Transforming drug delivery
Imagine being given a task to land someone onto the moon. You have two methods. In one, you gather one million people in one place. You throw these million people into space, hoping that one or two of them land on the moon. “This is the pill and tablet method. You are giving drugs in milligrams when only nanograms or micrograms of that drug are needed,” says Abhay Chauhan, PhD, MPharm, BPharm, Associate Professor of Biopharmaceutical Sciences at the Medical College of Wisconsin (MCW) School of Pharmacy.
Now imagine a second method. This time you build a rocket, put two people into the rocket, and then equip it with an auto-pilot guidance system. Both people reach the moon. This is the analogy that Dr. Chauhan uses to introduce his pharmacy students to the concept of advanced drug delivery systems. He is working on novel drug delivery systems that bring smaller amounts of drugs to exactly where they need to go using drug targeting. Current drug delivery methods such as pills don’t target the disease area directly. Instead, they enter the bloodstream and are delivered to all areas of the body, which may cause undesirable side effects.
Dr. Chauhan is working on a new nanoscale drug delivery system called dendrimers. One nanometer is a bit less than half of the length of a strand of DNA, so dendrimers exist on the same scale as the parts of the cell they are targeting. Dendrimers are a fourth class of polymers. In general, polymers are usually long, non-uniform structures made up of smaller repeating units. Examples of polymers are plastics, like soda bottles and Styrofoam.
The name “dendrimer” comes from the Greek word “dendron,” which means tree. Dendrimers are different than traditional polymers because they have well-defined, three-dimensional structures consisting of a core, generations, and a surface. In the center, dendrimers have a three-dimensional core. The core is grown outward into an attached branching structure. Each new layer of branching is called a generation and is added in steps, with the outermost layer ending in the form of outside surface groups.
The main features that make dendrimers ideal for drug delivery are its spherical structure and its polyvalent surface groups. Polyvalency means that dendrimers are able to have multiple surface groups attached to a single core structure. Drugs can either be physically entrapped within the dendrimers in their spherical structure or chemically bonded to its surface using covalent bonds, which are a strong type of chemical bonds in which atoms share their electrons.
“Dendrimers are like a smartphone. A smartphone delivers a single platform for multiple apps. In dendrimers we are trying to create a nanodevice which goes into the body and does multiple jobs,” says Dr. Chauhan. For example, if a physician wanted to find out if a patient had cancer, they would be able to use something like a dendrimer nanodevice that could find the cancerous cells, light up in an MRI scan so the cancer could be diagnosed, and deliver a treatment at the same time.
Dendrimers can provide help in various stages of drug development. One way in which they help is by enhancing the ability of drugs to dissolve in water. “Solubility is important because almost the entire body is made of water, so drugs have to travel through it,” says Dr. Chauhan. “There are many drugs which have been discovered that could be great, but they have solubility issues.”
Dr. Chauhan pioneered work showing that dendrimers can solubilize drugs that usually would be insoluble in water. Dendrimers also can increase the stability of drugs, which can lead to better bioavailability, which is the amount of drug that reaches the intended site and the rate at which it is done.
Dr. Chauhan is currently working to develop a smart drug delivery system that targets brain tumors. Drugs being delivered to the brain have the added difficulty of needing to pass through the blood-brain barrier, which filters out most drugs from reaching the brain. Dr. Chauhan attached transferrin, which is a protein that carries iron, to the dendrimer surface. Receptors in the blood-brain barrier bind to transferrin and allow the dendrimer to pass through. Brain tumors have a higher-than-usual amount of transferrin receptors, ensuring that the dendrimers will be able to find and pass into the tumors, where they can deliver medication. Other targeting ligands, such as folic acid and mannose, were also attached to dendrimers to target cancerous cells. This gives the dendrimers a better chance to reach their destination while avoiding other parts of the brain. “We are making sure that the dendrimer goes to one specific area, stays there, and keeps on releasing the drug,” says Dr. Chauhan.
So far, Dr. Chauhan and his team have formulated a dendrimer that was able to orally deliver an anticancer chemotherapy drug and work equivalently to the drug’s current formulation which is delivered intravenously. An oral version of the drug would allow patients to treat themselves at home instead of needing an infusion at the hospital. Dendrimer delivery would also decrease the current side effects of the drug which include low blood counts, hair loss, and nausea and vomiting.
His next step is to work on an antitumor nanodevice that could be delivered intranasally, which could increase the efficiency and safety of cancer drug delivery. Dendrimers can travel to the brain directly from the nasal cavity, which can further help target drugs to the brain and reduce side effects elsewhere in the body. Dr. Chauhan has previously developed a nanodevice for delivering the antipsychotic drug Haloperidol to the brain intranasally, which was able to deliver the same effects to mice as with a greater dosage by injection.
Dendrimers currently are being applied mainly to applications for chronic diseases such as cancer or HIV because there is a lack of safety data to date. “The main issue is that we need more toxicity data on dendrimers. We need to show how they behave inside the body and how they leave the body,” says Dr. Chauhan. Dendrimers also take months to create and are expensive. After each generation of branching is created, the dendrimers must be cleaned and tested. “Conventionally, we can use this in chronic diseases where the cost of drugs won’t be much more and where better treatment, rather than cost, is an issue.”
The only therapeutic dendrimer product currently granted regulatory approval for testing in humans is VivaGel, which is a gel for the possible prevention of HIV. There are other dendrimer products available for medical uses, such as Stratus, which is a cardiovascular diagnostic test, and Alert Ticket, which can detect Anthrax.
Dendrimers are versatile enough to have potential transport applications everywhere, such as through the skin, which is Dr. Chauhan’s other main research focus. He currently holds a patent application for transdermal dendrimer delivery of an antioxidant called reservatrol. Reservatrol has anti-aging properties and is naturally found in peanuts, grapes, and berries. It is best known for making headlines after being controversially thought to be responsible for the positive cardiovascular effects of red wine.
Current high-end skin creams containing resveratrol can sell on the market for around $200, although the amount of reservatrol customers are paying for differs. “We bought many products and extracted resveratrol from them. We found that it is not what they claim, and their product is degrading very fast,” says Dr. Chauhan. Resveratrol has stability and water solubility issues. To get around its solubility, most products add filler ingredients. “I’m making a next generation product which is environmentally friendly and has no oil, no alcohol, and no surfactants,” says Dr. Chauhan.
Before he can bring a product to the market, Dr. Chauhan must account for where dendrimer nanodevices travel after going through the skin. “We need to show that it either is not going into the blood after being applied topically, or if it is going into the blood, that it is safe.”
Dr. Chauhan says it’s hard to tell what area of medicine could be most impacted by dendrimer drug delivery. “Anything can be possible,” he says. “It’s a new technology that you can use in all possible ways.”
The beauty of dendrimers is that they serve as a multi-tool that can be engineered to be effective against a variety of different diseases. It speaks to their wide potential that their applications range from improving cancer treatment to creating better skincare products. “My goal is to create multifunctional dendrimers that will serve as nanodevices,” says Dr. Chauhan. “I think that what I do today will have benefits in the long-run.”