Radiation-enhanced delivery of plasmid DNA to tumors utilizing a novel PEI polyplex.
Oliver K AppelbeBieong-Kil KimNick RymutJianping WangStephen J KronYoon YeoPublished in: Cancer gene therapy (2017)
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.
Keyphrases
- gene therapy
- nucleic acid
- circulating tumor
- early stage
- primary care
- single molecule
- cell free
- escherichia coli
- radiation induced
- healthcare
- radiation therapy
- crispr cas
- type diabetes
- metabolic syndrome
- oxidative stress
- single cell
- quality improvement
- climate change
- papillary thyroid
- mass spectrometry
- pet imaging
- squamous cell carcinoma
- skeletal muscle
- drug delivery
- risk assessment
- positron emission tomography
- water soluble
- heat shock protein
- pet ct