Speakers confirmed for Oct. 24 INBT student symposium

Student-run symposiums are held in the fall and early spring.

Graduate students and postdoctoral fellows from the Johns Hopkins Institute for NanoBioTechnology, Center of Cancer Nanotechnology Excellence and Physical Science-Oncology Center are hosting a mini-symposium highlighting current research in these entities on Wednesday, October 24 from 9 a.m. to 4 p.m. in the Clipper Room of Shriver Hall on the Homewood campus of Johns Hopkins University. In addition to student presenters, the symposium features a faculty expert speaker and invited guest lectures from the National Institutes of Health program managers for both the CCNEs and the PS-OCs.

Confirmed speakers include:
  • 10:00 am – 10:20 am Zachary Gagnon, assistant prof. of chemical and biomolecular engineering: “Nonlinear electrokinetics at microfluidic liquid/liquid interfaces
  • 10:20 am – 10:40 am Laura Ensign: Mucus-penetrating particles for vaginal drug delivery (CCNE)
  • 10:40 am – 11:00 am Wei-Chien Hung: alpha4-tail-mediated Rac1 and RhoA-myosin II in optimizing 2D versus confined migration (PS-OC)
  • 11:00 am – 11:20 am Iwen Wu: An adipose-derived biomaterial for soft tissue reconstruction (INBT)
  • 11:20 am – 11:50 pm Sean Hanlon: NCI Physical Science–Oncology Centers (PS-OC) Program, bringing a new perspective to cancer research
  • 11:50 am – 1:00 pm Break/Lunch
  • 1:00 pm – 1:30 pm David Weitz: Drop-based microfluidics: Biology one picoliter at a time (INBT)
  • 1:30 pm -2:00 pm Sara S. Hook, projects manager for the Alliance for Nanotechnology in Cancer program within the Center for Strategic Scientific Initiatives (CSSI) at the National Cancer Institute
  • 2:00 pm – 2:20 pm Break
  • 2:20 pm – 2:40 pm Phrabha Raman: A microfluidic device to measure traction forces during confined cancer cell migration towards chemoattractant (PS-OC)
  • 2:40 pm – 3:00 pm Allison Chambliss: Single-cell epigenetics to retain cell morphology (PS-OC)
  • 3:00 pm – 3:20 pm Sravanti Kusuma: Tissue engineering approaches to study blood vessel growth (PS-OC)
  • 3:20 pm – 3:40 pm Benjamin Lin: Using synthetic spatial signaling perturbations to probe directed cell migration (INBT)
  • 3:40 pm – 4:00 pm Stephany Tzeng: Cancer-specific gene delivery to liver cell cultures using synthetic poly(beta-amino esters) (INBT)
  • 4:00 – 4:15 pm Brian Keeley: An epigenetic approach to assessing specificity and sensitivity of DNA methylation (CCNE)

The symposium talks are free and open to the Hopkins community as space allows.

 

 

DNA folded into shapes offers alternative gene delivery vehicle

DNA molecules (light green) packaged into nanoparticles of different shapes using a polymer with two different segments. Cartoon illustrations created by Wei Qu, Northwestern University and Martin Rietveld, Johns Hopkins /INBT. Microscopic images created by Xuan Jiang, Johns Hopkins University.

Using snippets of DNA as building blocks to create nanoscale rods, worms and spheres, researchers at Johns Hopkins and Northwestern universities have devised a means of delivering gene therapy that avoids some of the undesirable aspects of using viruses to deliver genes to treat disease. The shape and size of the DNA-based nanoparticle also affected how well the genes were delivered.

Worm shapes, for example, were particularly effective.

“The worm-shaped particles resulted in 1,600 times more gene expression in the liver cells than the other shapes,” said Hai-Quan Mao, an associate professor ofmaterials science and engineering in Johns Hopkins’ Whiting School of Engineering. “This means that producing nanoparticles in this particular shape could be the more efficient way to deliver gene therapy to these cells.”

This study was published in the Oct. 12 online edition of Advanced Materials.

Initial funding for the research came from a seed grant provided by the Johns Hopkins Institute for NanoBioTechnology, of which Mao is an affiliate. The Johns Hopkins-Northwestern partnership research was supported by a National Institutes of Health grant.

Read the entire Johns Hopkins press release by Phil Sneiderman (JHU) and Megan Fellman (Northwestern) here.

 

 

Siebel scholars demonstrate INBT’s multidisciplinary advantage

Siebel scholar Laura Ensign. Photo by Marty Katz.

Four of the five recently named Johns Hopkins University graduate students who were listed among the 2013 Siebel Scholars are affiliated with Johns Hopkins Institute for NanoBioTechnology laboratories. Three of the four were also part of INBT’s Nanobio IGERT, or Integrative Graduate Education Research Traineeship, a National Science Foundation funded program. The Siebel Scholars program recognizes the most talented students at the world’s leading graduate schools of business, bioengineering, and computer science.

INBT affiliated winners include Laura Ensign, Mustapha Jamal, Garrett Jenkinson and Yi Zhang. Ensign, Jamal and Jenkinson were INBT IGERT fellows. All note that their involvement with INBT to one degree or another has played a role in their academic success at Hopkins.

Laura Ensign, in the Department of Chemical and BioMolecular Engineering, works in the laboratory of Justin Hanes, who is director of the Center for Nanomedicine and investigator with the Center of Cancer Nanotechnology Excellence (CCNE). Ensign’s research involves understanding the mucus barrier in the female reproductive tract and how it protects and also inhibits the delivery of drugs to this part of the body. Using specially engineered mucus penetrating nanoparticles designed in the Hanes labs, she is working on more effective drug delivery systems. Ensign is listed as an inventor on three patents that have been licensed to private industry.

“As an engineer, the multidisciplinary nature of INBT has allowed me to do research that has the potential to help patients in the clinic,” Ensign said. Furthermore, Ensign noted that having two advisors, a requirement for INBT’s IGERT program, played an important role in her graduate work and discoveries. In addition to being advised by Hanes, Ensign also was mentored by Richard Cone, professor in the Department of Biophysics in the Krieger School of Arts and Sciences. “The trajectory of my research has been greatly influenced by having two advisers with different backgrounds. My research has included engineering and formulation aspects, as well as biological and translational aspects, resulting in higher impact results with broader implications. “

Siebel scholar Mustapha Jamal

Mustapha Jamal, also in the Department of Chemical and Biomolecular Engineering, worked in the laboratory of associate professor David Gracias. Jamal has developed self-assembling structures that provide a framework for 3D tissue culture. In addition, these self-assembling structures let him study how geometry affects cell behavior. Jamal is a co-inventor on a patent application in connection with this research.

“Working in a multidiscplinary lab has helped me engineer miniaturized 3D cell culture platforms utilizing techniques from seemingly disparate research areas: semiconductor processing and tissue engineering,” Jamal said. “With a bit of creativity, this diverse skill set has proven useful in forging exciting and fruitful collaborations and should serve me well for years to come. From the annual INBT Symposium to the courses and workshops, I have shared my own research with the community and engaged in academic discussions that have helped me keep on top of research conducted here at Hopkins and abroad.”

Siebel scholar Garrett Jenkinson learning wet lab skills during INBT’s nanobio bootcamp. Photo by Mary Spiro.

Mathematics is the tool that W. Garrett Jenkinson uses in his research in the Complex Systems Science Laboratory of John Goutsias, professor of electrical and computer engineering. Jenkinson’s work can be applied to such real-life problems as how infections spread through a population via social interaction or how processes occur inside the cell, both of which can help inform the development of drugs to fight disease.

“The Complex Systems Science Laboratory takes the INBT spirit of interdisciplinary research to heart. The lab focuses on rigorous mathematical formulations that will simultaneously advance as many branches of science and engineering as possible,” Jenkinson said. “My graduate work has allowed me to follow my mathematical interests toward whatever application they might lead. In my tenure at Hopkins, I have published papers on a diverse array of topics including biochemical reaction networks, epidemiology, neurobiology, ecology, thermodynamics, unmanned automated vehicles, evolutionary game theory, pharmacokinetics, and social networks.

Through the IGERT program, Jenkinson said, INBT “trained me in fields that an electrical and computer engineer might otherwise find foreign, such as biology, nanotechnology, and wet lab techniques. Furthermore, the INBT has fostered relationships with my peers from diverse scientific backgrounds, with whom I have collaborated on multiple occasions to lend or receive advice in scientific matters that required expertise in multiple fields. I am excited to be joining the Siebel Scholars program which facilitates relationships across universities in the same way the INBT fosters these relationships across departments at Johns Hopkins University.”

Siebel scholar Yi Zhang. Photo by Mary Spiro.

Yi Zhang conducts his research in the lab of Jeff Tza-Huei Wang, an associate professor of mechanical engineering, biomedical engineering and oncology and also a project leader in the Center of Cancer Nanotechnology Excellence. Zhang’s work developing micro- and nanoscale molecular techniques to help diagnose cancer and infectious diseases has supported one of the core research goals of the CCNE. He is listed as an inventor on four patent applications, one of which has been licensed by a biotechnology company.

Said Zhang, “Being associated with an INBT affiliated laboratory offers me ample opportunities to collaborate with researchers in various fields and get help from my fellow students. Biomedical engineering is multidisciplinary in nature. My research focuses on bridging the gap between medical science and engineering, and my thesis is committed to improving molecular diagnostics using advanced nanotechnology. An integrated center like CCNE presents a new research paradigm by bringing together all necessary expertise from various fields to tackle one big problem in an extremely efficient way. It has definitely changed my view of conducting translational research.”

According to the organization’s website, Siebel Scholars and are chosen by the dean of their respective schools on the basis of outstanding academic achievement and demonstrated leadership. On average, Siebel Scholars rank in the top 5 percent of their class, many within the top 1 percent. The merit-based program provides $35,000 to each student for use in his or her final year of graduate studies.

The Siebel Scholars program was established in 2000 by the Siebel Foundation through a grant of more than $45 million to Carnegie Mellon University; Harvard University; The Johns Hopkins University; Massachusetts Institute of Technology; Northwestern University; Stanford University; Tsinghua University; University of California, Berkeley; University of California, San Diego; University of Chicago; University of Illinois at Urbana-Champaign; and University of Pennsylvania. Each year, five graduate students from each of the 17 partner institutions are honored as Siebel Scholars and receive a $35,000 award for their final year of studies.

Established in 2006, the Institute for NanoBioTechnology at Johns Hopkins brings together 223 researchers from every division of the University to create new knowledge and new technologies at the interface of nanoscience and medicine.

 

Konstantopoulos named BMES fellow

Konstantinos Konstantopoulos (Photo by Mary Spiro)

Konstantinos Konstantopoulos, professor and chair of the Department of Chemical and Biomolecular Engineering at Johns Hopkins University’s Whiting School of Engineering has been named a Fellow of the Biomedical Engineering Society (BMES). Konstantopoulos was one of only nine fellows elected to the Society’s Class of 2012.

BMES states that Konstantopoulos received this honor in recognition of his “seminal bioengineering research contributions involving the discovery and characterization of novel selectin ligands expressed by metastatic tumor cells.”  Formal installation of fellows will take place at the BMES annual meeting  October 24-27 in Atlanta.

Konstantopoulos is an affiliated faculty member of Johns Hopkins Institute for NanoBioTechnology. He is also a project leader with the Johns Hopkins Physical Sciences-Oncology Center. Together with Martin Pomper, a School of Medicine professor of radiology and co-principal investigator of the Johns Hopkins Center of Cancer Nanotechnology Excellence, Konstantopoulos is researching mechanochemical effects on metastasis.

Specifically, his work investigates the effects of fluid mechanical forces at different oxygen tension microenvironments on tumor cell signaling, adhesion and migration. Fluid flow in and around tumor tissue modulates the mechanical microenvironment, including the forces acting on the cell surface and the tethering force on cell-substrate connections. Cells in the interior of a tumor mass experience a lower oxygen tension microenvironment and lower fluid velocities than those at the edges in proximity with a functional blood vessel, and are prompted to produce different biochemical signals. These differential responses affect tumor cell fate that is, whether a cell will live or die, and whether it will be able to detach and migrate to secondary sites in the body.

According to the BMES website, members who demonstrate exceptional achievements and experience in the field of biomedical engineering, as well as a record of membership and participation in the Society, have the opportunity to become fellows. Fellows are selected and conferred  by the BMES board of directors through a highly selective process. Nominations for each of these categories may be made by Society members and the board of directors.

Learn more about research in the Konstantopoulos Lab here.

 

 

Coated nanoparticles move easily into brain tissue

Real-time imaging of nanoparticles green) coated with polyethylene-glycol (PEG), a hydrophilic, non-toxic polymer, penetrate within normal rodent brain. Without the PEG coating, negatively charged, hydrophobic particles (red) of a similar size do not penetrate. Image by Elizabeth Nance, Kurt Sailor, Graeme Woodworth.

Johns Hopkins researchers report they are one step closer to having a drug-delivery system flexible enough to overcome some key challenges posed by brain cancer and perhaps other maladies affecting that organ. In a report published online Aug. 29 in Science Translational Medicine, the Johns Hopkins team says its bioengineers have designed nanoparticles that can safely and predictably infiltrate deep into the brain when tested in rodent and human tissue.

“We are pleased to have found a way to prevent drug-embedded particles from sticking to their surroundings so that they can spread once they are in the brain,” said Justin Hanes, Lewis J. Ort Professor of Ophthalmology and project leader in the Johns Hopkins Center of Cancer Nanotechnology Excellence.

Standard protocols following the removal of brain tumors include chemotherapy directly applied to the surgical site to kill any cancer cells left behind. This method, however, is only partially effective because it is hard to administer a dose of chemotherapy high enough to sufficiently penetrate the tissue to be effective and low enough to be safe for the patient and healthy tissue. Furthermore, previous versions of drug-loaded nanoparticles typically adhere to the surgical site and do not penetrate into the tissue.

These newly engineered nanoparticles overcome this challenge. Elizabeth Nance, a graduate student in chemical and biomolecular engineering, and Johns Hopkins neurosurgeon Graeme Woodworth, suspected that drug penetration might be improved if drug-delivery nanoparticles interacted minimally with their surroundings. Nance achieved this by coating nano-scale beads with a dense layer of PEG or poly(ethylene glycol). The team then injected the coated beads, which had been marked with a fluorescent tag,  into slices of rodent and human brain tissue. They found that a dense coating of PEG allowed larger beads to penetrate the tissue, even those beads that were nearly twice the size previously thought to be the maximum possible for penetration within the brain. They then tested these beads in live rodent brains and found the same results.

Elizabeth Nance. Photo by Ming Yang.

The results were similar when biodegradable nanoparticles carrying the chemotherapy drug paclitaxel and coated with PEG were used. “It’s really exciting that we now have particles that can carry five times more drug, release it for three times as long and penetrate farther into the brain than before,” said Nance. “The next step is to see if we can slow tumor growth or recurrence in rodents.”

Woodworth added that the team “also wants to optimize the particles and pair them with drugs to treat other brain diseases, like multiple sclerosis, stroke, traumatic brain injury, Alzheimer’s and Parkinson’s.” Another goal for the team is to be able to administer their nanoparticles intravenously, which is research they have already begun.

Additional authors on the paper include Kurt Sailor, Ting-Yu Shih, Qingguo Xu, Ganesh Swaminathan, Dennis Xiang, and Charles Eberhart, all from The Johns Hopkins University.

Story adapted from an original press release by Cathy Kolf.

 

Additional news coverage of this research can be found at the following links:

Nanotechnology/Bio & Medicine

Death and Taxes Mag

New Scientist Health

Nanotech Web

Portugese news release (in Portugese)

German Public Radio (in German)

Light-activated synthetic protein illuminates disease destruction

Illustration of collagen’s rope-like structure. Click to watch video. (INBT Animation Studios)

Johns Hopkins researchers have created a synthetic protein that, when activated by ultraviolet light, can guide doctors to places within the body where cancer, arthritis and other serious medical disorders can be detected. The synthetic protein does not zero in directly on the diseased cells. Instead, it binds to nearby collagen that has been degraded by disease or injury.

“These disease cells are like burglars who break into a house and do lots of damage but who are not there when the police arrive,” said S. Michael Yu, a faculty member in the Whiting School of Engineering’s Department of Materials Science and Engineering. “Instead of looking for the burglars, our synthetic protein is reacting to evidence left at the scene of the crime,” said Yu, who was principal investigator in the study.

The technique could lead to a new type of diagnostic imaging technology and may someday serve as a way to move medications to parts of the body where signs of disease have been found. In a study published in the Aug. 27-31 Online Early Edition of Proceedings of the National Academy of Sciences, the researchers reported success in using the synthetic protein in mouse models to locate prostate and pancreatic cancers, as well as to detect abnormal bone growth activity associated with Marfan syndrome.

Collagen, the body’s most abundant protein, provides structure and creates a sturdy framework upon which cells build nerves, bone and skin. Some buildup and degradation of collagen is normal, but disease cells such as cancer can send out enzymes that break down collagen at an accelerated pace. It is this excessive damage, caused by disease, that the new synthetic protein can detect, the researchers said.

A key collaborator was Martin Pomper, a School of Medicine professor of radiology and co-principal investigator of the Johns Hopkins Center of Cancer Nanotechnology Excellence. Pomper and Yu met as fellow affiliates of the Johns Hopkins Institute for NanoBioTechnology. “A major unmet medical need is for a better non-invasive characterization of disrupted collagen, which occurs in a wide variety of disorders,” Pomper said. “Michael has found what could be a very elegant and practical solution, which we are converting into a suite of imaging and potential agents for diagnosis and treatment.”

The synthetic proteins used in the study are called collagen mimetic peptides or CMPs. These tiny bits of protein are attracted to and physically bind to degraded strands of collagen, particularly those damaged by disease. Fluorescent tags are placed on each CMP so that it will show up when doctors scan tissue with fluorescent imaging equipment. The glowing areas indicate the location of damaged collagen that is likely to be associated with disease.

In developing the technique, the researchers faced a challenge because CMPs tend to bind with one another and form their own structures, similar to DNA, in a way that would cause them to ignore the disease-linked collagen targeted by the researchers.

To remedy this, the study’s lead author, Yang Li, synthesized CMPs that possess a chemical “cage” to keep the proteins from binding with one another. Just prior to entering the bloodstream to search for damaged collagen, a powerful ultraviolet light is used to “unlock” the cage and allow the CMPs to initiate their disease-tracking mission. Li is a doctoral student from the Department of Chemistry in the Krieger School of Arts and Sciences at Johns Hopkins. Yu, who holds a joint appointment in that department, is his doctoral adviser.

Yu’s team tested Li’s fluorescently tagged and caged peptides by injecting them into lab mice that possessed both prostate and pancreatic human cancer cells. Through a series of fluorescent images taken over four days, researchers tracked single strands of the synthetic protein spreading throughout the tumor sites via blood vessels and binding to collagen that had been damaged by cancer.

Similar in vivo tests showed that the CMP can target bones and cartilage that contain large amounts of degraded collagen. Therefore, the new protein could be used for diagnosis and treatment related to bone and cartilage damage.

Although the process is not well understood, the breakdown and rebuilding of collagen is thought to play a role in the excessive bone growth found in patients with Marfan syndrome. Yu’s team tested their CMPs on a mouse model for this disease and saw increased CMP binding in the ribs and spines of the Marfan mice, as compared to the control mice.

Funding for the research was provided by the National Science Foundation, the National Institutes of Health and the Department of Defense. The synthetic protein process used in this research is protected by patents obtained through the Johns Hopkins Technology Transfer Office.

Along with Yu, Li and Pomper, co-authors of this study were instructor Catherine A. Foss and medical resident Collin M. Torok from the Department of Radiology and Radiological Science at the Johns Hopkins School of Medicine; Harry C. Dietz, a professor, and Jefferson J. Doyle, a doctoral student, both of the Howard Hughes Medical Institute and Institute of Genetic Medicine at the School of Medicine; and Daniel D. Summerfield a former master’s student in the Department of Materials Science and Engineering.

Adapted from an original press release by Phil Sneiderman.

 

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.

Save the date: fall mini-symposium set for Oct. 24

Graduate students and post doctoral fellows from the Johns Hopkins Institute for NanoBioTechnology, Center of Cancer Nanotechnology Excellence and Physical Science-Oncology Center will host a mini-symposium highlighting some of the current investigations occurring in these research entities. The symposium will include short talks from six to eight researchers and will be held on Wednesday, Oct. 24 from 9 a.m. to noon at a Homewood campus location to be determined. Check back for location and agenda.

View the agendas from previous INBT/CCNE/PSOC mini-symposiums  at the links below:

Spring 2012

Fall 2011

Spring 2011

Killing prostate cancer cells with out harming the healthy cells

Experimenting with human prostate cancer cells and mice, cancer imaging experts at Johns Hopkins say they have developed a method for finding and killing malignant cells while sparing healthy ones.

The method, called “theranostic” imaging, targets and tracks potent drug therapies directly and only to cancer cells. It relies on binding an originally inactive form of drug chemotherapy, with an enzyme, to specific proteins on tumor cell surfaces and detecting the drug’s absorption into the tumor. The binding of the highly specific drug-protein complex, or nanoplex, to the cell surface allows it to get inside the cancerous cell, where the enzyme slowly activates the tumor-killing drug.

Researchers say their findings, published in the journal American Chemical Society Nano online Aug. 6, are believed to be the first to show that chemotherapies can be precisely controlled at the molecular level to maximize their effectiveness against tumors, while also minimizing their side effects.

Senior study investigator Zaver Bhujwalla, Ph.D., a professor at the Johns Hopkins University School of Medicine and its Kimmel Cancer Center, notes that a persistent problem with current chemotherapy is that it attacks all kinds of cells and tissues, not just cancerous ones.

In the theranostic imaging experiments, overseen by Bhujwalla and study co-investigator Martin Pomper, M.D., Ph.D., investigators directed drugs only to cancer cells, specifically those with prostate-specific membrane antigen, or PSMA cell surface proteins. Both Pomper and Bhujwalla are affiliated faculty members of Johns Hopkins Institute for NanoBioTechnology.

“Our results show a non-invasive imaging approach to following and delivering targeted therapy to any cancer that expresses PSMA,” says Bhujwalla, who also serves as director of the Johns Hopkins In Vivo Cellular and Molecular Imaging Center (ICMIC), where the theranostic imaging studies were developed.

Bhujwalla says the new technique potentially will work against any cancer in which tumors elevate production of certain cell surface proteins. Examples would include breast cancers with HER-2/neu and CXCR4 proteins, and some liver, lung and kidney cancers also known to express particular proteins. She notes that PSMA is expressed in the vessels of most solid tumors, suggesting that the nanoplex reported in the latest study could be used in general to image and treat a variety of cancers.

In their latest series of experiments, primarily in mice injected with human prostate tumor cells, Bhujwalla and the Johns Hopkins team tested their ability to track with imaging devices the delivery of anti-cancer drugs directly to tumors. Some of the tumors comprised cells with PSMA, while other so-called control tumors had none. Included in the drug nanoplex were small strands of RNA, cell construction acids that can be used instead to block and turn down production of a well-known enzyme, choline kinase, whose levels usually rise with tumor growth. All nanoplex components were imaged inside the tumor, in addition to dropping choline kinase production, which decreased by 80 percent within 48 hours of nanoplex absorption into cells with ample PSMA. When researchers used antibodies to block the action of PSMA, down went the level of nanoplex uptake and drug activation in cancerous cells as measured by dimming of the image.

Different concentrations of the drug nanoplex, tagged with radioactive and fluorescent molecules, were mixed in the lab with prostate cancer tissue cells, some of which had extra PSMA and others which had none. Only those cells with extra PSMA showed nanoplex uptake, as measured by image intensity, which later decreased when PSMA-blocking chemicals were added (back to levels seen in cells with almost no PSMA).

Additional experiments involving injections of three different concentrations of the drug nanoplex showed no damage to other vital mouse organs, such as the kidney and liver, nor any uptick in the mouse immune system response.

“Our theranostic imaging approach shows how the best methods of detection and treatment can be combined to form highly specialized, more potent and safer forms of chemotherapy,” says Pomper, a professor at Johns Hopkins who also serves as an associate director at ICMIC.

He says that an important goal for theranostic imaging is to move it beyond standard chemotherapy that attacks one target molecule at a time.

“With theranostic imaging, we can attack multiple tumor targets, making it harder for the tumor to evade drug treatment,” says Pomper, who is already working with colleagues at Johns Hopkins to identify other molecular targets.

The most recent studies were performed at Johns Hopkins over two years, starting in 2010, with funding support from the National Cancer Institute, part of the National Institutes of Health. The corresponding grant numbers are P50-CA103175, RO1-CA138515 and RO1-CA134675.

In addition to Bhujwalla and Pomper, other Johns Hopkins researchers from the Russell H. Morgan Department of Radiology involved in this imaging study were lead investigators Zhihang Chen, Ph.D., and Mary-France Penet, Ph.D. Additional study co-investigators were Sridhar Nimmagadda, Ph.D.; Li Cong, Ph.D.; Sangeeta Banerjee, Ph.D.; Paul Winnard Jr., Ph.D.; Dmitri Artemov, Ph.D.; and Kristine Glunde, Ph.D.

Press release by David March

Therapeutic nanolex containing multi-modal imaging reporters targeted to prostate specific membrane antigen (PSMA), which is expressed on the cell surface of castrate resistant PCa. (Image by Chen et al. from ACS Nano 2012).

 

High schoolers to show off their summer research

Stephanie Keyaka (left) working with Jincy Abraham (Notre Dame) in the Craig Montell Lab. Photo by Mary Spiro.

The Summer Academic Research Experience (SARE) pairs specially selected teens who come from academically disadvantaged homes with university mentors who guide them through a mini research project. The students gain valuable work skills, learn about scientific careers, get tutoring help, practice their writing, gather data for their projects and earn some cash for the future. The group will present their research findings during a poster session at the Johns Hopkins University medical campus on August 20 in the Bodian Room (1830 Building Rm 2-200) from 3:30 to 4:30 p.m.

“This is way better than flipping burgers,” laughed Stephanie Keyaka, as she prepared an image of a Western Blot performed on  Drosophila (fly) eye genes.

Keyaka is one of three high school students who worked in a biological chemistry laboratory  this summer with financial support from Johns Hopkins University Institute for NanoBioTechnology and School of Medicine.

Christopher Miller (right) with his mentor Hoku West-Foyle. Photo by Mary Spiro.

Keyaka, a rising 10th grader from The SEED School of Maryland, will be joined at the poster session by Christopher Miller, also a rising 10th grader from The SEED School of Maryland and Shaolin Holloman, a rising 11th grader at Baltimore Polytechnic Institute who is part of the Boys Hope Girls Hope of Baltimore.

The SEED School of Maryland is a public boarding school that accepts qualified children from across the state entering the 6th grade.  Boys Hope Girls Hope is a privately funded nonprofit that offers students the chance to attend academically challenging public or private schools and the opportunity to live in the Boys Hope or Girls Hope home.

Miller studied the protein myosin in the cell biology laboratory of  associate professor Douglas Robinson. Holloman worked in the cell biology lab of professor Carolyn Machamer on a project that sought to understand why the SARS coronavirus localized in the Golgi apparatus of the cell. Keyaka studied rhodopsin in the eyes of flies the lab of professor Craig Montell.

Shaolin Holloman (left) with professor Carolyn Machamer. Photo by Mary Spiro.

Help celebrate the accomplishments of our summer high school students who participated in the Summer Academic Research Experience. This event is free and open to the entire Hopkins  community. Light refreshments will be served. Students, faculty and mentors will available to discus the projects.