Abstract
Abstract
Ovarian carcinoma remains the cancer with the highest mortality among gynecological tumors. Development of novel strategies for the diagnosis and treatment of chemotherapy resistant ovarian disease remains a high priority. Magnetic iron oxide nanoparticles (NP) consist of an iron oxide core and hydrophilic coating. NP can establish magnetic field gradients that alter proton relaxation properties, thus providing an excellent source of contrast for magnetic resonance imaging (MRI). Moreover, since they can be heated in alternating magnetic fields (AMF), they may also provide an effective form of hyperthermia for cancer therapy. Unfortunately, currently available iron oxide NP, although potentially able to allow MRI detection of single cells in vivo, are not tumor specific. Our group has recently analyzed the genetic fingerprints of ovarian cancer identifying extremely high expression of the genes encoding the proteins claudin-3 and -4, the epithelial receptors for Clostridium perfringens enterotoxin (CPE). Since the C-terminus domain (C-CPE) of the toxin is sufficient for CPE binding and it is not toxic to cells, we used iron oxide NP complexed to C-CPE peptide to target chemotherapy resistant ovarian cancer cells overexpressing claudin-3 and -4. We report that NP functionalized by the fluorescent C-CPE peptide effectively bind and rapidly internalize into ovarian cancer cells using flow cytometry,confocal microscopy and Prussian blue staining. A 5-fold increase in iron cellular uptake after incubation of tumor cells with C-CPE NP was consistently detected when compared to tumor cells exposed to non specific control NP [i.e., iron concentration of (mean ± STDV) 20.3 ± 0.5 vs 4.1 ± 1.3 nmoles/5*10 cells respectively; p<0.01]. Importantly, only tumor cells exposed to C-CPE NP were detectable in MRI in vitro experiments using a Bruker 4.7Tmagnet. Finally, to assess the potential of C-CPE NP to be used for hyperthermia therapy against chemotherapy resistant ovarian cancer, we characterized the magnetic heating capacity of C-CPE NP using an induction heating system (Ambrell, Easy Heat). Our results show a temperature increase of 7.85 ± 0.6 °C (mean ± STDV) when C-CPE NP were subjected to an AMF of 343 kHz of frequency and 2 KW of power for 10 minutes. Our data clearly suggest that C-CPE NP may represent a novel theranostic tool to specifically target chemotherapy resistant ovarian cancer.
Citation Format: Emiliano Cocco, Ileana Bortolomai, Stefania Bellone, Sara Gasparrini, Diana English, Erik Shapiro, Sergio Pecorelli, Dan-Arin Silasi, Masoud Azodi, Elena Ratner, Thomas Rutherford, Peter Schwartz, Alessandro Santin. Iron oxide nanoparticles functionalized with the Clostridium Perfringens Enterotoxin carboxi-terminal fragment peptide: A novel diagnostic and therapeutic approach to specifically target ovarian cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 732. doi:10.1158/1538-7445.AM2013-732