Utilization of Nucleobase Interactions to Develop Supramolecular: Polymer Hybrid as Biocompatible Mimics and Delivery Systems

Faculty: Dr. Candace Lawrence

This project will be used to examine synthetically modified nucleic acids (nucleobases) polymer hybrids in higher order hydrogen-bonded supramolecular polymer networks.  There are several motivations for developing synthetically modified nucleobases as hydrogelator: polymer blends.  First, we want to exploit the self-aggregation of small molecular nucleobases (guanosine, inosine, deazaguanosine, diaminopurine, and isoguanosine) appended to polymer backbones, either in homogenous or in heterogeneous combinations, to study the optimal pH and salt concentration needed to stabilize each polymer hybrid.  Secondly, we want to determine which biologically relevant polymers (polyamines, polyesters, polyhexamethacrylates, polyazides, and polyethylene glycols) would enable us to develop optimal drug delivery carriers and biocompatible tissue mimics.
In the last several decades, nucleobases and biocompatible polymers that exploit the self-aggregation or self-assembly have produced a number of “smart-materials”.  This has led to some interesting developments in the fields of biomaterials, sensors, and stimuli-responsive materials.  Many of these systems adapt to their environment via their added benefit of utilizing supramolecular forces that provide a panoply of motifs.  Most of the proposed systems here will be based on the formation of nucleobase quartets, which can be used to develop biologically compatible hydrogels.  The formation is commonly driven by various factors such as cross-linking or supramolecular assembly.
The first systems we are exploring are utilizing guanosine, which is known to form so-called G-quartets in the presence of sodium (Na+) or potassium (K+) through hydrogen bonds that use both the Watson-Crick and Hoogsteen faces of the nucleobase.  When G-quartets stack upon one another in the presence of sodium or potassium, they form higher order structures called G-quadruplexes, which form subsequent hydrogels.  However, guanosine, as found in its natural form, does not maintain a gel-like consistency for an extended period of time (guanosine gels will crystallize approximately after ten minutes).  Former collaborative efforts with the Stuart Rowan group at Case Western Reserve University have shown that a small change at the 8-position of guanosine by using a vinyl group has stabilized guanosine gelation. 
The first of many goals is to study the limits of the bulkiness of the group at the 8-position; it is uncertain to what extent gelation is hindered by group size.    Designs using more bulky substrates at the 8-position have been shown to stabilize the g-quartet even without the presence in Na+ or K+ media.  To complement the gelation studies of guanosine, we will explore other purines, including, but not limited to, inosine, 3-deazaguanosine, and 7-deazaguanosine.  Inosine quartets would enable us to determine the importance of the exocyclic amine in quartet formation, while the use of 7-deazaguanosine would be used to determine if a four-point hydrogen-bonded quartet would be stable with a bulky substrate at the 8-position.  While both inosine and deazaguanosines are non-natural nucleobases, they both exhibit anti-cancer properties by disrupting replication pathways and can provide for an additional drug delivery or antiviral component when appended to polymer backbones.
Our second goal is to functionalize the ribose sugar hydroxyl groups in an effort to copolymerize the nucleobases to covalent polymer backbones.  Copolymerization methods with the nucleobases seem inevitable for the ability to control many physical and chemical properties desired in hydrogel drug delivery systems and biocompatible tissue mimics.  Most mixed polymers can occur from copolymerization methods using azide, alkynyl, and vinyl functionalized nucleobases since modification at the 5¢-position (on the ribose sugar) has been widely studied.
In an effort to utilize substrates for the use of hydrogels to copolymerize with covalent polymers and that would be a good candidate for polymerization techniques, efforts will focus on vinyl substrates, which are known to polymerize via radical polymerization methods.  For water-soluble polymers, the focus will be on appending vinylnucleobases to other polymers, such as hydroxyethylmethacrylate, ethylene glycol, and ethylene oxide.
Additionally, keeping the concentration of the research on the development of copolymers, nucleobases containing ethynyl or azide functionalities are good candidates to undergo Click reactions.  Azide polymers have shown a wide array of properties, including the ability to form micelles, biocompatible prosthetic implants, antivirals, and antibacterials.  Starting azide polymers such as 6-azidohexyl methacrylate and glycidal azide polymers and their properties have been extensively studied and used as precursors for Click reactions.  Therefore, it is conceivable that these two starting polymers can be advantageous for the Click reactions utilizing synthetically modified nucleobases.
Designing several nucleobase: polymer systems is extremely advantageous to the development of biocompatible mimics.  By utilizing nucleobases, we can control the various hydrogen-bonding interactions and motifs to develop smart materials that can respond to their environments.  To control length, size, and physical properties, we will benefit from the use of different biocompatible polymer backbones.   By combining the many properties of polymeric materials with the tunability of hydrogen-bonded nucleobases, we can design a very tailored material to a variety of certain targeted areas and functionalities.

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