Abstract 5314: Development of theranostic nanoparticles for targeted tumor imaging and treatment of HER-2/neu positive cancer

Abstract

Abstract BACKGROUND: Overexpression of HER-2/neu is found in several types of human cancers and is associated with a poorer prognosis for breast, ovary, lung and bladder cancers. Novel approaches are urgently needed for the early detection of the cancer for improving survival of the patients. In this study, we are developing a HER-2/neu targeted nanoparticle for image-based detection and targeted therapy. Small size and high affinity affibodies have been investigated for tumor targeting both for imaging and targeted therapy by several groups. In this study, we have develop a dual imaging modality and therapeutic nanoparticle system that is targeted to HER-2/neu using an affibody and detected the targeting specificity in vitro and in vivo in animal models. METHODS: The HER-2/neu affibody was firstly conjugated with a near infrared dye-830 (NIR-830) maleimide. The amphiphilic polymer-coated iron oxide nanoparticles (IONP) were activated with ethyl-3-dimethyl amino propyl carbodiimide (EDAC) and sulfo-N-hydroxysuccinimide (NHS). Activated IONP were then reacted with NIR-830 conjugated HER-2/neu affibody. The final HER-2/neu affibody labeled NIR-830 dye-IONPs were purified using Nanosep 100K column filtration. The specificities of the conjugates (HER-2/neu-NIR-830 -IONP) were validated by Prussian blue staining. An orthotopic ovarian tumor model was established by injecting SKOV3-luc+ cells into the ovary of nude mice. The targeted IONP was then injected into the tumor bearing nude mice via tail vein to determine in vivo tumor targeting and optical imaging. To add a therapeutic capability, we coupled an anti-cancer drug cisplatin to the HER-2/neu targeted-IONP and tested its anti-tumor effect in vitro. Cytotoxicity of the targeted drug-IONPs was determined in high HER-2/neu expressing SKOV3 cells and low HER-2/neu expressing OVCAR3 cells by using the Alamar Blue Cell Proliferation Assay. RESULTS: We have demonstrated targeted specificity of the HER-2/neu targeted-IONPs in a high level of HER-2/neu(+) SKOV3 cells using Prussian blue staining. Systemic delivery of the HER-2/neu targeted-IONPs resulted in selective accumulation of the IONPs in the orthotopic SKOV3 ovarian tumor model since a strong NIR signal was detected in the tumor mass 24 hours after administration of the nanoparticle into the tumor bearing nude mice. Our in vitro cell viability assay showed that HER-2/neu-NIR-830-IONP-cisplatin exhibited a higher cytotoxicity in high HER-2/neu expressing SKOV3 cells compared to low HER-2/neu expressing OVCAR3 cells. Further studies are in the process to evaluate the efficient anti-tumor effects of the cisplatin loaded conjugates in vivo in orthotopic ovarian tumor and breast cancer models. CONCLUSION: Taken together, our preliminary results suggest that the NIR bioconjugates developed for this study may be an ideal system for therapeutic application and molecular imaging. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5314. doi:10.1158/1538-7445.AM2011-5314