title: Multifunctional aptamer-based nanoparticles for targeted drug delivery to circumvent cancer resistance.
abstract: By its unique advantages over traditional medicine, nanomedicine has offered new strategies for cancer treatment. In particular, the development of drug delivery strategies has focused on nanoscale particles to improve bioavailability. However, many of these nanoparticles are unable to overcome tumor resistance to chemotherapeutic agents. Recently, new opportunities for drug delivery have been provided by oligonucleotides that can self-assemble into three-dimensional nanostructures. In this work, we have designed and developed functional DNA nanostructures to deliver the chemotherapy drug doxorubicin (Dox) to resistant cancer cells. These nanostructures have two components. The first component is a DNA aptamer, which forms a dimeric G-quadruplex nanostructure to target cancer cells by binding with nucleolin. The second component is double-stranded DNA (dsDNA), which is rich in -GC- base pairs that can be applied for Dox delivery. We demonstrated that Dox was able to efficiently intercalate into dsDNA and this intercalation did not affect the aptamer's three-dimensional structure. In addition, the Aptamer-dsDNA (ApS) nanoparticle showed good stability and protected the dsDNA from degradation in bovine serum. More importantly, the ApS&Dox nanoparticle efficiently reversed the resistance of human breast cancer cells to Dox. The mechanism circumventing doxorubicin resistance by ApS&Dox nanoparticles may be predominantly by cell cycle arrest in S phase, effectively increased cell uptake and decreased cell efflux of doxorubicin. Furthermore, the ApS&Dox nanoparticles could effectively inhibit tumor growth, while less cardiotoxicity was observed. Overall, this functional DNA nanostructure provides new insights into the design of nanocarriers to overcome multidrug resistance through targeted drug delivery.
authors.affiliation: CAS Center for Excellence in Nanoscience, Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, and Laboratory of Controllable Nanopharmaceuticals, National Center for Nanoscience and Technology of China, Beijing 100190, China.
authors.forename: Juan
authors.initials: J
authors.lastname: Liu
authors.affiliation: CAS Center for Excellence in Nanoscience, Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, and Laboratory of Controllable Nanopharmaceuticals, National Center for Nanoscience and Technology of China, Beijing 100190, China.
authors.forename: Tuo
authors.initials: T
authors.lastname: Wei
authors.affiliation: CAS Center for Excellence in Nanoscience, Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, and Laboratory of Controllable Nanopharmaceuticals, National Center for Nanoscience and Technology of China, Beijing 100190, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhao
authors.affiliation: Laboratory of Nucleic Acid Technology, Institute of Molecular Medicine, Peking University, Beijing 100871, China.
authors.forename: Yuanyu
authors.initials: Y
authors.lastname: Huang
authors.affiliation: CAS Center for Excellence in Nanoscience, Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, and Laboratory of Controllable Nanopharmaceuticals, National Center for Nanoscience and Technology of China, Beijing 100190, China.
authors.forename: Hua
authors.initials: H
authors.lastname: Deng
authors.affiliation: CAS Center for Excellence in Nanoscience, Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, and Laboratory of Controllable Nanopharmaceuticals, National Center for Nanoscience and Technology of China, Beijing 100190, China.
authors.forename: Anil
authors.initials: A
authors.lastname: Kumar
authors.affiliation: CAS Center for Excellence in Nanoscience, Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, and Laboratory of Controllable Nanopharmaceuticals, National Center for Nanoscience and Technology of China, Beijing 100190, China.
authors.forename: Chenxuan
authors.initials: C
authors.lastname: Wang
authors.affiliation: Laboratory of Nucleic Acid Technology, Institute of Molecular Medicine, Peking University, Beijing 100871, China.
authors.forename: Zicai
authors.initials: Z
authors.lastname: Liang
authors.affiliation: CAS Center for Excellence in Nanoscience, Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, and Laboratory of Controllable Nanopharmaceuticals, National Center for Nanoscience and Technology of China, Beijing 100190, China. Electronic address: maxw@nanoctr.cn.
authors.forename: Xiaowei
authors.initials: X
authors.lastname: Ma
authors.affiliation: CAS Center for Excellence in Nanoscience, Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, and Laboratory of Controllable Nanopharmaceuticals, National Center for Nanoscience and Technology of China, Beijing 100190, China. Electronic address: liangxj@nanoctr.cn.
authors.forename: Xing-Jie
authors.initials: XJ
authors.lastname: Liang
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage* / Q000494:pharmacology / Q000627:therapeutic use; D052157:Aptamers, Nucleotide / Q000737:chemistry* / Q000378:metabolism; D001483:Base Sequence; D001940:Breast / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D004317:Doxorubicin / Q000008:administration & dosage* / Q000494:pharmacology / Q000627:therapeutic use; D004337:Drug Carriers / Q000737:chemistry* / Q000378:metabolism; D016503:Drug Delivery Systems; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D005260:Female; D054856:G-Quadruplexes; D006801:Humans; D007364:Intercalating Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D061986:MCF-7 Cells; D008807:Mice, Inbred BALB C; D008958:Models, Molecular; D053758:Nanoparticles / Q000737:chemistry* / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000378:metabolism; D000097796:Nucleolin
chemical_list: D000903:Antibiotics, Antineoplastic; D052157:Aptamers, Nucleotide; D004317:Doxorubicin; D004337:Drug Carriers; D007364:Intercalating Agents; D010750:Phosphoproteins; D016601:RNA-Binding Proteins; D000097796:Nucleolin
keywords: Aptamer; Cancer therapy; Drug delivery; Drug resistance; Self-assembly