Overcoming drug delivery barriers

Editor’s Note: The following is a summary of one of the talks from the 2013 Nano-bio Symposium hosted by Johns Hopkins Institute for NanoBioTechnology held May 17. This summary was written by Randall Meyer, a doctoral candidate in the biomedical engineering and a member of the Cancer Nanotechnology Training Center. Look for other symposium summaries on the INBT blog.

Nanotechnology bears a multitude of possibilities to systematically and specifically treat many well-characterized and currently untreatable diseases.  Despite this, there exist multiple barriers to its development including challenges related to delivery in the human body.

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Justin Hanes, a professor of Chemical and Biomolecular Engineering at Johns Hopkins University, highlighted some of the exciting advances that his laboratory has developed to overcoming these challenges.  According to Hanes, one of the primary functions of nanobiotechnology is to enable a therapy to be delivered to a specific location and only remain there for as long as it is needed.  He likened this idea to applying weed poison to a rose garden.  You only want to apply a little bit of poison to a targeted area, not flood the whole garden.  Unfortunately conventional cancer chemotherapy is like flooding the garden, but only 1 percent of the drug reaches the tumor.  Hanes stated the goal of his work is to flip that so that all but 1 percent of the drug makes it to the site of delivery.

With that in mind, Hanes summarized two stories from his lab of ideas that are successfully being translated from bench to bedside.  One therapy involves the use of custom designed nanoparticles that are capable of penetrating the mucus layers of various human tissues to enable a controlled release of drug into the body.  The second therapy involves the use of injectable particles to the eye that inhibit blood vessel formation,  which is related to diseases such as macular degeneration.

These therapies are being developed by biotech companies launched by Hanes, GrayBug and Kala Pharmaceuticals.

Self-assembling drug molecules could fight cancer

A popular method of targeted drug delivery for anti-cancer drugs involves doping another material with the desired pharmaceutical to obtain better targeting efficiency to tumor sites. The problem with this method, researchers have discovered, is that the quantity of drug payload per delivery unit can vary widely and that the materials used for delivery can have toxic side effects.

But what if you could turn the drug molecule itself into a nanoscale delivery system, cutting out the middleman completely?

TEM image of nanotubes formed by self-assembly of an anticancer drug amphiphile. These nanotubes possess a fixed drug loading of 38% (w/w). Image from Cui Lab.

TEM image of nanotubes formed by self-assembly of an anticancer drug amphiphile. These nanotubes possess a fixed drug loading of 38% (w/w). Image from Cui Lab.

Using the process of molecular self-assembly, that is what Honggang Cui, an assistant professor in the Department of Chemical and Biomolecular Engineering at Johns Hopkins University, is attempting to do. His efforts have netted him the prestigious Faculty Early Career Development (CAREER) Award from the National Science Foundation. Cui, an affiliated faculty member of the Johns Hopkins Institute for NanoBioTechnology, will receive the $500,000 award over five years.

Cui explained that a current method of delivering anti-cancer drugs is to enclose them in a nanoscale carrier made of natural or synthetic materials, but this method presents several challenges. “The amount of drug loaded per carrier is very much limited and varies from batch to batch. Even in the same batch, there is a drug loading variation from carrier to carrier. Additionally, the carrier material itself may have toxic side effects,” he said.

Cui’s research seeks to eliminate the need for the carrier by coaxing the drug molecules themselves to form their own carrier through the process of self-assembly. His team is developing new molecular engineering strategies to assemble anti-cancer drugs into supramolecular nanostructures.

“Such supramolecules could carry as much as 100 percent of the drug, would possess a fixed amount of drug per nanostructure and would minimize the potential toxicity of the carrier,” Cui said.

To learn more about research in the Cui lab go to http://www.jhu.edu/cui/

 

Tackling the brain’s barrier

Watch this video now. Click the image.

Much like a sentry at a border crossing, the network of tiny blood vessels surrounding the brain only allows a few important molecules in or out. Of course, there is good reason for this. The brain controls the senses, motor skills, breathing, and heart rate, as well as being the seat of thoughts and emotional experiences. Just as our tough plated skull offers a physical armor for the brain, the blood-brain barrier shields our brain from potentially harmful substances at the molecular level.

“Despite its powerful role in controlling bodily functions, the brain is extremely sensitive to chemical changes in environment,” said Peter Searson, director of Johns Hopkins Institute for NanoBioTechnology (INBT) and lead on the Blood Brain Barrier Working Group (BBBWG). The BBBWG is a collaboration between INBT and the Brain Science Institute at the Johns Hopkins School of Medicine.

Oxygen, sugars (such as glucose), and amino acids used to build proteins can enter the brain from the bloodstream with no trouble, while waste products, such as carbon dioxide, exit the brain just as easily. But for most everything else, there’s just no getting past this specialized hurdle. In fact, the blood-brain barrier protects the brain so effectively that it also prevents helpful drugs and therapeutic agents from reaching diseased areas of the brain. And because scientists know very little about the blood-brain barrier, discovering ways to overcome the blockade has been a challenge.

“We still don’t know very much about the structure and function of the blood-brain barrier,” Searson said. “Because we don’t know how the blood-brain barrier works, it presents a critical roadblock in developing treatment for diseases of the central nervous system, including Amyotrophic Lateral Sclerosis (Lou Gehrig’s disease), Alzheimer’s, autism, brain cancer, Huntington’s disease, meningitis, Multiple Sclerosis (MS), neuro-AIDS, Parkinson’s, and stroke. Treatable brain disorders are limited to depression, schizophrenia, chronic pain, and epilepsy. If we had a better understanding of how the blood-brain barrier worked, we would be in a better position to develop treatments for many diseases of the brain,” Searson said. But he added, even with a better understanding of the blood-brain barrier, humans cannot be used to study new therapies.

One way the BBBWG plans to surmount this roadblock is by creating an artificially engineered (or simulated) blood-brain barrier. An engineered artificial blood-brain barrier would allow researchers to conduct studies that simulate trauma to or diseases of the blood-brain barrier, such as stroke, infection, or cancer.

“It would also give us insight into understanding of the role of the blood-brain barrier in aging,” said Searson. Drug discovery and the development of new therapies for central nervous system diseases would be easier with an artificial blood-brain barrier and certainly safer than animal or human testing. Such an artificial membrane could be used as a platform to screen out drugs used to treat maladies outside the brain, but which have unwanted side effects, such as drowsiness.

The creation of such a platform will require the skills of a multidisciplinary team that includes engineers, physicists, neuroscientists and clinicians working together to bring new ideas and new perspectives, Searson added, and will build on recent advances in stem cell engineering and the development of new biomaterials. Current members of the BBBWG include researchers from the departments of neuroscience, anesthesiology, psychiatry, pathology and pharmacology from the Hopkins School of Medicine and from the departments of mechanical engineering, chemical and biomolecular engineering and materials science from the Whiting School of Engineering.

One member of that multidisciplinary team is Lew Romer, MD, associate professor of Anesthesiology and Critical Care Medicine, Cell Biology, Biomedical Engineering, and Pediatrics at the Center for Cell Dynamics at the Johns Hopkins School of Medicine.

“At a cellular level, the focus here is on the adhesive interface of the neurovascular unit – the place where the microcirculation meets the complex parenchyma (or functional surface) of the brain,” Romer said. “This is a durable but delicate and highly specialized region of cell-cell interaction that is responsive to biochemical and mechanical cues.”

Romer said work on the blood-brain barrier is a “fascinating and essential frontier in cell biology and translational medicine, and one that clinicians struggle to understand and work with at the bedsides of some of our sickest and most challenging patients from the ICU’s to the Oncology clinics. Development of an in vitro blood-brain barrier model system” that could be used in molecular biology and engineering manipulations would provide investigators with a powerful window into this vital interface,” Romer added.

Visit the Blood-Brain Barrier Working Group website here.

Watch a student video about current blood-brain barrier research here.

Story by Mary Spiro first appears in the 2012 edition of Nano-Bio Magazine.

Shaping up nanoparticles for DNA delivery to cancer cells

Hai-Quan Mao, 2012 Johns Hopkins Nano-Bio Symposium. Photo by Mary Spiro

To treat cancer, scientists and clinicians have to kill cancer cells while minimally harming the healthy tissues surrounding them. However, because cancer cells are derived from healthy cells, targeting only the cancer cells is exceedingly difficult. According to Dr. Hai-Quan Mao of the Johns Hopkins University Department of Materials Science and Engineering, the “key challenge is between point of delivery and point of target tissue” when it comes to delivering cancer therapeutics. Dr. Mao spoke about the difficulties of specifically delivering drugs or genetic material to cancer cells at the 2012 Johns Hopkins University Nano-Bio Symposium. Scientists had originally thought they could create a “magic bullet” to patrol for cancer cells in the body. However, this has not been feasible; only 5 percent of injected nanoparticles reach the targeted tumor using current delivery techniques. Simply put, scientists need to figure out how to inject a treatment into the body and then selectively direct that treatment to cancer cells if the treatments are to work to their full potential.

With this in mind, Dr. Mao and his research team aim to optimize nanoparticle design to improve delivery to tumor cells by making the nanoparticles more stable in the body’s circulatory system. Mao’s group uses custom polymers and DNA scaffolds to create nanoparticles. The DNA serves dual purposes, as a building block for the particles and as a signal for cancer cells to express certain genes (for example, cell suicide genes). By tuning the polarity of the solvent used to fabricate the nanoparticles, the group can control nanoparticle shape, forming spheres, ellipsoids, or long “worms” while leaving everything else about the nanoparticles constant. This allows them to test the effects of nanoparticle size on gene delivery. Interestingly, “worms” appear more stable in the blood stream of mice and are therefore better able to deliver targeted DNA. Studies of this type will allow intelligent nanoparticle design by illuminating the key aspects for efficient tumor targeting.

Currently, Dr. Mao’s group is extending their fabrication methods to deliver other payloads to cancer cells. Small interfering ribonucleic acid (siRNA), which can suppress expression of certain genes, can also be incorporated into nanoparticles. Finally, Mao noted that the “worm”-shaped nanoparticles created by the group look like naturally occurring virus particles, including the Ebola and Marburg viruses. In the future, the group hopes to use their novel polymers and fabrication techniques to see if shape controls virus targeting to specific tissues in the body. This work could have important applications in virus treatment.

Story by Colin Paul, a Ph.D. student in the Department of Chemical and Biomolecular Engineering at Johns Hopkins with interests in microfabrication and cancer metastasis.