Layer-by-Layer Assembled Antisense DNA Microsponge Particles for Efficient Delivery of Cancer Therapeutics
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 oligonucleotide...
| Main Authors: | , , , , , , , , , |
|---|---|
| Other Authors: | |
| Format: | Article |
| Language: | en_US |
| Published: |
American Chemical Society (ACS)
2016
|
| Online Access: | http://hdl.handle.net/1721.1/101178 https://orcid.org/0000-0002-4954-8443 https://orcid.org/0000-0003-3988-0837 https://orcid.org/0000-0003-3243-8536 |
| _version_ | 1826200580070047744 |
|---|---|
| author | 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 |
| author2 | Massachusetts Institute of Technology. Department of Chemical Engineering |
| author_facet | Massachusetts Institute of Technology. Department of Chemical Engineering 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 |
| author_sort | Roh, Young Hoon |
| collection | MIT |
| description | 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. |
| first_indexed | 2024-09-23T11:38:35Z |
| format | Article |
| id | mit-1721.1/101178 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T11:38:35Z |
| publishDate | 2016 |
| publisher | American Chemical Society (ACS) |
| record_format | dspace |
| spelling | mit-1721.1/1011782022-09-27T20:59:02Z Layer-by-Layer Assembled Antisense DNA Microsponge Particles for Efficient Delivery of Cancer Therapeutics 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 Massachusetts Institute of Technology. Department of Chemical Engineering Koch Institute for Integrative Cancer Research at MIT Roh, Young Hoon Lee, Jong Bum Shopsowitz, Kevin Dreaden, Erik Christopher Morton, Stephen Winford Poon, Zhiyong Hong, Jinkee Yamin, Inbar Bonner, Daniel K. Hammond, Paula T. 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. United States. Dept. of Defense. Ovarian Cancer Research Program (Teal Innovator Award Grant OC120504) Natural Sciences and Engineering Research Council of Canada (Postdoctoral Fellowship) National Institutes of Health (U.S.) (Ruth L. Kirschstein National Research Service Award 1F32EB017614-01) National Science Foundation (U.S.). Graduate Research Fellowship 2016-02-12T20:26:57Z 2016-02-12T20:26:57Z 2014-09 2014-05 Article http://purl.org/eprint/type/JournalArticle 1936-0851 1936-086X http://hdl.handle.net/1721.1/101178 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 https://orcid.org/0000-0002-4954-8443 https://orcid.org/0000-0003-3988-0837 https://orcid.org/0000-0003-3243-8536 en_US http://dx.doi.org/10.1021/nn502596b ACS Nano Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use. application/pdf American Chemical Society (ACS) ACS |
| spellingShingle | 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 Layer-by-Layer Assembled Antisense DNA Microsponge Particles for Efficient Delivery of Cancer Therapeutics |
| title | Layer-by-Layer Assembled Antisense DNA Microsponge Particles for Efficient Delivery of Cancer Therapeutics |
| title_full | Layer-by-Layer Assembled Antisense DNA Microsponge Particles for Efficient Delivery of Cancer Therapeutics |
| title_fullStr | Layer-by-Layer Assembled Antisense DNA Microsponge Particles for Efficient Delivery of Cancer Therapeutics |
| title_full_unstemmed | Layer-by-Layer Assembled Antisense DNA Microsponge Particles for Efficient Delivery of Cancer Therapeutics |
| title_short | Layer-by-Layer Assembled Antisense DNA Microsponge Particles for Efficient Delivery of Cancer Therapeutics |
| title_sort | layer by layer assembled antisense dna microsponge particles for efficient delivery of cancer therapeutics |
| url | http://hdl.handle.net/1721.1/101178 https://orcid.org/0000-0002-4954-8443 https://orcid.org/0000-0003-3988-0837 https://orcid.org/0000-0003-3243-8536 |
| work_keys_str_mv | AT rohyounghoon layerbylayerassembledantisensednamicrospongeparticlesforefficientdeliveryofcancertherapeutics AT leejongbum layerbylayerassembledantisensednamicrospongeparticlesforefficientdeliveryofcancertherapeutics AT mortonstephenwinford layerbylayerassembledantisensednamicrospongeparticlesforefficientdeliveryofcancertherapeutics AT poonzhiyong layerbylayerassembledantisensednamicrospongeparticlesforefficientdeliveryofcancertherapeutics AT hongjinkee layerbylayerassembledantisensednamicrospongeparticlesforefficientdeliveryofcancertherapeutics AT yamininbar layerbylayerassembledantisensednamicrospongeparticlesforefficientdeliveryofcancertherapeutics AT bonnerdanielk layerbylayerassembledantisensednamicrospongeparticlesforefficientdeliveryofcancertherapeutics AT shopsowitzkevin layerbylayerassembledantisensednamicrospongeparticlesforefficientdeliveryofcancertherapeutics AT hammondpaulat layerbylayerassembledantisensednamicrospongeparticlesforefficientdeliveryofcancertherapeutics AT dreadenerik layerbylayerassembledantisensednamicrospongeparticlesforefficientdeliveryofcancertherapeutics |