Synthesis and characterization of CREKA-conjugated iron oxide nanoparticles for hyperthermia applications

Abstract

One of the current challenges in the systemic delivery of nanoparticles in cancer therapy applications is the lack of effective tumor localization. Iron oxide nanoparticles (IONPs) coated with crosslinked dextran were functionalized with the tumor-homing peptide CREKA, which binds to fibrinogen complexes in the extracellular matrix of tumors. This allows for the homing of these nanoparticles to tumor tissue. The IONP 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 of the system. Magnetically mediated hyperthermia (MMH) allows for the heating of tumor tissue to increase the efficacy of traditional cancer treatments using IONPs. While MMH provides the opportunity for localized heating, this method is currently limited by the lack of particle penetration into tumor tissue, even after effective targeted delivery to the tumor site. The CREKA-conjugated nanoparticles presented were characterized for their size, stability, heating capabilities and biocompatibility. The particles had a hydrated diameter of 52nm, were stable in phosphate buffered saline solution and media with 10% v/v fetal bovine serum over at least 12h, and generated enough heat to raise solution temperatures well into the hyperthermia range (41-45°C) when exposed to an AMF, owing to an average specific absorption rate of 83.5Wg(-1). Cytotoxicity studies demonstrated that the particles have low cytotoxicity over long exposure times at low concentrations. A fibrinogen clotting assay was used to determine the binding affinity of CREKA-conjugated particles, which was significantly greater than the binding affinity of dextran, only coated IONPs demonstrating the potential for this particle system to effectively home to a variety of tumor locations. Finally, it was shown that in vitro MMH increased the effects of cisplatin compared with cisplatin or MMH treatments alone.

Keywords: CREKA; Fibrinogen; Iron oxide nanoparticles; Magnetically mediated hyperthermia.