New drug delivery mechanism could aid breast cancer treatment
GAINESVILLE, Fla. — In a study published in the Journal of Extracellular Vesicles, scientists from the UF Health Cancer Institute have found a way to make treatment for a notoriously aggressive breast cancer more effective.
Using a delivery system that relies on extracellular vesicles (small, lipid nanoparticles secreted from a myriad of cell types), the team was able to circumvent two common difficulties associated with a targeted treatment for triple negative breast cancer: access to tumor sites and stable and effective transport in the body.
“We wanted to see if extracellular vesicles (EVs) might overcome these challenges of poor delivery and instability of this targeted drug,” said Nina Erwin, a doctoral candidate in the department of pharmaceutics at the UF College of Pharmacy.
When EVs were loaded with proteolysis-targeting chimaeras, or PROTACs, the team saw significantly reduced tumor growth and enhanced survival in mouse models. PROTACs work by cajoling the cell’s in-house cleaning cycle, a process known as proteolysis, into removing errant guests — like irregular proteins — that are leading the creation of tumors.
Enabling EVs to deliver PROTACs drugs more efficiently could prove essential to more effectively treating triple negative breast cancer. The tumors associated with this form of cancer vary not only in molecular makeup but also in sensitivity to different therapies, and grow rapidly and aggressively. They spread early and have a high probability of recurrence.
Although PROTACs showed promise in vitro, the treatment struggled to do the same in living systems. Hurdles like limited tumor penetration, and how easily the drug disintegrated along its journey to the tumor sites, have stalled further use.
Researchers addressed this by introducing a new “carrier” for the PROTACs therapy: extracellular vesicles.
Using a new method, these microscopic, unassuming sacs were infused with a specific type of PROTACs developed to suppress breast cancer tumor growth without inciting dysfunction in healthy cells.
This method not only improved how well the drugs could attach to carriers, but also helped give a “second life” to the drugs as they were ferried to tumor sites, Erwin said. The therapy could better reach and tackle the tumors.
“I think this proof-of-concept study opens a door to using extracellular vesicles as a delivery platform technology,” Erwin said. “It’s not necessarily limited to one type of drug, or even to once type of cancer. It could resolve other challenges that PROTACs struggles with to help move these effective drugs toward clinical use.”
In short: An extracellular-vesicle-based delivery system can significantly enhance therapeutic outcomes by improving how drugs reach the tumor, and their antitumor effects once they arrive, according to the study.
“Solving this delivery issue could allow for a quicker clinical translation for other similar drugs,” said Mei He, Ph.D., an associate professor in the department of pharmaceutics and the senior author on the paper.
With enhanced drug stability and bioavailability — most organisms have extracellular vesicles to spare — researchers believe this presents a meaningful step toward treating a disease known for resisting it.
The paper is born of interdisciplinary collaboration, He said, citing the meaningful contributions and support of colleagues from the the College of Medicine and UF’s Department of Medicinal Chemistry that complemented her lab’s expertise in extracellular vesicles and related engineering.
“I’m grateful for the opportunity to share the work,” Erwin said. “It’s always an honor to contribute to ongoing efforts in making treatments not only more successful, but more accessible.”
Other team members include Guangrong Zheng, Ph.D., professor in the UF College of Pharmacy; Daiqing Liao, Ph.D, associate professor in the UF College of Medicine; and Weizhou Zhang, Ph.D., professor and vice chair of research in the UF College of Medicine.