(783b) Synthesis and Characterization of Peptide-Conjugated Iron Oxide Nanoparticles for Hyperthermia Applications

One of the current challenges in the delivery of systemic nanoparticle systems in cancer therapy applications is the lack of effective tumor penetration. In this research, a nanoparticle system composed of an iron oxide core with a crosslinked dextran coating functionalized with the tumor homing peptide, CREKA, has been developed to overcome this limitation by homing to and penetrating into tumor tissue. The iron oxide core allows for particle heating upon exposure to an alternating magnetic field (AMF) while the dextran coating stabilizes the particles in suspension and decreases the cytotoxicity. The overall goal of this study was to develop and optimize these systems for effective hyperthermia treatment applications. Hyperthermia, the heating of tissue between 42 and 45°C, has been shown to enhance the effects of radiation and chemotherapeutics, but current methods of hyperthermia often result in severe side effects due to lack of localization and overheating of tissue. Magnetically mediated hyperthermia provides the opportunity for localized heating, however, this method is currently limited by the lack of particle penetration into tumor tissue. It is hypothesized that this specific particle system can enhance particle accumulation at the tumor site, providing a high enough concentration to induce localized hyperthermia conditions. The particles were characterized for size, stability, biocompatibility, and heating capabilities. The particles were stable in PBS and media over at least twelve hours, had a hydrated diameter of 50 nm, and generated enough heat to raise solution temperatures well into the hyperthermia range when exposed to an AMF. The biocompatibility of the particles was analyzed through cytotoxicity studies on A549 lung cancer cells and NIH 3T3 fibroblasts. These studies were completed for both high particle concentrations with low exposure time and low particle concentrations with high exposure time, and the results determined that the particles have low cytotoxicity over both time frames and concentrations. Fibrinogen clots were used to determine the binding affinity of CREKA. The equilibrium dissociation constant was determined for CREKA alone and for CREKA-conjugated particles. The binding affinity of CREKA conjugated iron oxide nanoparticles to fibrinogen gels is significantly greater than the binding affinity of dextran coated iron oxide nanoparticles. The binding of CREKA conjugated iron oxide nanoparticles to multicellular spheroids was also evaluated.  Results demonstrated that this novel system has the potential to be used for effective localized hyperthermia treatment of tumors.