Research Interests
Statistical physics of macromolecules, computer modeling and statistical analysis of associating, supramolecular, biocompatible, hydrogen bonded, and water-soluble polymers (their properties and applications for biomimetics and drug delivery); nanoparticle targeting for drug delivery and drug release; ligand-cell receptor interactions; nanoparticle–surface interactions under flow fields; phase behavior of complex polymer and biopolymer systems; polymer micelles (at thermodynamic equilibrium and micellization kinetics including the incorporation of hydrophobic materials); supramolecular polymers and biopolymers at surfaces and interfaces.
Overview of Research
Reversibly Associated Self-Healing polymers in the bulk and at surfaces.
Recent progress in supramolecular chemistry has made available a new class of polymers based on noncovalent interactions that combine the properties of traditional synthetic polymers with the versatility of biomolecules. The self-healing nature and responsiveness of these polymers to temperature, external fields, etc. implies a large range of potential applications in the general area of “smart materials” or in devices that effect energy, electron or ion exchange. Taking into account that noncovalent association is the central element of the “nature” of supramolecular polymers, their properties are ruled by the principles of self-assembly to a much larger extent than for traditional chemically bonded polymers. We use Monte Carlo simulations along with a mean-field approach to study self-assembly of head-to-tail associating polymers in the bulk and on surfaces and to understand the effects of the energy of association, concentration, orientational specificity of reversible complexes, oligomer length, rigidity and temperature on the properties of the system.
Our simulation and analytical results show that an increase of orientational specificity of reversible bonding (or an increase in rigidity of spacers) decreases the degree of association and molecular weight and leads to the suppression of small rings. As a result the ring-chain crossover concentration (i.e., the concentration at which the number of reversible bonds in chains and rings coincide) decreases and exhibits a maximum as a function of oligomer length. With a decrease in the energy of reversible association or increase in temperature the ring-chain crossover shifts to lower concentrations and in some concentration range (corresponding to ring-dominated regime at low temperature) the molecular weight can increase with an increase of temperature before it exhibits a maximum. Our model allows us to predict the corresponding range of concentrations and temperatures when this anomalous temperature-driven increase in molecular weight can be observed. We show that higher orientational specificity of association in combination with a short spacer length ensures a larger value of the molecular weight at its maximum.
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Typical configuration for head-to-tail reversibly associated polymers red arrow: linear chain; blue arrow: ring (left). The temperature dependence of the average degree of polymerization (DP) for head-to-tail associating polymers for different concentrations and the range of concentrations where a maximum of DP with increasing temperature can be observed. (right). |
One of the recent interesting developments in experimental characterization of reversibly associated polymers is the application of atomic force microscopy (AFM) techniques to study the behavior of these polymers end-grafted to surfaces. Using Monte Carlo simulations to study reversible end-adsorption of head-to-tail associating polymers on a surface containing adsorption sites, we found that the chain length distribution for adsorbed polymer follows a similar exponential dependence as in the bulk, except for an enhancement of short chains in the distribution. We predict that up to a certain density of adsorption sites the fraction of occupied sites on the surface remains nearly constant, whereas the chain length continuously decreases to avoid stretching. At the same time the average height of the polymer layer adsorbed from concentrated solutions increases due to chain orientation in the direction perpendicular to the surface.
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Schematic presentation of end-adsorbed head-to-tail associated polymers (left). The average height of end-adsorbed layer of head-to-tail associated polymers as a function of adsorption site density and polymer bulk concentration. (right) |
Polymers for biomedical applications
In recent years, polymer micelles have received significant attention as a promising nanomedicine platform
for pharmaceutical delivery. Despite their considerable therapeutic promise, many aspects of micellar drug delivery remain to be fully characterized and understood. Among them, the release behavior of the drug from micelles is of extreme importance for drug bioavailability and efficacy. In our joint theoretical-experimental study with Prof. Jinming Gao’s group (UT Southwestern Medical Center) we have shown that different core materials have considerable influence on the drug release kinetics: the more hydrophobic poly(e-caprolactone) PCL core showed slower drug release rates compared with the less hydrophobic poly(D,L-lactide) PLA core. Utilizing mathematical solutions of both Higuchi’s model and Fickian diffusion equations we found that the neutral and smaller of the two drugs tested, b-lap, demonstrated faster, pH-independent release, suggesting that no substantial changes occurred in either micelle core at lower pH. In contrast, the release rate of doxorubicin (DOX) was found to noticeably increase at lower pH with a larger cumulative amount of drug released. Our molecular dynamic calculations also indicated large degree of hydrogen bonding between DOX and PCL.
Among synthetic polymers there has been special interest in biocompatible polymers, such as PEO, PAA (polyacrylic acid) and PVP (polyvinylpyrrolidone). These polymers are water-soluble due to extensive hydrogen bond formation with water. In addition, PEO inhibits protein adsorption. These properties make biocompatible polymers the best candidates for biomedical applications. For that reason understanding the behavior of these polymers in aqueous solutions is very desirable. Applying a statistical mean field-like approach which describes the competition of PEO and water as proton acceptors in hydrogen bond formation, we were able to predict the temperature and concentration dependence of the average fraction of hydrogen bonds between PEO and water and calculate the phase diagram for PEO in aqueous solutions using experimentally reported data for the energy and entropy of association. We achieved very good quantitative agreement with most of the experimental data reported, in particular reproducing the closed loop regions of phase coexistence. Comparing the critical points (UCST and LCST) for PEO chains terminated by different end groups we found that while all curves merge in the long chain limit (N > 300 for LCST and N > 500 for UCST), for shorter chain lengths curves deviate from each other considerably, reaching double critical points (where the UCST merges with the LCST) at different N. Termination of PEO by one hydroxyl group improves the solubility of PEO chains to an extent that it is equivalent to decreasing of chain length by 10 monomer units and adding a second hydroxyl group doubles the effect.
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Comparison of predicted (line) and experimental (points) phase diagram for PEO in water showing the upper- and lower critical solution temperatures for the phase diagram for different degrees of polymerization. |
Current Activity
Targeting in drug delivery
Targeted gene and drug delivery
holds great potential for the successful treatment of many deadly diseases. Whereas many studies provide rather positive results of targeting, there is also a range of problems encountered in specific targeting (such as shielding of the targeting functional groups by the protective polymer layer). To improve the targeting efficiency a more careful consideration of the factors influencing the distribution and binding capability of ligands attached to hydrophilic chains is required. Computer modeling has proved to be an effective tool in studying various factors influencing complex behavior of polymers tethered to surfaces and receptor-ligand interactions. Using Monte Carlo simulations we study the influence of ligand and polymer layer architecture on efficiency of receptor targeting on a cell surface. Simulations of receptor binding show a high efficiency of receptor targeting by multivalent ligands and bidisperse polymer layers, which should be carefully designed to reflect the properties of cell surface containing receptors. The concepts of multivalent ligands and a bidisperse protective polymer layer each have their own advantages, which can be combined for an enhanced targeting effect.
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Schematic representation of polymer nanoparticle functionalized with monovalent or tetravalent ligands (left). The absolute value of the equilibrium free energy of binding for monovalent and tetravalent ligands in monodisperse and bidisperse protective layers (right). |
Metallo-Supramolecular networks
Supramolecular polymers have attracted considerable interest during the past decade for their exceptional self-healing properties based on noncovalent interactions and a wide range of potential applications. Versatile metallo-supramolecular networks have been synthesized with various mechanical, chemical and stimuli-responsive properties that can be easily tailored by fine tuning the molecular architecture, thermodynamic and kinetic stability by choosing appropriate metal–ligand pairs. The rational design of the supramolecular networks requires a full understanding and exploration of the underlying interconnection between molecular components and the resulting bulk material's properties. Computer simulation and theoretical modeling represent highly efficient tools to investigate the microscopic details and analyze the underlying mechanism of polymerization and gel formation. Using a combined computer simulation and theoretical modeling approach we predict the fraction of 1:1, 2:1 and 3:1 ligand–metal complexes, molecular weight distribution and the average molecular weight as a function of oligomer concentration, and metal-to-oligomer ratio. We found that network formation occurs in a limited range of metal-to-oligomer ratios at sufficiently large oligomer concentrations. At oligomer concentrations slightly exceeding the onset of network formation growth occurs by means of incorporation of sol molecules into the dangling parts of the network. We show that the average molecular weight between effective crosslinks decreases with oligomer concentration and reaches its minimum at the stoichiometric composition, where the high-frequency elastic plateau modulus approaches its maximal value. The value of the latter can be strongly influenced by the metal/oligomer ratio and oligomer concentration, as showed on the accompanying diagram.
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Schematic representation of metallo-supramolecular network (left) and the predicted elastic plateau modulus of the network as a function of oligomer concentration and metal/oligomer ratio (right). |
Recent Publications
M. Hagy, S. Wang, E. E. Dormidontova Tuning Architectures of Ligand-Terminated Polymer Layers to Achieve Specific Targeting, Langmuir (accepted)
S. Wang, C-C. Chen, E.E. DormidontovaReversible Association and Gelation in 3:1 Ligand-Metal Polymer Solutions, Soft Matter (in press) DOI: 10.1039/b802839g
D. Sutton, S. Wang, N. Nasongkla, J.Gao, E.E. Dormidontova, Doxorubicin and b-lapachone Release and Interaction with Micelles Core Materials: Experiment and Modeling, Experimental Biology and Medicine 232, 1090-1099, 2007
M. Hagy, C.-C .Chen, E.E. Dormidontova The Effect of Orientational Specificity of Complexation on the Behavior of Supramolecular Polymers: Theory and Simulation,
Macromolecules 40, 3408 – 3421,2007
C.-C. Chen, E.E. Dormidontova Monte Carlo Simulations of End-Adsorption of Head-to-Tail Reversibly Associated Polymers, Macromolecules 39,9528-9538, 2006
Reidar Lund; Lutz Willner, Dieter Richter, E.E. Dormidontova Equilibrium Chain Exchange Kinetics of Diblock Copolymer Micelles: Tuning and Logarithmic Relaxation, Macromolecules, 39, 4566-4575, 2006
C.-C. Chen, E.E. Dormidontova Architectural and Structural Optimization of Protective Polymer Layer for Enhanced Targeting, Langmuir, 21,5605-5615, 2005
C.-C .Chen, E.E. Dormidontova Supramolecular Polymer Formation by Metal-Ligand Complexation: Monte Carlo Simulations and Analytical Modeling JACS, 126, 14972-14978, 2004
E.E. Dormidontova The Influence of Terminal Groups on Phase Behavior and Properties of PEO in Aqueous Solutions Macromolecules, 37, 7747-7761, 2004
C.-C. Chen, E.E. Dormidontova Ring-Chain Equilibrium in Reversibly Associated Polymer Solutions: Monte Carlo Simulations Macromolecules, 37 (10), 3905-3917, 2004
Recent Presentations
Optimization of Nanoparticle Architecture for Enhanced Targeting in Drug Delivery, presented at Particles 2008 (Particle Synthesis, Characterization, and Particle-Based Advanced Materials), 10-13 May 2008, Orlando, Florida
Theoretical Modeling of Equilibrium Metallo-Supramolecular Gels, at the Symposium on Metal-Containing and Metallo-Supramolecular Polymers and Materials, ACS meeting, August 2007, Boston, USA
Mathematical Modeling of Reversibly Associated Polymers, presented at University of Akron (Department of Polymer Engineering), April 2007
End-adsorption of head-to-tail associating polymers on surfaces, presented at University of Twente, February 2007
Reversibly Associating Polymers: Versatility of Properties and Complexity of Behavior, presented at TU Delft, February 2007
Theoretical Aspects of Nanoparticle Targeting in Drug Delivery, presented at the Nanomedicine Symposium 2006, Dallas, Texas, Dec.11, 2006
Theoretical Modeling of Hydrogen Bonded and Metal-Ligand Associating Polymers presented at the APS meeting, Baltimore, USA, March 13-17, 2006
Theoretical and Computer Modeling of Reversibly Associated Polymers, presented at Georgia Institute of Technology (School of Polymer, Textile and Fiber Engineering) October 2005.
Theoretical Modeling of Phase Separated and Reversibly Associating Polymer Systems, presented at Specialty Minerals Inc., Bethlehem, PA, July 2005
Theoretical and Computer Modeling of Complex Polymer Systems: Associating Polymers and Ligand-Receptor Interactions, presented at John Carroll University (Chemistry Department), December 2004.
Computer Modeling of Targeting Enhancement for Gene/Drug Delivery, presented at the Rolduc Polymer Meeting, Kerkrade, The Netherlands, June 27-30, 2004.
Theoretical insights on reversible associations of polyethylene oxide in aqueous solutions and blends, presented at Max-Planck-Institute for Polymer Research, Mainz, Germany, June 4, 2004
Micellization Kinetics in Diblock Copolymer Solutions, presented at the University of Juelich, Germany, July 4, 2004
Hydrogen Bonding in Aqueous Solutions of PEO: Theoretical Insights, presented at the APS meeting, Montreal, Canada, March 22-26, 2004
Awards
01.2007 – present Climo Professorship for the Case School of Engineering
NSF CAREER Award: “Theoretical Modeling of Head-to-Tail Reversibly Associated Polymers in Solution and at Surfaces”, 2004-2009 |
