research

01 macroscale materials for oral drug delivery

My postdoctoral research in the Langer & Traverso labs at MIT sought to expand access to advanced therapeutics for vulnerable patients. Pediatric and geriatric patients struggle with swallowing solids, which can complicate their compliance with medications. We sought to develop a formulation that was broadly compatible with various drug classes, could transition from a liquid state (to facilitate ingestion) to a solid state in the stomach (to act as a drug depot), and was mechanically tough (to resist compressive forces in the gastrointestinal tract). 

To realize these goals, we developed a liquid in situ-forming and tough (LIFT) hydrogel formulation comprising a crosslinker and polymer solution that are ingested in series. Mixing of the two solutions in the stomach results in crosslinking of two polymer networks, resulting in rapid formation of a tough material (see figure). 

Highlights of this work include:

• LIFT forms tough hydrogels even in complex gastric fluid, and is mechanically tougher than single-network hydrogels

• by self-assembling into macroscale structures, LIFT is able to control the release of small molecules due to reduced surface area-to-volume ratios compared to suspension and nanoscale formulations

• in situ formation of a depot enables co-formulation of drug-stabilizing excipients, prolonging the activity and viability of therapeutic enzymes and bacteria

This work is published in Nature Materials (link). 

02 materials design for renal tropism

My Ph.D. research in the Pun lab at University of Washington, in collaboration with the Shankland lab, sought to understand nanoscale materials interactions with renal biology. This fundamental knowledge could inform the design of drug delivery vehicles for renal disease. We focused on the materials properties of polymer- and nanoparticle-based delivery systems and studied the impact of disease state and materials charge and size on their distribution within the kidneys. 

Highlights of this work include: 

• negatively charged polymers exhibit greater accumulation in renal proximal tubule cells compared to neutral polymers (see figure), and this effect is enhanced during renal disease

• nanoparticles of size 20-100 nm accumulate in renal vasculature, and this effect is enhanced during renal disease

These works are published in Biomaterials (link) and Physiological Reports (link).

03 bioresponsive materials

Materials that are responsive to biological stimuli such as proteases, pH, temperature, and reactive oxygen species can be programmed with context-dependent actions. 

For drug delivery applications, such stimuli can program drug release only at the site of disease and internalization into cells of interest. My Ph.D. work developed a pH-sensitive linker as a triggered drug release mechanism from drug carriers. 

For diagnostic applications, such stimuli can be leveraged to activate disease sensors. During my postdoctoral fellowship, I developed a protease-sensitive sensor to detect inflammation. 

Highlights of this work include: 

• via a pH-reversible boronic ester bond, the renal drug candidate Bis-T-23 can be released from boronic acid drug carriers (see figure) after internalization into cellular endosomes and lysosomes

• in a porcine model of intestinal inflammation, inflammation-sensing sutures applied locally in the intestines were able to detect inflammation through cleavage of a peptide linker and release of fluorophore into the urine

These works are published in ACS Biomaterials Science & Engineering (link) and Matter (link).

04 ligand discovery and deep sequencing

Peptides are attractive materials as linkers and binding ligands due to their small size and ease of synthesis. Peptide phage display is a powerful tool to discover new peptide ligands against targets of interest. Sanger sequencing is typically utilized to deduce peptide identity but is low-throughput and prone to false-positives. To overcome this barrier, we developed methods for deep sequencing of phage display libraries. 

Highlights of this work include: 

• characterization of parasitic and binder sequence enrichment kinetics over sequential rounds of phage display

• greater ligand identification efficiency compared to Sanger sequencing

• identification of 6 new peptides that bind preferentially to alternatively activated M2 macrophage over classically activated M1 macrophage (see figure)

This work is published in Bioconjugate Chemistry (link).