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Molecular Assembly of an Aptamer–Drug Conjugate for Targeted Drug Delivery to Tumor Cells

Authors

  • Yu-Fen Huang Dr.,

    1. Department of Chemistry and Department of Physiology and Functional Genomics, Shands Cancer Center and Center for Research at the Bio/Nano Interface, Genetics Institute and McKnight Brain Institute, University of Florida, Gainesville, FL 32611 (USA), Fax: (+1) 352-846-2410
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  • Dihua Shangguan Dr.,

    1. Department of Chemistry and Department of Physiology and Functional Genomics, Shands Cancer Center and Center for Research at the Bio/Nano Interface, Genetics Institute and McKnight Brain Institute, University of Florida, Gainesville, FL 32611 (USA), Fax: (+1) 352-846-2410
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  • Haipeng Liu Dr.,

    1. Department of Chemistry and Department of Physiology and Functional Genomics, Shands Cancer Center and Center for Research at the Bio/Nano Interface, Genetics Institute and McKnight Brain Institute, University of Florida, Gainesville, FL 32611 (USA), Fax: (+1) 352-846-2410
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  • Joseph A. Phillips Dr.,

    1. Department of Chemistry and Department of Physiology and Functional Genomics, Shands Cancer Center and Center for Research at the Bio/Nano Interface, Genetics Institute and McKnight Brain Institute, University of Florida, Gainesville, FL 32611 (USA), Fax: (+1) 352-846-2410
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  • Xiaoling Zhang Dr.,

    1. Department of Chemistry and Department of Physiology and Functional Genomics, Shands Cancer Center and Center for Research at the Bio/Nano Interface, Genetics Institute and McKnight Brain Institute, University of Florida, Gainesville, FL 32611 (USA), Fax: (+1) 352-846-2410
    2. Department of Chemistry, School of Science, Beijing Institute of Technology, Beijing 100081, (P. R. China)
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  • Yan Chen,

    1. Department of Chemistry and Department of Physiology and Functional Genomics, Shands Cancer Center and Center for Research at the Bio/Nano Interface, Genetics Institute and McKnight Brain Institute, University of Florida, Gainesville, FL 32611 (USA), Fax: (+1) 352-846-2410
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  • Weihong Tan Dr.

    1. Department of Chemistry and Department of Physiology and Functional Genomics, Shands Cancer Center and Center for Research at the Bio/Nano Interface, Genetics Institute and McKnight Brain Institute, University of Florida, Gainesville, FL 32611 (USA), Fax: (+1) 352-846-2410
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Abstract

Special delivery! An aptamer-directed anticancer drug was molecularly engineered to be delivered to target cells for efficient therapeutic application. The covalent conjugation of drug and aptamer creates alternative opportunities for targeted therapy, as multiple yet specific aptamers can be “generated” relatively easily by cell-SELEX for any target cells; this demonstrates the full potential of cell-SELEX as a molecular discovery tool for biomedical studies and drug development.

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The conjugation of antitumor drugs to targeting reagents such as antibodies is a promising method that can increase the efficacy of chemotherapy and reduce the overall toxicity of the drugs. In this study, we covalently link the antitumor agent doxorubicin (Dox) to the DNA aptamer sgc8c, which was selected by the cell-SELEX method. In doing so, we expected that this sgc8c–Dox conjugate would specifically kill the target CCRF-CEM (T-cell acute lymphoblastic leukemia, T-cell ALL) cells, but with minimal toxicity towards nontarget cells. The results demonstrated that the sgc8c–Dox conjugate possesses many of the properties of the sgc8c aptamer, including high binding affinity (Kd=2.0±0.2 nM) and the capability to be efficiently internalized by target cells. Moreover, due to the specific conjugation method, the acid-labile linkage connecting the sgc8c–Dox conjugate can be cleaved inside the acidic endosomal environment. Cell viability tests demonstrate that the sgc8c–Dox conjugates not only possess potency similar to unconjugated Dox, but also have the required molecular specificity that is lacking in most current targeted drug delivery strategies. Furthermore, we found that nonspecific uptake of membrane-permeable Dox to nontarget cell lines could also be inhibited by linking the drug with the aptamer; thus, the conjugates are selective for cells that express higher amounts of target proteins. Compared to the less effective Dox-immunoconjugates, these sgc8c–Dox conjugates make targeted chemotherapy more feasible with drugs having various potencies. When combined with the large number of recently created DNA aptamers that specifically target a wide variety of cancer cells, this drug-aptoconjugation method will have broad implications for targeted drug delivery.

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