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Medical Researchers Find Gold at Portland State University
Medical Researchers Find Gold at Portland State University

In a sunlit lab on the fifth floor of the Science Building at Portland State University, Marilyn Mackiewicz, a bioinorganic, organometallic, and nanomaterials chemist, is pulling an assortment of small glass bottles from drawers and lining them up in a row on a counter. All around the room are shelves neatly stocked with chemicals, an assortment of machinery, and other paraphernalia. Spanning the anterior wall is the hood, within which a variety of distillation apparatus and flasks are stitched together with hoses and hang suspended in clasps. To the uninitiated, this could be any lab, but, in fact, it is in this room that scientists are transforming gold and silver atoms into the delivery vehicles medical researchers in the nascent field of precision medicine believe could change the way we diagnose and treat diseases.


As Mackiewicz, a non-tenure research assistant professor in the Chemistry Department at PSU, continues removing bottles from various drawers, she explains how the undergraduate students she mentors, and who volunteer their time to staff the lab are responsible for most of the synthesis, characterization, functionalization, and microscopy work involved in the production of the nanostructure platform she’s designed. Each individually labeled bottle contains a liquid that looks as if it has been dyed with food coloring. With a flick of her wrist, Mackiewicz gives a bottle a twirl to agitate the fluid inside.


“This one that looks like red wine has gold nanorods in it,” she says. “This one that looks like apple juice has silver nanospheres. And this one,” raising a bottle of blue liquid up to the light, “has silver nanoparticles clustered together in the shape of triangles.”


Just a milliliter of this liquid, she explains, contains as many as ten thousand nanoparticles. It’s those nanoparticles that give the liquid in the bottles their distinct color. By chemically coaxing gold and silver atoms into rods, spheres, and triangles in a process called “tuning,” Mackiewicz and her students can tailor the optical and electrical properties of the nanostructures, which changes the wavelengths of visible light they reflect and absorb, and therefore the color of the liquid. Tuning the nanostructures, Mackiewicz notes, is the first step in functionalizing these tiny pieces of precious metals so medical researchers in search of new methods for detecting and treating diseases can use them.


“So, this is the place,” Mackiewicz says. “This is where we design and build our nanostructures.”


• • • •


While the concept of working with nanomaterials has been around since the late 1950s, it didn’t become possible to work with materials at this scale (there are 25,400,000 nanometers in an inch) until the 1980s, when the introduction of new technologies allowed scientists and engineers to begin manipulating individual atoms for the very first time. Since then, nanotechnologies have proven useful in a range of applications from clean energy to computing to bacteria-resistant coatings. Nano has even found its way into everyday consumer products such as toothpaste, cosmetics, and sunscreen. But perhaps the most promising application of nanotechnologies are in the fields of medicine and medical research, where advances in nanoscience are pushing the boundaries of diagnostics, drug delivery, and our understanding of disease at the molecular level.
 
(Image: Dr. Marilyn Mackiewicz)


In the lab, Mackiewicz and her research team are designing, shaping, and functionalizing nanostructures for applications in diagnostic imaging, the study of disease processes, and the relatively new field of image-guided drug delivery (IGDD). IGDD combines the imaging capabilities of radiological medicine with targeted delivery of therapeutics. In IGDD, nanostructures are tagged with imaging agents and encased in protective coatings to which antibodies, targeting agents, and other medically useful molecules can be attached. Those nanostructures then hone in on specific cell types, such as cancer cells, and enter the target cells, where they release their payloads of drugs. In contrast to chemotherapy, which floods the body with drugs, affecting both cancer and healthy cells, IGDD promises to deliver chemotherapy drugs only to cancer cells, leaving healthy cells to go about their business unharmed. Meanwhile, attending medical personnel can use imaging technologies to monitor the nanostructures as they travel through the body and deliver the accompanying therapeutics.


According to Mackiewicz, some of the significant challenges facing scientists developing nanoscale drug and imaging agent delivery vehicles, as well as for the medical researchers testing them, is that nanostructures don’t always go where they’re supposed to or behave as their designers intended them to in situ. Their protective coatings can fail, and they can become unstable in complex intracellular environments, which can render them unreliable, ineffective, and can lead to the uneven distribution and uncontrolled release of therapeutics, resulting in toxicity.


“For nanostructure platforms to gain FDA approval, you need them to be stable. You need them to be non-toxic. And you need them to do the job they’re designed to do,” Mackiewicz says. “Not only that; they have to be reliable. They have to work the same way every time. Getting all that right in a cellular environment is tough to do.”


The patent-pending process Mackiewicz has developed addresses many of those challenges by adding an extra layer of protective coating to the nanostructures she creates. The process involves coating gold and silver nanostructures in a hybrid, bilayer-membrane that enhances their overall stability and ability to carry and deliver imaging agents, targeting molecules, and therapeutics. The lipid-based coatings also provide the nanostructures a “stealth-like” quality, which helps them avoid contact with cells other than those they’re designed to target. Mackiewicz has been working with PSU’s Office of Innovation and Intellectual Property to secure IP protection for her innovations and to identify new collaborators whose research could benefit from the superior nanostructures she designs and builds.


“What we did was figure out a better way to shield our nanostructures,” Mackiewicz says. “And that shield helps protect them from interactions with biomolecules that typically result in destabilization and the rearrangement of the structure’s lipid coating, which in turn affects the drugs, imaging agents, and targeting molecules attached to the lipid coating or the nanostructure itself.”


• • • •


The sturdiness and reliability of the nanostructures Mackiewicz develops have resulted in several partnerships and collaborations with researchers up and down the Willamette Valley. At Oregon State University, Dr. Stacey Harper, a nanotoxicologist, has been evaluating the safety of Mackiewicz’s nanostructures in zebrafish models. Using biochemical tests that measure the presence and concentration of nanostructures in the cells of zebrafish embryos, Harper’s team can evaluate the toxic potential of the gold and silver nanostructures Mackiewicz makes in the lab.
 
(Image: Functionalized nanoparticle)


“So far we’re seeing positive results coming out of Stacey’s shop,” Mackiewicz said. “We have an even distribution of the materials within cells. And we’re not having issues with toxicity. These are critical milestones for nanostructures to reach if medical researchers are going to use them in vivo.”


Back at PSU, Mackiewicz is in the process of building a biosafety lab adjacent to her office so that she and her students can further study the interactions of their nanostructures with living cells. Once complete, the lab will allow the research team to investigate the ways nanostructures with unique architectures enter cells, which is critical to a variety of tasks such as tagging cells with imaging agents to track drug delivery and detecting labeled cells with imaging technologies.


Just a short distance from Mackiewicz’s lab, at Oregon Health and Science University’s (OHSU) Casey Eye Institute, researchers are using gold nanorods produced by Mackiewicz’s students in a study evaluating cell-based therapies for diseases of the retina like macular degeneration. The researchers, Drs. David Huang and Trevor McGill are tagging stem cells with gold nanorods tuned with specific imaging properties to help them track transplanted stem cells to gain a better understanding of where the labeled cells go and how long they live after transplantation.


“We’re working towards developing stem-cell-based therapies for macular degeneration,” McGill said. “When we started our study, we found that the nanoparticles we were working with couldn’t do the job required of them. So we reached out to Marilyn who had these gold nanorods with a better coating and an imaging agent that did what we wanted. At this stage in the study, we’re working on demonstrating the efficacy of using the nanorods to tag and image stem cells transferred from one culture to another. So far, we’re getting excellent results. In the next phase of the study, we plan to start using the tagged cells in animal models.”


• • • •


In this image, gold nanorods, embedded in a cell-populated collagen gel, scatter light as viewed under a darkfield microscope. Credit: The USC NanocenterBack in the lab, Karen Kinnison and Julie Reed, both juniors, are beginning the process of synthesizing silver, triangular nanostructures. Kinnison is part of a team working on another of Mackiewicz’s collaborations with the Legacy Devers Eye Institute in Portland, where researchers are using nanostructures to study the progression of glaucoma. Kinnison is also on the team producing the nanorods used by Huang and McGill at OHSU. Reed is busy measuring minute amounts of the silver nitrate, sodium chlorate, and borohydride used to coax the silver atoms into triangular plates. Kinnison, meanwhile, prepares the hood for synthesis. Watching the process, which takes roughly twenty minutes from start to finish, and appears effortless for these two undergraduate students, it’s easy to forget the studying, training, and practice required to do this kind of work.

 

(Image: In this image, gold nanorods, embedded in a cell-populated collagen gel, scatter light as viewed under a darkfield microscope.)

“This lab is unique on campus in that it’s staffed entirely by undergrad volunteers from various programs across PSU,” Mackiewicz says as Reed and Kinnison go about their work. “I have students from the BUILD EXITO program and the McNair and LSAMP programs. These students blow me away with their dedication and hard work. It’s just amazing to watch them as they create libraries of different nanomaterials.”


When the synthesis is complete, Reed removes the tinfoil she’s wrapped around the Erlenmeyer flask to protect the chemicals inside from interactions with light. The mixture, which had been clear, is now blue, meaning the process of synthesis has been a success. The silver atoms have taken their intended triangular shapes. At this point, the nanostructures are ready to be shielded in their hybrid lipid bilayer coating to be used in several other collaborative projects. Some of the newly designed hybrid silver nanomaterials Reed produces will go to Stacey Harper’s group at Oregon State. There, they’ll undergo testing for toxicity and to assure they don’t leach silver ions, two benchmarks that must be met before other researchers can begin evaluating the effect of the nanostructures on the environment and human health. Other nanostructures the students produce that day will go to PSU biology professor Ken Stedman’s lab, where Stedman’s group is collaborating with Mackiewicz to explore the materials’ usefulness as anti-viral agents.


“The focus of all the work we’re doing in the lab is on developing tools for researchers to use in the fight against diseases,” Mackiewicz said. “Whether it’s macular degeneration, glaucoma, cancer, or other diseases, this technology has the potential to change the way we approach medical sciences and healthcare, which is why it’s such an exciting field to be a part of.”