Using the Body’s Internal Electric Fields to Overcome the Tissue Barrier for Targeted Drug Delivery
Negatively charged tissues that also tend to be dense and avascular are ubiquitous in the human body and remain an outstanding challenge in the field of targeted drug delivery. Examples include cartilage, meniscus, intervertebral discs, mucosal membrane, and the eye’s vitreous humor. Their degeneration is associated with several common diseases such as osteoarthritis, lower back pain, inflammatory bowel disease, and macular and retinal degeneration, which in total affect over 20% of American adults but remain untreatable due to a lack of delivery systems that can enable drugs to penetrate the negatively charged tissues and reach their matrix and cellular targets. The high negative fixed charge density (FCD), however, can be converted from being a challenge to an opportunity by modifying therapeutics to add positively charged domains such that electrostatic interactions can enhance their transport, uptake and retention rather than hindering them. This presentation challenges the conventional wisdom that charge interactions cannot enable adequate intra-tissue retention due to their weak binding affinity and proposes that the weak and reversible binding nature of electrostatic interactions is, in fact, an essential characteristic that enables drug carriers to unbind after their initial binding with negatively charged groups, find another binding site, and continue this process until they diffuse through full tissue thickness. It is the high negative FCD that ensures their long residence time despite weak binding and also creates a steep drop in electrical potential resulting in a sharp increase in concentration of cationic drugs at the tissue interface that drastically accelerates their transport. These concepts will be discussed in the context of drug delivery to cartilage for treatment of osteoarthritis, a disease that remains untreated primarily due to a lack of effective delivery systems. In-vitro experimental validation, modeling of transport and binding mechanisms, and pre-clinical animal models will also be discussed.
Ambika Bajpayee is an Assistant Professor in the Department of Bioengineering at Northeastern University. Her interests include targeted drug delivery, bio-electrostatics, protein-based nano-carriers, and modeling of bio-transport and biomechanics, with a specific focus on degenerative musculoskeletal diseases. Ambika received her PhD in Mechanical Engineering at Massachusetts Institute of Technology (MIT), where she focused on developing charge-based cartilage penetrating carriers for targeted drug delivery to chondrocytes. Her post-doctoral work at MIT focused on developing devices for oral drug delivery to the gastrointestinal tract and investigating disease-related changes in mechanics and permeability of mucosal membranes. Previously, she worked as a medical device engineer on development and FDA approval of orthopedic and dental implants. She also holds a Masters degree from MIT and an undergraduate degree from the University of Delhi, India.