(292f) Award Submission: PEG-Based Magnetic Hydrogel Nanocomposites for Combined Chemotherapy and Hyperthermia Treatment of Cancer

Hyperthermia, the heating of tissue to 41 to 45°C, has been shown to improve the efficacy of cancer therapy when used in conjunction with irradiation and/or chemotherapy. Current limitations include but are not limited to non-homogeneous distribution of temperature over the cancer site, low specificity, patient discomfort, and lack of localized delivery of heat. These shortcomings can be overcome through the utilization of polymeric biomaterials which can be delivered at tumor sites and remotely heated from outside the body while simultaneously delivering therapeutic drugs. Hydrogel nanocomposites which are composed of biocompatible crosslinked polymeric material and nanoparticulates capable of heating upon exposure to an electromagnetic field are a potential platform of polymeric biomaterials for this application. In addition to the remote heating, the network structure of the hydrogel allows for the tailored delivery of therapeutic agents. In this work, hydrogel nanocomposites have been developed that can be implanted or injected within or near a tumor site and deliver both heat and a chemotherapeutic agent (e.g., paclitaxel). In previous studies, the efficacy of paclitaxel has been proven to increase when combined with elevated temperatures. Here, the nanocomposites studied involve a stealth, poly(ethylene glycol) and iron oxide nanoparticle-based system. The iron oxide nanoparticles were physically entrapped in the hydrogel matrix which was comprised of poly(ethylene glycol) methyl methacrylate macromer and poly(ethylene glycol) dimethacrylate as the crosslinker.

Thermal analysis showed the capability of the hydrogels to be heated in an alternating magnetic field to various target surface temperatures depending on the strength of the field and composition of the hydrogel matrix. Hydrogels with lower swelling ratios proved to heat better than those with higher ratios due to the greater polymeric content in the gels which corresponds to higher iron oxide loading in the gels. The heating of the hydrogel nanocomposites was controlled by the strength of the magnetic field and hyperthermia-specific temperature ranges were reached for all hydrogel systems at field strengths ranging from 12.7 to 17.4 kA/m. To examine the cytocompatibility of the hydrogels, NIH 3T3 murine fibroblasts were exposed to the hydrogel systems, and the viability of the cells was not affected by leachants from the hydrogels. The delivery of a model drug, rifampicin, from the hydrogel nanocomposites was investigated and was shown to be controlled via the hydrogel matrix. This drug was chosen due to its similarity in hydrophobicity and molecular weight to paclitaxel. The delivery of paclitaxel from the hydrogels is also being investigated. An initial proof-of-concept demonstration was completed where M059K glioblastoma multiforme cells were heated to thermoablative temperatures (above 55°C) with the hydrogel nanocomposites exposed to the AMF and cell death was demonstrated. Studies with both M059K glioblastoma and MDA MB 231 breast adenocarcinoma cells where the cells are exposed to both hyperthermia-specific temperatures and paclitaxel (i.e., delivered directly in the cell media) to study if the efficacy of paclitaxel in inducing cell death with and without moderate heat are underway. In summary, the ability of these systems to heat and their capability to deliver drugs to specific sites make them viable systems for treating of deep-seated tumors or reoccurring cancer.

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