Abstract 5379: Targeting epidermal growth factor receptor positive breast cancer using nanoparticles loaded with the anti-cancer drug aminoflavone

Abstract

Abstract Breast cancer is the second leading cause of cancer-related death in American women. Triple negative breast cancers (TNBCs), which lack expression of common therapeutic targets ERα and HER2, are particularly aggressive and correlated with decreased survival. While TNBCs make up 15-20% of all breast cancer cases, they account for a disproportionately large amount of breast cancer morbidity. Recently, our group has developed a novel therapeutic approach utilizing nanoparticle technology to increase targeted delivery of chemotherapeutic agents, specifically aminoflavone (AF, NSC 686288) to a model TNBC cell line that shows exquisite sensitivity to AF. We have found that AF, a synthetic flavonoid compound, exerts growth inhibitory effects in two TNBC cell lines, MDA-MB-468 and Cal51, with IC50 values in the low nanomolar range. However, in vivo studies examining the efficacy of AF indicate dose-limiting pulmonary toxicity, creating a need for drug delivery systems that circumvent toxicity through specific targeting mechanisms. This method exploits the overexpression of epidermal growth factor receptor (EGFR) commonly associated with TNBC by utilizing a unimolecular micelle nanoparticle conjugated with an EGFR-specific peptide (GE11) formed by dendritic poly(amido amine) (PAMAM) polylactide (PLA)- polyethylene glycol (PEG) amphiphilic block copolymers. The unimolecular micelle nanoparticle was also conjugated with Cy5.5 dye to allow for visualization and detection of the particles at the cellular level. Uniform size distribution and spherical morphology of the particles was confirmed using dynamic light scattering and transmission electron microscopy. Using the EGFR-overexpressing and AF-sensitive human MDA-MB-468 TNBC cell line, we were able to show that nanoparticles containing the EGFR-specific peptide GE11 exhibited increased cellular uptake, as shown using confocal microscopy for imaging and subsequent fluorescence intensity analysis. Furthermore, flow cytometric analysis confirmed that MDA-MB-468 cells treated with GE11-containing nanoparticles exhibit increased fluorescence intensity as compared to cells treated with non-targeting particles, which were not conjugated to GE11. This data suggests that the use of GE11-conjugated unimolecular micelles is an effective means of specifically targeted drug delivery in an EGFR-overexpressing TNBC cell line. The preparation and development of these nanoparticles has established a basis for further studies involving cellular toxicity and in vivo anti-tumor action of AF loaded, EGFR-targeted nanoparticles. Citation Format: Ashley M. Brinkman, Guojun Chen, Nathan Sherer, Shaoqin Gong, Wei Xu. Targeting epidermal growth factor receptor positive breast cancer using nanoparticles loaded with the anti-cancer drug aminoflavone. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5379. doi:10.1158/1538-7445.AM2014-5379