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A Combined Computational and Experimental Investigation of Polynucleotide Binding Polymers for Therapeutic Applications Open Access


Other title
Antithrombotic polymers
Molecular dynamics simulations
Nucleic acid binding polymers
Gene therapy
Short interfering RNA
Type of item
Degree grantor
University of Alberta
Author or creator
Meneksedag Erol, Deniz
Supervisor and department
Uludag, Hasan (Deparment of Chemical and Materials Engineering, Department of Biomedical Engineering)
Tang, Tian (Department of Mechanical Engineering, Department of Biomedical Engineering)
Examining committee member and department
Brown, Alex (Department of Chemistry)
Choi, Phillip (Department of Chemical and Materials Engineering)
Liu, Yaling (Department of Mechanical Engineering & Mechanics, Bioengineering Program, Lehigh University)
Unsworth, Larry D. (Department of Chemical and Materials Engineering)
Department of Biomedical Engineering
Department of Chemical and Materials Engineering

Date accepted
Graduation date
2017-11:Fall 2017
Doctor of Philosophy
Degree level
Polynucleotide binding polymers have a wide range of therapeutic applications including delivery systems for therapeutic polynucleotides, and antithrombotic drugs for extracellular nucleic acid-mediated thrombogenic events. This dissertation explores polynucleotide binding polymers in these two avenues, with combined computational and experimental approaches. Particular emphasis was placed on computational studies to probe structural features of polymers and polymer-polynucleotide complexes at the all-atom level. The first line of studies in this dissertation explored polymers employed in the delivery of short interfering RNA (siRNA), a synthetic polynucleotide capable of silencing the overly-expressed genes in malignant cells. Particularly, polymer design and dynamics of polymer-siRNA complex formation, structural features of polymer-siRNA complexes for enhanced functional performance, and the effect of anionic substances of the physiological milieu on polymer-siRNA complex integrity were investigated. The results demonstrated that there exists a hydrophobic-hydrophilic balance in designing siRNA delivery systems, determining the functional performance of the resulting complexes. Polymer-siRNA complexes were found to accommodate the presence of other polynucleotides in their periphery without losing their integrity; however, they experienced a vast variety of conformational states in the presence of heparin, a sulfated glycosaminoglycan found on cell membrane and extracellular milieu. Our efforts to investigate the polynucleotide binding polymers designed to arrest the prothrombotic activity of DNA revealed the importance of polymer structural design; self-interacting polymers exhibited poor DNA binding, which could be detrimental for their functional antithrombotic performance. This dissertation demonstrated the proof-of-concept for employing computational approaches in conjunction with experimental studies where applicable, in efforts to develop “better” polymer therapeutics for different applications.
This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for the purpose of private, scholarly or scientific research. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.
Citation for previous publication
Meneksedag-Erol D, Tang T, & Uludağ H (2014) Molecular Modeling of Polynucleotide Complexes. Biomaterials 35: 7068-7076.Meneksedag-Erol D, Sun C, Tang T, & Uludağ H (2014) Molecular Dynamics Simulations of Polyplexes and Lipoplexes Employed in Gene Delivery. Intracellular Delivery II, Fundamental Biomedical Technologies, eds Prokop A, Iwasaki Y, Harada A (Springer Netherlands), Vol 7, pp 277-311.Meneksedag-Erol D, KC RB, Tang T, & Uludağ H (2015) A Delicate Balance When Substituting a Small Hydrophobe onto Low Molecular Weight Polyethylenimine to Improve Its Nucleic Acid Delivery Efficiency. ACS Appl. Mater. Interfaces 7: 24822−24832.Meneksedag-Erol D, Tang T, & Uludağ H (2015) Probing the Effect of miRNA on siRNA−PEI Polyplexes. J. Phys. Chem. B 119: 5475−5486.

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