Significant interests exist for using oligonucleotides as therapeutic agents, which face several biopharmaceutical difficulties, including stability and delivery issues, and sequence- and/or chemical structure-specific, non-hybridization activities, such as coagulopathies and stimulation of the immune system. These difficulties have been in part overcome by chemical modification of the oligonucleotide backbone or by using delivery systems (oftentimes polycationic structures), which enhance nuclease stability and improve delivery efficiency. However, these approaches either give rise to new challenges (e.g. toxicity and immunogenicity), or cannot adequately address all of the negative aspects. Therefore, a system that can improve nuclease stability, preserve target-binding capability, minimize all off-target effects, and improve biodistribution is still very much sought after. Our preliminary studies have demonstrated that ?compaction? of DNA can be achieved by inserting it into a high-density brush polymer environment, which enables the DNA to bind selectively to a complementary DNA strand, while access by various proteins is limited. The binding of DNA with proteins such as nucleases, toll-like receptor 9, and thrombin is generally the first step to non-hybridization side effects. Therefore, the brush polymer- DNA conjugates should bypass many of the side effects of oligonucleotides and has the potential to be applied to essentially all forms of oligonucleotides, i.e. antisense DNA, siRNA, microRNA, aptamers, ribozymes, etc., to improve their biopharmaceutical characteristics. The outcome of this study would be a new class of biocompatible and non-immunostimulatory oligonucleotide-based gene therapy agents, and a fundamental understanding of how its molecular parameters can impact its in vivo and in vitro properties.
Unlike other biologics such as antibodies and insulin, nucleic acids have inherently unfavorable biopharmaceutical properties due to specific and non-specific binding with proteins (enzyme stability, immunostimulation, coagulopathy, etc), which hamper their development as therapeutic agents. Here, we propose a novel mechanism for nucleic acid protection and delivery, termed polymer-assisted compaction of DNA (pacDNA), which facilitates duplex formation but disfavors protein recognition (generally the first step to undesirable non-hybridization side effects). We will investigate and understand the molecular parameters that differentiate pacDNA from molecular DNA, probe its in vitro characteristics, and demonstrate efficacy against drug-resistant cancer in vivo.
|Li, Hui; Zhang, Bohan; Lu, Xueguang et al. (2018) Molecular spherical nucleic acids. Proc Natl Acad Sci U S A 115:4340-4344|