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Posted on Sep 11, 2014

New Nanomedicine Provides Faster, More Efficient Stem Cell Therapy

A targeted nanoparticle created by researchers at North Carolina State University and the Cedars-Sinai Heart Institute may help heart attack patients regenerate healthy heart tissue without using donated or processed stem cells. This new nanomedicine could also alleviate some of the difficulties involved with stem cell therapy, including treatment delays and invasive procedures.

The particle, a “magnetic bi-functional cell engager” called MagBICE, consists of an iron platform with two different antibodies attached. These antibodies have different functions – one locates a patient’s own stem cells after a heart attack, and the other grabs injured tissue, allowing MagBICE to act as a matchmaker between injury and repair crew. The iron platform makes MagBICE magnetically active, allowing physicians to direct the particles to the heart with an external magnetic field. The iron platform also enables magnetic resonance imaging (MRI).

Ke Cheng, associate professor of regenerative medicine at NC State, and his colleagues at Cedars-Sinai Heart Institute tested MagBICE in rats and found that the particle was effective in redirecting stem cells in the blood to the injured heart. Additionally, MagBICE was easier and faster to administer than current stem cell therapy products.

“MagBICE optimizes and amplifies the body’s own repair process, which means we don’t have to worry about patient rejection of donated stem cells, or delay treatment while a patient’s stem cells are being processed, purified and prepared,” Cheng says. “The drug can be offered to patients immediately after blood vessels to the damaged areas are reopened and can be given intravenously, which isn’t possible with stem cell therapy.”

The researchers’ results appear online in Nature Communications. Co-authors include Taylor Hensley from NC State, Ryan Middleton, Baiming Sun, Weixin Liu, Geoffrey De Couto and Eduardo Marbán from Cedars-Sinai Heart Institute, and Deliang Shen from First Affiliated Hospital of Zhengzhou University, Zhengzhou, China. Cheng worked on the development of MagBICE while at Cedars-Sinai.

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Note to editors:  An abstract of the paper follows.

“Magnetic antibody-linked nanomatchmakers for therapeutic cell targeting”

DOI: 10.1038/ncomms5880

Authors:  Ke Cheng and Taylor Hensley, North Carolina State University; Eduardo Marbán, Ryan Middleton, Baiming Sun, Weixin Liu and Geoffrey De Couto, Cedars-Sinai Heart Institute; Deliang Shen, First Affiliated Hospital of Zhengzhou University, Zhengzhou, China

Published: Online in Nature Communications

Abstract: Stem cell transplantation is a promising strategy for therapeutic cardiac regeneration, but current therapies are limited by inefficient interaction between potentially beneficial cells (either exogenously transplanted or endogenously recruited) and the injured tissue. Here we apply targeted nanomedicine to achieve in vivo cell-mediated tissue repair, imaging and localized enrichment without cellular transplantation. Iron nanoparticles are conjugated with two types of antibodies (one against antigens on therapeutic cells and the other directed at injured cells) to produce magnetic bifunctional cell engager (MagBICE). The antibodies link the therapeutic cells to the injured cells, whereas the iron core of MagBICE enables physical enrichment and imaging. We treat acute myocardial infarction by targeting exogenous bone marrow-derived stem cells (expressing CD45) or endogenous CD34-positive cells to injured cardiomyocytes (expressing myosin light chain). Targeting can be further enhanced by magnetic attraction, leading to augmented functional benefits. MagBICE represents a generalizable platform technology for regenerative medicine.

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Posted on Mar 25, 2014

Lobo’s Hope

Lobo is a five-year-old binturong with a tail that wouldn’t uncurl – a definite problem for a tree-dwelling carnivore who needs a flexible tail in order to get around. But Lobo’s crooked tail is just part of his story, which began a few years ago when he was rescued from a living situation that left him with several health issues. Following his rescue, Lobo found a home at the Conservators’ Center, a nonprofit organization in Burlington, N.C. that preserves a variety of threatened species. The Center’s staff brought Lobo to NC State’s College of Veterinary Medicine in order to help him regain his health and see what could be done to rehabilitate his tail.

Exotic animals like Lobo can pose a challenge for traditional veterinarians, who probably don’t see a lot of lions, tigers or binturongs – none of which are native to the Southeastern U.S.; binturongs hail from Southeast Asia – in their local practices. But NC State is trying to remedy that situation through the carnivore team, a group of veterinary students who work with the kinds of animals that you may find only in zoos or private conservation reserves.

Suzanne Kennedy-Stoskopf is the faculty creator and advisor of the carnivore team. With a clinical background in zoological and wildlife medicine, she felt that it was important that students be able to work with non-domestic species.

“There is a significant population of exotic animals in the U.S.,” says Kennedy-Stoskopf, “and it’s really important that these animals have access to quality veterinary care. In traditional curriculums most students do not get exposure to how to safely work around these animals, so the carnivore team was created to allow them to get experience while they’re still veterinary students.”

CVM Carnivore Team

College of Veterinary Medicine Carnivore Team members Kim Boykin, Michelle Schisa and Adeline Noger (left to right) at the Conservators’ Center

The team was founded three years ago, and students can join in their first, second or third year of vet school. There are around 40 members of the team, and each member devotes three days per month to team projects. Kennedy-Stoskopf has partnered with the Conservators’ Center, which keeps numerous exotic species, including lions and other wild cats, wolves, and of course, binturongs.

Michelle Schisa is one of the founding members of the carnivore team. She is responsible for organizing the other team members for trips out to the Conservators’ Center. Lobo’s case gave the team a great opportunity to learn more about binturongs, as well as some hands-on practical experience.

“The carnivore team was responsible for conducting the initial head-to-toe physical exam,” Schisa says. “That included making sure he was comfortable under anesthesia, administering intravenous fluids and monitoring his condition throughout the exam. This is a unique experience that many vet students don’t get while they’re in school – and I’m hoping it will help me get a job with a zoological facility, either somewhere like the Conservators’ Center or at a typical zoo.”

While the team provides an excellent training opportunity for veterinary students who want to go into zoological or wildlife medicine, it also fills medical care needs for organizations like the Conservators’ Center.

According to Mindy Stinner, executive director of the Conservators’ Center, “Binturongs are one of the more unusual species living at the Center, so we’re really pleased that the veterinarians at NC State have enough experience with these animals to take on some of our more difficult cases, like Lobo.

Lobo

“When he arrived he received the urgent care he required, but he needed some follow-up care. Lobo had several medical issues, including the fact that the end of his tail wouldn’t unfurl properly. We were concerned about the pain this caused him because it got caught on the edges of platforms, his denbox and other items when he moved around his habitat. We kept it bandaged and softened the edges of the enrichment in his habitat to minimize damage. But every time it started to heal he managed to snag it on something and re-open the wounds. So we consulted the experts at NC State.”

With guidance from the veterinarians, Lobo’s caregivers gave him daily tail massage and stretching exercises in an effort to rehabilitate it. They also began a modified diet featuring fruit smoothies to help him with a kidney issue. Over time it became clear to the Center’s staff and the NC State veterinarians that the best option for Lobo was to amputate part of his tail.

Fortunately for this feisty binturong, his outlook is good. Stinner says that he has adjusted well to his new tail length. Although he cannot grasp with it, now that he is unencumbered by the weight of the damaged section and the hooked tip, he is better able to climb about his habitat. And his kidney function is normal, thanks to the diet he had been prescribed.

“We’re really pleased with Lobo’s improvement,” Stinner says. “The carnivore team offered excellent medical guidance to our vet tech, who oversees his ongoing care. The specialty care that NC State provided for Lobo will ensure him a very good quality of life.”

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Posted on Dec 12, 2013

Medicinal Microbes

If you asked most undergraduates whether they would be interested in factory work, you’d probably get some puzzled looks. But what if the “factory” was E. coli bacteria, and the “work” involved creating entire libraries of enzymes that might help defeat antibiotic resistance or cancer?

Undergraduates in Dr. Gavin Williams’ lab get to do just that, with hands-on, real research experience that starts as soon as they walk through the door.

Nature’s Factories

Williams is interested in drug development. Specifically, he’s interested in using E. coli as a factory to produce molecules that can be used as anti-cancer, anti-microbial and anti-viral drugs. What does that mean? Think about penicillin – it comes from a natural product (mold) that has antibacterial properties.

Nature makes these complex molecules by putting different types of enzymes into assembly lines, each of which can construct a molecule that may have a desirable quality, like the ability to stop bacterial growth or kill cancerous cells. In traditional drug development, scientists try to mimic natural processes by using chemicals. The problem is that these chemical processes are wasteful: in some cases it can take almost a ton of starting materials to produce one gram of the compound needed.

“I came to NC State because I knew I wanted to do research” — Matthew Draelos, senior chemistry and biochemistry major.

Williams and other chemists have found a shortcut. They go straight to the source – DNA – and pull out the particular genes that encode the enzymes they’re interested in. They can then manipulate those enzymes so that they only bind to other specific proteins. It’s like assembling a LEGO sculpture – but one in which the individual blocks, or enzymes, can only fit together in a certain way.

Then they put the enzymes they want inside E. coli bacteria. The enzymes self-assemble (by snapping together like LEGO bricks), and create the molecules needed for drug development. By piggybacking on nature, Williams and his team can quickly and inexpensively create huge numbers of different kinds of molecules that they can test, to find out which ones are the most effective against the diseases they want to treat.

Hands-on Research

Matthew Draelos and Taylor Courtney are both undergraduates doing work in the Williams lab. Draelos is a senior majoring in chemistry and biochemistry. He’s been part of the Williams lab since his freshman year.

“I came to NC State because I knew I wanted to do research and had heard it was easy to do undergraduate research here,” he says. “What captured my imagination about Williams’ research was that it’s both basic research and it’s medically relevant – we’re creating enzyme ‘mutants’ that have practical uses in creating new drugs.”

Undergraduates Taylor Courtney, Vishwas Rao and Matthew Draelos work in Gavin Williams' chemistry lab.

Undergraduates Taylor Courtney, Vishwas Rao and Matthew Draelos work in Gavin Williams’ biochemistry lab.

Courtney, a junior who is also majoring in chemistry and biochemistry, has only been with the lab for a few months, although she has previous research experience. “This kind of chemical biology meets a growing need in drug discovery, and I want to pursue this research in graduate school, so it’s a great opportunity for me,” she says.

Both students were encouraged to jump into the research from day one.

“You get trained to become a full partner in the lab,” Draelos says. “From the beginning I learned how to do DNA extraction, purification and analysis to make sure that we had what we wanted in its purest form. Now I’m creating my own libraries of enzyme mutants to test for usefulness in drug development. As each year passes, you are given more leeway to pursue projects independently that contribute to the lab.”

Courtney agrees. “You are definitely a full member of this lab – not just an assistant or someone who takes care of the supplies. And you’re definitely ready for graduate school or research work when you graduate.”

Hemant Desai, who earned a B.S. in chemistry and a B.A. in chemistry this year, is one of those graduates.

“I came in as a freshman, and even when my first project didn’t quite work out, it taught me a lot. My experiences in the lab prepared me really well for the topics I’m studying now in medical school.”

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