Physically Crosslinked Thermoresponsive Polymer Hydrogels for Cooling-Triggered Drug Release

Physically crosslinked thermoresponsive polymer hydrogels undergo a well-known gel-to-sol transition upon being cooled below their LCST. Accompanying this transition is a massive increase in the release rate of sequestered payloads. We explore the possibility of using such a system for cooling-triggered, local release of pain relief therapeutics. Currently, opioid addiction and abuse result in over 115 deaths per day in the US alone. A safer, non-systemic, local mechanism for relief from acute (e.g. perioperative pain) and chronic pain is therefore needed. Ideally, patients and caregivers should be able to trigger this mechanism, non-invasively and on demand, via an external stimulus. As icepacks are already widely applied to temporarily ease local pain, introducing a drug delivery mechanism switched “ON” by cooling would enable long duration, enhanced pain relief triggered by a method with which patients are already familiar. Herein, we describe how cooling-triggered drug release can be achieved using a drug-loaded physically crosslinked thermoresponsive polymer hydrogel encapsulated in a rate-limiting nanoporous membrane. <br/>We formulated a Soluplus (a polyvinyl caprolactam copolymer from BASF) solution (10%-30% w/v, with 3% CaCl₂) and loaded 0.5%-1%w/w_gel Nile Red (NR, as a model molecule for bupivacaine, a common anesthetic) into it. We then heated this solution above its LCST within a mold to form 0.2 ml hydrogel pellets. Finally, we dipped these pellets in an alginate bath for 4 minutes to encapsulate them in ~500-micron-thick, calcium-crosslinked alginate shells. We placed these pellets in a 40°C PBS well for 3 hours to account for any initial burst release. Next, we alternated each pellet between warm (40°C) and cool (~23°C) separate wells, allowing the pellets to spend 24 hours at each temperature. The amount of NR released into the wells at the different temperatures was then determined using a plate reader. Additionally, to ensure that the NR is released in a form accessible to cells, we exposed HUVEC cells to solution drawn from the wells containing the pellets and observed their fluorescence (NR fluoresces minimally in water but becomes very fluorescent in nonpolar environments such as lipid membranes).<br/>We observed that pellets released ~100 times more NR into the surrounding PBS when kept at ~23°C compared to when kept at 40°C. As the LCST of our Soluplus formulation is ~30°C, this indicates that its gel-to-sol transition results in a huge increase in the rate of release of NR. When HUVEC cells were exposed to the PBS into which a hydrogel device had released NR, they showed clear signs of NR uptake, indicating availability to cells. NR release from the pellets described above can therefore be switched ON by cooling below the LCST of the constituent hydrogel and OFF again by heating above said LCST. The payload released is shown to be available to cells. These results demonstrate that physically crosslinkled thermoresponsive polymer hydrogels can be used for cooling-activated drug release, a promising new approach for patient triggered, on-demand delivery of therapeutics.