COVER STORY
SCAFFOLD Highly branched dendrimers, depicted here among cells shown in green; may one day deliver drug molecules.
DRUG DELIVERY Materials scientists look for new materials and ways to manipulate existing ones in order to fulfill unmet needs CELIA M. HENRY, C&EN WASHINGTON
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N THE CONTEXT OF DRUG DELIVERY, THE NEEDS FOR MATE-
rials 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 HTTP://PUBS.ACS.ORG/CEN
reducing the toxicity of drugs, increasing their absorption, and improving their release profile. In one fertile area ofresearch, 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 C & E N / A U G U S T 2 6 , 2002
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COVER STORY to passively target tumors. Because tumor blood vessels are more permeable than bloodvessels 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.
IMPRINTS Recognition capabilities can be built into drug delivery usine 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 te trigger drug delivery in response to the presence of a particular compound—for example, insulin in the presence of glucose.
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.
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 ONE AREA THAT researchers have partic- wanted. Antibodies, meanwhile, have the ularly been focusing on is the delivery of an- disadvantage that most receptors on tuticancer agents. Polymers have already mor cells are also present on normal cells, been shown to form effective delivery sys- making it hard tofindones that are unique tems for localized treatment of cancer. But to cancer. Ruth Duncan, director of the Center for In contrast, water-soluble polymers alPolymer Therapeutics at the Welsh School low Duncan to work with a singje moleof Pharmacy at Cardiff University, wants cule rather than a large particle. "%u can to use polymer-drug conjugates to treat choose a material which doesn't go to the metastatic cancers as well, which are much liver and the spleen and to which you can more difficult to deal with. bind an anticancer agent using a linkage "If we can give {the conjugates] by in- that's designed to be more specifically jection, then we have an opportunity to clipped at the tumor tissue," she says. "It's target the micrometastases that can be in effect a macromolecular prodrug." present throughout the whole organism," To avoid the liver and spleen, Duncan Duncan says. works with uncharged hydrophilic polyPolymer carriers have several advantages mers, such as PEG and N-(2-hydroxyover other delivery methods such as lipo- propyD methacrylamide. When these polysomes and antibodies, according to Dun- mers are hydrated, they can circulate in the can. Because liposomes—spherical vesi- blood for periods of up to about 24 hours, cles made ofphospholipids—are particles, according to Duncan. they get taken up by macrophages. High Like many others, Duncan uses the fact levels can be found in the liver and spleen, that new blood vessels in tumors are "leaky"
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 ofpolymeric 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 finetune 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
Learning how to say no to some cell types or some biological responses is probably as important as saying yes to others." 40
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COVER STORY know what would happen ifthose 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 lifethreatening fungal infections. The drug is now formulated with liposomes, which re duce its toxicity but also diminish anti fungal activity In ad dition, the liposome formulations are ex pensive, costing ap proximately $1,000 a dose, Kwon said. T h e longer side chains interact more strongly with am photericin than the shorter side chains do, they found. The strong interaction Peppas with the stearic side chains means that the drug is released more slowly iC 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 tis sue," Kwon told C&EN. Bioadhesive polymers to help improve the absorption of drugs are the focus of work by Edith Mathiowitz, an associate
"%u don't want covalent bonding." Math iowitz has started a company called Spher ics 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 ad vantages of dendrimers is their relatively small size, according to James R. Baker Jr., director of the Center for Biologi cal Nanotechnolo gy 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 vascu lar pores and into tissue more effi Mathiowitz Kwon ciently than larger carriers," he says. er the drug. If the particle is small, the Another advantage of dendrimers is that chances of being taken up are much high their synthesis results in a single molecu er. In the last case, the entire delivery sys lar weight rather than a distribution of tem with the drug is delivered to the sys sizes. 'Although they're rather complicat temic circulation." ed, they can be synthesized so that you To accomplish this improved delivery, have a single molecular weight, a single Mathiowitz designs polymers with a high species in the bottle," notes Duncan, who amount of carboxylic acid, which hydrogen also works with dendrimers. bonds with the carboxylic acids in epithe In addition, dendrimers have a high lial cells. "%u want light bonding," she says. drug-carrying capacity because of their multivalency, according to Jean M . J . C O M I N G UP Frechet, a chemistry professor at the University of California, Berkeley. "You have many functional groups and can de liver a high payload," he says. "If you CS Prospectives wilt be tackling the topic of drug delivery later this year in a spend the effort for targeting, you are conference titled "Future Directions of Drug Delivery Technologies: Molecular targeting a high payload as opposed to a Design, Cellular Response, and Nanotechnology." The conference wilt include single molecule." presentations on the design of new drug carriers, nanotechnology, protein delivery, Duncan has done work with platinate gene delivery, medical applications, and tissue engineering. The meeting will be held Oct 13-16 in Boston. anticancer agents conjugated either to lin ear polymers or to dendrimers. The linear A goal of the meeting is to "bring together scientists with chief technical officers, polymer could carry 10 wt % of the plati chief executive officers, and other businesspeople who are interested in new technolo nate, whereas the dendrimer could handle gies and new applications," says Nicholas A. Peppas, one of the meeting chairs and a professor of chemical and biomedical engineering at Purdue University. I t was impor 25wt%. tant for us to concentrate on the future." The other meeting chairs are Robert S. However, "the advantages of den Langer, professor of chemical and biomedical engineering at Massachusetts Institute drimers are still being worked out," Dun of Technology, and Patrick Couvreur, pharmacy professor at Paris-Sud University, can cautions. "The dendrimers seem to "We want to have a realty good scientific meeting, with leading speakers and cut move out of the tumor tissue rather quick ting-edge topics from both academics and industry," Langer says. "Our goal is to have ly," which can prevent the drug from con a forum for people to hear the latest cutting-edge science, with really good things and centrating in the tumor. people they may not have seen all the time" at other drug delivery conferences. Baker and his colleagues use poly(amiACS Prospectives conferences are small meetings geared toward senior-level in doamine) dendrimers to deliver anticancer dustry scientists on topics at chemistry's interdisciplinary frontiers. Other meetings agents such as cisplatin and methotrex this fall include one on combinatorial chemistry and another on proteomics. More in ate. The drugs are conjugated to the den formation can be found on the Web at http://www.acsprospectives.org. drimers using photocleavable or labile linkers, which can be made to release the professor of medical science and engi neering at Brown University "Ifou 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 deliv ery "The adhesive molecules bring the de livery system closer to the mucosa. If the particle is larger than 10 μπι in diameter, it will stay for a prolonged time and deliv-
Meeting Targets Future Of Drug Delivery
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drug using light or through acid cleavage. So far, dendrimers have not been used in people. "We haven't done large-scale hu man toxicity studies," Baker says, "but we've given up to 8 or 10 mg of this mate rial in a single dose to a mouse without any toxicity It's encouraging." THE LACK OF experience with drug deliv ery systems composed of dendrimers is a disadvantage to people who are develop ing them now, according to Frechet. "Ifou are starting a whole new ball game," he says. "Ύου have no history of their application." Frechet collaborates with Francis C. Szokajr. of the departments of biopharmaceutical sciences and pharmaceutical chemistry at the University of California, San Francisco, to deliver anticancer agents such as doxorubicin with 2,2bis(hydroxymethyl) propanoic acid den drimers [Bioconjugate Chem., 13,443 and 453(2002)}. One of the molecules Frechet is work ing on is actually a hybrid between a linear polymer and a dendrimer, consisting of a three-arm poly(ethylene oxide) star at tached to dendritic moieties. "Essentially,
TWEAKING Replacing aromatic side chains with acyl side chains improves the interaction between the block copolymer and the drug amphotericin B. we are using the dendrimer to provide us with multiple sites of attachment, and we are using the linear polymer to provide us with water solubility," Frechet says. The doxorubicin is attached to the den drimer through a hydrazone linker, which can be cleaved simply by changing the pH. "It's a fairly simple bond to break. It's a linkage between the amino group of a hy drazine and keto group of the drug. Dox orubicin has a ketone that can be used for that purpose," Frechet says. "Most people have chosen to attach doxorubicin through
its amino group, but that gives an amide. Amide linkages are very hard to break, so we have avoided that." It's necessary to adapt dendrimers to different drugs, Frechet says, although his group is interested in making as generic a system as possible. They are simplifying the system by breaking it into two parts: a drug carrier and a portion that would con fer solubility and the ability to circulate in the system. iC We are looking at making them such that they will self-assemble. %u have two com-
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COVER STORY ponents, you mix them, and bang, you get one," he says. "To the outside world, it would look just like the solubilizing component. It will essentially surround, engulf the other one, and help in its transport and delivery" So far, Frechet only has chemical data about this system, but biological studies with Szoka will start later this year, Frechet says. "You provide a quantifiable benefit by attaching a drug—a very toxic drug used in chemotherapy— to a dendrimer," Frechet says. "You may reduce or eliminate its tox icity Ifyou can target it properly, you elim inate the side effects." Frechet describes their initial mouse in vivo work as "pretty good." AT THE CRS MEETING, AlexanderT. Flo rence, dean of the University of London School of Pharmacy, described his group's work in forming particles with dendrimers to serve as drug carriers. Dendrimers can aggregate to form larg er structures that Florence called "dendrisomes" and "dendriplexes." Dendrisomes are formed by combining dendrons (den drimer segments) with cholesterol to form a vesicle. Dendrisomes are similar to lipo
somes, which have long been the work horses of drug delivery One of the ways that Florence is us ing dendrimers is to form complexes with DNA. The resulting particles are then used to orally administer DNA. For example, mice that were fed particles containing D N A coding for β-galactosidase did indeed express the protein. In addition, Florence's group is inter ested in using targeting ligands to direct where the particles go. For example, they have used internalin, a protein from the bacterium Listeria monocytogenes, as a tar geting ligand. Internalin is a ligand for the receptor E-cadherin, which is expressed in the intestine. So far, the research "has not gone as far as hoped," Florence said. Despite much talk about targeting li gands, it has proven to be more difficult than anticipated to develop active target ing strategies. "It's easy to put up a car toon," Florence said, "but difficult to ac tually do." Duncan believes that people were "a bit naive" about active targeting of drugs. Tar geting cells in a dish is one thing, but the physiological system is much more com-
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plex. On the issue of targeting in cancer applications, Duncan tells C&EN: "Imag ine an intravenous injection, with all the complexity of blood proteins, the cells lin ing the vessels, the endothelial cells of the vessel wall, and other cells which interface with the blood in the liver. You have to make sure that you're not getting any in teraction with all those normal cells before you arrive at the tumor site." Another focus for drug delivery re searchers is D N A delivery, in which D N A is treated as a macromolecular drug (C&EN, Nov 26,2001, page 35). Nonviral gene delivery has several advantages over gene delivery with viral vectors, ac cording to Sung Wan Kim, a professor of pharmaceutics and pharmaceutical chem istry at the University of Utah. These ad vantages include versatility, no integration into the host chromosome, and fewer problems with immunogenicity he told the audience for his plenary lecture at the CRS meeting. POLYMERS SERVE TO condense D N A and protect it from degradation before it can express the desired protein. But be cause what works in vitro doesn't always work in vivo and vice versa, coming up with a good gene carrier can be tough. "In vivo, you have to go through more barriers than in cell culture," says Kam W Leong, pro fessor of biomedical engineering at Johns Hopkins University There are three stages in delivering the D N A to the nucleus. First, the particle has to be taken up by the cell through endocytosis. After it's in the cell, the polymer must be able to escape the endosome (a type of vesicle) by disrupting the mem brane. Then the polymer has to transport the D N A to the cell nucleus. "We can con trol the specific design ofpolymers for each function," Kim says. The polymer requirements for gene de livery depend on how the D N A will be ad ministered, according to Kim. "Ifwe want to deliver the gene systemically I think we have to use a water-soluble, biodegradable, cationic polymer," he told C&EN. For lo cal delivery, Kim conjugates cholesterol with polymers to promote interaction with cells in the vascular wall and enhance up take. In addition, targeting ligands can di rect the D N A to a specific location. For example, Kim has used galactose to target the liver and various antibodies to home in on leukemia cells, myocardial cells, and angiogenic tissue. Leong has used both naturally occurring polymers, such as chitosan, and synthetic polymers for D N A delivery. Designing HTTP://PUBS.ACS.ORG/CEN
polymers for D N A delivery in volves a "tricky balance," he says. "The D N A has to be free before it can work, but part of the function of the gene carri er is to protect the D N A from enzymatic degradation before it can reach the nucleus of the cell. If the nanoparticle is break ing down too fast, then it will not work well." Leong and Hai-Quan Mao developed new polyphosphoesters as D N A carriers at the Johns Hopkins Singapore Bio medical Center. T h e re ANCHORED When the angiogenic growth factor VEGF is incorporated into a fibrin searchers chose the polyphos- matrix but allowed to diffuse freely, angiogenesis occurs both in the matrix and phoesters because of their elsewhere on the chorioallantoic membrane of a fertile chicken egg (left). When an structural versatility, as they can engineered form of VEGF is covalently coupled to the fibrin matrix, cells migrate into the be varied at either the back matrix, cleave the coupled growth factor, and release it on demand, resulting in a much bone or the side chain. At the more localized response (right). CRS meeting, Leong described research in which they systematically eval ticularly complex environment in devel "Doing tissue engineering with factors uated different poly(phosphoroamidates), opment. Cells are evolved to respond to to stimulate cells in the body is really just which consist of a phosphoester backbone fancy drug delivery," Hubbell says. "One is them in that complex environment," with amine side chains. Hubbell says. delivering a drug—like a protein, a morAnother application in which drug de phogenic factor—that stimulates cellular "The naive approach from drug deliv livery and materials development play a responses at a site with the goal of ending ery was just to take materials that were role is in tissue engineering. At first the re up with some overall tissue reconstruction developed to deliver steroids—utterly lationship between the two areas seems or regeneration at that site." Hubbell is us different molecules —and to use those tenuous, but for some types of tissue en ing drug delivery for such tissue engineer same sorts of materials," Hubbell says. gineering, it's not a stretch at all. ing applications as angiogenesis, bone re Such an approach has been ineffective, he pair, and nerve regeneration. notes, because the growth factors "have For example, Jeffrey A. Hubbell, pro been presented completely out of con fessor of biomedical engineering and di rector of the Institute for Biomedical En THIS APPLICATION OF drug delivery pres text, completely in a different environ ment than nature intended them to be gineering at the University of Zurich and ents challenges for materials development. presented." One of the main needs in the Swiss Federal Institute of Technology, Hubbell is using naturally occurring mol drug delivery for tissue engineering, Zurich, performs tissue engineering by de ecules that are normally involved in devel therefore, is the development of materilivering growth factors to the desired site. opment. These molecules "operate in a par
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COVER STORY als that will present the growth fac tors in the way that they would be presented during development. One challenge, Hubbell believes, is to use biochemical approaches in materials development. That means designing materials that degrade by processes o t h e r than hydrolysis. "Building in biological character to synthetic materials or to natural ma terials that have been engineered—I GOOD CHOLESTEROL The cholesterol think that's a route that is likely to side chain in this water-soluble lipopolymer meet with success." One example of promotes interactions between the gene this biological character is making carrier and cells. "the material degrade in a way that's triggered by the healing response." Hubbell and his group mimic the natu much work already," Hubbell says. "Na ral system by chemically coupling the ture had already figured out how to make growth factors to a gel matrix or by build these materials from liquids into solids. ing affinity sites into the material. "The Nature had already figured out how to growth factors are coupled to the matrix by make them remodel as cells migrate into a linker that cells can cleave," Hubbell says. them." However, he doesn't want "to be The matrix "can release the factor when limited by the decisions that evolution the cells are ready for it." made." Hubbell has used natural materials such T h e synthetic materials that H u b as fibrin and synthetic materials as matri bell's group uses are intended to be de ces for delivering factors. He thinks that livered to the body as a liquid, then to so synthetic materials will ultimately be the lidify to form gels. In the past, they have way to go. 'Άί the end of the day, you have accomplished that by photopolymerizmuch more control over the characteristics ing acrylates or methacrylates in the of the material," he says. "You should be body. Performing the polymerization in able to design everything, select every the body allows the precursors to be de thing, instead ofjust modifying what nature livered through minimally invasive sur gave you. gical procedures. Now Hubbell is working with Michael"THE REASON we started working with type additions involving thiols. One com materials like fibrin and asking how to ponent has a Michael-type donor, and an change them, how to fix them up as it other has a Michael-type acceptor. A were, was that evolution had done so 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 gener ating so much heat." In addition, the reaction should be tolerant of both water and oxygen. "It's al so pretty important to use precursors that don't easily cross cell membranes," Hubbell says. "If you keep this Michael-type reac tion outside the cells, it is really very non toxic, but if you allow it to happen inside the cell, it can be very toxic." T h e re searchers 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 for ward 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 ma nipulate the characteristics of the materi-
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als 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 ofglucose 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. • HTTP://PUBS.ACS.ORG/CEN
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