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August 26, 2002
Volume 80, Number 34
CENEAR 80 34 pp. 39-47
ISSN 0009-2347

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"THE REASON we started working with materials like fibrin and asking how to change them, how to fix them up as it were, was that evolution had done so much work already," Hubbell says. "Nature had already figured out how to make these materials from liquids into solids. Nature had already figured out how to make them remodel as cells migrate into them." However, he doesn't want "to be limited by the decisions that evolution made."

The synthetic materials that Hubbell's group uses are intended to be delivered to the body as a liquid, then to solidify to form gels. In the past, they have accomplished that by photopolymerizing acrylates or methacrylates in the body. Performing the polymerization in the body allows the precursors to be delivered through minimally invasive surgical procedures.

Now Hubbell is working with Michael-type additions involving thiols. One component has a Michael-type donor, and another has a Michael-type acceptor. A cross-linking reaction occurs in the body when the components are mixed.

One of the challenges is to make sure that no reaction causes heating. Hubbell accomplishes this by making sure that the number of moles of the reactive group is very low. "Even if the reaction is exothermic, you just don't have much of the reaction going on in order to get solidification," he says. "By using reactions that are not so exothermic and by using materials with macromonomers rather than low-molecular-weight monomers, you can get solidification without generating so much heat."

In addition, the reaction should be tolerant of both water and oxygen. "It's also pretty important to use precursors that don't easily cross cell membranes," Hubbell says. "If you keep this Michael-type reaction outside the cells, it is really very nontoxic, but if you allow it to happen inside the cell, it can be very toxic." The researchers keep the precursors out of the cells by making sure the precursors are large enough and hydrophilic enough not to cross the cell membrane.

In the area of angiogenesis, it's difficult to get normal blood vessels to form if the growth factors are free, Hubbell says. However, when they are complexed to a matrix, the resulting blood vessels are more normal.

Several things are necessary to move forward with this type of tissue engineering, according to Hubbell. First, materials must be tested in the clinic and be optimized. Second, it is necessary to learn how to manipulate the characteristics of the materials at different length scales. "Making hierarchically ordered materials is an important challenge to engineering their characteristics," Hubbell says. In addition, Hubbell would like to make materials that are conducive to one cell type but not another--for example, promoting healing but inhibiting scar formation. "Learning how to say no to some cell types or some biological responses is probably as important as saying yes to others."

Another type of material being developed for drug delivery is the so-called intelligent biomaterials. Such materials would combine molecular recognition with drug release. Nicholas A. Peppas, a chemical engineering professor at Purdue University, believes that such a strategy represents the future of drug delivery. Peppas will soon be moving to the chemical and biomedical engineering departments at the University of Texas, Austin, to head a new initiative in this field. In his vision, the recognition of a particular agent in the body--desirable or undesirable--would trigger the release of a therapeutic agent. Achieving this would result in a "new generation of drug delivery systems," he says.

Peppas and his group make polymers capable of recognizing certain compounds by using the technique of molecular imprinting, which is more often associated with chromatography. The molecule that the polymer will sense is used as a template around which the monomers are allowed to polymerize. The template molecule is then extracted from the polymer. 

"WHAT IS LEFT behind are nanopores or micropores that hopefully remember only the specific template," Peppas says. "For example, in the case of glucose, if I prepare a solution of glucose, sucrose, and galactose, this particular compound would recognize only the glucose. We've come close, but we're not at 100% recognition."

In the example of glucose-sensing molecularly imprinted nanoparticles, Peppas hopes that the detection of glucose would trigger the release of insulin from within the particle. "I'm describing to you something futuristic," Peppas tells C&EN, "something that is more or less like science fiction but is not 100% science fiction because we're already working on parts of it."

These are just a few examples of the work that materials scientists are doing to develop new polymers to effectively deliver drugs. As drugs become larger and less water soluble, the importance of new delivery systems will only increase.

GOOD CHOLESTEROL The cholesterol side chain in this water-soluble lipopolymer promotes interactions between the gene carrier and cells.

COMING UP

Meeting Targets Future Of Drug Delivery

ACS ProSpectives will be tackling the topic of drug delivery later this year in a conference titled "Future Directions of Drug Delivery Technologies: Molecular Design, Cellular Response, and Nanotechnology." The conference will include presentations on the design of new drug carriers, nanotechnology, protein delivery, gene delivery, medical applications, and tissue engineering. The meeting will be held Oct. 13–16 in Boston.

A goal of the meeting is to "bring together scientists with chief technical officers, chief executive officers, and other businesspeople who are interested in new technologies and new applications," says Nicholas A. Peppas, one of the meeting chairs and a professor of chemical and biomedical engineering at Purdue University. "It was important for us to concentrate on the future." The other meeting chairs are Robert S. Langer, professor of chemical and biomedical engineering at Massachusetts Institute of Technology, and Patrick Couvreur, pharmacy professor at Paris-Sud University.

"We want to have a really good scientific meeting, with leading speakers and cutting-edge topics from both academics and industry," Langer says. "Our goal is to have a forum for people to hear the latest cutting-edge science, with really good things and people they may not have seen all the time" at other drug delivery conferences.

ACS ProSpectives conferences are small meetings geared toward senior-level industry scientists on topics at chemistry's interdisciplinary frontiers. Other meetings this fall include one on combinatorial chemistry and another on proteomics. More information can be found on the Web at http://www.acsprospectives.org.

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