Polish Dumpling-Like Particle Has Potential In Drug Delivery

They're called knedels (k-ned-l), after a popular Polish dumpling filled either with meat or sweets. While the Polish knedel is a sumptuous taste treat, the Washington University knedl is a synthetic nano-sized particle that its creators hope someday will be the carrier of drugs or genes for biomedical applications and therapies.

Karen Wooley, Ph.D., assistant professor of chemistry at Washington University, recently announced a new breakthrough in the particle that K. Bruce Thurmond, II, a graduate student in Wooley's group, first synthesized in 1996. Wooley and post-doctoral researcher Haiyong Huang, Ph.D., have changed the composition of their knedel's core from a glassy to a rubbery substance similar to the interior of a golf ball. Additionally, this core can be hollowed out, creating a capsule into which large amounts of drugs -- or DNA, for gene therapy -- may be loaded for delivery.

Huang presented a talk on the advance at the Spring Meeting of the American Chemical Society, March 29, in Dallas, TX.

"They're like golf ball molecules in this form" says Wooley. "This advance moves us along in our goal of making knedels potential drug- and gene- carrying systems. It makes the particle a lot more versatile and the rubbery core should allow a higher loading capacity We've gotten lots of interest in the knedels, for their potential, they're novelty, and their name."

The work is funded by the National Science Foundation and Monsanto Company, St. Louis.

Wooley and her colleagues recently have been focusing on the knedel's water-soluble shell that allows them to bind DNA to its surface. This in turn causes small aggregates to form that protect the genetic material from being digested by enzymes. The chemists charge the shell positively so the knedel attracts DNA, which has a negative charge. Thus, the shell itself can play a key role in drug delivery.

Knedels are variations and improvements on a class of polymers -- chain-like structures of repeating compound assemblies -- called micelles. There has been lots of interest this decade in micelles for drug delivery, but they have a major drawback for this purpose. They are dynamic and unstable. If they are diluted or subjected to force in a system, they tend to fall apart.

Knedels, on the other hand, assemble and behave much the way proteins such as insulin do. With insulin, which our pancreas secrete to regulate our blood sugar rates, there are two linear polymer chains of amino acids -- the chemical units that are the building blocks of proteins. The linear chains self-assemble into a three-dimensional structure stabilized by linking with chemical bonds between two residues of amino acids. These cross-linkings hold everything together.

The knedel is constructed in a similar fashion. Wooley and her colleagues form a polymer micelle composed of as few as 10 to several hundred chains, assembled into a glassy sphere with a core that does not mix with the shell or the outer environment. Chemical reactions within the shell bind the chains together and give the stabilized, cross-linked structure.

"The knedel is a very simple approach that offers versatility for composition of the particles," she says. "We can control the size of the core, the thickness of the shell and the overall size of particles as well as the core and shell compositions. This will enable us to control the properties and function of the particles in their environment."

Originally Wooley and her group placed polystyrene -- the basic stuff of which disposable coffee cups are made -- into the core, but found it was too inflexible. They could not place material into the core unless a solvent was used. The new core is made of a more flexible material, polyisoprene, which has cross-linking capabilities that give the structure its rubbery property.

Wooley has future plans of incorporating degradable polymers into the knedel structure. She and graduate students Jennifer Weinberg and Min Wang have developed new degradable polymers that they can time to fall apart in water anywhere from a few minutes to a few months. Adding this feature to a drug-bearing knedel would give the particle the ability to be time-released.

Wooley also is working on modifications to the knedel's shell. She wants to make it flexible so that when it comes into contact with proteins, the shell won't cause proteins to stick and denature, which is an altering of molecular structure.

As for that name: After Wooley and her group constructed the polymer particles, they tried to see them with a standard electron microscope, but the particles were too small. They turned to colleague Tomasz Kowalewski, Ph.D., research assistant professor of chemistry at Washington University, a Polish native who is an expert in atomic force microscopy (AFM), and operates one at Washington University. This microscope is a new, powerful tool that can visualize nature's tiniest objects.

"Tomasz said, 'Oh, they look like knedels. You must call them that', And that's how they got their name," Wooley says.