Thermally Triggered Drug Release from Injectable Hydrogel Composite for Local Chemotherapy Delivery to Tumors

A drug delivery system was designed to induce the controlled release of encapsulated anticancer agents in response to elevated temperatures using thermosensitive liposomes suspended in a thermally sensitive polymer, poly(N-isopropylacrylamide)-graft-chondrotin sulfate. Drug release is triggered by a heated environment at the temperature range of cancer tissue hyperthermia (T > 40°C). Heat and anticancer agents were utilized for this system because their combination is believed to have a synergistic cytotoxic effect on internal cancerous tissue. Two types of liposomes were produced using 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) and 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), which have transition temperatures of 41°C and 50°C, respectively. The lipid bilayers of the liposomes melt above these temperatures, which allows the release of the entrapped drug. The main objective of this study was to determine if the release of a model molecule, calcein, from the liposome-hydrogel composite occurs in a pulsatile manner in response to multiple spikes in temperature. Three types of liposome-hydrogel composites were used, which consisted of DPPC liposomes, DSPC liposomes, and a 50/50 mixture of DPPC and DSPC liposomes. The composites were maintained in phosphate buffered saline (PBS) and incubated in vitro at physiological temperature, 37°C. Every 24 hours, the samples were exposed to a temperature spike lasting 30 minutes, with the first two spikes at 41 °C and the last two at 50 °C. The amount of calcein released during each temperature spike was quantified with fluorescence spectroscopy and normalized to the total loaded calcein. The composite containing only DPPC liposomes released calcein after the first temperature spike with the ability for continued release with each subsequence spike. The composite containing only DSPC liposomes had very little calcein release at the 41°C spikes, and released calcein at a greater rate of release during the 50°C spikes. The composite containing both liposome types was able to release calcein equally at both temperatures but not to the same intensity as the other two samples types. Overall, the data indicate the potential for heat-triggered release of chemotherapy drug capable of repeated release after multiple temperature spikes. These results are significant because they suggest that this injectable hydrogel has potential for clinical relevance. When implanted within a tumor, the composites can release chemotherapy drugs in a pulsatile manner in response to hyperthermia. The combination of lipid types provide a greater temperature control to extend the treatment time. Future work will focus on characterizing the thermal properties of the hydrogel to have the composite be heated internally by ferromagnetic nanoparticles.