(2io) Bending the Drug Delivery Paradigm By Targeting Nanocarriers for Accumulation within the Body’s Intrinsic Barriers

Drug delivery engineering drives innovation in transporting therapeutic cargos across the body’s innate barriers, including cell membranes and epithelial or endothelial tissues, but often overlooks the need to deliver therapeutic drugs for action within these barriers. For example, oral delivery of macromolecule drugs is dependent on strategies to permeabilize the intestinal epithelial lining or to encapsulate drugs into nanocarriers targeted for epithelial crossing. However, development of inflammatory bowel diseases results from overly permeable intestines allowing the infiltration of intestinal bacteria into the intestinal wall. In a parallel example, the design and construction of nanoparticles to penetrate the formidable blood brain barrier (BBB) and deliver drugs into the brain space is a current holy grail of drug delivery, with a wide variety of ongoing efforts. Yet, the same endothelial tissue that makes up the BBB can become leaky, a factor which has been implicated in the development and progression of several neurological diseases. In both cases, and in several other epithelia- and endothelia-driven diseases through the body, there is an opportunity to flip the current script for drug delivery across these barriers, instead creating therapeutics and drug delivery vehicles that combine to accumulate within and strengthen the body’s own barriers. As faculty, I will leverage my experience with manipulating the body’s epithelial and endothelial barriers, treatment of leaky gut diseases, and design of targeted nanocarriers to build a research group focused on targeting and treating dysfunctional barrier tissues in the body.

My PhD work in the lab of Professor Kathryn Whitehead at Carnegie Mellon University (CMU) leveraged permeabilization of the intestinal epithelium for oral drug delivery. While my experiments were designed to use natural product development or nanoparticle drug delivery strategies to increase permeability of therapeutic molecules across intestinal tissue, I also investigated the effects of my drug carriers on intestinal models to ensure that any increase in permeability was reversible and did not induce chronic inflammatory responses. In one project, while I identified the molecule pelargonidin from strawberries as a potent, reversible permeabilizer of the intestinal epithelium to enable oral insulin delivery, I also discovered that raspberry extracts caused the opposite effect. These treatments tightened the junctions between cells in both cell culture intestinal models and mouse intestines, which could help to reduce the passage of bacteria, endotoxins, and other unwanted materials through a leaky epithelium and into the surrounding tissue and bloodstream. In a mouse model of ulcerative colitis, the tight junction repair effect of the raspberry led to mild improvements in disease outcome. However, the treatments were being administered simply as aqueous solutions through oral gavage, spreading through the whole gastrointestinal tract and leading to poor accumulation of the extract near the target cells in the large intestine. By encapsulating these raspberry abstracts or other tight junction fortifying drugs (e.g. short chain fatty acids, beta-casein, or cucurmin) in epithelial-targeting nanovehicles, my lab will work to enable a new class of treatments for debilitating inflammatory bowel diseases.

In complement, my postdoctoral work in the lab of Professor Paula Hammond at the Massachusetts Institute of Technology (MIT) has leveraged the rational design and construction of self-assembled, layer-by-layer polymer nanoparticles to assess how nanocarrier size, stiffness, surface chemistry, and targeting strategies all contribute to accumulation across the blood brain barrier (BBB). Beyond candidates for transcytosis and delivery into the brain, I have identified nanoparticle surface chemistries that lead to terminal uptake and cargo delivery into the endothelial cells themselves. This direct targeting of nanoparticles into endothelial cells presents an opportunity to cut off pathogenesis of several neurological diseases. For example, multiple sclerosis (MS) is a progressive autoimmune disease that presents with BBB dysfunction preceding the onset of clinical symptoms. It is hypothesized that early treatment and mitigation of this endothelial leakiness can slow the progression of MS, though it has yet to be investigated whether targeted delivery of barrier fortifying drugs can prevent disease progression. In my lab, I will both expand understanding of this concept of endothelial-associating vehicles by extending it to new nanomaterials, as well as combine it with endothelium-strengthening therapeutics to prevent the development or progression of neurological diseases such as Alzheimer’s disease, seizures and, strokes. Continuing forward, I will drive these concepts into new organs with new challenges, including leaky bile duct epithelia in nonviral liver cirrhosis and damaged lung epithelia in acute respiratory distress syndrome.

Teaching Interests:

My teaching philosophy is built upon the principles that chemical engineers must be able to critically evaluate the strengths and weaknesses of information presented to them, to work in teams to process this information, and to clearly communicate their findings and conclusions to a broad audience. My passion as an instructor is to impart these abilities into my students by leveraging my current day-to-day experience with literature review and scientific communication, as well as my prior experience in Chemical and Biological Engineering coursework. As a senior undergraduate and as a graduate student, I served as a teaching assistant (TA) for biomaterials, core chemical engineering, and graduate level bioengineering elective courses. As a TA, I oversaw lab experiments, graded lab reports and examinations, held office hours, provided one-on-one course assistance, and prepared and delivered guest lectures. I also completed the Future Faculty program through the Eberly Teaching Center at CMU, which places a heavy focus on research-based pedagogy that maximizes critical thinking, among other learning outcomes. Moving forward, I am interested and qualified to teach both Chemical Engineering and Bioengineering courses, at both the undergraduate and graduate level, in the areas of biomaterials, fluid dynamics, and heat and mass transfer. Additionally, I am excited to create a special topics graduate course in the rapidly expanding fields of Drug Delivery and Nanomedicine.