CAREER: Developing electrically charged biomaterials for targeted drug delivery to negatively charged complex tissue environments

This award is funded in whole or in part under the American Rescue Plan Act of 2021 (Public Law 117-2). Non-Technical Abstract:

There are tissues within the human body that are not receptive to systemic or local drug delivery methods due to their high negative charge density and lack of blood vessels. The proposed work will investigate how to improve drug delivery in these less receptive tissues by using charge interactions. The impact of modifying different physical and chemical properties of positively charged biomaterials on their transport will be evaluated using cartilage and joint fluid, as a model of negatively charged tissue environment.

The study will reveal key structure-property relationships in electrically charged biomaterials and complex negatively charged musculoskeletal tissue environments in both healthy and diseased states that can be generalized and tuned to target other charged tissue systems. Long-term, the program has wide applicability as it can be extended to other tissues with similar properties (meniscus, intervertebral disc, fracture callus, eye, mucus), diseases and for delivery of various drugs and imaging agents – ultimately facilitating their clinical translation.

Complementing this research program is an integrative education plan designed to train students to approach research with a view towards translatability and creating real-world impact. The education program will establish a collaborative translational biomaterials conference to engage local industry to provide undergraduate and graduate students with professional developmental opportunities.

New modules and demonstration videos focused on biomaterials design and electric charge-based drug delivery will be developed that target high school, undergraduate women and underrepresented minorities. Finally, a unique intra-American scientific exchange program will be established to foster relationship between diverse communities within the US to help create more understanding and broadly effective scientific leaders.

Technical Abstract:

This proposal investigates how physicochemical properties of polyvalent cationic macromolecules affect their electro-diffusive transport within negatively charged tissues and their cellular microenvironments and uses this knowledge to rationally design cationic carriers for targeted drug delivery to tissues based on their negative fixed charge density (FCD). Human body contains several negatively charged tissues that are inaccessible to both systemic and local drug delivery due to their avascular, dense extracellular matrix.

This high negative FCD, however, can be converted to an opportunity by modifying therapeutics to add optimally charged cationic domains such that electrostatic interactions can enhance their transport rather than hindering them. This long-range, weak-reversible charge-based intra-tissue binding can be synergistically stabilized by short-range binding effects (H-bond, hydrophobicity) such that these carriers can have long residence times even in degenerated tissues with diminished FCD.

Using cartilage as a model target tissue of high negative FCD owing to its high density of glycosaminoglycans (GAGs), this proposal will investigate the effects of physicochemical properties of cationic carriers on their transport in aim 1. Cationic peptide carriers (CPCs) with the same short length but varying net charge comprising of arginine (exhibits H-bonds and charge interactions) or lysine (primarily charge) will be designed to determine an optimal configuration for fastest intra-tissue diffusivity, full-depth penetration, highest equilibrium uptake, and long-term binding to target chondrocytes residing in both healthy and arthritic cartilage.

In addition to short intra-joint residence time of drugs due to rapid exit from lymphatics, cartilage targeting is further compromised by competitive binding with synovial fluid, that comprises of both negatively charged hyaluronic acid and hydrophobic globulins. In aim 2, hydrophobic or hydrophilic tails will be added to the optimized CPC designs to investigate the synergistic or competitive effects on charge-based binding within cartilage of varying FCD in presence of synovial fluid.

In aim 3, these optimized cationic motifs will be anchored on exosome’s anionic surface in varying densities to demonstrate improved targeting of arthritic cartilage in presence of synovial fluid.

This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.