Public Release: 

Molecular Gates Show Promise For Drug Delivery

Purdue University

NOTE TO JOURNALISTS: A color graphic depicting a molecular gate delivering insulin is available. Ask for the photo called Peppas/Gates.

WEST LAFAYETTE, Ind.--A graduate student at Purdue University has developed a gel-like material that may someday be used to deliver insulin to diabetic patients in a way that mimics the natural response of the body--by responding to changing glucose levels in the blood.

Christie Dorski Hassan, a doctoral student in Purdue's School of Chemical Engineering, developed the gel, which expands and contracts as the acidity in its environment changes. When a special enzyme is added to the gel, it also changes shape in response to glucose levels.

Hassan says the new gel could be used to make a "molecular gate," where high glucose levels would make the gel shrink away from both sides of a tiny pore, opening the pore like a gate and allowing molecules of insulin on the other side of the pore to pass through.

"By varying the enzyme incorporated in the gel, it might also be made to change shape in response to changes in other chemicals in the environment, and possibly be used for blood pressure or cholesterol control," Hassan says.

Hassan, from Naples, Fla., will talk about the gel, its characteristics and how it might be used in molecular gates Tuesday, April 15, at a meeting of the American Chemical Society in San Francisco.

Nicholas Peppas, Hassan's faculty adviser and the Showalter Distinguished Professor of Biomedical Engineering at Purdue, says Hassan's research shows promise for future drug delivery systems, but he cautions that any practical device based on the technology is many years away.

"There are several issues that still need to be addressed, including just how such a molecular gate would be brought into contact with a patient's blood," he says. "One possible way would be to surgically insert a device into the peritoneal cavity, just outside the stomach, and add insulin to a reservoir as needed. But we are only at the first step in the research, and are far from having a workable device."

The gel Hassan developed contains two polymers--polymethacrylic acid, which is widely used in the manufacture of soft contact lenses, and polyethylene glycol, a non-toxic, non-carcinogenic substance used in many biomedical applications.

By itself, the gel expands in a high pH environment (low acidity) and shrinks at low pH (higher acidity). Adding an enzyme called glucose oxidase to the gel during its preparation makes it also respond to changes in glucose levels because the glucose and the enzyme chemically react to produce an acid.

Hassan says the gel could be used as a gate by depositing the gel into the pores of a disk of porous material. The porous material, or membrane, could be made from any number of synthetic materials, such as plastic or ceramic, she says, and placed in contact with the blood in a way yet to be determined.

Insulin could be added to a reservoir on one side of the porous disk. As glucose levels rise on the other side of the disk, the gel would shrink between the pores like a gate opening and allow molecules of insulin to pass through and break down the glucose.

"Before this type of system could be used in a practical device, however, we would need to be able to accurately control the amount of insulin delivered by the molecular gate," Hassan says.

Frank Doyle, associate professor of chemical engineering at Purdue, is developing control mechanisms for Hassan's molecular gate and other types of biological systems.

"In this case, we're looking closely at the dynamics of the system, the expansion and contraction of the gel," he says. "It's too simplistic to view these drug delivery systems as just opening when you need the drug and closing when you don't need it. Even the term 'gate' may be too simplistic.

"You not only have to open and close the gate, you have to open it at the right speed, deliver only the amount of insulin appropriate for the patient and at the appropriate rate, plus close the gate before too much insulin is released or other substances come back through the gate. The challenge is to fully understand the dynamic characteristics of the gel. Ideally, we would like those characteristics to operate at least as well as, or even better than, the pancreas," Doyle says.

Diabetes, a disease characterized by poor control of glucose levels in the blood, is usually attributed to inadequate secretion of the hormone insulin by the pancreas. When their blood glucose level gets too high, diabetics must often deliver insulin to the body by alternative methods, such as injections. Diabetes afflicts nearly 14 million Americans.

Hassan's research is funded by the Showalter Foundation.

aas/Peppas.gates/9704f18

Sources: Christie Dorski Hassan, (765) 494-3331; e-mail, dorski@ecn.purdue.edu
Nicholas Peppas, (765) 494-7944; e-mail, peppas@ecn.purdue.edu
Francis Doyle, (765) 494-9472; e-mail, fdoyle@ecn.purdue.edu
Writer: Amanda Siegfried, (765) 494-4709; home, (765) 497- 1245; e-mail, amanda_siegfried@uns.purdue.edu

ABSTRACT Preparation and Characterization of Glucose-Sensitive P(MAA-g- EG) Hydrogels Christie M. Dorski Hassan, Francis J. Doyle III, Nicholas A. Peppas, Department of Chemical Engineering, Purdue University, West Lafayette, Indiana, 47907-1283

Graft copolymers of pH-sensitive poly(methacrylic acid-g-ethylrnr glycol) (P(MAA-g-EG)) were investigated for use in a novel self- regulated device that delivers appropriate amounts of insulin in response to changing glucose levels. This approach involves the incorporation of pH-sensitive P(MAA-g-EG) with immobilized glucose oxidase to yield a glucose-sensitive polymer. Glucose- sensitive gels were synthesized by first activating glucose oxidase and then polymerizing P(MAA-g-EG) in the presence of the activated enzyme. The equilibrium swelling behavior of the gels was examined as a function of pH. At low pH values the gels were in a collapsed state due to complexation. At high pH values, the gels swelled to approximately 20 times their dry weights. Glucose-sensitive P(MAA- g-EG) gels showed lower initial degrees of swelling for higher glucose concentrations. The swelling/syneresis behavior of the glucose oxidase-containing gels was investigated under varying pH conditions to characterize their dynamic swelling behavior. Glucose- sensitive gels were capable of releasing 0.5 mg of insulin in 5 minutes and an additional 0.5 mg over 3.5 hours.

Caption for graphic: Christie Dorski Hassan, a Purdue doctoral student, has developed a gel, shown in pink, that expands and contracts in response to the level of glucose and acid in its environment. The graphic depicts how the gel might be used to deliver insulin in a diabetic patient. (Graphic courtesy Christie Hassan, Purdue School of Chemical Engineering),

Color photo, electronic transmission, and Web and ftp download available. Photo ID: Peppas/Gates

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