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Radiation-enhanced delivery of plasmid DNA to tumors utilizing a novel PEI polyplex

Cancer Gene Therapyvolume 25pages196206 (2018) | Download Citation

Abstract

The excitement surrounding the potential of gene therapy has been tempered due to the challenges that have thus far limited its successful implementation in the clinic such as issues regarding stability, transfection efficiency, and toxicity. In this study, low molecular weight linear polyethyleneimine (2.5 kDa) was modified by conjugation to a lipid, lithocholic acid, and complexed with a natural polysaccharide, dermatan sulfate (DS), to mask extra cationic charges of the modified polymer. In vitro examination revealed that these modifications improved complex stability with plasmid DNA (pDNA) and transfection efficiency. This novel ternary polyplex (pDNA/3E/DS) was used to investigate if tumor-targeted radiotherapy led to enhanced accumulation and retention of gene therapy vectors in vivo in tumor-bearing mice. Imaging of biodistribution revealed that tumor irradiation led to increased accumulation and retention as well as decreased off-target tissue buildup of pDNA in not only pDNA/3E/DS, but also in associated PEI-based polyplexes and commercial DNA delivery vehicles. The DS-containing complexes developed in this study displayed the greatest increase in tumor-specific pDNA delivery. These findings demonstrate a step forward in nucleic acid vehicle design as well as a promising approach to overall cancer gene therapy through utilization of radiotherapy as a tool for enhanced delivery.

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Acknowledgements

This work was supported by NIH R01s CA199663 to SJK and EB017791 to YY as well as NSF DMR-1056997 to YY.

Author contributions

OKA, BKK, YY, and SJK initiated the project. OKA led in vivo experimental design, data acquisition and analysis, and manuscript preparation. BKK designed and prepared all novel PEI polyplexes and performed in vitro data acquisition and analysis. NR and JW aided in data acquisition. YY and SJK participated in experimental design, data analysis, and manuscript preparation.

Author information

Affiliations

  1. Ludwig Center for Metastasis Research, The University of Chicago, 5758 South Maryland Avenue, MC 9006, Chicago, IL, 60637, USA

    • Oliver K. Appelbe
    • , Nick Rymut
    •  & Stephen J. Kron
  2. Department of Molecular Genetics and Cellular Biology, The University of Chicago, 929 East 57th Street, GCIS W519, Chicago, IL, 60637, USA

    • Oliver K. Appelbe
    • , Nick Rymut
    •  & Stephen J. Kron
  3. Department of Industrial and Physical Pharmacy, Purdue University, 575 Stadium Mall Dr., West Lafayette, IN, 47907, USA

    • Bieong-Kil Kim
    • , Jianping Wang
    •  & Yoon Yeo
  4. Department of Pharmaceutics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China

    • Jianping Wang
  5. Weldon School of Biomedical Engineering, Purdue University, West Lafayette, IN, 47907, USA

    • Yoon Yeo

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Conflict of interest

The authors declare that thay have no competing interests.

Corresponding author

Correspondence to Stephen J. Kron.

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DOI

https://doi.org/10.1038/s41417-017-0004-z