Influence of polymer size on uptake and cytotoxicity of doxorubicin-loaded DNA–PEG conjugates

Purdie, Laura; Alexander, Cameron; Spain, Sebastian G.; Magnusson, Johannes P.

Abstract

Intercalation of drugs into assembled DNA systems offers versatile new mechanisms for controlled drug delivery. However, current systems are becoming increasingly complex, reducing the practicality of large scale production. Here, we demonstrate a more pragmatic approach where a short DNA sequence was modified with poly(ethylene glycol) (PEG) of various lengths at both 5′-termini to provide serum stability and compatibility. The anticancer drug doxorubicin was physically loaded into two designed binding sites on the dsODN. The polymer conjugation improved the stability of the dsODN toward serum nucleases while its doxorubicin binding affinity was unaffected by the presence of the polymers. We examined the effects of polymer size on the dsODN carrier characteristics and studied the resulting DOX@DNA–PEG systems with respect to cytotoxicity, cellular uptake, and localization in A549 and MCF7 cell lines. For the A549 cell line the DOX@DNA-PEG1900 exhibited the best dose response of the conjugates while DOX@DNA-PEG550 was the least potent. In MCF-7, a more doxorubicin sensitive cell line, all conjugates exhibited similar dose response to that of the free drug. Confocal microscopy analysis of doxorubicin localization shows that conjugates successfully deliver doxorubicin to the cell nucleus and also the lysosome. These data provide a valuable insight into the complexities of designing an oligonucleotide based drug delivery system and highlight some practical issues that need to be considered when doing so.

Citation

Purdie, L., Alexander, C., Spain, S. G., & Magnusson, J. P. (2016). Influence of polymer size on uptake and cytotoxicity of doxorubicin-loaded DNA–PEG conjugates. Bioconjugate Chemistry, 27(5), https://doi.org/10.1021/acs.bioconjchem.6b00085

• Journal Article Type: Article
• Acceptance Date: Feb 16, 2016
• Online Publication Date: Apr 14, 2016
• Publication Date: May 18, 2016
• Deposit Date: Nov 30, 2016
• Publicly Available Date: Nov 30, 2016
• Journal: Bioconjugate Chemistry
• Print ISSN: 1043-1802
• Electronic ISSN: 1520-4812
• Publisher: American Chemical Society
• Peer Reviewed: Peer Reviewed
• Volume: 27
• Issue: 5
• DOI: https://doi.org/10.1021/acs.bioconjchem.6b00085
• Public URL: https://nottingham-repository.worktribe.com/output/789680
• Publisher URL: http://pubs.acs.org/doi/abs/10.1021/acs.bioconjchem.6b00085