Nucleic acid therapeutics have the potential to be the most effective disease treatment strategy due to their intrinsic precision and selectivity for coding highly specific biological processes. Recently, the delivery of therapeutic nucleic acids to modify gene expression has emerged as a promising way to treat a range of inherited or acquired diseases. The G-quadruplex, a stacked series of G-tetrads in guanine-rich DNA, is a unique DNA structure that can be found within promotor regions of oncogenes as well as in the telomeric regions of the chromosome. The G-quadruplex is nuclease resistant and plays a role in transcriptional regulation. As chromosomes with damaged or shortened telomeres have been shown to cause miscoding that may result in cancerous cells, delivery of G-quadruplex DNA is being investigated as a component of gene-mediated anticancer treatment. However, freely administered nucleic acids of any type are quickly destroyed or rendered inert by a host of defense mechanisms in the body. To combat this, a versatile method to encapsulate the DNA and protect it from degradation until reaching the desired location is required. We show that the G-quadruplex sequence can be encapsulated within two-component hydrogel microcapsules of poly(methacrylic acid)/poly(N-vinylpyrrolidone) (PMAA/PVPON) obtained via multilayer assembly of polymers onto sacrificial calcium carbonate microparticles, crosslinking with cystamine, and template dissolution under physiologically safe conditions. We demonstrate that the PMAA/PVPON capsules can release the nucleic acid payload on demand in response to safe &lt;14 W/cm<sup>2</sup> ultrasound irradiation as well as in response to enzymatic degradation of the capsule shell by intracellular concentrations of reduced glutathione. The encapsulation and controlled release of G-quadruplex oligonucleotides herein can be applied to new therapeutic strategies and may provide a promising methodology for the design of effective carriers for DNA vaccines and medicines for a wide range of immunotherapies, cancer therapy and/or tissue regeneration therapies in the future.

Encapsulation and ultrasound-triggered release of G-quadruplex DNA in hydrogel microcapsules

2019 Spring National Meeting

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