Abstract
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. However, freely administered nucleic acids of any type are quickly destroyed or rendered inert by a host of defense mechanisms in the body. In this work, we address the challenge of using nucleic acids as drugs by preparing stimuli responsive poly(methacrylic acid)/poly(N-vinylpyrrolidone) (PMAA/PVPON)n multilayer hydrogel capsules loaded with ~7 kDa G-quadruplex DNA. The capsules are shown to release their DNA cargo on demand in response to both enzymatic and ultrasound (US)-triggered degradation. The unique structure adopted by the G-quadruplex is essential to its biological function and we show that the controlled release from the microcapsules preserves the basket conformation of the oligonucleotide used in our studies. We also show that the (PMAA/PVPON) multilayer hydrogel capsules can encapsulate and release ~450 kDa double stranded DNA. The encapsulation and release approaches for both oligonucleotides in multilayer hydrogel microcapsules developed here can be applied to create methodologies for new therapeutic strategies involving the controlled delivery of sensitive biomolecules. Our study provides 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.
Highlights
Nucleic acids are the universal biological code and dictate the essential processes in all organisms.Owing to their biological relevance, thorough characterization including everything from fundamental structural studies [1,2] to their potential use in a variety of applications has been reported [3,4,5].In recent years, the delivery of therapeutic nucleic acids to modify gene expression has emerged as a promising therapeutic method for a range of inherited or acquired diseases [6,7,8]
We demonstrated in a recent study that increasing the molecular weight of PVPON within cross-linked PMAA multilayer hydrogel films obtained by spin-assisted multilayer assembly decreases the ability of the PVPON to be released from the network after the pH is increased above the pKa of PMAA [76]
We have demonstrated that hydrogel capsules made of interpenetrated (PMAA/PVPON) multilayers can be obtained by dipped multilayer assembly of PMAA (Mw = 150,000 Da) and PVPON (Mw = 1,300,000 Da) on porous and solid silica microparticles followed by chemical crosslinking of PMAA [71]
Summary
Nucleic acids are the universal biological code and dictate the essential processes in all organisms.Owing to their biological relevance, thorough characterization including everything from fundamental structural studies [1,2] to their potential use in a variety of applications has been reported [3,4,5].In recent years, the delivery of therapeutic nucleic acids to modify gene expression has emerged as a promising therapeutic method for a range of inherited or acquired diseases [6,7,8]. Nucleic acids are the universal biological code and dictate the essential processes in all organisms. Owing to their biological relevance, thorough characterization including everything from fundamental structural studies [1,2] to their potential use in a variety of applications has been reported [3,4,5]. The delivery of therapeutic nucleic acids to modify gene expression has emerged as a promising therapeutic method for a range of inherited or acquired diseases [6,7,8]. Among the multitude of repeating nucleic acid motifs, the human G-quadruplex sequence has emerged as a potentially relevant key to new therapeutic possibilities [9].
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