本文采用的英格恩产品: DNA-Entranster-invivo
Radiation-enhanced delivery of plasmid DNA to tumors utilizing a novel PEI polyplex
Affiliations
- 1 Ludwig Center for Metastasis Research, The University of Chicago, 5758 South Maryland Avenue, MC 9006, Chicago, IL, 60637, USA.
- 2 Department of Molecular Genetics and Cellular Biology, The University of Chicago, 929 East 57th Street, GCIS W519, Chicago, IL, 60637, USA.
- 3 Department of Industrial and Physical Pharmacy, Purdue University, 575 Stadium Mall Dr., West Lafayette, IN, 47907, USA.
- 4 Department of Pharmaceutics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China.
- 5 Ludwig Center for Metastasis Research, The University of Chicago, 5758 South Maryland Avenue, MC 9006, Chicago, IL, 60637, USA. skron@uchicago.edu.
- 6 Department of Molecular Genetics and Cellular Biology, The University of Chicago, 929 East 57th Street, GCIS W519, Chicago, IL, 60637, USA. skron@uchicago.edu.
- 7 Weldon School of Biomedical Engineering, Purdue University, West Lafayette, IN, 47907, USA.
- PMID: 29255216
- PMCID: PMC6008165
- DOI: 10.1038/s41417-017-0004-z
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.
