Layer-by-Layer Assembled Antisense DNA Microsponge Particles for Efficient Delivery of Cancer Therapeutics
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Author(s)
Roh, Young Hoon
Lee, Jong Bum
Morton, Stephen Winford
Poon, Zhiyong
Hong, Jinkee
Yamin, Inbar
Bonner, Daniel K.
Shopsowitz, Kevin
Hammond, Paula T
Dreaden, Erik
Date Issued
September 2014
Journal
ACS Nano
Publisher
American Chemical Society (ACS)
Citation
Roh, Young Hoon, Jong Bum Lee, Kevin E. Shopsowitz, Erik C. Dreaden, Stephen W. Morton, Zhiyong Poon, Jinkee Hong, Inbar Yamin, Daniel K. Bonner, and Paula T. Hammond. “Layer-by-Layer Assembled Antisense DNA Microsponge Particles for Efficient Delivery of Cancer Therapeutics.” ACS Nano 8, no. 10 (October 28, 2014): 9767–9780. © 2014 American Chemical Society
Version
Final published version
Abstract
Antisense oligonucleotides can be employed as a potential approach to effectively treat cancer. However, the inherent instability and inefficient systemic delivery methods for antisense therapeutics remain major challenges to their clinical application. Here, we present a polymerized oligonucleotides (ODNs) that self-assemble during their formation through an enzymatic elongation method (rolling circle replication) to generate a composite nucleic acid/magnesium pyrophosphate sponge-like microstructure, or DNA microsponge, yielding high molecular weight nucleic acid product. In addition, this densely packed ODN microsponge structure can be further condensed to generate polyelectrolyte complexes with a favorable size for cellular uptake by displacing magnesium pyrophosphate crystals from the microsponge structure. Additional layers are applied to generate a blood-stable and multifunctional nanoparticle via the layer-by-layer (LbL) assembly technique. By taking advantage of DNA nanotechnology and LbL assembly, functionalized DNA nanostructures were utilized to provide extremely high numbers of repeated ODN copies for efficient antisense therapy. Moreover, we show that this formulation significantly improves nucleic acid drug/carrier stability during in vivo biodistribution. These polymeric ODN systems can be designed to serve as a potent means of delivering stable and large quantities of ODN therapeutics systemically for cancer treatment to tumor cells at significantly lower toxicity than traditional synthetic vectors, thus enabling a therapeutic window suitable for clinical translation.
MIT Department
Massachusetts Institute of Technology. Department of Chemical Engineering
Koch Institute for Integrative Cancer Research at MIT
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DOI of Published Version
https://doi.org/10.1021/nn502596b
