Toward Modeling Thermoresponsive Polymer Networks: A Molecular Dynamics Simulation Study of N-Isopropyl Acrylamide Co-oligomers Ester Chiessi,* Alice Lonardi, and Gaio Paradossi Dipartimento di Scienze e Tecnologie Chimiche, UniVersity of Rome Tor Vergata, Via della Ricerca Scientifica I, 00133 Rome, Italy ReceiVed: December 28, 2009; ReVised Manuscript ReceiVed: April 30, 2010 Polymer microgels of poly(vinyl alcohol)/poly(methacrylate-co-N-isopropyl acrylamide) showed a thermo- responsive behavior, suitable for application in drug delivery (Biomacromolecules 2009, 10, 1589). In this work molecular dynamics (MD) methods were used to explain which structural aspects are determining for thermoresponsivity and how water properties in the hydrogel are influenced. Two topologically different models of the junction domain in the hydrogel at the experimental hydration degree were studied at 293 and 323 K, below and above the transition temperature. MD simulations of the corresponding oligomers of poly(N- isopropyl acrylamide) were also performed for a comparison. Simulation results provided an atomic detailed description of the temperature induced modifications in the microgel network and of water dynamics, in agreement with available experimental findings. 1. Introduction In the last decades, a large research effort has been devoted to exploit the peculiar properties of soft matter in biomedical applications 1-4 and, in this context, several studies have been reported about the development of microgels based on biocom- patible polymer matrixes for controlled drug delivery. 3,5,6 One of the most valuable requirements in these systems is the capability to modify properties such as hydration degree, internal texture, specific surface as a function of external stimuli, such as a change in temperature, pH, and ionic strength. 7 Polymer residues with ionizable groups can impart a sensitivity to pH and/or ionic strength, 8-10 whereas the sensitivity of the network to temperature in water is obtained with amphiphilic polymers, when the balance between hydrophilicity and hydrophobicity can be modulated by temperature. In the latter systems, the polymer-solvent interaction is thermodynamically favorable for temperatures lower than an intrinsic lower critical solution temperature (LCST), and under this value a relaxed solvated conformational state is preferred. When the temperature exceeds the LCST, the polymer-polymer interactions become preferable, and the chains collapse in a coiled state. This behavior is shown in aqueous environment by a few polymers, such as poly(oxy- ethylene) in dilute solution, 11,12 poly(vinyl methyl ether), 13 hydroxypropyl-cellulose, 14 and more complex macromolecular systems, such as pluronic triblock copolymers composed of poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene ox- ide). 15 An example of LCST-type phase separation in non aqueous solvent is provided by poly(benzyl methacrylate) in hydrophobic ionic liquids. 16 However, among the thermosen- sitive polymers, the poly-N-isopropyl acrylamide (p(NIPAAm)) is undoubtedly the most studied. 17 The volume phase transition of linear p(NIPAAm) as a function of temperature, known since the 1960s, 18 is evidenced in aqueous solutions with an increase of the turbidity eventually followed by precipitation at around 307 K, the p(NIPAAm) LCST. 17 A large number of papers continues to be published in the scientific literature, both on the experimental characterization of the volume phase transition 19-25 and on the development of complex polymer systems based on p(NIPAAm) for several applications. 26-28 In this outline, the leading idea to obtain an injectable polymer microdevice for a targeted and controlled drug release guided us to synthesize novel temperature-sensitive hydrogel micro- particles of poly(vinyl alcohol)/poly(methacrylate-co-N-isopro- pyl acrylamide) (PVA-MA-NIPAAm). 6 In PVA-MA-NIPAAm microgels, the polymer scaffold forms a chemically cross-linked network with a residue composition PVA:MA:NIPAAm of 20: 1:2.5 and 20:1:4, depending on the synthesis conditions, and a maximum hydration degree of about 90% (w/w) at room temperature. 6 Dynamic light scattering experiments showed an abrupt volume decrease of about 50% moving from 293 to 320 K for the microparticles with the highest content of NIPAAm and this temperature triggered shrinking can be used for an enhanced drug release at physiological temperature. 6 The rationale behind the sensitivity to the temperature of the PVA-MA-NIPAAm microgel particles resides in the incorpora- tion of oligo-N-isopropyl acrylamide sequences inside the covalent polymer scaffold, assuming that the network regions containing the N-isopropyl acrylamide residues maintain the thermosensitivity of p(NIPAAm). The transition from a relaxed, swollen state to a collapsed state of the polymer chains including NIPAAm should therefore determinate the deswelling of the microgel at a temperature near to the p(NIPAAm) LCST. The aim of the present investigation is to support this hypothesis with a description at a molecular level of the network behavior and of the polymer-water interaction, in view of an optimization of the structural and dynamical properties of the system as a device for controlled drug delivery. A simulation study of the PVA-MA-NIPAAm hydrogel has, moreover, an intrinsic inter- est, since it tackles aspects ranging from the modulation of hydrophilic/hydrophobic character of a polymer matrix by temperature and residue composition, to the polymer-induced modifications on the structure and dynamics of water. We approached the problem by molecular dynamics (MD), a consolidated tool in the study of protein dynamics and, in recent years, also used for simulating polymer systems, both in bulk and in solution. 29-35 A few MD simulations of poly(vinyl * Corresponding author. E-mail: ester.chiessi@uniroma2.it. J. Phys. Chem. B 2010, 114, 8301–8312 8301 10.1021/jp912209z  2010 American Chemical Society Published on Web 06/03/2010