Abstract 3675: Double receptor targeting multifunctional iron oxide nanoparticles drug delivery system for the treatment and imaging of prostate cancer

Purpose: As an alternative to the drawbacks of current advanced prostate cancer chemotherapy, we propose a multifunctional double targeting drug delivery system that utilizes the combination of two cancer-targeting peptides: a modified luteinizing hormone releasing hormone (LHRH), the ligand for luteinizing hormone releasing hormone receptor (LHRH-R), and AE105, the ligand for urokinase type plasminogen activation receptor (uPAR). Both ligands are fused to amphiphilic polymer coated iron oxide nanoparticles (IONPs) and loaded with the anticancer drug Paclitaxel (PTX) as the payload. Materials and Methods: Targeted IONPs were characterized by both gel electrophoresis and dynamic light scattering (DLS). PTX was absorbed on the IONPs. Drug loading and release characteristics were conducted by HPLC. The binding specificity and the internalization efficiency of the targeted IONPs were both examined by Prussian blue staining and magnetic resonance imaging (MRI). Cytotoxicity of the targeted IONPs was evaluated by MTT assay. Results: Characterization of targeted IONPs by gel electrophoresis confirmed the successful attachment of the peptides to IONPs. Conjugation of peptides to carboxylic groups of polymer coating on IONPs resulted in an increase in the average hydrodynamic size of targeted IONPs (16.34 nm) as compared to non-targeted IONPs (12.51 nm), as well as a decrease of zeta potential from -70.43 mV to -58.06 mV, respectively. Prussian blue staining demonstrated that both, LHRH and AE105 conjugated IONPs were internalized efficiently by cells of the human prostate cancer cell line, PC3. In vitro MRI results showed that double-targeted IONPs significantly maintained T2 MRI contrast effect and reduction of T2 values upon internalization by PC3 cells. MRI imaging confirmed the preferential binding and accumulation of double-targeted IONPs in PC3 cells when compared to normal prostate epithelial cells (RC77N/E). PTX loaded double-targeted IONPs were stable at physiological pH and efficiently released around pH 4, the optimum pH inside the tumor cells. PTX loaded double-targeted IONPs showed an approximately 2-fold reduction in PC3 cell viability when compared to non-targeted IONPs. In addition, the percentage of cell death resulting from the PTX loaded, double-targeted IONPs was very similar to the percentage of cell death attributed to 100 ng/ml of free PTX, thereby demonstrating that their capability of reducing drug concentration. Conclusions: Our results indicate that we have developed a LHRH-R and uPAR targeted IONPs drug delivery system that potentially provides a MRI tractable delivery of cancer therapeutics such as PTX to prostate cancer cells. Therefore, our optimized double-targeted IONPs drug delivery system has the potential to significantly improve the health outcomes and quality of life for cancer patients as a novel type of targeted nanomedicine therapy. Citation Format: Md Shakir U. Ahmed, Mohamed O. Abdalla, Clayton Yates, Jesse Jaynes, Timothy Turner. Double receptor targeting multifunctional iron oxide nanoparticles drug delivery system for the treatment and imaging of prostate cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3675. doi:10.1158/1538-7445.AM2015-3675