(128e) Tuning Size and Charge of a Multivalent Polymer Library for Enhanced Drug Delivery to Cartilage

Efficient transport of therapeutics through dense biological tissues has proven to be a complex challenge, especially for osteoarthritis, a degenerative joint disease characterized by gradual cartilage degradation. In fact, the avascular, densely packed, and negatively charged cartilage extracellular matrix has stood a barrier to the transport and, thus, therapeutic effect of even locally administered disease modifying osteoarthritis drugs. Such a challenge stems from the fact that achieving cartilage protection by maintaining chondrocyte viability, inhibiting matrix degradation, and stimulating matrix biosynthesis requires that therapeutics be delivered to the middle and deep zones of cartilage. In efforts to transform cartilage from a drug barrier into a drug reservoir, we screened a library of cationic dendritic polymers for cartilage uptake capability and cytotoxicity. Facile control over size and charge of the carriers was achieved through modification of the polymer’s periphery with poly-ethylene glycol (PEG) molecules of various lengths. Fluorescence intensity measurements of nanoparticles incubated in approximately human-thick bovine cartilage explants revealed a significant influence of size and charge on uptake capabilities of the polymers. Larger constructs with higher degrees of charge shielding maintained excellent chondrocyte viability but displayed poor uptake into cartilage. Smaller, more cationic nanoparticles yielded superior tissue binding but exhibited cytotoxic behavior at physiologically-relevant doses. Formulations demonstrating an optimal balance of uptake and cell viability were conjugated with a cartilage-repairing growth factor (GF), and were superior to free GF in transporting it through cartilage.