Materials scientists look for new materials and ways to manipulate existing ones in order to fulfill unmet needs
|SCAFFOLD Highly branched dendrimers, depicted here among cells shown in green, may one day deliver drug molecules
CENTER FOR BIOLOGICAL NANOTECHNOLOGY, UNIVERSITY OF MICHIGAN
CELIA M. HENRY, C&EN WASHINGTON
In the context of drug delivery, the needs for materials can generally be broken into two categories, notes Robert S. Langer, a professor of chemical and biomedical engineering at Massachusetts Institute of Technology: the creation of new materials and better understanding of how to manipulate existing materials.
In both cases and in whatever route of administration, "you go to the unmet needs," Langer says. "The unmet needs lead you to where materials can do something." Current needs include reducing the toxicity of drugs, increasing their absorption, and improving their release profile.
In one fertile area of research, scientists are tailoring polymers to address those needs. They are using long-standing polymers like poly(ethylene glycol) (PEG) and newer types like dendrimers. And they are forming polymeric micelles and using polymer-drug conjugates as prodrugs, just to name a few.
Last month, scientists presented examples of research on materials for drug delivery at the annual meeting of the Controlled Release Society (CRS). More than a thousand scientists gathered in Seoul, South Korea, to hear talks on topics ranging from polymeric carriers for anticancer agents to particles for gene delivery to scaffolds for cell delivery and tissue engineering.
ONE AREA THAT researchers have particularly been focusing on is the delivery of anticancer agents. Polymers have already been shown to form effective delivery systems for localized treatment of cancer. But Ruth Duncan, director of the Center for Polymer Therapeutics at the Welsh School of Pharmacy at Cardiff University, wants to use polymer-drug conjugates to treat metastatic cancers as well, which are much more difficult to deal with.
"If we can give [the conjugates] by injection, then we have an opportunity to target the micrometastases that can be present throughout the whole organism," Duncan says.
Polymer carriers have several advantages over other delivery methods such as liposomes and antibodies, according to Duncan. Because liposomes--spherical vesicles made of phospholipids--are particles, they get taken up by macrophages. High levels can be found in the liver and spleen, even when the liposomes are given "stealth" characteristics by coating them with PEG. In addition, Duncan says, stealth liposomes have other side effects, such as extravasation, in which the liposome moves from the blood vessel into tissue where it's not wanted. Antibodies, meanwhile, have the disadvantage that most receptors on tumor cells are also present on normal cells, making it hard to find ones that are unique to cancer.
In contrast, water-soluble polymers allow Duncan to work with a single molecule rather than a large particle. "You can choose a material which doesn't go to the liver and the spleen and to which you can bind an anticancer agent using a linkage that's designed to be more specifically clipped at the tumor tissue," she says. "It's in effect a macromolecular prodrug."
To avoid the liver and spleen, Duncan works with uncharged hydrophilic polymers, such as PEG and N-(2-hydroxypropyl) methacrylamide. When these polymers are hydrated, they can circulate in the blood for periods of up to about 24 hours, according to Duncan.
Like many others, Duncan uses the fact that new blood vessels in tumors are "leaky" to passively target tumors. Because tumor blood vessels are more permeable than blood vessels in other tissue, drugs enter tumor tissue fairly easily. This effect, known as the enhanced permeability and retention effect, was first discovered by Hiroshi Maeda of the University of Kumamoto in Japan in 1986.
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|IMPRINTS Recognition capabilities can be built into drug delivery using molecular imprinting. Monomers polymerize around a template molecule. The template is then removed, leaving a site that will interact selectively with the template. Such a site can be used to trigger drug delivery in response to the presence of a particular compound--for example, insulin in the presence of glucose.
ANOTHER ADVANTAGE of polymers is that the linkage can be designed to control where and when the drug is released. Duncan uses peptide linkages, which are cleaved after the polymer-drug conjugate is taken up into cells by the process of endocytosis. Within the resulting endosome, a family of enzymes called the lysosomal thiol-dependent proteases catalyzes the cleavage of the polymer-drug connection.
However, polymer carrier systems also have their disadvantages, Duncan points out. Compared to liposomes, which are basically empty vesicles that can be "stuffed full of drug," polymers have a low drug-carrying capacity. The payload that each polymer molecule can carry depends on the number of reactive groups where the drug can be attached. PEG, for example, can carry only two drug molecules, but other polymers can carry as much as 25 wt %, Duncan says.
At the CRS meeting, Glen S. Kwon, associate professor of pharmacy at the University of Wisconsin, Madison, described the development of polymeric micelles for drug delivery. The micelles are made of block copolymers of PEG and a poly(l-aspartamide) derivative. The copolymer forms a structure in which PEG serves as a hydrophilic shell and the amino acid forms the core. By fine-tuning the composition of the block copolymer, Kwon and his coworkers can control the structure of the resulting micelles, which are about 30 to 50 nm in diameter.
The side chains of the amino acid portion of the copolymer are crucial to the interactions with encapsulated drugs, so that portion is where Kwon and his group fine-tune the chemistry. The core-forming block needs to have a lower molecular weight than the PEG block or the micelles won't form.
Kwon started with an amino acid block with aromatic side chains. He wanted to know what would happen if those aromatic side chains were replaced with acyl chains. He chose hexyl, lauric, and stearic acyl chains.
Kwon and his group used the micelles to deliver the antifungal agent amphotericin B, which he said is called "amphoterrible" by AIDS patients who take it for life-threatening fungal infections. The drug is now formulated with liposomes, which reduce its toxicity but also diminish antifungal activity. In addition, the liposome formulations are expensive, costing approximately $1,000 a dose, Kwon said.
The longer side chains interact more strongly with amphotericin than the shorter side chains do, they found. The strong interaction with the stearic side chains means that the drug is released more slowly.
"We envision long-circulating nanoscopic drug depots that may produce controlled levels of free drug in blood over time and perhaps drug release solely at disease tissue," Kwon told C&EN.
Bioadhesive polymers to help improve the absorption of drugs are the focus of work by Edith Mathiowitz, an associate professor of medical science and engineering at Brown University. "You can find applications for bioadhesive polymers in almost any region that you have epithelial cells," she says, including oral, buccal (cheek), GI tract, rectal, or vaginal delivery. "The adhesive molecules bring the delivery system closer to the mucosa. If the particle is larger than 10 mm in diameter, it will stay for a prolonged time and deliver the drug. If the particle is small, the chances of being taken up are much higher. In the last case, the entire delivery system with the drug is delivered to the systemic circulation."
To accomplish this improved delivery, Mathiowitz designs polymers with a high amount of carboxylic acid, which hydrogen bonds with the carboxylic acids in epithelial cells. "You want light bonding," she says. "You don't want covalent bonding." Mathiowitz has started a company called Spherics to commercialize the polymeric drug delivery systems.
Relative newcomers to the collection of materials used for drug delivery are dendrimers, a type of highly branched macromolecule. One of the major advantages of dendrimers is their relatively small size, according to James R. Baker Jr., director of the Center for Biological Nanotechnology at the University of Michigan. "We can get a platform that we can target that's less than 5 nm in diameter. It provides a very nice scaffold and one that certainly can get through vascular pores and into tissue more efficiently than larger carriers," he says.
Another advantage of dendrimers is that their synthesis results in a single molecular weight rather than a distribution of sizes. "Although they're rather complicated, they can be synthesized so that you have a single molecular weight, a single species in the bottle," notes Duncan, who also works with dendrimers.
In addition, dendrimers have a high drug-carrying capacity because of their multivalency, according to Jean M. J. Frechet, a chemistry professor at the University of California, Berkeley. "You have many functional groups and can deliver a high payload," he says. "If you spend the effort for targeting, you are targeting a high payload as opposed to a single molecule."
Duncan has done work with platinate anticancer agents conjugated either to linear polymers or to dendrimers. The linear polymer could carry 10 wt % of the platinate, whereas the dendrimer could handle 25 wt %.
However, "the advantages of dendrimers are still being worked out," Duncan cautions. "The dendrimers seem to move out of the tumor tissue rather quickly," which can prevent the drug from concentrating in the tumor.
Baker and his colleagues use poly(amidoamine) dendrimers to deliver anticancer agents such as cisplatin and methotrexate. The drugs are conjugated to the dendrimers using photocleavable or labile linkers, which can be made to release the drug using light or through acid cleavage.
So far, dendrimers have not been used in people. "We haven't done large-scale human toxicity studies," Baker says, "but we've given up to 8 or 10 mg of this material in a single dose to a mouse without any toxicity. It's encouraging."
PHOTO BY LINDA FREI
BROWN MEDICINE PHOTO
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