Biodegradable nanoparticles ideal carrier for drug delivery

Johns Hopkins University researchers have created biodegradable nanosized particles that can easily slip through the body’s sticky and viscous mucus secretions to deliver a sustained-release medication cargo. The researchers say that these nanoparticles, which degrade over time into harmless components, could one day carry life-saving drugs to patients suffering from dozens of health conditions, including diseases of the eye, lung, gut or female reproductive tract.

The mucus-penetrating biodegradable nanoparticles were developed by an interdisciplinary team led by Justin Hanes, a professor of chemical and biomolecular engineering in Johns Hopkins’ Whiting School of Engineering*. The team’s work was reported recently in the Proceedings of the National Academy of Sciences. Hanes’ collaborators included cystic fibrosis expert Pamela Zeitlin, a professor of pediatrics at the Johns Hopkins School of Medicine and director of Pediatric Pulmonary Medicine at Johns Hopkins Children’s Center.

Individual biodegradable nanoparticle developed by the Justin Hanes Lab at Johns Hopkins University (shown here at microscale for easier imaging) displaying polymer coating as a red fluorescent glow. Hanes' biodegradable nanoparticles have the ability to penetrate mucus barriers in the body to deliver drugs. (Photo by Jie Fu/JHU)

Individual biodegradable nanoparticle developed by the Justin Hanes Lab at Johns Hopkins University (shown here at microscale for easier imaging) displaying polymer coating as a red fluorescent glow. Hanes’ biodegradable nanoparticles have the ability to penetrate mucus barriers in the body to deliver drugs. (Photo by Jie Fu/JHU)

These nanoparticles, Zeitlin said, could be an ideal means of delivering drugs to people with cystic fibrosis, a disease that kills children and adults by altering the mucus barriers in the lung and gut. “Cystic fibrosis mucus is notoriously thick and sticky and represents a huge barrier to aerosolized drug delivery,” she said. “In our study, the nanoparticles were engineered to travel through cystic fibrosis mucus at a much greater velocity than ever before, thereby improving drug delivery. This work is critically important to moving forward with the next generation of small molecule– and gene-based therapies.”

Beyond their potential applications for cystic fibrosis patients, the nanoparticles also could be used to help treat disorders such as lung and cervical cancer and inflammation of the sinuses, eyes, lungs and gastrointestinal tract, said Benjamin C. Tang, lead author of the journal article and a postdoctoral fellow in the Department of Chemical and Biomolecular Engineering. “Chemotherapy is typically given to the whole body and has many undesired side effects,” he said. “If drugs are encapsulated in these nanoparticles and inhaled directly into the lungs of lung cancer patients, drugs may reach lung tumors more effectively and improved outcomes may be achieved, especially for patients diagnosed with early stage non–small cell lung cancer.”

“If drugs are encapsulated in these nanoparticles and inhaled directly into the lungs of lung cancer patients, drugs may reach lung tumors more effectively and improved outcomes may be achieved, especially for patients diagnosed with early stage non–small cell lung cancer.” ~ Ben Tang

In the lungs, eyes, gastrointestinal tract and other areas, the human body produces layers of mucus to protect sensitive tissue. But an undesirable side effect is that these mucus barriers can also keep helpful medications away.

In proof-of-concept experiments, previous research teams led by Hanes earlier demonstrated that latex particles coated with polyethylene glycol could slip past mucus coatings. But latex particles are not a practical material for delivering medication to human patients because they are not broken down by the body. In the new study, the researchers described how they took an important step forward in making new particles that biodegrade into harmless components while delivering their drug payload over time.

“The major advance here is that we were able to make biodegradable nanoparticles that can rapidly penetrate thick and sticky mucus secretions, and that these particles can transport a wide range of therapeutic molecules, from small molecules such as chemotherapeutics and steroids to macromolecules such as proteins and nucleic acids,” Hanes said. “Previously, we could not get these kinds of sustained-release treatments through the body’s sticky mucus layers effectively.”

The new biodegradable particles comprise two parts made of molecules routinely used in existing medications. An inner core, composed largely of polysebacic acid, or PSA, traps therapeutic agents inside. A particularly dense outer coating of polyethylene glycol, or PEG, molecules, which are linked to PSA, allows a particle to move through mucus nearly as easily as if it were moving through water and also permits the drug to remain in contact with affected tissues for an extended period of time.

In Hanes’ previous studies with mucus-penetrating particles, latex particles could be effectively coated with PEG but could not release drugs or biodegrade. Unlike latex, however, PSA can degrade into naturally occurring molecules that are broken down and flushed away by the body through the kidney, for example. As the particles break down, the drugs loaded inside are released.

This property of PSA enables the sustained release of drugs, said Samuel Lai, assistant research professor in the Department of Chemical and Biomolecular Engineering, while designing them for mucus penetration allows them to more readily reach inaccessible tissues.

Biodegradable nanoparticles produced by the Justin Hanes Lab at Johns Hopkins University visualized under a scanning electron microscope. (Photo by Ben Tang and Mark Koontz/JHU)

Biodegradable nanoparticles produced by the Justin Hanes Lab at Johns Hopkins University visualized under a scanning electron microscope. (Photo by Ben Tang and Mark Koontz/JHU)

Jie Fu, an assistant research professor, also from the Department of Chemical and Biomolecular Engineering, said, “As it degrades, the PSA comes off along with the drug over a controlled amount of time that can reach days to weeks.”

PEG acts as a shield to protect the particles from interacting with proteins in mucus that would cause them to be cleared before releasing their contents. In a related research report, the group showed that the particles can efficiently encapsulate several chemotherapeutics, and that a single dose of drug-loaded particles was able to limit tumor growth in a mouse model of lung cancer for up to 20 days.

Hanes, Zeitlin, Lai and Fu are all affiliated with the Johns Hopkins Institute for NanoBioTechnology. Other authors on the paper are Ying-Ying Wang, Jung Soo Suk and Ming Yang, doctoral students in the Johns Hopkins Department of Biomedical Engineering; Michael P. Boyle, an associate professor in Pulmonary and Critical Care Medicine at the Johns Hopkins School of Medicine; and Michelle Dawson, an assistant professor at the Georgia Institute of Technology.

This work was supported in part by funding from the National Institutes of Health, a National Center for Research Resources Clinical and Translational Science Award, the Cystic Fibrosis Foundation, the National Science Foundation and a Croucher Foundation Fellowship.

The technology described in the journal article is protected by patents managed by the Johns Hopkins Technology Transfer Office and is licensed exclusively by Kala Pharmaceuticals. Justin Hanes is a paid consultant to Kala Pharmaceuticals, a startup company in which he holds equity, and is a member of its board. The terms of these arrangements are being managed by The Johns Hopkins University in accordance with its conflict-of-interest policies.

(*At the time that this research was published, Hanes had his primary affiliation with the Whiting School of Engineering Department of Chemical and Biomolecular Engineering. Hanes’ current primary affiliation is with the Johns Hopkins School of Medicine Department of Ophthalmology.)

Related Links

Biodegradable polymer nanoparticles that rapidly penetrate the human mucus barrier. PNAS 2009 106:19268-19273; published online before print November 9, 2009.  [Institutional access required.]

Hanes Lab

Johns Hopkins Children’s Center

Institute for NanoBioTechnology

Story by Mary Spiro and Jacob Koskimaki with materials provided by Johns Hopkins Technology Transfer.

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Cell’s ‘cap’ of bundled fibers could yield clues to disease

Newsletter readers! If you are looking for the 2010 NanoBio Symposium story go to: http://inbt.jhu.edu/outreach/symposium
Doctoral student Shyam Khatau, left, and Denis Wirtz, director of the Johns Hopkins Engineering in Oncology Center, played a key role in finding a bundled “cap” of thread-like fibers that holds a cell’s nucleus in its proper place. Photo by Will Kirk, Homewoodphoto.jhu.edu.

Doctoral student Shyam Khatau, left, and Denis Wirtz, director of the Johns Hopkins Engineering in Oncology Center, played a key role in finding a bundled “cap” of thread-like fibers that holds a cell’s nucleus in its proper place. Photo by Will Kirk, Homewoodphoto.jhu.edu.

It turns out that wearing a cap is good for you, at least if you are a mammal cell.

Researchers from the Johns Hopkins Engineering in Oncology Center have shown that in healthy cells, a bundled “cap” of thread-like fibers holds the cell’s nucleus, its genetic storehouse, in its proper place. Understanding this cap’s influence on cell and nuclear shape, the researchers say, could provide clues to the diagnosis and treatment of diseases such as cancer, muscular dystrophy and the age-accelerating condition known as progeria.

“Under a microscope, the nucleus of a sick cell appears to bulge toward the top, while the nucleus of a healthy cell appears as a flattened disk that clings to the base,” said principal investigator Denis Wirtz, professor of chemical and biomolecular engineering and director of the Engineering in Oncology Center. “If we can figure out how and why this shape-changing occurs, we may learn how to detect, treat or perhaps even prevent some serious medical disorders.”

Scientists have known that misshapen nuclei are an indicator of disease, Wirtz said, but they were not certain how a cell controlled the shape of its nucleus, the structure in mammal cells where genetic material resides. In a study published in the Nov. 10 issue of the Proceedings of the National Academy of Sciences, however, the research team led by Wirtz reported the discovery of a fibrous structure that holds the nucleus in its place. The researchers call this new network structure the perinuclear actin cap.

“In healthy cells, the perinuclear actin cap is a domed structure of bundled filaments that sits above the nucleus, sort of like a net that is tethered all around to the perimeter of the cell membrane,”

Wirtz said. This configuration pushes the nucleus down toward the base of the cell and also creates the distinctive flattened shape of normal cells. Cells with cancer, muscular dystrophy or progeria, however, lack this distinctive cap, allowing the nucleus to float upward toward the top of the cell’s membrane. These diseased cells may appear more rounded and bulbous.

“The cap controls the shape of the nucleus by controlling the shape of the cell itself,” Wirtz said.

The perinuclear actin cap was discovered while the team was trying to find out if cell shape controls nucleus shape. By growing cells on a surface with alternating sticky and non-sticky stripes, the researchers noticed that as cells grew along a sticky stripe, their nuclei elongated as well. Using a confocal microscope — a special kind of microscope that can view an object one “slice” at a time — doctoral student Shyam Khatau was able to reconstruct the cell in three dimensions. By stacking the confocal microscope images together, Khatau, who is affiliated with the Johns Hopkins Institute for NanoBioTechnology, was able to produce short movies showing the 3-D structure of the cells, the nucleus and the perinuclear actin cap. (The movies are online here or below.)

“That’s when we saw the cap,” Khatau said, “and Dr. Wirtz realized we were on to something.”

The cap’s role in disease became evident when Khatau tested cells without the gene to produce lamin A/C, a protein found in the membrane of the nucleus of normal cells but absent in the nuclear membrane of cells from people with muscular dystrophy. Cells without lamin A/C failed to produce the perinuclear actin cap.

“We next plan to study how the cap’s effect on the shape of the nucleus affects what genes the cells express,” said Wirtz.

Khatau, who is pursuing his doctorate in the Department of Chemical and Biomolecular Engineering, is lead author of the journal article.

Additional Johns Hopkins authors on this paper are Wirtz; doctoral student Christopher M. Hale and senior Meet Patel from the Whiting School of Engineering’s  Department of Chemical and Biomolecular Engineering; and Peter C. Searson, a professor in the school’s Department of Materials Science and Engineering. Other co-authors were P. J. Stewart-Hutchinson and Didier Hodzic from the School of Medicine at the Washington University in St. Louis and Colin L. Stewart from the Institute of Medical Biology, Singapore.

This work was funded by the National Institutes of Health and the Muscular Dystrophy Association.

Story by Mary Spiro

PNAS journal article.

Johns Hopkins Engineering in Oncology Center

Johns Hopkins Institute for NanoBioTechnology

Department of Chemical and Biomolecular Engineering

Podcast: Nanotech method to study cell detachment could lead to improved cancer therapies

Peter Searson

Peter Searson

Cancer spreads from organ to organ when cells break free from one site and travel to another. Understanding this process, known as metastasis, is critical for developing ways to prevent the spread and growth of cancer cells. Peter Searson, Reynolds Professor of Materials Science and Engineering in the Whiting School of Engineering and director of the Institute for NanoBioTechnology, led a team of engineers who have developed a method to specifically measure detachment in individual cells.

The method, which uses lab-on-a-chip technology, allows researchers to observe and record the exact point when a cell responds to electrochemical cues in its environment and releases from the surface upon which it is growing. Better knowledge of the biochemistry of cell detachment could point the way to better cancer therapies. In this “Great Ideas” podcast, Elizabeth Tracey, communications associate for the School of Medicine, interviews Searson about this current research.

“…We know that processes like cell detachment are important in cancer metastasis, where cells become detached from tumors…” Peter Searson

Click here to listen:  Great Ideas Podcast: Peter Searson

Related links:

You can watch a video and read more about Searson’s method of studying cell detachment here.

Peter Searson’s INBT profile page.

This podcast was originally posted to the Johns Hopkins University “Great Ideas” web page. To view the original posting, click here.

Maitra’s Cancer Preventive Nano-Spice Featured on WJZ-TV

The spice, turmeric, contains a substance that has shown promise in the prevention and treatment of several diseases, including cancer. The only drawback is that the substance—curcumin—does not easily enter the bloodstream. Now, Anirban Maitra, associate professor at the Johns Hopkins School of Medicine and affiliated faculty member of the Institute for NanoBioTechnology, has created tiny, nano-curcumin particles so small they can be absorbed into the bloodstream through the stomach. Maitra was interviewed October 28, 2008 by Kellye Lynn of WJZ-TV in Baltimore.

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New Postdoc Program in Nanotechnology for Cancer Medicine Launched at Johns Hopkins

New postdoc program in nanobiotechnology at Johns Hopkins University. Credit: HIPS/JHU.

The Institute for NanoBioTechnology (INBT) has recently launched a postdoctoral fellowship in Nanotechnology for Cancer Medicine (NTCM). Funded by the National Cancer Institute, the goal of this new postdoctoral training program is to ensure that a diverse and highly trained workforce is available to assume leadership roles in biomedical, behavioral and clinical research. This is the first T-32 grant awarded in the Whiting School of Engineering. Applications are now being accepted for this one-of-a-kind program that will allow two new postdoctoral fellows to enter the program each year.

Denis Wirtz, professor of Chemical and Biomolecular Engineering in the Whiting School of Engineering, and Kenneth Kinzler, professor of Oncology at the School of Medicine will co-direct the NTCM training program. Wirtz is associate director of INBT and Kinzler is a member of INBT’s executive committee.

Postdoctoral fellows will learn new methods for molecular imaging, develop high-throughput diagnostic tools, and engineer novel drug, antibody, or genetically based delivery systems to treat human cancers, Wirtz explains. “They will be laying the foundations for technologies that will enable an inside-view of cancer cell functions, as opposed to the limited ‘blackbox’ input-output techniques currently used,“ Wirtz says.

NTCM fellows will view interactions between nanostructures and biological systems in physical, biological, and biomedical terms and will become adept at emerging concepts in biomolecular engineering, protein engineering, materials synthesis and surface modification. Fellows will be able to take advantage of research and clinical resources at the Johns Hopkins Hospital, the National Cancer Institute-designated Sidney Kimmel Comprehensive Cancer Center, the Ludwig Center for Cancer Genetics and Therapeutics, The Sol Goldman Pancreatic Cancer Center, and the In Vivo Cellular and Molecular Imaging Center, as well as the educational resources and experimental facilities available through INBT.

Each fellow will be supported for two years and will be co-advised by a faculty member in oncology or medicine and a faculty member in engineering. (There are 20 participating faculty members, please go to http://inbt.jhu.edu/postdoc-faculty.php to view the full list.) Fellows will take a core lecture course in either nanotechnology or cancer biology, a core laboratory course in nanobiotechnology for cancer medicine, and will attend a weekly journal club. In addition, fellows will participate in an annual retreat in the fall and the annual NanoBio Symposium in the spring. After two, 6-week rotations in the laboratories of participant faculty, fellows will embark on co-advised research in nanotechnology for cancer medicine.

Only U.S. citizens and permanent residents are eligible to apply for the NTCM program. Requirements for admission include a PhD in an engineering discipline or biological/oncology discipline or an MD degree. A concentration in cancer is helpful. Interested applicants should send their C.V. and two letters of recommendation to: Ashanti Edwards / Prof. Denis Wirtz, Institute for NanoBioTechnology, Johns Hopkins University, NEB 100, 3400 N. Charles St. Baltimore, MD 21218. For more information, e-mail aedwards@jhu.edu.

The Institute for NanoBioTechnology at Johns Hopkins University brings together internationally renowned expertise in medicine, engineering, the sciences and public health to foster the next wave of nanobiotechnology innovation. Faculty members affiliated with INBT are members of the Johns Hopkins Krieger School of Arts and Sciences, Whiting School of Engineering, School of Medicine, Bloomberg School of Public Health and Applied Physics Laboratory. For more information about INBT, go to http://inbt.jhu.edu.

Story by Mary Spiro