Antibody loaded collapsible hyaluronic acid hydrogels for intraocular delivery

Injectable gels have the potential to encapsulate drugs for sustained release of protein therapeutics for use in the eye. Hyaluronic acid (HA) is a biodegradable clinically used material and poly N-isopropylacrylamide (pNIPAAM) is a stimuli responsive polymer that can display a lower critical solution temperature (LCST) at physiological conditions. Two gel systems incorporating HA were prepared in the presence of the antibody infliximab (INF): i) 1% and 5% tyramine-substituted HA (HA-Tyr) was enzymatically crosslinked in the presence of INF to form HA-Tyr-INF and ii) NIPAAM was chemically crosslinked in the presence of HA and INF with 1 and 3% poly(ethylene glycol) diacrylate (PEGDA) to form PEGDA-pNIPAAM-HA-INF. The PEGDA-pNIPAAM-HA-INF hydrogels displayed LCSTs at temperatures ranging from 31.4 +/- 0.2 to 35.7 +/- 0.3 degrees C. Although all the gels prepared were injectable, INF-loaded gels with lower crosslinking density (1% PEGDA-pNIPAAM-HA and 1% HA -Tyr) showed lower elastic (G') and viscous (G '') moduli compared to higher crosslinked gels (3% PEGD-ApNIPAAM-HA-INF and 5% HA-Tyr-INF) resulting in differences in swelling ratio (SR). Moduli may be correlated with overall stiffness of the gel. All hydrogels demonstrated sustained release of INF in a two-compartment in vitro outflow model of the human eye called the PK-Eye. The 1% PEGDA-pNIPAAM-HA-INF hydrogel displayed the slowest release (24.9 +/- 0.4% INF release by day 9) in phosphate buffered saline (PBS, pH 7.4), which is a better release profile than the free drug alone (tested under the same conditions). These results suggest that PEGDA-pNIPAAM-HA has potential for the continued development of formulations to prolong the intraocular release of proteins.