SpringerLink
Log in

Efficient lung orthotopic tumor-growth suppression of oncolytic adenovirus complexed with RGD-targeted bioreducible polymer

  • Original Article
  • Published:
Gene Therapy Submit manuscript

Abstract

Oncolytic adenoviruses (Ad) have been developed for the eradication of tumors. Although they hold much promise as a cancer therapy, they have a short blood circulation time and high liver toxicity. An effective strategy to overcome these problems has been complexing Ad with shielding materials. However, the therapeutic efficacy of the Ad complexes has also been an issue because passive accumulation does not allow for sufficient delivery of Ad to the cancer cells. To enhance the therapeutic efficacy of the polymer-coated Ads, the attachment of a targeting moiety to polymer-coated Ad vectors is inescapable. Our lab has previously reported the potential use of Arg-Gly-Asp (RGD)-targeted bioreducible polymers with a polyethylene glycol (PEG) linker for delivering oncolytic Ads. We have shown the enhanced in vitro transduction efficiency and increased cancer-killing effect with producing progeny oncolytic Ad particles. In addition, we have shown significant tumor-growth inhibition of the polymer-shielded Ad in an in vivo lung orthotopic tumor model. The shielding effect of the Ad surface with the polymers allowed evasion of host immune responses and reduction of liver toxicity. This data demonstrates that the RGD-conjugated bioreducible polymer for delivering the oncolytic Ad vectors could be utilized for cancer therapy via systemic administration.

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

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
EUR 32.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or Ebook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price includes VAT (France)

Instant access to the full article PDF.

Institutional subscriptions

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5

Similar content being viewed by others

References

  1. Bischoff JR, Kirn DH, Williams A, Heise C, Horn S, Muna M et al. An adenovirus mutant that replicates selectively in p53-deficient human tumor cells. Science 1996; 274: 373–376.

    Article  CAS  PubMed  Google Scholar 

  2. Jounaidi Y, Doloff JC, Waxman DJ . Conditionally replicating adenoviruses for cancer treatment. Curr Cancer Drug Targets 2007; 7: 285–301.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Pesonen S, Kangasniemi L, Hemminki A . Oncolytic adenoviruses for the treatment of human cancer: focus on translational and clinical data. Mol Pharm 2011; 8: 12–28.

    Article  CAS  PubMed  Google Scholar 

  4. Kim J, Cho JY, Kim JH, Jung KC, Yun CO . Evaluation of E1B gene-attenuated replicating adenoviruses for cancer gene therapy. Cancer Gene Ther 2002; 9: 725–736.

    Article  CAS  PubMed  Google Scholar 

  5. Kim J, Kim JH, Choi KJ, Kim PH, Yun CO . E1A- and E1B-Double mutant replicating adenovirus elicits enhanced oncolytic and antitumor effects. Hum Gene Ther 2007; 18: 773–786.

    Article  CAS  PubMed  Google Scholar 

  6. DeWeese TL, van der Poel H, Li S, Mikhak B, Drew R, Goemann M et al. A phase I trial of CV706, a replication-competent, PSA selective oncolytic adenovirus, for the treatment of locally recurrent prostate cancer following radiation therapy. Cancer Res 2001; 61: 7464–7472.

    CAS  PubMed  Google Scholar 

  7. Kim J, Lee B, Kim JS, Yun CO, Kim JH, Lee YJ et al. Antitumoral effects of recombinant adenovirus YKL-1001, conditionally replicating in alpha-fetoprotein-producing human liver cancer cells. Cancer Lett 2002; 180: 23–32.

    Article  CAS  PubMed  Google Scholar 

  8. Li Y, Chen Y, Dilley J, Arroyo T, Ko D, Working P et al. Carcinoembryonic antigen-producing cell-specific oncolytic adenovirus, OV798, for colorectal cancer therapy. Mol Cancer Ther 2003; 2: 1003–1009.

    CAS  PubMed  Google Scholar 

  9. Kim E, Kim JH, Shin HY, Lee H, Yang JM, Kim J et al. Ad-mTERT-delta19, a conditional replication-competent adenovirus driven by the human telomerase promoter, selectively replicates in and elicits cytopathic effect in a cancer cell-specific manner. Hum Gene Ther 2003; 14: 1415–1428.

    Article  CAS  PubMed  Google Scholar 

  10. Kwon OJ, Kim PH, Huyn S, Wu L, Kim M, Yun CO . A hypoxia- and {alpha}-fetoprotein-dependent oncolytic adenovirus exhibits specific killing of hepatocellular carcinomas. Clin Cancer Res 2011; 16: 6071–6082.

    Article  Google Scholar 

  11. Koo T, Choi IK, Kim M, Lee JS, Oh E, Kim J et al. Negative regulation-resistant p53 variant enhances oncolytic adenoviral gene therapy. Hum Gene Ther 2012; 23: 609–622.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Shewach DS, Zerbe LK, Hughes TL, Roessler BJ, Breakefield XO, Davidson BL . Enhanced cytotoxicity of antiviral drugs mediated by adenovirus directed transfer of the herpes simplex virus thymidine kinase gene in rat glioma cells. Cancer Gene Ther 1994; 1: 107–112.

    CAS  PubMed  Google Scholar 

  13. Hirschowitz EA, Ohwada A, Pascal WR, Russi TJ, Crystal RG . In vivo adenovirus-mediated gene transfer of the Escherichia coli cytosine deaminase gene to human colon carcinoma-derived tumors induces chemosensitivity to 5-fluorocytosine. Hum Gene Ther 1995; 6: 1055–1063.

    Article  CAS  PubMed  Google Scholar 

  14. Choi KJ, Kim JH, Lee YS, Kim J, Suh BS, Kim H et al. Concurrent delivery of GM-CSF and B7-1 using an oncolytic adenovirus elicits potent antitumor effect. Gene Ther 2006; 13: 1010–1020.

    Article  CAS  PubMed  Google Scholar 

  15. Lee YS, Kim JH, Choi KJ, Choi IK, Kim H, Cho S et al. Enhanced antitumor effect of oncolytic adenovirus expressing interleukin-12 and B7-1 in an immunocompetent murine model. Clin Cancer Res 2006; 12: 5859–5868.

    Article  CAS  PubMed  Google Scholar 

  16. Yoo JY, Kim JH, Kwon YG, Kim EC, Kim NK, Choi HJ et al. VEGF-specific short hairpin RNA-expressing oncolytic adenovirus elicits potent inhibition of angiogenesis and tumor growth. Mol Ther 2007; 15: 295–302.

    Article  CAS  PubMed  Google Scholar 

  17. Yoo JY, Kim JH, Kim J, Huang JH, Zhang SN, Kang YA et al. Short hairpin RNA-expressing oncolytic adenovirus-mediated inhibition of IL-8: effects on antiangiogenesis and tumor growth inhibition. Gene Ther 2008; 15: 635–651.

    Article  CAS  PubMed  Google Scholar 

  18. Yun CO, Kim E, Koo T, Kim H, Lee YS, Kim JH . ADP-overexpressing adenovirus elicits enhanced cytopathic effect by induction of apoptosis. Cancer Gene Ther 2005; 12: 61–71.

    Article  CAS  PubMed  Google Scholar 

  19. Kim JH, Lee YS, Kim H, Huang JH, Yoon AR, Yun CO . Relaxin expression from tumor-targeting adenoviruses and its intratumoral spread, apoptosis induction, and efficacy. J Natl Cancer Inst 2006; 98: 1482–1493.

    Article  CAS  PubMed  Google Scholar 

  20. Choi IK, Lee YS, Yoo JY, Yoon AR, Kim H, Kim DS et al. Effect of decorin on overcoming the extracellular matrix barrier for oncolytic virotherapy. Gene Ther 2010; 17: 190–201.

    Article  CAS  PubMed  Google Scholar 

  21. Alemany R, Suzuki K, Curiel DT . Blood clearance rates of adenovirus type 5 in mice. J Gen Virol 2000; 81: 2605–2609.

    Article  CAS  PubMed  Google Scholar 

  22. Nemunaitis J, O’Brien J . Head and neck cancer: gene therapy approaches. Part II: genes delivered. Expert Opin Biol Ther 2002; 2: 311–324.

    Article  CAS  PubMed  Google Scholar 

  23. Liu Q, Zaiss AK, Colarusso P, Patel K, Haljan G, Wickham TJ et al. The role of capsid-endothelial interactions in the innate immune response to adenovirus vectors. Hum Gene Ther 2003; 14: 627–643.

    Article  CAS  PubMed  Google Scholar 

  24. Molnar-Kimber KL, Sterman DH, Chang M, Kang EH, ElBash M, Lanuti M et al. Impact of preexisting and induced humoral and cellular immune responses in an adenovirus-based gene therapy phase I clinical trial for localized mesothelioma. Hum Gene Ther 1998; 9: 2121–2133.

    Article  CAS  PubMed  Google Scholar 

  25. Sumida SM, Truitt DM, Lemckert AA, Vogels R, Custers JH, Addo MM et al. Neutralizing antibodies to adenovirus serotype 5 vaccine vectors are directed primarily against the adenovirus hexon protein. J Immunol 2005; 174: 7179–7185.

    Article  CAS  PubMed  Google Scholar 

  26. O'Riordan CR, Lachapelle A, Delgado C, Parkes V, Wadsworth SC, Smith AE et al. PEGylation of adenovirus with retention of infectivity and protection from neutralizing antibody in vitro and in vivo. Hum Gene Ther 1999; 10: 1349–1358.

    Article  CAS  PubMed  Google Scholar 

  27. Kreppel F, Kochanek S . Modification of adenovirus gene transfer vectors with synthetic polymers: a scientific review and technical guide. Mol Ther 2008; 16: 16–29.

    Article  CAS  PubMed  Google Scholar 

  28. Fisher KD, Seymour LW . HPMA copolymers for masking and retargeting of therapeutic viruses. Adv Drug Deliv Rev 2010; 62: 240–245.

    Article  CAS  PubMed  Google Scholar 

  29. Kang E, Yun CO . Current advances in adenovirus nanocomplexes: more specificity and less immunogenicity. BMB Rep 2010; 43: 781–788.

    Article  CAS  PubMed  Google Scholar 

  30. Choi JW, Lee JS, Kim SW, Yun CO . Evolution of oncolytic adenovirus for cancer treatment. Adv Drug Deliv Rev 2012; 64: 720–729.

    Article  CAS  PubMed  Google Scholar 

  31. Seymour LW . Passive tumor targeting of soluble macromolecules and drug conjugates. Crit Rev Ther Drug Carrier Syst 1992; 9: 135–187.

    CAS  PubMed  Google Scholar 

  32. Matsumura Y, Maeda H . A new concept for macromolecular therapeutics in cancer chemotherapy: mechanism of tumoritropic accumulation of proteins and the antitumor agent smancs. Cancer Res 1986; 46: 6387–6392.

    CAS  PubMed  Google Scholar 

  33. Kim J, Kim PH, Kim SW, Yun CO . Enhancing the therapeutic efficacy of adenovirus in combination with biomaterials. Biomaterials 2012; 33: 1838–1850.

    Article  CAS  PubMed  Google Scholar 

  34. Kim PH, Sohn JH, Choi JW, Jung Y, Kim SW, Haam S et al. Active targeting and safety profile of PEG-modified adenovirus conjugated with herceptin. Biomaterials 2011; 32: 2314–2326.

    Article  CAS  PubMed  Google Scholar 

  35. Veikkola T, Karkkainen M, Claesson-Welsh L, Alitalo K . Regulation of angiogenesis via vascular endothelial growth factor receptors. Cancer Res 2000; 60: 203–212.

    CAS  PubMed  Google Scholar 

  36. Suh W, Han SO, Yu L, Kim SW . An angiogenic, endothelial-cell-targeted polymeric gene carrier. Mol Ther 2002; 6: 664–672.

    Article  CAS  PubMed  Google Scholar 

  37. Kim WJ, Yockman JW, Lee M, Jeong JH, Kim YH, Kim SW . Soluble Flt-1 gene delivery using PEI-g-PEG-RGD conjugate for anti-angiogenesis. J Control Release 2005; 106: 224–234.

    Article  CAS  PubMed  Google Scholar 

  38. Kim J, Nam HY, Kim TI, Kim PH, Ryu J, Yun CO et al. Active targeting of RGD-conjugated bioreducible polymer for delivery of oncolytic adenovirus expressing shRNA against IL-8 mRNA. Biomaterials 2011; 32: 5158–5166.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Ou M, Wang XL, Xu R, Chang CW, Bull DA, Kim SW . Novel biodegradable poly(disulfide amine)s for gene delivery with high efficiency and low cytotoxicity. Bioconjug Chem 2008; 19: 626–633.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Ou M, Kim TI, Yockman JW, Borden BA, Bull DA, Kim SW . Polymer transfected primary myoblasts mediated efficient gene expression and angiogenic proliferation. J Control Release 2010; 142: 61–69.

    Article  CAS  PubMed  Google Scholar 

  41. Kanerva A, Hemminki A . Modified adenoviruses for cancer gene therapy. Int J Cancer 2004; 110: 475–480.

    Article  CAS  PubMed  Google Scholar 

  42. Hofherr SE, Shashkova EV, Weaver EA, Khare R, Barry MA . Modification of adenoviral vectors with polyethylene glycol modulates in vivo tissue tropism and gene expression. Mol Ther 2008; 16: 1276–1282.

    Article  CAS  PubMed  Google Scholar 

  43. Muruve DA, Barnes MJ, Stillman IE, Libermann TA . Adenoviral gene therapy leads to rapid induction of multiple chemokines and acute neutrophil-dependent hepatic injury in vivo. Hum Gene Ther 1999; 10: 965–976.

    Article  CAS  PubMed  Google Scholar 

  44. Gao JQ, Eto Y, Yoshioka Y, Sekiguchi F, Kurachi S, Morishige T et al. Effective tumor targeted gene transfer using PEGylated adenovirus vector via systemic administration. J Control Release 2007; 122: 102–110.

    Article  CAS  PubMed  Google Scholar 

  45. Weaver EA, Barry MA . Effects of shielding adenoviral vectors with polyethylene glycol on vector-specific and vaccine-mediated immune responses. Hum Gene Ther 2008; 19: 1369–1382.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This work was supported by grants from NIH CA107070 (SWK), the Ministry of Knowledge Economy (10030051, C-OY), the Korea Science Engineering Foundation (R15-2004-024-02001-0, 2009K001644, 2010–0029220, C-OY) and the research fund of Hanyang University (HY-2011-G-201100000001880).

Author information

Authors and Affiliations

  1. Department of Pharmaceutics and Pharmaceutical Chemistry, Center for Controlled Chemical Delivery, University of Utah, Salt Lake City, UT, USA

    J Kim & S W Kim

  2. Samyang Biopharmaceuticals Corporation, Daejeon, South Korea

    H Y Nam

  3. Department of Bioengineering, College of Engineering, Hanyang University, Seoul, South Korea

    J W Choi, C-O Yun & S W Kim

Authors
  1. J Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. H Y Nam
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. J W Choi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. C-O Yun
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. S W Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to S W Kim.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kim, J., Nam, H., Choi, J. et al. Efficient lung orthotopic tumor-growth suppression of oncolytic adenovirus complexed with RGD-targeted bioreducible polymer. Gene Ther 21, 476–483 (2014). https://doi.org/10.1038/gt.2014.18

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/gt.2014.18

  • Springer Nature Limited

Search

Navigation