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Nano Research 2015, 8(11): 3447-3460 https://doi.org/10.1007/s12274-015-0841-8
Research Article | Issue | Published: 15 September 2015

Self-assembled multifunctional DNA nanoflowers for the circumvention of multidrug resistance in targeted anticancer drug delivery

Show Author's Information Lei Mei1,§,  Guizhi Zhu1,2,§,†,  Liping Qiu1,2,  Cuichen Wu2,  Huapei Chen1,  Hao Liang1,  Sena Cansiz2,  Yifan Lv1,  Xiaobing Zhang1( ),  Weihong Tan1,2( )
Molecular Sciences and Biomedicine LaboratoryState Key Laboratory for Chemo/Biosensing and ChemometricsCollege of Chemistry and Chemical EngineeringCollege of BiologyCollaborative Innovation Center for Chemistry and Molecular MedicineHunan UniversityChangsha410082China
Departments of ChemistryPhysiology and Functional GenomicsCenter for Research at the Bio/Nano InterfaceShands Cancer CenterUF Genetics Institute and McKnight Brain InstituteUniversity of Florida, Gainesville, FL32611-7200USA

§ These authors contributed equally.

Keywords:
self-assembly, DNA nanotechnology, aptamer, multidrug resistance, rolling circle replication, targeted cancer therapy
Cite this article:
Mei L, Zhu G, Qiu L, et al. Self-assembled multifunctional DNA nanoflowers for the circumvention of multidrug resistance in targeted anticancer drug delivery. Nano Research, 2015, 8(11): 3447-3460. https://doi.org/10.1007/s12274-015-0841-8
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Abstract Full text Electronic supplementary material About this article

Cancer chemotherapy has been limited by its side effects and multidrug resistance (MDR), the latter of which is partially caused by drug efflux from cancer cells. Thus, targeted drug delivery systems that can circumvent MDR are needed. Here, we report multifunctional DNA nanoflowers (NFs) for targeted drug delivery to both chemosensitive and MDR cancer cells that circumvented MDR in both leukemia and breast cancer cell models. NFs are self-assembled via potential co-precipitation of DNA and magnesium pyrophosphate generated by rolling circle replication, during which NFs are incorporated using aptamers for specific cancer cell recognition, fluorophores for bioimaging, and doxorubicin (Dox)-binding DNA for drug delivery. NF sizes are tunable (down to ~200 nm in diameter), and the densely packed drug-binding motifs and porous intrastructures endow NFs with a high drug-loading capacity (71.4%, wt/wt). Although the Doxloaded NFs (NF-Dox) are stable at physiological pH, drug release is facilitated under acidic or basic conditions. NFs deliver Dox into target chemosensitive and MDR cancer cells, preventing drug efflux and enhancing drug retention in MDR cells. NF-Dox induces potent cytotoxicity in both target chemosensitive cells and MDR cells, but not in nontarget cells, thus concurrently circumventing MDR and reducing side effects. Overall, these NFs are promising tools for circumventing MDR in targeted cancer therapy.


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Electronic supplementary material
About this article

Self-assembled multifunctional DNA nanoflowers for the circumvention of multidrug resistance in targeted anticancer drug delivery

Show Author's information Lei Mei1,§, Guizhi Zhu1,2,§,†, Liping Qiu1,2, Cuichen Wu2, Huapei Chen1, Hao Liang1, Sena Cansiz2, Yifan Lv1, Xiaobing Zhang1( ), Weihong Tan1,2( )
Molecular Sciences and Biomedicine LaboratoryState Key Laboratory for Chemo/Biosensing and ChemometricsCollege of Chemistry and Chemical EngineeringCollege of BiologyCollaborative Innovation Center for Chemistry and Molecular MedicineHunan UniversityChangsha410082China
Departments of ChemistryPhysiology and Functional GenomicsCenter for Research at the Bio/Nano InterfaceShands Cancer CenterUF Genetics Institute and McKnight Brain InstituteUniversity of Florida, Gainesville, FL32611-7200USA

§ These authors contributed equally.

Abstract

Cancer chemotherapy has been limited by its side effects and multidrug resistance (MDR), the latter of which is partially caused by drug efflux from cancer cells. Thus, targeted drug delivery systems that can circumvent MDR are needed. Here, we report multifunctional DNA nanoflowers (NFs) for targeted drug delivery to both chemosensitive and MDR cancer cells that circumvented MDR in both leukemia and breast cancer cell models. NFs are self-assembled via potential co-precipitation of DNA and magnesium pyrophosphate generated by rolling circle replication, during which NFs are incorporated using aptamers for specific cancer cell recognition, fluorophores for bioimaging, and doxorubicin (Dox)-binding DNA for drug delivery. NF sizes are tunable (down to ~200 nm in diameter), and the densely packed drug-binding motifs and porous intrastructures endow NFs with a high drug-loading capacity (71.4%, wt/wt). Although the Doxloaded NFs (NF-Dox) are stable at physiological pH, drug release is facilitated under acidic or basic conditions. NFs deliver Dox into target chemosensitive and MDR cancer cells, preventing drug efflux and enhancing drug retention in MDR cells. NF-Dox induces potent cytotoxicity in both target chemosensitive cells and MDR cells, but not in nontarget cells, thus concurrently circumventing MDR and reducing side effects. Overall, these NFs are promising tools for circumventing MDR in targeted cancer therapy.

Keywords: self-assembly, DNA nanotechnology, aptamer, multidrug resistance, rolling circle replication, targeted cancer therapy

References(44)

1

Minotti, G.; Menna, P.; Salvatorelli, E.; Cairo, G.; Gianni, L. Anthracyclines: Molecular advances and pharmacologic developments in antitumor activity and cardiotoxicity. Pharmacol. Rev. 2004, 56, 185-229.
DOI Google Scholar
2

Holohan, C.; Van Schaeybroeck, S.; Longley, D. B.; Johnston, P. G. Cancer drug resistance: An evolving paradigm. Nat. Rev. Cancer 2013, 13, 714-726.
DOI Google Scholar
3

Wiernik, P. H. Anthracyclines: Current status and new development. Academic Press, NY 1980.
4

Chatterjee, K.; Zhang, J. Q.; Honbo, N.; Karliner, J. S. Doxorubicin cardiomyopathy. Cardiol. 2010, 115, 155-162.
DOI Google Scholar
5

Szakacs, G.; Paterson, J. K.; Ludwig, J. A.; Booth-Genthe, C.; Gottesman, M. M. Targeting multidrug resistance in cancer. Nat. Rev. Drug Discov. 2006, 5, 219-234.
DOI Google Scholar
6

Gottesman, M. M.; Fojo, T.; Bates, S. E. Multidrug resistance in cancer: Role of atp-dependent transporters. Nat. Rev. Cancer 2002, 2, 48-58.
DOI Google Scholar
7

Aller, S. G.; Yu, J.; Ward, A.; Weng, Y.; Chittaboina, S.; Zhuo, R.; Harrell, P. M.; Trinh, Y. T.; Zhang, Q.; Urbatsch, I. L. et al. Structure of p-glycoprotein reveals a molecular basis for poly-specific drug binding. Science 2009, 323, 1718-1722.
DOI Google Scholar
8

Burns, J. S.; Abdallah, B. M.; Guldberg, P.; Rygaard, J.; Schroder, H. D.; Kassem, M. Tumorigenic heterogeneity in cancer stem cells evolved from long-term cultures of telomerase-immortalized human mesenchymal stem cells. Cancer Res. 2005, 65, 3126-3135.
DOI Google Scholar
9

Peer, D.; Karp, J. M.; Hong, S.; Farokhzad, O. C.; Margalit, R.; Langer, R. Nanocarriers as an emerging platform for cancer therapy. Nat. Nanotechnol. 2007, 2, 751-760.
DOI Google Scholar
10

Hughes, B. Antibody-drug conjugates for cancer: Poised to deliver? Nat. Rev. Drug Discov. 2010, 9, 665-667.
DOI Google Scholar
11

Zhu, G.; Ye, M.; Donovan, M. J.; Song, E.; Zhao, Z.; Tan, W. Nucleic acid aptamers: An emerging frontier in cancer therapy. Chem. Comm. 2012, 10472-10480.
DOI Google Scholar
12

Santra, S.; Kaittanis, C.; Santiesteban, O. J.; Perez, J. M. Cell- specific, activatable, and theranostic prodrug for dual-targeted cancer imaging and therapy. J. Am. Chem. Soc. 2011, 133, 16680-16688.
DOI Google Scholar
13

Ellington, A. D.; Szostak, J. W. In vitro selection of rna molecules that bind specific ligands. Nature 1990, 346, 818-822.
DOI Google Scholar
14

Tuerk, C.; Gold, L. Systematic evolution of ligands by exponential enrichment: Rna ligands to bacteriophage t4 DNA polymerase. Science 1990, 249, 505-510.
DOI Google Scholar
15

Shangguan, D. H.; Li, Y.; Tang, Z. W.; Cao, Z.; Chen, H. W.; Mallikaratchy, P.; Sefah, K.; Yang, C. J.; Tan, W. Aptamers evolved from live cells as effective molecular probes for cancer study. Proc. Natl. Acad. Sci. U.S.A. 2006, 103, 11838-11843.
DOI Google Scholar
16

Sefah, K.; Tang, Z.; Shangguan, D.; Chen, H.; Lopez-Colon, D.; Li, Y.; Parekh, P.; Martin, J.; Meng, L.; Phillips, J. A. et al. Molecular recognition of acute myeloid leukemia using aptamers. Leukemia 2009, 23, 235-244.
DOI Google Scholar
17

Tang, Z.; Shangguan, D. H.; Wang, K.; Shi, H.; Sefah, K.; Mallikaratchy, P.; Chen, H. W.; Li, Y.; Tan, W. Selection of aptamers for molecular recognition and characterization of cancer cells. Anal. Chem. 2007, 79, 4900-4907.
DOI Google Scholar
18

Group, T. E. S. Preclinical and phase 1a clinical evaluation of an anti-vegf pegylated aptamer (eye001) for the treatment of exudative age-related macular degeneration. Retina 2002, 2, 143-152.
DOI Google Scholar
19

Keefe, A. D.; Pai, S.; Ellington, A. Aptamers as therapeutics. Nat. Rev. Drug Discov. 2010, 9, 537-550.
DOI Google Scholar
20

Petros, R. A.; DeSimone, J. M. Strategies in the design of nanoparticles for therapeutic applications. Nat. Rev. Drug Discov. 2010, 9, 615-627.
DOI Google Scholar
21

MacDiarmid, J. A.; Amaro-Mugridge, N. B.; Madrid-Weiss, J.; Sedliarou, I.; Wetzel, S.; Kochar, K.; Brahmbhatt, V. N.; Phillips, L.; Pattison, S. T.; Petti, C. et al. Sequential treatment of drug-resistant tumors with targeted minicells containing sirna or a cytotoxic drug. Nat. Biotechnol. 2009, 27, 643-651.
DOI Google Scholar
22

Jiang, Q.; Song, C.; Nangreave, J.; Liu, X. W.; Lin, L.; Qiu, D. L.; Wang, Z. G.; Zou, G. Z.; Liang, X. J.; Yan, H. et al. DNA origami as a carrier for circumvention of drug resistance. J. Am. Chem. Soc. 2012, 134, 13396-13403.
DOI Google Scholar
23

Wang, F.; Wang, Y. C.; Dou, S.; Xiong, M. H.; Sun, T. M.; Wang, J. Doxorubicin-tethered responsive gold nanoparticles facilitate intracellular drug delivery for overcoming multidrug resistance in cancer cells. ACS Nano 2011, 5, 3679-3692.
DOI Google Scholar
24

Li, R.; Wu, R.; Zhao, L.; Wu, M.; Yang, L.; Zou, H. P-glycoprotein antibody functionalized carbon nanotube overcomes the multidrug resistance of human leukemia cells. ACS Nano 2010, 4, 1399-1408.
DOI Google Scholar
25

Chow, E. K.; Zhang, X. Q.; Chen, M.; Lam, R.; Robinson, E.; Huang, H.; Schaffer, D.; Osawa, E.; Goga, A.; Ho, D. Nanodiamond therapeutic delivery agents mediate enhanced chemoresistant tumor treatment. Sci. Transl. Med. 2011, 3, 73ra21.
DOI Google Scholar
26

Meng, H.; Mai, W. X.; Zhang, H.; Xue, M.; Xia, T.; Lin, S.; Wang, X.; Zhao, Y.; Ji, Z.; Zink, J. I. et al. Codelivery of an optimal drug/sirna combination using mesoporous silica nanoparticles to overcome drug resistance in breast cancer in vitro and in vivo. ACS Nano 2013, 7, 994-1005.
DOI Google Scholar
27

Xue, X.; Hall, M. D.; Zhang, Q.; Wang, P. C.; Gottesman, M. M.; Liang, X. J. Nanoscale drug delivery platforms overcome platinum-based resistance in cancer cells due to abnormal membrane protein trafficking. ACS Nano 2013, 7, 10452-10464.
DOI Google Scholar
28

Yang, L.; Meng, L.; Zhang, X. B.; Chen, Y.; Zhu, G. Z.; Liu, H. P.; Xiong, X. L.; Sefah, K.; Tan, W. H. Engineering polymeric aptamers for selective cytotoxicity. J. Am. Chem. Soc. 2011, 133, 13380-13386.
DOI Google Scholar
29

Wu, C. C.; Han, D.; Chen, T.; Peng, L.; Zhu, G. Z.; You, M. X.; Qiu, L. P.; Sefah, K.; Zhang, X. B.; Tan, W. H. Building a multifunctional aptamer-based DNA nanoassembly for targeted cancer therapy. J. Am. Chem. Soc. 2013, 135, 18644-18650.
DOI Google Scholar
30

Kang, H.; Trondoli, A. C.; Zhu, G.; Chen, Y.; Chang, Y. J.; Liu, H.; Huang, Y. F.; Zhang, X.; Tan, W. Near-infrared light-responsive core-shell nanogels for targeted drug delivery. ACS Nano 2011, 5, 5094-5099.
DOI Google Scholar
31

Bhirde, A. A.; Chikkaveeraiah, B. V.; Srivatsan, A.; Niu, G.; Jin, A. J.; Kapoor, A.; Wang, Z.; Patel, S.; Patel, V.; Gorbach, A. M. et al. Targeted therapeutic nanotubes influence the viscoelasticity of cancer cells to overcome drug resistance. ACS Nano 2014, 8, 4177-4189.
DOI Google Scholar
32

Seeman, N. C. Nanomaterials based on DNA. Annu. Rev. Biochem. 2010, 79, 65-87.
DOI Google Scholar
33

Li, J.; Pei, H.; Zhu, B.; Liang, L.; Wei, M.; He, Y.; Chen, N.; Li, D.; Huang, Q.; Fan, C. H. Self-assembled multivalent DNA nanostructures for noninvasive intracellular delivery of immunostimulatory cpg oligonucleotides. ACS nano 2011, 5, 8783-8789.
DOI Google Scholar
34

Zhu, G. Z.; Zheng, J.; Song, E.; Donovan, M.; Zhang, K. J.; Liu, C.; Tan, W. H. Self-assembled, aptamer-tethered DNA nanotrains for targeted transport of molecular drugs in cancer theranostics. Proc. Natl. Acad. Sci. U.S.A. 2013, 110, 7998-8003.
DOI Google Scholar
35

Zhu, G.; Meng, L.; Ye, M.; Yang, L.; Sefah, K.; O'Donoghue, M. B.; Chen, Y.; Xiong, X.; Huang, J.; Song, E. et al. Self-assembled aptamer-based drug carriers for bispecific cytotoxicity to cancer cells. Chem. Asian J. 2012, 7, 1630-1636.
DOI Google Scholar
36

Lee, H.; Lytton-Jean, A. K. R.; Chen, Y.; Love, K. T.; Park, A. I.; Karagiannis, E. D.; Sehgal, A.; Querbes, W.; Zurenko, C. S.; Jayaraman, M. et al. Molecularly self-assembled nucleic acid nanoparticles for targeted in vivo siRNA delivery. Nat. Nanotechnol. 2012, 7, 389-393.
DOI Google Scholar
37

Zhu, G. Z.; Hu, R.; Zhao, Z. L.; Chen, Z.; Zhang, X. B.; Tan, W. H. Noncanonical self-assembly of multifunctional DNA nanoflowers for biomedical applications. J. Am. Chem. Soc. 2013, 135, 16438-16445.
DOI Google Scholar
38

Shopsowitz K.; Roh Y.; Deng Z.; Morton S.; Hammond P. RNAi-microsponges form through self-assembly of the organic and inorganic products of transcription. Small 2014, 10, 1623-1633.
DOI Google Scholar
39

Bagalkot, V.; Farokhzad, O. C.; Langer, R.; Jon, S. An aptamer-doxorubicin physical conjugate as a novel targeted drug-delivery platform. Angew. Chem. Int. Ed. 2006, 45, 8149-8152.
DOI Google Scholar
40

Tamkovich, S. N.; Cherepanova, A. V.; Kolesnikova, E. V.; Rykova, E. Y.; Pyshnyi, D. V.; Vlassov, V. V.; Laktionov, P. P. Circulating DNA and dnase activity in human blood. Ann. N Y Acad. Sci. 2006, 1075, 191-196.
DOI Google Scholar
41

Clarke, R.; Currier, S.; Kaplan, O.; Lovelace, E.; Boulay, V.; Gottesman, M. M.; Dickson, R. B. Effect of p-glycoprotein expression on sensitivity to hormones in mcf-7 human breast cancer cells. J. Natl. Cancer Inst. 1992, 84, 1506-1512.
DOI Google Scholar
42

Langer, R.; Folkman, J. Polymers for the sustained release of proteins and other macromolecules. Nature 1976, 263, 797-800.
DOI Google Scholar
43

Alama, A.; Barbieri, F.; Cagnoli, M.; Schettini, G. Antisense oligonucleotides as therapeutic agents. Pharmacol. Res. 1997, 36, 171-178.
DOI Google Scholar
44

Liu, H.; Moynihan, K. D.; Zheng, Y.; Szeto, G. L.; Li, A. V.; Huang, B.; Van Egeren, D. S.; Park, C.; Irvine, D. J. Structure-based programming of lymph-node targeting in molecular vaccines. Nature 2014, 507, 519-522.
DOI Google Scholar
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Publication history
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Acknowledgements

Publication history

Received: 26 November 2014
Revised: 15 June 2015
Accepted: 18 June 2015
Published: 15 September 2015
Issue date: November 2015

Copyright

© Tsinghua University Press and Springer‐Verlag Berlin Heidelberg 2015

Acknowledgements

Acknowledgements

We thank Dr. M. M. Gottesman at the National Cancer Institute for providing MCF7/MDR cells. We thank Dr. K. R. Williams for manuscript review. This work was supported by the National Institutes of Health (Nos. GM079359 and CA133086) and National Key Scientific Program of China (No. 2011CB911000), the National Natural Science Foundation of China (NSFC) (Nos. 21325520, J1210040, 20975034 and 21177036), the Foundation for Innovative Research Groups of NSFC (No. 21221003), the National Key Natural Science Foundation of China (No. 21135001), National Instrumentation Program (No. 2011YQ030124), the Ministry of Education of China (No. 20100161110011), and the Hunan Provincial Natural Science Foundation (Nos. 12JJ6012 and 11JJ1002).

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