Worth Longest, Ph.D.

Alice T. and William H. Goodwin Jr. Endowed Chair Professor, Department of Mechanical and Nuclear Engineering VCU College of Engineering

  • Engineering East Hall, Room E3248, Richmond VA

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

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4 min

Researchers explore alternate delivery method for potential Alzheimer’s treatment

“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.”

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

5 min

Worth Longest research on more targeted aerosol drug delivery systems

Michael Hindle, Ph.D., a professor in the VCU Department of Pharmaceutics, and P. Worth Longest, a professor in the VCU Department of Mechanical and Nuclear Engineering, have invested years of time and millions of dollars to address challenges found in the field of medical aerosols. In particular: While smaller particles are more effective in delivering drugs into the lungs and airways, these tiny particles are often exhaled out immediately when taking a dose. Current aerosol delivery systems — think asthma inhalers — effectively deliver just 10 percent of an aerosolized dose. That’s fine for most asthma and COPD sufferers who use standard inhalers with existing medications, as these patients only need a small amount of the potent drugs to reach the lungs and have an effect. “But the medical world wants to use the lungs for delivery of other drugs, whether it’s locally to the airways or systemically to the body, and for that, you need more efficient devices,” Hindle says. To effectively use inhaled drugs for complex medical conditions requires more of the aerosol to reach the airways and to potentially target different regions of the airways — plus the devices to get them there. “Our work is about doing something different — changing that ballgame from having 90% of the drug wasted and 10% make it to the lungs, and flip it so that we get just 10% lost and 90% in the lungs,” Hindle says. “That’s always been our goal.” Taking aerosols from lab to lung Over more than a decade, the duo and their teams have created the three keys to making aerosol drug-delivery work: “developing the strategy, developing the device, and developing the formulation,” says Longest, the College of Engineering’s Louis S. and Ruth S. Harris Exceptional Scholar Professor. “When you see inhalation of aerosols fail, or a new pharmaceutical aerosol product fail, one of these areas has often been neglected. Between my lab and the Hindle lab, we have expertise in each of these different areas.” The fourth component — commercializing their inventions — is underway through a partner in Quench Medical in a deal signed in 2020 thanks to VCU Innovation Gateway. The Minnesota-based company, led by founder and CEO Bryce Beverlin II, Ph.D., has identified lung cancer, severe asthma, and cystic fibrosis as potential initial applications using VCU’s intellectual property, the licensing of which covers both the aerosols and the delivery devices. “It’s very difficult for an academic institution to develop a drug product,” says Hindle, the Peter R. Byron Distinguished Professor in Pharmaceutics. “So Bryce has moved forward with a team of manufacturers, clinical testing plans, and is talking to the Food and Drug Administration.” The VCU researchers had not previously pursued lung cancer as a possible application until Quench came along, Hindle says. “The idea that you could deliver a chemotherapy locally to the lungs is obviously very advantageous, because you don’t get the systemic side effects through the body like with traditional chemotherapy,” he says. “You’re just delivering drugs direct to that site of action for targeting the metastases in the lung.” In May, Quench presented data using the VCU technology to the Respiratory Drug Delivery conference in Florida showing that using a chemotherapeutic dry powder aerosol in rats was highly effective. It significantly reduced tumor burden but used half of the standard IV-delivered chemo dose. “This approach also aims to decrease the total drug delivered with reduced systemic drug levels in the circulation to decrease systemic toxicity,” the report read. It noted the efforts “solve a critical unmet medical need to develop new strategies to improve treatment outcomes in patients with lung cancer.” Heavy interest nationally Hindle and Longest have millions of dollars in funded projects underway, backed by the National Institutes of Health, U.S. Food & Drug Administration, and the Bill & Melinda Gates Foundation. Their work is building on the reputation of VCU’s Aerosol Research Group, founded in 1988 by emeritus professor Dr. Peter Byron (the name on Hindle’s professorship). The group’s work spans a wide variety of research areas in aerosol formulation and delivery. Hindle and Longest have worked together since 2006. While Hindle is focused on drug formulations, Longest is the engineering and computer modeling expert. His background is in biological fluid flow, and prior to joining VCU in 2004 had worked in the area of blood flow in vascular disease. But he wanted to differentiate his work, and found VCU’s reputation in medical aerosols was the place he could, in his words, “make an impact.” Through computer models, Longest and his team can understand how powders or liquids will turn into aerosol particles and the behaviors they will undertake when delivered into the body. “The lung is an area of the body where we have all these complex phenomena occurring with airflow and moving walls,’” he says. “It really takes high performance computers to understand it.” Drs. Longest and Hindle have developed a series of technology platforms that produce particles that are tiny when entering the lungs to minimize deposition losses in the mouth and throat — but grow in size as they travel down the warm, humid airways. One of the devices uses a mixer-heater to produce tiny particles, other technologies use a pharmaceutical powder or liquid containing a simple hygroscopic excipient such as sodium chloride; it is this excipient that attracts water from the lungs and makes the particles grow and deposit in the lungs with high efficiency. Eyes on infants Lately, the pair have been working on a method of aerosol drug delivery to newborns and prematurely born babies. “It’s a different set of challenges when you’re trying to deliver aerosols to infants who are born prematurely, and don’t have the ability to breathe on their own due to the lack of airway surfactant,” Hindle says. “And that’s something that, academically, we thought we were in a position to try and make a contribution to the field.” The group is working with funding from the NIH and the Bill and Melinda Gates Foundation to develop a method of delivering an aerosol surfactant to infants that will hopefully remove the need to intubate these fragile babies. In addition to striking licensing deals with Quench and building relationships with additional partners, Innovation Gateway has backed the pair’s work with an initial $25,000 from VCU’s Commercialization Fund as well as a just-awarded additional $35,000. “We turned that into a series of intellectual property that has resulted in three licensed patents and a whole family of IP in relation to both formulations and devices,” Hindle says. “There’s been lots of interest in delivering drugs to the lungs, it’s just been very difficult to institute any sea change, because the pharmaceutical industry is relatively risk averse.” And so their research continues, as Quench moves forward to bring their inventions to the bedside. “What I’m doing, I don’t really consider it work — it’s an opportunity to interact with great colleagues and contribute to a mission that will be very helpful to a broad range of people,” Longest says. “I also see it as a big responsibility. We want to do this in the right way. Because people’s health and lives are at stake. We want to make sure we approach this with a large sense of responsibility, and do our best.”

Worth Longest, Ph.D.

Areas of Expertise

Infant Aerosol Delivery
Targeting Inhaled Medications within the Lungs
Inhaled Medications
Respiratory Drug Delivery
Particle Engineering
Inhaler Design and Development
Pediatric Aerosol Delivery
Inhaled Antibiotics
Inhaled Surfactants
Inhaled Anti-inflammatories
Computational Fluid Dynamics
Pharmacutical Aerosol Product Development Pipeline
Transport Theory
Realistic In Vitro Aerosol Testing
Development of Inhaled Generic Medications

Accomplishments

Editorial Board Membership

2019-03-07

Journal of Aerosol Science

Editorial Board Membership

2018-06-01

Journal of Aerosol Medicine and Pulmonary Drug Delivery

Louis S. and Ruth S. Harris Exceptional Scholar Professor

2017-08-01

Endowed Professorship

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Education

North Carolina State University

Ph.D.

Mechanical Engineering

2002

North Carolina State University

M.S.

Mechanical Engineering

1999

North Carolina State University

B.S.

Mechanical Engineering

1996

Selected Articles

Initial Development of an Air-Jet Dry Powder Inhaler for Rapid Delivery of Pharmaceutical Aerosols to Infants

Journal of aerosol medicine and pulmonary drug delivery 34 (1), 57-70

C Howe, M Hindle, S Bonasera, V Rani, PW Longest

2021-01-05

Background: Positive-pressure dry powder inhalers (DPIs) have recently been developed that in combination with highly dispersible spray-dried powder formulations can achieve high efficiency aerosolization with low actuation air-volumes (AAVs). The objective of this study was to initially develop the positive-pressure air-jet DPI platform for high efficiency aerosol delivery to newborn infants by using the nose-to-lung route.

Methods: Aerosolization performance metrics of six air-jet DPIs were first assessed at AAVs that were consistent with full-term (30 mL) and preterm (10 mL) neonates. Designs of the air-jet DPIs varied based on geometry of the inlet and outlet flow passages and shape of the aerosolization chamber. Aerosolization metrics evaluated at the device outlet were emitted dose (ED) and mass median aerodynamic diameter (MMAD). Designs with the best aerosolization performance were connected to a smoothly expanding nasal interface and full-term infant (3550 g) nose-throat (NT) model with tracheal filter.

Results: The three best performing devices had characteristics of a cylindrical and horizontal aerosolization chamber with a flush or protruding outlet orifice. Including multiple air inlets resulted in meeting the aerosolization targets of >80% ED (based on loaded dose) and MMAD

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Characterization of excipient enhanced growth (EEG) tobramycin dry powder aerosol formulations

International Journal of Pharmaceutics 591, 120027

A Hassan, D Farkas, W Longest, M Hindle

2021-02-09

Spray drying can be utilized to produce highly dispersible powder aerosol formulations. However, these formulations are known to be hygroscopic, leading to potential solid-state stability and aerosol performance issues. This study aims to investigate if control of the spray drying particle formation conditions could be employed to improve the solid-state stability and alter the aerosol performance of tobramycin EEG formulations. Eight formulations were prepared, each had the same drug:excipient ratio of 60%w/w tobramycin, 20% w/w l-leucine, 18% w/w mannitol, and 2% w/w poloxamer 188. An experimental design matrix was performed with drying air water content of 1 or 10 g/m3 and spray drying solution l-leucine concentrations of 4.6, 7.6, 15.2 or 23.0 mmol/L. The particle size, morphology and crystallinity of spray dried formulations were characterized together with their dynamic moisture vapor sorption and aerosol performance. Higher crystallization and glass transition %RH were observed for the formulations spray dried using drying air with higher water content indicating more stable characteristics. Initial screening using a handheld dry powder inhaler of the realistic aerosol performance revealed that neither changing l-leucine concentration nor the drying gas water content affect the in-vitro expected lung dose. However, using a novel positive pressure inhaler, formulations produced using spray drying solutions with lower l-leucine concentrations showed better aerosol performance with MMAD around 2 µm and FPF < 5 µm around 80%.

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Excipient Enhanced Growth Aerosol Surfactant Replacement Therapy in an In Vivo Rat Lung Injury Model

Journal of aerosol medicine and pulmonary drug delivery 33 (6), 314-322

Franck J Kamga Gninzeko, Michael S Valentine, Cindy K Tho, Sahil R Chindal, Susan Boc, Sneha Dhapare, Mohammad Abdul Motalib Momin, Amr Hassan, Michael Hindle, Dale R Farkas, P Worth Longest, Rebecca L Heise

2021-03-17

Background: In neonatal respiratory distress syndrome, breathing support and surfactant therapy are commonly used to enable the alveoli to expand. Surfactants are typically delivered through liquid instillation. However, liquid instillation does not specifically target the small airways. We have developed an excipient enhanced growth (EEG) powder aerosol formulation using Survanta®.

Methods: EEG Survanta powder aerosol was delivered using a novel dry powder inhaler via tracheal insufflation to surfactant depleted rats at nominal doses of 3, 5, 10, and 20 mg of powder containing 0.61, 0.97, 1.73, and 3.46 mg of phospholipids (PL), whereas liquid Survanta was delivered via syringe instillation at doses of 2 and 4 mL/kg containing 18.6 and 34 mg of PL. Ventilation mechanics were measured before and after depletion, and after treatment. We hypothesized that EEG Survanta powder aerosol would improve lung mechanics compared with instilled liquid Survanta in surfactant depleted rats.

Results and Conclusion: EEG Survanta powder aerosol at a dose of 0.61 mg PL significantly improved lung compliance and elastance compared with the liquid Survanta at a dose of 18.6 mg, which represents improved primary efficacy of the aerosol at a 30-fold lower dose of PL. There was no significant difference in white blood cell count of the lavage from the EEG Survanta group compared with liquid Survanta. These results provide an in vivo proof-of-concept for EEG Survanta powder aerosol as a promising method of surfactant replacement therapy.

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