RESEARCH PROJECTS

CENTER OF BIOMATERIALS, DRUG DELIVERY, BIONANOTECHNOLOGY AND MOLECULAR RECOGNITION

2009 PhD Research Projects Under the Direction of

Prof. Nicholas A Peppas

Director of the Biomaterials, Drug Delivery and Molecular Recognition Laboratories

Director of National Science Foundation Program on

Cellular and Molecular Imaging for Diagnostics and Therapeutics

Fletcher S Pratt Chair of Chemical Engineering, Biomedical Engineering and Pharmaceutics

CPE 3-466; Phone: 512-471-6644; Fax: 512-471-8227

E-mail:

Web:

Graduate Students Presently Working with Prof. Peppas

(Visit them for more information and the inside story!)

  1. Carolyn Bayer from the Case Western Reserve University, a Thrust Fellow and supported by an NIH grant (started in August 2005, working towards a PhD degree in BME, will graduate in August 2010). CPE room 5.402
  2. Adam Ekenseair from the University of Arkansas, now a NSF Fellow and a Thrust Fellow (started in August 2005, working towards a PhD degree in ChE, will graduate in August 2010). CPE room 3.426
  3. Steve Marek from the Georgia Institute of Technology, now a NIH Research Assistant and a COE Fellow (started in August 2005, working towards a PhD degree in ChE, will graduate in August 2009). CPE room 3.406
  4. Diana Snelling from the Ohio State University, now a NSF Fellow and a Thrust Fellow (started in August 2006, working towards a PhD degree in ChE, will graduate in December 2009). CPE room 3.434
  5. Marty Gran from the Iowa State University, now a Thrust Fellow and a NIH Research Assistant (started in August 2006, working towards a PhD degree in ChE, will graduate in August 2010). CPE room 3.420
  6. Brandon Slaughter from the University of Texas, now a NSF Fellow and a Thrust Fellow (started in August 2006, working towards a PhD degree in BME, will graduate in December 2010). CPE room 3.406
  7. Maggie Phillips from St Louis University, now a NIH Research Fellow and a Cockrell Fellow (started in August 2006, working towards a PhD degree in BME, will graduate in August 2010). CPE room 3.434
  8. Shahana Khurshid from MIT, now a Thrust Fellow (started in August 2006, working towards a degree in BME, will graduate in 2009).
  9. David Kryscio from the University of Kentucky, now a NSF Fellow and a Thrust Fellow (started in August 2007, working towards a PhD degree in ChE, will graduate in August 2010). CPE room 3.420
  10. Bill Liechty from the University of Iowa, now a NSF Fellow and a Thrust Fellow (started in August 2008, working towards a PhD degree in ChE, will graduate in August 2011). CPE room 3.420
Funding

National Science Foundation, National Institutes of Health, Pratt Foundation, Industry

Summary of Work

Over the past 34 years, a distinct strength of our biomedical and polymer engineering research has been the development of novel biomaterials, drug delivery systems, biomedical devices and therapeutic systems. In this effort, we have been in the forefront of bionanotechnology and nanomaterials analysis. We have utilized the basics of biomedical transport phenomena, kinetics, thermodynamics and control theory to design novel devices and to begin to optimize their behavior in contact with the body. Adjustment and optimization of functional components of these devices has been based on simple or sophisticated control or on physiology-based models. In addition to experience in device design, operation and control systems, we have a well-defined ability to link these to cellular and whole animal physiological responses.

These links provide us with knowledge of cellular response mechanisms that may be related to changes in immunological status, physical tissue damage or chemical irritation. For example, we have a well-developed range of cellular physiology function tests that allow us to determine increase in cellular activation or responsiveness, signals that often provide advance warning of whole body physiology responses.

For example, our contributions to chemical, materials and biomedical engineering are well known, as we have significant contributions to the development of novel biomaterials for a wide range of blood compatible and biocompatible applications, new oral delivery systems for treatment of diabetes and osteoporosis, new membranes for artificial kidneys, new defibrillator units, and improved tissue engineered constructs.

In our research and educational efforts, we pay particular attention to materials design and characterization, to cell/cell and cell/material interactions, and to application of nanotechnology principles to the design of new devices. Special emphasis is given to the elucidation of the importance of such molecular and cellular phenomena in the improvement of device performance. Such an effort will greatly enhance and benefit from our emerging research in biomedical nanotechnology. Our effort are directed towards the use of micropatterning, molecular imprinting, self-assembled monolayer structures, environmentally sensitive (smart) materials, microcircuits, micro- and nanolithographic processes, and biochip technologies for the improvement of the performance of such devices.

PhD PROJECTS AVAILABLE IN 2009

In 2009 we expect to offer 3-4 projects for PhD in ChE or BMEin the following areas. We urge you to read about them on our extensively detailed Web site to ask Professor Peppas and our students, about details or previous publications.

Projects on New Systems for Oral Protein Delivery: Developing Improved Polymer and Biomaterial Structures for Better Protein Delivery

Considering the acidic conditions and the proteolytic enzymes present in the stomach, the effective oral delivery of therapeutic proteins and peptides to the small intestine is a formidable task. It is further complicated by difficulties in getting relatively large therapeutic protein molecules to be absorbed by the selectively permeable epithelium of the small intestine.

A unique, controlled-release system for oral delivery of proteins has been invented by a unique molecular design of its carrier components. See a very nice presentation in system consists of a gel-like material that exhibits “complexation by hydrogen bonding” and has pH-dependent swelling properties. This means that it exhibits properties of fast expansion and contraction. It is stable in the acidic conditions of the stomach before swelling rapidly and releasing the therapeutic proteins upon transition to the basic conditions of the small intestine. The unique components of the system provide total protection of the therapeutic protein until it is released in the small intestine. The Whitaker Foundation that funds a portion of this work along with NIH had a very nice article recently

In addition, the new protein release system exhibits properties of mucoadhesion to the mucosa of the upper small intestine by “intelligent tethers” that protrude from the carrier. The system can bind calcium locally, thus leading to opening of the tight junctions between the epithelial cells of the upper small intestine. Some inhibition of the proteolytic activity of the enzymes in the upper small intestine has been shown.

In-vivo studies using insulin in Wistar rats have demonstrated the return of diabetic rats to normal glucose levels hours after administration of this oral delivery system without harmful hypoglycemic effects. A significant bioavailabilty of the orally delivered protein has been observed, reaching levels as high as 20% in rats. We have recently demonstrated the ability to deliver calcitonin using this same delivery system. Studies with other proteins are in progress.

We are now investigating the development of new protein delivery systems for oral applications. Such systems will be used for the release of insulin, interferon, anti-hemophilic factors and other important proteins. In the past decade, cell cultures from human colon adenocarcinoma cells were developed as a new approach to model gastrointestinal absorption. The Caco-2 cell line has attracted the interest of the research community due to its ability to differentiate without difficult cell culturing techniques. We will investigate the behavior of the new protein delivery systems on a model biological environment. For this purpose, a gastrointestinal cell culture model, the Caco-2 cell line, will be employed to investigate the cytotoxic effects of the polymeric carrier and its effects on the cell monolayer integrity. We will examine the importance of various P-glycoproteins as “positive transporters” for the facilitated transport of proteins across epithelial cell sin the CaCo-2 line. The safety and pharmacokinetics of different dosages of selective modulators of the P-glycoprotein efflux transporter, administered alone or with different dosages of the protein delivery systems will be studied.

For more information talk toMaggie Phillips, Bill Liechty, Brandon Slaughter

Projects on Nanotechnology-based Systems for Detection and Smart Therapy

The proposed research seeks to develop novel sensing and recognition nanodevices that are entirely synthetic and tailored to have various biorecognitive properties. We investigate nanosystems based on intelligent recognitive polymer systems such as ionic and biomimetic networks.

Microcantilever-based DDS Schematic of therapeutic microcantilever array. The molecularly imprinted polymer patterned onto the microcatilever is able to recognize and respond to a target analyte causing a transducer to open the well and release a therapeutic compound.

These networks are desirable alternatives to biological entities because they can be designed to mimic biological recognition pathways and at the same time exhibit properties that are more favorable for nanosensing applications. Procedures will be developed to facilitate integration of intelligent polymer networks and silicon substrates at the nanoscale. Mask aligned systems will be utilized to precisely micropattern ultra-thin polymers films into silicon biomolecule will be micropatterned onto silicon substrates via UV free-radical polymerization. Due to the inherent dissimilarities of organic polymer networks and inorganic silicon devices, either an organosilane coupling agent will be utilized to gain covalent adhesion between the polymer network and the silicon surface or an Iniferter-based method will be applied. These general procedures will be applied to multiple intelligent polymer networks. Biomimetic recognitive networks specific for a target substrates and characterized by single and competitive fluorescent and confocal microscopy studies, SEM, and profilometry. Specifically, we micropattern biomimetic recognitive hydrogel networks that selectively recognizes D-glucose, cholesterol and other biomolecules among similar molecules via non-covalent complexation. Novel copolymer networks containing poly(ethylene glycol) dimethacrylate and functional monomers such as acrylic acid, methacrylic acid, and acrylamide will be synthesized in polar, aprotic solvent including dimethyl sulfoxide. Preliminary studies demonstrate that these recognitive networks are effectively micropatterned in fine dimensions and are specific for the target molecule. In other studies, anionic hydrogels are precisely micropatterned onto silicon microcantilevers, for application as MEMS and bioMEMS sensors. Specifically, crosslinked poly(methacrylic acid) network containing significant amounts of poly(ethylene glycol) dimethacrylate are utilized as sensing elements responsive to external pH or analyte concentrations.

For more information talk toCarolyn Bayer, Diana Snelling, Marty Gran, David Kryscio, Steve Marek

Projects on Intelligent Nanotechnology-based Systems for Detection of Biologicals

Recent advances in the discovery and delivery of drugs to cure chronic diseases have been achieved by the combination of intelligent material design with advances in nanotechnology. In particular, there has been considerable work in preparing nanostructured biomaterials for various applications, such as carriers for controlled and targeted drug delivery, micropatterned devices, systems for biological recognition. Since many drugs act as protagonists or antagonists to different chemicals in the body, a delivery system that can respond to the concentrations of certain molecules in the body is invaluable. For this purpose, intelligent therapeutics or “smart drug delivery” calls for the design of the next generation of responsive devices and materials.

In particular, biomimetic materials, especially polymeric networks, capable of molecular recognition have been prepared by designing interactions between the building blocks of biocompatible networks and the desired specific ligands and by stabilizing these interactions by a three-dimensional structure. These structures are at the same time flexible enough to allow for diffusion of solvent and ligand into and out of the networks. Synthetic networks that can be designed to recognize and bind biologically significant molecules are of great importance and influence a number of emerging technologies. These artificial materials can be used as unique systems or incorporated into existing drug delivery technologies that can aid in the removal or delivery of biomolecules and restore the natural profiles of compounds in the body.

In addition, biomimetic methods are now used to build biohybrid systems or even biomimetic materials (mimicking biological recognition) for drug delivery, drug targeting, and tissue engineering devices. The synthesis and characterization of biomimetic gels and molecularly imprinted drug release and protein delivery systems is a significant focus of recent research. Configurational biomimetic imprinting of an important analyte on an intelligent gel leads to preparation of new biomaterials that not only recognize the analyte but also act therapeutically by locally or systemically releasing an appropriate drug.

The design of a precise macromolecular chemical architecture that can recognize target molecules from an ensemble of closely related molecules has a large number of potential applications. The main thrust of research in this field has included separation processes (chromatography, capillary electrophoresis, solid-phase extraction, membrane separations), immunoassays and antibody mimics, biosensor recognition elements, and catalysis and artificial enzymes. Nanoimprinting creates stereo-specific three-dimensional binding cavities based on the template of interest. Efforts for the imprinting of large molecules and proteins have focused upon two-dimensional surface imprinting, a method of recognition at a surface rather than within a bulk polymer matrix. More recently, by using an epitope approach and imprinting a short peptide chain representing an exposed fragment of the total protein, three-dimensional imprinting of proteins within a bulk matrix has been successfully prepared.

Additionally, micro- and nanofabrication techniques have enabled the development of novel drug delivery devices that can improve the therapeutic effect of a drug, such as micro- and nanoscale needles, pumps, valves, and implantable drug delivery devices. Why do we observe such explosion in the field now? Electronic devices have now reached a stage of dimensions comparable to those of biological macromolecules. This raises exciting possibilities for combining microelectronics and biotechnology to develop new technologies with unprecedented power and versatility. Thus, in recent years we have seen an explosion in the field of novel microfabricated and nanofabricated devices (e.g. for drug delivery). Such devices seek to develop platforms with well controlled functions at the micro- or nanoscale, and they include nanoparticulate systems, recognitive molecular systems, biosensing devices, and microfabricated and microelectronic devices.

For more information talk toCarolyn Bayer, Diana Snelling, David Kryscio

Novel Methods of Cancer Therapy Using Functional Nanoparticles

Oral delivery of chemotherapeutic agents has shown some promising results when compared to the conventional intravenous administration. Some of the agents that have been used in oral treatment of cancer include hormones, like tamoxifen, taxanes, like paclitaxel, epipodophyllotoxins, like etoposide, antimetabolites, like 5-fluorouracil (5-FU), and camptothecin derivatives, like topotecan. Recent clinical studies using these agents comparing oral to intravenous administration found that not only was the toxicity lower with oral dosage forms but clinical outcome was comparable, and in some cases improved, with oral administration. When dealing with chemotherapeutic agents, a concern regarding the agent in the agent in the gastrointestinal tract is the potential toxicity of these agents. Not only does the agent have to be protected from the low pH of the stomach and degradative enzymes present, but also the lining of the gastrointestinal tract must be protected from the potentially cytotoxic agent. If the chemotherapeutic agent is contained within its carrier until it reaches the site of release and, hopefully, absorption, then the toxicity of the agent to the tissue at this site must be investigated. If the agent produces unacceptable levels of toxicity at this site, the site of delivery must be changed or this agent will be deemed unsuitable for oral administration.

Intelligent, highly biocompatible carriers can be used to direct chemotherapeutic agents to specific sites and transport them across epithelial cells from the lumen to the blood. This process requires analysis of the physics of cellular transport. Complexation hydrogels, pH-responsive hydrogels star polymers, and copolymers with tethered or decorated structures are structures that will be studied in this proposal. Previous work sought to design systems for controlled release of chemotherapeutic agents from matrices for oral and implantable delivery systems.

One of the primary sites for absorption in the body is the small intestine. Other areas are involved, for example the large intestine is involved in regulating water and ion retention, but the small intestine is the most promising location for this application. The small intestine is lined with epithelial cells and a layer of mucus exists between these cells and the intestinal lumen. Proteins are broken down in the lumen and are then transported through the epithelial cells to reach the bloodstream. Sugars are also transported from the intestinal lumen through these cells and a therapeutic agent released from a carrier would need to follow a similar path. In addition to passing through the epithelial cells, it is possible for compounds to pass from the lumen between the epithelial cells if the tight junctions between them are compromised. These tight junctions are the most leaky in the duodenum and become progressively tighter as passing towards the colon. This makes the duodenum an attractive site for release and potential absorption of a chemotherapeutic agent.

The overall goal of this research is to study the physics of cancer therapy in the GI tract and to develop and understand the behavior of carriers to deliver cancer therapeutics orally. The carrier must be composed of materials that themselves also do not present unacceptable levels of toxicity when in close proximity to cultured intestinal epithelial cells. The ability of the delivered agent to subsequently pass through epithelial cell monolayer will also be evaluated. The composition of the carrier may have an impact on the ability of the agent to pass through this cell layer and the composition will therefore be optimized to maximize transport while maintaining low levels of toxicity to these cells. The carrier should be able to efficiently load and release therapeutic agents, be biocompatible when exposed to the tissues lining the gastrointestinal tract and aid in the transport of the released agent as necessary.