Skip to main content
SpringerLink
Log in

Linear polyethyleneimine-doxorubicin conjugate for pH-responsive synchronous delivery of drug and microRNA-34a

  • Articles
  • Published:
Macromolecular Research Aims and scope Submit manuscript

Abstract

Although stimuli-responsive co-delivery systems of chemotherapy drugs and microRNA (miRNA) can serve as a promising treatment strategy for cancer, to our best knowledge, pH-responsive nanocarriers for the codelivery of chemical drugs and microRNAs (miRNAs) have not yet been reported. In this study, we synthesized doxorubicin (DOX)-tethered linear polyethylenimine (LPEI) conjugates linked via a pH-responsive hydrazone bond (LPEI-HZ-DOX) for the synchronous delivery of DOX and miRNA-34a. The free DOX was successfully released from the LPEI-HZ-DOX conjugates at acidic pH, which provided selective toxicity against cancer cells in a pH-sensitive manner. The resulting LPEI-HZ-DOX conjugates formed nano-sized complexes with chemically modified long-chain miRNAs with a size of ∼200 nm, which exhibited synergistic toxicity and anti-proliferation activity against PC-3 cancer cells. This platform of cationic conjugates with high biocompatibility could serve as a pH-sensitive in vitro system for gene and drug delivery.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. B. Vogelstein, N. Papadopoulos, V. E. Velculescu, S. Zhou, L.A. Diaz, Jr., and K. W. Kinzler, Science, 339, 1546 (2013).

    Article  CAS  Google Scholar 

  2. H. Oettle, Cancer Treat. Rev., 40, 1039 (2014).

    Article  Google Scholar 

  3. R. Drost and J. Jonkers, Oncogene 33, 3753 (2014).

    Article  CAS  Google Scholar 

  4. X. Y. Xu, K. Xie, X. Q. Zhang, E. M. Pridgen, G. Y. Park, D. S. Cui, J. J. Shi, J. Wu, P. W. Kantoff, S. J. Lippard, R. Langer, G. C. Walker, and O. C. Farokhzad, Proc. Natl. Acad. Sci. U.S.A., 110, 18638 (2013).

    Article  CAS  Google Scholar 

  5. W. Gao, Z. Q. Lin, M. W. Chen, X. C. Yang, Z. Cui, X. F. Zhang, L. Yuan, and Q. Zhang, Int. J. Nanomedicine, 9, 3425 (2014).

    Article  CAS  Google Scholar 

  6. F. J. Huang, M. X. You, T. Chen, G. Z. Zhu, H. J. Liang, and W. H. Tan, Chem. Commun., 50, 3103 (2014).

    Article  CAS  Google Scholar 

  7. M. Saad, O. B. Garbuzenko, and T. Minko, Nanomedicine (Lond), 3, 761 (2008).

    Article  CAS  Google Scholar 

  8. D. Cheng, N. Cao, J. Chen, X. Yu, and X. Shuai, Biomaterials, 33, 1170 (2012).

    Article  CAS  Google Scholar 

  9. H. Meng, W. X. Mai, H. Y. Zhang, M. Xue, T. Xia, S. J. Lin, X. Wang, Y. Zhao, Z. X. Ji, J. I. Zink, and A. E. Nel, ACS Nano, 7, 994 (2013).

    Article  CAS  Google Scholar 

  10. J. Li, Y. Wang, Y. Zhu, and D. Oupicky, J. Control. Release, 172, 589 (2013).

    Article  CAS  Google Scholar 

  11. T. Liu, W. Xue, B. Ke, M. Q. Xie, and D. Ma, Biomaterials, 35, 3865 (2014).

    Article  CAS  Google Scholar 

  12. M. Gujrati, A. Malamas, T. Shin, E. L. Jin, Y. L. Sun, and Z. R. Lu, Mol. Pharm., 11, 2734 (2014).

    Article  CAS  Google Scholar 

  13. C. Y. Chen, T. H. Kim, W. C. Wu, C. M. Huang, H. Wei, C. W. Mount, Y. Tian, S. H. Jang, S. H. Pun, and A. K. Jen, Biomaterials, 34, 4501 (2013).

    Article  CAS  Google Scholar 

  14. S. Mura, J. Nicolas, and P. Couvreur, Nat. Mater., 12, 991 (2013).

    Article  CAS  Google Scholar 

  15. R. Mo, T. Jiang, and Z. Gu, Angew. Chem. Int. Ed. Engl., 53, 5815 (2014).

    Article  CAS  Google Scholar 

  16. C. J. Ke, W. L. Chiang, Z. X. Liao, H. L. Chen, P. S. Lai, J. S. Sun, and H. W. Sung, Biomaterials, 34, 1 (2013).

    Article  CAS  Google Scholar 

  17. S. Quader, H. Cabral, Y. Mochida, T. Ishii, X. Liu, K. Toh, H. Kinoh, Y. Miura, N. Nishiyama, and K. Kataoka, J. Control. Release, 188, 67 (2014).

    Article  CAS  Google Scholar 

  18. H. Mok, O. Veiseh, C. Fang, F. M. Kievit, F. Y. Wang, J. O. Park, and M. Zhang, Mol. Pharm., 7, 1930 (2010).

    Article  CAS  Google Scholar 

  19. D. W. Dong, B. Xiang, W. Gao, Z. Z. Yang, J. Q. Li, and X. R. Qi, Biomaterials, 34, 4849 (2013).

    Article  CAS  Google Scholar 

  20. D. W. Dong, S. W. Tong, and X. R. Qi, J. Biomed. Mater. Res. A, 101, 1336 (2013).

    Article  Google Scholar 

  21. S. Lee, H. Koo, J. H. Na, K. E. Lee, S. Y. Jeong, K. Choi, S. H. Kim, I. C. Kwon, and K. Kim, ACS Nano, 8, 4257 (2014).

    Article  CAS  Google Scholar 

  22. A. C. Hunter, Adv. Drug Deliv. Rev., 58, 1523 (2006).

    Article  CAS  Google Scholar 

  23. D. Fischer, Y. Li, B. Ahlemeyer, J. Krieglstein, and T. Kissel, Biomaterials, 24, 1121 (2003).

    Article  CAS  Google Scholar 

  24. D. P. Bartel, Cell, 136, 215 (2009).

    Article  CAS  Google Scholar 

  25. F. Li and R. I. Mahato, Mol. Pharm., 11, 2539 (2014).

    Article  CAS  Google Scholar 

  26. Y. Fujita, K. Kojima, R. Ohhashi, N. Hamada, Y. Nozawa, A. Kitamoto, A. Sato, S. Kondo, T. Kojima, T. Deguchi, and M. Ito, J. Biol. Chem., 285, 19076 (2010).

    Article  CAS  Google Scholar 

  27. X. Deng, M. Cao, J. Zhang, K. Hu, Z. Yin, Z. Zhou, X. Xiao, Y. Yang, W. Sheng, Y. Wu, and Y. Zeng, Biomaterials, 35, 4333 (2014).

    Article  CAS  Google Scholar 

  28. A. A. Takwi, Y. M. Wang, J. Wu, M. Michaelis, J. Cinatl, and T. Chen, Oncogene, 33, 3717 (2014).

    Article  CAS  Google Scholar 

  29. C. A. Hong, J. S. Kim, S. H. Lee, W. H. Kong, T. G. Park, H. Mok, and Y. S. Nam, Adv. Funct. Mater., 23, 316 (2013).

    Article  CAS  Google Scholar 

  30. H. Jung, S. A. Kim, Y. G. Yang, H. Yoo, S. J. Lim, and H. Mok, Arch. Pharm. Res., DOI: 10.1007/s12272-014-0451-0 (2014).

    Google Scholar 

  31. Q. Peng, Z. Zhong, and R. Zhuo, Bioconjug. Chem., 19, 499 (2008).

    Article  CAS  Google Scholar 

  32. J. L. Zimmermann, T. Nicolaus, G. Neuert, and K. Blank, Nat. Protoc., 5, 975 (2010).

    Article  CAS  Google Scholar 

  33. P. Ge and P. R. Selvin, Bioconjug. Chem., 14, 870 (2003).

    Article  CAS  Google Scholar 

  34. H. S. Yoo, E. A. Lee, and T. G. Park, J. Control. Release, 82, 17 (2002).

    Article  CAS  Google Scholar 

  35. M. Hruby, C. Konak, and K. Ulbrich, J. Control. Release, 103, 137 (2005).

    Article  CAS  Google Scholar 

  36. L. Zhou, R. Cheng, H. Q. Tao, S. B. Ma, W. W. Guo, F. H. Meng, H. Y. Liu, Z. Liu, and Z. Y. Zhong, Biomacromolecules, 12, 1460 (2011).

    Article  CAS  Google Scholar 

  37. H. J. Yoon and W. D. Jang, J. Mater. Chem., 20, 211 (2010).

    Article  CAS  Google Scholar 

  38. H. Mok, S. H. Lee, J. W. Park, and T. G. Park, Nat. Mater., 9, 272 (2010).

    CAS  Google Scholar 

  39. S. Y. Lee, M. S. Huh, S. Lee, S. J. Lee, H. Chung, J. H. Park, Y. K. Oh, K. Choi, K. Kim, and I. C. Kwon, J. Control. Release, 141, 339 (2010).

    Article  CAS  Google Scholar 

  40. T. Yoshida, T. C. Lai, G. S. Kwon, and K. Sako, Expert Opin. Drug Deliv., 10, 1497 (2013).

    Article  CAS  Google Scholar 

  41. Z. G. Gao, L. Tian, J. Hu, I. S. Park, and Y. H. Bae, J. Control. Release, 152, 84 (2011).

    Article  CAS  Google Scholar 

  42. M. Breunig, U. Lungwitz, R. Liebl, C. Fontanari, J. Klar, A. Kurtz, T. Blunk, and A. Goepferich, J. Gene Med., 7, 1287 (2005).

    Article  CAS  Google Scholar 

  43. E. S. Lee, Z. G. Gao, and Y. H. Bae, J. Control. Release, 132, 164 (2008).

    Article  CAS  Google Scholar 

  44. A. E. Felber, M. H. Dufresne, and J. C. Leroux, Adv. Drug Deliv. Rev., 64, 979 (2012).

    Article  CAS  Google Scholar 

  45. J. W. Yoo, N. Doshi, and S. Mitragotri, Adv. Drug Deliv. Rev., 63, 1247 (2011).

    Article  CAS  Google Scholar 

  46. L. Y. Chou, K. Ming, and W. C. Chan, Chem. Soc. Rev., 40, 233 (2011).

    Article  CAS  Google Scholar 

  47. N. Raver-Shapira, E. Marciano, E. Meiri, Y. Spector, N. Rosenfeld, N. Moskovits, Z. Bentwich, and M. Oren, Mol. Cell, 26, 731 (2007).

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Bioscience and Biotechnology, Konkuk University, Seoul, 143-701, Korea

    Hyosook Jung, Seung An Kim, Eunjoo Lee & Hyejung Mok

Authors
  1. Hyosook Jung
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Seung An Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Eunjoo Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hyejung Mok
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Hyejung Mok.

Additional information

These authors contributed equally to this work.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Jung, H., Kim, S.A., Lee, E. et al. Linear polyethyleneimine-doxorubicin conjugate for pH-responsive synchronous delivery of drug and microRNA-34a. Macromol. Res. 23, 449–456 (2015). https://doi.org/10.1007/s13233-015-3060-y

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13233-015-3060-y

Keywords

Search

Navigation