Siebel scholars demonstrate INBT’s multidisciplinary advantage

September 28, 2012 By

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.

 

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Coated nanoparticles move easily into brain tissue

September 17, 2012 By

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)

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Light-activated synthetic protein illuminates disease destruction

September 5, 2012 By

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.

 

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It’s a small world: Micro/nanotechnology in regenerative medicine and cancer

March 2, 2012 By

Sageeta Bhatia

Nanotechnology, regenerative medicine and cancer will be the topic of a special biomedical engineering seminar on March 6 at 3 p.m. in the Darner Conference Room, Ross Building, Room G007 at the Johns Hopkins School of Medicine. Speaker Sangeeta Bhatia, MD, PhD, director, of the Laboratory for Multiscale Regenerative Technologies at Massachusetts Institute of Technology will present “It’s a small world: Micro/Nanotechnology in Regenerative Medicine and Cancer. ” She will discuss the role of micro and nanotechnology for mimicking, monitoring and perturbing the tissue microenvironment.

“I will present our work on reconstructing normal liver microenvironments using microtechnology, biomaterials and induced pluripotent stem cells as well as our work on normalizing diseased cancer microenvironments using both inorganic and organic nano materials,” Bhatia noted in an announcement.  Bhatia is a professor of Health Sciences and Technology and professor of Electrical Engineering and Computer Science at MIT.

The talk is hosted by associate professor of Materials Science and Engineering and affiliated faculty member of the Institute for NanoBioTechnology Hai-Quan Mao. The event is free and open to the Johns Hopkins Community. Refreshments will be served.

 

 

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Engineered hydrogel helps grow new, scar-free skin

December 13, 2011 By

In early testing, this hydrogel, developed by Johns Hopkins researchers, helped improve healing in third-degree burns. Photo by Will Kirk/HomewoodPhoto.jhu.edu

Johns Hopkins researchers have developed a jelly-like material and wound treatment method that, in early experiments on skin damaged by severe burns, appeared to regenerate healthy, scar-free tissue.

In the Dec. 12-16 online Early Edition of Proceedings of the National Academy of Sciences, the researchers reported their promising results from mouse tissue tests. The new treatment has not yet been tested on human patients. But the researchers say the procedure, which promotes the formation of new blood vessels and skin, including hair follicles, could lead to greatly improved healing for injured soldiers, home fire victims and other people with third-degree burns.

The treatment involved a simple wound dressing that included a specially designed hydrogel—a water-based, three-dimensional framework of polymers. This material was developed by researchers at Johns Hopkins’ Whiting School of Engineering, working with clinicians at the Johns Hopkins Bayview Medical Center Burn Center and the Department of Pathology at the university’s School of Medicine.

Third-degree burns typically destroy the top layers of skin down to the muscle. They require complex medical care and leave behind ugly scarring. But in the journal article, the Johns Hopkins team reported that their hydrogel method yielded better results. “This treatment promoted the development of new blood vessels and the regeneration of complex layers of skin, including hair follicles and the glands that produce skin oil,” said Sharon Gerecht, an assistant professor of chemical and biomolecular engineering who was principal investigator on the study.

Guoming Sun, left, a postdoctoral fellow, and Sharon Gerecht, an assistant professor of chemical and biomolecular engineering, helped develop a hydrogel that improved burn healing in early experiments. Photo by Will Kirk/HomewoodPhoto.jhu.edu

Gerecht said the hydrogel could form the basis of an inexpensive burn wound treatment that works better than currently available clinical therapies, adding that it would be easy to manufacture on a large scale. Gerecht suggested that because the hydrogel contains no drugs or biological components to make it work, the Food and Drug Administration would most likely classify it as a device. Further animal testing is planned before trials on human patients begin. But Gerecht said, “It could be approved for clinical use after just a few years of testing.”

John Harmon, a professor of surgery at the Johns Hopkins School of Medicine and director of surgical research at Bayview, described the mouse study results as “absolutely remarkable. We got complete skin regeneration, which never happens in typical burn wound treatment.”

If the treatment succeeds in human patients, it could address a serious form of injury. Harmon, a coauthor of the PNAS journal article, pointed out that 100,000 third-degree burns are treated in U. S. burn centers like Bayview every year. A burn wound dressing using the new hydrogel could have enormous potential for use in applications beyond common burns, including treatment of diabetic patients with foot ulcers, Harmon said.

Guoming Sun, Gerecht’s Maryland Stem Cell Research Postdoctoral Fellow and lead author on the paper, has been working with these hydrogels for the last three years, developing ways to improve the growth of blood vessels, a process called angiogenesis. “Our goal was to induce the growth of functional new blood vessels within the hydrogel to treat wounds and ischemic disease, which reduces blood flow to organs like the heart,” Sun said. “These tests on burn injuries just proved its potential.”

Gerecht says the hydrogel is constructed in such a way that it allows tissue regeneration and blood vessel formation to occur very quickly. “Inflammatory cells are able to easily penetrate and degrade the hydrogel, enabling blood vessels to fill in and support wound healing and the growth of new tissue,” she said. For burns, the faster this process occurs, Gerecht added, the less there is a chance for scarring.

Originally, her team intended to load the gel with stem cells and infuse it with growth factors to trigger and direct the tissue development. Instead, they tested the gel alone. “We were surprised to see such complete regeneration in the absence of any added biological signals,” Gerecht said.

Sun added, “Complete skin regeneration is desired for various wound injuries. With further fine-tuning of these kinds of biomaterial frameworks, we may restore normal skin structures for other injuries such as skin ulcers.”

Gerecht and Harmon say they don’t fully understand how the hydrogel dressing is working. After it is applied, the tissue progresses through the various stages of wound repair, Gerecht said. After 21 days, the gel has been harmlessly absorbed, and the tissue continues to return to the appearance of normal skin.

The hydrogel is mainly made of water with dissolved dextran—a polysaccharide (sugar molecule chains). “It also could be that the physical structure of the hydrogel guides the repair,” Gerecht said. Harmon speculates that the hydrogel may recruit circulating bone marrow stem cells in the bloodstream. Stem cells are special cells that can grow into practically any sort of tissue if provided with the right chemical cue. “It’s possible the gel is somehow signaling the stem cells to become new skin and blood vessels,” Harmon said.

Additional co-authors of the study included Charles Steenbergen, a professor in the Department of Pathology; Karen Fox-Talbot, a senior research specialist from the Johns Hopkins School of Medicine; and physician researchers Xianjie Zhang, Raul Sebastian and Maura Reinblatt from the Department of Surgery and Hendrix Burn and Wound Lab. From the Whiting School’s Department of Chemical and Biomolecular Engineering, other co-authors were doctoral students Yu-I (Tom) Shen and Laura Dickinson, who is a Johns Hopkins Institute for NanoBioTechnology (INBT) National Science Foundation IGERT fellow. Gerecht is an affiliated faculty member of INBT.

The work was funded in part by the Maryland Stem Cell Research Fund Exploratory Grant and Postdoctoral Fellowship and the National Institutes of Health.

The Johns Hopkins Technology Transfer staff has filed a provisional patent application to protect the intellectual property involved in this project.

Related links:

Sharon Gerecht’s Lab

Johns Hopkins Burn Center

Johns Hopkins Institute for NanoBioTechnology

 

Story by Mary Spiro

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Hopkins faculty to present at American Society for NanoMedicine meeting

October 12, 2011 By

© Liudmila Gridina | Dreamstime.com

The American Society for NanoMedicine (ASNM) will hold its third annual meeting November 9 -11 at the Universities at Shady Grove Conference Center in Gaithersburg, Md. This year ASNM has worked closely with the Cancer Imaging Program, National Cancer Institute, and National Institutes of Health to create a conference with a special focus on nano-enabeled cancer diagnostics and therapies, and the synergy of the combination of nano-improved imaging modalities and targeted delivery.

The program also focuses on updates on the newest Food and Drug Administration, nanotoxicity, nanoparticle characterization, nanoinformatics, nano-ontology, results of the latest translational research and clinical trials in nanomedicine, and funding initiatives. This year’s keynote speaker is Roger Tsien, 2008 Nobel Prize Laureate. Numerous other speakers and breakout sessions are planned for the three day event. Two speakers affiliated with Johns Hopkins include Justin Hanes and Dmitri Artemov. Hanes is a professor of nanomedicine in the department of ophthalmology at the Johns Hopkins School of Medicine. Artemov is an associate professor of radiology/magnetic resonance imaging research, also at the School of Medicine.

The deadline for the poster abstracts is October 1. The top four posters submitted by young (pre and post doctoral) investigators will be selected to give a short 10-minute (eight slides) oral presentation on November 11.

ASNM describes itself as a “a non-profit, open, democratic and transparent professional society…focus(ing) on cutting-edge research in nanomedicine and moving towards realizing the potential of nanomedicine for diagnosis, treatment, and prevention of disease.” More information about the ASNM can be found on the Society’s official website.

 

 

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Agenda set for Oct. 10 mini-symposium on cancer, nanotech

October 7, 2011 By

From the spring mini-symposium.

Johns Hopkins Physical Sciences-Oncology Center and Center of Cancer Nanotechnology Excellence will host a mini-symposium on Monday Oct., 10 in the Hackerman Hall Auditorium. Talks on topics related to cancer and nanotechnology begin at 9 a.m.

Speakers include:

  • 9:15 a.m.: The pulsating motion of breast cancer cell is regulated by surrounding epithelial cells. Speaker: Meng Horng Lee
  • 9:40 a.m.: Breast tumor extracellular matrix promotes vasculogenesis. Speaker: Abigail Hielscher
  • 10:00 a.m.: Attachment to growth substrate regulates expression of GDF15, an important molecule in metastatic cancer. Speaker: Koh Meng Aw Yong
  • 10:20 a.m.: Mucin 16 is a functional selectin ligand on pancreatic cancer cells. Speaker: Jack Chen
  • 10:40 a.m.: Particle tracking in vivo. Speaker: Pei-Hsun Wu

These talks are open to the entire Hopkins community. No RSVP is required. Refreshments will be served.

 

 

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Nanobio postdocs offer trusted tips on getting grant money

July 22, 2011 By

Photo illustration by Mary Spiro.

Three postdoctoral fellows from Johns Hopkins Institute for NanoBioTechnology will offer a one-hour crash course in how to get those research dollars; July 27, 11 a.m. Krieger 205. Free for Hopkins community.

Funding dollars make the research world go ‘round. Few know that better than postdoctoral fellows, who would be out of work without it. As part of Johns Hopkins Institute for NanoBioTechnology’s last professional development seminar of the summer, three INBT affiliated postdoctoral fellows will offer their sage advice on preparing winning research grants.

Topics to be covered on the basic aspects of grant writing include:

  • knowing when to write a grant
  • identifying funding sources
  • planning a timeline
  • how to structure a competitive proposal
  • do’s and dont’s of grant writing and planning
  • basic science writing tips for conveying ideas clearly and succinctly

This seminar will be led by Eric Balzer, postdoctoral fellow with professor Konstantinos Konstantopoulos (ChemBE); Yanique Rattigan, postdoctoral fellow with professor Anirban Maitra (Oncology/Pathology); and Daniele Gilkes, postdoctoral fellow with professor Denis Wirtz (ChemBE).

For additional information on INBT’s professional development seminar series, contact Ashanti Edwards, INBT’s Academic Program Administrator at Ashanti@jhu.edu.

 

 

 

 

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‘Just add water’ to activate freeze-dried brain cancer fighting nanoparticles

July 18, 2011 By

A fluorescence micrograph showing brain cancer cells producing a green fluorescent protein. DNA encoded to produce the protein was delivered to the cancer cells by new freeze-dried nanoparticles produced by Johns Hopkins biomedical engineers. Image: Stephany Tzeng/JHU

Biomedical engineers and clinicians at Johns Hopkins University have developed freeze-dried nanoparticles made of a shelf-stable polymer that only need the addition of water to activate their cancer-fighting gene therapy capabilities.

Principal investigator Jordan Green, assistant professor in the department of Biomedical Engineering at the Johns Hopkins School of Medicine, led the team that fabricated the polymer-based particles measuring 80 to 150 nanometers in diameter. Each particle, which is about the size of a virus, has the ability to carry a genetic cocktail designed to produce brain cancer cell-destroying molecules. After manufacture, the nanoparticles can be stored for up to 90 days before use. In principle, cancer therapies based on this technology could lead to a convenient commercial product that clinicians simply activate with water before injection into brain cancer tumor sites.

Because this method avoids the common, unpleasant side effects of traditional chemotherapy, “nanoparticle-based gene therapy has the potential to be both safer and more effective than conventional chemical therapies for the treatment of cancer,” Green said. But, he added current gene therapy nanoparticle preparations are just not practical for clinical use.

“A challenge in the field is that most non-viral gene therapy methods have very low efficacy. Another challenge with biodegradable nanoparticles, like the ones used here is that particle preparation typically takes multiple time-sensitive steps.” Green said. “Delay with formulation results in polymer degradation, and there can be variability between batches. Although this is a simple procedure for lab experiments, a clinician who wishes to use these particles during neurosurgery will face factors that would make the results unpredictable.”

In contrast, the nanoparticles developed by the Green lab are a freeze-dried, or “lyophilized,” formulation. “A clinician would simply add water, and it is ready to inject,” Green said. Green thinks this freeze-dried gene-delivery nanoparticle could be easily manufactured on a large scale.

Co-investigator Alfredo Quinones-Hinojosa, a Johns Hopkins Hospital clinician-scientist and associate professor in the departments of Neurosurgery and Oncology at the Johns Hopkins School of Medicine, said he could imagine particles based on this technology being used in conjunction with, and even instead of, brain surgery. “I envision that one day, as we understand the etiology and progression of brain cancer, we will be able to use these nanoparticles even before doing surgery,” Quinones said. “How nice would that be? Imagine avoiding brain surgery all together!”

Currently, patients with glioblastoma, or brain cancer, only have a median survival of about 14 months, Green said. “Methods other than the traditional chemotherapy drugs and radiation—or in combination with them—may improve prognosis,” he said.

Gene therapy approaches could also be personalized, Green said. “Because gene therapy can take advantage of many naturally-existing pathways and can be targeted to the cancer type of choice through nanoparticle design and transcriptional control, several levels of treatment specificity could be provided,” Green said.

The nanoparticles self-assemble from a polymer structural unit, so fabrication is fairly simple, said Green. Finding the right polymer to use, however, proved to be a challenge. Lead author Stephany Tzeng, a PhD student in biomedical engineering in Green’s lab screened an assortment of formulations from a “polymer library” before hitting on a winning combination.

“One challenge with a polymer library approach is that there are many polymers to be synthesized and nanoparticle formulations to be tested. Another challenge is designing the experiments to find out why the lead formulation works so well compared to other similar polymers and to commercially available reagents,” Green said.

Tzeng settled on a particular formulation of poly(beta-amino ester)s specifically attracted to glioblastoma (GB) cells and to brain tumor stem cells (BTSC), the cells responsible for tumor growth and spread. “Poly(beta-amino ester) nanoparticles are generally able to transfect many types of cells, but some are more specific to GBs and BTSCs,” Tzeng said.

The nanoparticles work like a virus, co-opting the cell’s own protein-making machinery, but in this case, to produce a reporter gene (used to delineate a tumor’s location) or new cancer fighting molecule. “It is possible that glioblastoma-derived cells, especially brain tumor stem cells, are more susceptible to our gene delivery approach because they divide much faster,” Tzeng added.

Not only are the particles convenient to use, the team discovered that dividing cells continued to make the new protein for as long as six weeks after application. “The gene expression peaked within a few days, which would correspond to a large initial dose of a therapeutic protein,” said Green. “The fact that gene expression can continue at a low level for a long time following injection could potentially cause a sustained, local delivery of the therapeutic protein without requiring subsequent injection or administration. The cells themselves would act as a ‘factory’ for the drug.”

Once the nanoparticles release their DNA cargo, Tzeng said the polymer quickly degrades in water, usually within days. “From there, we believe the degradation products are processed and excreted with other cellular waste products,” Tzeng said.

Members of the Green Lab are now working on identifying the intracellular mechanism responsible for facilitating cell-specific delivery. “We also plan to build additional levels of targeting into this system to make it even more specific. This includes modifying the nanoparticles with ligands to specifically bind to glioblastoma cells, making the DNA cargo able to be expressed only in GB cells, and using a DNA sequence whose product is only effective in GB cells.”

So far, the team has only successfully transfected brain tumor stem cells using these nanoparticles in a plastic dish. The next step is to test the particle in animal models.

“We hope to begin tests in vivo in the near future by implanting brain tumor stem cells into a mouse and injecting particles. We also hope to begin using functional genes that would kill cancer cells in addition to the fluorescent proteins that serve only as a marker,” Tzeng said.

Other authors who contributed to this work are Hugo Guerrero-Cázares, postdoctoral fellow in Neurosurgery and Oncology, and Joel Sunshine, an M.D.-Ph.D. candidate, and Elliott Martinez, an undergraduate leadership alliance summer student, both from Biomedical Engineering. Funding for this work came from the National Institutes of Health, Howard Hughes Medical Institute, the Robert Wood Johnson Foundation and a pilot-grant from Johns Hopkins Institute for NanoBioTechnology (INBT). Green is an affiliated faculty member of INBT. The research will be published in Issue #23 (August 2011) of the journal Biomaterials and is currently available online.

Freeze-dried gene therapy system avoids virus, complications

Story by Mary Spiro

 

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Collagen video scores high in magazines reader’s choice vote

July 1, 2011 By

Screen capture from INBT’s video on collagen mimetic peptides.

The Scientist magazine has announced its annual Multimedia Awards—the Labbys—and Johns Hopkins Institute for NanoBioTechnology’s video on collagen mimetic peptides has been selected as a finalist. According to the voting, we are a strong second in the race. It appears voting is continuing well past the original June 30 deadline. So keep voting!

Help choose us as the top science video by going to this website (http://the-scientist.com/2011/06/15/2011-labby-video-finalists/#vote)  and selecting “Mimicking Collagen.” The video features Michael Yu, associate professor of materials science and engineering and some fantastic animations and illustration from INBT’s Animation studio. Animations in the video were created by Ella McCrea, a graduate from the Maryland Institute College of Art, and Nathan Weiss, a masters graduate from Johns Hopkins University.

Winners of the reader’s choice will be announced in the magazine and online in September. Top picks will also be chosen by The Scientist’s panel of judges, which includes the father of the infographic Nigel Holmes, Kirsten Sanford of the Science Channel (aka Dr. KiKi), Jeffrey Segall of the Albert Einstein College of Medicine in New York City, and David Kirby of the University of Manchester.

You can only vote once, so share this link with your friends.

 

 

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