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Symposium 2007

Plenary Presentations

  Artificial Chaperones by Stimuli-Responsive Nanogels and Application to Protein Delivery

Kazunari Akiyoshi
Tokyo Medical and Dental University

In the post-genome era, molecular chaperone technology is important in protein science such as in the regeneration of proteins from protein aggregations (inclusion bodies). In living systems, molecular chaperones selectively trap heat-denatured proteins or their intermediates in order to prevent their irreversible aggregations.  Then, with the aid of ATP and another co-chaperone, the host chaperone releases the protein in its refolded form.  Molecular chaperone systems have inspired us to explore new concepts in designing artificial chaperones to assist protein folding and to develop protein delivery in DDS.  To simulate the function of molecular chaperones, an artificial host with a nanocage to bind denatured proteins and the control of the dynamics of catching and releasing proteins are indispensable.   We develop stimuli-responsive nanogels as artificial chaperones.  Tailor-made nanogels and macrogels with well-defined nanostructures were obtained by self-assembly of functional associating polymers.  Nanogels of hydrophobized polysaccharides effectively prevented protein aggregation during protein refolding from heat or GdmCl denaturation.  Enzyme activity recovered in high yields upon dissociation of gel structure, in which the proteins were trapped, by the addition of cyclodextrins. Nanogel-crosslinking hydrogel (artificial chaperone immobilized hydrogels) showed excellent activity for refolding denatured protein. A photo-responsive artificial nanogel chaperone was also designed by the self-assembly of spiropyrane-bearing pullulan.  The concept of molecular chaperon is important to develop new protein delivery system.

Stimuli-Responsive Polymers for Biomedical Applications

Cameron Alexander
School of Pharmacy

Advanced and ‘active’ materials are a major research focus in electronics and construction, and are integral to developments in medicine and biotechnology. New materials are needed with ‘bio-like’ behaviour, such as a response to a stimulus or local environment, but without the disadvantages of biological systems such as poor processability or potential for immune response. Importantly, these novel materials must possess ‘smart’ properties without incurring toxicological problems or environmental penalties. Successful generation of such active or ‘smart’ synthetic polymers will mark a ‘step-change’ in therapeutic delivery technologies and biomedical materials.

 

  Intelligent Manipulation of Free Volume Transitions in Polymer Brushes Grafted by Atom Transfer Radical Polymerization

Paul W. Bohn
University of Notre Dame

Exploiting external stimuli to operate an intelligently switchable molecular gate to control transport has a variety of applications in microfluidic systems. For example, the cylindrical nanochannels of the polymer-grafted membrane can be implemented as an actively-switchable nanofluidic interconnect to establish controllable fluidic communication between micrometer-scale channels operating in different planes of an integrated microfluidic device. We are pursuing the construction and characterization of nanometer-scale analogs of fluidic valves, ratchets and diodes by combining free-volume transitions in network polymers prepared by grafting-from atom-transfer radical polymerization with the nanopores found on the surface of nanocapillary array membranes (NCAMs). On the applications side we have demonstrated actively controlled transport that is thermally-switchable and size-selective in structures prepared by grafting poly(N-isopropylacrylamide) (PNIPAAm) brushes onto the exterior surface of a Au-coated polycarbonate track-etched membrane. To understand the molecular level phenomena supporting this behavior, we are studying single molecule diffusion to characterize the free volume changes in polymer brushes in response to external stimuli. Single molecule tracking is performed on a widefield single molecule fluorescence microscope built specifically for this purpose; the resulting mean-square displacement profiles can be used to determine diffusion coefficients which can then be compared to theoretical models.

 

Graft and IPNs Stimuli-Responsive Polymers, Synthesized by Ionizing Radiation

Guillermina Burillo
Instituto de Ciencias Nucleares

We synthetized different polymeric systems as binary grafting films, comb type hydrogels, and interpenetrating networks of stimuli-responsive monomers, by gamma  or electron beam irradiation, using a Co60 source and a Van de Graaff accelerator respectively.  Different systems with the pair of monomers, acrylic acid (AAc), a pH responsive monomer and N-isopropylacrylamide (NIPAAm), a thermo-responsive monomer were studied, with the objective to enhance velocity of response (limit swelling time), mechanic properties, to conserve reversibility on swelling-deswelling process, and LCST or critical pH point. The pair dimethylaminoethlmethacrylate and vinylpyridine were also studied; a surprising transition corresponding to an upper critical solution temperature (UCST) was found in this systhem.  Another synthesized system with the thermo-responsive PNIPAAm and polyacryloxisuccinimide were sinthesized as interpenetrating networks and some studies about immobilization of lipid vesicles in this last system are in progress.  Different polymeric systems were characterized in their chemical composition by FTIR and elemental analysis, Thermal analysis by DSC and morphology by SEM.

Adjusting Amphiphilic Balance with Temperature in Thermally-responsive Triblock Copolymer Aggregates

Robert B. Grubbs
Dartmouth College

Controlled radical polymerization methods, including nitroxide-mediated radical polymerization, atom transfer radical polymerization (ATRP), and reversible addition-fragmentation chain transfer polymerization, have been used for the preparation of aqueous stimulus-responsive block copolymer assemblies.  Amphiphilic block copolymers designed to assemble in water into aggregates that reversibly change shape and size as a function of temperature have been prepared from poly(ethylene oxide) macroinitiators.  Aspects of the synthesis and characterization of these materials will be discussed, as will potential materials and medical applications.

  Applications of Stimuli-Responsive Polymers in Applied Biocatalysis

M. N. Gupta
IIT Delhi, India

Stimuli-responsive polymers which change their solubility in aqueous media in response to specific stimulus have found a variety of applications in applied enzymology. Techniques like affinity precipitation, aqueous two-phase affinity partitioning and macro- (affinity ligand) facilitated three phase partitioning which use smart polymers have emerged as powerful tools in bioseparation of proteins. Both naturally occurring polymers and synthetic polymers have been used. These bioseparation strategies based upon stimuli-responsive polymers have been used to separate amylase, pullulanase, lipase, chitinase, pectinase, xylanase, alcohol dehydrogenase and lectins.  The second major application has been the design of smart polymer-enzyme bioconjugates which can function as homogenous catalysts and can be recovered for reuse by precipitation by applying the suitable stimulus.  The stimuli-responsive polymers have also emerged as pseudochaperonins. Some examples wherein their addition facilitated protein refolding would be described.  The talk would also mention the applications of these polymers in the areas of tissue engineering, gene therapy and design of molecular gates and valves.

  Atomistic Simulation of Inorganic-Biological Interfaces and Optically Switchable Materials

Hendrik Heinz
University of Akron

The understanding and design of novel materials relies increasingly on modeling and simulation. The availability of physically justified, force-field based models for inorganic components in hybrid materials is still a challenge, and we explain how deviations of several 100% in computed surface energies relative to experiment have been eliminated in energy models for fcc metals and sheet silicates.  The self-assembly of peptides on the surfaces of metallic and layered silicate nanoparticles has been analyzed by simulation to understand experimental results from screening of multibillion phage libraries (TEM, XRD, binding strength, spectroscopy etc). Peptide binding is due to a unique combination of surface geometry (crystal facet, shape) and surface polarity to match complimentary amino acid sequences. Adsorption energies on even Au or Pd surfaces range from 0 to 80 kcal/mol for dodecapeptides (average ca. 6 kcal/mol per amino acid), and the effect of polarization at a Pd−Au bimetallic junction increases the binding energy by about 10 kcal/mol per peptide. On layered silicates surfaces, peptide binding can follow an ion-exchange mechanism (Lys side chains) which can be directly observed in molecular simulation, or involve energetically favorable solvation by superficial sodium in the case of peptides without ion-exchange capability.   Further, the light-induced cis-trans isomerization of azobenzene has been investigated in simulation and experiment to estimate the potential for actuation under confinement in layered silicates, and a method to analyze stress tensors at the nanoscale will be presented.

Responsive Water-Based Formulations

Dominique Hourdet
University of Paris

Poly(N-isopropylacrylamide) [PNIPA] is a very interesting macromolecular tool characterised in water by a Lower Critical Solution Temperature (LCST) close to 32°C. It has been extensively studied and described for instance in the preparation of stimuli-responsive chemical gels with potential applications in the field of drug release. Similarly, the thermodynamic properties of PNIPA can also be used to tailor responsive thickeners able to self-associate in aqueous media under given environmental conditions.  In this presentation, we will describe different responsive systems involving PNIPA moieties. We will focus more specifically on the relation existing between the primary structure of the copolymers, their responsive assemblies in aqueous media and the resulting viscoelastic properties which can be tuned using various triggers like temperature, shear rate, pH and ionic strength or by introducing interacting additives like surfactants or inorganic particles.

  Covalently Bonded Versus Physically Bonded Networks of Microgels

Zhibing Hu
University of North Texas

Monodispersed spheres of polymer microgels have been synthesized using a precipitation polymerization method.  The dispersions of these microgels exhibit various phases such as liquid, crystal, and glass phases, which are functions of polymer concentration, temperature, and cross-linking density. These microgels can be used as building blocks to form three-dimensional microgel networks. Such networks can have a permanent structure if the neighboring particles are covalently bonded. On the other hand, a physical bond between neighboring particles provides a reversible structure.  Specifically, it is found that microgels consisting of polymer interpenetrating networks of poly-N-isopropylacrylamide and polyacrylic acid have a physical bond between the neighboring particles that is thermally tunable. This system exhibits a rich phase behavior including a sol-gel transition at an elevated temperature. Using an animal implantation model, the biocompatibility and drug release properties of this microgel dispersion have been studied.

Novel pH or Thermosensitive Block Copolymers for Triggered Drug-Delivery Systems

Christine Jerome
University of Liege, CERM

Over the last decade, polymer micelles and nanoparticles have attracted an increasing interest as efficient drug delivery systems. Polymer micelles from amphiphilic block copolymers are supramolecular core-shell type assemblies of some tens of nanometers in diameter. They are highly stable in aqueous solution because of their low intrinsic critical micelle concentration, which prevents their dissociation upon dilution in the blood stream after intravenous injection.  The combination of poly(ethylene oxide) (PEO) with hydrophobic aliphatic polyesters, such as poly(-caprolactone) (PCL) or polylactide (PLA), allows to prepare stealthy drug nanocarriers (thanks to PEO), which are biodegradable and biocompatible and capable of encapsulating a hydrophobic drug (due to the aliphatic polyester).  In this field, the inclusion of an additional pH-responsive block in the supramolecular assembly is a promising strategy to improve the targeting of tumor tissues by taking advantage of the lower pH at the vicinity of tumor cells.  A variety of novel amphiphilic and pH-sensitive copolymers have been synthesized and tested as building blocks for the design of smart nanocarriers able to expose selectively the targeting unit at the vicinity of tumor. Various macromolecular architectures combining PEO, PCL and P2VP have been accordingly synthesized such as linear and star shape di- and triblock copolymers. Their (co)-micellization has been studied in terms of size, particle shape (DLS, TEM) and stealth behavior.  Besides, thermo-responsive copolymers combining PEO, polyacrylic acid and poly-N-isopropyl-acrylamide have been synthesized and found efficient in stabilizing stealthy magnetic nanoparticles promising for thermally triggered release of drugs during hyperthermia.

 

  Insight into the Growth of Responsive Polymer Brushes via Kinetic Modeling

S. Michael Kilbey, II
Clemson University

Polymer brushes continue to be of significant interest for their ability to confer desired properties to surfaces, and a variety of controlled (free) radical polymerization techniques have been adapted for creating polymer brushes.  This contribution describes our efforts to directly prepare polyelectrolyte (PE) brushes in aqueous solution by surface-confined atom transfer radical polymerization (SC-ATRP) and bi-level brushes of poly(methacrylic acid)-block-poly(N-isopropyl acrylamide) by surface-initiated photopolymerization.  SC-ATRP of PEs in aqueous solution is complicated by several deleterious side reactions that result in loss of control and cessation of polymerization.  Insights gained through kinetic modeling point to an effective strategy for overcoming catalyst loss, enabling “weak” and “strong” PE brushes to be grown with improved control.  In the case of the bi-level brushes made by surface-initiated, photoiniferter-mediated photopolymerization, kinetic modeling suggests useful strategies to better control layer growth and retain functional end-groups.  This imparts the ability to create a bi-level, block copolymer brushes, including stimuli-responsive brushes containing thermo- and pH-responsive blocks.  The swelling response of these systems as functions of pH, temperature and salt concentration will be detailed and compared to the responsive behaviors of other copolymer architectures based on methacrylic acid and N-isopropyl acrylamide.  

  Self-Assembly of Block and Graft Copolymers Mediated by Coiled-Coil Domains

Jindrich Kopecek
University of Utah

Traditional synthetic methods have produced numerous biomaterials with excellent properties.  Hydrogels were the first example rationally designed for biomedical use.  They demonstrated outstanding long-term biocompatibility resulting in clinical applications.  However, these synthetic methods have an inherent deficiency in precise control of primary structure, making it difficult to engineer responsive hydrogels with predetermined properties.  Consequently, novel approaches to hydrogel synthesis need to be developed.  Supramolecular biological structures are often formed through self-assembly of natural polymeric building blocks.  They have several characteristic features: First, the assembly process is highly specific and is mediated by molecular recognition.  Second, it is a stimuli responsive process in which external signals, such as temperature and pH, can trigger or terminate the assembly.  Finally, the assembly and disassembly processes are typically reversible, allowing precise and dynamic control of the structure and properties of materials.  Several examples of self-assembly systems will be provided in which the coiled-coil, one of the basic folding domains of native proteins, was introduced to biological and synthetic macromolecules and anticipated to serve as physical crosslinkers: i) genetically engineered ABA triblock copolymers containing a random coil block flanked by two coiled-coil forming blocks; ii) synthetic N-(2-hydroxypropyl)methacrylamide-based copolymers with coiled-coil forming peptide grafts.  The results indicated that the self-assembly into hydrogels was mediated by coiled-coil domains; the change of peptide sequence has enormous effects on the properties of the products; the stimuli-responsive and reversible systems were rationally designed, and may have potential in tailoring supramolecular structures for drug delivery, tissue engineering, and other biomedical applications.

Artificial Nucleic Acid Chaperone for Boosting DNA-Fueled Nanomachines

Atsushi Maruyama
Kyushu University

For the better applications and developments of DNA nanomachines, their responding kinetics, output, and sequence-selectivity need to be improved.  Furthermore, the DNA nanomachines currently have several limitations in operating conditions. Here we show that a simple addition of a cationic comb-type copolymer, which exhibits nucleic acid chaperoning activity, produces the robust and quick responses of DNA nanomachines under moderate conditions including physiologically relevant conditions even at very low strand concentrations (nanomoles per liter range) through hybrid stabilization and DNA strand exchange acceleration.

  Chemical gating with responsive thin films

Sergiy Minko
Clarkson University

We develop a novel approach to chemical gating exploring switching properties of responsive thin polymer films assembled on an electrode surface. We demonstrate that the morphological transitions in the thin polymer films can be used to open, close or precisely tune permeability of the ion transport channels formed in the nanostructured thin film upon external stimuli – adding or removing signalling chemicals (pH change or binding cholesterol, for example).  The ion transport channels were reversibly closed and opened upon addition and washing out chemicals, respectively. Thus, the electrochemical process of a soluble redox probe, [Fe(CN)6]3-/4-, at the polymer-modified electrode was reversibly switched “ON-OFF” by the cyclic addition and washing out signaling chemicals. The electrochemical reaction was also tuned by the variation of the concentration of the added chemicals that controlled the extent of the channels closing. The switchable and tuneable operation of the chemically-controlled electrochemical gate was characterized by Faradaic impedance spectroscopy and atomic force microscopy, indicating that the extent of the pores opening/closing is controlled by the concentration of the signalling chemicals. We suggest that this approach could find important applications for sensors and devices with tuneable release. 

  Multi-Functional Thin Film Coatings from Polyelectrolyte Multilayers

Michael Rubner
Massachusetts Institute of Technology

The availability of nanoparticles of various materials with a wide range of sizes (from a few nanometers to hundreds of nanometers) opens up new possibilities for creating multifunctional thin film coatings.  Realizing the full potential of these materials however requires processing techniques that enable nanometer-scale control over the placement and arrangement of the nanoparticles.  For example, by controlling the packing of nanoparticles in a thin film coating, it is possible to manipulate important parameters such as porosity, refractive index and mechanical durability.  This level of control can be achieved by using layer-by-layer processing schemes involving either nanoparticle/polymer assemblies or all nanoparticle assemblies.  Using this approach, we have created thin film coatings with tunable refractive indexes (from about n= 1.8 to 1.2) and extreme wetting behavior. Both superhydrophobic and superhydrophilic coatings have been realized by controlling surface texture and chemistry at the nano- and microscale.  In the case of the superhydrophilic coatings, nearly instantaneous water wetting is observed as well as uniform water sheeting across the surface during drying.  Current efforts to develop coatings that exhibit stimuli-responsive capabilities will be discussed.

  Smart Biohybrid Materials That Talk and Listen in Nanospace

Patrick S. Stayton
University of Washington

“Smart” materials can reversibly change their structural and physical-chemical properties in response to environmental signals.  Our group has been interested in developing biohybrid materials that bring together “smart” polymers and biomolecules for biotechnology applications.  The physical transitions of the synthetic polymer can be triggered reversibly by small changes in pH, temperature, or light, and we use the transitions to “talk” to the corresponding biomolecular component.  In a first example, we have developed new pH-responsive polymeric carrier systems for biomolecular drugs such as proteins and nucleic acids.  These polymers reversibly display membrane-destabilizing activity in response to small pH changes around physiological pH, and mimic the intracellular transport enhancing activity of viruses and pathogens.  Our synthetic carriers have been used to enhance protein and nucleic acid delivery, and potentially open the pharmaceutical use of new categories of biomolecular drugs.  In a second example, we have developed new smart reagents for performing diagnostic sample processing and assays in lab-on-a-chip microfluidic cards.  These systems are being developed for global health applications that run diagnostic panels for infectious diseases in resource-poor distributed settings. 

  Responsive Hydrogen-Bonded Films and Capsules

Svetlana Sukhishvili
Stevens Institute of Technology

The role of hydrogen-bonding and electrostatic interactions in self-assembly and response of multilayer polymer films to environmental stimuli will be discussed. The polymer films or capsules are produced by sequential self-assembly of water-soluble hydrogen-bonding polymers at a surface of a solid substrate. The amount of polymers adsorbed, the degree of ionization of carboxylic groups within the multilayers and the fraction of hydrogen bonds are quantified by in situ Fourier transform infrared spectroscopy in attenuated total reflection (FTIR-ATR), and the degree of interpenetration of polymer layers is measured by neutron reflectivity. Variation of the nature of polymeric hydrogen-bonding components, as well as the conditions for chemical cross-linking afford surface-attached polymer films and polymer capsules, whose pH response characteristics can be tuned in a wide pH range. Such surface-attached films or hollow capsules are capable of absorbing/encapsulating, and then releasing a wide variety of functional materials ranging from low molecular weight organic to biological molecules in response to environmental stimuli.   

  Stimuli-Responsive Materials Prepared by Orthogonal End Group Modification of Well-Defined Macromolecules

Brent S. Sumerlin
Southern Methodist University

Combining the beneficial characteristics of recently improved small molecule synthetic techniques with the ability of controlled radical polymerization (CRP) to tailor polymers with specific macromolecular features affords a variety of precise synthetic tools to prepare functional polymeric materials.  Due to the plurality of functional groups available in diverse copolymers, postpolymerization modification methods should be not only efficient, but also highly specific.  The copper-catalyzed coupling of azides and terminal alkynes has shown particular promise as a means to prepare functional polymeric materials and has been included in the class of reactions commonly called “click chemistry.”  We have prepared a range of advanced macromolecular architectures by these methods, including macromonomers, polymer brushes, biologically-functional block copolymers, and temperature-responsive hyperbranches.  This presentation will discuss the recent advances made in these efforts, with particular attention given to materials that are responsive to temperature and glucose concentration.

  Responsive Polymers and Their Biological and Drug Release Applications

Heikki Tenhu
University of Helsinki

Water soluble and amphiphilic polymers may respond to various stimuli in aqueous solutions. Changes in the dimensions or the degree of aggregation may find use in several applications.Thermally responsive polymers like poly(N-isopropylacrylamide), PNIPAM, poly(vinylcaprolactam), PVCL, and poly(vinylmethylether), PVME, have been extensively investigated during the last decade. These polymers dissolve in cold water but phase separate upon increasing temperature at a certain critical temperature. Polymers either precipitate or, in very dilute solutions, form colloidally stable particles. Crosslinked polymers (gels) collapse upon heating at the critical temperature but reswell upon cooling. PVCL microgel particles, for example, may find use as drug carriers and in controlled drug release. For this application it is beneficial to stabilise the particles against coagulation.  Polyelectrolytes respond to changes of pH and ionic strength. As an example, the synthesis and properties of amphiphilic star diblock copolymers will be described. In these stars, the outer block of the arm is a polyelectrolyte whereas the inner one is hydrophobic. Aggregation and self assembling of these polymers is affected by the number of arms, as well as by changes in the solvent composition.

Assembling Polymeric Materials for Environmentally Responsive Structures

Vladimir Tsukruk
Georgia Institute of Technology

The talk is focused on recent developments in my research group on designing, fabrication, and characterization of nanostructured polymeric materials responsive to external stimuli (temperature, chemicals, and air pressure). I will summarize our recent progress on free standing flexible nanocomposite structures fabricated with spin-assisted layer-by-layer (LbL) assembly and bimaterial microcantilevers.  In the past years, we expanded our efforts towards new types of flexible freely-standing structures with encapsulated uniform and patterned gold nanoparticles, carbon nanotubes, silver nanowires, and quantum dots as well as 3D sculptured LbL films. Examples of structures with ultrathin polymer coatings responsive to temperature, humidity, chemical vapors, and  air pressure will be demonstrated.               

  New Surface Switching and Bioactive Coatings using Co-Polyoxetane Soft Blocks

Kenneth J. Wynne
Virginia Commonwealth University

Co-polyoxetane telechelics may be represented as P(AB), where A and B are repeat units with differing side chains. These telechelics are incorporated into polyurethanes and used as polymer surface modifiers. As an example, polyurethanes were prepared with alkylammonium side chains in the soft block and used as polymer surface modifiers for a conventional polyurethane. First, random copolymer 1,3-propylene oxide telechelics having segments with alkylammonium bromide and either semifluorinated or PEGlyated side chains were prepared. Alkylammonium telechelics were introduced as soft blocks in polyurethanes using conventional polyurethane chemistry. At 2wt% in a conventional polyurethane, two of the modifiers effect 100% kill of a 10^7 CFU/ml aerosol challenge of both Gram negative and Gram positive bacterial pathogens in 30 min. The effectiveness of the new PSMs may be due in part to surface nano-topology and spatial distribution of alkylammonium groups mimicking naturally occurring biocidal peptides such as the magainins and cecropins. As time permits, other co-polyoxetane surface science will be discussed including human cell compatibility, contraphilic wettting, and progress toward ultrahydrophobic behavior.

  Responsive Nanoporous Organic-Inorganic Colloidal Materials

Ilya Zharov
University of Utah

I will describe our work on the preparation and study of nanoporous colloidal films and membranes that form via self-assembly of nanoscale-sized silica spheres into a close-packed face-centered cubic lattice and contain highly ordered arrays of three-dimensional interconnected pores 5-100 nm in size.  We modify the surface of colloidal nanopores with organic moieties that can non-covalently interact with ions and molecules, and whose charge and shape respond to external stimuli, such as pH or light.  As a result of the surface modification, we are able to control the molecular transport through the colloidal nanopores, either by tuning the nature and strength of the non-covalent interactions or by changing the environmental conditions.  I will address fundamental problems of controlling the molecular transport through nanoscale-sized artificial pores and will discuss application of responsive colloidal materials in drug delivery, separations, sensing and fuel cells.

 

School of Polymers and High Performance Materials
Shelby F. Thames Polymer Science Research Center
University of Southern Mississippi
118 College Drive # 5050, Hattiesburg, MS 39406
allena.moses@usm.edu
Ph: 601-266-6868 Fax: 601-266-4216