title: Layer-by-layer assembled antisense DNA microsponge particles for efficient delivery of cancer therapeutics.
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.
authors.affiliation: Department of Chemical Engneering and The Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology , Cambridge, Massachusetts 02139, United States.
authors.forename: Young Hoon
authors.initials: YH
authors.lastname: Roh
authors.forename: Jong Bum
authors.initials: JB
authors.lastname: Lee
authors.forename: Kevin E
authors.initials: KE
authors.lastname: Shopsowitz
authors.forename: Erik C
authors.initials: EC
authors.lastname: Dreaden
authors.forename: Stephen W
authors.initials: SW
authors.lastname: Morton
authors.forename: Zhiyong
authors.initials: Z
authors.lastname: Poon
authors.forename: Jinkee
authors.initials: J
authors.lastname: Hong
authors.forename: Inbar
authors.initials: I
authors.lastname: Yamin
authors.forename: Daniel K
authors.initials: DK
authors.lastname: Bonner
authors.forename: Paula T
authors.initials: PT
authors.lastname: Hammond
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage*; D016373:DNA, Antisense / Q000737:chemistry*; D004337:Drug Carriers; D046529:Microscopy, Electron, Transmission
chemical_list: D000970:Antineoplastic Agents; D016373:DNA, Antisense; D004337:Drug Carriers
keywords: DNA delivery; DNA nanotechnology; DNA oligonucleotide; antisense therapy; cancer; layer-by-layer; multifunctionality