The problem with pills
Did you know that when you take a pill, the active ingredient in that pill diffuses throughout your entire body? When you have a headache you may take an over-the-counter pain medication, but this drug does not just concentrate in your head, at the location of the pain. The drug also diffuses to other organs and tissues in your body, like your liver. Pharmacologists and scientists developing drugs use the term “pharmacokinetics” to describe the behavior of a drug as it moves throughout the body. This dispersal of a drug may be a good thing in some cases, like for a general pain pill. However, for other conditions, this way of administering drugs to the body falls short of ideal. The term “drug delivery” describes the ability to target a drug to a specific location in the body, much like a mail carrier would deliver a letter to the addressee on the envelope. Drug delivery research can garner big investment from large pharmaceutical companies as they try to find better ways of administering current or upcoming drugs . Aside from commercial interest, sophisticated drug delivery might be the best way to cure some diseases. In the case of many cancers, chemotherapy and radiation therapy are used conventionally because they counteract one of the most common characteristics of cancer cells: their ability to multiply rapidly and continuously. However, because the therapy is not targeted specifically to the tumor, non-cancerous cells invariably get in the line of fire. Lethargy, reduced immunity, nausea, and hair loss often accompany treatment due to the unintended damage of healthy tissue. Cancer patients are forced to endure these side effects, but with more efficient ways to target the tumor, this collateral damage could be minimized.
Challenges of drug delivery
Scientists have been pursuing better ways to deliver drugs to diseased tissues for a long time, and the resulting cross-disciplinary research among engineers, chemists, biologists, and physicians is beginning to yield innovative approaches. In the field of materials science, ever more complex materials are being developed to better deliver chemotherapeutic agents to tumors.
When a material needs to be engineered to enter the body and travel to a specific site, several challenges arise. The material must not be seen as a danger and thereby destroyed by the immune system. The material must concentrate at the intended site, instead of diffusing non-specifically to other areas of the body. Finally, the material must properly dispense its cargo of drugs at the target site. Although it may sound simple, meeting these demands is quite a challenge because these different aims are often in conflict. You might make a drug better at reaching the site of a tumor, but in doing so you might also unintentionally increase the chance that the immune system rejects the drug. Often, when engineers work with a new material to be used inside the body, they start with structures or compounds that already exist in the body and attempt to mimic them. In the remainder of the article, three approaches are briefly described to highlight the diversity of ideas being pursued.
New approaches to targeting disease: Nanoparticles, scaffolds, and hydrogels
In cancer therapy, nanoparticles are being developed that specifically ferry chemotherapeutic drugs to the site of a tumor. The nanoparticle itself is constructed to mimic a liposome (a small liquid-filled “bubble” that looks like a cell) (Figure 1). These particles are much smaller than a typical cell (one-thousandth the diameter), and they are coated with a membrane, similar to that of human cells. Since this membrane is so similar to a real cell, the immune system is less likely to see the particles as dangerous. In addition, the membrane-coated particles can more easily attach to and enter cells to dispense their cargo. Inside the particle, the drug is stored either as a liquid, or embedded in a solid. Recently, an approach has been reported where a solid material is at the core of the particle, but this material has fine pores, like a sponge. This advance makes the particle even more like a cell . In order to get the nanoparticle to the tumor, when the particles are being manufactured, specific proteins can be embedded into the membrane layer on the surface of the particle. These proteins can be engineered to specifically bind molecules that are only found in the cancerous tissue.
Figure 1. A model liposome nanoparticle for drug delivery. (Illustration by Shannon McArdel)
Another potential technique for drug delivery is the construction of three-dimensional scaffolds. In this strategy, a drug can be loaded into the scaffold material, which is then implanted into the body. As the scaffold is broken down and absorbed by the body the drug is released slowly in the local area. The scaffold materials are often engineered to mimic non-cellular structures found in the body, like collagen or keratin, which exist naturally as networks of fibers in the skin, joints, and most other tissues. Over the last two decades, as understanding of biology has grown, scientists have realized that these networks of fibers are not just a passive component of tissue, or just a place for cells to attach and reside, but are active components in their own right. These fibrous networks can provide mechanical cues to cells, sequester and release signals between cells, and direct developing tissues. Since these natural scaffolds can have such dynamic effects on cells, it makes sense to custom-engineer them to affect cells in a determined way. Materials engineers have created synthetic structures out of many different types of polymers (long molecules made of repeating units), ranging from spherical particles to bulk, porous structures (Figure 2). The main challenge in this area of research is to start with a material and a process that is non-toxic, and to make sure the final structure can interact with cells. These materials are being used in increasingly sophisticated ways. A recent report demonstrates the efficacy of delivering a tumor vaccine in mice by way of a scaffold .
Figure 2. A three-dimensional scaffold of poly(lactic-co-glycolic acid) (PLGA) at two different magnifications. (Image credit: DoITPoMS, University of Cambridge, UK)
Hydrogels represent yet another approach to making scaffolds. Hydrogels are most popularly used in contact lenses. This class of materials, like the name suggests, are polymers that readily absorb water. Therefore, the bulk structure can be more than 99% water by weight. Water is abundant in the body, and every biochemical reaction occurs in an aqueous environment, so it makes sense to engineer a drug delivery system to incorporate water. Even though only a small fraction of the weight is a connected network of polymer, a mechanically stable structure in any arbitrary shape (like a lens) can be formed. The advantage of using hydrogels is that they are not as rigid as other scaffold systems. They can be injected, instead of implanted. However, since the starting material is water-based, different strategies must be employed to incorporate active drugs.
Each of these materials system has limitations and special considerations. How much drug can be loaded, what types of drug molecules are compatible, what kind of dosing characteristics are desired — all of these questions make the selection of a suitable drug delivery method a complicated decision. But with all the possibilities that scientists are pursuing, the future of medicine seems bright for better treatments with fewer side effects.
Joe Akin is a PhD student in the Immunology program at Harvard Medical School.
 Wilson, D. Roche Backs New Method for Drug Delivery to Cells. The New York Times, 24 Aug 2010.
 Ashley, C.E., Carnes, E.C., Phillips G.K., Padilla, D., Durfee, P.N., Brown, P.A., et al. (2011) The targeted delivery of multicomponent cargos to cancer cells by nanoporous particle-supported lipid bilayers. Nat. Mater. 10:389-397.
 Ali, O., Emerich, D., Dranoff, G., & Mooney, D. (2009) In situ regulation of DC subsets and T cells mediates tumor regression in mice. Science Transl. Med., 1:8ra19.
Links of Interest:
ACS article on drug delivery: http://pubs.acs.org/cen/coverstory/8034/8034drugdelivery.html
Langer Lab, MIT: http://web.mit.edu/langerlab/