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Researchers explore alternate delivery method for potential Alzheimer’s treatment

Researchers at Virginia Commonwealth University’s College of Engineering and School of Pharmacy are working toward a proof of concept for a nose-to-brain delivery system of insulin to treat Alzheimer’s patients.

Sep 21, 2022

4 min

Laleh Golshahi, Ph.D.Worth Longest, Ph.D.

“Traditionally, the nose has been used as a route for delivery of locally acting drugs,” Laleh Golshahi, Ph.D., explained. “But recently, there has been a great deal of interest in the direct pathway through the olfactory region. That’s the same region where we smell, and that route is a direct pathway to the brain.”


Golshahi, associate professor in VCU’s Department of Mechanical and Nuclear Engineering, leads the collaboration. Other members of the group are Worth Longest, Ph.D., the Louis S. and Ruth S. Harris Exceptional Scholar and Professor in the Department of Mechanical and Nuclear Engineering; Michael Hindle, Ph.D., the Peter R. Byron Distinguished Professor in VCU’s Department of Pharmaceutics; and Arya Bazargani, a Ph.D. student in VCU’s Interdisciplinary Center for Pharmaceutical Engineering and Sciences.


The project is supported by a $200,000 internal grant from VCU Breakthroughs, a new internal funding mechanism as part of the Optimizing Health thrust of the One VCU Research Strategic Priorities Plan being implemented by the university’s Office of the Vice President for Research and Innovation.


Hindle said that studies of nasally administered insulin have shown some promise for reducing the effects of Alzheimer’s. Unfortunately, delivery by injection, the most common way to deliver insulin, is ineffective for Alzheimer’s and other cerebral conditions because of the blood-brain barrier. Bazargani explained that nose-to-brain delivery of pharmaceuticals circumvents the blood-brain barrier, the lining of the blood vessels that surround the brain, guarding the central nervous system against a host of pathogens.


“It’s usually a good thing,” he said. “But not when you’re trying to induce therapeutic effects into the brain.” Bazargani explained that insulin molecules are so large that the blood-brain barrier filters out most of the insulin. Hindle pointed out that even though the VCU team is avoiding the blood-brain barrier, insulin delivery still presents a number of challenges.


“Insulin is a pretty fragile molecule, you know. It’s stored in the fridge,” Hindle said. “We need to include insulin in some sort of stable formulation — either a powder or a liquid nasal spray. We have to create the right particle or droplet size to get it into the right area of the nose.”


Formulation development is only half of a two-pronged challenge, Golshahi said. The second aspect is the creation of a device that can deliver a dose way up to the olfactory region.


“The nose is a challenge, because it’s designed as a filter to keep aerosols out of the body,” said Longest, who, along with Golshahi and Hindle, brings expertise in computational fluid dynamics to the team. “And the olfactory region is an especially troubling or difficult region to target, because it’s designed just to let a few molecules of what we inhale deposit.”


Chief among the nasal filtering defenses, Golshahi said, is mucociliary clearance. Nasal passages are lined with mucous-coated cilia — moving microscopic projections on cells — sweeping foreign substances out of the air we breathe. The cilia do an excellent job, she said, but their efficiency makes it difficult to achieve a consistent delivery to the olfactory region. Another challenge, she added, lies in the fact that all noses are different.


The collaborators are using in vitro and in silico methodologies. For the in vitro work, they have an array of 3D printed nose models, based on computed tomography (CT) scans. Golshahi said they have multiple anatomical casts of human nasal airways to test likely device/formulation combinations for their insulin/Alzheimer’s initiative.


“We are going to use three of those nasal casts as our starting point,” she said. “We’ll connect the casts to a breathing simulator, which is basically a machine you can program to add the air going through — sort of bringing them to life.”


Golshahi added that data from the casts will inform the in-silico component of the work — computational analysis that is expected to verify or challenge observations from the lab.


Hindle said that once the team has developed a satisfactory formulation-device system, they can tackle the next challenge: identifying the dominant pathway from the olfactory region to the brain.


“There are a variety of theories out there,” he said. “It could go along the nerve passageway. It could go between the nerve walls and the cells linking them.”


“We have all the equipment and all the expertise necessary to be able to develop a formulation, and to put it in a device that leads to the highest amount of delivery to the target region,” Golshahi said. “And we are able to quantify how successful that combination of formulation and device is.”

Connect with:
Laleh Golshahi, Ph.D.

Laleh Golshahi, Ph.D.

Engineering Foundation Professor, Department of Mechanical and Nuclear Engineering

Dr. Golshahi specializes in aerosol science and in vitro-in vivo correlations for respiratory support, diagnosis and inhalation therapy.

Aerosol Science and MedicineIn Vitro and In Vivo Models Of Respiratory DepositionHealth-Related Aerosols Exposure ControlTargeted Respiratory Drug DeliveryAerosol filtration
Worth Longest, Ph.D.

Worth Longest, Ph.D.

Alice T. and William H. Goodwin, Jr. Distinguished Chair, Department of Mechanical and Nuclear Engineering

Professor Longest works to address significant current challenges in the field of medical aerosols

Infant Aerosol DeliveryTargeting Inhaled Medications within the LungsInhaled MedicationsRespiratory Drug DeliveryParticle Engineering
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VCU College of Engineering receives $600,000 for AI-driven cybersecurity research featured image

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Director Gennady Miloshevsky, Ph.D., shares his vision for the nuclear program at the VCU College of Engineering featured image

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Director Gennady Miloshevsky, Ph.D., shares his vision for the nuclear program at the VCU College of Engineering

Recently named the nuclear program director at the Virginia Commonwealth University (VCU) College of Engineering, Gennady Miloshevsky, Ph.D., associate professor in the Department of Mechanical & Nuclear Engineering, answers some questions about the direction of VCU Engineering’s nuclear program and what he hopes it can accomplish. What are your top priorities for the nuclear program at the VCU College of Engineering? I want to focus on student development, innovative research and our rankings in best program lists, but that is not everything. Strategy is important. We need to align ourselves with the country’s national energy needs. There are many new developments in the energy sector, like small modular reactors or fusion energy systems, and having the right faculty to engage with these advancements is important. Providing students with a well-rounded education and good opportunities for gaining experience benefits the College of Engineering’s public and private sector partners. Nuclear subject matter is complex, so higher education is very important for workforce development. We want to build partnerships, like the one we have with Dominion Energy, that support this goal. A priority for me is continuing to establish relationships with Commonwealth Fusion Systems, which seeks to build and operate the first commercial grid-scale fusion plant in Chesterfield County, Virginia. Our workforce partners will benefit from VCU’s well-trained nuclear engineering graduates joining the workforce. So, aligning our strategy with national energy needs, hiring the right faculty to support our programs and building industry partnerships that benefit our student’s education and career opportunities are important things for VCU Engineering’s nuclear program. Where would you like to see the College of Engineering’s nuclear program 10 years from now? I would like to see growth in the nuclear program. For example, some new graduate courses on topics like nuclear materials or fusion energy. In 2024, I developed a general course for fusion energy, so building out a curriculum that goes more in-depth would be good. When you look at small modular reactors and micro reactors, current energy policy does not allow private companies to build their own. However, as energy demands increase, policy could change to where you see these compact devices installed in places like data centers, for example. A more in-depth curriculum allows VCU Engineering students to step into industry roles that lead growth of the energy industry while also ensuring students are capable of adapting to the changing field and taking advantage of new developments. What sort of cross-disciplinary opportunities are there for the College of Engineering’s nuclear program? Nuclear engineering and nuclear science are very interdisciplinary fields. You have physics that covers the nuclear reaction and the radiation it generates, for example, then chemistry is needed when talking about nuclear fuel cycles and nuclear waste. You also need materials science because good materials capable of withstanding radiation and high temperatures are needed in nuclear fission and fusion energy systems. This science then connects to engineering, building the reactors, the energy distribution systems like a power grid. It is a small sample of the overall work, but you see how mechanical and electrical engineering are key to this part. All these disciplines come together to solve the same problem. One researcher might be figuring out how to confine plasma and make it stable, then another researcher is looking at how plasma can disrupt the containment wall and how to make materials to protect the wall. 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