Warren symposium follows legacy of geneticist giant

If we want to understand how the brain creates memories, and how genetic disorders distort the brain’s machinery, then the fragile X gene is an ideal place to start. That’s why the Stephen T. Warren Memorial Symposium, taking place November 28-29 at Emory, will be a significant event for those interested in neuroscience and genetics. Stephen T. Warren, 1953-2021 Warren, the founding chair of Emory’s Department of Human Genetics, led an international team that discovered Read more

Mutations in V-ATPase proton pump implicated in epilepsy syndrome

Why and how disrupting V-ATPase function leads to epilepsy, researchers are just starting to figure Read more

Tracing the start of COVID-19 in GA

At a time when COVID-19 appears to be receding in much of Georgia, it’s worth revisiting the start of the pandemic in early 2020. Emory virologist Anne Piantadosi and colleagues have a paper in Viral Evolution on the earliest SARS-CoV-2 genetic sequences detected in Georgia. Analyzing relationships between those virus sequences and samples from other states and countries can give us an idea about where the first COVID-19 infections in Georgia came from. We can draw Read more

nanoparticles

Fighting cancer with combinatorial imagination

In his undergraduate days, Winship Cancer Institute dermatologist and cancer researcher Jack Arbiser was an organic chemist. That may be why he recognized an organic synthesis reagent based on the metal palladium as a potential anti-cancer drug.

We’re talking about Tris-DBA-palladium. Arbiser and colleagues showed in a 2008 Clinical Cancer Research paper that this deep purple stuff (see photo) is active against melanoma, and since then, against other types of cancer such as pancreatic cancer, multiple myeloma, and CLL leukemia.

Tris-DBA-PD has a deep purple color. The palladium atoms can be seen in the diagram as two blue balls at the center. From Wikipedia.

Since it’s used in organic synthesis, you might expect Tris-DBA-palladium not to be very soluble in water. A new paper in Scientific Reports demonstrates that this issue can be addressed by hooking up the reagent to nanoparticles made of hyaluronic acid, which targets tumor cells. They are effective against melanoma in mice, the paper shows.

“We have already demonstrated that Tris DBA palladium by itself has activity against melanoma in mice,” Arbiser writes (in his VA grant summary). “However, we believe that we can make Tris DBA palladium into an even more powerful drug by adding it to nanoparticles that are guided to the tumor.”

In an email to Lab Land, Arbiser says he arrived at Tris-DBA-palladium by using his chemist’s imagination, in a “your chocolate landed in my peanut butter” kind of way.

“I got the idea for looking at this compound because it is a complex of Pd with a curcumin-like structure, and I figured it might have the characteristics of platinum and curcumin together,” he says. Read more

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For nanomedicine, cell sex matters

The biological differences between male and female cells may influence their uptake of nanoparticles, which have been much discussed as specific delivery vehicles for medicines.

Biomedical engineer Vahid Serpooshan, PhD

New Emory/Georgia Tech BME faculty member Vahid Serpooshan has a recent paper published in ACS Nano making this point. He and his colleagues from Brigham and Women’s Hospital and Stanford/McGill/UC Berkeley tested amniotic stem cells, derived from placental tissue. They found that female amniotic cells had significantly higher uptake of nanoparticles (quantum dots) than male cells. The effect of cell sex on nanoparticle uptake was reversed in fibroblasts. The researchers also found out that female versus male amniotic stem cells exhibited different responses to reprogramming into induced pluripotent stem cells (iPSCs).

Female human amniotic stem cells with nanoparticles .Green: quantum dots/ nanoparticles; red: cell staining; blue: nuclei.

“We believe this is a substantial discovery and a game changer in the field of nanomedicine, in taking safer and more effective and accurate steps towards successful clinical applications,” says Serpooshan, who is part of the Department of Pediatrics and the Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory.

Serpooshan’s interests lie in the realm of pediatric cardiology. His K99 grant indicates that he is planning to develop techniques for recruiting and activating cardiomyoblasts, via “a bioengineered cardiac patch delivery of small molecules.” Here at Emory, he joins labs with overlapping interests such as those of Mike Davis, Hee Cheol Cho and Nawazish Naqvi. Welcome!

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Three-stage delivery for platinum-based ‘cluster bombs’ against cancer

Scientists have devised a triple-stage ‘cluster bomb’ system for delivering the chemotherapy drug cisplatin, via tiny nanoparticles designed to break up when they reach a tumor.

Details of the particles’ design and their potency against cancer in mice are described this week in PNAS Early Edition. They have not been tested in humans, although similar ways of packaging cisplatin have been in clinical trials. Anticancer cluster bombs

What makes these particles distinctive is that they start out relatively large — 100 nanometers wide — to enable smooth transport into the tumor through leaky blood vessels. Then, in acidic conditions found close to tumors, the particles discharge “bomblets” just 5 nanometers in size.

Inside tumor cells, a second chemical step activates the platinum-based cisplatin, which kills by crosslinking and damaging DNA. Doctors have used cisplatin to fight several types of cancer for decades, but toxic side effects — to the kidneys, nerves and inner ear — can limit its effectiveness.

The PNAS paper is the result of a collaboration between a team led by professor Jun Wang, PhD at the University of Science and Technology of China, and researchers led by professor Shuming Nie, PhD in the Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory. Nie is a member of the Discovery and Developmental Therapeutics research program at Winship Cancer Institute of Emory University. The lead authors are graduate student Hong-Jun Li and postdoctoral fellows Jinzhi Du, PhD and Xiao-Jiao Du, PhD.

“The negative side effects of cisplatin are a long-standing limitation for conventional chemotherapy,” says Jinzhi Du. “In our study, the delivery system was able to improve tumor penetration to reach more cancer cells, as well as release the drugs specifically inside cancer cells through their size-transition property.”

The researchers showed that their nanoparticles could enhance cisplatin drug accumulation in tumor tissues. When mice bearing human pancreatic tumors were given the same doses of free cisplatin or cisplatin clothed in pH-sensitive nanoparticles, the level of platinum in tumor tissues was seven times higher with the nanoparticles. This suggests the possibility that nanoparticle delivery could restrain the toxic side effects of cisplatin during cancer treatment. Read more

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Deliver, but not to the liver

The potential of a gene-silencing technique called RNA interference has long enticed biotechnology researchers. It’s used routinely in the laboratory to shut down specific genes in cells. Still, the challenge of delivery has held back RNA-based drugs in treating human disease.

RNA is unstable and cumbersome, and just getting it into the body without having it break down is difficult. One that hurdle is met, there is another: the vast majority of the drug is taken up by the liver. Many current RNA-based approaches turn this apparent bug into a strength, because they seek to treat liver diseases. See these articles in The Scientist and in Technology Review for more.

But what if you need to deliver RNA somewhere besides the liver?

Biomedical engineer Hanjoong Jo’s lab at Emory/Georgia Tech, working with Katherine Ferrara’s group at UC Davis, has developed technology to broaden the liver-dominant properties of RNA-based drugs.

Hanjoong Jo, PhD

The results were recently published in ACS Nano. The researchers show they can selectively target an anti-microRNA agent to inflamed blood vessels in mice while avoiding other tissues.

“We have solved a major obstacle of using anti-miRNA as a therapeutic by being able to do a targeted delivery to only inflamed endothelial cells while all other tissues examined, including liver, lung, kidney, blood cells, spleen, etc showed no detectable side-effects,” Jo says. Read more

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Regenerative Engineering & Medicine highlights

Last week on Friday, Lab Land attended the annual Regenerative Engineering & Medicine center get-together to hear about progress in this exciting area.

During his talk, Tony Kim of Georgia Tech mentioned a topic that Rose Eveleth recently explored in The Atlantic: why aren’t doctors using amazing “nanorobots” yet? Or as Kim put it, citing a recent review, “So many papers and so few drugs.”

[A summary: scaling up is difficult, testing pharmacokinetics, toxicity and efficacy is difficult, and so is satisfying the FDA.]

The talks Friday emerged from REM seed grants; many paired an Emory medical researcher with a Georgia Tech biomedical engineer. All of these projects take on challenges in delivering regenerative therapies: getting cells or engineered particles to the right place in the body.

For example, cardiologist W. Robert Taylor discussed the hurdles his team had encountered in scaling up his cells-in-capsules therapies for cardiovascular diseases to pigs, in collaboration with Luke Brewster. The pre-pig phase of this research is discussed in more detail here and here. Read more

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Fragile but potent: RNA delivered by nanoparticle

An intriguing image for November comes from biomedical engineer Mike Davis’ lab, courtesy of BME graduate student Inthirai Somasuntharam.

Each year, thousands of children undergo surgery for congenital heart defects. A child’s heart is more sensitive to injury caused by interrupting blood flow during surgery, and excess reactive oxygen species are a key source of this damage.

Macrophages with blue nuclei and red cytoskeletons, being treated with green nano particles. The particles carry RNA that shut off reactive oxygen species production.

Macrophages with blue nuclei and red cytoskeletons, being treated with green nano particles. The particles carry RNA that shut off reactive oxygen species production.

Davis and his colleagues are able to shut off cheap oakley reactive oxygen species at the source by targeting the NOX (NADPH oxidase*) enzymes that produce them. This photo, from a 2013 Biomaterials paper, shows green fluorescent nanoparticles carrying small interfering RNA. The RNA precisely shuts down one particular gene encoding a NOX enzyme. Eventually, similar nanoparticles may shield the heart from damage during pediatric heart surgery.

In the paper, Somasuntharam used particles made of a slowly dissolving polymer called polyketals. The particles delivered fragile but potent RNA molecules into macrophages, inflammatory cells that swarm into cardiac tissue after a heart attack. Davis and Georgia Tech colleague Niren Murthy previously harnessed this polymer to deliver drugs that can be toxic to the rest of the body.

The polyketal particles are especially well-suited for delivering a payload to macrophages, since those types of cells (as the name implies) are big eaters. Davis reports his lab has been working on customizing the particles so they can deliver RNA molecules into cardiac muscle cells as well.

*While we’re on the topic of NADPH oxidases, Susan Smith and David Lambeth have been looking for and finding potential drugs that inhibit them.

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Strengthening bone with silica nanoparticles

Tiny particles of silicon dioxide – essentially, extremely fine sand — can strengthen bones when introduced into animals, researchers at Emory University School of Medicine have discovered.

The particles stimulate the generation of bone-forming cells and inhibit other cells that break down bone. The findings could someday form the basis for an alternative treatment for osteoporosis.

The results were published recently in the journal Nanomedicine.

The paper represents a collaboration between the laboratories of George Beck and Neale Weitzmann, both in the Division of Endocrinology, Metabolism and Lipids. The project started when Jin-Kyu Lee, now at Seoul National University, came to Beck’s lab with silica nanoparticles he had developed that contained fluorescent dyes. This allowed researchers to track the particles within the body and within cells.

In the laboratory, the nanoparticles stimulate the generation of bone-forming osteoblasts and inhibit the maturation of bone-remodeling osteoclasts. Beck says that the particles’ properties seem to depend on their size (50 nanometers wide) and shape, because larger particles don’t have the same effects. The nanoparticles appear to work by being taken up by the cells and then by inhibiting NF-kB, a molecule that controls inflammation.

Silicon is a trace element in the diet of most people. Scientists have known for several years that dietary silicon is linked to strong bones, but how silicon influences bone growth has remained unclear: it could become physically incorporated into bone, or it could provide signals to the cells that make up bone. To be sure, silica nanoparticles may be acting in a way that is different than dietary silicon.

The particles’ ability to stimulate osteoblasts distinguish them from bisphosphonates, the most common drugs now used to treat osteoporosis, Beck says. Bisphosphonates only inhibit bone breakdown and do not stimulate bone formation.

The Emory team has found that injecting silica nanoparticles can increase the bone density of young mice by roughly 15 percent over six weeks, augmenting the increases coming from adolescent growth.

To test the particles’ potential for use with humans, the researchers are examining whether injection is the best way to deliver the nanoparticles, and whether long-term toxicity is an issue. Inhalation of larger particles of silica dust, an occupational hazard for miners and construction workers, can result in the lung disease silicosis. However, silicosis arises because the lungs can’t absorb and remove the larger dust particles. Since cells clearly can take up the nanoparticles (see video), it is possible that they will not induce the body to respond similarly.

Emory has applied for patents on this technology. A presentation by Emory’s Office of Technology Transfer is available here.

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Nanotechnology may help surgeons detect cancer

What a cancer patient wants to know after surgery can be expressed succinctly: “Did you get everything?” Having a confident answer to that question can be difficult, because when they originate or metastasize, tumors are microscopic.

Considerable advances have been made in “targeted therapy” for cancer, but the wealth of information available on the molecular characteristics of cancer cells hasn’t given doctors good tools for detecting cancer during surgery – yet.

Even the much-heralded advent of robotic surgery has not led to clear benefits for prostate cancer patients in the area of long-term cancer control, a recent New York Times article reports.

At Emory and Georgia Tech’s joint department for biomedical engineering, Shuming Nie and his colleagues are developing tools that could help surgeons define tumor margins in human patients.

Read more

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