Rachael Sirianni, PhD, knows how to impress. After a stint as an undergraduate research assistant in a polymeric biomaterials lab, her insightful questions at a professional conference prompted the chair of the Biomedical Engineering Department at Yale University to encourage her to apply to their graduate program.
No surprise–she was accepted.
This event was not the only one at which she glittered. Success was fast becoming her signature trait.
In another remarkable adventure, she pitched a project for funding at a conference modeled after Shark Tank. Her presentation held sway and the conference organizers funded her project.
This conference yielded more than one opportunity, providing a connection to a clinical partner and eventually an offer to join the faculty at the University of Texas Health Science Center in Houston. This proposition initially made her chuckle—there was no way she was moving to Texas! But their professional interests perfectly aligned, her goal was patient impact, and the offer was too tempting to resist. So, off to Texas, she went.
In June 2022, Dr. Sirianni arrived at UMass Chan with a host of ideas on how to deliver drugs directly to the brain. This research has broad implications for brain cancer and neurodegenerative disorders. With better drug delivery options available, patients will suffer less toxicity, drugs can be engineered for better potency, and the hope is that survival statistics will improve.
How did you choose nanotechnology as a field of study?
I always loved math, biology, and medicine, so I majored in bioengineering at Arizona State University. I decided to work in a lab to combine my quantitative skills with my passion for basic science. However, my choice of the lab was somewhat random. I have a friend who worked in a polymeric biomaterials lab and since I was also interested in that field, I asked the lab director if I could join. I like to tell this story of happenstance to encourage folks without clear career goals.
What was the focus of your PhD research at Yale?
During my first years of graduate school, I helped develop mathematical models to understand how drugs move through the body. I also explored how encapsulating drugs inside polymers can change how they move through the body.
For the second half of graduate school, I combined my passion for polymeric science with my desire to study the brain. My mentor and I designed biomaterials capable of releasing growth factors. We delivered these drugs directly to the hippocampus in mice to assess anti-depressant efficacy.
When you chose a post-doctoral lab, you decided to stay at Yale. How did you pivot your research program to broaden your skill set?
It was during my post-doctoral years that my current career interests took shape. Until that point, my career revolved around designing nanoparticles for drug delivery. The next logical step was to trace where the nanoparticles went once inside the body. I learned how to track nanoparticle fate using positron emission tomography (PET).
By visualizing the path nanoparticles took once deposited, we can improve our design protocols by engineering biomaterials that can travel and clear the brain productively and safely.
What brought you to Barrows Neurological Institute for your first faculty position?
At the time, Barrow Neurological Institute had just opened a new initiative, the Barrow Brain Tumor Research Center. They were interested in building collaborations between their clinicians and basic scientists and recruited new faculty skilled in developing technologies. And so, I began my first foray into oncology.
While there, I pitched ideas to the clinicians and learned an incredible amount about their clinical practice and patient needs. This experience gave me a clearer understanding of how clinical trials develop. Viewing my research through a different lens helped me gain insight into ways to tweak my research so it might eventually translate [to the clinic] and have a greater impact.
You moved to the University of Texas Health Science Center in Houston to begin the research program that you continue today. Can you tell us about this research program?
The program focuses on bringing drugs directly to the brain.
The treatment options currently available for brain tumors aren’t always effective. Chemotherapy is delivered systemically, but because it is so toxic, patients suffer terrible side effects, and this limits both the dose of drug that we can use and the potential for that drug to be effective. There are other kinds of drugs that could be less toxic, but they can’t reach the tumor due to the blood-brain barrier. So, there is a longstanding need to reduce toxicity and enhance delivery of drugs to the brain.
I am testing new ways to get drugs into the brain that may potentially treat some forms of brain cancer. Some kinds of cancers exhibit a pattern in which they spread from the primary tumor to fill the subarachnoid space—the area between the surfaces of the brain and spinal cord and the underside of the skull (see Figure 1, left, region between the double arrows). Cancer cells often invade this space, forming metastases that are difficult to access through conventional (systemic) chemotherapy. The subarachnoid space is filled with cerebrospinal fluid (CSF), blood vessels, nerve roots, and anchoring connective structures called trabeculae, all of which influence how drugs move and whether they can reach their target tissues or cells (see Figure 1, right, black and white image). My research team and I are specifically focused on delivery of drugs to the CSF so that we can enhance delivery of drugs to metastatic cells while reducing peripheral side effects
Using this technique, I may be able to make a significant impact on the field because more of the drug may be able to reach the tumors.
Figure 1: Illustration of the location of subarachnoid space between skull and brain surfaces (left). Photo of subarachnoid space in the mouse (right).
There are some clinical approaches whereby drugs are administered—in free, normal form—directly to the CSF. But natural barriers in the brain and clearance of the CSF prevent the entire dose from reaching the tumors. My team is engineering nanoparticles that can navigate these barriers, allowing high doses of drug to travel to malignant cells, ensuring effective tumor kill. We are also working on ways to prevent the drug from clearing the brain before it has time to take effect.
Figure 2 below illustrates how nanoparticles that have been delivered to the subarachnoid space reach their target tissue.
Figure 2: Left: Nanoparticles (red) reached all CSF-exposed surfaces of cerebellum. Right: Nanoparticles (yellow) within the subarachnoid space penetrated a focal tumor metastasis (outlined in white). Cell nuclei are stained in blue in both images.
What diseases could be helped by your approach?
Tumors that travel through the CSF can benefit from this approach. For example, medulloblastoma, a relatively rare pediatric brain tumor, sometimes gains access to the CSF, scattering metastases on various surfaces of the brain and spinal cord in much the same way butter spreads on toast. With tumor tissue distributed in a thin layer, the cancer is impossible to surgically resect.
These tumors also do not respond well to chemotherapy, requiring children to receive high doses of cranial spinal radiation. Such harsh therapy inevitably presents challenges later. If we administer the drug directly to the subarachnoid space, the drug is often undetectable in peripheral circulation, and peripheral toxicity is minimized.
About Rachael Sirianni, PhD
Rachael Sirianni, PhD, is a professor and vice chair of research in the Department of Neurological Surgery at the University of Massachusetts Chan Medical School. She earned her PhD, in Biomedical Engineering at Yale University. She is Principal Investigator on three active NIH grants.
