Researchers at the University of Cambridge have developed a polymer-based cartilage-like material that can release anti-inflammatory medications within the body in response to heightened joint inflammation. According to the research, published in the Journal of the American Chemical Society, the material reacts to small changes in acidity that occur during inflammation by softening and releasing its therapeutic cargo at the site of the inflammation. This new technique has the potential to change how inflammatory conditions such as arthritis are treated in the future.
“For a while now, we’ve been interested in using these materials in joints, since their properties can mimic those of cartilage,” said senior author Oren Scherman, PhD, professor of supramolecular and polymer chemistry and director of the Melville Laboratory for Polymer Synthesis at the University of Cambridge. “But to combine that with highly targeted drug delivery is a really exciting prospect.”
Arthritis affects roughly half-a-billion people globally and more than 53 million in the U.S., or about 21% of the adult population. Current treatments skew heavily toward the systemic delivery of non-steroidal anti-inflammatory drugs (NSAIDS) or corticosteroids. Both classes of medications come with a range of side effects: stomach pain, ulcers, and kidney damage for NSAIDs; and weight gain, osteoporosis, and high blood sugar, among others, for corticosteroids. The new material developed by the team at Cambridge could provide a needed alternative capable delivering anti-inflammatory drugs only when and where they are needed.
To create this novel cartilage-like material, the researchers used cucurbit[n]uril (CB[n]) which have been widely employed in a range of materials including supramolecular oligomers, polymers, hydrogels, functional interfaces, and molecular separators. CB[n] host-guest interactions can be designed whereby these complexes respond to external stimuli. In the case of this new material, it was specifically designed to respond within the physiological pH range of 4.5–7.5, where local acidosis can indicate inflammation or tissue damage.
“Achieving sensitive and reversible responsivity over physiologically relevant pH ranges (4.5–7.5) remains of great interest for the design of next-generation autonomous drug delivery devices,” the researchers wrote.
The key mechanism behind the material’s behavior is a pH-sensitive “kinetic locking” process. At normal pH, the guest molecules can slide in and out of the host CB[7] or CB[8] rings, but as the pH drops, a carboxylic acid group becomes negatively charged, which repels the host’s carbonyl-lined portal, locking the guest molecule in place and altering the crosslinking structure of the polymer.
The research builds on prior research which has shown that localized pH changes are reliable biomarkers for inflammation, especially in arthritis. “We envisioned that kinetic-locking of host–guest complexes could be achieved in accordance within this narrow pH range, offering the potential to realize rapid, reversible, and sensitive stimuli-responsive materials,” the researchers wrote.
Other researchers have sought to create drug delivery triggered by changes in pH employing nanoparticles or chemical bonds that react to certain acidic conditions. But, these attempts have shown challenges with regard to reversibility of drug release, limited control over disassembly, and responsiveness across only narrow pH ranges. The kinetic locking mechanism developed by the Cambridge team addresses these limitations by providing a tunable, stable, and reversible system.
To create a practical application, the team synthesized a guest monomer (VBPI) containing a polymerizable vinyl group. This was polymerized with acrylamide to form hydrogels cross-linked by CB[8] host–guest complexes. “Employing these complexes as dynamic crosslinks within polymer networks gives rise to materials with highly pH-responsive mechanical and viscoelastic properties,” the researchers wrote. Mechanical testing of the material showed that it becomes softer and more deformable at lower pH values typical of inflamed joints.
To understand how the cartilage-like material releases its cargo, the team used a small molecule dye to mimic drug behavior. Under compressive stress, the material released 32% more dye at pH 5.5 (arthritic conditions) than at pH 7.5 (healthy conditions) over a three-hour period. “By tuning the chemistry of these gels, we can make them highly sensitive to the subtle shifts in acidity that occur in inflamed tissue,” said co-author Jade McCune, PhD, science strategy manager at University of Cambridge. “That means drugs are released when and where they are needed most.”
Next steps will be in vivo testing of the material to assess biocompatibility, safety, and efficacy. If successful in further trials, the material could become a new platform for self-regulating drug delivery, reducing systemic exposure in long-term disease management. Because of this, it could eventually be used not only for the delivery of arthritis medications, but also for therapies treating cancer and other chronic inflammatory conditions. “It’s a highly flexible approach, so we could in theory incorporate both fast-acting and slow-acting drugs, and have a single treatment that lasts for days, weeks or even months,” said first author Stephen O’Neill, PhD, a research associate at University of Cambridge.