targeted drug delivery and cancer therapy.

SUBMITTER: Wu C

PROVIDER: S-EPMC3891927 | biostudies-literature | 2013 Dec

REPOSITORIES: biostudies-literature

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Building a multifunctional aptamer-based DNA nanoassembly for targeted cancer therapy.

Wu Cuichen C Han Da D Chen Tao T Peng Lu L Zhu Guizhi G You Mingxu M Qiu Liping L Sefah Kwame K Zhang Xiaobing X Tan Weihong W

Journal of the American Chemical Society 20131125 49

The ability to self-assemble one-dimensional DNA building blocks into two- and three-dimensional nanostructures via DNA/RNA nanotechnology has led to broad applications in bioimaging, basic biological mechanism studies, disease diagnosis, and drug delivery. However, the cellular uptake of most nucleic acid nanostructures is dependent on passive delivery or the enhanced permeability and retention effect, which may not be suitable for certain types of cancers, especially for treatment in vivo. To ...[more]

PMID: 24245521

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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

Building a multifunctional aptamer-based DNA nanoassembly for targeted cancer therapy.

Publications

Building a multifunctional aptamer-based DNA nanoassembly for targeted cancer therapy.

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